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WO2025117886A1 - Modulateurs du complexe ulk et leurs utilisations - Google Patents

Modulateurs du complexe ulk et leurs utilisations Download PDF

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Publication number
WO2025117886A1
WO2025117886A1 PCT/US2024/057958 US2024057958W WO2025117886A1 WO 2025117886 A1 WO2025117886 A1 WO 2025117886A1 US 2024057958 W US2024057958 W US 2024057958W WO 2025117886 A1 WO2025117886 A1 WO 2025117886A1
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optionally substituted
aliphatic
compound
heteroatoms selected
membered
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WO2025117886A8 (fr
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Jian Lin
Jeffrey Owen SAUNDERS
Jorge Garcia FORTANET
Erik Lee MEREDITH
Andrew Thomas Maynard
Brent A. Appleton
Matthew Ryan BROADUS
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Casma Therapeutics Inc
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Casma Therapeutics Inc
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    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • ULK complexes are important parts of the autophagy pathway. Wong, et al. Autophagy, 9(2): 124-137 (Feb. 1, 2013).
  • the autophagy pathway utilizes lysosomal activity to degrade large objects such as molecular aggregates, organelles, and intracellular pathogens.
  • the autophagy process degrades these materials by forming a membrane structure called the “phagophore,” which encapsulates a target of interest and seals into a double-membrane structure called the “autophagosome.”
  • the autophagosome fuses with lysosomes, resulting in degradation of the encapsulated materials and release of metabolic byproducts such as amino acids.
  • the present disclosure provides alternative strategies to achieve targeted degradation.
  • the present disclosure provides an insight that recruitment of a ULK initiation complex can be used to induce selective autophagy, a process by which the degradative mechanism is targeted to specific substrates.
  • ULK initiation complexes include ULK1 and ULK2, where a ULK initation complex comprises FIP200, ATG13, and ATG101. These complexes are important parts of the autophagy pathway. Wong, et al. Autophagy, 9(2): 124-137 (Feb. 1, 2013); Turco, et al., Mol. Cell, 74(2):330- 346.e6 (2019); Hurley JH, et al. Annu Rev Biochem. 2017 Jun 20;86:225-244.
  • Initiation of the autophagy pathway via the ULK initiation complex includes: 1) recognition of cargo (i.e., the target to be degraded), typically by adapter proteins that bind to the target cargo (e.g., to modifications, such as ubiquitin or beta-galactoside, on the cargo); and 2) recruitment of a ULK initiation complex by the cargo adapter proteins.
  • ULK initiation complex is believed to be driven by the interaction of the FIP200 protein with cargo adapter proteins, such as p62 (also known as SQSTM1) which binds to ubiquitinated cargo, or NDP52 (i.e., Nuclear domain 10 protein 52; also known as Calcium Binding and Coiled-Coil Domain 2, or CALCOCO2) which binds to cytosolically exposed beta-galactoside via galectin-8.
  • cargo adapter proteins such as p62 (also known as SQSTM1) which binds to ubiquitinated cargo, or NDP52 (i.e., Nuclear domain 10 protein 52; also known as Calcium Binding and Coiled-Coil Domain 2, or CALCO2) which binds to cytosolically exposed beta-galactoside via galectin-8.
  • ULK initiation complex e.g., a ULK1 initiation complex
  • a ULK1 initiation complex represents a particularly useful and/or effective strategy for achieving selective removal of cellular components via the autophagy pathway.
  • Recent studies have explored interactions involved in selective autophagy mechanisms by, for example, in vitro binding studies and/or genetic modification (e.g., knock out and/or mutagenesis of interacting components).
  • the present disclosure surprisingly demonstrates that small molecule agents can be developed that target the ULK initiation complex and can be used to recruit the complex to cargo, and/or to initiate its assembly thereon.
  • the present disclosure provides ULK initiation complex binding moieties, compounds that comprise them, and various compositions and/or methods relating thereto, including using them to induce targeted autophagy of particular cargo.
  • the present disclosure provides compounds for binding to the ULK initiation complex and a target of interest.
  • the present disclosure provides compounds of formula I: A-B-C I or a pharmaceutically acceptable salt thereof, wherein A is a ULK complex binding moiety; B is a linker; and C is a target binding moiety, wherein the target binding moiety binds or associates with a target selected from the mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A/B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1/2, CISD1, MTARC1, ACSL1, BAK1, BAX, HK1/2, GPAM, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE, VCP, LSS, AIFM2, C18orf32
  • the present disclosure provides moieties and/or compounds useful for binding to the ULK initiation complex.
  • the present disclosure provides compounds of formula II: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , CR 7 , S, NR 7 , S(O), S(O) 2 , C(O), or O;
  • X 2 is N, C, or CR 9 ;
  • X 3 is N, NR 9 , O, CR 9 , C(R 9 ) 2 ;
  • X 4 is N, NR 2 , CR 2 , C(R 2 ) 2 , or C(NR 2 );
  • X 5 is N, NR 3 , CR 3 , C(R 3 ) 2 , or C(O);
  • each R 1 is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S
  • compounds provided herein are useful for treating certain diseases, disorders, and conditions described herein.
  • DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS [0012]
  • the present disclosure provides compounds and compositions useful for modulating a ULK initiation complex (e.g., a ULK1 initiation complex and/or ULK2 initiation complex) for selective autophagy.
  • ULK initiation complex e.g., a ULK1 initiation complex and/or ULK2 initiation complex
  • such compounds include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
  • Definitions [0013] 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.
  • each stereocenter the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • Tables 2A, 3A, and 4A show one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure. [0015] Unless otherwise indicated, 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, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon 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 “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule.
  • an aliphatic group can, in some embodiments, be a bivalent group.
  • aliphatic groups contain 1-12 aliphatic carbon atoms.
  • aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 ).
  • aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 ).
  • aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 ).
  • 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, or alkynyl groups and hybrids thereof.
  • a preferred aliphatic group is C 1-6 alkyl.
  • Alkyl refers to a saturated, optionally substituted straight or branched chain or cyclic 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 (e.g., n-propyl, iso- propyl), butyl (e.g., n-butyl, sec-butyl, iso-butyl, tert-butyl), pentyl, hexyl, and heptyl.
  • Alkylene The term "alkylene” and “alkylenyl” are used interchangeably and refer to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group.
  • an "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system.
  • alkenyl refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group 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.
  • Alkenylene The term “alkenylene” and “alkenylenyl” are used interchangeably and refers to a bivalent alkenyl group. In some embodiments, “alkenylene” is a bivalent straight or branched alkenyl group.
  • Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple 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 ).
  • exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Alkynylene The term “alkynylene” and “alkynylenyl” are used interchangeably and refers to a bivalent alkynyl group. In some embodiments, “alkynylene” is a bivalent straight or branched alkynyl group.
  • Aryl The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C 5-14 ), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C 6-12 ).
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl groups are hydrocarbons.
  • an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl).
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
  • carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • carriers are or include one or more solid components.
  • Cycloaliphatic refers to a monocyclic C 3-8 hydrocarbon or a bicyclic C 7-10 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.
  • Cycloalkyl refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Heteroaliphatic denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight–chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • nitrogen also includes a substituted nitrogen.
  • heteroaliphatic groups contain 1–10 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1–4 carbon atoms, wherein 1–2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1–3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.
  • Heteroaryl refers to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-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.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrol
  • 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, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, benzoisoxazolyl.
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently 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”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic 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, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl, 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.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
  • bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, and .
  • 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)).
  • a bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.
  • Modulator refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein).
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a type of molecule as compared to the magnitude of the activity in the absence of the modulator.
  • a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein.
  • a modulator is an agonist.
  • a modulator is an antagonist.
  • Oral The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
  • parenteral administration and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
  • compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions or vehicles such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in Pharmaceutical Sciences, 66: 1-19 (1977).
  • pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • nontoxic acid addition salts which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate,
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions
  • Polycyclic refers to a saturated or unsaturated ring system having two or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 9 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings.
  • a polycyclic ring system refers to a saturated or unsaturated ring system having three or more rings (for example, heterocyclyl rings, heteroaryl rings, cycloalkyl rings, or aryl rings), having between 14 and 20 atoms, in which one or more carbon atoms are common to two adjacent rings.
  • the rings in a polycyclic ring system may be fused (i.e., bicyclic or tricyclic), spirocyclic, or a combination thereof.
  • Prevent or prevention when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • Substituted or optionally substituted As described herein, compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least ; and refers to at least Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each 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 ) 0–
  • 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 5- 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, unsubstituted –OPh, 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,
  • 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.
  • Small molecule means a low molecular weight organic and/or inorganic compound.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.
  • a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD.
  • the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D.
  • a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer.
  • a small molecule does not include a polymeric moiety.
  • a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide).
  • a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc ). In some embodiments, a small molecule is not a lipid.
  • a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent).
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety).
  • a small molecule is a therapeutic agent.
  • small molecule compounds have structures that can exist in one or more steroi someric forms.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
  • certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accoradance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.
  • certain small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H for H; 11 C, 13 C or 14 C for 12 C; 13 N or 15 N for 14 N; 17 O or 18 O for 16 O; 36 Cl for 35 Cl or 37 Cl; 18 F for 19 F; 131 I for 127 I; etc.).
  • such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
  • a small molecule compound is one that exists or is found in nature
  • that compound may be provided and/or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature.
  • a reference preparation of interest e.g., in a primary sample from a source of interest such as a biological or environmental source
  • a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
  • a bond designated as in a small molecule structure refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond.
  • the following structure is intended to encompass both .
  • the symbol and , as used herein refers to a point of attachment between two atoms.
  • Treat As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • the present disclosure provides compounds for binding a ULK initiation complex (e.g., a ULK1 initiation complex or a ULK2 initiation complex).
  • a ULK initiation complex e.g., a ULK1 initiation complex or a ULK2 initiation complex.
  • such compounds comprise a targeting moiety for binding a target, thereby promoting autophagy of said target.
  • ULK binding is determined described according to methods described herein, for example in Example 52.
  • a compound for binding a ULK initiation complex and a target is a compound of formula I: A-B-C I or a pharmaceutically acceptable salt thereof, wherein A is a ULK complex binding moiety; B is a linker; and C is a target binding moiety, wherein the target binding moiety binds or associates with a target selected from the mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A/B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1/2, CISD1, MTARC1, ACSL1, BAK1, BAX, HK1/2, GPAM, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE
  • a ULK complex binding moiety (i.e., moiety A) is a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , CR 7 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is N, C, or CR 9 ; X 3 is N, NR 9 , O, CR 9 , C(R 9 ) 2 ; X 4 is N, NR 2 , CR 2 , C(R 2 ) 2 , or C(NR 2 ); X 5 is N, NR 3 , CR 3 , C(R 3 ) 2 , or C(O); each R 1 is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -
  • a compound of formula II is, in some embodiments, a moiety A (as part of formula I), and where one of variable R 4 or R 5 is replaced with variable B to thereby attach to the rest of the compound of formula I.
  • X 1 is C(R 7 ) 2 , CR 7 , S, NR 7 , S(O), S(O) 2 , C(O), or O.
  • X 1 is C(R 7 ) 2 , S, or NR 7 . In some embodiments, X 1 is S or C(R 7 ) 2 . In some embodiments, X 1 is S. In some embodiments, X 1 is C(R 7 ) 2 . In some embodiments, X 1 is CH 2 . In some embodiments, X 1 is CH(CH 3 ). In some embodiments, X 1 is: [0067] In some embodiments, X 1 is NR 7 . In some embodiments, X 1 is NH. In some embodiments, X 1 is N(CH 3 ). In some embodiments, X 1 is S(O). In some embodiments, X 1 is S(O) 2 .
  • X 1 is C(O). In some embodiments, X 1 is O.
  • X 2 is N, C, or CR 9 . In some embodiments, X 2 is N or CR 9 . In some embodiments, X 2 is N. In some embodiments, X 2 is C (e.g., when a bond between X 1 and X 2 is a double bond). In some embodiments, X 2 is CR 9 . In some embodiments, X 2 is CR 9 , and R 9 is H, halo, or C 1 -C 6 aliphatic. In some embodiments, X 2 is CH or C(CH 3 ).
  • a bond between X 1 and X 2 is a single bond, and X 1 is C(R 7 ) 2 , S, NR 7 , S(O), S(O) 2 , C(O), or O, and X 2 is N or CR 9 .
  • a bond between X 1 and X 2 is a single bond, and X 1 is C(R 3 ) 2 , S, or NR 7 , and X 2 is N or CR 9 .
  • a bond between X 1 and X 2 is a single bond, and X 1 is C(R 7 ) 2 , S, or NR 7 , and X 2 is N or CR 9 , and R 9 is H, halo, or C 1- C 6 aliphatic.
  • a bond between X 1 and X 2 is a single bond, and X 1 is C(R 3 ) 2 , S, or NR 7 , and X 2 is N or CR 9 , and R 9 is H, halo, or CH 3 .
