Pyridazinon derivatives as kat2 degraders for the treatment of proliferative disorders

Abstract

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

Description

Attorney Docket No.: 2013405-0010 HETEROCYCLIC PHENYL COMPOUNDS AS KAT2 DEGRADERS RELATED APPLICATIONS

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

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

[0003] The present disclosure provides compounds useful to regulate KAT2, for example to reduce KAT2 activity, for example by degrading (e.g., increasing degradation of) KAT2 (e.g., KAT2A and / or KAT2B). In some embodiments, provided compounds are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with KAT2 (e.g., KAT2A and / or KAT2B), e.g., with level and / or activity of KAT2 (e.g., KAT2A and / or KAT2B) protein.

[0004] Provided compounds comprise a protein binding moiety capable of binding a KAT2 protein (e.g., KAT2A and / or KAT2B) and an E3 ligase binding moiety capable of binding an E3 ubiquitin ligase. In some embodiments, provided compounds may recruit a KAT2 protein to an E3 ubiquitin ligase, thereby promoting degradation of (or otherwise inhibiting) the KAT2 protein (e.g., KAT2A and / or KAT2B). Page 1 of 783 11575796v1Attorney Docket No.: 2013405-0010

[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 Compounds and Definitions

[0006] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

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

[0008] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0009] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”). Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In Page 2 of 783 11575796v1Attorney Docket No.: 2013405-0010 some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation.

[0010] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl,

[0011] Carbocyclyl: The terms as refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8hydrocarbon, or an optionally substituted C5-C10bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

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

[0013] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having Page 3 of 783 11575796v1Attorney Docket No.: 2013405-0010 (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0014] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but is not 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, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin– 3(4H)–one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[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 either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, Page 4 of 783 11575796v1Attorney Docket No.: 2013405-0010 the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N- substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3- dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).

[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 having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0019] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0020] Specific binding: As used herein, the term “specific binding” refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur. A binding agent that interacts with one particular target when other potential targets are present is said to "bind specifically" to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining degree and / or rate of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree and / or rate of dissociation of a binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining ability of the binding agent to compete an alternative interaction between its Page 5 of 783 11575796v1Attorney Docket No.: 2013405-0010 partner and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations across a range of concentrations.

[0021] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., ,or ). Unless otherwise indicated, an “optionally substituted” group may have a suitablesubstitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0022] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R ^; –(CH2)0–4OR ^; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR ^)2; –(CH2)0–4SR ^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; – (CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R ^)2; – (CH2)0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH2)0–4N(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)0–4C(O)R ^; –C(S)R ^; –(CH2)0–4C(O)OR ^; –(CH2)0–4C(O)SR ^; -(CH2)0–4C(O)OSiR ^3; –(CH2)0–4OC(O)R ^; – Page 6 of 783 11575796v1Attorney Docket No.: 2013405-0010 OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; – C(NOR ^)R ^; -(CH2)0–4SSR ^; –(CH2)0–4S(O)2R ^; –(CH2)0–4S(O)2OR ^; –(CH2)0–4OS(O)2R ^; – S(O)2NR ^2; -(CH2)0–4S(O)(NH)R ^ ^ -(CH2)0–4S(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; –(C1–4straight or branched alkylene)O–N(R ^)2; or –(C1–4straight or branched alkylene)C(O)O–N(R ^)2, wherein each R ^ may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2- (5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0023] Suitable monovalent substituents on R ^ (or the ring formed by taking two independent occurrences of R ^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, – (haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2, -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, – (CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, – (CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^,–(C1–4straight or branched alkylene)C(O)OR^, or – SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S.

[0024] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Page 7 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0025] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, – OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] Suitable substituents on the aliphatic group of R†are independently halogen, –R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder, and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. Provided Compounds

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

[0030] In some embodiments, the present disclosure provides a compound of Formula I PBM – linker – LBM I Page 8 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a pharmaceutically acceptable salt thereof, wherein: PBM is a KAT2 protein binding moiety; linker is an optional linking moiety; and LBM is an E3 ubiquitin ligase binding moiety.

[0031] In some embodiments, the present disclosure provides a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: ; Ring B is a 5- to selected from N, O,and S; L1is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; each R1is independently optionally substituted C1-6aliphatic or optionally substituted C3-6cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; Page 9 of 783 11575796v1Attorney Docket No.: 2013405-0010 R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0032] In some embodiments, the present disclosure provides a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: ; Ring B is a 5-selected from N, O, and S; L1is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; each R1is independently optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; n is 0, 1, 2, 3, or 4; Page 10 of 783 11575796v1Attorney Docket No.: 2013405-0010 Z is N or CR3; R2is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0033] In some embodiments, the present disclosure provides a compound of Formula IIA: Page 11 of 783 11575796v1Attorney Docket No.: 2013405-0010or a pharmaceutically R9, n, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0034] In some embodiments, the present disclosure provides a compound of Formula IIA-1, IIA-2, IIA-3, or IIA-4:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R9, X, Z, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIA-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIA-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIA-3, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIA-4, or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the present disclosure provides a compound of Formula IIA-1: Page 12 of 783 11575796v1Attorney Docket No.: 2013405-0010or a pharmaceutically R1is optionally substituted C1-6aliphatic; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen or halogen; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R9is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-; each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or optionally substituted C1-6aliphatic; ;group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; each Rais hydrogen; L2is a covalent bond, -CH2-, –O-, or -N(R)-; and Y is N or CH.

[0036] In some embodiments, the present disclosure provides a compound of Formula IIA-1: Page 13 of 783 11575796v1Attorney Docket No.: 2013405-0010or a pharmaceutically R1is C1-6alkyl; Z is N or CR3; R2is hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl; each R3is independently hydrogen or halogen; R4is C1-6alkyl; R9is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-; each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or C1-6alkyl; ;group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; each Rais hydrogen; L2is a covalent bond, -CH2-, –O-, or -N(R)-; and Y is N or CH.

[0037] In some embodiments, the present disclosure provides a compound of Formula IIA-5: Page 14 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a pharmaceutically linker, and LBM are as defined above for Formula II andsingly and in combination.

[0038] In some embodiments, the present disclosure provides a compound of Formula IIA-6:or a pharmaceutically acceptable salt thereof, wherein Ring A, R9, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0039] In some embodiments, the present disclosure provides a compound of Formula III: or an, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each Rais independently hydrogen or an optionally substituted C1-6aliphatic, or two Ragroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L2is a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH. Page 15 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0040] In some embodiments, the present disclosure provides a compound of Formula IIIA:or a n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0041] In some embodiments, the present disclosure provides a compound of Formula IIIB:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rb, Rc, m, and linker are as defined above for Formula IIIA and described in classes and subclasses herein, both singly and in combination.

[0042] In some embodiments, the present disclosure provides a compound of Formula IIIB-1 or IIIB-2:Page 16 of 783 11575796v1Attorney Docket No.: 2013405-0010or a are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IIIB-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IIIB-2, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the present disclosure provides a compound of Formula IIIC: or a R9, Y, n, and linker areas defined above for Formula III and described in classes and subclasses herein, both singly and in combination; and each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0044] In some embodiments, the present disclosure provides a compound of Formula IIID: or aY, m, and linker are as defined above for Formula IIIC and described in classes and subclasses herein, both singly and in combination. Page 17 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0045] In some embodiments, the present disclosure provides a compound of Formula IIID:or a ; R1is C1-6aliphatic;Z is or R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen or halogen; R4is optionally substituted C1-6aliphatic; R9is hydrogen; linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-; each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or optionally substituted C1-6aliphatic; L2is a covalent bond, -CH2-, –O-, or -N(R)-; Y is N or CH; each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3. Page 18 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0046] In some embodiments, the present disclosure provides a compound of Formula IIID:or a ;is hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl; each R3is independently hydrogen or halogen; R4is C1-6alkyl; R9is hydrogen; ;,Page 19 of 783 11575796v1Attorney Docket No.: 2013405-0010 Y is CH; each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -O(C1-6alkyl), and C1-6alkyl; and m is 0, 1, 2, or 3.

[0047] In some embodiments, the present disclosure provides a compound of Formula IV:or a n, linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg; each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6aliphatic, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6aliphatic; Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6aliphatic; each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; Rhis hydrogen, halogen, or optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3.

[0048] In some embodiments, the present disclosure provides a compound of Formula IVA: Page 20 of 783 11575796v1Attorney Docket No.: 2013405-0010 or aRg, Rh, p, n, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0049] In some embodiments, the present disclosure provides a compound of Formula IVA-1:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Rd, Re, Rf, Rg, Rh, p, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0050] In some embodiments, the present disclosure provides a compound of Formula V:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rithat is not the point of attachment of the linker is independently halogen, optionally substituted C1-6aliphatic, -C(O)N(R)2, or -N(R)C(O)R, or Page 21 of 783 11575796v1Attorney Docket No.: 2013405-0010 two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis an optionally substituted group selected from C1-6aliphatic and C3-7cycloaliphatic, or Rjcombines with one instance of Ri, together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; Rkis an optionally substituted C1-6aliphatic; r is 1, 2, 3, 4, or 5; and q is 1 or 2.

[0051] In some embodiments, the present disclosure provides a compound of Formula VA: or a Rj, Rk, n, q, r, andlinker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0052] In some embodiments, the present disclosure provides a compound of Formula VA-1:or a pharmaceutically acceptable salt thereof, wherein Ring A, R1, R9, Ri, Rj, Rk, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0053] In some embodiments, the present disclosure provides a compound of Formula VB: Page 22 of 783 11575796v1Attorney Docket No.: 2013405-0010 or aRi, Rj, Rk, n, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0054] In some embodiments, the present disclosure provides a compound of Formula VB-1:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R, R1, R9, Rj, Rk, n, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.

[0055] In some embodiments, the present disclosure provides a compound of Formula VI:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and Rmis optionally substituted C1-6aliphatic; each Rnis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; and s is 0, 1, 2, 3, 4, or 5.

[0056] In some embodiments, the present disclosure provides a compound of Formula VIA: Page 23 of 783 11575796v1Attorney Docket No.: 2013405-0010 or an, s, and linker are as defined above for Formula VI and described in classes and subclasses herein, both singly and in combination.

[0057] In some embodiments, the present disclosure provides a compound of Formula VIA-1: or a are as definedabove for Formula VI and described in classes and subclasses herein, both singly and in combination.

[0058] In some embodiments, the present disclosure provides a compound of Formula VII:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each Rpis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rqis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rris independently hydrogen or optionally substituted C1-6aliphatic; each Rsis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. Page 24 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0059] In some embodiments, the present disclosure provides a compound of Formula VIIA:or a Rs, u, t, and linker are as defined above for Formula VII and described in classes and subclasses herein, both singly and in combination.

[0060] In some embodiments, the present disclosure provides a compound of Formula VIII:or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L1, R1, R9, n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each Rtis independently hydrogen or optionally substituted C1-6aliphatic, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6aliphatic; each Rvis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rv, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or Page 25 of 783 11575796v1Attorney Docket No.: 2013405-0010 one instance of Ruand Rw, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each v is independently 0, 1, 2, 3, 4, or 5.

[0061] In some embodiments, the present disclosure provides a compound of Formula VIIIA:or a pharmaceutically Ru, Rv, Rw, v, and linker are as defined above for Formula VIII and described in classes and subclasses herein, both singly and in combination.

[0062] In some embodiments, the present disclosure provides a compound of Formula IX: or a pharmaceuticallyRing A is selected from: ; L3, L4, and L5bivalent C1-6straight or branched hydrocarbon chain; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; Page 26 of 783 11575796v1Attorney Docket No.: 2013405-0010 each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; each R8is independently hydrogen or optionally substituted C1-6aliphatic; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0063] In some embodiments, the present disclosure provides a compound of Formula IX, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: Page 27 of 783 11575796v1Attorney Docket No.: 2013405-0010 ; L3, L4, and L5bivalent C1-6straight orZ is N or CR3; R2is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; each R8is independently hydrogen or optionally substituted C1-6aliphatic; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Page 28 of 783 11575796v1Attorney Docket No.: 2013405-0010 each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety.

[0064] In some embodiments, the present disclosure provides a compound of Formula IXA, IXB, IXC, or IXD:or a pharmaceutically acceptable salt thereof, wherein L3, L4, L5, R2, R3, R4, R5, R6, R8, R9, X, Z, linker, and LBM are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula IXA, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IXB, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IXC, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IXD, or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the present disclosure provides a compound of Formula X: Page 29 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a linker are as definedabove for Formula in combination; and Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each Rais independently hydrogen or an optionally substituted C1-6aliphatic, or two Ragroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L2is a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH.

[0066] In some embodiments, the present disclosure provides a compound of Formula XA:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0067] In some embodiments, the present disclosure provides a compound of Formula XA-1 or XA- 2: Page 30 of 783 11575796v1Attorney Docket No.: 2013405-0010or a pharmaceutically acceptable salt thereof, wherein Ring A, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination. In some embodiments, the present disclosure provides a compound of Formula XA-1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula XA-2, or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the present disclosure provides a compound of Formula XB: O A Oor a pharmaceutically acceptable salt thereof, wherein Ring A, L2, L3, L4, L5, R8, R9, Y, and linker are as defined above for Formula X and described in classes and subclasses herein, both singly and in combination; and each B is independently selected from N, C, and CH, provided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0069] In some embodiments, the present disclosure provides a compound of Formula XI: Page 31 of 783 11575796v1Attorney Docket No.: 2013405-0010 or aare as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one of Rd, Re, Rf, or Rg; each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6aliphatic, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6aliphatic; Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6aliphatic; each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; Rhis hydrogen, halogen, or optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3.

[0070] In some embodiments, the present disclosure provides a compound of Formula XIA:Page 32 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, Rd, Re, Rf, Rg, Rh, p, and linker are as defined above for Formula XI and described in classes and subclasses herein, both singly and in combination.

[0071] In some embodiments, the present disclosure provides a compound of Formula XII:or a pharmaceutically acceptable salt thereof, wherein Ring A, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rithat is not the point of attachment of the linker is independently halogen, optionally substituted C1-6aliphatic, -C(O)N(R)2, or -N(R)C(O)R, or two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis an optionally substituted group selected from C1-6aliphatic and C3-7cycloaliphatic, or Rjcombines with one instance of Ri, together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; Rkis an optionally substituted C1-6aliphatic; r is 1, 2, 3, 4, or 5; and q is 1 or 2.

[0072] In some embodiments, the present disclosure provides a compound of Formula XIIA:Page 33 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, Ri, Rj, Rk, q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.

[0073] In some embodiments, the present disclosure provides a compound of Formula XIIB:or a pharmaceutically acceptable salt thereof, wherein Ring A, R, Ri, Rj, Rk, q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.

[0074] In some embodiments, the present disclosure provides a compound of Formula XIIB-1:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R, R8, R9, Rj, Rk, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.

[0075] In some embodiments, the present disclosure provides a compound of Formula XIII:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and Rmis optionally substituted C1-6aliphatic; each Rnis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; and Page 34 of 783 11575796v1Attorney Docket No.: 2013405-0010 s is 0, 1, 2, 3, 4, or 5.

[0076] In some embodiments, the present disclosure provides a compound of Formula XIIIA:or a Rn, s, and linker are as defined above for Formula XIII and described in classes and subclasses herein, both singly and in combination.

[0077] In some embodiments, the present disclosure provides a compound of Formula XIV:or a pharmaceutically acceptable salt thereof, wherein Ring A, L3, L4, L5, R8, R9, and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each Rpis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rqis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rris independently hydrogen or optionally substituted C1-6aliphatic; each Rsis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5.

[0078] In some embodiments, the present disclosure provides a compound of Formula XV: Page 35 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a pharmaceuticallyand linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each Rtis independently hydrogen or optionally substituted C1-6aliphatic, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6aliphatic; each Rvis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rv, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rw, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each v is independently 0, 1, 2, 3, 4, or 5.

[0079] In some embodiments of any Formula described herein, PBM is a KAT2 protein binding moiety, i.e., is a moiety that is capable of binding a KAT2 protein. In some embodiments, a PBM is a KAT2A protein binding moiety, i.e., is a moiety that is capable of binding a KAT2A protein. In some embodiments, a PBM is a KAT2B protein binding moiety, i.e., is a moiety that is capable of binding a KAT2B protein. Typically, a PBM is considered to be capable of binding a KAT2 protein (e.g., KAT2A and / or KAT2B) if it specifically (i.e., preferentially) associates with the KAT2 protein when contacted with the KAT2 protein in the presence of at least one other protein. In some embodiments, a PBM is considered to be capable of binding a KAT2 protein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo).

[0080] In some embodiments, a PBM shares significant structural identity with a reference compound or moiety thereof that is capable of binding a KAT2 protein. For example, in some embodiments, a PBM comprises the same or similar structure as a reference compound, except that a Page 36 of 783 11575796v1Attorney Docket No.: 2013405-0010 PBM comprises a point of attachment to a linker. In some embodiments, a reference compound is characterized by a Kdof less than 1 µM in a biophysical assay, such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). In some embodiments, a reference compound is characterized by a IC50of less than 1 µM in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET). In some embodiments, a reference compound is characterized by an DC50of less than 30 nM in the Western Blot assay of Example B1. In some embodiments, a reference compound 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 hereby incorporated by reference. In some embodiments, a reference compound is GSK4027: . In some embodiments, a reference.

[0081] In some embodiments,, wherein Ring A, Ring B, L1, R1,Formula II and described in classes and subclasses herein, both singly and in combination.

[0082] In some embodiments, a PBM has the following structure: ,Page 37 of 783 11575796v1Attorney Docket No.: 2013405-0010 wherein Ring A, L1, R1, R9, and n are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.

[0083] In some embodiments, a PBM has the following structure: , wherein Ring A, R1, and R9are as and described in classes and subclassesherein, both singly and in

[0084] In some embodiments, a PBM has the following structure: , wherein Ring A, R1, and R9are asand described in classes and subclasses herein, both singly and in combination.

[0085] In some embodiments, a PBM has the following structure: , wherein Ring A, R1, and R9are asand described in classes and subclasses herein, both singly and in combination.

