WO2024050078A1 - Dérivés de pyridazinone utilisés comme agents de dégradation de kat2 pour le traitement de troubles prolifératifs - Google Patents

Dérivés de pyridazinone utilisés comme agents de dégradation de kat2 pour le traitement de troubles prolifératifs Download PDF

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WO2024050078A1
WO2024050078A1 PCT/US2023/031835 US2023031835W WO2024050078A1 WO 2024050078 A1 WO2024050078 A1 WO 2024050078A1 US 2023031835 W US2023031835 W US 2023031835W WO 2024050078 A1 WO2024050078 A1 WO 2024050078A1
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compound
optionally substituted
independently selected
attorney docket
aliphatic
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James Anthony NEEF
David Simon Millan
Andrew John MCRINER
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Auron Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • KAT2A also referred to as general control non-depressible 5 (GCN5)
  • KAT2B also referred to as p300/CBP-associated factor (PCAF)
  • GCN5 general control non-depressible 5
  • PCAF p300/CBP-associated factor
  • KAT2A and KAT2B are 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.
  • 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.
  • 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).
  • KAT2A and/or KAT2B e.g., adenosine triphosphate
  • 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.
  • 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.
  • 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).
  • 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 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.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed.
  • single stereochemical isomers, and/or enantiomeric, diastereomic, and/or geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • Table 1 and Table 2 show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture.
  • tautomeric forms of provided compounds are within the scope of the disclosure.
  • structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • 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.
  • aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 ). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 ). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 ). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C 1-3 ), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 ).
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.
  • “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation.
  • Alkyl refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 ).
  • 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.
  • “carbocyclyl” refers to an optionally substituted monocyclic C 3 -C 8 hydrocarbon, or an optionally substituted C 5 -C 10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic.
  • the term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Alkenyl refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2- 3 ).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.
  • Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having Page 3 of 783 11575796v1 Attorney Docket No.: 2013405-0010 (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2- 4 , or C 2-3 ).
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C 6-14 ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, naphthyl, and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.
  • Heteroaryl refers to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N- substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
  • a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings.
  • Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3- dihydrobenzofuranyl, and tetrahydroquinolinyl.
  • a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • spirocyclic ring system e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • Partially Unsaturated when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions.
  • a patient or subject displays one or more symptoms of a disorder or condition.
  • a patient or subject has been diagnosed with one or more disorders or conditions.
  • a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • Specific binding refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur. A binding agent that interacts with one particular target when other potential targets are present is said to "bind specifically" to the target with which it interacts.
  • specific binding is assessed by detecting or determining degree and/or rate of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree and/or rate of dissociation of a binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining ability of the binding agent to compete an alternative interaction between its Page 5 of 783 11575796v1 Attorney 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.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., , or ). Unless otherwise indicated, an “optionally substituted” group may have a suitable substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
  • Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on R ⁇ are independently halogen, —(CH 2 ) 0–2 R ⁇ , – (haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 , -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , – (CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , –(CH 2 )
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), -OH, – OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2, –C(S)NR ⁇ 2, – C(NH)NR ⁇ 2, or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • treat refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • treatment may be of a subject who does not exhibit signs of the relevant disease, disorder, and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
  • KAT2 degrader compounds comprising a KAT2 protein binding moiety, a linker, and an E3 ubiquitin ligase binding moiety.
  • the present disclosure provides a compound of Formula I PBM – linker – LBM I Page 8 of 783 11575796v1 Attorney 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.
  • 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; L 1 is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or
  • 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; L 1 is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Page 10 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Z is N or CR 3 ; R 2 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic;
  • the present disclosure provides a compound of Formula IIA: Page 11 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically R 9 , n, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIA-1, IIA-2, IIA-3, or IIA-4: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , X, Z, linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIA-1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-3, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-4, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIA-1: Page 12 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically
  • R 1 is optionally substituted C 1-6 aliphatic
  • Z is N or CR 3
  • R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic
  • each R 3 is independently hydrogen or halogen
  • R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic
  • R 9 is hydrogen
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-,
  • the present disclosure provides a compound of Formula IIA-1: Page 13 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically
  • R 1 is C 1-6 alkyl
  • Z is N or CR 3
  • R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl
  • each R 3 is independently hydrogen or halogen
  • R 4 is C 1-6 alkyl
  • R 9 is hydrogen
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-
  • each Cy is independently an optionally substituted group selected from phen
  • the present disclosure provides a compound of Formula IIA-5: Page 14 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically linker, and LBM are as defined above for Formula II and singly and in combination.
  • the present disclosure provides a compound of Formula IIA-6: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 9 , linker, and LBM are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula III: 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 Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic, or two R a groups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a straight or branched C 1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-,
  • 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 R b is hydrogen, or two R b groups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula IIIB: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R b , R c , m, and linker are as defined above for Formula IIIA and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIIB-1 or IIIB-2: Page 16 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IIIB-1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIIB-2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IIIC: or a R 9 , Y, n, and linker are as defined above for Formula III and described in classes and subclasses herein, both singly and in combination; and each B is independently selected from N, C, and CH, provided that no more than two B are N; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula IIID: or a Y, 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 11575796v1 Attorney Docket No.: 2013405-0010
  • the present disclosure provides a compound of Formula IIID: or a ;
  • R 1 is C 1-6 aliphatic;
  • Z is or R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen or halogen;
  • R 4 is optionally substituted C 1-6 aliphatic;
  • R 9 is hydrogen;
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are replaced by –O-, -N(R)-, -C
  • the present disclosure provides a compound of Formula IIID: or a ; is hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl; each R 3 is independently hydrogen or halogen; R 4 is C 1-6 alkyl; R 9 is hydrogen; ; , Page 19 of 783 11575796v1 Attorney 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 R c is independently selected from halogen, -O(C 1-6 alkyl), and C 1-6 alkyl; and m is 0, 1, 2, or 3.
  • 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 R d , R e , R f , or R g ; each R d that is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic, or two R d , together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each R e that is not the point of attachment for the linker is independently hydrogen or optionally substituted C 1-6 aliphatic; R f ,
  • the present disclosure provides a compound of Formula IVA: Page 20 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a R g , R h , p, n, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IVA-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R d , R e , R f , R g , R h , p, and linker are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one R i or the ring formed when two R i groups are taken together; each R i that is not the point of attachment of the linker is independently halogen, optionally substituted C 1-6 aliphatic, -C(O)N(R) 2 , or -N(R)C(O)R, or Page 21 of 783 11575796v1 Attorney Docket No.: 2013405-0010 two R i groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; R
  • the present disclosure provides a compound of Formula VA: or a R j , R k , n, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VA-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 , R 9 , R i , R j , R k , q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VB: Page 22 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a R i , R j , R k , n, q, r, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VB-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R, R 1 , R 9 , R j , R k , n, and linker are as defined above for Formula V and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and R m is optionally substituted C 1-6 aliphatic; each R n is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; and s is 0, 1, 2, 3, 4, or 5.
  • the present disclosure provides a compound of Formula VIA: Page 23 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a n, s, and linker are as defined above for Formula VI and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VIA-1: or a are as defined above for Formula VI and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VII: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R q is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R r is independently hydrogen or optionally substituted C 1-6 aliphatic; each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5.
  • the present disclosure provides a compound of Formula VIIA: or a R s , u, t, and linker are as defined above for Formula VII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula VIII: or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L 1 , R 1 , R 9 , n, and linker are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination; and each R t is independently hydrogen or optionally substituted C 1-6 aliphatic, or both R t groups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each R u is independently hydrogen, halogen, -CN, or optionally substituted C 1-6 aliphatic; each R v is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic, or one instance of R u and R v , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7;
  • the present disclosure provides a compound of Formula VIIIA: or a pharmaceutically R u , R v , R w , v, and linker are as defined above for Formula VIII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IX: or a pharmaceutically Ring A is selected from: ; L 3 , L 4 , and L 5 bivalent C 1-6 straight or branched hydrocarbon chain; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; Page 26 of 783 11575796v1 Attorney Docket No.: 2013405-0010 each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic, or R 2 and R 5 , together with the atoms to which they are
  • 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 11575796v1 Attorney Docket No.: 2013405-0010 ; L 3 , L 4 , and L 5 bivalent C 1-6 straight or Z is N or CR 3 ; R 2 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 5 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic, or R 2 and R 5 , together with the atoms to which they are attached, combine to
  • the present disclosure provides a compound of Formula IXA, IXB, IXC, or IXD: or a pharmaceutically acceptable salt thereof, wherein L 3 , L 4 , L 5 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , X, Z, linker, and LBM are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula IXA, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IXB, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula IXC, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound of Formula IXD, or a pharmaceutically acceptable salt thereof. [0065] In some embodiments, the present disclosure provides a compound of Formula X: Page 29 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a linker are as defined above 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 R a is independently hydrogen or an optionally substituted C 1-6 aliphatic, or two R a groups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a straight or
  • the present disclosure provides a compound of Formula XA: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each R b is hydrogen, or two R b groups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula XA-1 or XA- 2: Page 30 of 783 11575796v1 Attorney Docket No.: 2013405-0010 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.
  • the present disclosure provides a compound of Formula XA-1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula XA-2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula XB: O A O or a pharmaceutically acceptable salt thereof, wherein Ring A, L 2 , L 3 , L 4 , L 5 , R 8 , R 9 , Y, and linker are as defined above for Formula X and described in classes and subclasses herein, both singly and in combination; and each B is independently selected from N, C, and CH, provided that no more than two B are N; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the present disclosure provides a compound of Formula XI: Page 31 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and linker is attached to the bracketed moiety at one of R d , R e , R f , or R g ; each R d that is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic, or two R d , together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and optionally fused to a phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; each R e that is not the point of attachment for the linker
  • the present disclosure provides a compound of Formula XIA: Page 32 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R d , R e , R f , R g , R h , p, and linker are as defined above for Formula XI and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula 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 R i or the ring formed when two R i groups are taken together; each R i that is not the point of attachment of the linker is independently halogen, optionally substituted C 1-6 aliphatic, -C(O)N(R) 2 , or -N(R)C(O)R, or two R i groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S; R j is an optionally substituted group selected from C 1-6 aliphatic and C 3-7 cycloaliphatic, or R j combines with one
  • the present disclosure provides a compound of Formula XIIA: Page 33 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , R i , R j , R k , q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIIB: or a pharmaceutically acceptable salt thereof, wherein Ring A, R, R i , R j , R k , q, r, and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIIB-1: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R, R 8 , R 9 , R j , R k , and linker are as defined above for Formula XII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIII: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and R m is optionally substituted C 1-6 aliphatic; each R n is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; and Page 34 of 783 11575796v1 Attorney Docket No.: 2013405-0010 s is 0, 1, 2, 3, 4, or 5.
  • the present disclosure provides a compound of Formula XIIIA: or a R n , s, and linker are as defined above for Formula XIII and described in classes and subclasses herein, both singly and in combination.
  • the present disclosure provides a compound of Formula XIV: or a pharmaceutically acceptable salt thereof, wherein Ring A, L 3 , L 4 , L 5 , R 8 , R 9 , and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R q is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; each R r is independently hydrogen or optionally substituted C 1-6 aliphatic; each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic; t is 0, 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5.
  • the present disclosure provides a compound of Formula XV: Page 35 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically and linker are as defined above for Formula IX and described in classes and subclasses herein, both singly and in combination; and each R t is independently hydrogen or optionally substituted C 1-6 aliphatic, or both R t groups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each R u is independently hydrogen, halogen, -CN, or optionally substituted C 1-6 aliphatic; each R v is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic, or one instance of R u and R v , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-
  • PBM is a KAT2 protein binding moiety, i.e., is a moiety that is capable of binding a KAT2 protein.
  • a PBM is a KAT2A protein binding moiety, i.e., is a moiety that is capable of binding a KAT2A protein.
  • a PBM is a KAT2B protein binding moiety, i.e., is a moiety that is capable of binding a KAT2B protein.
  • a PBM is considered to be capable of binding a KAT2 protein (e.g., KAT2A and/or KAT2B) if it specifically (i.e., preferentially) associates with the KAT2 protein when contacted with the KAT2 protein in the presence of at least one other protein.
  • a PBM is considered to be capable of binding a KAT2 protein if it specifically associates with that protein within a cell (e.g., in vitro or in vivo).
  • a PBM shares significant structural identity with a reference compound or moiety thereof that is capable of binding a KAT2 protein.
  • a PBM comprises the same or similar structure as a reference compound, except that a Page 36 of 783 11575796v1 Attorney Docket No.: 2013405-0010 PBM comprises a point of attachment to a linker.
  • a reference compound is characterized by a K d of less than 1 ⁇ M in a biophysical assay, such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC).
  • a reference compound is characterized by a IC 50 of less than 1 ⁇ M in a competition or functional assay, such as time-resolved fluorescence resonance energy transfer (TR-FRET).
  • a reference compound is characterized by an DC 50 of less than 30 nM in the Western Blot assay of Example B1.
  • a reference compound 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.
  • a reference compound is GSK4027: . In some embodiments, a reference .
  • a reference wherein Ring A, Ring B, L 1 , R 1 , Formula II and described in classes and subclasses herein, both singly and in combination.
  • a PBM has the following structure: , Page 37 of 783 11575796v1 Attorney Docket No.: 2013405-0010 wherein Ring A, L 1 , R 1 , R 9 , and n are as defined herein for Formula II and described in classes and subclasses herein, both singly and in combination.
  • a PBM has the following structure: , wherein Ring A, R 1 , and R 9 are as and described in classes and subclasses herein, both singly and in [0084] In some embodiments, a PBM has the following structure: , wherein Ring A, R 1 , and R 9 are as and described in classes and subclasses herein, both singly and in combination. [0085] In some embodiments, a PBM has the following structure: , wherein Ring A, R 1 , and R 9 are as and described in classes and subclasses herein, both singly and in combination.
  • a PBM is selected from: , Page 38 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , wherein R 1 , in classes and subclasses
  • a PBM has the following structure: , wherein Ring A, L 3 , L 4 , L 5 , R 8 , and IX and described in classes and subclasses herein, both singly and in combination.
  • a PBM is selected from: , wherein L 3 , L 4 , IX and described in classes and subclasses herein, both singly and in combination.
  • a PBM is selected from: Page 39 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , , Page 40 of 783 11575796v1 Attorney 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 , In some embodiments, Ring A is selected . Page 41 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0091] In some embodiments of any Formula described herein, Ring A is . In some embodiments, Ring A is .