  • a bond between X 1 and X 2 is a single bond, and X 1 is C(R 7 ) 2 , S, or NR 7 , and X 2 is N or CH.
  • a bond between X 1 and X 2 is a double bond, and X 1 is CR 7 , and X 2 is C.
  • X 3 is N, NR 9 , O, CR 9 , C(R 9 ) 2 .
  • X 3 is N or CR 9 .
  • X 3 is N.
  • X 3 is NR 9 .
  • X 3 is O.
  • X 3 is CR 9 . In some embodiments, X 3 is CR 9 , where R 9 is H or halo. In some embodiments, X 3 is CH. In some embodiments, X 3 is C(R 9 ) 2 . [0072] As defined generally herein, X 4 is N, NR 2 , CR 2 , C(R 2 ) 2 , or C(NR 2 ). In some embodiments, when a bond between X 4 and X 5 is a single bond, X 4 is N(R 2 ), C(R 2 ) 2 , or C(NR 2 ). In some embodiments, X 4 is NR 2 or C(R 2 ) 2 .
  • X 4 is NR 2 or C(R 2 ) 2 , where each R 2 is independently selected from H, optionally substituted C 1 -C 6 aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X 4 is NR 2 . In some embodiments, X 4 is NR 2 , where R 2 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X 4 is NR 2 , where R 2 is optionally substituted C 1 -C 6 aliphatic. [0073] In some embodiments, X 4 is C(R 2 ) 2 .
  • X 4 is C(R 2 ) 2 , where each R 2 is independently selected from H, optionally substituted C 1 -C 6 aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic. [0074] In some embodiments, X 4 is C(NR 2 ). [0075] In some embodiments, when a bond between X 4 and X 5 is a double bond, X 4 is N or CR 2 . In some embodiments, X 4 is N. In some embodiments, X 4 is CR 2 . In some embodiments, X 4 is CR 2 . In some embodiments, X 4 is CR 2 , and R 2 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6- membered heteroaliphatic.
  • X 5 is N, NR 3 , CR 3 , C(R 3 ) 2 , or C(O). In some embodiments, when a bond between X 4 and X 5 is a single bond, X 5 is NR 3 , C(R 3 ) 2 or C(O). In some embodiments, X 5 is NR 3 . In some embodiments, X 5 is C(O). In some embodiments, X 5 is C(R 3 ) 2 . [0077] In some embodiments, when a bond between X 4 and X 5 is a double bond, X 5 is N or CR 3 . In some embodiments, X 5 is N. In some embodiments, X 5 is CR 3 .
  • each R 1 is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C 12 aryl, wherein each R 1 is optionally substituted with one or more R 1a .
  • R 1 is 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O.
  • R 1 is 4- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is 4-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is thiophenyl, pyridinyl, pyrazolyl, or imidazolyl, optionally substituted with one or more R 1a .
  • R 1 is 8- to 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is 8-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is 9-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is 10-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a . In some embodiments, R 1 is 11-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a . In some embodiments, R 1 is 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R 1a .
  • R 1 is pyrrolopyridinyl, benzimidazolyl, imidazopyridinyl, indolyl, or benzoxazolyl, optionally substituted with one or more R 1a .
  • R 1 is a 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 4- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 4-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 5-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 6- to 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 9- to 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 9- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 10- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 11- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is a 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • R 1 is C 6 -C 12 aryl, optionally substituted with one or more R1a.
  • R 1 is phenyl, optionally substituted with one or more R 1a . In some embodiments, R 1 is naphthyl optionally substituted with one or more R 1a . [0083] In some embodiments, two R 1 are taken together with the atoms to which they are attached to form a 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, C 5 - C 12 aryl, or C 3 -C 12 cycloaliphatic, each optionally substituted with one or more R 1a .
  • two R 1 can be taken together with the atoms to which they are attached to form a 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 4- to 6- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 4- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 5- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 5- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 9- to 12- membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 9-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 10-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 11-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 4- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 4-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 5-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 8- to 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 8-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 9-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 10-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 11-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a 12-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a C 5 -C 12 aryl, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a phenyl ring, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a naphthyl ring, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a C 3 -C 12 cycloaliphatic, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a monocylic C 3 -C 7 cycloaliphatic, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, optionally substituted with one or more R 1a .
  • two R 1 are taken together with the atoms to which they are attached to form a bicyclic C 8 -C 12 cycloaliphatic, optionally substituted with one or more R 1a .
  • each R 1a is independently halogen, -OH, -CN, -N(R 9 ) 2 , - NH-S(O) 2 -R 7 , -NH-C(O)-NHR 7 , -NHC(O)-OR 7 , -C(O)-NH 2 , oxo, Z, or an optionally substituted group selected from C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3 -C 12 cycloaliphatic, 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 1a is halogen. In some embodiments, R 1a is fluoro, chloro, bromo, or iodo. In some embodiments, R 1a is fluoro. In some embodiments, R 1a is chloro. In some embodiments, R 1a is bromo. In some embodiments, R 1a is iodo. [0092] In some embodiments, R 1a is –OH. [0093] In some embodiments, R 1a is –CN. [0094] In some embodiments, R 1a is -NHC(O)-OR 7 . In some embodiments, R 1a is -NHC(O)- O(C 1 -C 6 aliphatic).
  • R 1a is -NHC(O)-OC(CH 3 ) 3 .
  • R 1a is -N(R 9 ) 2 .
  • R 1a is –NH 2 .
  • R 1a is –NH(R 9 ).
  • R 1a is –NH(C 1 -C 6 aliphatic).
  • R 1a is -NH-S(O) 2 -R 7 .
  • R 1a is -NH-S(O) 2 - C 1 -C 6 aliphatic.
  • R 1a is -NH-S(O) 2 -CH 3 .
  • R 1a is - NH-S(O) 2 -CH 2 -CH 3 .
  • R 1a is -NH-C(O)-NHR 7 .
  • R 1a is -NH- C(O)-NH 2 .
  • R 1a is -NH-C(O)-NHCH 3 .
  • R 1a is -C(O)-NH 2 .
  • R 1a is oxo.
  • R 1a is Z.
  • R 1a is an optionally substituted group selected from C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3 -C 12 cycloaliphatic, 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 1a is an optionally substituted C 1 -C 12 aliphatic.
  • R 1a is C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0–4 R° or –(CH 2 ) 0–4 OR°. In some embodiments, R 1a is C 1 -C 12 aliphatic optionally substituted with R° or OR°, where R° is halo, C 1 -C 6 aliphatic, or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where R° is optionally substituted with C 1 -C 6 aliphatic or halo. In some embodiments, R 1a is methyl, ethyl, propyl, or butyl.
  • R 1a is optionally substituted -O-C 1 -C 12 aliphatic. In some embodiments, R 1a is O-C 1 -C 12 aliphatic optionally substituted with R°. In some embodiments, R 1a is -O-CH 3 . [0104] In some embodiments, R 1a is optionally substituted C 3 -C 12 cycloaliphatic. [0105] In some embodiments, R 1a is optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 1a is optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R 1a is optionally substituted pyrrolidinyl. In some embodiments, R 1a is pyrrolidinyl. [0106] In some embodiments, R 1a is optionally substituted 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O. [0107] In some embodiments, R 1a is optionally substituted C 6 -C 12 aryl. In some embodiments, R 1a is phenyl.
  • each R 1a is independently selected from -Br, -Cl, -F, -CH 3 , - CH 2 -CH 3 , -OCH 3 , -CN, -CF 3 , -OH, -NH 2 , .
  • n is 0, 1, or 2.
  • n is 0.
  • n is 1.
  • n is 2.
  • R 1 is substituted with m instances of R 1a , e.g., (R 1a ) m , wherein m is 0, 1, 2, 3, 4, 5, or 6.
  • R 1 is substituted with 0, 1, 2, 3, 4, 5, or 6 instances of R 1a , e.g., R 1 is substituted with (R 1a ) m , wherein m is 0, 1, 2, 3, 4, 5, or 6.
  • m is 0.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • n is 1, and R 1 is selected from [0112]
  • n is 2, and two R 1 come together to form:
  • each R 2 is independently hydrogen, halogen, or an optionally substituted group selected from C 1 -C 6 aliphatic, -O-C 1 -C 6 aliphatic, C 3 -C 6 cycloaliphatic, 2- to 6-membered heteroaliphatic, C 6 -C 12 aryl, 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, and 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2 is H or optionally substituted C 1 -C 6 aliphatic.
  • R 2 is H.
  • R 2 is optionally substituted C 1 -C 6 aliphatic.
  • R 2 is C 1 -C 6 aliphatic substituted with –(CH 2 ) 0–4 R° or –(CH 2 ) 0–4 OR°.
  • R 2 is C 1 -C 6 aliphatic substituted with halo, OH, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2 is methyl, ethyl, propyl, butyl, pentyl or hexyl.
  • R 2 is ethyl. In some embodiments, R 2 is -CF 3 . In some embodiments, R 2 is ethyl substituted with halo. [0116] In some embodiments, R 2 is optionally substituted -O-C 1 -C 6 aliphatic. In some embodiments, R 2 is –O-CH 3 or –O-CH 2 -CH 3 . [0117] In some embodiments, R 2 is optionally substituted C 3 -C 6 cycloaliphatic. In some embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, R 2 is –CH 2 -CH 2 -O-CH 2 -CH 2 -O-R°. [0119] In some embodiments, R 2 is optionally substituted C 6 -C 12 aryl. In some embodiments, R 2 is phenyl. [0120] In some embodiments, R 2 is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O. [0121] In some embodiments, R 2 is optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2 is optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2 is H, Cl, -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -F, -CH 2 CHF 2 , - CH 2 CF 3 , -O-CH 3 , -CF 3 , -O-CH 2 -CH 3 , -CH 2 -CH 2 -OH, or –CH 2 -CH 2 -NH 2 .
  • each R 3 is independently selected from -H, -OH, -N(R 7 ) 2 , halogen, CN, C 1 -C 6 aliphatic, and C 3 -C 6 cycloaliphatic.
  • R 3 is H.
  • R 3 is OH.
  • R 3 is halogen.
  • R 3 is CN.
  • R 3 is -N(R 7 ) 2 .
  • R 3 is –NH 2 .
  • R 3 is –NH(C 1 -C 6 aliphatic).
  • R 3 is –N(C 1 -C 6 aliphatic) 2 .
  • R 3 is C 1 -C 6 aliphatic.
  • R 3 is methyl, ethyl, propyl, butyl, or hexyl.
  • R 3 is C 3 -C 6 cycloaliphatic.
  • R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • two R 3 are taken together with the atom to which they are attached to form a C 3 -C 6 spirocycloalkyl.
  • R 3 are taken together to form a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, or spirocyclohexyl.
  • R 2 and R 3 are taken together, with the atoms to which they attach, to form a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2 and R 3 are taken together to form: [0128]
  • R 4 is hydrogen, or an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4 is hydrogen, or a group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R 4 is optionally substituted with Z.
  • R 4 is hydrogen or an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4 is an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4 is hydrogen.
  • R 4 is optionally substituted C 1 -C 12 aliphatic.
  • R 4 is optionally substituted C 1 -C 12 alkyl.
  • R 4 is C 1 -C 12 alkyl optionally substituted with –(CH 2 ) 0–4 R° or –(CH 2 ) 0–4 OR°. In some embodiments, R 4 is C 1 -C 12 alkyl substituted with –OH or O(C 1 -C 6 aliphatic). [0134] In some embodiments, R 4 is optionally substituted 2- to 12-membered heteroaliphatic. [0135] In some embodiments, R 4 is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments, R 4 is optionally substituted monocyclic C 3 -C 6 cycloaliphatic.
  • R 4 is optionally substituted monocyclic C 3 -C 6 cycloalkyl. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. [0136] In some embodiments, R 4 is optionally substituted C 6 -C 12 aryl. In some embodiments, R 4 is optionally substituted phenyl. [0137] In some embodiments, R 4 is optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4 is optionally substituted 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted 5- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4 is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH 2 ) 0–4 R°, –(CH 2 ) 0– 4 OR° or –(CH 2 ) 0–4 C(O)R°.
  • R 4 is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –R°, –(CH 2 ) 1–4 OR° or C(O)R°.
  • R 4 is tetrahydropyranyl or piperidinyl optionally substituted with C(O)R°.
  • R 4 is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted imidazolyl. In some embodiments, R 4 is imidazolyl substituted with R°.
  • R 4 is optionally substituted with –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, - O(CH 2 ) 0-4 R°, –(CH 2 ) 0–4 NR°C(O)R°, or –(CH 2 ) 0–4 C(O)R°.
  • R 4 is optionally substituted with Z.
  • a bond between X 2 and R 4 is in an (R) stereochemical configuration.
  • a bond between X 2 and R 4 is in an (S) stereochemical configuration.