[0086] In some embodiments, a PBM is selected from: ,Page 38 of 783 11575796v1Attorney Docket No.: 2013405-0010 , wherein R1, in classes and subclasses

[0087] In some embodiments, a PBM has the following structure: , wherein Ring A, L3, L4, L5, R8, andIX and described in classes and subclasses herein, both singly and in combination.

[0088] In some embodiments, a PBM is selected from: , , wherein L3, L4,IX and described in classes and subclasses herein, both singly and in combination.

[0089] In some embodiments, a PBM is selected from: Page 39 of 783 11575796v1Attorney Docket No.: 2013405-0010 , ,Page 40 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0090] In some embodiments of any Formula described herein, In some,. In some embodiments, Ring A is. In some embodiments, Ring A is, Insome embodiments, Ring A is selected .Page 41 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0091] In some embodiments of any Formula described herein, Ring A is . In some embodiments, Ring A is . In some such embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring A is .

[0092] In some embodiments of any Formula described herein, . In someembodiments, . In some embodiments, In some such embodiments, R2the atoms to whichto form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some such embodiments, R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, Ring A is selected from: .Page 42 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0093] In some embodiments of any Formula described herein, In someembodiments, .

[0094] In any Formula described herein, Z is N or CH. In some embodiments,Z is N. In some (e.g., CH).

[0095] In some embodiments of any Formula described herein, R2is hydrogen, halogen, -CN, or optionally substituted C1-6aliphatic. In some embodiments, R2is hydrogen, halogen, -CN, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, R2is hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, R2is halogen or C1-6alkyl. In some embodiments, R2is chloro, bromo, or methyl. In some embodiments, R2is hydrogen. In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is –CN. In some embodiments, R2is optionally substituted C1-6aliphatic. In some embodiments, R2is optionally substituted C1-6alkyl. In some embodiments, R2is C1-2alkyl (e.g., methyl or ethyl). In some embodiments, R2is optionally substituted C3-6cycloaliphatic. In some embodiments, R2is optionally substituted C3-6cycloalkyl. In some embodiments, R2is C3-4cycloalkyl (e.g., cyclopropyl).

[0096] In some embodiments of any Formula described herein, each R3is independently hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, each R3is hydrogen. In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is optionally substituted C1-6aliphatic. In some embodiments, R3is optionally substituted C1-6alkyl. In some embodiments, R3is C1-2alkyl (e.g., methyl). In some embodiments, R3is optionally substituted C3-6cycloaliphatic. In some embodiments, R3is optionally substituted C3-6cycloalkyl. In some embodiments, R3is C3-4cycloalkyl (e.g., cyclopropyl).

[0097] In some embodiments of any Formula described herein, R4is hydrogen or optionally substituted C1-6aliphatic. In some embodiments, R4is hydrogen. In some embodiments, R4is optionally substituted C1-6aliphatic. In some embodiments, R4is optionally substituted C1-6alkyl. In some embodiments, R4is C1-6alkyl. In some embodiments, R4is optionally substituted C1-2alkyl. In some embodiments, R4is C1-2alkyl (e.g., methyl). In some embodiments, R4is optionally substituted C3-6Page 43 of 783 11575796v1Attorney Docket No.: 2013405-0010 cycloaliphatic. In some embodiments, R4is optionally substituted C3-6cycloalkyl. In some embodiments, R4is C3-4cycloalkyl (e.g., cyclopropyl).

[0098] In some embodiments of any Formula described herein, R5is hydrogen, halogen, or optionally substituted C1-6aliphatic. In some embodiments, R5is hydrogen. In some embodiments, R5is halogen. In some embodiments, R5is fluoro. In some embodiments, R5is chloro. In some embodiments, R5is bromo. In some embodiments, R5is optionally substituted C1-6aliphatic. In some embodiments, R5is optionally substituted C1-6alkyl. In some embodiments, R5is C1-2alkyl (e.g., methyl). In some embodiments, R5is optionally substituted C3-6cycloaliphatic. In some embodiments, R5is optionally substituted C3-6cycloalkyl. In some embodiments, R5is C3-4cycloalkyl (e.g., cyclopropyl).

[0099] In some embodiments of any Formula described herein, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, R2and R5, together with the atoms to which they are attached, combine to form an 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S, and optionally substituted on a substitutable carbon atom with one or more halogen, –R ^, -OR ^, -N(R ^)2, and –CN, and on a substitutable nitrogen atom with one or more –R†and –C(O)R†. In some embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5-membered aromatic ring having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R2and R5combine to form an optionally substituted pyrrole. In some embodiments, R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, R2and R5combine to form an optionally substituted phenyl or pyridine.

[0100] In some embodiments of any Formula described herein, R6is hydrogen or optionally substituted C1-6aliphatic. In some embodiments, R6is hydrogen. In some embodiments, R6is optionally substituted C1-6aliphatic. In some embodiments, R6is optionally substituted C1-6alkyl. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is optionally substituted C1-2alkyl. In some embodiments, R6is C1-2alkyl (e.g., methyl). In some embodiments, R6is optionally substituted C3-6cycloaliphatic. In some embodiments, R6is optionally substituted C3-6cycloalkyl. In some embodiments, R6is C3-4cycloalkyl (e.g., cyclopropyl).

[0101] In some embodiments of any Formula described herein, X is O. In some embodiments, X is NR7. In some embodiments, when X is NR7, then R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. Page 44 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0102] In some embodiments of any Formula described herein, R7is hydrogen or optionally substituted C1-6alkyl. In some embodiments, R7is hydrogen. In some embodiments, R7is optionally substituted C1-6aliphatic. In some embodiments, R7is optionally substituted C1-6alkyl. In some embodiments, R7is C1-6alkyl. In some embodiments, R7is optionally substituted C1-2alkyl. In some embodiments, R7is C1-2alkyl (e.g., methyl).

[0103] In some embodiments of any Formula described herein, R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S, and optionally substituted on a substitutable carbon atom with one or more halogen, –R ^, -OR ^, -N(R ^)2, and –CN, and on a substitutable nitrogen atom with one or more –R†and –C(O)R†. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S, and optionally substituted with one or more C1-6alkyl. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 5-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R4and R7combine to form an optionally substituted triazole. In some embodiments, R4and R7, together with the atoms to which they are attached, combine to form a 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.

[0104] In some embodiments of any Formula described herein, R9is hydrogen or optionally substituted C1-6alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is optionally substituted C1-6aliphatic. In some embodiments, R9is optionally substituted C1-6alkyl. In some embodiments, R9is C1-6alkyl. In some embodiments, R9is optionally substituted C1-2alkyl. In some embodiments, R9is C1-2alkyl (e.g., methyl).

[0105] In some embodiments of any Formula described herein, Ring B is a 5- to 6-membered heterocyclyl having 1 heteroatom independently selected from N, O, and S. In some embodiments, Ring B is a 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N. In some embodiments, Ring B is a 5-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring B is a 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some Page 45 of 783 11575796v1Attorney Docket No.: 2013405-0010 embodiments, Ring B is piperidine. In some embodiments, Ring B . In someembodiments, .

[0106] In any Formulae described herein, L1is a covalent bond. In some 1embodiments, L a3or branched hydrocarbon chain. In some embodiments, L1is a bivalent C1-3straight hydrocarbon chain. In some embodiments, L1is a bivalent C1-2straight hydrocarbon chain. In some embodiments, L1is –CH2-.

[0107] In some embodiments of any Formulae described herein, each R1is independently optionally substituted C1-6alkyl or optionally substituted C3-6cycloalkyl. In some embodiments, R1is optionally substituted C1-6aliphatic. In some embodiments, R1is optionally substituted C1-6alkyl. In some embodiments, R1is C1-6alkyl. In some embodiments, R1is optionally substituted C1-2alkyl. In some embodiments, R1is C1-2alkyl (e.g., methyl). In some embodiments, R1is optionally substituted C3-6cycloaliphatic. In some embodiments, R1is optionally substituted C3-6cycloalkyl. In some embodiments, R1is C3-4cycloalkyl (e.g., cyclopropyl).

[0108] In some embodiments of any Formulae 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.

[0109] In some embodiments of any Formulae described herein, L3is a covalent bond or an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L3is a covalent bond. In some embodiments, L3is an optionally substituted bivalent C1-6straight or branched hydrocarbon chain. In some embodiments, L3is a bivalent C1-6straight or branched hydrocarbon chain. In some embodiments, L3is an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L3is a bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L3is selected from –CH2- and –CH(CH3)-.

[0110] In some embodiments of any Formulae described herein, L4is a covalent bond or an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L4is a covalent bond. In some embodiments, L4is an optionally substituted bivalent C1-6straight or branched hydrocarbon chain. In some embodiments, L4is a bivalent C1-6straight or branched hydrocarbon chain. In some embodiments, L4is an optionally substituted bivalent C1-3straight or branched hydrocarbon Page 46 of 783 11575796v1Attorney Docket No.: 2013405-0010 chain. In some embodiments, L4is a bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L4is selected from –CH2- and –CH(CH3)-.

[0111] In some embodiments of any Formulae described herein, L5is a covalent bond or an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L5is a covalent bond. In some embodiments, L5is an optionally substituted bivalent C1-6straight or branched hydrocarbon chain. In some embodiments, L5is a bivalent C1-6straight or branched hydrocarbon chain. In some embodiments, L5is an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L5is a bivalent C1-3straight or branched hydrocarbon chain. In some embodiments, L5is selected from –CH2- and –CH(CH3)-.

[0112] In some embodiments of any Formulae described herein, each R8is independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is optionally substituted C1-6aliphatic. In some embodiments, R8is optionally substituted C1-6alkyl. In some embodiments, R8is C1-6alkyl. In some embodiments, R8is optionally substituted C1-2alkyl. In some embodiments, R8is C1-2alkyl (e.g., methyl). In some embodiments, each R8is C1-2alkyl (e.g., methyl).

[0113] In some embodiments of any Formulae described herein, linker is a linking moiety (i.e., any suitable bivalent moiety that connects a PBM to a LBM). In some embodiments, linker is a particular length (e.g., as measured by number of atoms). It will be appreciated that when the length of linker is described, the longest contiguous chain of atoms is used. For example, in some embodiments, linker has the following structure, which is 14 atoms in length (counted as shown with italicized numbers): .

[0114] In somesome embodiments, a linker is 2- 13 atoms in length. In some embodiments, a linker is 2-10 atoms in length. In some embodiments, a linker is 2-8 atoms in length. In some embodiments, a linker is 2-7 atoms in length. In some embodiments, a linker is 0-16 atoms in length. In some embodiments, a linker is 0-13 atoms in length. In some embodiments, a linker is 0-10 atoms in length. In some embodiments, a linker is 0-7 atoms in length. In some embodiments, a linker is 4-16 atoms in length. In some embodiments, a linker is 4-13 atoms in length. In some embodiments, a linker is 4-10 atoms in length. In some embodiments, a linker is 4-8 atoms in length. In some embodiments, a linker is 4-7 atoms in length. In some embodiments, a linker is less than 14 atoms in length. In some embodiments, a linker is less than 11 atoms in length. In Page 47 of 783 11575796v1Attorney Docket No.: 2013405-0010 some embodiments, a linker is less than 9 atoms in length. In some embodiments, a linker is less than 8 atoms in length.

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

[0116] In some embodiments of any Formulae described herein, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0117] In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - Page 48 of 783 11575796v1Attorney Docket No.: 2013405-0010 N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-.

[0118] In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- . In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, - C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon 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-.

[0119] In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- . In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, - C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, or –Cy-.

[0120] In some embodiments, linker comprises an ether moiety (e.g., -O-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-.

[0121] In some embodiments, linker comprises an amine moiety (e.g., -N(R)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C1-6alkyl)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by - N(R)- (e.g., -NH- or –N(C1-6alkyl)-).

[0122] In some embodiments, linker comprises a carbonyl moiety. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-. In some embodiments, linker is an Page 49 of 783 11575796v1Attorney Docket No.: 2013405-0010 optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-.

[0123] In some embodiments, linker comprises an ester moiety. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-.

[0124] In some embodiments, linker comprises an amide moiety. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or –C(O)N(C1-6alkyl)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or –C(O)N(C1-6alkyl)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., -N(H)C(O)- or –N(C1-6alkyl)C(O)-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., - N(H)C(O)- or –N(C1-6alkyl)C(O)-).

[0125] In some embodiments, linker comprises a bivalent ring moiety (e.g., -Cy-). In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. In some such embodiments, Cy is not phenyl.

[0126] In some embodiments, linker comprises a triple bond. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C20hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C10hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, - N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, - Page 50 of 783 11575796v1Attorney Docket No.: 2013405-0010 C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1- C20hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-. In some embodiments, linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C1-C10hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

[0127] In some embodiments of any Formulae described herein, linker has the following structure: , wherein Cy is as defined herein for classes and subclasses herein, both singlyand in combination; and: M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0128] In some embodiments of any Formulae described herein, linker is selected from: ,Page 51 of 783 11575796v1Attorney Docket No.: 2013405-0010 ,or.embodiments of any Formulae described herein, linker is selected from: , , , , ,Page 52 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0131] In some embodiments of any Formulae described herein, linker has the following structure: , wherein: M1and M2are each, , -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0132] In some embodiments of any Formulae described herein, linker is selected from: ,, wherein:M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L8is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0134] In some embodiments of any Formulae described herein, linker is selected from: Page 53 of 783 11575796v1Attorney Docket No.: 2013405-0010 , C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, is absent. In some embodiments, M1is –CH2-. In some embodiments, M1is –O-. In some embodiments, M1is -N(R)- (e.g., - N(H)- or –N(CH3)-). In some embodiments, M1is -C(O)-. In some embodiments, M1is -OC(O)-. In some embodiments, M1is -C(O)O-. In some embodiments, M1is -C(O)N(R)- (e.g., -C(O)N(H)- or – C(O)N(CH3)-). In some embodiments, M1is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH3)C(O)-).

[0136] In some embodiments of any Formulae described herein, M2is –CH2-, –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, M2is absent. In some embodiments, M2is –CH2-. In some embodiments, M2is –O-. In some embodiments, M2is -N(R)- (e.g., - N(H)- or –N(CH3)-). In some embodiments, M2is -C(O)-. In some embodiments, M2is -OC(O)-. In some embodiments, M2is -C(O)O-. In some embodiments, M2is -C(O)N(R)- (e.g., -C(O)N(H)- or – C(O)N(CH3)-. In some embodiments, M2is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH3)C(O)-).

[0137] In some embodiments of any Formulae described herein, L6is a covalent bond.

[0138] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, Page 54 of 783 11575796v1Attorney Docket No.: 2013405-0010 saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0139] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-.

[0140] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1- C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0141] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O-.

[0142] In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated C1-C10hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L6is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain. Page 55 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0143] In some embodiments of any Formulae described herein, L7is a covalent bond.

[0144] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0145] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-.

[0146] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1- C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. Page 56 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0147] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein at least two methylene units are replaced by – O-.

[0148] In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated C1-C10hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L7is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain.

[0149] In some embodiments of any Formulae described herein, both L6and L7are a covalent bond.

[0150] In some embodiments of any Formulae described herein, L8is a covalent bond.

[0151] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, - N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, - SO2N(R)-, -N(R)SO2-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, - N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, - N(R)SO2-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by – O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, - OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

[0152] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Page 57 of 783 11575796v1Attorney Docket No.: 2013405-0010 C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-.

[0153] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1- C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.

[0154] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain, wherein at least two methylene units are replaced by – O-.

[0155] In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C15hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated C1-C15hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C6hydrocarbon chain. In some embodiments, L8is an optionally substituted, bivalent, straight or branched, saturated C1-C6hydrocarbon chain.

[0156] In some embodiments of any Formulae described herein, linker is selected from: , ,Page 58 of 783 11575796v1Attorney Docket No.: 2013405-0010Page 59 of 783 11575796v1Attorney Docket No.: 2013405-0010 , ,Page 60 of 783 11575796v1Attorney Docket No.: 2013405-0010 , , ,Page 61 of 783 11575796v1Attorney Docket No.: 2013405-0010 , , ,Page 62 of 783 11575796v1Attorney Docket No.: 2013405-0010 N N .

[0158] In some each Cy is independently anoptionally substituted, mono- or ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently an optionally substituted group selected from phenyl, C9-10bicyclic aryl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic C3-7cycloaliphatic, 5- to 10-membered bicyclic cycloaliphatic, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.

[0159] In some embodiments, Cy is optionally substituted phenyl. In some embodiments, Cy is phenyl. In some embodiments, Cy is not phenyl.

[0160] In some embodiments, Cy is optionally substituted C9-10bicyclic aryl. In some embodiments, Cy is optionally substituted C13-16polycyclic aryl.

[0161] In some embodiments, Cy is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted triazole. In some embodiments, Cy is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted pyridine, pyridazine, or pyrimidine.

[0162] In some embodiments, Cy is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

[0163] In some embodiments, Cy is an optionally substituted monocyclic C3-7cycloaliphatic. In some embodiments, Cy is an optionally substituted monocyclic C3-7cycloalkyl. In some embodiments, Page 63 of 783 11575796v1Attorney Docket No.: 2013405-0010 Cy is an optionally substituted monocyclic C4-6cycloalkyl (e.g., cyclobutane, cyclopentane, or cyclohexane).

[0164] In some embodiments, Cy is an optionally substituted 5- to 10-membered bicyclic cycloaliphatic. In some embodiments, Cy is an optionally substituted 6- to 10-membered bicyclic cycloaliphatic. In some embodiments, Cy is an optionally substituted bicyclic 6- to 10-membered bridged, fused, or spirocyclic cycloaliphatic.