  • R 2 and R 5 together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S.
  • Ring A is . [0092] In some embodiments of any Formula described herein, . In some embodiments, . In some embodiments, . In some such embodiments, R 2 the atoms to which to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S.
  • R 4 and R 7 together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.
  • Ring A is selected from: . Page 42 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0093]
  • Z is N or CH. In some embodiments, Z is N. In some (e.g., CH).
  • R 2 is hydrogen, halogen, -CN, or optionally substituted C 1-6 aliphatic.
  • R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, or C 3-6 cycloalkyl. In some embodiments, R 2 is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R 2 is halogen or C 1-6 alkyl. In some embodiments, R 2 is chloro, bromo, or methyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo. In some embodiments, R 2 is –CN. In some embodiments, R 2 is optionally substituted C 1-6 aliphatic.
  • R 2 is optionally substituted C 1-6 alkyl. In some embodiments, R 2 is C 1-2 alkyl (e.g., methyl or ethyl). In some embodiments, R 2 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 2 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 2 is C 3-4 cycloalkyl (e.g., cyclopropyl). [0096] In some embodiments of any Formula described herein, each R 3 is independently hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, each R 3 is hydrogen. In some embodiments, R 3 is hydrogen.
  • R 3 is halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is bromo. In some embodiments, R 3 is optionally substituted C 1-6 aliphatic. In some embodiments, R 3 is optionally substituted C 1-6 alkyl. In some embodiments, R 3 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 3 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 3 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 3 is C 3-4 cycloalkyl (e.g., cyclopropyl).
  • R 4 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is optionally substituted C 1-6 alkyl. In some embodiments, R 4 is C 1-6 alkyl. In some embodiments, R 4 is optionally substituted C 1-2 alkyl. In some embodiments, R 4 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 4 is optionally substituted C 3-6 Page 43 of 783 11575796v1 Attorney Docket No.: 2013405-0010 cycloaliphatic.
  • R 4 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 4 is C 3-4 cycloalkyl (e.g., cyclopropyl).
  • R 5 is hydrogen, halogen, or optionally substituted C 1-6 aliphatic. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is halogen. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 is optionally substituted C 1-6 aliphatic. In some embodiments, R 5 is optionally substituted C 1-6 alkyl.
  • R 5 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 5 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 5 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 5 is C 3-4 cycloalkyl (e.g., cyclopropyl). [0099] In some embodiments of any Formula described herein, R 2 and R 5 , together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S.
  • R 2 and R 5 together with the atoms to which they are attached, combine to form an 5- to 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S, and optionally substituted on a substitutable carbon atom with one or more halogen, –R ⁇ , -OR ⁇ , -N(R ⁇ ) 2 , and –CN, and on a substitutable nitrogen atom with one or more –R ⁇ and –C(O)R ⁇ .
  • R 2 and R 5 together with the atoms to which they are attached, combine to form an optionally substituted 5-membered aromatic ring having 1-2 heteroatoms independently selected from N, O, and S.
  • R 2 and R 5 combine to form an optionally substituted pyrrole. In some embodiments, R 2 and R 5 , together with the atoms to which they are attached, combine to form an optionally substituted 6-membered aromatic ring having 0-2 heteroatoms independently selected from N, O, and S. In some embodiments, R 2 and R 5 combine to form an optionally substituted phenyl or pyridine. [0100] In some embodiments of any Formula described herein, R 6 is hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is optionally substituted C 1-6 aliphatic. In some embodiments, R 6 is optionally substituted C 1-6 alkyl.
  • R 6 is C 1-6 alkyl. In some embodiments, R 6 is optionally substituted C 1-2 alkyl. In some embodiments, R 6 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 6 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 6 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 6 is C 3-4 cycloalkyl (e.g., cyclopropyl). [0101] In some embodiments of any Formula described herein, X is O. In some embodiments, X is NR 7 .
  • R 7 is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is optionally substituted C 1-6 aliphatic. In some embodiments, R 7 is optionally substituted C 1-6 alkyl. In some embodiments, R 7 is C 1-6 alkyl.
  • R 7 is optionally substituted C 1-2 alkyl. In some embodiments, R 7 is C 1-2 alkyl (e.g., methyl). [0103] In some embodiments of any Formula described herein, R 4 and R 7 , together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.
  • R 4 and R 7 together with the atoms to which they are attached, combine to form a 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S, and optionally substituted on a substitutable carbon atom with one or more halogen, –R ⁇ , -OR ⁇ , -N(R ⁇ ) 2 , and –CN, and on a substitutable nitrogen atom with one or more –R ⁇ and –C(O)R ⁇ .
  • R 4 and R 7 together with the atoms to which they are attached, combine to form a 5- to 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S, and optionally substituted with one or more C 1-6 alkyl. In some embodiments, R 4 and R 7 , together with the atoms to which they are attached, combine to form a 5-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S. In some embodiments, R 4 and R 7 combine to form an optionally substituted triazole.
  • R 4 and R 7 together with the atoms to which they are attached, combine to form a 6-membered aromatic ring having 2-3 heteroatoms independently selected from N, O, and S.
  • R 9 is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is optionally substituted C 1-6 aliphatic. In some embodiments, R 9 is optionally substituted C 1-6 alkyl. In some embodiments, R 9 is C 1-6 alkyl. In some embodiments, R 9 is optionally substituted C 1-2 alkyl. In some embodiments, R 9 is C 1-2 alkyl (e.g., methyl).
  • 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.
  • Ring B is piperidine. In some embodiments, Ring B . In some embodiments, . [0106] In any Formulae described herein, L 1 is a covalent bond. In some 1 embodiments, L a 3 or branched hydrocarbon chain. In some embodiments, L 1 is a bivalent C 1-3 straight hydrocarbon chain. In some embodiments, L 1 is a bivalent C 1-2 straight hydrocarbon chain. In some embodiments, L 1 is –CH 2 -. [0107] In some embodiments of any Formulae described herein, each R 1 is independently optionally substituted C 1-6 alkyl or optionally substituted C 3-6 cycloalkyl.
  • R 1 is optionally substituted C 1-6 aliphatic. In some embodiments, R 1 is optionally substituted C 1-6 alkyl. In some embodiments, R 1 is C 1-6 alkyl. In some embodiments, R 1 is optionally substituted C 1-2 alkyl. In some embodiments, R 1 is C 1-2 alkyl (e.g., methyl). In some embodiments, R 1 is optionally substituted C 3-6 cycloaliphatic. In some embodiments, R 1 is optionally substituted C 3-6 cycloalkyl. In some embodiments, R 1 is C 3-4 cycloalkyl (e.g., cyclopropyl).
  • 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, L 3 is a covalent bond or an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L 3 is a covalent bond. In some embodiments, L 3 is an optionally substituted bivalent C 1-6 straight or branched hydrocarbon chain. In some embodiments, L 3 is a bivalent C 1-6 straight or branched hydrocarbon chain.
  • L 3 is an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L 3 is a bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L 3 is selected from –CH 2 - and –CH(CH 3 )-. [0110] In some embodiments of any Formulae described herein, L 4 is a covalent bond or an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L 4 is a covalent bond. In some embodiments, L 4 is an optionally substituted bivalent C 1-6 straight or branched hydrocarbon chain. In some embodiments, L 4 is a bivalent C 1-6 straight or branched hydrocarbon chain.
  • L 4 is an optionally substituted bivalent C 1-3 straight or branched hydrocarbon Page 46 of 783 11575796v1 Attorney Docket No.: 2013405-0010 chain.
  • L 4 is a bivalent C 1-3 straight or branched hydrocarbon chain.
  • L 4 is selected from –CH 2 - and –CH(CH 3 )-.
  • L 5 is a covalent bond or an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain.
  • L 5 is a covalent bond.
  • L 5 is an optionally substituted bivalent C 1-6 straight or branched hydrocarbon chain.
  • L 5 is a bivalent C 1-6 straight or branched hydrocarbon chain. In some embodiments, L 5 is an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L 5 is a bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, L 5 is selected from –CH 2 - and –CH(CH 3 )-. [0112] In some embodiments of any Formulae described herein, each R 8 is independently hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is optionally substituted C 1-6 aliphatic. In some embodiments, R 8 is optionally substituted C 1-6 alkyl.
  • R 8 is C 1-6 alkyl. In some embodiments, R 8 is optionally substituted C 1-2 alkyl. In some embodiments, R 8 is C 1-2 alkyl (e.g., methyl). In some embodiments, each R 8 is C 1-2 alkyl (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.
  • linker has the following structure, which is 14 atoms in length (counted as shown with italicized numbers): .
  • a linker is 2- 13 atoms in length.
  • a linker is 2-10 atoms in length.
  • a linker is 2-8 atoms in length.
  • a linker is 2-7 atoms in length.
  • a linker is 0-16 atoms in length.
  • a linker is 0-13 atoms in length.
  • a linker is 0-10 atoms in length.
  • a linker is 0-7 atoms in length.
  • 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 11575796v1 Attorney 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.
  • linker is a covalent bond.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- .
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, - C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, or –Cy-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy- .
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, - C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)- , -N(R)C(O)-, or –Cy-.
  • linker comprises an ether moiety (e.g., -O-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-.
  • linker comprises an amine moiety (e.g., -N(R)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)- (e.g., -NH- or –N(C 1- 6 alkyl)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by - N(R)- (e.g., -NH- or –N(C 1-6 alkyl)-).
  • linker comprises a carbonyl moiety.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-.
  • linker is an Page 49 of 783 11575796v1 Attorney Docket No.: 2013405-0010 optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)-.
  • linker comprises an ester moiety.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -OC(O)- or -C(O)O-.
  • linker comprises an amide moiety.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or –C(O)N(C 1-6 alkyl)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)- (e.g., -C(O)NH- or –C(O)N(C 1-6 alkyl)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., -N(H)C(O)- or –N(C 1-6 alkyl)C(O)-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by -N(R)C(O)- (e.g., - N(H)C(O)- or –N(C 1-6 alkyl)C(O)-).
  • linker comprises a bivalent ring moiety (e.g., -Cy-).
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-.
  • Cy is not phenyl.
  • linker comprises a triple bond.
  • linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C 1 - C 20 hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-.
  • linker is an optionally substituted, bivalent, straight or branched, partially unsaturated C 1 -C 10 hydrocarbon chain comprising at least one triple bond, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • linker is selected from: , Page 51 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , or .
  • linker is selected from: , , , , , , Page 52 of 783 11575796v1 Attorney Docket No.: 2013405-0010
  • linker has the following structure: , wherein: M 1 and M 2 are each , , -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and L 6 and L 7 are each independently a covalent bond or an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally
  • linker is selected from: Page 53 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • M 1 is –CH 2 -.
  • M 1 is –O-.
  • M 1 is -N(R)- (e.g., - N(H)- or –N(CH 3 )-).
  • M 1 is -C(O)-.
  • M 1 is -OC(O)-. In some embodiments, M 1 is -C(O)O-. In some embodiments, M 1 is -C(O)N(R)- (e.g., -C(O)N(H)- or – C(O)N(CH 3 )-). In some embodiments, M 1 is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH 3 )C(O)-).
  • M 2 is –CH 2 -, –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • M 2 is absent.
  • M 2 is –CH 2 -.
  • M 2 is –O-.
  • M 2 is -N(R)- (e.g., - N(H)- or –N(CH 3 )-).
  • M 2 is -C(O)-.
  • M 2 is -OC(O)-. In some embodiments, M 2 is -C(O)O-. In some embodiments, M 2 is -C(O)N(R)- (e.g., -C(O)N(H)- or – C(O)N(CH 3 )-. In some embodiments, M 2 is -N(R)C(O)- (e.g., -N(H)C(O)- or –N(CH 3 )C(O)-). [0137] In some embodiments of any Formulae described herein, L 6 is a covalent bond.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 - C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by – O-. [0142] In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain. In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 10 hydrocarbon chain.
  • L 6 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain. In some embodiments, L 6 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 6 hydrocarbon chain. Page 55 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0143] In some embodiments of any Formulae described herein, L 7 is a covalent bond.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 - C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain, wherein at least two methylene units are replaced by – O-.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 10 hydrocarbon chain.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 10 hydrocarbon chain.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain.
  • L 7 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 6 hydrocarbon chain.
  • both L 6 and L 7 are a covalent bond.
  • L 8 is a covalent bond.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated Page 57 of 783 11575796v1 Attorney Docket No.: 2013405-0010 C 1 -C 15 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, - OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, - N(R)C(O)-, or –Cy-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 - C 15 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, - C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, or -N(R)C(O)-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced by –O-.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-. In some embodiments, L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain, wherein at least two methylene units are replaced by – O-. [0155] In some embodiments, L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 15 hydrocarbon chain. In some embodiments, L 8 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 15 hydrocarbon chain.
  • L 8 is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 6 hydrocarbon chain. In some embodiments, L 8 is an optionally substituted, bivalent, straight or branched, saturated C 1 -C 6 hydrocarbon chain.
  • linker is selected from: , , Page 58 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Page 59 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , , Page 60 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , , Page 61 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , , Page 62 of 783 11575796v1 Attorney Docket No.: 2013405-0010 N N .
  • each Cy is independently an optionally 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.
  • each Cy is independently an optionally substituted group selected from phenyl, C 9-10 bicyclic aryl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic C 3-7 cycloaliphatic, 5- to 10-membered bicyclic cycloaliphatic, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • each Cy is independently an optionally substituted group selected from phenyl, 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • Cy is optionally substituted phenyl.
  • Cy is phenyl.
  • Cy is not phenyl.
  • Cy is optionally substituted C 9-10 bicyclic aryl.
  • Cy is optionally substituted C 13-16 polycyclic aryl.
  • Cy is optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted triazole.
  • Cy is an optionally substituted 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted pyridine, pyridazine, or pyrimidine.
  • Cy is an optionally substituted 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted 10- to 16-membered polycyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. [0163] In some embodiments, Cy is an optionally substituted monocyclic C 3-7 cycloaliphatic. In some embodiments, Cy is an optionally substituted monocyclic C 3-7 cycloalkyl.
  • Cy is an optionally substituted monocyclic C 4-6 cycloalkyl (e.g., cyclobutane, cyclopentane, or cyclohexane).
  • Cy is an optionally substituted 5- to 10-membered bicyclic cycloaliphatic.
  • Cy is an optionally substituted 6- to 10-membered bicyclic cycloaliphatic.