  • R 4 is -H, -CH 3 , -CH 2 -CH 3 ,
  • R 5 is–C(O)-R 6 , -C(O)N(R 6 )(R 7 ), -N(R 7 )C(O)-R 6 , -S(O) 2 - R 6 , -S(O) 2 N(R 6 )(R 7 ), -OC(O)-R 6 , -C(O)OR 6 , -C(NH)N(R 6 )(R 7 ), optionally substituted C 1 -C 12 aliphatic-R 6 , or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 5 is –C(O)-R 6 .
  • R 5 is -C(O)N(R 6 )(R 7 ).
  • R 5 is - C(O)NH(R 7 ).
  • R 5 is -C(O)NH(R 6 ).
  • R 5 is -N(R 7 )C(O)-R 6 .
  • R 5 is -NHC(O)- R 6 .
  • R 5 is -S(O) 2 -R 6 .
  • R 5 is -S(O) 2 N(R 6 )(R 7 ). In some embodiments, R 5 is - S(O) 2 NH(R 6 ). [0148] In some embodiments, R 5 is -OC(O)-R 6 . [0149] In some embodiments, R 5 is -C(O)OR 6 . [0150] In some embodiments, R 5 is -C(NH)N(R 6 )(R 7 ). In some embodiments, R 5 is - C(NH)NH(R 6 ). [0151] In some embodiments, R 5 is optionally substituted C 1 -C 12 aliphatic-R 6 .
  • R 5 is –CH 2 -R 6 .
  • R 5 is optionally substituted 5- to 6-membered heteroaryl.
  • R 5 is oxadiazolyl or imidazolyl.
  • R 6 is Z, -OH, -N(R 7 ) 2 , -S(O) 2 -R 8 , C 3 -C 12 cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, each optionally substituted with one or more R 8 .
  • R 6 is Z.
  • R 6 is –OH.
  • R 6 is –N(R 7 ) 2 . In some embodiments, R 6 is –NHR 7 . In some embodiments, R 6 is NH 2 . In some embodiments, R 6 is –N(C 1 -C 6 aliphatic), wherein C 1 -C 6 aliphatic is optionally substituted with R 8 . In some embodiments, R 6 is –N(C 1 -C 6 aliphatic), wherein C 1 -C 6 aliphatic is optionally substituted with Z. In some embodiments, R 6 is –N(CH 3 ). [0157] In some embodiments, R 6 is -S(O) 2 -R 8 .
  • R 6 is C 3 -C 12 cycloaliphatic optionally substituted with one or more R 8 . In some embodiments, R 6 is C 3 -C 6 cycloaliphatic optionally substituted with one or more R 8 . In some embodiments, R 6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more R 8 . [0159] In some embodiments, R 6 is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 3- to 7-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8 .
  • R 6 is a 3-membered monocyclic heterocyclic having 1 heteroatom selected from N, S, and O, optionally substituted with one or more R 8 .
  • R 6 is a 4-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8 .
  • R 6 is a 5-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8 .
  • R 6 is a 6- membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8 .
  • R 6 is a 7-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8 .
  • R 6 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, optionally substituted with one or more R 8 .
  • R 6 is 6- to 12-membered bicyclic (e.g., fused bicyclic or spirocyclic) heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 6-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 7-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 8-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 9-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 10-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 11-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • R 6 is 12-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • each R 7 is independently selected from H, optionally substituted C 1 -C 12 aliphatic, optionally substituted C 3 -C 12 cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C 6 -C 12 aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 7 is H.
  • R 7 is optionally substituted C 1 -C 12 aliphatic.
  • R 7 is optionally substituted C 1 -C 12 alkyl.
  • R 7 is optionally substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 7 is C 1 -C 12 aliphatic optionally substituted with one or more –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, or –(CH 2 ) 0– 4 C(O)OR°.
  • R 7 is C 1 -C 12 aliphatic optionally substituted with one or more of halogen, –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, –(CH 2 ) 0–4 C(O)NR°2, or –(CH 2 ) 0–4 C(O)OR°, where R° is H, C 1–6 aliphatic, or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and R° is optionally substituted with –(CH 2 ) 0–2 R ⁇ or –(CH 2 ) 0–2 OH, where R ⁇ is a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 7 is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments, R 7 is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. [0165] In some embodiments, R 7 is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R 7 is 2- to 9- membered heteroaliphatic comprising one or more oxygen atoms.
  • R 7 is –(CH 2 CH 2 O) 2 CH 2 CH 2 OH, –CH 2 CH 2 OCH 2 CH 2 CH 2 OH, - CH 2 CH 2 CH 2 N(CH 3 )CH 2 C ⁇ CH. [0166] In some embodiments, R 7 is optionally substituted C 6 -C 12 aryl. In some embodiments, R 7 is optionally substituted phenyl. [0167] In some embodiments, R 7 is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 7 is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.
  • R 7 and R 2 can be taken together, with the atoms to which they attach, to form a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • each R 8 is independently -OH, -NH 2 , Z, or an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, -O-C 1 -C 12 aliphatic, -NH-C(O)-C 1 -C 12 aliphatic, -C(O)-NH-C 1 -C 12 aliphatic, -C(O)-N(C 1 -C 12 aliphatic) 2 , - C(O)O-C 1 -C 12 aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 8 is –OH. [0171] In some embodiments, R 8 is NH 2 . [0172] In some embodiments, R 8 is Z. [0173] In some embodiments, R 8 is optionally substituted C 1 -C 12 aliphatic.
  • R 8 is C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, – (CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 C(O)N(R°) 2 , –(CH 2 ) 0–4 N(R°)C(O)R°, or –(CH 2 ) 0–4 N(R°)C(O)OR°.
  • R 8 is C 1 -C 12 aliphatic optionally substituted with –OH, -NH 2 , -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic) 2 , -NHC(O)(C 1 -C 6 aliphatic), -C(O)NH(C 1 -C 6 aliphatic), or 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 8 is -CH2OH, -CH2CH2C ⁇ CH, -CH2-C ⁇ CH, -C ⁇ CH, .
  • R 8 is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R 8 2- to 9- membered heteroaliphatic comprising one or more oxygen atoms. In some embodiments, R 8 is –(CH 2 CH 2 O) 2 CH 2 CH 2 OH or –CH 2 CH 2 OCH 2 CH 2 CH 2 OH. [0175] In some embodiments, R 8 is optionally substituted -O-C 1 -C 12 aliphatic. In some embodiments, R 8 is optionally substituted –O-C 1 -C 12 alkyl. [0176] In some embodiments, R 8 is optionally substituted -NH-C(O)-C 1 -C 12 aliphatic.
  • R 8 is -NH-C(O)-C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0– 4 N(R°)C(O)R°, –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0177] In some embodiments, R 8 is optionally substituted -C(O)-NH-C 1 -C 12 aliphatic.
  • R 8 is -C(O)-NH-C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0– 4 N(R°)C(O)R°, –(CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0178] In some embodiments, R 8 is optionally substituted -C(O)-N(C 1 -C 12 aliphatic) 2 .
  • R 8 is -C(O)-N(C 1 -C 12 aliphatic) 2 optionally substituted with –(CH 2 ) 0– 4 N(R°)C(O)R°, –(CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0179] In some embodiments, R 8 is optionally substituted -C(O)O-C 1 -C 12 aliphatic.
  • R 8 is -C(O)O-C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0–4 N(R°)C(O)R°, – (CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0180] In some embodiments, R 8 is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 8 is 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 N(R°) 2 , or –(CH 2 ) 0–4 C(O)R°.
  • each R 9 is independently selected from H, halo, OH, and optionally substituted C 1 -C 12 aliphatic.
  • R 9 is H.
  • R 9 is halo (e.g., bromo, chloro, iodo, fluoro).
  • R 9 is OH.
  • R 9 is optionally substituted C 1 -C 12 aliphatic. In some embodiments, R 9 is C 1 -C 12 alkyl. In some embodiments, R 9 is methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl.
  • Z is an optionally substituted C 2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NR Z -, -N(R Z )C(O)-, - C(O)N(R Z )-, -N(R Z )C(O)O-, -OC(O)N(R Z )-, -N(R Z )C(O)N(R Z ) -, -OC(O)O-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -SO-, -SO 2 -, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C 3 -C 6 cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having
  • each R Z is independently H, C 1 -C 6 aliphatic, or C 3 -C 12 cycloaliphatic. In some embodiments, R Z is H. In some embodiments, R Z is C 1 -C 6 aliphatic. In some embodiments, R Z is C 3 -C 12 cycloaliphatic. [0184] In some embodiments, R 5 is:
  • the present disclosure provides a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein X 1 is S or NR 7 ; X 2 is CR 9 ; X 3 is N or CR 9 ; X 4 is N, NR 2 , CR 2 , C(R 2 ) 2 , or C(NR 2 ); X 5 is NR 3 , C(R 3 ) 2 , or C(O); a bond between X 1 and X 2 is a single bond; a bond between X 4 and X 5 is a single bond; n is 2; two R 1 can be taken together with the atoms to which they are attached to form a 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, C 5 -C 12 aryl, or C 3 -C 12 cycloaliphatic, each
  • a compound of formula II is a compound of formula IIa: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1a , R 4 and R 5 are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of formula IIa or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is CR 9 ; X 3 is N or CR 9 ; X 4 is NR 2 , C(R 2 ) 2 , or C(NR 2 ); X 5 is C(R 3 ) 2 or C(O); each R 1a is independently halogen, -OH, -CN, -N(R 9 ) 2 , -NH-S(O) 2 -R 7 , -NH-C(O)-NHR 7 , -NHC(O)-OR 7 , -C(O)-NH 2 , oxo, Z, or an optionally substituted group selected from, C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3
  • a compound of formula II is a compound of formula IIa-1: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , R 1a , R 4 and R 5 are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound of formula IIa-1: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is CR 9 ; each R 1a is independently halogen, -OH, -CN, -N(R 9 ) 2 , -NH-S(O) 2 -R 7 , -NH-C(O)-NHR 7 , -NHC(O)-OR 7 , -C(O)-NH 2 , oxo, Z, or an optionally substituted group selected from, C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, and 5- to
  • a compound of formula II is a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1a , R 4 and R 5 are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, 4, 5, or 6.
  • the present disclosure provides a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is CR 9 ; X 3 is N or CR 9 ; X 4 is NR 2 , C(R 2 ) 2 , or C(NR 2 ); X 5 is C(R 3 ) 2 or C(O); each R 1a is independently halogen, -OH, -CN, -N(R 9 ) 2 , -NH-S(O) 2 -R 7 , -NH-C(O)-NHR 7 , -NHC(O)-OR 7 , -C(O)-NH 2 , oxo, Z, or an optionally substituted group selected from, C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3
  • a compound of formula II is a compound of formula IIIa: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , R 1a , R 2 , R 4 , R 5 are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, 4, 5, or 6.
  • the present disclosure provides a compound of formula IIIa: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is CR 9 ; each R 1a is independently halogen, -OH, -CN, -N(R 9 ) 2 , -NH-S(O) 2 -R 7 , -NH-C(O)-NHR 7 , -NHC(O)-OR 7 , -C(O)-NH 2 , oxo, Z, or an optionally substituted group selected from, C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, and 5- to 12-
  • a compound of formula II is a compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , R 1 , R 3 , R 4 , and R 5 are as defined in classes and subclasses herein, both singly, and in combination.
  • the present disclosure provides a compound of formula IVa: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is N or CR 9 ; X 3 is N or CR 9 ; X 4 is NR 2 , N, CR 2 , C(R 2 ) 2 , or C(NR 2 ); R 1 is selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C 12 aryl, wherein each R 1 is optionally substituted with one or more R 1a ; each R 1a is independently halogen, -OH, -CN, -N(R 9 ) 2 , -NH-S(O) 2 -R 7 , -
  • a compound of formula II is a compound of formula IVb: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 5 , R 1 , R 2 , R 4 , and R 5 are as defined in classes and subclasses herein, both singly, and in combination.
  • the present disclosure provides a compound of formula IVb: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is N or CR 9 ; X 3 is N or CR 9 ; X 5 is N, CR 3 , C(R 3 ) 2 , or C(O); R 1 is selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C 12 aryl, wherein each R 1 is optionally substituted with one or more R 1a ; each R 1a is independently halogen, -OH, -CN, -N(R 9 ) 2 , -NH-S(O) 2 -R 7 , -NH-C(O)-
  • a compound of formula II is a compound of formula V: or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 4 , R 5 , and n are as defined in classes and subclasses herein, both singly, and in combination.