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

[0166] In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 6- to 11-membered bridged, fused, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7- to 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered bridged heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 8-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 9-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. Page 64 of 783 11575796v1Attorney Docket No.: 2013405-0010 , ,In , ,optionally substituted C1-6aliphatic, or optionally substituted C3-7cycloaliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is C1-6alkyl. In some embodiments, R is optionally substituted C1-2alkyl. In some embodiments, R is C1-2alkyl (e.g., methyl). In some embodiments, each R is C1-2alkyl (e.g., methyl). In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted C3-7cycloaliphatic. In some embodiments, R is optionally substituted C3-7cycloalkyl (e.g., cyclopropyl). In some embodiments, R is optionally substituted 5- to 6- membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, R is optionally substituted Page 65 of 783 11575796v1Attorney Docket No.: 2013405-0010 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0168] In some embodiments of any Formulae described herein, LBM is an E3 ubiquitin ligase binding moiety, i.e., is a moiety that is capable of binding an E3 ubiquitin ligase. Typically, an LBM is considered to be capable of binding an E3 ubiquitin ligase if it specifically (i.e., preferentially) associates with the E3 ubiquitin ligase when contacted with the E3 ubiquitin ligase in the presence of at least one other protein. In some embodiments, an LBM is considered to be capable of binding an E3 ubiquitin ligase if it specifically associates with that protein within a cell (e.g., in vitro or in vivo). An LBM may be capable of binding any suitable E3 ubiquitin ligase, including cereblon, Von Hippel-Lindau protein, Inhibitor of Apoptosis protein, MDM2, RNF114, DCAF16, DCAF15, KEAP1, FEM1B, Arylhydrocarbon Receptor, etc. Some moieties capable of binding an E3 ubiquitin ligase are known in the art – see, e.g., Sun, X., et al., Signal Transduction and Targeted Therapy, 2019, 4, 64; Ishida, T., et al., SLAS Discovery, 2021, 26(4), 484-502; Bricelj, A., et al., Frontiers in Chemistry, 2021, 9, Article 707317; Min, J., et al., Angew. Chem. Int. Ed., 2021, 60, 26663-70; and WO 2019 / 140387, the entire contents of each of which are hereby incorporated by reference.

[0169] In some embodiments of any Formulae described herein, a LBM is a cereblon (CRBN) binding moiety, i.e., is a moiety that is capable of binding cereblon.

[0170] In some embodiments of any Formulae described herein, a LBM has the following structure: wherein Ring C, L2, and Raare asand described in classes and subclasses herein, both singly and in combination.

[0171] In some embodiments of any Formulae described herein, a LBM has the following structure: wherein Rb, Rc, and m are asand described in classes and subclasses herein, both singly and in combination; and each A is independently N, C, or CH, provided that no more than two A groups are N. It will be appreciated that A is C when it is the point of attachment to the rest of the molecule.

[0172] In some embodiments of any Formulae described herein, a LBM has the following structure: Page 66 of 783 11575796v1Attorney Docket No.: 2013405-0010 wherein Rb, Rc, and m are as and described in classes and subclasses herein, both singly and in

[0173] In some embodiments of any Formulae described herein, a LBM is selected from: .

[0174] In some the following structure:wherein B, L2, Rc, Y, and m are asIIIC and described in classes and subclasses herein, both singly and in combination. It will be appreciated that B is C when it is the point of attachment to the rest of the molecule.

[0175] In some embodiments of any Formulae described herein, a LBM has the following structure: wherein B, L2, Rc, Y, and m areIIIC and described in classes and subclasses herein, both singly and in combination.

[0176] In some embodiments of any Formulae described herein, a LBM has the following structure: wherein B, L2, Rc, Y, and m are asand described in classes and subclasses herein, both singly and in combination.

[0177] In some embodiments of any Formulae described herein, a LBM is selected from: Page 67 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0178] In some embodiments of any Formulae described herein, a LBM is selected from: O O NH ,Page 68 of 783 11575796v1Attorney Docket No.: 2013405-0010 , , ,11575796v1Attorney Docket No.: 2013405-0010 , ,or optionally substituted C1-6aliphatic. In some embodiments, each Rais independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, each Rais hydrogen. In some embodiments, Rais hydrogen. In some embodiments, Rais optionally substituted C1-6aliphatic. In some embodiments, Rais optionally substituted C1-6alkyl. In some embodiments, Rais C1-6alkyl. In some embodiments, Rais optionally substituted C1-2alkyl. In some embodiments, Rais C1-2alkyl (e.g., methyl). In some embodiments, two Ragroups, together with the atom to which they are attached, combine to form a 3- to Page 70 of 783 11575796v1Attorney Docket No.: 2013405-0010 6-membered saturated or partially unsaturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Ragroups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Ragroups, together with the atom to which they are attached, combine to form a 3- to 4-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S).

[0180] In some embodiments of any Formulae described herein, Y is N. In some embodiments, Y is CH.

[0181] In some embodiments of any Formulae described herein, L2is a covalent bond or a straight or branched C1-3hydrocarbon chain. In some embodiments, L2is a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, L2is a covalent bond. In some embodiments, L2is a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, - SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a C1hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a straight or branched C2hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a straight or branched C3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, - SO2-, -C(O)N(R)-, or -N(R)C(O)-. In some embodiments, L2is a covalent bond, -CH2-, –O-, or -N(R)-. In some embodiments, L2is –CH2-. In some embodiments, L2is –CH2-, -O-, or –N(R)-. In some embodiments, L2is –CH2-, -O-, or –N(H)-. In some embodiments, L2is –O- or –S-. In some embodiments, L2is –O-. In some embodiments, L2is -S-. In some embodiments, L2is –N(R)-. In some embodiments, L2is –N(H)-. In some embodiments, L2is –SO2-. In some embodiments, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, L2is –C(O)N(R)-. In some embodiments, L2is –N(R)C(O)-.

[0182] In some embodiments of any Formulae described herein, Ring C is an optionally substituted, mono- or bicyclic, 3- to 10-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is an optionally substituted group selected from phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C 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- Page 71 of 783 11575796v1Attorney Docket No.: 2013405-0010 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted C3-C7cycloaliphatic or optionally substituted 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0183] In some embodiments, Ring C is optionally substituted phenyl. In some embodiments, Ring C is phenyl.

[0184] In some embodiments, Ring C is optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 5- to 6-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 5-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a pyrrole. In some embodiments, Ring C is optionally substituted 6-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a pyridine, pyridone, or pyrimidine.

[0185] In some embodiments, Ring C is optionally substituted C3-C7cycloaliphatic. In some embodiments, Ring C is optionally substituted C3-C7cycloalkyl. In some embodiments, Ring C is optionally substituted C5-C6cycloaliphatic. In some embodiments, Ring C is optionally substituted C5-C6cycloalkyl. In some embodiments, Ring C is a cyclohexane.

[0186] In some embodiments, Ring C is optionally substituted 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is a piperidine or piperazine.

[0187] In some embodiments, Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring C is optionally substituted phthalimide, isoindolin-1-one, indazole, benzo[d][1,2,3]triazole, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-benzo[d]imidazole-2-one, or isoquinoline. In some embodiments, Ring C is optionally substituted phthalimide or isoindolin-1-one. In some embodiments, Ring C is optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

[0188] In some embodiments, Ring C is optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Ring Page 72 of 783 11575796v1Attorney Docket No.: 2013405-0010 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).

[0189] In some embodiments, , wherein: each A is independently N, C, or than two A groups are N; each Rbis hydrogen, or two Rbare taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; m is 0, 1, 2, or 3.

[0190] In some embodiments, .

[0191] .

[0192] In some embodiments, , wherein: each B is independently selectedprovided that no more than two B are N; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

[0193] In some embodiments, , wherein: each Rcis independently selected-N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3. Page 73 of 783 11575796v1Attorney Docket No.: 2013405-0010 , , , , , , ,Page 74 of 783 11575796v1Attorney Docket No.: 2013405-0010 , , , ,embodiments, one A is N and the other A groups are CH. In some embodiments, two A groups are N, and the other A groups are CH. It will be appreciated that when A is CH, it may be substituted with Rc, as defined herein, such that the ring contains a –C(Rc)- moiety. It will also be appreciated that A is C, when it is the point of attachment to the rest of the molecule.

[0197] In some embodiments of any Formulae described herein, each Rbis hydrogen. In some embodiments, two Rbgroups, on the same carbon, are taken together to form an oxo. In some embodiments, two Rbgroups, on the same carbon, combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a C3-6cycloaliphatic or 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S). In some embodiments, two Rbgroups, on the same carbon, combine to form C3-6cycloalkyl (e.g., cyclopropyl). In some embodiments, two Rbgroups, on the same carbon, combine to form a 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

[0198] In some embodiments of any Formulae described herein, each B is CH, C-Rc, or C. In some embodiments, one B is N and the other B groups are CH or C. In some embodiments, two B groups are N and the other B groups are CH or C. In some embodiments, B is N. In some embodiments, B is CH. In Page 75 of 783 11575796v1Attorney Docket No.: 2013405-0010 some embodiments, B is C-Rc. In some embodiments, B is C. It will be appreciated that B is C, when it is the point of attachment to the rest of the molecule.

[0199] In some embodiments of any Formulae described herein, each Rcis independently selected from halogen, -OH, -O(C1-6alkyl), -O(C1-6haloalkyl), -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CN, and optionally substituted C1-6alkyl. In some embodiments, each Rcis independently selected from halogen, - OH, -O(C1-6alkyl), -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CN, and optionally substituted C1-6alkyl. In some embodiments, each Rcis independently selected from halogen, -O(C1-6alkyl), -O(C1-6haloalkyl), C1-6alkyl, and C1-6haloalkyl. In some embodiments, each Rcis independently selected from halogen, - O(C1-6alkyl), C1-6alkyl, and C1-6haloalkyl. In some embodiments, each Rcis independently selected from halogen, -O(C1-6alkyl), and C1-6alkyl. In some embodiments, Rcis halogen (e.g., fluoro or chloro). In some embodiments, Rcis –OR (e.g., -OH, -O(C1-6alkyl), or -O(C1-6haloalkyl)). In some embodiments, Rcis –OCH3or –OCF3. In some embodiments, Rcis -N(R)2(e.g., -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)2). In some embodiments, Rcis –CN. In some embodiments, Rcis optionally substituted C1-6aliphatic. In some embodiments, Rcis optionally substituted C1-6alkyl. In some embodiments, Rcis C1-6alkyl optionally substituted with one or more halogen. In some embodiments, Rcis C1-6alkyl. In some embodiments, Rcis optionally substituted C1-2alkyl. In some embodiments, Rcis optionally substituted C1-2alkyl optionally substituted with one or more halogen. In some embodiments, Rcis C1-2alkyl (e.g., methyl). In some embodiments, Rcis C1-6haloalkyl. In some embodiments, Rcis C1-2haloalkyl (e.g., - CF3).

[0200] In some embodiments of any Formulae described herein, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0201] In some embodiments of any Formulae described herein, a LBM is a Von Hippel-Lindau protein (VHL) binding moiety, i.e., is a moiety that is capable of binding Von Hippel-Lindau protein.

[0202] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Rd, Re, Rf, Rg,and described in classes and subclasses herein, both singly and in combination.

[0203] In some embodiments of any Formulae described herein, a LBM is selected from: Page 76 of 783 11575796v1Attorney Docket No.: 2013405-0010 , whereinclasses and subclasses herein, both singly and in combination.

[0204] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Rd, Re, Rf, Rg,and described in classes and subclasses herein, both singly and in combination.

[0205] In some embodiments of any Formulae described herein, a LBM has the following structure: Page 77 of 783 11575796v1Attorney Docket No.: 2013405-0010 , whereinclasses and subclasses herein, both singly and in combination.

[0206] In some embodiments of any Formulae described herein, a LBM moiety (e.g., VHL binding moiety) is attached to linker at a Rd. In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at a Re. In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at Rf. In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at a Rg.

[0207] In some embodiments of any Formulae described herein, each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6aliphatic. In some embodiments, Rdis hydrogen. In some embodiments, Rdis –C(O)R. In some embodiments, Rdis – C(O)(optionally substituted C1-6alkyl). In some embodiments, Rdis –C(O)(optionally substituted C3-6cycloalkyl). In some embodiments, Rdis optionally substituted C1-6aliphatic. In some embodiments, Rdis optionally substituted C1-6alkyl. In some embodiments, Rdis C1-6alkyl. In some embodiments, Rdis optionally substituted C1-2alkyl. In some embodiments, Rdis C1-2alkyl (e.g., methyl). In some embodiments, two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and Page 78 of 783 11575796v1Attorney Docket No.: 2013405-0010 optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S that is fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S.

[0208] In some embodiments of any Formulae described herein, each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, each Reis optionally substituted C1-6aliphatic. In some embodiments, each Reis optionally substituted C1-6alkyl (e.g., methyl). In some embodiments, Reis hydrogen. In some embodiments, Reis optionally substituted C1-6aliphatic. In some embodiments, Reis optionally substituted C1-6alkyl. In some embodiments, Reis C1-6alkyl. In some embodiments, Reis optionally substituted C1-2alkyl. In some embodiments, Reis C1-2alkyl (e.g., methyl).

[0209] In some embodiments of any Formulae described herein, Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6alkyl. In some embodiments, Rfis hydrogen. In some embodiments, Rfis optionally substituted C1-6aliphatic. In some embodiments, Rfis optionally substituted C1-6alkyl. In some embodiments, Rfis C1-6alkyl. In some embodiments, Rfis optionally substituted C1-2alkyl. In some embodiments, Rfis C1-2alkyl (e.g., methyl).

[0210] In some embodiments of any Formulae described herein, each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6alkyl. In some embodiments, Rgis halogen (e.g., fluoro or chloro). In some embodiments, Rgis –OR (e.g., -OH or –O(C1-6alkyl)). In some embodiments, Rgis –CN. In some embodiments, Rgis optionally substituted C1-6aliphatic. In some embodiments, Rgis optionally substituted C1-6alkyl. In some embodiments, Rgis C1-6alkyl. In some embodiments, Rgis optionally substituted C1-2alkyl. In some embodiments, Rgis C1-2alkyl (e.g., methyl).

[0211] In some embodiments of any Formulae described herein, Rhis hydrogen, halogen, or optionally substituted C1-6alkyl. In some embodiments, Rhis hydrogen. In some embodiments, Rhis halogen (e.g., fluoro or chloro). In some embodiments, Rhis optionally substituted C1-6aliphatic. In some embodiments, Rhis optionally substituted C1-6alkyl. In some embodiments, Rhis C1-6alkyl. In some embodiments, Rhis optionally substituted C1-2alkyl. In some embodiments, Rhis C1-2alkyl (e.g., methyl). Page 79 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0212] In some embodiments of any Formulae 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.

[0213] In some embodiments of any Formulae described herein, a LBM is an Inhibitor of Apoptosis protein (IAP) binding moiety, i.e., is a moiety that is capable of binding Inhibitor of Apoptosis protein.

[0214] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Ri, Rj, Rk, r, and q are as described in classes and subclassesherein, both singly and in combination.

[0215] In some embodiments of any Formulae described herein, a LBM is selected from: ,herein, both singly and in combination; and Ring D is the ring formed when two groups, together with the atoms to which they are attached, combine.

[0216] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Ri, Rj, Rk, r, and q aredescribed in classes and subclasses herein, both singly and in combination.

[0217] In some embodiments of any Formulae described herein, a LBM is selected from: ,Page 80 of 783 11575796v1Attorney Docket No.: 2013405-0010 wherein Ri, Rj, Rk, r, and q are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ring D is the ring formed when two Rigroups, together with the atoms to which they are attached, combine.

[0218] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein R, Ri, Rj, Rk, r, and q are described in classes and subclassesherein, both singly and in combination.

[0219] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein R, Rj, and Rkare asin classes and subclasses herein, both singly and in combination.

[0220] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Rm, Rn, and s are asdescribed in classes and subclasses herein, both singly and in combination.

[0221] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Rm, Rn, and s are asdescribed in classes and subclasses herein, both singly and in combination.

[0222] In some embodiments of any Formulae described herein, a LBM moiety (e.g., IAP binding moiety) is attached to linker at a Ri. In some embodiments, a LBM moiety (e.g., IAP binding moiety) is Page 81 of 783 11575796v1Attorney Docket No.: 2013405-0010 attached to linker at the ring formed when two Rigroups, together with the atoms to which they are attached, combine.

[0223] In some embodiments of any Formulae described herein, each Rithat is not the point of attachment of the linker is independently halogen, optionally substituted C1-6aliphatic, -C(O)N(R)2, or - N(R)C(O)R. In some embodiments, Riis halogen (e.g., fluoro or chloro). In some embodiments, Riis optionally substituted C1-6aliphatic. In some embodiments, Riis optionally substituted C1-6alkyl. In some embodiments, Riis C1-6alkyl. In some embodiments, Riis optionally substituted C1-2alkyl. In some embodiments, Riis C1-2alkyl (e.g., methyl). In some embodiments, Riis -C(O)N(R)2. In some embodiments, at least one Riis -C(O)N(R)2. In some embodiments, Riis -N(R)C(O)R. In some embodiments, two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl. In some embodiments, two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S.

[0224] In some embodiments of any Formulae described herein, Rjis an optionally substituted group selected from C1-6aliphatic and C3-7cycloaliphatic. In some embodiments, Rjis optionally substituted C1-6aliphatic. In some embodiments, Rjis optionally substituted C1-6alkyl. In some embodiments, Rjis C1-6alkyl (e.g., tert-butyl or isopropyl). In some embodiments, Rjis optionally substituted C1-2alkyl. In some embodiments, Rjis C1-2alkyl (e.g., methyl). In some embodiments, Rjis optionally substituted C3-7cycloaliphatic. In some embodiments, Rjis optionally substituted C3-7cycloalkyl. In some embodiments, Rjis C3-7cycloalkyl (e.g., cyclohexyl). In some embodiments, Rjcombines with one instance of Ri, together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.

[0225] In some embodiments of any Formulae described herein, Rkis an optionally substituted C1-6alkyl. In some embodiments, Rkis C1-6alkyl. In some embodiments, Rkis optionally substituted C1-2alkyl. In some embodiments, Rkis C1-2alkyl (e.g., methyl).

[0226] In some embodiments of any Formulae 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.

[0227] In some embodiments of any Formulae described herein, q is 1. In some embodiments, q is 2. Page 82 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0228] In some embodiments of any Formulae described herein, Rmis optionally substituted C1-6alkyl. In some embodiments, Rmis C1-6alkyl (e.g., isobutyl). In some embodiments, Rmis optionally substituted C1-2alkyl. In some embodiments, Rmis C1-2alkyl (e.g., methyl).