  • Cy is an optionally substituted bicyclic 6- to 10-membered bridged, fused, or spirocyclic cycloaliphatic.
  • Cy is an optionally substituted monocyclic 4- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted monocyclic 4-membered heterocyclyl having 1 heteroatom independently selected from N, O, and S. In some embodiments, Cy is azetidine. In some embodiments, Cy is an optionally substituted monocyclic 5- membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is pyrrolidine.
  • Cy is an optionally substituted monocyclic 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.
  • Cy is piperidine or piperazine.
  • Cy is an optionally substituted monocyclic 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted bicyclic 6- to 11-membered heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted bicyclic 6- to 11-membered bridged, fused, or spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7- to 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 7-membered bridged heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • Cy is an optionally substituted bicyclic 8-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 9-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, Cy is an optionally substituted bicyclic 11-membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S.
  • each R is independently hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, each R is independently hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted C 1-6 alkyl. In some embodiments, R is C 1-6 alkyl. In some embodiments, R is optionally substituted C 1-2 alkyl.
  • R is C 1-2 alkyl (e.g., methyl). In some embodiments, each R is C 1-2 alkyl (e.g., methyl). In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted C 3-7 cycloaliphatic. In some embodiments, R is optionally substituted C 3-7 cycloalkyl (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.
  • 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 11575796v1 Attorney Docket No.: 2013405-0010 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.
  • LBM is an E3 ubiquitin ligase binding moiety, i.e., is a moiety that is capable of binding an E3 ubiquitin ligase.
  • an LBM is considered to be capable of binding an E3 ubiquitin ligase if it specifically (i.e., preferentially) associates with the E3 ubiquitin ligase when contacted with the E3 ubiquitin ligase in the presence of at least one other protein.
  • an LBM is considered to be capable of binding an E3 ubiquitin ligase if it specifically associates with that protein within a cell (e.g., in vitro or in vivo).
  • An LBM 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.
  • a LBM is a cereblon (CRBN) binding moiety, i.e., is a moiety that is capable of binding cereblon.
  • a LBM has the following structure: wherein Ring C, L 2 , and R a are as and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: wherein R b , R c , and m are as and described in classes and subclasses herein, both singly and in combination; and each A is independently N, C, or CH, provided that no more than two A groups are N. It will be appreciated that A is C when it is the point of attachment to the rest of the molecule.
  • a LBM has the following structure: Page 66 of 783 11575796v1 Attorney Docket No.: 2013405-0010 wherein R b , R c , and m are as and described in classes and subclasses herein, both singly and in [0173]
  • a LBM is selected from: .
  • B, L 2 , R c , Y, and m are as IIIC and described in classes and subclasses herein, both singly and in combination. It will be appreciated that B is C when it is the point of attachment to the rest of the molecule.
  • a LBM has the following structure: wherein B, L 2 , R c , Y, and m are IIIC 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, L 2 , R c , Y, and m are as and described in classes and subclasses herein, both singly and in combination.
  • a LBM is selected from: Page 67 of 783 11575796v1 Attorney 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 11575796v1 Attorney Docket No.: 2013405-0010 , , , 11575796v1 Attorney Docket No.: 2013405-0010 , or optionally substituted C 1-6 aliphatic. In some embodiments, each R a is independently hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, each R a is hydrogen. In some embodiments, R a is hydrogen.
  • R a is optionally substituted C 1-6 aliphatic. In some embodiments, R a is optionally substituted C 1-6 alkyl. In some embodiments, R a is C 1-6 alkyl. In some embodiments, R a is optionally substituted C 1-2 alkyl. In some embodiments, R a is C 1-2 alkyl (e.g., methyl).
  • two R a groups, together with the atom to which they are attached combine to form a 3- to Page 70 of 783 11575796v1 Attorney 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).
  • two R a groups, together with the atom to which they are attached combine to form a 3- to 6-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S).
  • two R a groups together with the atom to which they are attached, combine to form a 3- to 4-membered saturated ring (e.g., a carbocycle or heterocycle having 1-2 heteroatoms independently selected from N, O, and S).
  • Y is N.
  • Y is CH.
  • L 2 is a covalent bond or a straight or branched C 1-3 hydrocarbon chain.
  • L 2 is a covalent bond or a straight or branched C 1-3 hydrocarbon chain wherein one methylene is replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-, or - N(R)C(O)-.
  • L 2 is a covalent bond.
  • L 2 is a straight or branched C 1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, - SO 2 -, -C(O)N(R)-, or -N(R)C(O)-.
  • L 2 is a C 1 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-, or -N(R)C(O)-.
  • L 2 is a straight or branched C 2 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-, or -N(R)C(O)-.
  • L 2 is a straight or branched C 3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, - SO 2 -, -C(O)N(R)-, or -N(R)C(O)-.
  • L 2 is a covalent bond, -CH 2 -, –O-, or -N(R)-.
  • L 2 is –CH 2 -.
  • L 2 is –CH 2 -, -O-, or –N(R)-.
  • L 2 is –CH 2 -, -O-, or –N(H)-.
  • L 2 is –O- or –S-. In some embodiments, L 2 is –O-. In some embodiments, L 2 is -S-. In some embodiments, L 2 is –N(R)-. In some embodiments, L 2 is –N(H)-. In some embodiments, L 2 is –SO 2 -. In some embodiments, -C(O)N(R)-, or - N(R)C(O)-. In some embodiments, L 2 is –C(O)N(R)-. In some embodiments, L 2 is –N(R)C(O)-.
  • Ring C is an optionally substituted, mono- or bicyclic, 3- to 10-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-4 heteroatoms independently selected from N, O, and S.
  • Ring C is an optionally substituted group selected from phenyl, C 5-6 cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Ring C is an optionally substituted group selected from phenyl, 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and 9- to 10- Page 71 of 783 11575796v1 Attorney Docket No.: 2013405-0010 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Ring C is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Ring C is optionally substituted C 3 -C 7 cycloaliphatic or optionally substituted 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S.
  • Ring C is optionally substituted phenyl.
  • Ring C is phenyl.
  • Ring C is optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Ring C is optionally substituted 5- to 6-membered heteroaryl having 1-2 heteroatoms independently selected from N, O, and S.
  • 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 C 3 -C 7 cycloaliphatic. In some embodiments, Ring C is optionally substituted C 3 -C 7 cycloalkyl. In some embodiments, Ring C is optionally substituted C 5 -C 6 cycloaliphatic.
  • Ring C is optionally substituted C 5 -C 6 cycloalkyl. 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.
  • 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.
  • 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.
  • Ring Page 72 of 783 11575796v1 Attorney 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).
  • each A is independently N, C, or than two A groups are N; each R b is hydrogen, or two R b are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; m is 0, 1, 2, or 3. [0190] In some embodiments, . [0191] .
  • each B is independently selected provided that no more than two B are N; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • each R c is independently selected -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • Page 73 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , , , , , , Page 74 of 783 11575796v1 Attorney 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 R c , as defined herein, such that the ring contains a –C(R c )- moiety. It will also be appreciated that A is C, when it is the point of attachment to the rest of the molecule.
  • each R b is hydrogen.
  • two R b groups, on the same carbon are taken together to form an oxo.
  • two R b groups, on the same carbon combine to form a 3- to 6-membered saturated or partially unsaturated ring (e.g., a C 3-6 cycloaliphatic or 3- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S).
  • two R b groups, on the same carbon combine to form C 3-6 cycloalkyl (e.g., cyclopropyl).
  • each B is CH, C-R c , or C.
  • one B is N and the other B groups are CH or C.
  • two B groups are N and the other B groups are CH or C.
  • B is N.
  • B is CH.
  • B is C-R c .
  • B is C.
  • each R c is independently selected from halogen, -OH, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -CN, and optionally substituted C 1-6 alkyl.
  • each R c is independently selected from halogen, - OH, -O(C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -CN, and optionally substituted C 1-6 alkyl.
  • each R c is independently selected from halogen, -O(C 1-6 alkyl), -O(C 1-6 haloalkyl), C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R c is independently selected from halogen, - O(C 1-6 alkyl), C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R c is independently selected from halogen, -O(C 1-6 alkyl), and C 1-6 alkyl.
  • R c is halogen (e.g., fluoro or chloro).
  • R c is –OR (e.g., -OH, -O(C 1-6 alkyl), or -O(C 1-6 haloalkyl)).
  • R c is –OCH 3 or –OCF 3 .
  • R c is -N(R) 2 (e.g., -NH 2 , NH(C 1-6 alkyl), or -N(C 1-6 alkyl) 2 ).
  • R c is –CN. In some embodiments, R c is optionally substituted C 1- 6 aliphatic. In some embodiments, R c is optionally substituted C 1-6 alkyl. In some embodiments, R c is C 1- 6 alkyl optionally substituted with one or more halogen. In some embodiments, R c is C 1-6 alkyl. In some embodiments, R c is optionally substituted C 1-2 alkyl. In some embodiments, R c is optionally substituted C 1-2 alkyl optionally substituted with one or more halogen. In some embodiments, R c is C 1-2 alkyl (e.g., methyl). In some embodiments, R c is C 1-6 haloalkyl.
  • R c is C 1-2 haloalkyl (e.g., - CF 3 ).
  • m is 0, 1, or 2.
  • m is 0 or 1.
  • m is 0.
  • m is 1.
  • m is 2.
  • m is 3.
  • a LBM is a Von Hippel-Lindau protein (VHL) binding moiety, i.e., is a moiety that is capable of binding Von Hippel-Lindau protein.
  • VHL Von Hippel-Lindau protein
  • a LBM has the following structure: , wherein R d , R e , R f , R g , and described in classes and subclasses herein, both singly and in combination.
  • a LBM is selected from: Page 76 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , wherein classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: , wherein R d , R e , R f , R g , and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: Page 77 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , wherein classes and subclasses herein, both singly and in combination.
  • a LBM moiety e.g., VHL binding moiety
  • linker at a R d .
  • a LBM moiety (e.g., VHL binding moiety) is attached to linker at a R e . In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at R f . In some embodiments, a LBM moiety (e.g., VHL binding moiety) is attached to linker at a R g .
  • each R d that is not the point of attachment for the linker is independently hydrogen, -C(O)R, or optionally substituted C 1-6 aliphatic. In some embodiments, R d is hydrogen. In some embodiments, R d is –C(O)R.
  • R d is – C(O)(optionally substituted C 1-6 alkyl). In some embodiments, R d is –C(O)(optionally substituted C 3-6 cycloalkyl). In some embodiments, R d is optionally substituted C 1-6 aliphatic. In some embodiments, R d is optionally substituted C 1-6 alkyl. In some embodiments, R d is C 1-6 alkyl. In some embodiments, R d is optionally substituted C 1-2 alkyl. In some embodiments, R d is C 1-2 alkyl (e.g., methyl).
  • two R d together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S and Page 78 of 783 11575796v1 Attorney 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.
  • two R d together with the atom to which they are attached, combine to form an optionally substituted 5- to 6-membered ring having 1-3 heteroatoms independently selected from N, O, and S.
  • each R e that is not the point of attachment for the linker is independently hydrogen or optionally substituted C 1-6 alkyl.
  • each R e is optionally substituted C 1-6 aliphatic.
  • each R e is optionally substituted C 1-6 alkyl (e.g., methyl).
  • R e is hydrogen. In some embodiments, R e is optionally substituted C 1-6 aliphatic. In some embodiments, R e is optionally substituted C 1-6 alkyl. In some embodiments, R e is C 1-6 alkyl. In some embodiments, R e is optionally substituted C 1-2 alkyl. In some embodiments, R e is C 1-2 alkyl (e.g., methyl). [0209] In some embodiments of any Formulae described herein, R f , when it is not the point of attachment for the linker, is hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R f is hydrogen. In some embodiments, R f is optionally substituted C 1-6 aliphatic.
  • R f is optionally substituted C 1-6 alkyl. In some embodiments, R f is C 1-6 alkyl. In some embodiments, R f is optionally substituted C 1-2 alkyl. In some embodiments, R f is C 1-2 alkyl (e.g., methyl). [0210] In some embodiments of any Formulae described herein, each R g that is not the point of attachment for the linker is independently halogen, -OR, -CN, or optionally substituted C 1-6 alkyl. In some embodiments, R g is halogen (e.g., fluoro or chloro).
  • R g is –OR (e.g., -OH or –O(C 1-6 alkyl)). In some embodiments, R g is –CN. In some embodiments, R g is optionally substituted C 1- 6 aliphatic. In some embodiments, R g is optionally substituted C 1-6 alkyl. In some embodiments, R g is C 1- 6 alkyl. In some embodiments, R g is optionally substituted C 1-2 alkyl. In some embodiments, R g is C 1-2 alkyl (e.g., methyl). [0211] In some embodiments of any Formulae described herein, R h is hydrogen, halogen, or optionally substituted C 1-6 alkyl.
  • R h is hydrogen. In some embodiments, R h is halogen (e.g., fluoro or chloro). In some embodiments, R h is optionally substituted C 1-6 aliphatic. In some embodiments, R h is optionally substituted C 1-6 alkyl. In some embodiments, R h is C 1-6 alkyl. In some embodiments, R h is optionally substituted C 1-2 alkyl. In some embodiments, R h is C 1-2 alkyl (e.g., methyl). Page 79 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0212] In some embodiments of any Formulae described herein, p is 0, 1, or 2.
  • a LBM is an Inhibitor of Apoptosis protein (IAP) binding moiety, i.e., is a moiety that is capable of binding Inhibitor of Apoptosis protein.
  • IAP Inhibitor of Apoptosis protein
  • a LBM has the following structure: , wherein R i , R j , R k , r, and q are as described in classes and subclasses herein, both singly and in combination.
  • 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.
  • a LBM has the following structure: , wherein R i , R j , R k , r, and q are described in classes and subclasses herein, both singly and in combination.
  • a LBM is selected from: , Page 80 of 783 11575796v1 Attorney Docket No.: 2013405-0010 wherein R i , R j , R k , r, and q are as defined herein for Formula V and described in classes and subclasses herein, both singly and in combination; and Ring D is the ring formed when two R i groups, together with the atoms to which they are attached, combine.
  • a LBM has the following structure: , wherein R, R i , R j , R k , r, and q are described in classes and subclasses herein, both singly and in combination. [0219] In some embodiments of any Formulae described herein, a LBM has the following structure: , wherein R, R j , and R k are as in 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 R m , R n , and s are as described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: , wherein R m , R n , and s are as described in classes and subclasses herein, both singly and in combination.