  • a ULK complex binding moiety (i.e., moiety A) is a compound of formula V: or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 7 ) 2 , CR 7 , S, NR 7 , S(O), S(O) 2 , C(O), or O; X 2 is N, C, or CR 9 ; X 3 is N, NR 9 , CR 9 , or C(R 9 ) 2 ; X 4 is N, NR 2 , CR 2 , C(R 2 ) 2 , or C(NR 2 ); X 5 is N, NR 3 , CR 3 , C(R 3 ) 2 , or C(O); each R 1 is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C
  • the present disclosure provides compounds of formula I, A-B-C I or a pharmaceutically acceptable salt thereof, wherein A is a ULK complex binding moiety; B is a linker; and C is a target binding moiety, wherein the target binding moiety binds or associates with a target selected from the mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A/B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1/2, CISD1, MTARC1, ACSL1, BAK1, BAX, HK1/2, GPAM, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE, VCP, LSS, AIFM2, C
  • A is a compound of formula II, wherein variables R 4 or R 5 is replaced with -B-C (i.e., wherein R 4 or R 5 are the positions that connect moiety A to the rest of the compound of formula I), and the remaining variables of formula II are as defined in classes and subclasses herein, both singly and in combination.
  • B is a linker moiety. That is, B is a bivalent moiety covalently bonded to moiety A and moiety C.
  • B is Z, wherein Z is an optionally substituted C 2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NR Z -, -N(R Z )C(O)-, -C(O)N(R Z )-, -N(R Z )C(O)O-, - OC(O)N(R Z )-, -N(R Z )C(O)N(R Z ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO 2 -, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C 3 -C 6 cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having
  • C is a target binding moiety, wherein the target binding moiety binds or associates with a target selected from the mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A/B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1/2, CISD1, MTARC1, ACSL1, BAK1, BAX, HK1/2, GPAM, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE, VCP, LSS, AIFM2, C18orf32, RAB1B, RAB5A, a peroxisome, a myddosome, MYD88
  • C is a moiety that binds or associates with mitochondria.
  • C is a moiety that binds or associates with mitochrondria as described in WO 2008/074692, WO 2008/145596, WO 2013/071169, Griffith, et al., J. Med. Chem., 57:10512-10526 (2014), Madauss, et al., Acta Cryst., D65:449-461 (2009), Yamashita, et al., Bioorganic & Med. Chem.
  • C is a moiety that binds or associates with a bacterium.
  • C is a moiety that binds or associates with a lipid droplet.
  • C is a moiety that binds or associates with a peroxisome.
  • C is a moiety that binds or associates with COP9. [0210] In some embodiments, C is a moiety that binds or associates with MYC. [0211] In some embodiments, C is a moiety that binds or associates with a myddosome. In some embodiments, C is a moiety that binds or associates with a myddosome, as described in WO 2019/099926, WO 2019/133531, WO 2019/160915, WO 2015/103453, Nunes, et al., Med. Chem. Lett., 10:1081-1085 (2019), Zhang, et al., Cell Chem.
  • C is a moiety that binds or associates with a myddosome, and is a compound, or derived from a compound, of the following structure: [0213] In some embodiments, C is a moiety that binds or associates with myddosome, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I:
  • C is a moiety that binds or associates with inflammasome. In some embodiments, C is a moiety that binds or associates with NLRP3 inflammasome. In some embodiments, C is a moiety that binds or associates with NLRP3 inflammasome as described in WO 2019/092170, which is incorporated herein by reference in its entirety.
  • C is a moiety that binds or associates with NLRP3 inflammasome
  • C is a moiety that binds or associates with NLRP3 inflammasome, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I: [0217]
  • C is a moiety that binds or associates with EGFR.
  • C is a moiety that binds or associates with EGFR as described in Burslem et al., Cell Chemical Biology, 25: 67–77 (2016), which is incorporated herein by reference in its entirety.
  • C is a moiety that binds or associates with EGFR, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I: [0218] In some embodiments, C is a moiety that binds or associates with KRAS. [0219] In some embodiments, C is a moiety that binds or associates with ⁇ -synuclein.
  • C is a moiety that binds or associates with ⁇ -synuclein as described in WO 2020/041331, Josephson, et al., Molecular Imaging, 17:1-6 (2016), and Hsieh, et al., [0220]
  • C is a moiety that binds or associates with tau.
  • C is a moiety that binds or associates with tau, as described in WO 2021/011913, Walji, et al., J. Med. Chem., 59:4778-4789 (2016), Kroth, et al., E. J. of Nuclear Med. And Mol.
  • C is a moiety that binds or associates with tau and is a compound, or derived from a compound, of the following structure: [0222] In some embodiments, C is a moiety that binds or associates with tau, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I:
  • C is a moiety that binds or associates with estrogen receptor alpha (ER- ⁇ ).
  • C is a moiety that binds or associates with an androgen receptor (AR).
  • AR androgen receptor
  • C is a moiety that binds or associates with AR as described in Scott, et al., ACS Med. Chem. Lett., 11:1539-1547 (2020).
  • C is a moiety that binds or associates with tau, and is represented by the structure below, where represents a point of attachment between moiety C and a compound of formula I: [0225]
  • C is a moiety that binds or associates with acetyl coenzyme A2 (ACC2).
  • ACC2 acetyl coenzyme A2
  • C is a moiety that binds or associates with ACC2 as described in W02013/07169 and Yamashita, et al., Bioorganic & Med. Chem. Lett., 21 (21 ):6314-6318 (2011), each of which is incorporated herein by reference in its entirety.
  • C is a moiety that binds or associates with ACC2, and is a compound, or derived from a compound, of the following structure:
  • C is a moiety that binds or associates with ACC2, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I:
  • C is a moiety that binds or associates with kynurenine 3- monooxygenase (KMO). In some embodiments, C is a moiety that binds or associates with KMO as described in Walker, et al., J. Med. Chem., 60(8):3383-3404 (2017). In some embodiments, C is a moiety that binds or associates with KMO and is a compound, or derived from a compound, of the following structure:
  • C is a moiety that binds or associates with KMO, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I: [0230] In some embodiments, C is a moiety that binds or associates with KSR1. [0231] In some embodiments, C is a moiety that binds or associates with IAPP. In some embodiments, C is a moiety that binds or associates with IAPP as described in Templin, et al., Diabetologia, 61(10):2215-2224 (2016).
  • C is a moiety that binds or associates with IAPP, and is a compound, or derived from a compound, of the following structure: [0232] In some embodiments, C is a moiety that binds or associates with IAPP, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I: [0233] In some embodiments, C is a moiety that binds or associates with IRAK1/2/4. In some embodiments, C is a moiety that binds or associates with IRAK4.
  • C is a moiety that binds or associates with IRAK4, as described in WO 2019/099926, WO 2019/133531, WO 2019/160915, WO 2015/103453, Nunes, et al., Med. Chem. Lett., 10:1081-1085 (2019), Zhang, et al., Cell Chem. Biol., 27:1-10 (2020), McElroy, Expert Opinion on Therapeutic Patents, 29(4):243-259 (2019), Genung and Guckian, Progress in Med. Chem., 56:117-163 (2017), Seganish, Expert Opinion on Therapeutic Patents, 26(8):917-932 (2016), Chen, et al., J. Med.
  • C is a moiety that binds or associates with TSPO. In some embodiments, C is a moiety that binds or associates with TSPO as described in Daniele, et al., J. Med.
  • C is a moiety that binds or associates with TSPO, and is a compound, or derived from a compound, from the table below: , .
  • C is a moiety that binds or associates with TSPO, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I: , [0237] In some embodiments, C is a moiety that binds or associates with rubicon. [0238] In some embodiments, C is a moiety that binds or associates with FKBP12. [0239] In some embodiments, C is a moiety that binds or associates with Fis1. [0240] In some embodiments, C is a moiety that binds or associates with PINK1 .
  • C is a moiety that binds or associates with huntingtin.
  • C is a moiety that binds or associates with huntingtin as described in W02020/176424, WO 2018/118598, WO 2016/033445, Tomoshige, et al., Angew. Chem. Int. Ed., 56: 11530-11533 (2017), Liu, et al., J. Med. Chem., 63(15):8608-8633 (2020), each of which is incorporated by reference in its entirety.
  • C is a moiety that binds or associates with huntington and is a compound, or derived from a compound, of the following structure;
  • C is a moiety that binds or associates with huntington, and is selected from the table below, where represents a point of attachment between moiety C and a compound of formula I:
  • C is a moiety that binds or associates with TDP43.
  • C is a moiety that binds or associates with HSP90.
  • C is a moiety that binds or associates with Hap40.
  • C is a moiety that binds or associates with RNA.
  • C is a moiety that binds or associates with NLRP3.
  • C is a moiety that binds or associates with MCL1.
  • C is a moiety that binds or associates with BCL-XL. [0251] In some embodiments, C is a moiety that binds or associates with BCL2. [0252] In some embodiments, C is a moiety that binds or associates with BAD. [0253] In some embodiments, C is a moiety that binds or associates with PARKIN. [0254] In some embodiments, C is a moiety that binds or associates with CPT1A/B. [0255] In some embodiments, C is a moiety that binds or associates with cardiolipin. [0256] In some embodiments, C is a moiety that binds or associates with Miro-1.
  • C is a moiety that binds or associates with MAOA.
  • C is a moiety that binds or associates with MAOB.
  • C is a moiety that binds or associates with VDAC1/2.
  • C is a moiety that binds or associates with CISD1.
  • C is a moiety that binds or associates with MTARC1.
  • C is a moiety that binds or associates with ACSL1.
  • C is a moiety that binds or associates with BAK1.
  • C is a moiety that binds or associates with BAX.
  • C is a moiety that binds or associates with HK1/2.
  • C is a moiety that binds or associates with GPAM.
  • C is a moiety that binds or associates with a virus.
  • C is a moiety that binds or associates with PNLPA2.
  • C is a moiety that binds or associates with PNPLA3.
  • C is a moiety that binds or associates with ABHD5.
  • C is a moiety that binds or associates with perilipin 2. [0272] In some embodiments, C is a moiety that binds or associates with perilipin 3. [0273] In some embodiments, C is a moiety that binds or associates with HSD17B13. [0274] In some embodiments, C is a moiety that binds or associates with HSD17B7. [0275] In some embodiments, C is a moiety that binds or associates with HSD17B11. [0276] In some embodiments, C is a moiety that binds or associates with LPCAT1.
  • C is a moiety that binds or associates with HSDHL. [0278] In some embodiments, C is a moiety that binds or associates with SQLE. [0279] In some embodiments, C is a moiety that binds or associates with EPHX2. [0280] In some embodiments, C is a moiety that binds or associates with LIPE. [0281] In some embodiments, C is a moiety that binds or associates with VCP. [0282] In some embodiments, C is a moiety that binds or associates with LSS. [0283] In some embodiments, C is a moiety that binds or associates with AIFM2.
  • C is a moiety that binds or associates with C18orf32. [0285] In some embodiments, C is a moiety that binds or associates with RAB1B. [0286] In some embodiments, C is a moiety that binds or associates with RAB5A. [0287] In some embodiments, C is a moiety that binds or associates with MYD88. [0288] In some embodiments, C is a moiety that binds or associates with ASC. [0289] In some embodiments, C is a moiety that binds or associates with an endosome.
  • C is a moiety that binds or associates with receptor tyrosine kinases. [0291] In some embodiments, C is a moiety that binds or associates with cMet. [0292] In some embodiments, C is a moiety that binds or associates with LRP5/6. [0293] In some embodiments, C is a moiety that binds or associates with frizzled. [0294] In some embodiments, C is a moiety that binds or associates with oncogenic signaling complexes. [0295] In some embodiments, C is a moiety that binds or associates with RAF.
  • C is a moiety that binds or associates with RAS. [0297] In some embodiments, C is a moiety that binds or associates with polyQ/CAG repeat proteins. [0298] In some embodiments, C is a moiety that binds or associates with autophagy cargo adapter proteins. [0299] In some embodiments, C is a moiety that binds or associates with p62. [0300] In some embodiments, C is a moiety that binds or associates with NBR1. [0301] In some embodiments, C is a moiety that binds or associates with OPTN.
  • C is a moiety that binds or associates with TAX1BP1. [0303] In some embodiments, C is a moiety that binds or associates with NDP52. [0304] In some embodiments, C is a moiety that binds or associates with liquid-liquid phase separation condensates. [0305] In some embodiments, C is a moiety that binds or associates with Shp2. [0306] In some embodiments, C is a moiety that binds or associates with endoplasmic reticulum. [0307] In some embodiments, C is a moiety that binds or associates with AXTN3.
  • C is a moiety that binds or associates with FLCN. [0309] In some embodiments, C is a moiety that binds or associates with FNIP. [0310] In some embodiments, C is a moiety that binds or associates with mTOR. [0311] In some embodiments, C is a moiety that binds or associates with ABHD6. [0312] In some embodiments, C is a moiety that binds or associates with damaged lysosomes [0313] In some embodiments, C is a moiety derived from a compound of Table 1A: Table 1A
  • C is a moiety selected from Table 1B, where represents a point of attachment between moiety C and the remainder of a compound of formula I: Table 1B
  • a compound of formula I is a compound of formula la, lb, lc, or Id
  • X 1’ is C(R 7’ ) 2 , CR 7’ , S, NR 7’ , S(O), S(O) 2 , C(O), or O;
  • X 2’ is N, C, or CR 9’
  • X 3’ is N, NR 9’ , O, CR 9’ , C(R 9’ ) 2 ;
  • X 4’ is N, NR 2’ , CR 2’ , C(R 2’ ) 2 , or C(NR 2’ );
  • X 5’ is N, NR 3’ , CR 3’ , C(R 3’ ) 2 , or C(O);
  • each R 1’ is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C 12 aryl, wherein each R 1’ is optionally substituted
  • X 1’ is C(R 7’ ) 2 , CR 7’ , S, NR 7’ , S(O), S(O) 2 , C(O), or O.