[0229] In some embodiments of any Formulae described herein, each Rnis independently halogen, - OR, -CN, or optionally substituted C1-6alkyl. In some embodiments, Rnis halogen (e.g., fluoro or chloro). In some embodiments, Rnis –OR. In some embodiments, Rnis –CN. In some embodiments, Rnis optionally substituted C1-6aliphatic. In some embodiments, Rnis optionally substituted C1-6alkyl. In some embodiments, Rnis C1-6alkyl. In some embodiments, Rnis optionally substituted C1-2alkyl. In some embodiments, Rnis C1-2alkyl (e.g., methyl).

[0230] In some embodiments of any Formulae 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.

[0231] In some embodiments of any Formulae described herein, a LBM is a MDM2 binding moiety, i.e., is a moiety that is capable of binding MDM2.

[0232] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Rp, Rq, Rr, Rs, u and tVII and described in classes and subclasses herein, both singly and in combination.

[0233] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein Rt, Ru, Rv, Rw, and v areVIII and described in classes and subclasses herein, both singly and in combination. Page 83 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0234] In some embodiments of any Formulae described herein, each Rpis independently halogen, - OR, -CN, or optionally substituted C1-6alkyl. In some embodiments, each Rpis halogen (e.g., chloro). In some embodiments, Rpis halogen (e.g., chloro or fluoro). In some embodiments, Rpis –OR. In some embodiments, Rpis –CN. In some embodiments, Rpis optionally substituted C1-6aliphatic. In some embodiments, Rpis optionally substituted C1-6alkyl. In some embodiments, Rpis C1-6alkyl. In some embodiments, Rpis optionally substituted C1-2alkyl. In some embodiments, Rpis C1-2alkyl (e.g., methyl).

[0235] In some embodiments of any Formulae described herein, each Rqis independently halogen, - OR, -CN, or optionally substituted C1-6alkyl. In some embodiments, each Rqis halogen (e.g., chloro). In some embodiments, Rqis halogen (e.g., chloro or fluoro). In some embodiments, Rqis –OR. In some embodiments, Rqis –CN. In some embodiments, Rqis optionally substituted C1-6aliphatic. In some embodiments, Rqis optionally substituted C1-6alkyl. In some embodiments, Rqis C1-6alkyl. In some embodiments, Rqis optionally substituted C1-2alkyl. In some embodiments, Rqis C1-2alkyl (e.g., methyl).

[0236] In some embodiments of any Formulae described herein, each Rris independently hydrogen or optionally substituted C1-6alkyl. In some embodiments, Rris hydrogen. In some embodiments, Rris optionally substituted C1-6aliphatic. In some embodiments, Rris optionally substituted C1-6alkyl. In some embodiments, Rris C1-6alkyl. In some embodiments, Rris optionally substituted C1-2alkyl. In some embodiments, Rris C1-2alkyl (e.g., methyl). In some embodiments, each Rris methyl.

[0237] In some embodiments of any Formulae described herein, each Rsis independently halogen, - OR, -CN, or optionally substituted C1-6alkyl. In some embodiments, each Rsis halogen (e.g., chloro). In some embodiments, Rsis halogen (e.g., chloro or fluoro). In some embodiments, Rsis –OR (e.g., -O(C1-6alkyl)). In some embodiments, Rsis –CN. In some embodiments, Rsis optionally substituted C1-6aliphatic. In some embodiments, Rsis optionally substituted C1-6alkyl. In some embodiments, Rsis C1-6alkyl (e.g., tert-butyl). In some embodiments, Rsis optionally substituted C1-2alkyl. In some embodiments, Rsis C1-2alkyl (e.g., methyl).

[0238] In some embodiments of any Formulae 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.

[0239] In some embodiments of any Formulae described herein, each u is independently 0, 1, or 2. In some embodiments, each u is independently 1, 2, or 3. In some embodiments, each u is independently 0 or 1. In some embodiments, 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. Page 84 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0240] In some embodiments of any Formulae described herein, each Rtis independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, Rtis hydrogen. In some embodiments, Rtis optionally substituted C1-6aliphatic. In some embodiments, Rtis optionally substituted C1-6alkyl. In some embodiments, Rtis C1-6alkyl (e.g., tert-butyl or isobutyl). In some embodiments, Rtis optionally substituted C1-2alkyl. In some embodiments, Rtis C1-2alkyl (e.g., methyl). In some embodiments, at least one Rtis optionally substituted C1-6aliphatic. In some embodiments, both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted C3-7cycloaliphatic (e.g., C3-7cycloalkyl, such as cyclohexyl). In some embodiments, both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.

[0241] In some embodiments of any Formulae described herein, each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6alkyl. In some embodiments, Ruis hydrogen. In some embodiments, at least one Ruis hydrogen. In some embodiments, Ruis halogen (e.g., fluoro or chloro). In some embodiments, Ruis –CN. In some embodiments, Ruis optionally substituted C1-6aliphatic. In some embodiments, Ruis optionally substituted C1-6alkyl. In some embodiments, Ruis C1-6alkyl. In some embodiments, Ruis optionally substituted C1-2alkyl. In some embodiments, Rtis C1-2alkyl (e.g., methyl).

[0242] In some embodiments of any Formulae described herein, each Rvis independently halogen, - OR, -CN, or optionally substituted C1-6alkyl. In some embodiments, each Rvis halogen (e.g., chloro). In some embodiments, Rvis halogen (e.g., chloro or fluoro). In some embodiments, Rvis –OR (e.g., -O(C1-6alkyl)). In some embodiments, Rvis –CN. In some embodiments, Rvis optionally substituted C1-6aliphatic. In some embodiments, Rvis optionally substituted C1-6alkyl. In some embodiments, Rvis C1-6alkyl (e.g., tert-butyl). In some embodiments, Rvis optionally substituted C1-2alkyl. In some embodiments, Rvis C1-2alkyl (e.g., methyl). In some embodiments, one instance of Ruand Rv, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, one instance of Ruand Rv, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic. In some embodiments, one instance of Ruand Rv, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S. Page 85 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0243] In some embodiments of any Formulae described herein, each Rwis independently halogen, - OR, -CN, or optionally substituted C1-6alkyl. In some embodiments, each Rwis halogen (e.g., chloro). In some embodiments, Rwis halogen (e.g., chloro or fluoro). In some embodiments, Rwis –OR (e.g., -O(C1-6alkyl)). In some embodiments, Rwis –CN. In some embodiments, Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis optionally substituted C1-6alkyl. In some embodiments, Rwis C1-6alkyl (e.g., tert-butyl). In some embodiments, Rwis optionally substituted C1-2alkyl. In some embodiments, Rwis C1-2alkyl (e.g., methyl). In some embodiments, one instance of Ruand Rw, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, one instance of Ruand Rw, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic. In some embodiments, one instance of Ruand Rw, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.

[0244] In some embodiments of any Formulae 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.

[0245] In some embodiments of any Formulae described herein, the compound is not: .

[0246] In somefrom Table 1, or a pharmaceutically acceptable salt thereof. Table 111575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 87 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 88 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 89 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 90 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 91 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 92 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 93 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 94 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 95 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 96 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 97 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 98 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 99 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 100 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 101 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 102 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 103 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 104 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 105 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 106 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 107 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 108 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 109 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 110 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 111 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 112 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 113 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. Structure O O N O NPage 114 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 115 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 116 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 117 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 118 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 119 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 120 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 121 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 122 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 123 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 124 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 125 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 126 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 127 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 128 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 129 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 130 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 131 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 132 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 133 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 134 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 135 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 136 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 137 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 138 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 139 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 140 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 141 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 142 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 143 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 144 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 145 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 146 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. Structure11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 148 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. Structure O Br NPage 149 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 150 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 151 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 152 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 153 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 154 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 155 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 156 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 157 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 158 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 159 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 160 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 161 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 162 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 163 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 164 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 165 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 166 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 167 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 168 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 169 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 170 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 171 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 172 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 173 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 174 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 175 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 176 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 177 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 178 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 179 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 180 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 181 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 182 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 183 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 184 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 185 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 186 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 187 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 188 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 189 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 190 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. Structure11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 192 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 193 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 194 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 195 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 196 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. Structure H O N OPage 197 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 198 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 199 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 200 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 201 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 202 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 203 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 204 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 205 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. Structure11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 207 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 208 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 209 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 210 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 211 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 212 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 213 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 214 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 215 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 216 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 217 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 218 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 219 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 220 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 221 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 222 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 223 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 224 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 225 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 226 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 227 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 228 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 229 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 230 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 231 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 232 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 233 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 234 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 235 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 236 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 237 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 238 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 239 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 240 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 241 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 242 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 243 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 244 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 245 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 246 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 247 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 248 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 249 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 250 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. StructurePage 251 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No. Structure

[0247] In some embodiments, the present disclosure provides compounds selected from Table 2, or a pharmaceutically acceptable salt thereof. Page 252 of 783 11575796v1Attorney Docket No.: 2013405-0010 Table 2. Compound No.StructureOPage 253 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 254 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 255 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 256 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 257 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 258 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 259 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 260 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 261 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 262 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 263 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 264 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 265 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 266 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 267 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 268 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 269 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 270 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 271 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 272 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.StructurePage 273 of 783 11575796v1Attorney Docket No.: 2013405-0010 Compound No.Structure

[0248] In some embodiments, the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds (such as GSK983, GSK699, and / or GSK702, described in Bassi, Z.I., et al. ACS Chem. Biol., 2018, 13, 2862- 67). 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, as measured by, e.g., kinetic and / or thermodynamic solubility assays. In some embodiments, provided compounds have improved metabolic stability than certain known compounds, as measured by, e.g., intrinsic clearance using an in vitro liver microsomal stability assay and / or an in vivo pharmacokinetic analysis. In some embodiments, provided compounds have improved permeability, as measured by, e.g., a MDCK and / or Page 274 of 783 11575796v1Attorney Docket No.: 2013405-0010 Caco2 permeability assays. Without wishing to be bound by theory, it will be appreciated that provided compounds that display a suitable balance of any two or more of these properties may be particularly suitable for development as a drug, as evidenced, in some embodiments, by pharmacokinetic properties, such as AUC, T1 / 2, MRT, or CL.

[0249] In some embodiments, the present disclosure encompasses the recognition that provided compounds are capable of degrading KAT2A, KAT2B, or both KAT2A and KAT2B. In some embodiments, it will be appreciated that compounds capable of degrading both KAT2A and KAT2B provide benefits over compounds that only degrade one of KAT2A or KAT2B. In other embodiments, compounds that selectively degrade KAT2A over KAT2B may be desirable. In other embodiments, compounds that selectively degrade KAT2B over KAT2A may be desirable.

[0250] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977).

[0251] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include Formulae II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA-6, III, IIIA, IIIB, IIIB-1, IIIB-2, IIIC, IIID, IV, IVA, IVA-1, V, VA, VA-1, VB, VB-1, VI, VIA, VIA-1, VII, VIIA, VIII, VIIIA, IX, IXA, IXB, IXC, IXD, X, XA, XA-1, XA-2, XB, XI, XIA, XII, XIIA, XIIB, XIIB-1, XIII, XIIIA, XIV, and XV, and compound species of such formulas disclosed herein. Preparing Provided Compounds

[0252] Provided compounds may generally be made by the processes described in the ensuing schemes and examples. In some embodiments, provided compounds (e.g., compounds with a linker comprising an amide) are prepared according to the following Scheme: wherein PBM, linker, LBM, and R are as defined in Formulae herein. Accordingly, 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'- Page 275 of 783 11575796v1Attorney Docket No.: 2013405-0010 tetramethylchloroformamidinium hexafluorophosphate), optionally in the presence of a suitable base (e.g., N-methylimidazole). In some embodiments, intermediate A.1 has the following structure: . In some embodiments,A L3L4.

[0253] In somewith a linker comprising an amide) are prepared according to the following Scheme: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: . In some embodiments,.Page 276 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0254] In some embodiments, provided compounds (e.g., compounds with a linker comprising an ester) are prepared according to the following Scheme: wherein PBM, linker, and LBM are as defined in Formulae herein. in some embodiments,compound C is prepared by a process comprising contacting intermediate A.1 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: . In some embodiments,.

[0255] In someaccording to the following Scheme:embodiments, compound D is prepared by a process comprising contacting intermediate D.1 with intermediate B.1 in the presence of a suitable reducing agent (e.g., NaCNBH3), optionally in the presence of a suitable acid (e.g., AcOH). In some embodiments, intermediate D.1 has the following structure: .Page 277 of 783 11575796v1Attorney Docket No.: 2013405-0010 In some embodiments, intermediate D.1 has the following structure: .

[0256] In some embodiments, according to one of the followingSchemes: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: . In some embodiments,.

[0257] In somewith a linker comprising a triazole ring) are prepared according to the following Scheme: Page 278 of 783 11575796v1Attorney Docket No.: 2013405-0010wherein PBM, linker, and LBM are as defined in Formulaeembodiments,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: . In some embodiments,.Compositions

[0258] The present disclosure also provides compositions that comprise or deliver a compound as provided herein. In some embodiments, the present disclosure provides compositions comprising a compound provided herein with one or more other components.

[0259] In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of Formulae I, II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA-6, 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).

[0260] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein (e.g., compounds of Formulae I, II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5, IIA-6, 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 comprises a pharmaceutically acceptable carrier. Page 279 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0261] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti- statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.

[0262] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.

[0263] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0264] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example as described herein.

[0265] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition. Uses

[0266] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In Page 280 of 783 11575796v1Attorney Docket No.: 2013405-0010 some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0267] In some embodiments, provided compounds are useful as KAT2 degraders and / or inhibitors. In some embodiments, provided compounds promote degradation of KAT2A. In some embodiments, provided compounds promote degradation of KAT2B.

[0268] In some embodiments, the present disclosure provides methods of degrading and / or inhibiting KAT2 (e.g., KAT2A and / or KAT2B), comprising contacting a provided compound with KAT2. In some embodiments, contacting occurs in a cell. In some embodiments, contacting occurs in a subject (e.g., a human subject).

[0269] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with KAT2 (e.g., KAT2A and / or KAT2B).

[0270] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with KAT2 (e.g., KAT2A and / or KAT2B), comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, provided methods are for treating cancer. In some embodiments, a cancer is characterized by a solid tumor. In some embodiments, a cancer is characterized by a hematologic tumor. In some embodiments, a cancer is selected from hematopoietic cancers, including leukemias, lymphomas (e.g., Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastro- intestinal cancers and nervous system cancers, benign lesions such as papillomas, and the like. In some embodiments, provided methods are for treating a leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.) In some embodiments, 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.

[0271] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a Page 281 of 783 11575796v1Attorney Docket No.: 2013405-0010 subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.

[0272] For example, in some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and / or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care). Exemplary Embodiments