  • a LBM moiety e.g., IAP binding moiety
  • a LBM moiety is attached to linker at a R i .
  • a LBM moiety e.g., IAP binding moiety
  • each R i that is not the point of attachment of the linker is independently halogen, optionally substituted C 1-6 aliphatic, -C(O)N(R) 2 , or - N(R)C(O)R.
  • R i is halogen (e.g., fluoro or chloro).
  • R i is optionally substituted C 1-6 aliphatic.
  • R i is optionally substituted C 1-6 alkyl.
  • R i is C 1-6 alkyl.
  • R i is optionally substituted C 1-2 alkyl.
  • R i is C 1-2 alkyl (e.g., methyl). In some embodiments, R i is -C(O)N(R) 2 . In some embodiments, at least one R i is -C(O)N(R) 2 . In some embodiments, R i is -N(R)C(O)R. In some embodiments, two R i groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl or 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O, and S. In some embodiments, two R i groups, together with the atoms to which they are attached, combine to form an optionally substituted phenyl.
  • R j is an optionally substituted group selected from C 1-6 aliphatic and C 3-7 cycloaliphatic. In some embodiments, R j is optionally substituted C 1- 6 aliphatic. In some embodiments, R j is optionally substituted C 1-6 alkyl. In some embodiments, R j is C 1-6 alkyl (e.g., tert-butyl or isopropyl).
  • R j is optionally substituted C 1-2 alkyl. In some embodiments, R j is C 1-2 alkyl (e.g., methyl). In some embodiments, R j is optionally substituted C 3-7 cycloaliphatic. In some embodiments, R j is optionally substituted C 3-7 cycloalkyl. In some embodiments, R j is C 3-7 cycloalkyl (e.g., cyclohexyl). In some embodiments, R j combines with one instance of R i , together with the atoms to which they are attached, to form an optionally substituted 5- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • R k is an optionally substituted C 1-6 alkyl. In some embodiments, R k is C 1-6 alkyl. In some embodiments, R k is optionally substituted C 1-2 alkyl. In some embodiments, R k is C 1-2 alkyl (e.g., methyl).
  • 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.
  • R m is optionally substituted C 1-6 alkyl.
  • R m is C 1-6 alkyl (e.g., isobutyl).
  • R m is optionally substituted C 1-2 alkyl.
  • R m is C 1-2 alkyl (e.g., methyl).
  • each R n is independently halogen, - OR, -CN, or optionally substituted C 1-6 alkyl.
  • R n is halogen (e.g., fluoro or chloro). In some embodiments, R n is –OR. In some embodiments, R n is –CN. In some embodiments, R n is optionally substituted C 1-6 aliphatic. In some embodiments, R n is optionally substituted C 1-6 alkyl. In some embodiments, R n is C 1-6 alkyl. In some embodiments, R n is optionally substituted C 1-2 alkyl. In some embodiments, R n is C 1-2 alkyl (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.
  • a LBM is a MDM2 binding moiety, i.e., is a moiety that is capable of binding MDM2.
  • a LBM has the following structure: , wherein R p , R q , R r , R s , u and t VII and described in classes and subclasses herein, both singly and in combination.
  • a LBM has the following structure: , wherein R t , R u , R v , R w , and v are VIII and described in classes and subclasses herein, both singly and in combination. Page 83 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0234]
  • each R p is independently halogen, - OR, -CN, or optionally substituted C 1-6 alkyl.
  • each R p is halogen (e.g., chloro).
  • R p is halogen (e.g., chloro or fluoro).
  • R p is –OR. In some embodiments, R p is –CN. In some embodiments, R p is optionally substituted C 1-6 aliphatic. In some embodiments, R p is optionally substituted C 1-6 alkyl. In some embodiments, R p is C 1-6 alkyl. In some embodiments, R p is optionally substituted C 1-2 alkyl. In some embodiments, R p is C 1-2 alkyl (e.g., methyl). [0235] In some embodiments of any Formulae described herein, each R q is independently halogen, - OR, -CN, or optionally substituted C 1-6 alkyl.
  • each R q is halogen (e.g., chloro). In some embodiments, R q is halogen (e.g., chloro or fluoro). In some embodiments, R q is –OR. In some embodiments, R q is –CN. In some embodiments, R q is optionally substituted C 1-6 aliphatic. In some embodiments, R q is optionally substituted C 1-6 alkyl. In some embodiments, R q is C 1-6 alkyl. In some embodiments, R q is optionally substituted C 1-2 alkyl. In some embodiments, R q is C 1-2 alkyl (e.g., methyl).
  • each R r is independently hydrogen or optionally substituted C 1-6 alkyl. In some embodiments, R r is hydrogen. In some embodiments, R r is optionally substituted C 1-6 aliphatic. In some embodiments, R r is optionally substituted C 1-6 alkyl. In some embodiments, R r is C 1-6 alkyl. In some embodiments, R r is optionally substituted C 1-2 alkyl. In some embodiments, R r is C 1-2 alkyl (e.g., methyl). In some embodiments, each R r is methyl.
  • each R s is independently halogen, - OR, -CN, or optionally substituted C 1-6 alkyl.
  • each R s is halogen (e.g., chloro).
  • R s is halogen (e.g., chloro or fluoro).
  • R s is –OR (e.g., -O(C 1-6 alkyl)).
  • R s is –CN.
  • R s is optionally substituted C 1-6 aliphatic.
  • R s is optionally substituted C 1-6 alkyl.
  • R s is C 1-6 alkyl (e.g., tert-butyl). In some embodiments, R s is optionally substituted C 1-2 alkyl. In some embodiments, R s is C 1-2 alkyl (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.
  • 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 11575796v1 Attorney Docket No.: 2013405-0010 [0240] In some embodiments of any Formulae described herein, each R t is independently hydrogen or optionally substituted C 1-6 aliphatic. In some embodiments, R t is hydrogen.
  • R t is optionally substituted C 1-6 aliphatic. In some embodiments, R t is optionally substituted C 1-6 alkyl. In some embodiments, R t is C 1-6 alkyl (e.g., tert-butyl or isobutyl). In some embodiments, R t is optionally substituted C 1-2 alkyl. In some embodiments, R t is C 1-2 alkyl (e.g., methyl). In some embodiments, at least one R t is optionally substituted C 1-6 aliphatic.
  • both R t groups, together with the atom to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • both R t groups, together with the atom to which they are attached combine to form an optionally substituted C 3-7 cycloaliphatic (e.g., C 3-7 cycloalkyl, such as cyclohexyl).
  • both R t groups, together with the atom to which they are attached combine to form an optionally substituted 3- to 7-membered heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • each R u is independently hydrogen, halogen, -CN, or optionally substituted C 1-6 alkyl.
  • R u is hydrogen.
  • at least one R u is hydrogen.
  • R u is halogen (e.g., fluoro or chloro).
  • R u is –CN.
  • R u is optionally substituted C 1-6 aliphatic.
  • R u is optionally substituted C 1-6 alkyl.
  • R u is C 1-6 alkyl.
  • R u is optionally substituted C 1-2 alkyl.
  • R t is C 1-2 alkyl (e.g., methyl).
  • each R v is independently halogen, - OR, -CN, or optionally substituted C 1-6 alkyl.
  • each R v is halogen (e.g., chloro).
  • R v is halogen (e.g., chloro or fluoro).
  • R v is –OR (e.g., -O(C 1-6 alkyl)).
  • R v is –CN.
  • R v is optionally substituted C 1-6 aliphatic.
  • R v is optionally substituted C 1-6 alkyl. In some embodiments, R v is C 1-6 alkyl (e.g., tert-butyl). In some embodiments, R v is optionally substituted C 1-2 alkyl. In some embodiments, R v is C 1-2 alkyl (e.g., methyl). In some embodiments, one instance of R u and R v , together with the atoms to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • each R w is independently halogen, - OR, -CN, or optionally substituted C 1-6 alkyl.
  • each R w is halogen (e.g., chloro). In some embodiments, R w is halogen (e.g., chloro or fluoro). In some embodiments, R w is –OR (e.g., -O(C 1- 6 alkyl)). In some embodiments, R w is –CN. In some embodiments, R w is optionally substituted C 1-6 aliphatic. In some embodiments, R w is optionally substituted C 1-6 alkyl. In some embodiments, R w is C 1-6 alkyl (e.g., tert-butyl). In some embodiments, R w is optionally substituted C 1-2 alkyl.
  • R w is C 1-2 alkyl (e.g., methyl).
  • one instance of R u and R w , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S.
  • one instance of R u and R w , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic.
  • 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: .
  • Table 1 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 87 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 88 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 89 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 90 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 91 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No.
  • Structure Page 92 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 93 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 94 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 95 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 96 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 97 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No.
  • Structure Page 128 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 129 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 130 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 131 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 132 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No. Structure Page 133 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Compound No.
  • the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds (such as GSK983, GSK699, and/or GSK702, described in Bassi, Z.I., et al. ACS Chem. Biol., 2018, 13, 2862- 67).
  • provided compounds are more potent than certain known compounds in one or more assays described herein, e.g., the Western Blot assay of Example B1.
  • provided compounds are more soluble than certain known compounds, as measured by, e.g., kinetic and/or thermodynamic solubility assays.
  • provided compounds have improved metabolic stability than certain known compounds, as measured by, e.g., intrinsic clearance using an in vitro liver microsomal stability assay and/or an in vivo pharmacokinetic analysis.
  • provided compounds have improved permeability, as measured by, e.g., a MDCK and/or Page 274 of 783 11575796v1 Attorney Docket No.: 2013405-0010 Caco2 permeability assays.
  • 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, T 1/2 , MRT, or CL.
  • the present disclosure encompasses the recognition that provided compounds are capable of degrading KAT2A, KAT2B, or both KAT2A and KAT2B.
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
  • 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.
  • Provided compounds may generally be made by the processes described in the ensuing schemes and examples.
  • provided compounds e.g., compounds with a linker comprising an amide
  • PBM, linker, LBM, and R are as defined in Formulae herein.
  • compound A is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable coupling agent (e.g., N,N,N',N'- Page 275 of 783 11575796v1 Attorney Docket No.: 2013405-0010 tetramethylchloroformamidinium hexafluorophosphate), optionally in the presence of a suitable base (e.g., N-methylimidazole).
  • a suitable coupling agent e.g., N,N,N',N'- Page 275 of 783 11575796v1 Attorney Docket No.: 2013405-0010 tetramethylchloroformamidinium hexafluorophosphate
  • a suitable base e.g., N-methylimidazole
  • compound B is prepared by a process comprising contacting intermediate A.1 with intermediate B.1 in the presence of a suitable coupling agent (e.g., N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate), optionally in the presence of a suitable base (e.g., N-methylimidazole).
  • a suitable coupling agent e.g., N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate
  • a suitable base e.g., N-methylimidazole
  • provided compounds are prepared according to the following Scheme: wherein PBM, linker, and LBM are as defined in Formulae herein.
  • compound C is prepared by a process comprising contacting intermediate A.1 intermediate C.1 in the presence of a suitable coupling agent (e.g., N,N'-diisopropylcarbodiimide), optionally in the presence of a suitable base (e.g., 4-dimethylaminopyridine).
  • a suitable coupling agent e.g., N,N'-diisopropylcarbodiimide
  • a suitable base e.g., 4-dimethylaminopyridine
  • intermediate A.1 has the following structure: . In some embodiments, .
  • 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., NaCNBH 3 ), optionally in the presence of a suitable acid (e.g., AcOH).
  • a suitable reducing agent e.g., NaCNBH 3
  • a suitable acid e.g., AcOH
  • intermediate D.1 has the following structure: .
  • Page 277 of 783 11575796v1 Attorney Docket No.: 2013405-0010
  • intermediate D.1 has the following structure: .
  • 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., Cs 2 CO 3 ).
  • 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., Cs 2 CO 3 ).
  • intermediate E.1 has the following structure: . In some embodiments, .
  • linker comprising a triazole ring
  • Page 278 of 783 11575796v1 Attorney Docket No.: 2013405-0010 wherein PBM, linker, and LBM are as defined in Formulae embodiments, intermediate F.2, optionally in the presence of a suitable catalyst (e.g., a copper catalyst).
  • a suitable catalyst e.g., a copper catalyst.
  • intermediate F.1 has the following structure: .
  • . 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.
  • 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).
  • a compound described herein e.g., compounds of Formulae I, II, IIA, IIA-1, IIA-2, IIA-3, IIA-4, IIA-5,
  • 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, XIIA, XIIB, XIIB-1, XIII, XIIIA, XIV, and XV) and further comprises a pharmaceutically acceptable carrier.
  • a compound provided herein e.g., compounds of Formulae I, II, IIA, IIA-1, IIA-2
  • compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects.
  • an active agent e.g., a compound described herein
  • provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and/or anti- statics, etc.
  • Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and/or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.
  • Provided pharmaceutical compositions can be prepared with any appropriate available technologies.
  • provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage.
  • the expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent.
  • a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect.
  • a unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.
  • compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and/or decreasing incidence and/or intensity of) a disease or disorder, for example as described herein.
  • a dosing regimen i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration
  • a dosing regimen i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration
  • a dosing regimen i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration
  • the present disclosure also provides methods of preparing pharmaceutical compositions provided herein.
  • provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt
  • provided compounds and compositions are useful in medicine (e.g., as therapy).
  • provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
  • provided compounds are useful as KAT2 degraders and/or inhibitors.
  • provided compounds promote degradation of KAT2A.
  • provided compounds promote degradation of KAT2B.
  • the present disclosure provides methods of degrading and/or inhibiting KAT2 (e.g., KAT2A and/or KAT2B), comprising contacting a provided compound with KAT2.
  • contacting occurs in a cell. 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.
  • KAT2A and/or KAT2B e.g., a disease, disorder, or condition associated with KAT2
  • 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.
  • provided methods are for treating cancer.
  • a cancer is characterized by a solid tumor.
  • a cancer is characterized by a hematologic tumor.
  • a cancer is selected from hematopoietic cancers, including leukemias, lymphomas (e.g., Hodgkin’s and non-Hodgkin’s), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, carcinomas of solid tissue, squamous cell carcinomas of the mouth, throat, larynx, and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine, and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, head and neck cancers, breast cancer, gastro- intestinal cancers and nervous system cancers, benign lesions such as papillomas, and the like.
  • leukemias e.g., lymphomas (e.g., Hodgkin’s and non-
  • provided methods are for treating a leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.)