  • X 1’ is C(R 7’ ) 2 , S, or NR 7’ .
  • X 1’ is S or C(R 7’ ) 2 .
  • X 1’ is S.
  • X 1’ is C(R 7’ ) 2 .
  • X 1’ is CH 2 .
  • X 1’ is CH(CH 3 ).
  • X 1’ is: [0317] In some embodiments, X 1’ is NR 7’ . In some embodiments, X 1’ is NH. In some embodiments, X 1’ is N(CH 3 ). In some embodiments, X 1’ is S(O). In some embodiments, X 1’ is S(O) 2 . In some embodiments, X 1’ is C(O). In some embodiments, X 1’ is O. [0318] As defined generally herein, X 2’ is N, C, or CR 9’ . In some embodiments, X 2’ is N or CR 9’ . In some embodiments, X 2’ is N.
  • X 2’ is C (e.g., when a bond between X 1’ and X 2’ is a double bond). In some embodiments, X 2’ is CR 9 . In some embodiments, X 2’ is CR 9’ , and R 9’ is H, halo, or C 1 -C 6 aliphatic. In some embodiments, X 2’ is CH or C(CH 3 ).
  • a bond between X 1’ and X 2’ is a single bond, and X 1’ is C(R 3’ ) 2 , S, NR 7’ , S(O), S(O) 2 , C(O), or O, and X 2’ is N or CR 9’ .
  • a bond between X 1’ and X 2’ is a single bond, and X 1’ is C(R 7’ ) 2 , S, or NR 7’ , and X 2’ is N or CR 9’ .
  • a bond between X 1’ and X 2’ is a single bond, and X 1’ is C(R 7’ ) 2 , S, or NR 7’ , and X 2’ is N or CR 9’ , and R 9’ is H, halo, or C 1- C 6 aliphatic.
  • a bond between X 1’ and X 2’ is a single bond, and X 1’ is C(R 7’ ) 2 , S, or NR 7’ , and X 2’ is N or CR 9’ , and R 9’ is H, halo, or CH 3 .
  • a bond between X 1’ and X 2’ is a single bond, and X 1’ is C(R 7’ ) 2 , S, or NR 7’ , and X 2’ is N or CH.
  • a bond between X 1’ and X 2’ is a double bond, and X 1’ is CR 7’ , and X 2’ is C.
  • X 3’ is N, NR 9’ , O, CR 9’ , C(R 9’ ) 2 .
  • X 3’ is N or CR 9’ .
  • X 3’ is N.
  • X 3’ is O.
  • X 3’ is CR 9 . In some embodiments, X 3’ is CR 9’ , where R 9’ is H or halo. In some embodiments, X 3’ is CH. [0322] As defined generally herein, X 4’ is N, NR 2’ , CR 2’ , C(R 2’ ) 2 , or C(NR 2’ ). In some embodiments, when a bond between X 4’ and X 5’ is a single bond, X 4’ is NR 2’ , C(R 2’ ) 2 , or C(NR 2’ ). In some embodiments, X 4’ is NR 2’ or C(R 2’ ) 2 .
  • X 4’ is NR 2’ or C(R 2’ ) 2 , where each R 2’ is independently selected from H, optionally substituted C 1 -C 6 aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X 4’ is NR 2’ . In some embodiments, X 4’ is NR 2’ , where R 2’ is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X 4’ is NR 2’ , where R 2’ is optionally substituted C 1 -C 6 aliphatic.
  • X 4’ is C(R 2’ ) 2 . In some embodiments, X 4’ is C(R 2’ ) 2 , where each R 2’ is independently selected from H, optionally substituted C 1 -C 6 aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic. [0324] In some embodiments, X 4’ is C(NR 2 ). [0325] In some embodiments, when a bond between X 4’ and X 5’ is a double bond, X 4’ is N or CR 2’ . In some embodiments, X 4’ is N. In some embodiments, X 4’ is CR 2’ .
  • X 4’ is CR 2’
  • R 2’ is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6- membered heteroaliphatic.
  • X 5’ is N, NR 3’ , CR 3’ , C(R 3’ ) 2 , or C(O).
  • X 5’ is NR 3’ , C(R 3’ ) 2 or C(O).
  • X 5’ is NR 3’ .
  • X 5’ is C(O).
  • X 5’ is C(R 3’ ) 2 . [0327] In some embodiments, when a bond between X 4’ and X 5’ is a double bond, X 5’ is N or CR 3’ . In some embodiments, X 5’ is N. In some embodiments, X 5’ is CR 3’ . In some embodiments, X 5’ is CH.
  • each R 1’ is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C 12 aryl, wherein each R 1’ is optionally substituted with one or more R 1a’ .
  • R 1’ is 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O.
  • R 1’ is 4- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 4-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is thiophenyl, pyridinyl, pyrazolyl, or imidazolyl, optionally substituted with one or more R1a ’ .
  • R 1’ is 8- to 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 8-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 9-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 10-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 11-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a ’ .
  • R 1’ is pyrrolopyridinyl, benzimidazolyl, imidazopyridinyl, indolyl, or benzoxazolyl, optionally substituted with one or more R1a ’ .
  • R 1’ is a 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 4- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 4-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 5-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 6- to 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 9- to 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 9- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 10- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 11- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is a 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a ’ .
  • R 1’ is C 6 -C 12 aryl, optionally substituted with one or more R1a ’ .
  • R 1’ is phenyl, optionally substituted with one or more R1a ’ .
  • R 1’ is naphthyl optionally substituted with one or more R1a ’ .
  • two R 1’ can be taken together with the atoms to which they are attached to form a 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, C 5 - C 12 aryl, or C 3 -C 12 cycloaliphatic, each optionally substituted with one or more R 1a’ .
  • two R 1’ can be taken together with the atoms to which they are attached to form a 4- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 4- to 6- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 4- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 5- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 5- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 9- to 12- membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 9-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 10-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 11-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 12- membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 4- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 4-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 5-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 8- to 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 8-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 9-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 10-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 11-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a 12-membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a C 5 -C 12 aryl, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a phenyl ring, optionally substituted with one or more R 1a’ . In some embodiments, two R 1’ are taken together with the atoms to which they are attached to form a naphthyl ring, optionally substituted with one or more R 1a’ . [0339] In some embodiments, two R 1’ are taken together with the atoms to which they are attached to form a C 3 -C 12 cycloaliphatic, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a monocylic C 3 -C 7 cycloaliphatic, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, optionally substituted with one or more R 1a’ .
  • two R 1’ are taken together with the atoms to which they are attached to form a bicyclic C 8 -C 12 cycloaliphatic, optionally substituted with one or more R 1a’ .
  • each R 1a’ is independently halogen, -OH, -CN, -N(R 9’ ) 2 , - NH-S(O) 2 -R 7’ , -NH-C(O)-NHR 7’ , -NHC(O)-OR 7’ , -C(O)-NH 2 , oxo, or an optionally substituted group selected from C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3 -C 12 cycloaliphatic, 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 1a’ is halogen. In some embodiments, R 1a’ is fluoro, chloro, bromo, or iodo. In some embodiments, R 1a’ is fluoro. In some embodiments, R 1a’ is chloro. In some embodiments, R 1a’ is bromo. In some embodiments, R 1a’ is iodo. [0342] In some embodiments, R 1a’ is –OH. [0343] In some embodiments, R 1a’ is –CN. [0344] In some embodiments, R 1a’ is -NHC(O)-OR 7’ .
  • R 1a’ is -NHC(O)- O(C 1 -C 6 aliphatic). In some embodiments, R 1a’ is -NHC(O)-OC(CH 3 ) 3 . [0345] In some embodiments, R 1a’ is -N(R 9’ ) 2 . In some embodiments, R 1a’ is –NH 2 . In some embodiments, R 1a’ is –NH(R 9’ ). In some embodiments, R 1a’ is –NH(C 1 -C 6 aliphatic). [0346] In some embodiments, R 1a’ is -NH-S(O) 2 -R 7’ .
  • R 1a’ is -NH- S(O) 2 -C 1 -C 6 aliphatic. In some embodiments, R 1a’ is -NH-S(O) 2 -CH 3 . In some embodiments, R 1a’ is -NH-S(O) 2 -CH 2 -CH 3 . [0347] In some embodiments, R 1a’ is -NH-C(O)-NHR 7’ . In some embodiments, R 1a’ is -NH- C(O)-NH 2 . In some embodiments, R 1a’ is -NH-C(O)-NHCH 3 . [0348] In some embodiments, R 1a’ is -C(O)-NH 2 .
  • R 1a’ is oxo.
  • R 1a’ is an optionally substituted group selected from C 1 -C 12 aliphatic, -O-C 1 -C 12 aliphatic, C 3 -C 12 cycloaliphatic, 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 1a’ is an optionally substituted C 1 -C 12 aliphatic.
  • R 1a’ is C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0–4 R° or –(CH 2 ) 0–4 OR°. In some embodiments, R 1a’ is C 1 -C 12 aliphatic optionally substituted with R° or OR°, where R° is halo, C 1 -C 6 aliphatic, or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where R° is optionally substituted with C 1 -C 6 aliphatic or halo. In some embodiments, R 1a’ is methyl, ethyl, propyl, or butyl.
  • R 1a’ is optionally substituted -O-C 1 -C 12 aliphatic. In some embodiments, R 1a’ is O-C 1 -C 12 aliphatic optionally substituted with R°. In some embodiments, R 1a’ is -O-CH 3 . [0353] In some embodiments, R 1a’ is optionally substituted C 3 -C 12 cycloaliphatic. [0354] In some embodiments, R 1a’ is optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 1a’ is optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R 1a’ is optionally substituted pyrrolidinyl. In some embodiments, R 1a’ is pyrrolidinyl. [0355] In some embodiments, R 1a’ is optionally substituted 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O. [0356] In some embodiments, R 1a’ is optionally substituted C 6 -C 12 aryl. In some embodiments, R 1a’ is phenyl.
  • each R 1a’ is independently selected from -Br, -Cl, -F, -CH 3 , - CH 2 -CH 3 , -OCH 3 , -CN, -CF 3 , -OH, -NH 2 , [0358] As defined generally herein, n’ is 0, 1, or 2. In some embodiments, n’ is 0. In some embodiments, n’ is 1. In some embodiments, n’ is 2. [0359] As defined generally herein, R 1’ is substituted with m instances of R 1a’ , e.g., (R 1a’ ) m .
  • R 1’ is substituted with 0, 1, 2, 3, 4, 5, or 6 instances of R 1a’ , e.g., R 1’ is substituted with (R 1a’ ) m’ , wherein m’ is 0, 1, 2, 3, 4, 5, or 6.
  • m’ is 0.
  • m’ is 1.
  • m’ is 2.
  • m’ is 3.
  • m’ is 4.
  • m’ is 5.
  • m’ is 6. [0360]
  • n’ is 1, and R 1’ is selected from
  • n’ is 2, and two R 1’ come together to form:
  • each R 2’ is independently hydrogen, halogen, or an optionally substituted group selected from C 1 -C 6 aliphatic, -O-C 1 -C 6 aliphatic, C 3 -C 6 cycloaliphatic, 2- to 6-membered heteroaliphatic, C 6 -C 12 aryl, 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, and 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2’ is H or optionally substituted C 1 -C 6 aliphatic.
  • R 2’ is H.
  • R 2’ is optionally substituted C 1 -C 6 aliphatic.
  • R 2’ is C 1 -C 6 aliphatic substituted with –(CH 2 ) 0–4 R° or –(CH 2 ) 0–4 OR°.
  • R 2’ is C 1 -C 6 aliphatic substituted with halo, OH, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 2’ is methyl, ethyl, propyl, butyl, pentyl or hexyl.
  • R 2’ is ethyl. In some embodiments, R 2’ is -CF 3 . In some embodiments, R 2’ is ethyl substituted with halo. [0365] In some embodiments, R 2’ is optionally substituted -O-C 1 -C 6 aliphatic. In some embodiments, R 2’ is –O-CH 3 or –O-CH 2 -CH 3 . [0366] In some embodiments, R 2’ is optionally substituted C 3 -C 6 cycloaliphatic. In some embodiments, R 2’ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2’ is optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, R 2’ is –CH 2 -CH 2 -O-CH 2 -CH 2 -O-R°. [0368] In some embodiments, R 2’ is optionally substituted C 6 -C 12 aryl. In some embodiments, R 2’ is phenyl. [0369] In some embodiments, R 2’ is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O. [0370] In some embodiments, R 2’ is optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2’ is optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2’ is H, Cl, -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -F, -CH 2 CHF 2 , - CH 2 CF 3 , -O-CH 3 , -CF 3 , -O-CH 2 -CH 3 , -CH 2 CH 2 OH, or -CH 2 CH 2 NH 2 .