[0273] The following enumerated embodiments, while non-limiting, are exemplary of certain aspects of the present disclosure: 1. A compound of Formula I: PBM – linker – LBM I wherein: PBM is a KAT2 protein binding moiety; linker is an optional linking moiety; and LBM is an E3 ubiquitin ligase binding moiety. 2. 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 1-3, wherein the linker is less than 14 atoms in length. 5. The compound of any one of embodiments 1-4, wherein the linker is less than 11 atoms in length. 6. The compound of any one of embodiments 1-5, wherein the LBM is a CRBN binding moiety. 7. The compound of any one of embodiments 1-5, wherein the LBM is a VHL binding moiety. 8. The compound of any one of embodiments 1-5, wherein the LBM is a IAP binding moiety. 9. The compound of any one of embodiments 1-5, wherein the LBM is a MDM2 binding moiety. 10. A compound of Formula II: Page 282 of 783 11575796v1Attorney Docket No.: 2013405-0010or a pharmaceutically Ring A is selected from: ; Ring B is a 5- to selected from N, O,and S; L1is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; each R1is independently optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or Page 283 of 783 11575796v1Attorney Docket No.: 2013405-0010 R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, or a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety. 11. The compound of embodiment 10, wherein R2is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic. 12. The compound of embodiment 10 or 11, wherein . 13. The compound of embodiment 12, wherein Ring A..Page 284 of 783 11575796v1Attorney Docket No.: 2013405-0010 15. The compound of embodiment 10 or 11, wherein . 16. The compound of embodiment 15, wherein R2and atoms to which they are attached, combine to form an optionally substituted 5- to 6-having 0-2 heteroatoms independently selected from N, O, and S. 17. The compound of embodiment 16, wherein .18. The compound of embodiment 10 or 11, wherein . The compound of embodiment 18, wherein R2and to which they arecombine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. 20. The compound of embodiment 19, wherein Ring A is selected from: . 21. The compound ofand R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. 22. The compound of embodiment 21, wherein .23. The compound of embodiment 10 or 11, wherein .Page 285 of 783 11575796v1Attorney Docket No.: 2013405-0010 24. The compound of embodiment 23, wherein . 25. The compound of any one of embodiments 10- 26. The compound of any one of embodiments 10-is a 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 27. The compound of embodiment 26, wherein .28. The compound of embodiment 27, wherein . 29. The compound of any one of embodiments 10- a covalent bond.30. The compound of any one of embodiments 10-29, wherein each R1is independently optionally substituted C1-6alkyl. 31. The compound of embodiment 28, wherein each R1is independently C1-6alkyl. 32. The compound of any one of embodiments 10-31, wherein n is 0 or 1. 33. The compound of any one of embodiments 10-32, wherein R2is halogen or C1-6alkyl. 34. The compound of any one of embodiments 10-33, wherein R2is halogen. 35. The compound of any one of embodiments 10-34, wherein each R3is hydrogen. 36. The compound of any one of embodiments 10-35, wherein R4is optionally substituted C1-6alkyl. 37. The compound of any one of embodiments 10-36, wherein R6is optionally substituted C1-6alkyl. 38. The compound of any one of embodiments 10-37, wherein X is O. 39. The compound of any one of embodiments 10-37, wherein X is NR7. 40. The compound of any one of embodiments 10-39, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. Page 286 of 783 11575796v1Attorney Docket No.: 2013405-0010 41. The compound of embodiment 40, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. 42. The compound of embodiment 40, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon 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 compound of embodiment 42, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. 44. The compound of any one of embodiments 40-43, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)-. 45. The compound of any one of embodiments 40-44, wherein linker comprises at least one triple bond. 46. The compound of any one of embodiments 40-45, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. 47. The compound of any one of embodiments 10-46, wherein linker is: , wherein:M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. 48. The compound of embodiment 47, wherein linker is selected from: Page 287 of 783 11575796v1Attorney Docket No.: 2013405-0010 , , ,Page 288 of 783 11575796v1Attorney Docket No.: 2013405-0010 50. The compound of any one of embodiments 47-49, wherein L6is a covalent bond. 51. The compound of any one of embodiments 47-50, wherein L7is a covalent bond. 52. The compound of any one of embodiments 40-51, wherein Cy is optionally substituted phenyl or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 53. The compound of any one of embodiments 40-51, wherein Cy is optionally substituted monocyclic 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 54. The compound of any one of embodiments 40-51, wherein Cy is optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 55. The compound of embodiment 54, wherein Cy is a spirocyclic 6- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 56. The compound of any one of embodiments 10-55, wherein each R is independently hydrogen or optionally substituted C1-6alkyl. 57. The compound of any one of embodiments 10-56, wherein LBM is a CRBN binding moiety. 58. The compound of any one of embodiments 10-56, wherein LBM is a VHL binding moiety. 59. The compound of any one of embodiments 10-56, wherein LBM is a IAP binding moiety. 60. The compound of any one of embodiments 10-56, wherein LBM is a MDM2 binding moiety. 61. The compound of any one of embodiments 10-60, wherein the compound is of Formula IIA: or a pharmaceutically62. The compound of embodiment 61, wherein the compound is of Formula IIA-1, IIA-2, IIA-3, or IIA-4:Page 289 of 783 11575796v1Attorney Docket No.: 2013405-00105:or a pharmaceutically acceptable salt thereof. 64. The compound of any one of embodiments 10-62, wherein the compound is of Formula IIA-6:or a pharmaceutically acceptable salt thereof. 65. The compound of any one of embodiments 10-64, wherein the compound is of Formula III:or a pharmaceutically acceptable salt thereof, wherein: Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Page 290 of 783 11575796v1Attorney Docket No.: 2013405-0010 each Rais independently hydrogen or an optionally substituted C1-6aliphatic, or two Ragroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L2is a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH. 66. The compound of embodiment 65, wherein Ring C is optionally substituted phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 67. The compound of embodiment 65, wherein Ring C is optionally substituted phenyl or 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 68. The compound of embodiment 67, wherein , wherein: each B is independently selected from N, C, and more than two B are N;each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3. 69. The compound of embodiment 68, wherein . 70. The compound of any one of embodiments 65-is of Formula IIIC: or a71. The compound of any one of embodiments 65-70, wherein the compound is of Formula IIID: Page 291 of 783 11575796v1Attorney Docket No.: 2013405-0010or a 72. The compound of embodiment 65, wherein Ring C is optionally substituted C3-C7cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 73. The compound of embodiment 65, wherein Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 74. The compound of embodiment 73, wherein Ring C is: wherein:each A is independently N, C, or CH, provided that no more than two A groups are N; each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3. 75. The compound of embodiment 74, wherein Ring C is: . 76. The compound of any one ofL2is a covalent bond. 77. The compound of any one of embodiments 65-75, wherein L2is –CH2-. 78. The compound of any one of embodiments 65-75, wherein L2is –O- or –S-. 79. The compound of any one of embodiments 65-75, wherein L2is -C(O)N(R)-, or -N(R)C(O)-. 80. The compound of any one of embodiments 65-79, wherein Y is N. 81. The compound of any one of embodiments 65-79, wherein Y is CH. Page 292 of 783 11575796v1Attorney Docket No.: 2013405-0010 82. The compound of any one of embodiments 68-81, wherein each Rcis independently selected from halogen, -O(C1-6alkyl), C1-6alkyl, and C1-6haloalkyl. 83. The compound of any one of embodiments 73-82, wherein the compound is of Formula IIIA:or a 84. The compound of embodiment 83, wherein the compound is of Formula IIIB:or a pharmaceutically acceptable salt thereof 85. The compound of embodiment 84, wherein the compound is of Formula IIIB-1 or IIIB-2:or a pharmaceutically acceptable salt thereof. 86. The compound of any one of embodiments 1-85, wherein the compound is not: Page 293 of 783 11575796v1Attorney Docket No.: 2013405-0010 . 87. The is of Formula IV:or a linker is attached to the bracketed moiety at one of Rd, Re, Rf, and Rg; each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6aliphatic, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6aliphatic; Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6aliphatic; each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; Rhis hydrogen, halogen, or optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3. 88. The compound of embodiment 87, wherein the compound is of Formula IVA: Page 294 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a89. The compound of embodiment 88, wherein the compound is of Formula IVA-1:or a pharmaceutically acceptable salt thereof. 90. The compound of any one of embodiments 10-64, wherein the compound is of Formula V: or alinker is attached to the bracketed moiety at one Rior the ring formed when two Rigroups are taken together; each Rithat is not the point of attachment of the linker is independently halogen, optionally substituted C1-6aliphatic, -C(O)N(R)2, or -N(R)C(O)R, or two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Rjis an optionally substituted group selected from C1-6aliphatic and C3-7cycloaliphatic, or Page 295 of 783 11575796v1Attorney Docket No.: 2013405-0010 Rjcombines with one instance of Ri, together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S; Rkis an optionally substituted C1-6aliphatic; r is 1, 2, 3, 4, or 5; and q is 1 or 2. 91. The compound of embodiment 90, wherein at least one Riis -C(O)N(R)2. 92. The compound of embodiment 90 or 91, wherein two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. 93. The compound of any one of embodiments 90-92, wherein the compound is of Formula VA:or a pharmaceutically acceptable salt thereof. 94. The compound of embodiment 93, wherein the compound is of Formula VA-1: or a95. The compound of embodiment 93, wherein the compound is of Formula VB:or a pharmaceutically acceptable salt thereof. 96. The compound of embodiment 95, wherein the compound is of Formula VB-1: Page 296 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a97. The compound of any one of embodiments 10-64, wherein the compound is of Formula VI: or aRmis optionally substituted C1-6aliphatic; each Rnis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; and s is 0, 1, 2, 3, 4, or 5. 98. The compound of embodiment 97, wherein the compound is of Formula VIA:or a pharmaceutically acceptable salt thereof. 99. The compound of embodiment 98, wherein the compound is of Formula VIA-1: or aPage 297 of 783 11575796v1Attorney Docket No.: 2013405-0010 100. The compound of any one of embodiments 10-64, wherein the compound is of Formula VII:or a each Rpis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rqis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rris independently hydrogen or optionally substituted C1-6aliphatic; each Rsis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. 101. The compound of embodiment 100, wherein the compound is of Formula VIIA:or a pharmaceutically acceptable salt thereof. 102. The compound of any one of embodiments 10-64, wherein the compound is of Formula VIII:or a pharmaceutically acceptable salt thereof, wherein: Page 298 of 783 11575796v1Attorney Docket No.: 2013405-0010 each Rtis independently hydrogen or optionally substituted C1-6aliphatic, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6aliphatic; each Rvis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rv, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rw, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each v is independently 0, 1, 2, 3, 4, or 5. 103. The compound of embodiment 102, wherein the compound is of Formula VIIIA:or a pharmaceutically acceptable salt thereof. 104. A compound of Formula IX:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: Page 299 of 783 11575796v1Attorney Docket No.: 2013405-0010 ; L3, L4, and L5bivalent C1-6straight orZ is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; each R8is independently hydrogen or optionally substituted C1-6aliphatic; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; Page 300 of 783 11575796v1Attorney Docket No.: 2013405-0010 each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, or a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety. 105. The compound of embodiment 104, wherein R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic. 106. The compound of embodiment 104 or 105, wherein . 107. The compound of embodiment 106, wherein Ring A is.108. The compound of embodiment 104 or 105, wherein . 109. The compound of embodiment 108, wherein R2andto which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. 110. The compound of embodiment 109, wherein .111. The compound of embodiment 104 or 105, wherein . 112. The compound of embodiment 111, wherein R2andto which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. 113. The compound of embodiment 112, wherein Ring A is selected from: Page 301 of 783 11575796v1Attorney Docket No.: 2013405-0010 . 114. The compound of R4and R7, together with the atoms to which they are attached, combineto 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. 115. The compound of embodiment 114, wherein .116. The compound of embodiment 104 or 105, wherein .117. The compound of embodiment 116, wherein . 118. The compound of any one of embodiments 104-a covalent bond. 119. The compound of any one of embodiments 104-117, wherein L3is an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. 120. The compound of any one of embodiments 104-119, wherein L4is a covalent bond. 121. The compound of any one of embodiments 104-119, wherein L4is an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. 122. The compound of any one of embodiments 104-121, wherein L5is a covalent bond. 123. The compound of any one of embodiments 104-121, wherein L5is an optionally substituted bivalent C1-3straight or branched hydrocarbon chain. 124. The compound of any one of embodiments 104-123, wherein each R8is C1-6alkyl. 125. The compound of any one of embodiments 104-124, wherein R9is hydrogen. 126. The compound of any one of embodiments 104-125, wherein R2is halogen. 127. The compound of any one of embodiments 104-126, wherein each R3is hydrogen. 128. The compound of any one of embodiments 104-127, wherein R4is optionally substituted C1-6alkyl. Page 302 of 783 11575796v1Attorney Docket No.: 2013405-0010 129. The compound of any one of embodiments 104-128, wherein R6is optionally substituted C1-6alkyl. 130. The compound of any one of embodiments 104-129, wherein X is O. 131. The compound of any one of embodiments 104-129, wherein X is NR7. 132. The compound of any one of embodiments 104-131, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, - C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. 133. The compound of embodiment 132, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. 134. The compound of embodiment 132, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon 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 compound of embodiment 134, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. 136. The compound of any one of embodiments 132-135, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)-. 137. The compound of any one of embodiments 132-136, wherein linker comprises at least one triple bond. 138. The compound of any one of embodiments 132-137, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. 139. The compound of any one of embodiments 104-138, wherein linker is: , wherein:Page 303 of 783 11575796v1Attorney Docket No.: 2013405-0010 M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-. 140. The compound of embodiment 139, wherein linker is selected from: , , 141., , , ,Page 304 of 783 11575796v1Attorney Docket No.: 2013405-0010 , , ,143. The compound of any one of embodiments 139-142, wherein is a covalent bond. 144. The compound of any one of embodiments 132-143, wherein Cy is optionally substituted phenyl or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 145. The compound of any one of embodiments 132-143, wherein Cy is optionally substituted monocyclic 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 146. The compound of any one of embodiments 132-143, wherein Cy is optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 147. The compound of embodiment 146, wherein Cy is a spirocyclic 6- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. 148. The compound of any one of embodiments 104-147, wherein each R is independently hydrogen or optionally substituted C1-6alkyl. 149. The compound of any one of embodiments 104-148, wherein LBM is a CRBN binding moiety. 150. The compound of any one of embodiments 104-148, wherein LBM is a VHL binding moiety. 151. The compound of any one of embodiments 104-148, wherein LBM is a IAP binding moiety. 152. The compound of any one of embodiments 104-148, wherein LBM is a MDM2 binding moiety. 153. The compound of any one of embodiments 104-152, wherein the compound is of Formula IXA, IXB, IXC, or IXD:Page 305 of 783 11575796v1Attorney Docket No.: 2013405-0010 IXA IXBor a 154. The compound of any one of embodiments 104-153, wherein the compound is of Formula X:or a pharmaceutically acceptable salt thereof, wherein: Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each Rais independently hydrogen or an optionally substituted C1-6aliphatic, or two Ragroups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L2is a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH. 155. The compound of embodiment 154, wherein Ring C is optionally substituted phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 156. The compound of embodiment 154, wherein Ring C is optionally substituted phenyl or 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. Page 306 of 783 11575796v1Attorney Docket No.: 2013405-0010 157. The compound of embodiment 156, wherein , wherein: each B is independently selected from N, C, and more than two B are N; each Rcis independently selected from halogen, -- - optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3. 158. The compound of embodiment 157, wherein . 159. The compound of any one of embodiments 154- is of Formula IIIC:or a pharmaceutically acceptable salt thereof. 160. The compound of any one of embodiments 154-159, wherein the compound is of Formula IIID: or a161. The compound of embodiment 154, wherein Ring C is optionally substituted C3-C7cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 162. The compound of embodiment 154, wherein Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 163. The compound of embodiment 162, wherein Ring C is: Page 307 of 783 11575796v1Attorney Docket No.: 2013405-0010 wherein: each A is independently N, C, or CH,than two A groups are N; each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3. 164. The compound of embodiment 163, wherein Ring C is: . 165. The compound of any one of2wherein L is a covalent bond. 166. The compound of any one of embodiments 154-164, wherein L2is –CH2-. 167. The compound of any one of embodiments 154-164, wherein L2is –O- or –S-. 168. The compound of any one of embodiments 154-164, wherein L2is -C(O)N(R)-, or -N(R)C(O)-. 169. The compound of any one of embodiments 154-168, wherein Y is N. 170. The compound of any one of embodiments 154-168, wherein Y is CH. 171. The compound of any one of embodiments 68-81, wherein each Rcis independently selected from halogen, -O(C1-6alkyl), C1-6alkyl, and C1-6haloalkyl. 172. The compound of any one of embodiments 154-171, wherein the compound is of Formula XA:or a pharmaceutically acceptable salt thereof, wherein: each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; Page 308 of 783 11575796v1Attorney Docket No.: 2013405-0010 each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3. 173. The compound of embodiment 172, wherein the compound is of Formula XA-1 or XA-2: or a174. The compound of any one of embodiments 104-153, wherein the compound is a compound of Formula XI:or a pharmaceutically acceptable salt thereof, wherein: linker is attached to the bracketed moiety at one of Rd, Re, Rf, and Rg; each Rdthat is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C1-6aliphatic, or two Rd, together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; Page 309 of 783 11575796v1Attorney Docket No.: 2013405-0010 each Rethat is not the point of attachment for the linker is independently hydrogen or optionally substituted C1-6aliphatic; Rf, when it is not the point of attachment for the linker, is hydrogen or optionally substituted C1-6aliphatic; each Rgthat is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; Rhis hydrogen, halogen, or optionally substituted C1-6aliphatic; and p is 0, 1, 2, or 3. 175. The compound of embodiment 174, wherein the compound is a compound of Formula XIA:or a pharmaceutically acceptable salt thereof. 176. The compound of any one of embodiments 104-153, wherein the compound is a compound of Formula XII:or a pharmaceutically acceptable salt thereof. 177. The compound of embodiment 176, wherein at least one Riis -C(O)N(R)2. 178. The compound of embodiment 176 or 177, wherein two Rigroups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. 179. The compound of embodiment 176, wherein the compound is a compound of Formula XIIA: Page 310 of 783 11575796v1Attorney Docket No.: 2013405-0010or a 180. The compound of embodiment 176 or 179, wherein the compound is a compound of Formula XIIB:or a pharmaceutically acceptable salt thereof. 181. The compound of embodiment 180, wherein the compound is a compound of Formula XIIB-1:or a pharmaceutically acceptable salt thereof. 182. The compound of any one of embodiments 104-153, wherein the compound is a compound of Formula XIII:or a pharmaceutically acceptable salt thereof, wherein: Rmis optionally substituted C1-6aliphatic; Page 311 of 783 11575796v1Attorney Docket No.: 2013405-0010 each Rnis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; and s is 0, 1, 2, 3, 4, or 5. 183. The compound of embodiment 182, wherein the compound is a compound of Formula XIIIA:or a 184. The compound of any one of embodiments 104-153, wherein the compound is a compound of Formula XIV:or a pharmaceutically acceptable salt thereof, wherein: each Rpis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rqis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; each Rris independently hydrogen or optionally substituted C1-6aliphatic; each Rsis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. 185. The compound of any one of embodiments 104-153, wherein the compound is a compound of Formula XV:Page 312 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a pharmaceutically acceptable salt thereof, wherein: each Rtis independently hydrogen or optionally substituted C1-6aliphatic, or both Rtgroups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Ruis independently hydrogen, halogen, -CN, or optionally substituted C1-6aliphatic; each Rvis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rv, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each Rwis independently halogen, -OR, -CN, or optionally substituted C1-6aliphatic, or one instance of Ruand Rw, together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each v is independently 0, 1, 2, 3, 4, or 5. 186. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. 187. A pharmaceutical composition comprising the compound of any one of embodiments 1-186, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 188. A method of preparing the pharmaceutical composition of embodiment 187, comprising: providing the compound of any one of embodiments 1-186, or a pharmaceutically acceptable salt thereof; and formulating the compound with suitable excipients to give the pharmaceutical composition. 189. A method, comprising administering the compound of any one of embodiments 1-186, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 187 to a subject in need thereof. 190. A method of treating a cancer, comprising administering the compound of any one of embodiments 1-186, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 187 to a subject in need thereof. 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 of degrading KAT2 in a subject, comprising administering the compound of any one of embodiments 1-186, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 187 to a subject in need thereof. Page 313 of 783 11575796v1Attorney Docket No.: 2013405-0010 193. An in vitro method of degrading KAT2, comprising contacting a biological sample with the compound of any one of embodiments 1-186, or a pharmaceutically acceptable salt thereof. EXAMPLES

[0274] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein. List of Abbreviations MeOH Methanol Boc2O Di-tert-but l dicarbonatePage 314 of 783 11575796v1Attorney Docket No.: 2013405-0010 DMSO Dimethylsulfoxide EDC.HCl 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochlorideAnalytical Methods

[0275] The following analytical methods are exemplary of those used to purify and / or characterize the compounds described herein: Page 315 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0276] Method A (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 µm, Eluents A: 0.1% TFA in Water, B: Acetonitrile; Flow Rate: 25.0 mL / min; Gradient: 0.0 min 5% B, 0.2-3.0 min 5-5% B, 3-40 min 60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-5% B, 48-55 min 5-5% B.

[0277] Method B (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 µm, Eluents A: 10 mM Ammonium Bicarbonate in Water, B: Acetonitrile; Flow Rate: 25.0 mL / min; Gradient: 0.0 min 5% B, 0.2-3.0 min 5-5% B, 3-40 min 60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95- 5% B, 48-55 min 5-5% B.