  • AML acute myeloid leukemia
  • NCSLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • colorectal cancer melanoma
  • prostate cancer melanoma
  • a provided compound or composition is administered as part of a combination therapy.
  • the term “combination therapy” refers to those situations in which a Page 281 of 783 11575796v1 Attorney 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).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
  • a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care).
  • 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.
  • PBM is a KAT2A protein binding moiety.
  • linker is an optional linking moiety; and LBM is an E3 ubiquitin ligase binding moiety.
  • PBM is a KAT2A protein binding moiety.
  • the compound of embodiment 1, wherein the PBM is a KAT2B protein binding moiety.
  • a compound of Formula II: Page 282 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a pharmaceutically Ring A is selected from: ; Ring B is a 5- to selected from N, O, and S; L 1 is a covalent bond or a bivalent C 1-3 straight or branched hydrocarbon chain; each R 1 is independently optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; n is 0, 1, 2, 3, or 4; Z is N or CR 3 ; R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; R 5 is hydrogen, halogen,
  • 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 R 1 is independently optionally substituted C 1-6 alkyl.
  • the compound of embodiment 28, wherein each R 1 is independently C 1-6 alkyl.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. 43.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. 44.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)-.
  • linker comprises at least one triple bond.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. 47.
  • 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 11575796v1 Attorney Docket No.: 2013405-0010 each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic, or two R a groups, together with the atom(s) to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring
  • L 2 is a covalent bond or a straight or branched C 1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-,
  • Ring C is optionally substituted phenyl, C 5-6 cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • Ring C is optionally substituted phenyl or 5- to 6- membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 68.
  • each B is independently selected from N, C, and more than two B are N; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3. 69.
  • the compound of any one of embodiments 65- is of Formula IIIC: or a 71.
  • Ring C is optionally substituted C 3 -C 7 cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 73.
  • Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 74.
  • each A is independently N, C, or CH, provided that no more than two A groups are N; each R b is hydrogen, or two R b groups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3. 75.
  • the compound of any one of L 2 is a covalent bond. 77.
  • each R c is independently selected from halogen, -O(C 1-6 alkyl), C 1-6 alkyl, and C 1-6 haloalkyl.
  • Ring A is selected from: Page 299 of 783 11575796v1 Attorney Docket No.: 2013405-0010 ; L 3 , L 4 , and L 5 bivalent C 1-6 straight or Z is N or CR 3 ;
  • R 2 is hydrogen, halogen, -CN, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic; each R 3 is independently hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic;
  • R 4 is hydrogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic;
  • R 5 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, or optionally substituted C 3-6 cycloaliphatic;
  • the compound of any one of embodiments 104- a covalent bond.
  • 119. The compound of any one of embodiments 104-117, wherein L 3 is an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain.
  • 120. The compound of any one of embodiments 104-119, wherein L 4 is a covalent bond.
  • 121. The compound of any one of embodiments 104-119, wherein L 4 is an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain.
  • 123. The compound of any one of embodiments 104-121, wherein L 5 is an optionally substituted bivalent C 1-3 straight or branched hydrocarbon chain.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-. 135.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least two methylene units are replaced by –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, or –Cy-.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by -C(O)N(R)-. 137.
  • linker comprises at least one triple bond.
  • linker is an optionally substituted, bivalent, straight or branched, saturated or unsaturated C 1 -C 20 hydrocarbon chain, wherein at least one methylene unit is replaced by –Cy-. 139.
  • linker is: , wherein: Page 303 of 783 11575796v1 Attorney Docket No.: 2013405-0010
  • M 1 and M 2 are each independently absent, –CH 2 -, –O-, -N(R)-, -C(O)-, -OC(O)-, -C(O)O-, - C(O)N(R)-, or -N(R)C(O)-; and
  • linker is selected from: , , 141. , , , Page 304 of 783 11575796v1 Attorney Docket No.: 2013405-0010 , , , 143.
  • Cy is optionally substituted phenyl or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 145.
  • Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system is fully saturated, partially saturated, or aromatic, and the ring system contains 0-6 heteroatoms independently selected from N, O, and S; each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic, or two R a groups, together with the atom to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated ring; L 2 is a covalent bond or a straight or branched C 1-3 hydrocarbon chain wherein one methylene is optionally replaced with –O-, -S-, -N(R)-, -SO 2 -, -C(O)N(R)-, or -N(R)C(O)-; and Y is N or CH.
  • Ring C is an optionally substituted, mono- or multicyclic, 3- to 16-membered bivalent ring system, wherein the ring system
  • Ring C is optionally substituted phenyl, C 5-6 cycloaliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, 5- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, or 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • 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 11575796v1 Attorney Docket No.: 2013405-0010 157.
  • each B is independently selected from N, C, and more than two B are N; each R c is independently selected from halogen, - - - optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3. 158.
  • the compound of any one of embodiments 154- is of Formula IIIC: or a pharmaceutically acceptable salt thereof.
  • the compound of any one of embodiments 154-159, wherein the compound is of Formula IIID: or a 161.
  • Ring C is optionally substituted C 3 -C 7 cycloaliphatic or 3- to 7-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S. 162.
  • Ring C is optionally substituted 9- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. 163.
  • Ring C is: Page 307 of 783 11575796v1 Attorney Docket No.: 2013405-0010 wherein: each A is independently N, C, or CH, than two A groups are N; each R b is hydrogen, or two R b groups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3. 164.
  • each R c is independently selected from halogen, -O(C 1-6 alkyl), C 1-6 alkyl, and C 1-6 haloalkyl.
  • each R b is hydrogen, or two R b groups, on the same carbon, are taken together to form an oxo or combine to form a 3- to 6-membered saturated or partially unsaturated ring; Page 308 of 783 11575796v1 Attorney Docket No.: 2013405-0010 each R c is independently selected from halogen, -OR, -N(R) 2 , -CN, and optionally substituted C 1-6 aliphatic; and m is 0, 1, 2, or 3.
  • the compound of embodiment 176 wherein the compound is a compound of Formula XIIA: Page 310 of 783 11575796v1 Attorney Docket No.: 2013405-0010 or a 180.
  • each R p is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • each R q is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • each R r is independently hydrogen or optionally substituted C 1-6 aliphatic
  • each R s is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic
  • t is 0, 1, 2, 3, 4, or 5
  • each u is independently 0, 1, 2, 3, 4, or 5.
  • each R t is independently hydrogen or optionally substituted C 1-6 aliphatic, or both R t groups, together with the atom to which they are attached, combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms independently selected from N, O, and S; each R u is independently hydrogen, halogen, -CN, or optionally substituted C 1-6 aliphatic; each R v is independently halogen, -OR, -CN, or optionally substituted C 1-6 aliphatic, or one instance of R u and R v , together with the atoms to which they are attached combine to form an optionally substituted 3- to 7-membered cycloaliphatic or heterocycle having 1-2 heteroatoms
  • a pharmaceutical composition comprising the compound of any one of embodiments 1-186, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • the cancer is selected from acute myeloid leukemia, neuroblastoma, non-small cell lung cancer, small cell lung cancer, colorectal cancer, melanoma, and prostate cancer.
  • a method of degrading KAT2 in a subject comprising administering 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 11575796v1 Attorney Docket No.: 2013405-0010 193.
  • Method B (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 10 mM Ammonium Bicarbonate in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: 0.0 min 5% B, 0.2-3.0 min 5-5% B, 3-40 min 60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95- 5% B, 48-55 min 5-5% B.
  • Method C (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 0.1% TFA in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: 0.0 min 10% B, 0.2-3.0 min 10- 10% B, 3-40 min 10-60% B, 40-41 min 60-95% B, 41-47 min 95-95% B, 47-48 min 95-10% B, 48-55 min 10-10%B.
  • Method D (Combiflash®): Column: YMC, Dimension: 4 g (irregular silica, 40-63 ⁇ m, 60 ⁇ ), Eluents A: DCM, B: MeOH, Gradient: 0-5% MeOH/DCM for 30 min, Flow Rate: 20.0 mL/min.
  • Method E prep-HPLC: Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 10 mM Ammonium Bicarbonate in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: Linear gradient.
  • Method F (prep-HPLC): Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 0.1% Formic Acid in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: 0.0 min 2% B, 0.2-3.0 min 2-2% B, 3-50 min 2-55% B, 50-51 min 55-95% B, 51-57 min 95-95% B, 57-58 min 95-2% B, 58-65 min 2-2% B.
  • Method G Column: X-SELECT CSH-C18, (250 x 30 mm) 5 ⁇ m, Eluents A: 0.1% Formic Acid in Water, B: Acetonitrile; Flow Rate: 25.0 mL/min; Gradient: Linear gradient.
  • Method H Column: SYNERGY C18, (150 x 19 mm) 5 ⁇ m, Eluents A: 10 mM ammonium bicarbonate in H 2 O, 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.
  • 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 NH 4 Cl solution. The aqueous layer was extracted with ethyl acetate.
  • 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), PtO 2 (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.
  • 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 NaHCO 3 solution and extracted with DCM.
  • 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 11575796v1
  • Attorney 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.
  • This compound was purified by chiral SFC to afford methyl 4-((3S,5S)-5-((5- bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3-yl)benzoate and methyl 4- ((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)benzoate (0.20 g, 24%).
  • the chiral SFC conditions were as follows: Phenomenex Cellulose-3 column (250 mm x 21.2 mm, 5 ⁇ m); mobile phase: methanol; flow rate: 18 mL/min; diluent: methanol; loading: 80 mg/injection. Isomer 1 at RT 10.5 min and Isomer 2 at 18 min.
  • 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.
  • 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.
  • 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.
  • 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.
  • Step-5 methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3-yl)benzoate carbonylamino)-3- piperidyl]benzoate (1.00 g, 2.80 mmol, from step 4) in water (50 mL) was added 12 N HCl solution (5 mL) 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.
  • Step-6 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)benzoic acid
  • 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoic acid was prepared from methyl 4-((3R,5R)-5-amino-1-methylpiperidin-3- yl)benzoate generally following the procedures in steps 5 and 7 of the Preparation of Intermediate 1 above.
  • Step-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.
  • reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na 2 SO 4 and 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.
  • 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 NaHCO 3 solution and extracted with ethyl acetate.
  • 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.
  • 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 11575796v1 Attorney 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.
  • 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.
  • 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 Na 2 SO 4 , filtered and concentrated under reduced pressure to afford ethyl 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoate (5.50 g, 29%) as an off white solid.
  • Step-2 4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid
  • Page 328 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0309] yl)amino]- 1- g, , mL) and H 2 O (10 mL) was added LiOH.H 2 O (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.
  • Step 2 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbaldehyde Page 329 of 783 11575796v1 Attorney 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.
  • 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 NaCNBH 3 (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.
  • 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.
  • 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.
  • Step-3 tert-butyl 4-[3-(p-tolylsulfonyloxy)prop-1-ynyl]piperidine-1-carboxylate (1.00 g, 4.18 step 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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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, 1.54 mmol, step tert- -3,6-dihydro-2H- pyridine-1-carboxylate (0.57 g, 1.85 mmol) in DMF (5 mL), K 2 CO 3 (0.42 g, 3.09 mmol) was added at RT. The reaction mixture was purged with argon for 30 min.
  • Step-3 tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperidine-1-carboxylate 5-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 H 2 gas 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.
  • 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.
  • 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.
  • Step-3 3-[1-oxo-4-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione piperazine-1-carboxylate (0.10 g, 0.16 mmol, from step 2) in DCM (2 mL) and 30% TFA in DCM (0.6 mL) was stirred at 0 °C for 5 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.
  • reaction mixture was purged with argon for 30 min.
  • PdCl 2 (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 Na 2 SO 4 and concentrated under reduced pressure to obtain crude.
  • Step-2 4-[(3R,5R)-5-[(1,5-dimethyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid: [0329] yl)amino]-1- methyl-3-piperidyl]benzoate (2.50 g, 6.20 mmol) in ethanol (20 mL) and H 2 O (4 mL) was added LiOH.H 2 O (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.
  • 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.
  • 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.
  • 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 Na 2 SO 4 and 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 11575796v1 Attorney 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.
  • 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.
  • Step 2 To a stirred solution of intermediate from step 1 (4.80 mmol) in ACN (40 mL) was added isoamyl nitrite (29.00 mmol) at RT and was stirred for 10 min.
  • Step 4 was added 10% Pd/C at RT.
  • the reaction mixture was stirred in a steel bomb under 50 psi H 2 gas pressure at RT for 16 h.
  • the progress of the reaction was monitored by TLC and LCMS.
  • 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 11575796v1 Attorney Docket No.: 2013405-0010 [0342] mL) was added TFA (2 RT for 3 h.
  • the progress of the reaction was monitored by TLC.
  • Step 6 added 1-methylimidazole (1.00 mmol) followed by a benzoic acid intermediate (0.30 mmol) and the reaction mixture was stirred at RT for 10 min. 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.
  • reaction mixture was purged with argon for 30 min.
  • PdCl 2 (dppf) 0.4 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 Na 2 SO 4 and 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 To a 1-carboxylate (0.16 mmol, from step 3) in DCM (2 mL) was added 30% TFA in DCM (4 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 5 min followed by at RT for 4 h.
  • Step 4 Page 344 of 783 11575796v1 Attorney 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.
  • 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 11575796v1 Attorney 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.
  • Step-2 2-(2,6-dioxopiperidin-3-yl)-4-(4-(methylamino)phenoxy)isoindoline-1,3-dione
  • a 1,3-dione (0.50 g, 1.81 mmol, from step 1) and 4-(methylamino)phenol (0.25 g, 1.99 mmol) in DMA (7 mL)
  • 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.
  • 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
  • Step-2 methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)propionate [0353] To mmol, from step 1) in 1,4-dioxane (100 mL), Na 2 CO 3 (8.90 g, 83.70 mmol) was added followed by (Boc) 2 O (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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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.
  • 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 NH 4 Cl solution, diluted with water and extracted with ethyl acetate.
  • 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.
  • 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 11575796v1 Attorney 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.
  • 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 Na 2 SO 4 and 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.
  • Step-7 2-(2,6-dioxopiperidin-3-yl)-4-(3-(4-(methylamino)phenyl)propoxy)isoindoline-1,3-dione 4- 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.
  • 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 11575796v1 Attorney 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
  • 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.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • tert-butyldiphenylchlorosilane (9.70 g, 35.60 mmol) was added at 0 °C, 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 filtered through Buchner funnel, and filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (5% ethyl acetate in hexane) to afford tert-butyl(pent-4-yn-1-yloxy)diphenylsilane (9.10 g, 83%) as a colorless oil.