  • each R 3’ is independently selected from -H, -OH, -N(R 7’ ) 2 , halogen, CN, C 1 -C 6 aliphatic, and C 3 -C 6 cycloaliphatic.
  • R 3’ is H.
  • R 3’ is OH.
  • R 3’ is halogen.
  • R 3’ is CN.
  • R 3’ is -N(R 7’ ) 2 .
  • R 3’ is –NH 2 .
  • R 3’ is –NH(C 1 -C 6 aliphatic).
  • R 3’ is –N(C 1 -C 6 aliphatic) 2 . [0373] In some embodiments, R 3’ is C 1 -C 6 aliphatic. In some embodiments, R 3’ is methyl, ethyl, propyl, butyl, or hexyl. [0374] In some embodiments, R 3’ is C 3 -C 6 cycloaliphatic. In some embodiments, R 3’ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • two R 3’ can be taken together with the atom to which they are attached to form a C 3 -C 6 spirocycloalkyl. In some embodiments, two R 3’ are taken together to form a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, or spirocyclohexyl. [0376] In some embodiments, R 2’ and R 3’ are taken together, with the atoms to which they attach, to form a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 2’ and R 3’ are taken together to form: [0377]
  • R 4’ is hydrogen, or an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4’ is hydrogen, or an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4’ is hydrogen or an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4’ is an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, C 3 -C 12 cycloaliphatic, C 6 -C 12 aryl, 4- to 12- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4’ is hydrogen.
  • R 4’ is optionally substituted C 1 -C 12 aliphatic.
  • R 4’ is optionally substituted C 1 -C 12 alkyl.
  • R 4’ is C 1 -C 12 alkyl optionally substituted with –(CH 2 ) 0–4 R° or –(CH 2 ) 0–4 OR°. In some embodiments, R 4’ is C 1 -C 12 alkyl substituted with –OH or –O-(C 1 -C 6 aliphatic). [0383] In some embodiments, R 4’ is optionally substituted 2- to 12-membered heteroaliphatic. [0384] In some embodiments, R 4’ is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments, R 4’ is optionally substituted monocyclic C 3 -C 6 cycloaliphatic.
  • R 4’ is optionally substituted monocyclic C 3 -C 6 cycloalkyl. In some embodiments, R 4’ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0385] In some embodiments, R 4’ is optionally substituted C 6 -C 12 aryl. In some embodiments, R 4’ is optionally substituted phenyl. [0386] In some embodiments, R 4’ is optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4’ is optionally substituted 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4’ is optionally substituted 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4’ is optionally substituted 5- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4’ is optionally substituted 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4’ is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH 2 ) 0– 4 R°, –(CH 2 ) 0–4 OR° or –(CH 2 ) 0–4 C(O)R°.
  • R 4’ is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –R°, –(CH 2 ) 1– 4 OR° or C(O)R°.
  • R 4’ is tetrahydropyranyl or piperidinyl optionally substituted with C(O)R°.
  • R 4’ is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4’ is optionally substituted 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4’ is optionally substituted 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4’ is optionally substituted imidazolyl. In some embodiments, R 4’ is imidazolyl substituted with R°.
  • R 4’ is optionally substituted with –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, - O(CH 2 ) 0-4 R°, –(CH 2 ) 0–4 NR°C(O)R°, or –(CH 2 ) 0–4 C(O)R°.
  • R 5’ is C(O)-R 6’ , -C(O)N(R 6’ )(R 7’ ), -N(R 7’ )C(O)-R 6’ , - S(O) 2 -R 6’ , -S(O) 2 N(R 6’ )(R 7’ ), -OC(O)-R 6’ , -C(O)OR 6’ , -C(NH)N(R 6’ )(R 7’ ), optionally substituted C 1 -C 12 aliphatic-R 6’ , or optionally substituted 5- to 6-membered heteroaryl.
  • R 5’ is -N(R 7’ )C(O)-R 6’ . In some embodiments, R 5’ is -NHC(O)- R 6’ . [0391] In some embodiments, R 5’ is -S(O) 2 -R 6’ . [0392] In some embodiments, R 5’ is -S(O) 2 N(R 6’ )(R 7’ ). In some embodiments, R 5’ is - S(O) 2 NH(R 6’ ). [0393] In some embodiments, R 5’ is -OC(O)-R 6’ , [0394] In some embodiments, R 5’ is -C(O)OR 6’ .
  • R 5’ is -C(NH)N(R 6’ )(R 7’ ). In some embodiments, R 5’ is - C(NH)NH(R 6’ ). [0396] In some embodiments, R 5’ is optionally substituted C 1 -C 12 aliphatic-R 6’ . In some embodiments, R 5’ is –CH 2 -R 6’ . [0397] In some embodiments, R 5’ is optionally substituted 5- to 6-membered heteroaryl. In some embodiments, R 5’ is oxadiazolyl or imidazolyl.
  • R 6’ is -OH, -N(R 7’ ) 2 , -S(O) 2 -R 8’ , or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, each optionally substituted with one or more R 8’ .
  • R 6’ is –OH.
  • R 6’ is –N(R 7’ ) 2 .
  • R 6’ is –NHR 7’ .
  • R 6’ is NH 2 .
  • R 6’ is –N(C 1 -C 6 aliphatic), wherein C 1 -C 6 aliphatic is optionally substituted with R 8’ .
  • R 6’ is –N(CH 3 ).
  • R 6’ is -S(O) 2 -R 8’ .
  • R 6’ is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 3- to 7-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8’ .
  • R 6’ is a 3- membered monocyclic heterocyclic having 1 heteroatom selected from N, S, and O, optionally substituted with one or more R 8’ .
  • R 6’ is a 4-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8’ .
  • R 6’ is a 5-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8’ .
  • R 6’ is a 6-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8’ .
  • R 6’ is a 7- membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R 8’ .
  • R 6’ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, optionally substituted with one or more R 8’ .
  • R 6’ is 6- to 12-membered bicyclic (e.g., fused bicyclic or spirocyclic) heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 6-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 7-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 8-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 9-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 10-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 11-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • R 6’ is 12-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8’ .
  • each R 7’ is independently selected from H, optionally substituted C 1 -C 12 aliphatic, optionally substituted C 3 -C 12 cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C 6 -C 12 aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 7’ is H.
  • R 7’ is optionally substituted C 1 -C 12 aliphatic. In some embodiments, R 7’ is optionally substituted C 1 -C 12 alkyl. In some embodiments, R 7’ is optionally substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 7’ is C 1 -C 12 aliphatic optionally substituted with one or more –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, or –(CH 2 ) 0– 4 C(O)OR°.
  • R 7’ is C 1 -C 12 aliphatic optionally substituted with one or more of halogen, –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, –(CH 2 ) 0–4 C(O)NR°2, or –(CH 2 ) 0–4 C(O)OR°, where R° is H, C 1–6 aliphatic, or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and R° is optionally substituted with –(CH 2 ) 0–2 R ⁇ or –(CH 2 ) 0–2 OH, where R ⁇ is a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 7’ is optionally substituted C 3 -C 12 cycloaliphatic. In some embodiments, R 7’ is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. [0408] In some embodiments, R 7’ is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R 7’ is 2- to 9- membered heteroaliphatic comprising one or more oxygen atoms.
  • R 7’ is –(CH 2 CH 2 O) 2 CH 2 CH 2 OH, –CH 2 CH 2 OCH 2 CH 2 CH 2 OH, - CH 2 CH 2 CH 2 N(CH 3 )CH 2 C ⁇ CH. [0409] In some embodiments, R 7’ is optionally substituted C 6 -C 12 aryl. In some embodiments, R 7’ is optionally substituted phenyl. [0410] In some embodiments, R 7’ is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • R 7’ is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.
  • R 7’ and R 2’ are taken together, with the atoms to which they attach, to form a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.
  • each R 8’ is independently -OH, -NH 2 , or an optionally substituted group selected from C 1 -C 12 aliphatic, 2- to 12-membered heteroaliphatic, -O-C 1 -C 12 aliphatic, -NH-C(O)-C 1 -C 12 aliphatic, -C(O)-NH-C 1 -C 12 aliphatic, -C(O)-N(C 1 -C 12 aliphatic) 2 , - C(O)O-C 1 -C 12 aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 8’ is –OH. [0414] In some embodiments, R 8’ is NH 2 . [0415] In some embodiments, R 8’ is optionally substituted C 1 -C 12 aliphatic. In some embodiments, R 8’ is C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 OR°, – (CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 C(O)N(R°) 2 , –(CH 2 ) 0–4 N(R°)C(O)R°, or –(CH 2 ) 0–4 N(R°)C(O)OR°.
  • R 8’ is C 1 -C 12 aliphatic optionally substituted with –OH, -NH 2 , -NH(C 1 -C 6 aliphatic), -N(C 1 -C 6 aliphatic) 2 , -NHC(O)(C 1 -C 6 aliphatic), -C(O)NH(C 1 -C 6 aliphatic), or 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 8’ is -CH2OH, - CH2CH2C ⁇ CH, -CH2-C ⁇ CH, -C ⁇ CH, .
  • R 8’ is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R 8’ 2- to 9- membered heteroaliphatic comprising one or more oxygen atoms. In some embodiments, R 8’ is –(CH 2 CH 2 O) 2 CH 2 CH 2 OH or –CH 2 CH 2 OCH 2 CH 2 CH 2 OH. [0417] In some embodiments, R 8’ is optionally substituted -O-C 1 -C 12 aliphatic. In some embodiments, R 8’ is optionally substituted –O-C 1 -C 12 alkyl.
  • R 8’ is optionally substituted -NH-C(O)-C 1 -C 12 aliphatic.
  • R 8’ is -NH-C(O)-C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0– 4 N(R°)C(O)R°, –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 8’ is optionally substituted -C(O)-NH-C 1 -C 12 aliphatic.
  • R 8’ is -C(O)-NH-C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0– 4 N(R°)C(O)R°, –(CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 8’ is optionally substituted -C(O)-N(C 1 -C 12 aliphatic) 2 .
  • R 8’ is -C(O)-N(C 1 -C 12 aliphatic) 2 optionally substituted with –(CH 2 ) 0– 4 N(R°)C(O)R°, –(CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 8’ is optionally substituted -C(O)O-C 1 -C 12 aliphatic.
  • R 8’ is -C(O)O-C 1 -C 12 aliphatic optionally substituted with –(CH 2 ) 0– 4 N(R°)C(O)R°, –(CH 2 ) 0–4 N(R°) 2 , –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 8’ is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 8’ is 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH 2 ) 0–4 R°, –(CH 2 ) 0–4 N(R°) 2 , or –(CH 2 ) 0–4 C(O)R°. [0423] As defined generally herein, each R 9’ is independently selected from H, halo, OH, and optionally substituted C 1 -C 12 aliphatic. In some embodiments, R 9’ is H.
  • R 9’ is halo (e.g., bromo, chloro, iodo, fluoro). In some embodiments, R 9’ is OH. In some embodiments, R 9’ is optionally substituted C 1 -C 12 aliphatic. In some embodiments, R 9’ is C 1 -C 12 alkyl. In some embodiments, R 9’ is methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl. [0424] In some embodiments, a compound of formula I is a compound of formula Ia:
  • a compound of formula I is a compound of formula Ib: or a pharmaceutically acceptable salt thereof, wherein X 1’ , X 2’ , X 3’ , X 4’ , X 5’ , R 1’ , R 4’ , R 5’ , n’, B and C are as defined herein.
  • a compound of formula I is a compound of formula Ib: or a pharmaceutically acceptable salt thereof, wherein X 1’ , X 2’ , X 3’ , X 4’ , X 5’ , R 1’ , R 4’ , R 5’ , n’, B and C are as defined herein.
  • a compound of formula I is a compound of formula Ic: ' or a pharmaceutically acceptable salt thereof, wherein X 1’ , X 2’ , X 3’ , X 4’ , X 5’ , R 1’ , R 4’ , R 5’ , n’, B and C are as defined herein.
  • a compound of formula I is a compound of formula Id: or a pharmaceutically acceptable salt thereof, wherein X 1’ , X 2’ , X 3’ , X 4’ , X 5’ , R 1’ , R 4’ , R 5’ , n’, B and C are as defined herein.
  • a compound described herein e.g., a compound of formula II is provided in Table 2A Table 2A
  • a compound described herein e.g., a compound of formula II
  • Table 2B a compound described herein (e.g., a compound of formula II) is provided in Table 2B:
  • a compound described herein e g., a compound of formula II
  • Table 3B a compound described herein (e g., a compound of formula II) is provided in Table 3B:
  • Table 3B [0432]
  • a compound described herein e.g., a compound of formula II is provided in Table 4A: Table 4A
  • a compound described herein e.g., a compound of formula II is provided in Table 4B:
  • a compound described herein e.g., a compound of formula I
  • Table 5A Table 5A
  • a compound described herein e.g., a compound of formula I
  • Table 5B Table 5B
  • 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.