[0278] Method C (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 µm, Eluents A: 0.1% TFA in Water, B: Acetonitrile; Flow Rate: 25.0 mL / min; Gradient: 0.0 min 10% B, 0.2-3.0 min 10- 10% B, 3-40 min 10-60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-10% B, 48-55 min 10-10%B.

[0279] Method D (Combiflash®): Column: YMC, Dimension: 4 g (irregular silica, 40-63 µm, 60 Å), Eluents A: DCM, B: MeOH, Gradient: 0-5% MeOH / DCM for 30 min, Flow Rate: 20.0 mL / min.

[0280] Method E (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 µm, Eluents A: 10 mM Ammonium Bicarbonate in Water, B: Acetonitrile; Flow Rate: 25.0 mL / min; Gradient: Linear gradient.

[0281] Method F (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 µm, Eluents A: 0.1% Formic Acid in Water, B: Acetonitrile; Flow Rate: 25.0 mL / min; Gradient: 0.0 min 2% B, 0.2-3.0 min 2-2% B, 3-50 min 2-55% B, 50-51 min 55-95% B, 51-57 min 95-95% B, 57-58 min 95-2% B, 58-65 min 2-2% B.

[0282] Method G: Column: X-SELECT CSH-C18, (250 x 30 mm) 5 µm, Eluents A: 0.1% Formic Acid in Water, B: Acetonitrile; Flow Rate: 25.0 mL / min; Gradient: Linear gradient.

[0283] Method H: Column: SYNERGY C18, (150 x 19 mm) 5 µm, Eluents A: 10 mM ammonium bicarbonate in H2O, B: Acetonitrile; Flow Rate: 25.0 mL / min; Gradient (Time / %B): 0 / 10 ,10 / 30, 20 / 40, 30 / 50, 40 / 60, 50 / 70, 55 / 98. 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 Step-1: methyl 4-(5-((tert-butoxycarbonyl)amino)pyridin-3-yl)benzoate Page 316 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0284] mmol) and tert-butyl, a solution of Na2CO3(18.60 g, 175.80 mmol) in water (3 mL) was added, and the reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, Pd(PPh3)4(4.23 g, 3.66 mmol) was added, and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (10% ethyl acetate in hexane) to afford methyl 4-(5-((tert- butoxycarbonyl)amino)pyridin-3-yl)benzoate (7.00 g, 58%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.77 - 9.69 (m, 1H), 8.63 (brs, 1H), 8.55 (s, 1H), 8.25 (brs, 1H), 8.08 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 8.3 Hz, 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

[0285] yl)benzoate (7.50 g, 22.80 mmol, from step 1) in ACN (70 mL), MeI (2.10 mL, 34.20 mmol) was added at RT. The reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution. The aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to give crude compound. The crude compound was washed with diethyl ether to afford 3-((tert-butoxycarbonyl)amino)-5-(4- (methoxycarbonyl)phenyl)-1-methylpyridin-1-ium (6.50 g, 83%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.57 (brs, 1H), 9.12 (d, J = 13.2 Hz, 2H), 8.64 - 8.52 (m, 1H), 8.19 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 4.42 (s, 3H), 3.91 (s, 3H), 1.53 (s, 9H). LC-MS: m / z 344.2 [M+H]+. Page 317 of 783 11575796v1Attorney Docket No.: 2013405-0010 Step-3: methyl 4-((cis)-5-((tert-butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate- -1- methylpyridin-1-ium (2.50 g, 7.28 mmol, from step 2) in methanol (50 mL), PtO2(1.25 g) was added at RT under hydrogen atmosphere. The reaction mixture was stirred at RT for 16 h. Progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated to give crude compound. The crude compound was purified by column chromatography (5% methanol in DCM) to afford compound methyl 4-((cis)-5-((tert- butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate (1.70 g, 68%) as an off-white solid along with compound methyl 4-((trans)-5-((tert-butoxycarbonyl)amino)-1-methylpiperidin-3-yl)benzoate. LC- MS:m / z 349.3 [M+H]+. Step-4: methyl 4-((cis)-5-amino-1-methylpiperidin-3-yl)benzoate-1-methylpiperidin-3- yl)benzoate (3.40 g, 7.28 mmol, from step 3) in DCM (30 mL), TFA (10 mL) was added slowly at 0 °C and the reaction mixture was stirred at RT for 16 h. Progress of reaction was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure and co-distilled with DCM and methanol. The residue was diluted with saturated NaHCO3solution and extracted with DCM. Combined organic layer was dried over anhydrous Na2SO4and concentrated to afford crude methyl 4-((cis)-5- amino-1-methylpiperidin-3-yl)benzoate (2.00 g, 83%) as a yellow sticky solid which was used as such for 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 merged in solvent peak. LC-MS: m / z 249.4 [M+H]+. Step-5 and 6: methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoate Page 318 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0288] (3.00 g,12.09 step , g, was 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. Progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was dissolved in water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by column chromatography (2% methanol in DCM) to afford 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 pale-yellow solid. This compound was purified by chiral SFC to afford methyl 4-((3S,5S)-5-((5- bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate and methyl 4- ((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)benzoate (0.20 g, 24%). The chiral SFC conditions were as follows: Phenomenex Cellulose-3 column (250 mm x 21.2 mm, 5 µm); mobile phase: methanol; flow rate: 18 mL / min; diluent: methanol; loading: 80 mg / injection. Isomer 1 at RT 10.5 min and Isomer 2 at 18 min.

[0289] 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 (400 MHz, DMSO-d6) δ = 7.96 - 7.85 (m, 3H), 7.42 (d, J = 7.8 Hz, 2H), 5.82 (d, J = 9.3 Hz, 1H), 4.03 - 3.91 (m, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 3.05 (t, J = 11.5 Hz, 1H), 2.95 (d, J = 7.3 Hz, 1H), 2.85 (d, J = 10.8 Hz, 1H), 2.25 (s, 3H), 2.07 - 1.87 (m, 3H), 1.72 (q, J = 11.7 Hz, 1H). LC-MS: m / z 435.0 [M+H]+. C-HPLC (Column: Chiralcel OJ-H (250*4.5 mm, 5 µm); Eluents A: CO2, B: 0.1% DEA in EtOH; A:B-40% B Isocratic): RT = 2.50 mins; 100.00%. SOR: - 19.16, Solvent: MeOH, Path length: 50 mm, Concentration: 0.1 w / v%.

[0290] Isomer 2: methyl 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)- 1-methylpiperidin-3-yl)benzoate:1H NMR (400 MHz, DMSO-d6) δ = 7.95 - 7.85 (m, 3H), 7.42 (d, J = 8.3 Page 319 of 783 11575796v1Attorney Docket No.: 2013405-0010 Hz, 2H), 5.82 (d, J = 9.3 Hz, 1H), 4.02 - 3.89 (m, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 3.05 (t, J = 11.5 Hz, 1H), 2.95 (d, J = 6.8 Hz, 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 (Column: Chiralcel OJ-H (250*4.5 mm, 5 µm); Eluents A: CO2, B: 0.1% DEA in EtOH; A:B-40% B Isocratic): RT = 3.26 mins; 99.17%. SOR: 21.04, Solvent: MeOH, Path length: 50 mm, 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

[0291] 6-oxo-1,6-- g, step 6) in ethanol (5 mL) and water (0.5 mL), lithium hydroxide (0.03 g, 0.63 mmol) was added and the reaction mixture was stirred at 70 °C for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude was acidified with 1N HCl to pH 3. Precipitated solid was filtered, washed and concentrated to yield 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.1H NMR (400 MHz, DMSO-d6) δ = 13.13 - 12.82 (m, 1H), 11.34 - 11.09 (m, 1H), 7.96 (d, J = 6.8 Hz, 3H), 7.43 (d, J = 8.3 Hz, 2H), 6.29 (d, J = 8.3 Hz, 1H), 4.53 - 4.36 (m, 1H), 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 = 8.8 Hz, 1H), 2.80 (s, 3H), 2.18 (d, J = 10.3 Hz, 1H), 2.12 - 2.01 (m, 1H). LC-MS: m / z 422.0 [M+H]+. Alternate 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 Step 1: tert-butyl (3R)-3-(pyridine-2-carbonylamino)piperidine-1-carboxylate

[0292] To a stirred(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 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated Page 320 of 783 11575796v1Attorney Docket No.: 2013405-0010 under reduced pressure. The residue was dissolved in ethyl acetate and washed with 0.05 M HCl and saturated NaHCO3solution. The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford tert-butyl (3R)- 3-(pyridine-2-carbonylamino)piperidine-1-carboxylate (13.17 g, 72%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.63 (d, J = 3.9 Hz, 1H), 8.55 (brs, 1H), 8.07 - 7.98 (m, 2H), 7.61 (t, J = 5.6 Hz, 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

[0293] with tert-butyl(3R)-3-(pyridine-2-carbonylamino)piperidine-1-carboxylate (10.00 g, 32.8 mmol, from step 1), silver carbonate (9 g, 32.8 mmol), Pd(OAc)2(0.74 g, 0.32 mmol), methyl 4-iodobenzoate (43 g, 164 mmol), 2,6-dimethylbenzoic acid (1.23 g, 8.2 mmol) and t-BuOH (100 mL). The vessel was flushed with argon, sealed with a crimp cap and heated to 120 °C. After 24 h, the reaction vessel was removed from the oil bath and cooled to room temperature and DCM was added to the reaction mixture. The progress of the reaction was monitored by TLC. The mixture was thoroughly stirred for 10 min and the solids were removed by filtration which was additionally rinsed with DCM. The combined filtrates were concentrated under reduced pressure and the residue was purified by column chromatography to afford tert-butyl (3R,5R)-3-(4-methoxycarbonylphenyl)-5-(pyridine-2-carbonylamino)piperidine-1-carboxylate (8.00 g, 56%) as a white solid. LC-MS: m / z 438.12 [M-H]-. Step 3: Methyl 4-[(3R,5R)-5-(pyridine-2-carbonylamino)-3-piperidyl]benzoate

[0294] -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. Then the resulting solution was slowly brought 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 Page 321 of 783 11575796v1Attorney Docket No.: 2013405-0010 organic layer was dried over anhydrous Na2SO4, 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 for the next reaction without any further purification.1H NMR (400 MHz, DMSO-d6) δ = 8.65 - 8.63 (m, 1H), 8.52 (d, J = 8.6 Hz, 1H), 8.05 - 7.97 (m, 2H), 7.92 - 7.89 (m, 2H), 7.62 - 7.58 (m, 1H), 7.41 (d, J = 8.3 Hz, 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 = 12.2 Hz, 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 -3-g, step (70 mL) was added 37% w / v formaldehyde (2.9 mL) and stirred for 5 h. Then sodium triacetoxyborohydride (6.53g, 31mmol) was added over a period of 30 min at 0 °C. The resulting solution was stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion of 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 layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Crude material was purified by CombiFlash® column chromatography to afford methyl 4-[(3R,5R)-1-methyl-5-(pyridine-2-carbonylamino)-3- piperidyl]benzoate (5.5 g, 75%).1H NMR (400 MHz, DMSO-d=) δ = 8.67 - 8.53 (m, 2H), 8.08 - 7.95 (m, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.63 - 7.55 (m, 1H), 7.44 (d, J = 8.3 Hz, 2H), 4.21 - 4.06 (m, 1H), 3.84 (s, 3H), 3.09 - 2.90 (m, 2H), 2.85 (d, J = 9.8 Hz, 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)benzoatecarbonylamino)-3- piperidyl]benzoate (1.00 g, 2.80 mmol, from step 4) in water (50 mL) was added 12 N HCl solution (5 mL) at 0 °C, followed by zinc powder (2.76 g, 42.00 mmol) and DCM (50 mL) the reaction mixture was stirred at rt for 12 h in a round bottomed flask. The progress of the reaction was monitored by TLC. After completion of the reaction, cooled to 0 °C and basified using NaOH (5M) until pH 9. Then the mixture Page 322 of 783 11575796v1Attorney Docket No.: 2013405-0010 was filtered through Celite® bed and washed with DCM (20 mL x 3). The filtrate was extracted with DCM (20 mL X 3), all organic layers were combined, and solvent was removed in vacuo. Crude material (700 mg) was purified by CombiFlash® column chromatography (DCM:MeOH:NH4OH 80:20:03) to afford 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

[0297] 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoic acid was prepared from methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3- yl)benzoate generally following the procedures in steps 5 and 7 of the Preparation of Intermediate 1 above. Preparation of Intermediate 2: 4,5-dibromo-2-methylpyridazin-3(2H)-one

[0298] To a 79.00 mmol) in DMF (200mL), K2CO3(21.00 g, 158.10 mmol) was added, followed by methyl iodide (8.80 mL, 118.10 mmol), and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was washed with diethyl ether to afford 4,5- dibromo-2-methylpyridazin-3(2H)-one (14.00 g, 66.8%) as colorless oil which was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6) δ = 8.12 (s, 1H), 3.67 (s, 3H). LC-MS: m / z 268.7 [M+H]+. Preparation of Intermediate 3: 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

[0299] To ag, 30.48 mmol) and 3- aminopiperidine-2,6-dione (5.00 g, 30.48 mmol) in acetic acid (10 mL), NaOAc (4.90 g, 60.97 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was Page 323 of 783 11575796v1Attorney Docket No.: 2013405-0010 monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered and washed with water. The crude compound was taken up in acetone. Charcoal was added, and the reaction mixture was refluxed for 30 min. The reaction mixture was filtered through Celite® and washed with acetone. The filtrate was concentrated to afford 2-(2,6-dioxo-3- piperidyl)-4-hydroxy-isoindoline-1,3-dione (6.5 g, 55%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ = 11.18 (brs, 1H), 11.08 (s, 1H), 7.65 (dd, J = 7.3, 8.4 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 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

[0300] To 1,3-dione (1.00 g,3.64 mmol, step , tert- g, mmol) was added, followed by DMAP (0.43 g, 3.64 mmol), and the reaction mixture was stirred at RT for 3 h. To the resulting reaction mixture, piperidine (0.30 g, 3.64 mmol) was added, and the reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography by (40% ethyl acetate in heptane) to afford tert-butyl 3-(4- hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate (0.8 g, 61.5%) as pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 11.21 (br s, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 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 [M-H]+. Preparation of Intermediate 4: 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-onePage 324 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0301] 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), LAH (2M in THF, 2.2 mL, 4.59 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated Na2SO4solution and diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude compound which was purified by silica-gel column chromatography (80% ethyl acetate in hexane) to afford 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.1H NMR (400 MHz, DMSO-d6) δ = 7.95 - 7.86 (m, 3H), 7.42 (d, J = 7.8 Hz, 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-1-methyl-3- piperidyl]amino]-2-methyl-pyridazin-3-one (0.45 g, 1.10 mmol, from step 1) in DCM (15 mL), Dess- Martin periodinane (0.93 g, 2.21 mmol) was added at 0 °C and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated NaHCO3solution and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude compound which was purified by silica-gel column chromatography (80% ethyl acetate in hexane) to afford 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.1H NMR (400 MHz, DMSO-d6) δ = 10.01 - 9.94 (m, 1H), 8.09 - 7.99 (m, 1H), 7.88 (d, J = 2.9 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 5.88 - 5.79 (m, 1H), 4.05 - 3.89 (m, 1H), 3.59 (s, 3H), 3.07 (t, J = 11.2 Hz, 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 Page 325 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0303] To mmol) and 3- aminopiperidine-, g, 38.58 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered and washed with water and dried under reduced pressure to afford 2- (2,6-dioxo-3-piperidyl)-5-methyl-isoindoline-1,3-dione (8.0 g, crude) as an off-white solid which was used as such for the next reaction.1H 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 in solvent peak. LC-MS: m / z 272.93 [M+H]+. Step-2: 5-(bromomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

[0304] (0.50 g,1.83 mmol, from step 1) and NBS (0.39 g, 2.20 mmol) in ACN (10 mL), benzoyl peroxide (0.11 g, 3.60 mmol) was added, and the reaction mixture was stirred at 90 °C for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude compound which was purified by silica gel column chromatography (30% ethyl acetate in hexane) to afford 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]+. Preparation of Intermediate 6: 4-bromo-5-[[(3R,5R)-5-[4-(chloromethyl)phenyl]-1-methyl-3- piperidyl]amino]-2-methyl-pyridazin-3-onePage 326 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0305] 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), thionyl chloride (0.05 g, 0.39 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and the aqueous layer was extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude compound which was purified by column chromatography (50% ethyl acetate in hexane) to afford 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]+. Preparation of Intermediate 7: 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

[0306] To ag, 12.15 mmol) and 3- aminopiperidine-2,6-dione (1.99 g, 12.15 mmol) in acetic acid (20 mL), NaOAc (1.03 g, 12.68 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered and washed with water. The crude compound was taken in acetone. Charcoal was added and the reaction mixture was refluxed for 30 min. The reaction mixture was filtered through Celite® and washed with acetone. The filtrate was concentrated to afford 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

[0307] (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) was Page 327 of 783 11575796v1Attorney Docket No.: 2013405-0010 added followed by DMAP (2.22 g, 18.24 mmol), and the reaction mixture was stirred at RT for 3 h. To the resulting reaction mixture, piperidine (1.55 g, 18.24 mmol) was added, and the reaction mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography by (40% ethyl acetate in heptane) to afford tert-butyl 3- (5-hydroxy-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate (3.0 g, 44%) as pale yellow solid.1H NMR (400 MHz, 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, 12.7 Hz, 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 [M-H]+. 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

[0308] (12.00 g,48.33 mmol, from step 5, alternate preparation of intermediate 1) and 4,5-dichloro-2-methyl-pyridazin-3- one (8.91 g, 48.33 mmol) in DMSO (60 mL) were added K2CO3(20.00 g, 144.00 mmol) and CsF (0.74 g, 4.83 mmol), respectively, at RT. The reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, respectively, followed by dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoate (5.50 g, 29%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 6.16 (d, J = 9.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.98 - 3.94 (m, 1H), 3.58 (s, 3H), 3.04 (t, J = 11.7 Hz, 1H), 2.97 - 2.84 (m, 2H), 2.25 (s, 3H), 2.07 - 1.95 (m, 2H), 1.91 (t, J = 11.1 Hz, 1H), 1.76 - 1.64 (m, 1H), 1.31 (t, J = 7.0 Hz, 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 Page 328 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0309] yl)amino]-1- g, , mL) and H2O (10 mL) was added LiOH.H2O (0.35 g, 14.82 mmol) at RT. The reaction mixture was stirred at 50 °C for 2 h. After completion of reaction, the reaction mixture was concentrated, and washed with diethyl ether to obtain crude. The crude was diluted with water, acidified with 1N HCl (pH 3) to get solid, which was filtered and washed with diethyl ether to afford 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4- yl)amino]-1-methyl-3-piperidyl]benzoic acid (2.10 g, 75%) as an off white solid. LC-MS: m / z 377.20 [M+H]+. Preparation of Intermediate 9: 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