  • Step-1b tert-butyl (4-bromobutyl)(methyl)carbamate Page 355 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0366] To a (4.70 g, 23.15 mmol) in DCM (75 mL), mixture was stirred at RT for 20 min. To the resulting reaction mixture, CBr 4 (9.10 g, 27.78 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-2 tert-butyl (9-((tert-butyldiphenylsilyl)oxy)non-5-yn-1-yl)(methyl)carbamate [0367] mmol, from step 1) in dry THF (35 mL), HMPA (8.70 g, 49.00 mmol) and NaI (0.14 g, 0.98 mmol) were added, followed by n-BuLi (1.6 M in hexane, 7.60 mL, 12.20 mmol) at 0 °C, and the reaction mixture was stirred for 15 min.
  • tert-butyl (4-bromobutyl)(methyl)carbamate (1.90 g, 7.35 mmol, from step 1b) was added, and the reaction mixture was 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 ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • tert-butyl (9- ((tert-butyldiphenylsilyl)oxy)non-5-yn-1-yl)(methyl)carbamate (1.50 g, 62%) as a colorless oil.
  • Step-3 tert-butyl (9-hydroxynon-5-yn-1-yl)(methyl)carbamate oxy)non-5-yn-1- yl)(methyl)carbamate (1.50 g, 3.00 mmol, from step 2) in THF (20 mL), TBAF (1 M in THF, 15 mL, 15.20 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 3 h. The progress of the Page 356 of 783 11575796v1 Attorney Docket No.: 2013405-0010 reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCO 3 solution and extracted with ethyl acetate.
  • Step-4 9-((tert-butoxycarbonyl)(methyl)amino)non-4-yn-1-yl methanesulfonate (0.70 g, 2.77 step , was at and the reaction mixture was stirred for 10 min.
  • Step-5 Tert-butyl (9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)non-5-yn-1- yl)(methyl)carbamate
  • non-4-yn-1-yl methanesulfonate (0.90 g, 2.72 mmol, from step 4)
  • 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline- 1,3-dione (0.70 g, 2.72 mmol) in DMF (10 mL), K 2 CO 3 (0.75 g, 5.45 mmol) was added at RT, and the reaction mixture was stirred at 80 °C for 12 h.
  • reaction mixture was diluted with ice cold water and filtered through Buchner funnel. The filtrate was extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-6 2-(2,6-dioxopiperidin-3-yl)-4-((9-(methylamino)non-4-yn-1-yl)oxy)isoindoline-1,3-dione 4- non- yn- g, , TFA (0.50 ml) was added, and the reaction mixture was stirred at 0 °C for 5 min, followed by at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (0.05 g, 0.17 mmol) was added and stirred at 80 Page 358 of 783 11575796v1 Attorney Docket No.: 2013405-0010 °C for 16 h.
  • the progress of the reaction was monitored by TLC.
  • the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Step-2 2-(2,6-dioxopiperidin-3-yl)-4-(4-(methylamino)piperidin-1-yl)isoindoline-1,3-dione
  • 4- yl)piperidin-4-yl)(methyl)carbamate (0.11 g, 0.23 mmol, from step 1) in DCM (5 mL), TFA (1.20 mL) was added, and the reaction mixture was stirred at 0 °C for 5 min, followed by at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-3 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)-N-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)-N-methylbenzamide Page 363 of 783 11575796v1 Attorney Docket No.: 2013405-0010 4- - , 2- (2,6-dioxopiperidin-3-yl)-4-(4-(methylamino)piperidin-1-yl)isoindoline-1,3-dione (0.04 g, 0.09 mmol, from step 2) was added, followed by N-methyl imidazole (0.03 g, 0.41 mmol), and the reaction mixture was stirred at RT for 10 min.
  • N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (0.04 g, 0.12 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Step-2 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione [0381] To a stirred 3-yl)-1,3-dioxoisoindolin-4- yl)piperazine-1-carboxylate (0.15 g, 0.33 mmol, from step 1) in DCM (2 mL), TFA (0.50 mL) was added, and the reaction mixture was stirred at 0 °C for 5 min, followed by at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-3 4-(4-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Page 365 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0382] 4- yl)amino)- (2 mL), 2- (2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione (0.03 g, 0.08 mmol, from step 2) was added, followed by N-methyl imidazole (0.03 g, 0.35 mmol), and the reaction mixture was stirred at RT for 10 min.
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Step-2 4-(4-aminopiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0384] To a dioxoisoindolin-4- yl)piperidin-4-yl)carbamate (0.27 g, 0.59 mmol, from step 1) in DCM (2 mL), TFA (0.80 mL) was added and the reaction mixture was stirred at 0 °C for 5 min, followed by at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-3 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)-N-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)benzamide Page 367 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0385] 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 (2 mL), 4-(4- aminopiperidin-1-yl)-2-(2,6
  • 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 Na 2 SO 4 and concentrated under reduced pressure.
  • reaction mixture was diluted with ice-cold water. Precipitated solid was filtered through Buchner funnel, washed with diethyl ether and heptane to afford tert-butyl (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)ethyl)carbamate (0.48 g, 68%) as a pale yellow solid.
  • Step-2 4-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [0387]
  • TFA 0.50 mL
  • Step-3 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1-methylpiperidin-3- yl)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)benzamide 4- yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.05 g, 0.11 mmol, intermediate 1) in DMF (1 mL), 4-(4- (2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.05 g, 0.13 mmol, from step 2) was added, followed by N-methyl imidazole (0.05 g, 0.55
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.05 g, 0.16 mmol) was added and stirred at 80 °C for 4 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Step-2 2-(2,6-dioxopiperidin-3-yl)-4-(3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione Page 370 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0390] To a stirred solution of tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.50 g, 0.11 mmol, from step 1) in DCM (10 mL), TFA (4.50 mL) was added, and the reaction mixture was stirred at 0 °C for 5 min, followed by at RT for 3 h.
  • Step-3 4-(9-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione [0391] 4- yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.05 g, 0.11 mmol, intermediate 1) in DMF (2.5 mL), 2- (2,6-dioxopiperidin-3-yl)-4-(3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione (0.04 g, 0.11 mmol, from step 2) was added, followed by N-methyl imidazo
  • N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (0.05 g, 0.17 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Step-2 2-(2,6-dioxopiperidin-3-yl)-4-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione [0393] To a -1,3-dioxoisoindolin-4-yl)- 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.85 g, 1.75 mmol, from step 1) in DCM (30 mL), TFA (7 mL) was added and the reaction mixture was stirred at 0 °C for 5 min, followed by at RT for 3 h.
  • Step-3 4-(7-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione [0394] 4- yl)amino)-1-methylpiperidin-3-yl)benzoic acid (0.05 g, 0.11 mmol, intermediate 1) in DMF (1 mL), 2- (2,6-dioxopiperidin-3-yl)-4-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (0.04 g, 0.11 mmol, from step 2) was added, followed by N-methyl imidazole (
  • N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (0.05 g, 0.17 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Step-2 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yloxy)isoindoline-1,3-dione 1,3-dioxoisoindolin-4- yl)oxy)piperidine-1-carboxylate (0.20 g, 0.43 mmol, from step 1) in DCM (2 mL), 30% TFA in DCM (0.50 mL) was added at 0 °C, and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC.
  • Step-3 4-((1-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Page 374 of 783 11575796v1 Attorney Docket No.: 2013405-0010 4- - , 2- (2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yloxy)isoindoline-1,3-dione (0.05 g, 0.13 mmol) was added, followed by N-methyl imidazole (0.05 g, 0.55 mmol), and the reaction mixture was stirred for 5 min.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.05 g, 0.16 mmol) 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 water and extracted with ethyl acetate.
  • Step-2 tert-butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)piperazine-1- carboxylate [0399] dione (0.18 g, 0.64 mmol) DMF , g, was by tert-butyl 4- (2-((methylsulfonyl)oxy)ethyl)piperazine-1-carboxylate (0.20 g, 0.64 mmol, from step 1) at RT, and the reaction mixture was stirred at 80 °C for 12 h. The progress of the reaction was monitored by TLC.
  • Step-3 2-(2,6-dioxopiperidin-3-yl)-4-(2-(piperazin-1-yl)ethoxy)isoindoline-1,3-dione dioxoisoindolin-4- yl)oxy)ethyl)piperazine-1-carboxylate (0.10 g, 0.20 mmol, from step 2) in DCM (5 mL), 30% TFA in DCM (1.50 mL) was added at 0 °C, and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC.
  • Step-4 4-(2-(4-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)amino)-1- methylpiperidin-3-yl)benzoyl)piperazin-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 4- - g, , 2- (2,6-dioxopiperidin-3-yl)-4-(2-(piperazin-1-yl)ethoxy)isoindoline-1,3-dione (0.04 g, 0.10 mmol, from step 3) was added, followed by N-methylimidazole (0.04 g, 0.51 mmol), and the reaction mixture was stirred at RT for 5 min.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.04 g, 0.15 mmol) 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 water and extracted with ethyl acetate.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.02 g, 0.07 mmol) was added and stirred at 80 °C for 8 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.01 g, 0.06 mmol) was added and stirred at 80 °C for 5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.02 g, 0.07 mmol) 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 water and extracted with ethyl acetate, the combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.02 g, 0.07 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 Na 2 SO 4 and concentrated under reduced pressure.
  • tert-butyl piperazine-1-carboxylate (0.06 g, 0.34 mmol) was added, and the reaction mixture was 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 water and extracted with ethyl acetate.
  • Step-2 2-(2,6-dioxo-3-piperidyl)-5-(piperazin-1-ylmethyl)isoindoline-1,3-dione Page 381 of 783 11575796v1
  • TFA (1 mL) was added at 0 °C.
  • the reaction mixture was stirred at RT for 3 h.
  • the progress of the reaction was monitored by TLC.
  • Step-3 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 -1- methyl-3-piperidyl]benzoic acid (0.053 g, 0.14 mmol, intermediate 1) in DMF (3 mL), N- methylimidazole (0.06 g, 0.78 mmol) was added, followed by N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (0.06 g, 0.22 mmol), and the reaction mixture was stirred at RT for 10 min.
  • Step-2 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]-N-[3-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyphenyl]-N-methyl-benzamide -1- methyl-3-piperidyl]benzoic acid (0.10 g, 0.26 mmol, intermediate 1) in DMF (2 mL), N-methylimidazole (0.10 g, 1.18 mmol) was added, followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.10 g, 0.35 mmol), and the reaction mixture was stirred at RT for 10 min.
  • Step-2 2-(2,6-dioxo-3-piperidyl)-4-piperazin-1-yl-isoindoline-1,3-dione Page 384 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0412]
  • tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]piperazine-1-carboxylate 0.3 g, 0.67 mmol, from step 1) in DCM (5 mL
  • TFA 1.5 mL
  • Step-3 4-[4-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione -1- methyl-3-piperidyl]benzaldehyde (0.10 g, 0.24 mmol, from step 2) in MeOH (3 mL), 2-(2,6-dioxo-3- piperidyl)-4-piperazin-1-yl-isoindoline-1,3-dione (0.10 g, 0.29 mmol, from step 2) was added, followed by acetic acid (catalytic) at RT.
  • reaction mixture was stirred at RT for 3 h.
  • sodium cyanoborohydride (0.03 g, 0.49 mmol) was added at 0 °C, 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 ethyl acetate.
  • Step-2 tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate [0415] (1.00 g, 3.60 mmol, from step 1) in DMSO (5 mL), tert-butyl piperazine-1-carboxylate (0.80 g, 4.30 mmol) was added, followed by N,N-diisopropylethylamine (2.30 g, 18.10 mmol) at RT, and the reaction mixture was stirred at 130 °C for 12 h. The progress of the reaction was monitored by TLC.
  • reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude compound, which was purified by silica gel column chromatography (5o% ethyl acetate in hexane) to afford tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine- 1-carboxylate (0.80 g, 50%), as an off white solid.
  • Step-3 2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione [0416] isoindolin-5- yl] g, was added, 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.
  • Step-4 5-[4-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione -1- methyl-3-piperidyl]benzaldehyde (0.10 g, 0.24 mmol, from step 3) in MeOH (3 mL), 2-(2,6-dioxo-3- piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (0.10 g, 0.29 mmol, from step 3) was added, followed by acetic acid (catalytic) at RT.
  • reaction mixture was stirred at RT for 4 h.
  • sodium cyanoborohydride (0.03 g, 0.49 mmol) was added at 0 °C, 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 ethyl acetate.
  • Step-2 4-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione
  • a isoindolin-4-yl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (0.20 g, 0.44 mmol, from step 1) and TFA (2 mL) in DCM (10 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.
  • Step-3 4-[2-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione 4- - g, DMF mL), 4- (2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.08 g, 0.26 mmol, from step 2) was added, followed by N-methylimidazole (0.08 g, 0.90 mmol), and the reaction mixture was stirred at RT for 10 min.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.08 g, 0.27 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 Na 2 SO 4 and concentrated under reduced pressure.
  • reaction mixture was stirred at RT for 15 min, followed by addition of DIAD (0.30 mL, 1.45 mmol) and 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.
  • Step-2 5-(azetidin-3-yloxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione isoindolin-5- yl]oxyazetidine-1-carboxylate (0.14 g, 0.32 mmol, from step 1) in DCM (5 mL), TFA (1.5 mL) was added at 0 °C, and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC.
  • Step-3 5-[1-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]azetidin-3-yl]oxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione Page 390 of 783 11575796v1 Attorney Docket No.: 2013405-0010 -1- , (0.12 g, 0.30 mmol) was added, followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.09 g, 0.33 mmol), and the reaction mixture was stirred at RT for 10 min.
  • Step-2 [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-piperidyl] 4-[(3R,5R)-5-[(5-bromo-1- methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate -1- methyl-3-piperidyl]benzoic acid (0.1 g, 0.23 mmol, intermediate 1) in DMF (3 mL), N,N'- diisopropylcarbodiimide (0.09 g, 0.71 mmol) was added and the reaction mixture was stirred at RT for 30 min.
  • Step-2 [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-piperidyl]methyl 4-[(3R,5R)-5-[(5- bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoate -1- methyl-3-piperidyl]benzoic acid (0.1 g, 0.23 mmol, intermediate 1) in DMF (3 mL), N,N'- diisopropylcarbodiimide (0.09 g, 0.71 mmol) was added at RT and stirred for 30 min.