  • the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions described herein is such that it is effective to measurably induce degradation of a target in a biological sample or in a patient.
  • a composition described herein is formulated for administration to a patient in need of such composition.
  • a composition described herein is formulated for oral administration to a patient.
  • Compounds and compositions, according to method of the present disclosure are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
  • compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternallyor via an implanted reservoir.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • Injectable formulations can be sterilized, for example, by fdtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adj
  • compositions described herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyl dodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions described herein may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Dosage forms for topical or transdermal administration of a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • ULK initiation complex e.g., a ULK1 initiation complex and/or a ULK2 initiation complex
  • Initiation of the autophagy pathway via a ULK initiation complex includes: 1) recognition of cargo (i.e., the target to be degraded), typically by adapter proteins that bind to the target cargo (e.g., to modifications, such as ubiquitin or beta galactoside, on the cargo) and, 2) recruitment of a ULK initiation complex by the cargo adapter proteins.
  • ULK initiation complex is believed to be driven by the interaction of the FIP200 protein with cargo adapter proteins, such as p62 (also known as SQSTM1) which binds to ubiquitinated cargo, or NDP52 (i.e., Nuclear domain 10 protein 52; also known as Calcium Binding and Coiled-Coil Domain 2, or CALCOCO2) which binds to cytosolically exposed beta-galactoside via galectin-8.
  • cargo adapter proteins such as p62 (also known as SQSTM1) which binds to ubiquitinated cargo, or NDP52 (i.e., Nuclear domain 10 protein 52; also known as Calcium Binding and Coiled-Coil Domain 2, or CALCO2) which binds to cytosolically exposed beta-galactoside via galectin-8.
  • ULK initiation complex e.g., a ULK1 initiation complex and/or a ULK2 initiation complex
  • the ULK initiation complexes include ULK1 and ULK2.
  • ULK initiation complexes comprise FIP200, ATG13, and ATG101, and are an important part of the autophagy pathway. Wong, et al. Autophagy, 9(2):124-137 (Feb.1, 2013); Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Hurley JH, et al. Annu Rev Biochem. 2017 Jun 20;86:225-244.
  • Recruitment a ULK initiation complex is driven by the interaction of the FIP200 protein with cargo adapter proteins, such as p62, that localize to the ubiquitinated cargo. This process of recognizing substrates for degradation and recruiting a ULK initiation complex is central to triggering the selective removal of cellular components via the autophagy pathway.
  • the present disclosure provides heterobifunctional compounds and compositions that, as described herein, can target a ULK initiation complex as well as certain target moieties, to thereby activate the autophagy pathway.
  • compounds and compositions described herein target a ULK1 initiation complex.
  • compounds and compositions described herein target a ULK2 initiation complex.
  • Diseases, Disorders, and Conditions [0464] The present disclosure encompasses an insight that compounds and compositions provided herein can be used to direct autophagy to a target. The present disclosure also encompasses an insight that directing autophagy to particular targets can be useful for treating particular diseases, disorders, and conditions.
  • a disease, disorder, or condition is disease, disorder, or condition is selected from NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B- cell-like diffuse large B-cell lymphomas, diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM-secreting lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer’s disease, diabetes (e.g., Type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes, Parkinson’s disease, Dementia with Lewy bodies, multiple systems atrophy, neuroaxonal dystrophies, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy, Progressive supranu
  • a particular target binding moiety e.g, moiety C in formula I, above
  • a target binding moiety can be selected to modulate (and thereby induce degradation of) a target of choice to to treat a disease, disorder, or condition of choice.
  • a person of skill in the art can identify particular binding moieties based on the desired disease, disorder, or condition to be treated, using known binding moieties. For example:
  • a target is a lipid droplet
  • a disease, disorder or condition to be treated is selected from NASH and NAFLD.
  • a target is COP9, and a disease, disorder or condition is cancer.
  • a target is MYC, and a disease, disorder or condition is Burkitt lymphoma, cervical cancer, colon cancer, breast cancer, lung cancer, or stomach cancer.
  • a target is myddosome
  • a disease, disorder or condition is active B -cell -like diffuse large B-cell lymphomas (ABC DLBCL), diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM-secreting lymphoplasmacytic lymphoma, or Waldenstrom macroglobulinemia.
  • a target is inflammasome
  • a disease, disorder or condition is gout, atherosclerosis, Alzheimer’s disease, Type-II diabetes, experimental autoimmune encephalitis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes (CAPS), colon cancer, breast cancer, melanoma, hepatitis C virus-associated hepatocellular carcinoma, or gastrointestinal cancers.
  • a disease, disorder or condition is gout, atherosclerosis, Alzheimer’s disease, Type-II diabetes, experimental autoimmune encephalitis, multiple sclerosis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes (CAPS), colon cancer, breast cancer, melanoma, hepatitis C virus-associated hepatocellular carcinoma, or gastrointestinal cancers.
  • CAPS cryopyrin-associated periodic syndromes
  • a target is KRAS, and a disease, disorder or condition is colorectal cancer, lung cancer, leukemia, or pancreatic cancer.
  • a target is ⁇ -synuclein, and a disease, disorder or condition is Parkinson’s disease, dementia with Lewy bodies, multiple systems atrophy, or neuroaxonal dystrophies.
  • a target is tau
  • a disease, disorder or condition is Alzheimer’s disease, Primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Lytico-bodig disease (Parkinson-dementia complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, or lipofuscinosis.
  • PART Primary age-related tauopathy
  • CTE chronic traumatic encephalopathy
  • PSP progressive supranuclear palsy
  • CBD corticobasal degeneration
  • FTDP-17 frontotemporal
  • a target is estrogen receptor- ⁇ , and a disease, disorder or condition is breast cancer.
  • a target is an androgen receptor, and a disease, disorder or condition is prostate cancer or spinal and bulbar muscular atrophy (SBMA)/ Kennedy’s disease.
  • SBMA spinal and bulbar muscular atrophy
  • a target is KSR1, and a disease, disorder or condition is cancer.
  • a target is islet amyloid polypeptide (IAPP), and a disease, disorder or condition is type-II diabetes.
  • IAPP islet amyloid polypeptide
  • a target is IRAK4, and a disease, disorder or condition is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or psoriasis.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • a target is PINK1, and a disease, disorder or condition is Parkinson’s disease, Huntingtin’s disease, or spinocerebellar ataxia.
  • a target is TDP43, and a disease, disorder or condition is familial amylotrophic lateral sclerosis or frontotemporal dementia (FTLD-TDP).
  • FTLD-TDP familial amylotrophic lateral sclerosis or frontotemporal dementia
  • X 1 is C(R 7 ) 2 , CR 7 , S, NR 7 , S(O), S(O) 2 , C(O), or O;
  • X 2 is N, C, or CR 9 ;
  • X 3 is N, O, or CR 9 ;
  • X 4 is NR 2 , N, CR 2 , C(R 2 ) 2 , or C(NR 2 );
  • X 5 is N, NR 3 , CR 3 , C(R 3 ) 2 , or C(O);
  • each R 1 is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C 12 aryl, wherein each R 1 is optionally substituted with one or more R 1a , or two R 1 can be taken together with the atoms to which they are attached to form a 4-
  • Embodiment 2 The compound of Embodiment 1, wherein the bond between X 4 and X 5 is a single bond.
  • Embodiment 3. The compound of Embodiments 1 or 2, wherein X 3 is N.
  • Embodiment 4. The compound of any one of Embodiments 1-3, wherein X 1 is S.
  • Embodiment 5. The compound of any one of Embodiments 1-4, wherein a bond between X 1 and X 2 is a single bond.
  • Embodiment 8 The compound of any one of Embodiments 1-6, wherein n is 2, and two R 1 are taken together with the atoms to which they are attached to form a C 6 aryl (e.g., phenyl) optionally substituted with one or more R 1a .
  • Embodiment 8 The compound of any one of Embodiments 1-6, wherein n is 2, and two R 1 are taken together with the atoms to which they are attached to form a C 12 aryl (e.g., naphthyl) optionally substituted with one or more R 1a .
  • each R 1a is independently selected from -Br, -Cl, -F, -CH 3 , -CH 2 -CH 3 , -OCH 3 , -CN, -CF 3 , OH, NH 2 , Z Embodiment 10.
  • R 4 is phenyl or 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 11 The compound of any one of Embodiments 1-10, wherein X 2 is CH.
  • Embodiment 13 The compound of any one of Embodiments 1-11, wherein R 2 is optionally substituted C 1 -C 12 aliphatic.
  • Embodiment 13 The compound of any one of Embodiments 1-12, wherein a bond between X 4 and X 5 is a single bond, and X 4 is NR 2 .
  • Embodiment 14 The compound of any one of Embodiments 1-13, wherein a bond between X 4 and X 5 is a single bond, and X 5 is C(O).
  • Embodiment 15 The compound of any one of Embodiments 1-14, wherein R 5 is -C(O)-R 6 .
  • Embodiment 17 The compound of any one of Embodiments 1-15, wherein R 6 is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R 8 .
  • Embodiment 17 The compound of any one of Embodiments 1-16, wherein R 6 is azetidinyl, pyrrolidinyl, or piperidinyl, optionally substituted with one or more R 8 .
  • Embodiment 18 The compound of Embodiment 1, wherein n is 2, and two R 1 come together to form: Embodiment 19.
  • Embodiment 20 The compound of Embodiment 20.
  • Embodiment 19 wherein R 1 is 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a.
  • Embodiment 21 The compound of Embodiment 1, wherein n is 1, and R 1 is selected from:
  • Embodiment 22 The compound of Embodiment 1, wherein R 2 is H, Cl, -CH 3 , -CH 2 -CH 3 , - CH 2 -CH 2 -F, -CH 2 CHF 2 , -CH 2 CF 3 , -O-CH 3 , -CF 3 , -O-CH 2 -CH 3 , -CH 2 -CH 2 -OH, or –CH 2 - CH 2 -NH 2 .
  • Embodiment 23 The compound of Embodiment 1, wherein R 4 is -H, -CH 3 , -CH 2 -CH 3 ,
  • Embodiment 24 The compound of Embodiment 1, wherein R 5 is:
  • Embodiment 25 The compound of Embodiment 1, wherein the compound is of formula Ila or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.
  • Embodiment 26 The compound of Embodiment 1, wherein the compound is of formula
  • Embodiment 27 The compound of Embodiment 1, wherein the compound is of formula III or a pharmaceutically acceptable salt thereof, wherein m is 0-6.
  • Embodiment 28 The compound of Embodiment 1, wherein the compound is of formula
  • Embodiment 29 The compound of Embodiment 1, wherein the compound is of formula
  • Embodiment 30 The compound of Embodiment 1, wherein the compound is of formula IVb or a pharmaceutically acceptable salt thereof.
  • Embodiment 31 The compound of Embodiment 1, wherein the compound is selected from Table 2A, Table 3A, or Table 4A.
  • Embodiment 32 The compound of Embodiment 1, wherein the compound is selected from Table 2B, Table 3B, or Table 4B.
  • Embodiment 33 The compound of Embodiment 1, wherein the compound is selected from Table 2B, Table 3B, or Table 4B.
  • a compound of formula I A-B-C I or a pharmaceutically acceptable salt thereof, wherein A is a ULK complex binding moiety; B is a linker; and C is a target binding moiety, wherein the target binding moiety binds or associates with a target selected from the mitochondria, Fis1, MCL1, BCL-XL, BCL2, BAD, PINK1, PARKIN, CPT1A/B, KMO, ACC2, TSPO, cardiolipin, Miro-1, MAOA, MAOB, VDAC1/2, CISD1, MTARC1, ACSL1, BAK1, BAX, HK1/2, GPAM, a bacterium, a virus, a lipid droplet, PNLPA2, PNPLA3, ABHD5, perilipin 2, perilipin 3, HSD17B13, HSD17B7, HSD17B11, LPCAT1, HSDHL, SQLE, EPHX2, LIPE, VCP, LSS, AIFM2, C18orf32, RAB1B, RAB
  • Embodiment 34 The compound of Embodiment 33, wherein the ULK complex binding moiety is a compound of any one of Embodiments 1-32.
  • Embodiment 35 The compound of Embodiment 33, wherein A-B-C is a compound of formula Ia, Ib, Ic, or Id
  • X 1’ is C(R 7’ ) 2 , CR 7’ , S, NR 7’ , S(O), S(O) 2 , C(O), or O;
  • X 2’ is N, NR 9’ , C, CR 9’ , or C(R 9’ ) 2
  • X 3’ is N, O, or CR 9’ ;
  • X 4’ is N, NR 2’ , CR 2’ , C(R 2’ ) 2 , or C(NR 2’ );
  • X 5’ is N, NR 3’ , CR 3’ , C(R 3’ ) 2 , or C(O);
  • each R 1’ is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C 6 -C 12 aryl, wherein each R 1’ is optionally substitute
  • Embodiment 36 The compound of any one of Embodiments 33-35, wherein the ULK complex binding moiety is a ULK1 complex binding moiety.