[0310] To ag, 11.80 mmol) in DMF (30 mL), 3-aminopiperidine-2,6-dione (2.33 g, 14.16 mmol) was added followed by TEA (8.20 mL, 59.03 mmol) at RT and the reaction mixture was stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH / DCM) to afford 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbonitrile (2.60 g, 82%) as blue solid.1H NMR (400 MHz, 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, 13.4 Hz, 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, 13.0 Hz, 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 Page 329 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0311] (2.00 g, 7.43 mmol,, added at RT and the reaction mixture was stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH / DCM) to afford 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 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), AcOH (0.2 mL) and NaCNBH3(0.83 g, 13.23 mmol) were added and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, all volatiles were evaporated. The reaction mixture was quenched with saturated NaHCO3solution and the compound was extracted with DCM. The crude compound was purified by silica gel column chromatography (10% MeOH / DCM) to afford 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 [M-H]-. Step 4: 3-[1-oxo-5-(piperazin-1-ylmethyl)isoindolin-2-yl]piperidine-2,6-dione

[0313] 5- yl]methyl]piperazine-1-carboxylate (1.60 g, 3.61 mmol, from step 3) in DCM (20 mL), TFA (5 mL) was added at 0 °C and the reaction mixture was stirred at RT for 5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with diethyl ether followed by pentane and dried well to Page 330 of 783 11575796v1Attorney Docket No.: 2013405-0010 afford 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 (400 MHz, DMSO-d6) δ = 10.99 (s, 1H), 8.65 (brs, 1H), 7.75 (d, J = 7.3 Hz, 1H), 7.61 (brs, 1H), 7.52 (d, J = 7.3 Hz, 1H), 5.12 (dd, J = 4.6, 13.0 Hz, 1H), 4.50 - 4.30 (m, 2H), 3.39 (q, J = 7.0 Hz, 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]+. Preparation of Intermediate 10: tert-butyl 4-[3-(p-tolylsulfonyloxy)prop-1-ynyl]piperidine-1- carboxylate Step-1: tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate

[0314] To a stirred in DCM (40 mL), CBr4(6.22 g, 18.77 mmol) was added at 0 °C and stirred for 1 h. 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 RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by silica gel column chromatography (30% ethyl acetate in hexane) to afford tert-butyl 4-(2,2-dibromovinyl)piperidine-1- carboxylate (0.70 g, 20%) as an off white solid.1H NMR (400 MHz, 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

[0315] To a(4.00 g, 10.84 mmol, from step 1) in THF (40 mL) was added n-butyl lithium 1.6 M (27 ml, 43.36 mmol) at -78 °C and stirred for 1 h. To the resulting reaction mixture was added paraformaldehyde (1.38 g, 43.36 mmol) at -78 °C and stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude compound which was purified by silica-gel column chromatography (80% ethyl acetate in hexane) to afford to tert-butyl 4-(3-hydroxyprop-1-ynyl)piperidine-1-carboxylate Page 331 of 783 11575796v1Attorney Docket No.: 2013405-0010 (1.0 g, 38%) as a pale yellow liquid.1H NMR (400 MHz, DMSO-d6) δ = 5.06 (t, J = 5.9 Hz, 1H), 4.04 (dd, J = 2.0, 5.9 Hz, 2H), 3.69 - 3.53 (m, 2H), 3.04 (t, J = 9.4 Hz, 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 (1.00 g, 4.18step p- g, ether (50 mL) was stirred at 0 °C for 30 min. To the resulting reaction mixture was added KOH (1.40 g, 25.08 mmol) and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography by (30% ethyl acetate in heptane) to afford (0.80 g, 48%) as a pale yellow liquid. LC-MS: m / z 338.2 [M+H]+(M-tBu). Preparation of Intermediate 11: 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine

[0317] To aand 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), Na2CO3(0.37 g, 3.53 mmol) was added dissolved in H2O (3 mL) at RT. The reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, PdCl2(dppf) (0.14 g, 0.17 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 2,6-dibenzyloxy-3-(4- bromophenyl)pyridine (0.70 g, 44%) as an off white solid which was used as such for 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 Page 332 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0318] Intermediate 12 was 6 using the ester of intermediate 8.1H NMR (400 MHz, DMSO-d6) δ =, Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.56 (d, J = 8.3 Hz, 1H), 4.76 (s, 2H), 4.27 (brs, 1H), 3.61 (s, 3H), 3.56 (d, J = 10.8 Hz, 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 = 12.2 Hz, 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

[0319] Intermediate 13 was 4 using ester of intermediate 8.1HNMR (400 MHz, DMSO-d6) δ = 9.98 (s, 1H), 7.97 (brs, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 7.3 Hz, 2H), 6.13 (d, J = 7.8 Hz, 1H), 3.95 (brs, 1H), 3.58 (brs, 3H), 3.08 (t, J = 9.8 Hz, 1H), 2.96 (d, J = 9.3 Hz, 1H), 2.88 (d, J = 10.3 Hz, 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

[0320] Intermediate 14 was6 using ester of intermediate 17. The crude material was used directly in the next step. Preparation of Intermediate 15: 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 O(2.50 g, 8.14 mmol) and 3-aminopiperidine-2,6-dione (1.93 g, 8.96 mmol) in ACN (25 mL), DIPEA (7.5 mL, 40.72 mmol) was Page 333 of 783 11575796v1Attorney Docket No.: 2013405-0010 added at RT. The reaction mixture was stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 3- (5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (2.3 g, crude) as blue solid which was used as such for 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

[0322] (0.50 g, 1.54mmol, step tert- -3,6-dihydro-2H- pyridine-1-carboxylate (0.57 g, 1.85 mmol) in DMF (5 mL), K2CO3(0.42 g, 3.09 mmol) was added at RT. The reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, PdCl2(dppf) (0.13 g, 0.15 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 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 black solid which was used as such for 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-carboxylate5-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (1.80 g, 4.23 mmol, from step 2) in dry THF (25 mL), Pd / C (1.0 g) was added at RT. The reaction mixture was stirred at 60 psi H2gas pressure at 45 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[2-(2,6- Page 334 of 783 11575796v1Attorney Docket No.: 2013405-0010 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 yl]piperidine-1-1,4-dioxane (20 mL) was stirred at 0 °C for 5 min followed by at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford 3-[1-oxo-5-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione (1.1 g, HCl salt) as white solid which was used as such for the next reaction;1H NMR (400 MHz, DMSO-d6) δ = 10.97 (s, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.46 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 5.10 (dd, J = 3.9, 12.7 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.34 - 4.28 (m, 1H), 3.56 (s, 1H), 3.36 (d, J = 11.7 Hz, 2H), 3.05 - 2.87 (m, 4H), 2.60 (d, J = 16.6 Hz, 1H), 2.38 (d, J = 10.3 Hz, 1H), 2.04 - 1.88 (m, 5H); LC-MS: m / z 328.2 [M+H]+. Preparation of Intermediate 16: 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

[0325] To a2,6-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), K2CO3(3.00 g, 21.67 mmol) was added and the reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, PdCl2(dppf) (0.45 g, 0.61 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in a sealed tube at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (40% ethyl acetate in hexane) to afford tert-butyl 4-[2- Page 335 of 783 11575796v1Attorney Docket No.: 2013405-0010 (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 [M-H]-. Step-2: tert-butyl 4-[[4-(2,6-dioxo-3-piperidyl)phenyl]methyl]piperazine-1-carboxylate

[0326] To a oxo-isoindolin-4-yl]-3,6-dihydro-2H-pyridine- g, mL) and 10% Pd / C (37 mg) at RT. The reaction mixture was heated at 50 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% MeOH in DCM) to afford tert-butyl 4-[[4-(2,6-dioxo-3- piperidyl)phenyl]methyl]piperazine-1-carboxylate (0.11 g, crude) as an brown solid.1H NMR (400 MHz, DMSO-d6) δ = 10.99 (brs, 1H), 7.62 - 7.48 (m, 3H), 5.14 (d, J = 10.2 Hz, 1H), 4.54 (d, J = 16.8 Hz, 1H), 4.37 (d, J = 15.3 Hz, 1H), 4.14 - 4.00 (m, 2H), 3.38 (brs, 2H), 2.98 - 2.80 (m, 3H), 2.61 (d, J = 17.2 Hz, 1H), 2.02 (brs, 1H), 1.75 (d, J = 9.0 Hz, 2H), 1.63 - 1.53 (m, 2H), 1.42 (s, 9H); LC-MS: m / z 426 [M-H]-. Step-3: 3-[1-oxo-4-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dionepiperazine-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 min followed by at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with diethyl ether followed by pentane and dried well to afford 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 [M-H]-. 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: Page 336 of 783 11575796v1Attorney Docket No.: 2013405-0010 - 1-in 1,4- dioxane (49 mL) and H2O (1 mL) was added methylboronic acid (1.33 g, 22.25 mmol) followed by Cs2CO3(10.90 g, 33.30 mmol) at RT. The reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, PdCl2(dppf).DCM (0.85 g, 1.11 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in a sealed tube at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through a pad of celite. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, respectively, dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain crude. The crude compound was purified by silica gel column chromatography (10% MeOH / DCM) to afford 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:

[0329] yl)amino]-1- methyl-3-piperidyl]benzoate (2.50 g, 6.20 mmol) in ethanol (20 mL) and H2O (4 mL) was added LiOH.H2O (0.54 g, 22.54 mmol) at RT. The reaction mixture was stirred at 70 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated, and the residue was washed with diethyl ether to obtain crude. The crude was diluted with water and acidified with 1N aq. HCl (pH 3) to get solid, which was filtered and washed with diethyl ether to afford 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid (2.10 g, 90%) as brown solid.1H NMR (400 MHz, DMSO-d6) δ = 7.89 (d, J = 7.8 Hz, 2H), 7.79 (s, 1H), 7.34 (d, J = 7.8 Hz, 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 = 11.7 Hz, 1H), 1.92 (t, J = 10.8 Hz, 2H), 1.86 (s, 3H), -COOH proton is absent. LC-MS: m / z 356.90 [M+H]+. Page 337 of 783 11575796v1Attorney Docket No.: 2013405-0010 Preparation of Intermediate 18: 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 in 1,4-(1.00 g, 4.00 mmol, from step 5 of intermediate 1) followed by Cs2CO3(4.00 g, 12.30 mmol) at RT. To the resulting reaction mixture were added Pd2(dba)3(0.37 g, 0.40 mmol) and Johnphos (0.24 g, 0.80 mmol) at RT. The reaction mixture was stirred at 110 °C for 16 h. 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 layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude compound, which was purified by 100-200 mesh silica-gel column chromatography (using 10% MeOH in DCM) to afford 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.1H NMR (400 MHz, DMSO- d6) δ = 7.91 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 7.3 Hz, 2H), 7.26 (d, J = 6.8 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 5.68 (d, J = 6.4 Hz, 1H), 5.24 (brs, 1H), 3.40 (s, 3H), 3.21 (s, 3H), 3.17 - 3.12 (m, 1H), 3.02 (d, J = 11.2 Hz, 2H), 2.90 - 2.83 (m, 1H), 2.24 (s, 3H), 2.10 (d, J = 16.6 Hz, 1H), 1.91 (t, J = 10.5 Hz, 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

[0331] dihydropyridin-4- yl)amino)piperidin-3-yl)benzoate (2.00 g, 5.41 mmol, from step 1) in DCM (20 mL) was added N- bromosuccinimide (0.95 g, 5.23 mmol) at -78 °C and the reaction mixture was stirred at -78 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with potassium hydrogen sulfate and diluted with water and extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica-gel column chromatography (5% MeOH / DCM) to afford ethyl 4- Page 338 of 783 11575796v1Attorney Docket No.: 2013405-0010 ((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 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

[0332] 4- yl)- mL) and water (2 mL) was added lithium hydroxide (0.06 g, 2.46 mmol) at RT. The reaction mixture was stirred at 80 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure, washed with diethyl ether, and concentrated under reduced pressure to afford 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 such as for 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]benzoatein 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 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude compound, which was purified by silica-gel column chromatography (10% MeOH in DCM) to afford methyl 4-[(3R,5R)-1- Page 339 of 783 11575796v1Attorney Docket No.: 2013405-0010 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 -3-1.40 mmol) and the reaction mixture was stirred at -30 °C for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude compound which was purified by silica-gel column chromatography (10% MeOH in DCM) to afford methyl 4-[(3R,5R)-5-[(3-chloro-1-methyl-2-oxo-4-pyridyl)amino]-1-methyl-3- piperidyl]benzoate (0.11 g, 20%) as liquid. LC-MS: m / z 390.10 [M+H]+.

[0335] The ester was then hydrolyzed to the acid analogously to step 3 intermediate 18 to give desired intermediate 19:

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

[0337] Intermediate 20-5-((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 analogously to step 1 and 2 of intermediate 17.1H NMR (400 MHz, DMSO-d6) δ = 11.55 (brs, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.79 - 7.69 (m, 1H), 7.49 - 7.42 (m, 2H), 6.15 (d, J = 7.8 Hz, 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 Page 340 of 783 11575796v1Attorney Docket No.: 2013405-0010 (m, 2H), 2.89 - 2.74 (m, 4H), 2.14 (d, J = 11.7 Hz, 1H), 2.04 - 1.94 (m, 1H), 1.84 (s, 2H). LC-MS: m / z 356.40 [M+H]+. Preparation of Compounds General Procedure 1:added 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15.00 mmol) followed by potassium carbonate (25.00 mmol) dissolved in water and the reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, [1,1′-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II), Pd(118) (1.30 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in a sealed tube at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford desired product. Step 2

[0339] To a stirred solution of intermediate from step 1 (4.80 mmol) in ACN (40 mL) was added isoamyl nitrite (29.00 mmol) at RT and was stirred for 10 min. To this was added copper(I) iodide (14.00 mmol) at RT. The reaction mixture was stirred at 60 °C for 1 h. The progress of reaction was monitored Page 341 of 783 11575796v1Attorney Docket No.: 2013405-0010 by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica- gel column chromatography to afford desired product. Step 3

[0340] was addedtert- (3.40 mmol) at RT. The reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.23 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.11 mmol) were added at RT and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in a sealed tube at 110 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica-gel column chromatography to afford the desired product. Step 4was added 10% Pd / C at RT. The reaction mixture was stirred in a steel bomb under 50 psi H2gas pressure at RT for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford the desired product. Step 5 Page 342 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0342] mL) was added TFA (2RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford the desired product. Step 6 added1-methylimidazole (1.00 mmol) followed by a benzoic acid intermediate (0.30 mmol) and the reaction mixture was stirred at RT for 10 min. To this was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.40 mmol) and the reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure, the crude compound was purified by prep HPLC to give the desired product. General Procedure 2: Step 1

[0344] (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- Page 343 of 783 11575796v1Attorney Docket No.: 2013405-0010 1-carboxylate (0.54 mmol) in 1,4-dioxane, Na2CO3(0.67 mmol) was added dissolved in H2O (1.2 mL) at RT. The reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, PdCl2(dppf) (0.04 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred in sealed tube at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford desired product. Step 2

[0345] -3,6-dihydro-2H-pyridine-1- step , 10% Pd / C was added followed by triethyl silane (2.55 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to afford desired product. Step 3

[0346] To a1-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 min followed by at RT for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford desired product. Step 4 Page 344 of 783 11575796v1Attorney Docket No.: 2013405-0010 step 3), by N-methyl imidazole (1.10 mmol) and the reaction mixture was stirred at RT for 10 min. To the resulting reaction mixture, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.33 mmol) was added and stirred at 85 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water. The precipitated solid was filtered to yield crude compound which was purified by prep HPLC to afford desired product. General Procedure 3:triethylamine (1.00 mmol) at RT. The reaction mixture was stirred at RT for 5 min. To this was added Intermediate 6, 12, or 15 (0.31 mmol) at RT and the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by prep HPLC to afford 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 Page 345 of 783 11575796v1Attorney Docket No.: 2013405-0010 Step-1: 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione

[0349] To a g, 6.02 mmol) and 3-aminopiperidine-2,6- g, , (0.52 g, 6.30 mmol) was added and the reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction the reaction mixture was quenched with ice-cold water. The precipitated solid was filtered and washed with water. The crude compound was taken up in acetone. Charcoal was added and the reaction mixture was refluxed for 30 min. The reaction mixture was filtered through Celite® and washed with acetone. The filtrate was concentrated to afford 2-(2,6-dioxopiperidin- 3-yl)-4-fluoroisoindoline-1,3-dione (1.20 g) as an off-white solid, which was used as such for 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 merged in 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

[0350] To a1,3-dione (0.50 g, 1.81 mmol, from step 1) and 4-(methylamino)phenol (0.25 g, 1.99 mmol) in DMA (7 mL), KF (0.16 g, 2.72 mmol) was added and the reaction mixture was stirred at 170 °C in microwave for 1.5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-cold water. Precipitated solid was filtered and residue was washed with water. The crude compound was purified by silica gel column chromatography (30% ethyl acetate in hexane) to afford 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 merged in solvent peak. LC-MS: m / z 380.0 [M+H]+. Page 346 of 783 11575796v1Attorney Docket No.: 2013405-0010 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 4-- g, (1.5 mL), N- methyl imidazole (0.03 g, 0.35 mmol) was added, followed by N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (0.03 g, 0.11 mmol), and the reaction mixture was stirred at RT for 10 min. To the resulting reaction mixture, 2-(2,6-dioxopiperidin-3-yl)-4-(4- (methylamino)phenoxy)isoindoline-1,3-dione (0.03 g, 0.07 mmol, from step 2) was added and the reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by Combiflash® column (Method D) to afford 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 pale- yellow solid.1H NMR (400 MHz, 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 = 5.4 Hz, 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