  • Step-3 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]-N-[[4-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyphenyl]methyl]-N-methyl-benzamide -1- methyl-3-piperidyl]benzoic acid (0.20 g, 0.58 mmol, intermediate 1) in DMF (2 mL), N-methylimidazole (0.19 g, 2.90 mmol) was added, followed by TCFH (0.20 g, 0.87 mmol), and the reaction mixture was stirred at RT for 10 min.
  • Step-2 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]-N-[3-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyphenyl]-N-methyl-benzamide -1- methyl-3-piperidyl]benzoic acid (0.10 g, 0.26 mmol, intermediate 1) in DMF (2 mL), N-methylimidazole (0.10 g, 1.18 mmol) was added, followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.09 g, 0.35 mmol), and the reaction mixture was stirred at RT for 10 min.
  • Step-3 4-[[1-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl]-4-piperidyl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione -1- methyl-3-piperidyl]benzaldehyde (0.12 g, 0.29 mmol, intermediate 4) in MeOH (8 mL), 2-(2,6-dioxo-3- piperidyl)-4-(4-piperidylmethoxy)isoindoline-1,3-dione (0.13 g, 0.35 mmol, from step 2) was added, followed by acetic acid (catalytic) at RT.
  • reaction mixture was stirred for 10 min.
  • sodium cyanoborohydride (0.04 g, 0.59 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 16 h.
  • the progress of the reaction was monitored by TLC.
  • the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate.
  • Example 36 Preparation of 4-((1-(4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)benzyl)piperidin-4-yl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione -1- g, , 3- piperidyl)-4-(4-piperidyloxy)isoindoline-1,3-dione (0.10 g, 0.29 mmol) was added, followed by acetic acid (catalytic) at RT.
  • reaction mixture was stirred at RT for 4 h.
  • sodium cyanoborohydride (0.03 g, 0.49 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for16 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.
  • Step-2 4-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione 4- yl)amino]-1-methyl-3-piperidyl]phenyl]methoxy]-1,3-dioxo-isoindolin-2-yl]-2,6-dioxo-piperidine-1- carboxylate (0.30 g, 0.89 mmol, from step 1) in 1,4-dioxane (5 mL), 4.0 M HCl in dioxane (1 mL) was added at 0 °C.
  • Step-2 5-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione N N H N N HN N [0441] pyridazin-4- yl)amino]-1-methyl-3-piperidyl]phenyl]methoxy]-1,3-dioxo-isoindolin-2-yl]-2,6-dioxo-piperidine-1- carboxylate (0.02 g, 0.02 mmol, from step 1) in DCM (1 mL), 4.0 M HCl in dioxane (0.3 mL) was added at 0 °C.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.02 g, 0.05 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.
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.02 g, 0.06 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.
  • Example 42 Preparation of 4-((3R,5R)-5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridazin-4- yl)amino)-1-methylpiperidin-3-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)octyl)benzamide Page 404 of 783 11575796v1 Attorney Docket No.: 2013405-0010 4- - g, , 4- ((8-aminooctyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.02 g, 0.04 mmol) was added, followed by N-methylimidazole (0.02 g, 0.04 mmol) was added, followed by N-methylimidazole (0.02 g,
  • N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.02 g, 0.06 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.
  • Step-2 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]-N-[2-[2-[4- [2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyethoxymethyl]triazol-1- yl]ethoxy]ethyl]benzamide 6-oxo- pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzamide (0.07 g, 0.12 mmol, from step 1) in THF (6 mL), DIPEA (0.03 mL, 0.18 mmol) and CuI (0.01 g, 0.06 mmol) were added, followed by 2-(2,6-dioxo-3- piperid
  • Step-2 2-(2,6-dioxo-3-piperidyl)-4-[2-(methylamino)ethoxy]isoindoline-1,3-dione Page 407 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0448] A ethoxy]-1,3-dioxo- isoindolin-2-yl]-2,6- g, step 1) and TFA (1.5 mL) in DCM (5 mL) was stirred at 0 °C for 5 min, followed by at RT for 2 h. The progress of the reaction was monitored by TLC.
  • Step-3 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]-N-[2-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyethyl]-N-methyl-benzamide 1,3- dione (0.04 g, 0.13 mmol, from step 2) and 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4- yl)amino]-1-methyl-3-piperidyl]benzoic acid (0.05 g, 0.11 mmol, intermediate 1) in DMF (1.5 mL), N- methylimidazole (0.04 g, 0.53 mmol) was added, followed by N,N,N',N'- tetramethylchloroformamidin
  • Step-2 tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxymethyl]piperidine-1- carboxylate
  • a 1-carboxylate (0.38 g, 1.31 mmol, from step 1)
  • 2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione (0.30 g, 1.09 mmol)
  • K 2 CO 3 (0.30 g, 2.19 mmol)
  • KI 0.04 g, 0.22 mmol
  • reaction mixture was quenched with ice cold water and extracted with ethyl Page 409 of 783 11575796v1 Attorney Docket No.: 2013405-0010 acetate.
  • the organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by flash column chromatography (30% ethyl acetate in hexane) to afford tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxymethyl]piperidine-1- carboxylate (0.05 g, 8.7%) as an off white solid.
  • reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to afford 2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylmethoxy)isoindoline-1,3- dione (TFA salt, 0.04 g) as an off white solid, which was used as such for the next reaction.
  • TFA salt 2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylmethoxy)isoindoline-1,3- dione
  • Step-4 4-[[1-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-4-piperidyl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione Page 410 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0453] To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylmethoxy)isoindoline-1,3- dione (0.04 g, 0.12 mmol, from step 3) and 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-
  • Example 46 4-[[4-[4-[(3R,5R)-5-[(5-chloro-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]benzamide -1- methyl-3-piperidyl]benzoic acid (0.05 g, 0.132 mmol, intermediate 8) in DMF (1 mL) was added N- methyl imidazole (0.05 g, 0.66 mmol) and N,N,N',N'- tetramethylchloroformamidiniumhexafluorophosphate (0.06 g, 0.19 mmol).
  • reaction mixture was stirred at RT for 10 min.
  • N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]-4-(piperazin-1-ylmethyl)benzamide (0.06 g, 0.13 mmol, Aldrich cat. 920754) was added and the reaction mixture was stirred at 80 °C for 12 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 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 NaHCO 3 and was extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to get the crude compound.
  • the crude compound was purified by 100-200 mesh silica gel column chromatography (30% EtOAc/n-hexane) to afford 8-chloro-6-methyl-pyrido[2,3-d]pyridazin-5- one (0.11 g, 24%) as an off white solid.
  • LC-MS m/z 194.99 [M+H] + .
  • Step-3 methyl 4-[(3R,5R)-1-methyl-5-[(6-methyl-5-oxo-pyrido[2,3-d]pyridazin-8-yl)amino]-3- piperidyl]benzoate [0457] To g, 1.02 mmol, from step-2) - 2.04 mmol, from step 4 intermediate 1) in toluene (10 mL), was added potassium tert-butoxide (0.22 g, 2.04 mmol) and the reaction mixture was purged with argon for 10 min.
  • Step-4 4-[(3R,5R)-1-methyl-5-[(6-methyl-5-oxo-pyrido[2,3-d]pyridazin-8-yl)amino]-3-piperidyl]benzoic acid [0458] oxo-pyrido[2,3- d]pyridazin-8-yl)amino]-3-piperidyl]benzoate (0.15 g, 0.36 mmol, from step 3) in EtOH (2 mL), was added LiOH.H 2 O (0.05 g, 0.73 mmol) and the reaction mixture was stirred at 70 °C for 2 h. The progress of the reaction was monitored by TLC.
  • Step-5 N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-[[4-[4-[(3R,5R)-1-methyl-5-[(6-methyl- 5-oxo-pyrido[2,3-d]pyridazin-8-yl)amino]-3-piperidyl]benzoyl]piperazin-1-yl]methyl]benzamide 8- - g, step was methyl imidazole (0.04 g, 0.51 mmol) followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.04 g, 0.15 mmol) and the reaction mixture was stirred at RT for 10 min.
  • N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-4-(piperazin-1- ylmethyl)benzamide (0.06 g, 0.12 mmol, cat. 920754) was added and the reaction mixture was stirred at 80 °C 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 ethyl acetate.
  • Example 48 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]- N-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyphenyl]methyl]-N-methyl-benzamide
  • Step-1 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione Page 414 of 783 11575796v1
  • 2013405-0010 [0460] To a g, 60.20 mmol) and 3- aminopiperidine-2,6- (100 mL), NaOAc (7.40 g, 90.30 mmol) was added and the reaction mixture was stirred at 100 °C for 12 h.
  • Step-2 tert-butyl N-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyphenyl]methyl]-N- methyl-carbamate (0.22 g, 0.79 mmol, from step 1) and tert-butyl (4-hydroxybenzyl)(methyl)carbamate (0.16 g, 0.79 mmol, CAS: 1046818-38-5, Enamine) in DMA (3 mL), potassium fluoride (0.07 g, 1.19 mmol) was added and the reaction mixture was stirred at 170 °C for 4 h under microwave irradiation followed by at 170 °C for 20 h.
  • Step-4 4-[4-[[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl-methyl-amino]methyl]phenoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione 4-[4- (methylaminomethyl)phenoxy]isoindoline-1,3-dione g, 2.54 mmol, from step 3) and 4-bromo-5- [[(3R,5R)-5-[4-(chloromethyl)phenyl]-1-methyl-3-piperidyl]amino]-2-methyl-pyridazin-3-one (0.10 g, 2.54 mmol, intermediate 6) in ACN (2 mL), was added cesium carbonate (0.41 g, 12.70 mmol) and the reaction mixture was stirred
  • reaction mixture was stirred at RT for 2 h.
  • sodium cyanoborohydride (2.00 g, 32.70 mmol) was added 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 diluted with ice-cold water and extracted with ethyl acetate.
  • Step-2 tert-butyl 4-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]oxyphenyl]methyl]piperazine-1-carboxylate g, 3.62 mmol) and tert-butyl 4-[(4-hydroxyphenyl)methyl]piperazine-1-carboxylate (1.05 g, 3.62 mmol, from step 1) in DMA (7 mL), KF (0.31 g, 5.43 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.
  • Step-3 2-(2,6-dioxo-3-piperidyl)-4-[4-(piperazin-1-ylmethyl)phenoxy]isoindoline-1,3-dione Page 417 of 783 11575796v1
  • 4- yl] mL was added TFA (2 mL) at 0 °C.
  • 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.
  • Step-4 4-[4-[[4-[4-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]phenoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione -1- methyl-3-piperidyl]benzoic acid (0.10 g, 0.22 mmol, intermediate 1) in DMF (2 mL), N-methyl imidazole (0.06 g, 0.78 mmol) was added followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.06 g, 0.23 mmol) and the reaction mixture was stirred at RT for 10 min.
  • Example 50 4-[4-[[4-[[4-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl]piperazin-1-yl]methyl]phenoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione 3- - one g, , carbonate (0.22 g, 0.70 mmol) was added followed by 2-(2,6-dioxo-3-piperidyl)-4-[4-(piperazin-1- ylmethyl)phenoxy]isoindoline-1,3-dione (0.12 g, 0.28 mmol, from step 3 previous example 49) and the reaction mixture was stirred at 80 °C for 16 h.
  • Step-2 4-(2,6-diazaspiro[3.3]heptan-2-yl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [0470] To a isoindolin-4-yl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (0.15 g, 0.33 mmol, from step 1) in DCM (15 mL) was added TFA (0.3 mL) 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.
  • Step-3 4-[6-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione Page 420 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0471] To yl)-2-(2,6-dioxo-3- piperidyl) , carbonate (0.45 g, 1.41 mmol) was added followed by 4-bromo-5-[[(3R,5R)-5-[4-(chloromethyl)phenyl]-1-methyl-3- piperidyl]amino]-2-methyl-pyridazin-3-one (0.13 g, 0.31
  • Example 52 4-[[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)-4-methyl-isoindoline-1,3-dione g, 30.86 mmol) in AcOH (60 mL), NaOAc (3.10 g, 38.00 mmol) was added at RT.
  • Step-2 4-(bromomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [0473] To a dione (2.0 g, 7.32 mmol, from step , g, was by NBS (1.50 g, 8.70 mmol) at RT. The reaction mixture was stirred at 90 °C for 12 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.
  • Step-3 tert-butyl 4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]methyl]piperazine-1- carboxylate [0474] To 1,3-dione (0.20 g, 0.56 mmol, from step 2) and K 2 CO 3 (0.11 g, 8.50 mmol) in ACN (5 mL), tert-butyl piperazine-1- carboxylate (0.12 g, 0.68 mmol) was added and the reaction mixture was 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 water and extracted with ethyl acetate.
  • Step-4 2-(2,6-dioxo-3-piperidyl)-4-(piperazin-1-ylmethyl)isoindoline-1,3-dione [0475] isoindolin-4- yl] g, DCM (3 mL) was stirred at 0 °C for 5 min followed by at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-5 4-[[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 yl)amino]-1- methyl-3-piperidyl]benzoic acid (0.10 g, 0.28 mmol, intermediate 1) in DMF (1 mL), N-methyl imidazole (0.11 g, 1.40 mmol) was added followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.11 g, 0.42 mmol) and the reaction mixture was stirred at RT for 10 min.
  • Example 53 4-[4-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl-methyl-amino]phenoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [0477] 1,3- g, step were (0.22 g, 0.70 mmol) and 4-bromo-5-[[(3R,5R)-5-[4-(chloromethyl)phenyl]-1-methyl-3-piperidyl]amino]-2- methyl-pyridazin-3-one (0.10 g, 0.23 mmol, intermediate 6) at RT.
  • Example 54 5-[3-[1-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-4-piperidyl]prop-2-ynoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione
  • Step-1 tert-butyl 4-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyprop-1-ynyl]piperidine-1- carboxylate Page 424 of 783 11575796v1 Attorney Docket No.: 2013405-0010 O BocN O OTs N O [0478] 1- 2-yl)- 2,6-dioxo-piperidine-1-carboxylate (0.38 g, 1.01 mmol
  • Step-2 2-(2,6-dioxo-3-piperidyl)-5-[3-(4-piperidyl)prop-2-ynoxy]isoindoline-1,3-dione isoindoline- 1,3-dione (0.5 g, 0.84 mmol, from step 1) in DCM (1 mL) was added TFA (1 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-3 5-[3-[1-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-4-piperidyl]prop-2-ynoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione -1- methyl-3-piperidyl]benzoic acid (0.09 g, 0.22 mmol, intermediate 1), N-methyl imidazole (0.08 g, 1.01 Page 425 of 783 11575796v1 Attorney Docket No.: 2013405-0010 mmol) in DMF (4 mL), was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.08 g, 0.30 mmol) and the reaction mixture was stirred at RT for 10 min.
  • Example 55 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]- N-[[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxymethyl]phenyl]methyl]-N-methyl- benzamide
  • Step-1 methyl 4-[[tert-butyl(dimethyl)silyl]oxymethyl]benzoate [0481] To mmol) in DCM (10 mL), imidazole (2.45 g, 36.14 mmol) was added followed by tert-butyldimethylsilyl chloride (5.40 g, 36.14 mmol)) at 0 °C and the reaction mixture was stirred at RT for 12 h.
  • reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude compound which was purified by silica gel column chromatography (50% ethyl acetate in hexane) to afford [4-[[tert- butyl(dimethyl)silyl]oxymethyl]phenyl]methanol (1.20 g, 70%) as a pale yellow liquid.
  • Step-3 tert-butyl 3-[4-[[4-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]methoxy]-1,3-dioxo-isoindolin-2- yl]-2,6-dioxo-piperidine-1-carboxylate 2,6-dioxo- piperidine-1-carboxylate (1.50 g, 4.01 mmol, from step 2) and [4-[[tert- butyl(dimethyl)silyl]oxymethyl]phenyl]methanol (1.01 g, 4.01 mmol, intermediate 3) in THF (3 mL) was added triphenyl phosphine (1.50 g, 6.01 mmol) at 0 °C and stirred for 10 min.
  • Step-4 tert-butyl 3-[4-[[4-(hydroxymethyl)phenyl]methoxy]-1,3-dioxo-isoindolin-2-yl]-2,6-dioxo- piperidine-1-carboxylate 3-[4-[[4-[[tert- - - 1- carboxylate (1.50 g, 2.46 mmol, from step 3) in THF (5 mL) was added 3M H 2 SO 4 (5 mL) at RT and the reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC.
  • Step-5 tert-butyl 3-(4-((4-formylbenzyl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate isoindolin-2-yl]-2,6-dioxo-piperidine-1-carboxylate (1.2 g, 2.42 mmol, from step 4) in DCM (12 mL) was added Dess–Martin periodinane (2.05 g, 4.86 mmol)) at 0 °C and the reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC.
  • Step-6 tert-butyl 3-(4-((4-((methylamino)methyl)benzyl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6- dioxopiperidine-1-carboxylate Page 428 of 783 11575796v1
  • 2-yl)-2,6- g, (0.18 g, 2.74 mmol) in 1,2-dichloroethane (30 mL) was added acetic acid (catalytic) at 0 °C. The reaction mixture was stirred at RT for 2 h.
  • Step-7 2-(2,6-dioxopiperidin-3-yl)-4-((4-((methylamino)methyl)benzyl)oxy)isoindoline-1,3-dione oxy)-1,3- dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate (0.10 g, 0.19 mmol, from step 6) in DCM (2 mL) was added TFA (0.5 mL) at 0 °C. 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.
  • Step-8 4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]-N-[[4-[[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxymethyl]phenyl]methyl]-N-methyl-benzamide
  • Page 429 of 783 11575796v1 Attorney Docket No.: 2013405-0010 -1- g, g, 0.98 mmol) in DMF (2 mL) was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.08 g, 0.29 mmol) and the reaction mixture was stirred at RT for 10 min.
  • Example 56 4-[[4-[4-[(3R,5R)-5-[(2,4-dimethyl-3,5-dioxo-1,2,4-triazin-6-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]benzamide
  • Step-1 6-bromo-2,4-dimethyl-1,2,4-triazine-3,5-dione [0489] To a stirred (1.00 g, 5.23 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 0.35 g, 13.08 mmol) at 0 °C followed by MeI (0.80 mL, 13.08 mmol) and the reaction mixture was stirred at RT for 16 h.
  • Step-2 methyl 4-[(3R,5R)-5-[(2,4-dimethyl-3,5-dioxo-1,2,4-triazin-6-yl)amino]-1-methyl-3- piperidyl]benzoate [0490] To a benzoate (2.00 g, 9.17 mmol, step was mL, 27.50 mmol) followed by 6-bromo-2,4-dimethyl-1,2,4-triazine-3,5-dione (4.50 g, 18.30 mmol, from step 1) and the reaction mixture was stirred at 160 °C for 16 h under microwave irradiation. The progress of the reaction was monitored by TLC.
  • Step-3 4-[(3R,5R)-5-[(2,4-dimethyl-3,5-dioxo-1,2,4-triazin-6-yl)amino]-1-methyl-3-piperidyl]benzoic acid [0491] To 1,2,4-triazin-6- yl)amino]-1-methyl-3-piperidyl]benzoate (0.1 g, 0.25 mmol, from step 1) in THF (2 mL) and water (0.5 mL) was added LiOH.H 2 O (0.01 g, 0.20 mmol) and the reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC.
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • the aqueous layer was acidified with 2N HCl to pH 3.
  • the aqueous layer was extracted with 10% MeOH/DCM.
  • Combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 4-[(3R,5R)-5-[(2,4-dimethyl-3,5- Page 431 of 783 11575796v1 Attorney Docket No.: 2013405-0010 dioxo-1,2,4-triazin-6-yl)amino]-1-methyl-3-piperidyl]benzoic acid (0.07 g, 72%) as a pale yellow liquid.
  • Step-4 4-[[4-[4-[(3R,5R)-5-[(2,4-dimethyl-3,5-dioxo-1,2,4-triazin-6-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]benzamide -1- g, step was imidazole (0.07 g, 0.80 mmol) followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.07 g, 0.24 mmol) and the reaction mixture was stirred at RT for 10 min.
  • N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-4-(piperazin-1- ylmethyl)benzamide (0.08 g, 0.16 mmol, cat. 920754) was added and the reaction mixture was stirred at 80 °C for 12 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Example 57 3-[[4-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]benzamide
  • Step-1 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione Page 432 of 783 11575796v1
  • 2013405-0010 To a mmol) in AcOH (100 mL) were added 3- g, by NaOAc (6.37 g, 77.71 mmol) at RT.
  • Step-2 tert-butyl 3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate
  • Boc anhydride (1.90 mL, 7.92 mmol)
  • DMAP (0.16 g, 1.32 mmol
  • Step-3 tert-butyl 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-carboxylate
  • 1- carboxylate (0.50 g, 1.24 mmol, from step-2) in THF (5 mL) was added 10% Pd/C (0.06 g) at RT.
  • the reaction mixture was stirred in a steel bomb under 50 psi of hydrogen pressure at RT for 3 h.
  • the progress Page 433 of 783 11575796v1 Attorney Docket No.: 2013405-0010 of the reaction was monitored by TLC.
  • Step-4 tert-butyl 3-[4-[[3-(chloromethyl)benzoyl]amino]-1,3-dioxo-isoindolin-2-yl]-2,6-dioxo- piperidine-1-carboxylate [0496] To a dioxo-piperidine- 1-carboxylate g, step- mL, in THF (10 mL) was added 3-(chloromethyl)benzoyl chloride (0.47 g, 2.50 mmol) at 0 °C and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC.
  • Step-5 tert-butyl 4-[[3-[[2-(1-tert-butoxycarbonyl-2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]carbamoyl]phenyl]methyl]piperazine-1-carboxylate amino]-1,3-dioxo- isoindolin-2-yl]-2,6-dioxo-piperidine-1-carboxylate (0.20 g, 0.38 mmol, from step 4) in DMF (3 mL) was added triethylamine (0.16 mL, 1.14 mmol) followed by tert-butyl piperazine-1-carboxylate (0.21 g, 1.14 mmol) at RT.
  • reaction mixture was stirred at 90 °C for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and Page 434 of 783 11575796v1 Attorney Docket No.: 2013405-0010 extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-6 N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-3-(piperazin-1-ylmethyl)benzamide -1,3- g, from step 5) in DCM (2 mL) was added TFA (0.4 mL) at 0 °C. The reaction mixture was 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.
  • Step-7 3-[[4-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4- yl]benzamide -1- methyl-3-piperidyl]benzoic acid (0.10 g, 0.23 mmol, intermediate 1) in DMF (3 mL) was added N-methyl imidazole (0.09 g, 1.05 mmol) followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.09 g, 0.31 mmol).
  • reaction mixture was stirred for 10 min.
  • N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-3-(piperazin-1- Page 435 of 783 11575796v1 Attorney Docket No.: 2013405-0010 ylmethyl)benzamide (0.10 g, 0.21 mmol, from step 6) was added 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.
  • Example 58 4-[[4-[[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]phenyl]methyl]piperazin-1-yl]methyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [0500] yl)amino]-1- methyl-3-piperidyl]benzaldehyde (0.10 g, 0.24 mmol, intermediate 4) in mixture of MeOH (3 mL), acetic acid (2 mL) and DMSO (catalytic) was added 2-(2,6-dioxo-3-piperidyl)-4-(piperazin-1- ylmethyl)isoindoline-1,3-dione (0.10 g, 0.29 mmol, from step 4 of example 52) at RT.
  • reaction mixture was stirred at RT for 4 h.
  • sodium cyanoborohydride (0.03 g, 0.49 mmol) was added 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 diluted with ice- cold water and extracted with ethyl acetate.
  • Example 59 4-[[2-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione
  • Step-1 tert-butyl 6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate [0501] 1,3-dione (0.15 g, step DMF were N,N- ethylamine (0.16 g, 1.20 mmol), NaI (0.01 g, 0.08 mmol) followed by tert
  • Step-2 4-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (0.13 g, 0.27 mmol, from step 1) and TFA (2 mL) in DCM (5 mL) was stirred at 0 °C for 5 min followed by at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-3 4-[[2-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione -1- g, , (0.11 g, 1.30 mmol) was added followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.11 g, 0.40 mmol) and the reaction mixture was stirred at RT for 10 min.
  • Example 60 5-[[2-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione
  • Step-1 tert-butyl 6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate Page 438 of 783 11575796v1 Attorney Docket No.: 2013405-0010 [0504] To a stirred solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carbox
  • reaction mixture was stirred at RT for 3 h.
  • sodium triacetoxyborohydride (0.35 g, 1.67 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h.
  • the progress of the reaction was monitored by TLC.
  • the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude compound.
  • Step-2 5-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione 5- yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.11 g, 0.23 mmol, from step 1) in DCM (3 mL) was added TFA (1.2 mL) and 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.
  • Step-3 5-[[2-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione -1- methyl-3-piperidyl]benzoic acid (0.11 g, 0.27 mmol, intermediate 1) in DMF (2 mL) was added N-methyl Page 439 of 783 11575796v1 Attorney Docket No.: 2013405-0010 imidazole (0.11 g, 0.1.35 mmol) followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.09 g, 0.32 mmol) and the reaction mixture was stirred at
  • Example 61 4-[[4-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl]benzamide
  • Step-1 2-(2,6-dioxo-3-piperidyl)-5-nitro-isoindoline-1,3-dione 103.62 mmol) in AcOH (100 mL) was added 3-aminopiperidine-2,6-dione (17.00 g, 103.62 mmol) at RT.
  • Step-2 tert-butyl 3-(5-nitro-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate 11575796v1 Attorney Docket No.: 2013405-0010 [0508] To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-5-nitro-isoindoline-1,3-dione (8.00 g, 26.40 mmol, from step 1) in 1,4-dioxane (50 mL) was added Boc-anhydride (11.50 g, 52.80 mmol) at RT.
  • Step-3 tert-butyl 3-(5-amino-1,3-dioxo-isoindolin-2-yl)-2,6-dioxo-piperidine-1-carboxylate
  • a dioxo-piperidine- 1-carboxylate (1.00 g, 2.48 mmol, from step 2) in THF (5 mL)
  • 10% Pd/C (0.20 g) was added at RT.
  • the reaction mixture was stirred in steel bomb (50 psi hydrogen gas pressure) 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®.
  • Step-4 tert-butyl 3-[5-[[4-(chloromethyl)benzoyl]amino]-1,3-dioxo-isoindolin-2-yl]-2,6-dioxo- piperidine-1-carboxylate dioxo-piperidine- 1-carboxylate (0.50 g, 1.34 mmol, from step 3) in THF (5 mL) were added 4-(chloromethyl)benzoyl chloride (0.50 g, 2.68 mmol) and pyridine (0.53 mL) and the reaction mixture was stirred at 0 °C for 5 min followed by at RT for 16 h. The progress of the reaction was monitored by TLC.
  • Step-5 tert-butyl 4-[[4-[[2-(1-tert-butoxycarbonyl-2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl]carbamoyl]phenyl]methyl]piperazine-1-carboxylate [0511] To -1,3-dioxo-isoindolin- 2-yl]-2,6-dioxo- g, step- (5 mL) was added tert-butyl piperazine-1-carboxylate (0.16 g, 0.85 mmol) at RT.
  • Step-6 N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-(piperazin-1-ylmethyl)benzamide -1,3- dioxo-isoindolin-5-yl]carbamoyl]phenyl]methyl]piperazine-1-carboxylate (0.07 g, 0.11 mmol, from step 5) in DCM (2 mL) was added 30% TFA in DCM (0.5 mL) and stirred at 0 °C for 5 min followed by at RT for 16 h. The progress of the reaction was monitored by TLC.
  • Step-7 4-[[4-[4-[(3R,5R)-5-[(5-bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3- piperidyl]benzoyl]piperazin-1-yl]methyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl]benzamide [0513] -4-(piperazin- 1- g, was -5-[(5- bromo-1-methyl-6-oxo-pyridazin-4-yl)amino]-1-methyl-3-piperidyl]benzoic acid (0.06 g, 0.13 mmol, intermediate 1) followed by N-methyl imidazole (0.05 g, 0.63 mmol) and the reaction mixture was stirred at RT for 10 min

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Abstract

L'invention concerne des composés phényle hétérocycliques utiles en tant qu'agents de dégradation de KAT2, ainsi que des compositions et des procédés d'utilisation de ceux-ci.
PCT/US2023/031835 2022-09-02 2023-09-01 Dérivés de pyridazinone utilisés comme agents de dégradation de kat2 pour le traitement de troubles prolifératifs WO2024050078A1 (fr)

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Citations (6)

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