[0352] To ammol) in MeOH (100 mL), SOCl2(4.50 mL, 60.60 mmol) was added 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 completion of reaction, the reaction Page 347 of 783 11575796v1Attorney Docket No.: 2013405-0010 mixture was concentrated under reduced pressure. The residue was quenched with saturated NaHCO3solution and extracted with DCM. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford methyl 3-(4-aminophenyl) propionate (10.00 g, 92%) as an off-white solid which was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6) δ = 6.84 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 8.3 Hz, 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

[0353] To mmol, from step1) in 1,4-dioxane (100 mL), Na2CO3(8.90 g, 83.70 mmol) was added followed by (Boc)2O (14.60 g, 67.00 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)propionate (14.00 g, 90%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.23 (brs, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 7.8 Hz, 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 [M-H]+. Step-3: methyl 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propionate

[0354] (0.10 g, 0.35 mmol, from step 2) in DMF (1 mL), NaH (60% in mineral oil, 0.02 g, 0.71 mmol) was added at 0 °C, and the reaction mixture was stirred for 30 min. To the resulting reaction mixture, MeI (0.11 g, 0.71 mmol) was added, and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford crude methyl 3-(4-((tert- Page 348 of 783 11575796v1Attorney Docket No.: 2013405-0010 butoxycarbonyl)(methyl)amino)phenyl)propionate (0.03 g, 28%) as an off white solid which was used as such for the next reaction. LC-MS: m / z 238.2 [M+H]+(M-tBu). Step-4: tert-butyl (4-(3-hydroxypropyl)phenyl)(methyl)carbamate

[0355] To a phenyl)propionate(0.12 g, 0.40 mmol, from step 3) in THF (4 mL), LAH (1.00 mL, 1.63 mmol) was added 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 completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution, diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 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 in solvent peak. LC-MS: m / z 210.2 [M+H]+(M-tBu). Step-5:3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propyl-4-methylbenzenesulfonate(1.10 g, 4.15 mmol, from step 4) in DCM (20 mL), TEA (0.56 mL, 6.20 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 15 min. To the resulting reaction mixture, tosylchloride (1.10 g, 6.22 mmol) was added and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice cold water and extracted with DCM. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford 3-(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)propyl-4- methylbenzenesulfonate (1.50 g, 86%) as colorless semi solid.1H NMR (400 MHz, DMSO-d6) δ = 7.78 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.14 - 7.09 (m, 2H), 7.07 - 6.98 (m, 2H), 3.99 (t, J = 5.9 Hz, 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 Page 349 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0357] To 1,3-dione (1.17 g,4.30 mmol) , g, was by 3-(4-((tert- butoxycarbonyl)(methyl)amino)phenyl)propyl-4-methylbenzenesulfonate (1.80 g, 4.30 mmol) in DMF slowly at RT. The reaction mixture was stirred at 90 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (35% ethyl acetate in hexane) to afford tert-butyl (4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)propyl)phenyl)(methyl)carbamate (1.20 g, 54%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 11.10 (s, 1H), 7.85 - 7.75 (m, 1H), 7.53 - 7.42 (m, 2H), 7.24 - 7.11 (m, 4H), 5.15 - 4.99 (m, 1H), 4.20 (t, J = 6.2 Hz, 2H), 3.18 - 3.13 (m, 3H), 2.97 - 2.82 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.65 - 2.53 (m, 2H), 2.10 - 2.00 (m, 3H), 1.43 - 1.29 (m, 9H). LC-MS: m / z 520.20 [M-H]+. Step-7: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(methylamino)phenyl)propoxy)isoindoline-1,3-dione4- yl)oxy)propyl)phenyl)(methyl)carbamate (1.20 g, 2.30 mmol, from step 6) in DCM (15 mL), TFA (4 mL) was added at 0 °C, and the reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with diethyl ether, followed by pentane and dried well to afford 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(methylamino)phenyl)propoxy)isoindoline-1,3-dione (TFA salt, 0.60 g, 66%) as an off white solid. LC-MS: m / z 422.2 [M+H]+. Step-8: 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 Page 350 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0359] 4-yl) - g, (1 mL), 2- (2,6-dioxopiperidin-3-yl)-4-(3-(4-(methylamino)phenyl)propoxy)isoindoline-1,3-dione (TFA salt, 0.03 g, 0.07 mmol, from step 7) was added, followed by N-methyl imidazole (0.03 g, 0.35 mmol), and the reaction mixture was stirred at RT for 10 min. To the resulting reaction mixture, N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (0.03 g, 0.10 mmol) was added and stirred at 80 °C for16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ice-cold water. The precipitated solid was filtered to yield crude compound which was purified by prep HPLC (Method C) to afford 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 (0.009 g, 15%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 11.09 (s, 1H), 9.49 (brs, 1H), 7.85 - 7.75 (m, 2H), 7.52 - 7.41 (m, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.18 - 7.04 (m, 6H), 6.30 - 6.16 (m, 1H), 5.16 - 5.02 (m, 1H), 4.20 - 4.11 (m, 2H), 4.09 - 3.92 (m, 1H), 3.66 - 3.46 (m, 5H), 3.43 (brs, 3H), 3.18 - 2.79 (m, 7H), 2.77 - 2.70 (m, 2H), 2.67 - 2.54 (m, 2H), 2.11 - 1.81 (m, 5H). LC-MS: m / z 824.2 and 826.2 [M+H]+. Example 3: Preparation of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)-N-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)- 10-oxodecyl)benzamidePage 351 of 783 11575796v1Attorney Docket No.: 2013405-0010

[0360] 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 mL), 10- amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)decanamide (0.03 g, 0.07 mmol) was added, followed by N-methyl imidazole (0.03 g, 0.35 mmol), and the reaction mixture was stirred at RT for 10 min. To the resulting reaction mixture, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.03 g, 0.10 mmol) was added and stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by prep HPLC (Method A) to afford 4-((3R,5R)-5- ((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)-N-(10-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-10-oxodecyl)benzamide (0.02 g, 37%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.96 (s, 1H), 10.19 (s, 1H), 9.79 - 9.60 (m, 1H), 8.50 - 8.32 (m, 1H), 7.97 (brs, 1H), 7.85 (d, J = 6.1 Hz, 3H), 7.70 - 7.54 (m, 2H), 7.36 (d, J = 7.8 Hz, 2H), 6.25 (brs, 1H), 5.07 (dd, J = 4.9, 13.1 Hz, 1H), 4.46 - 4.37 (m, 1H), 4.33 - 4.21 (m, 1H), 4.18 - 4.02 (m, 1H), 3.62 (s, 3H), 3.27 - 3.09 (m, 4H), 3.03 - 2.74 (m, 4H), 2.69 - 2.55 (m, 3H), 2.41 - 2.30 (m, 3H), 2.21 - 2.09 (m, 1H), 2.07 - 1.92 (m, 2H), 1.68 - 1.45 (m, 4H), 1.38 - 1.22 (m, 11H), 1H extra for TFA salt. LC-MS: m / z 829.2 and 831.0 [M-H]-. Example 4: Preparation of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)amino)-2-oxoethoxy)ethyl)benzamide4- yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.03 g, 0.07 mmol, intermediate 1) in DMF (1 mL), 2-(2- aminoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (0.03 g, 0.07 mmol) was added, followed by N-methyl imidazole (0.03 g, 0.35 mmol), and the reaction mixture was stirred at RT for 10 min. To the resulting reaction mixture, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.03 g, 0.10 mmol) was added and stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by prep HPLC (Method A) to afford 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- Page 352 of 783 11575796v1Attorney Docket No.: 2013405-0010 methylpiperidin-3-yl)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2- oxoethoxy)ethyl)benzamide (0.01 g, 16%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 11.02 - 10.93 (m, 1H), 10.00 (s, 1H), 9.63 - 9.46 (m, 1H), 8.67 - 8.58 (m, 1H), 8.03 (s, 1H), 7.89 (d, J = 7.0 Hz, 2H), 7.84 (s, 1H), 7.65 (s, 2H), 7.44 - 7.31 (m, 2H), 6.34 - 6.22 (m, 1H), 5.15 - 5.00 (m, 1H), 4.48 - 4.40 (m, 1H), 4.34 - 4.24 (m, 1H), 4.17 - 4.05 (m, 3H), 3.72 - 3.66 (m, 2H), 3.63 (s, 5H), 3.58 - 3.55 (m, 2H), 3.29 - 3.17 (m, 1H), 3.15 - 3.04 (m, 1H), 3.02 - 2.84 (m, 5H), 2.68 - 2.57 (m, 1H), 2.44 - 2.31 (m, 1H), 2.22 - 2.13 (m, 1H), 2.10 - 1.93 (m, 2H), 1H extra for TFA salt. LC-MS: m / z 763.2 and 765.2 [M+H]+. Example 5: Preparation of 3-(1-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)benzoyl)piperidin-4-yl)-N-(2-(2,6-dioxopiperidin-3- yl)1oxoisoindolin5yl)propiolamide 4-yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.03 g, 0.07 mmol, intermediate 1) in DMF (2 mL), N-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(piperidin-4-yl)propiolamide (0.03 g, 0.07 mmol) was added, followed by N-methyl imidazole (0.03 g, 0.35 mmol), and the reaction mixture was stirred at RT for 10 min. To the resulting reaction mixture, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.03 g, 0.10 mmol) was added and stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by prep HPLC (Method A) to afford 3-(1-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoyl)piperidin-4-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)propiolamide (0.03 g, 34%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.97 (s, 1H), 10.92 (s, 1H), 9.60 - 9....

Claims

Attorney Docket No.: 2013405-0010 CLAIMS 1. A compound of Formula II:or a Ring A is selected from: ; Ring B is a 5- to selected from N, O,and S; L1is a covalent bond or a bivalent C1-3straight or branched hydrocarbon chain; each R1is independently optionally substituted C1-6aliphatic or optionally substituted C3-6cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or Page 768 of 783 11575796v1Attorney Docket No.: 2013405-0010 R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and LBM is an E3 ubiquitin ligase binding moiety, wherein the compound is not: .

2. The compound of claim 1, wherein .

3. The compound of claim 2, whereinPage 769 of 783 11575796v1Attorney Docket No.: 2013405-0010 ,.

5. The compound of claim 1, wherein .

6. The compound of claim 5, wherein R2the atoms to which they are attached,combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S.

7. The compound of claim 6, wherein .

8. The compound of claim 1, wherein .

9. The compound of claim 8, wherein R2the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S.

10. The compound of claim 9, wherein Ring A is selected from: .Page 770 of 783 11575796v1Attorney Docket No.: 2013405-0010 11. The compound of claim 9, wherein X is NR7, and R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.

12. The compound of claim 11, wherein .

13. The compound of claim 1, wherein .

14. The compound of claim 13, wherein .

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

17. The compound of claim 16, wherein .

18. The compound of claim 17, wherein .

19. The compound of any one of claims 1-covalent bond.

20. The compound of any one of claims 1-19, wherein each R1is independently optionally substituted C1-6alkyl.

21. The compound of claim 20, wherein each R1is independently C1-6alkyl.

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

23. The compound of any one of claims 1-22, wherein R2is halogen or C1-6alkyl.

24. The compound of any one of claims 1-23, wherein R2is halogen.

25. The compound of any one of claims 1-24, wherein each R3is hydrogen. Page 771 of 783 11575796v1Attorney Docket No.: 2013405-0010 26. The compound of any one of claims 1-25, wherein R4is optionally substituted C1-6alkyl.

27. The compound of any one of claims 1-26, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, - C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

28. The compound of claim 27, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

29. The compound of claim 27, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon 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-.

30. The compound of claim 29, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.

31. The compound of any one of claims 27-30, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)-.

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

33. The compound of any one of claims 27-32, wherein linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-.

34. The compound of any one of claims 1-33, wherein linker is: , wherein:M1and M2are each independently absent, –CH2-, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L6and L7are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C10hydrocarbon chain, wherein one or more methylene Page 772 of 783 11575796v1Attorney Docket No.: 2013405-0010 units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, - C(NR)-, -C(NOR)-, -C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, - OC(NR)-, -C(NR)NR-, -N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, - N(R)C(O)S-, -SC(O)N(R)-, -N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-.

35. The compound of claim 34, wherein linker is selected from: , ,36. The compound of claim 35, wherein linker .

37. The compound of claim 34, wherein linker, , , ,Page 773 of 783 11575796v1Attorney Docket No.: 2013405-0010 , 38.

39. any one a 40. The compound of any one of claims 27-39, wherein 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.

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

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

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

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

45. The compound of any one of claims 27-39, wherein each Cy is independently selected from: ,Page 774 of 783 11575796v1Attorney Docket No.: 2013405-0010 , or47. The compound of any one of claims 1-46, wherein LBM is a CRBN binding moiety.

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

49. The compound of any one of claims 1-46, wherein LBM is a IAP binding moiety.

50. The compound of any one of claims 1-46, wherein LBM is a MDM2 binding moiety.

51. The compound of any one of claims 1-50, wherein the compound is of Formula IIA:or a pharmaceutically acceptable salt thereof.

52. The compound of claim 51, wherein the compound is of Formula IIA-1, IIA-2, IIA-3, or IIA-4:

53. The compound of any one of claims 1-52, wherein the compound is of Formula IIA-5: Page 775 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a pharmaceutically54. The compound of any one of claims 1-52, wherein the compound is of Formula IIA-6:or a pharmaceutically acceptable salt thereof.

55. The compound of any one of claims 1-54, wherein the compound is of Formula III:or a pharmaceutically acceptable salt thereof, wherein: Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each Rais independently hydrogen or an optionally substituted C1-6aliphatic, or two Ragroups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L2is a covalent bond or a straight or branched C1-3hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO2-, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH.

56. The compound of claim 55, wherein Ring C is an optionally substituted group selected from phenyl, C5-6cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, Page 776 of 783 11575796v1Attorney Docket No.: 2013405-0010 O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.

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

58. The compound of claim 57, wherein , wherein: each B is independently selected from N, C, that no more than two B are N;each Rcis independently selected from - -2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

59. The compound of claim 58, wherein .

60. The compound of any one of claims 55- is of Formula IIIC:or a pharmaceutically acceptable salt thereof.

61. The compound of any one of claims 55-60, wherein the compound is of Formula IIID: or a62. The compound of claim 55, wherein Ring C is optionally substituted C3-C7cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.

63. The compound of claim 55, wherein Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. Page 777 of 783 11575796v1Attorney Docket No.: 2013405-0010 64. The compound of claim 63, wherein Ring C is: wherein: each A is independently N, C, or CH,than two A groups are N; each Rbis hydrogen, or two Rbgroups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each Rcis independently selected from halogen, -OR, -N(R)2, -CN, and optionally substituted C1-6aliphatic; and m is 0, 1, 2, or 3.

65. The compound of claim 64, wherein Ring C is: .

66. The compound of any one of2L is a covalent bond.

67. The compound of any one of claims 55-65, wherein L2is -CH2-, –O-, or -N(R)-.

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

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

70. The compound of any one of claims 55-69, wherein each Rcis independently selected from halogen, -O(C1-6alkyl), -O(C1-6haloalkyl), C1-6alkyl, and C1-6haloalkyl.

71. The compound of any one of claims 63-70, wherein the compound is of Formula IIIA:or a pharmaceutically acceptable salt thereof.

72. The compound of claim 71, wherein the compound is of Formula IIIB: Page 778 of 783 11575796v1Attorney Docket No.: 2013405-0010 or a73. The compound of claim 72, wherein the compound is of Formula IIIB-1 or IIIB-2:or a pharmaceutically acceptable salt thereof.

74. A compound of Formula IX:or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: ;Page 779 of 783 11575796v1Attorney Docket No.: 2013405-0010 L3, L4, and L5are each independently a covalent bond or an optionally substituted bivalent C1-6straight or branched hydrocarbon chain; Z is N or CR3; R2is hydrogen, halogen, -CN, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; each R3is independently hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R4is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; R5is hydrogen, halogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic, or R2and R5, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S; R6is hydrogen, optionally substituted C1-6aliphatic, or optionally substituted C3-6cycloaliphatic; X is O or NR7; R7is hydrogen or optionally substituted C1-6aliphatic, or R4and R7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S; each R8is independently hydrogen or optionally substituted C1-6aliphatic; R9is hydrogen or optionally substituted C1-6aliphatic; linker is a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C1-C20hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -S-, -N(R)-, -N=N-, -C(O)-, -C(S)-, -C(NR)-, -C(NOR)-, - C(NNR2)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -C(NR)O-, -OC(NR)-, -C(NR)NR-, - N(R)C(NR)-, -N(R)C(O)N(R)-, -N(R)C(O)O-, -OC(O)N(R)-, -N(R)C(O)S-, -SC(O)N(R)-, - N(R)C(NR)N(R)-, -SO2-, -SO2N(R)-, -N(R)SO2-, or –Cy-; each Cy is independently an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, C3-7cycloaliphatic, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and a 3- to 7-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S; and Page 780 of 783 11575796v1Attorney Docket No.: 2013405-0010 LBM is an E3 ubiquitin ligase binding moiety.

75. A compound of Formula I: PBM – linker – LBM I wherein: PBM is a KAT2 protein binding moiety; linker is an optional linking moiety; and LBM is an E3 ubiquitin ligase binding moiety.

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

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

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

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

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

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

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

83. The compound of any one of claims 75-79, wherein the LBM is a MDM2 binding moiety.

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

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

86. A method of preparing the pharmaceutical composition of claim 85, comprising: providing the compound of any one of claims 1-84, or a pharmaceutically acceptable salt thereof; and formulating the compound with suitable excipients to give the pharmaceutical composition.

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

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

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, colorectal cancer, melanoma, and prostate cancer. Page 781 of 783 11575796v1Attorney Docket No.: 2013405-0010 90. A method of degrading KAT2 in a subject, comprising administering the compound of any one of claims 1-84, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 85 to a subject in need thereof.

91. An in vitro method of degrading KAT2, comprising contacting a biological sample with the compound of any one of claims 1-84, or a pharmaceutically acceptable salt thereof. Page 782 of 783 11575796v1

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