  • Embodiment 37 The compound of any one of Embodiments 33-36, wherein the linker is an optionally substituted C 2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NR Z -, -N(R Z )C(O)-, -C(O)N(R Z )-, -N(R Z )C(O)O-, - OC(O)N(R Z )-, -N(R Z )C(O) N(R Z ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO 2 -, wherein each -Cy- is independently an optionally substituted 3-8 member
  • Embodiment 39 The compound of Embodiment 33, wherein the target binding moiety is selected from Table 1B.
  • Embodiment 40 The compound of Embodiment 33, wherein C is a moiety that binds or associates with autophagy cargo adapter proteins.
  • Embodiment 41 The compound of Embodiment 33, wherein the compound is selected from Table 5A.
  • Embodiment 42 A pharmaceutical composition comprising a compound of any one of Embodiments 1-41, and a pharmaceutically acceptable excipient.
  • Embodiment 43 A method of inducing degradation of a target in a biological sample, comprising contacting the biological sample with a compound of any one of Embodiments 33-41.
  • Embodiment 44 A method of inducing degradation of a target in a biological sample, comprising contacting the biological sample with a compound of any one of Embodiments 33-41.
  • Embodiment 43 wherein the biological sample comprises a ULK initiation complex.
  • Embodiment 45 The method of Embodiment 44, wherein the biological sample comprises a ULK1 initiation complex.
  • Embodiment 46 A method of treating a disease, disorder, or condition in a patient, comprising administering a compound of Embodiment 33.
  • Embodiment 47 The method of Embodiment 46, wherein the disease, disorder, or condition is selected from NASH, NAFLD, cancer (e.g., cervical cancer, colon cancer, breast cancer, lung cancer, stomach cancer, gastrointestinal cancer, pancreatic cancer, prostate cancer, leukemia, melanoma, lymphoma), Burkitt lymphoma, active B-cell-like diffuse large B-cell lymphomas, diffuse large B-cell lymphomas, primary central nervous system lymphomas, IgM-secreting lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, gout, atherosclerosis, Alzheimer’s disease, diabetes (e.g., Type II diabetes), experimental autoimmune encephalitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cryopyrin-associated periodic syndromes, Parkinson’s disease, Dementia with Lewy bodies, multiple systems atrophy, neuroaxonal dystrophies, primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy,
  • Embodiment 48 In a method of inducing autophagy, the improvement that comprises contacting a biological sample comprising a ULK complex with an agent, wherein the agent comprises a ULK complex binding moiety, a linker, and a target binding moiety.
  • Embodiment 49 The method of Embodiment 48, wherein the ULK complex is a ULK1 initiation complex.
  • Embodiment 50 The method of Embodiment 48, wherein the agent is a compound of any one of Embodiments 33-41.
  • LCMS Instrument Details Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and ELS detectors. Softa model 400.
  • Example 2 Synthesis of 3-ethyl-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl ⁇ -3H,4H- benzo[g]quinazolin-4-one (A-44): [0494] The vial was charged with amine (1 equiv.), acid (1 equiv.), and ethylbis(propan-2- yl)amine (2.5 eq.) in DMSO (1 mL). Then HATU (1 equiv.) was added in one portion.
  • Example 3 Synthesis of 3-ethyl-2-[(2-hydroxy-1-phenylethyl)sulfanyl]-3H,4H- benzo[g]quinazolin-4-one (A-45)-: [0495] Step 1. Synthesis of 2-chloro-2-phenylethan-1-ol. Methyl 2-chloro-2-phenylacetate (2 g, 10.83 mmol) solution in ether (5 mL) was added dropwise at 0 oC toa suspension of LiAlH 4 (0.49 g, 12.9 mmol) in ether (25 mL) and the mixture was stirred for 1 h at 0 oC. Water (5 mL) was added dropwise at this temperature.
  • Example 4 - Synthesis of 2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl ⁇ sulfanyl)-4- hydroxy-N,N-dimethylbutanamide (A-46): [0497] Step 1. Synthesis of 3-ethyl-2-[(2-oxooxolan-3-yl)sulfanyl]-3H,4H- benzo[g]quinazolin-4-one.
  • Example 6 Synthesis of 3-ethyl-2- ⁇ [(1R)-2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl ⁇ - 3H,4H-benzo[g]quinazolin-4-one, (A-50) and 3-ethyl-2- ⁇ [(1S)-2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl ⁇ -3H,4H-benzo[g]quinazolin-4-one, (A-51): [0505] Step 1. Synthesis of 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin-4-one.
  • Step 2 Synthesis of ethyl 2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl ⁇ sulfanyl)-2-phenylacetate.
  • 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin-4- one (1.84 g, 7.17 mmol)
  • 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin-4-one (2.09 g, 8.60 mmol) in DMSO (20 mL) was added DIEA (1.38 g, 10.7 mmol) at 50 °C, and the reaction mixture was stirred for 16 h.
  • Step 3 Synthesis of 2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl ⁇ sulfanyl)-2- phenylacetic acid.
  • Example 7 3-ethyl-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl ⁇ -3H,4H,6H,7H,8H,9H- cyclohexa[g]quinazolin-4-one (A-58): [0513] Step 1. Synthesis of 3-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid.
  • Isothiocyanatoethane (636 mg, 7.30 mmol) was added to a mixture of 3-amino-5,6,7,8- tetrahydronaphthalene-2-carboxylic acid (1.27 g, 6.64 mmol) and triethylamine (1.47 g, 14.6 mmol) in anhydrous EtOH (50 mL). The mixture was refluxed for 4 h. The mixture was cooled to RT.
  • Step 3 Synthesis of ethyl 2-( ⁇ 3-ethyl-4-oxo-3H,4H,6H,7H,8H,9H- cyclohexa[g]quinazolin-2-yl ⁇ sulfanyl)-2-phenylacetate.
  • Step 6 Synthesis of 3-ethyl-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl ⁇ - 3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-4-one.
  • Example 8 Synthesis of 2- ⁇ [1-(4- ⁇ 2-[2-(2-aminoethoxy)ethoxy]ethoxy ⁇ phenyl)-2-[(3S)-3- hydroxypyrrolidin-1-yl]-2-oxoethyl]sulfanyl ⁇ -3-ethyl-3H,4H-benzo[g]quinazolin-4-one (A-61): [0520] Step 1. Synthesis of benzyl N- ⁇ 2-[2-(2-hydroxyethoxy)ethoxy]ethyl ⁇ carbamate.
  • Step 3 Synthesis of methyl 2-(4- ⁇ 2-[2-(2- ⁇ [(benzyloxy)carbonyl]amino ⁇ ethoxy)ethoxy]ethoxy ⁇ phenyl)acetate.
  • Step 10 Synthesis of 2- ⁇ [1-(4- ⁇ 2-[2-(2-aminoethoxy)ethoxy]ethoxy ⁇ phenyl)-2-[(3S)- 3-hydroxypyrrolidin-1-yl]-2-oxoethyl]sulfanyl ⁇ -3-ethyl-3H,4H-benzo[g]quinazolin-4-one (A- 61).
  • Example 9 Synthesis of 2- ⁇ [(1R*)-2-[(2R)-2-( ⁇ 1,4-dioxa-8-azaspiro[4.5]decan-8- yl ⁇ methyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl]sulfanyl ⁇ -3-ethyl-3H,4H-benzo[g]quinazolin-4- one (A-62): [0530] Step 1. Synthesis of tert-butyl (2R)-2-( ⁇ 1,4-dioxa-8-azaspiro[4.5]decan-8- yl ⁇ methyl)pyrrolidine-1-carboxylate.
  • Example 10 Synthesis of 2 ⁇ ( ⁇ 3 ⁇ ethyl ⁇ 4 ⁇ oxo ⁇ 3H,4H ⁇ benzo[g]quinazolin ⁇ 2 ⁇ yl ⁇ sulfanyl) ⁇ N,N ⁇ dimethyl ⁇ 3 ⁇ phenylpropanamide (A-64): [0534] Step 1. Synthesis of 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin-4-one.
  • Isothiocyanatoethane (10.2 g, 117 mmol) was added to a mixture of 3-aminonaphthalene-2- carboxylic acid (20 g, 106 mmol) and triethylamine (23.78 g, 234 mmol) in anhydrous ethanol (500 mL). The mixture was refluxed until the starting material was consumed (4 h; TLC, ethyl acetate/methanol, 99.9:0.1) and cooled to room temperature.
  • Step 2 Synthesis of methyl 2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl ⁇ sulfanyl)-3-phenylpropanoate.
  • Dimethylamine hydrochloride (0.0331 g, 0.407 mmol), ethylbis(propan-2-yl)amine (0.142 g, 1.10 mmol) and 1- [(dimethylamino)(dimethyliminiumyl)methyl]-3-oxo-1H,2H,3H-3 ⁇ 5-[1,2,3]triazolo[5,4- b]pyridin-3-ylium-2-ide; hexafluoro- ⁇ 5-phosphanuide (0.168 g, 0.443 mmol) were added to a stirred solution of 2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl ⁇ sulfanyl)-3- phenylpropanoic acid (0.15 g, 0.370 mmol) in DMF (10 mL), and the mixture was stirred at room temperature overnight.
  • Example 11 Synthesis of 2-( ⁇ 9-chloro-2H,3H-imidazo[1,2-c]quinazolin-5-yl ⁇ sulfanyl)-2- phenyl-1-(piperazin-1-yl)ethan-1-one (A-65): [0538] Step 1. Synthesis of 2-[(2,6-dichloroquinazolin-4-yl)amino]ethan-1-ol.
  • Example 10 Synthesis of 6-chloro-3-ethyl-2- ⁇ [2-oxo-1-phenyl-2-(pyrrolidin-1- yl)ethyl]sulfanyl ⁇ -3,4-dihydroquinazolin-4-one (C-1)
  • Scheme 1 Synthesis of 2-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-2- phenylacetic acid: [0545] Step 1. Synthesis of 6-chloro-3-ethyl-2-mercaptoquinazolin-4(3H)-one.
  • Step 3 Synthesis of 2-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-2- phenylacetic acid.
  • Example 11 Synthesis of 6-chloro-3-ethyl-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl ⁇ -3,4-dihydroquinazolin-4-one (C-12): [0550] A vial was charged with amine (1.1 eq.), acid (1 eq.), and ethylbis(propan-2-yl)amine (2.5 eq.) in DMSO (1 mL). Then, HATU (1.15 eq.) was added in one portion. The reaction mixture was stirred at room temperature for 2 h and at 80 oC overnight. Then, the mixture was cooled to room temperature and evaporated to dryness.
  • Example 12 Synthesis of rel-6-chloro-3-ethyl-2- ⁇ [(1R)-2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl ⁇ -3,4-dihydroquinazolin-4-one (C-14) and rel-6-chloro-3-ethyl-2- ⁇ [(1S)-2-oxo- 1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl ⁇ -3,4-dihydroquinazolin-4-one (C-15): [0552] Step 1.
  • Example 13 Synthesis of 2-( ⁇ 2-[(3R)-3-aminopyrrolidin-1-yl]-2-oxo-1-phenylethyl ⁇ sulfanyl)-6- chloro-3-ethyl-3,4-dihydroquinazolin-4-one (C-25): [0555] Acetyl acetate (0.0118 g, 0.115 mmol, 0.011 mL) was added to a stirred solution of 2- ( ⁇ 2-[(3R)-3-aminopyrrolidin-1-yl]-2-oxo-1-phenylethyl ⁇ sulfanyl)-6-chloro-3-ethyl-3,4- dihydroquinazolin-4-one (0.13 g, 0.0293 mmol, 10% crude) and ethylbis(propan-2-yl)amine (0.0148 g, 0.114 mmol, 0.02 mL) in dichloromethane (2 mL) at room temperature.
  • Example 14 Synthesis of N-[(3S)-1- ⁇ 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl ⁇ pyrrolidin-3-yl]-4-oxo-4-(pyrrolidin-1-yl)butanamide (C-27): [0557] Step 1.
  • Step 2 Synthesis of 2-( ⁇ 2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxo-1- phenylethyl ⁇ sulfanyl)-6-chloro-3-ethyl-3,4-dihydroquinazolin-4-one.
  • Step 2 Synthesis of 2-( ⁇ 2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-2-oxo-1- phenylethyl ⁇ sulfanyl)-6-chloro-3-ethyl-3,4-dihydroquinazolin-4-one.
  • Example 16 Synthesis of (3S)-1- ⁇ 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl ⁇ -N-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]pyrrolidine-3- carboxamide (C-29) [0564] Step 1. Synthesis of tert-butyl (3S)-3- ⁇ [3-(4-methylpiperazin-1-yl)-3- oxopropyl]carbamoyl ⁇ pyrrolidine-1-carboxylate.
  • the obtained mixture was diluted with water (25 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (20 mL x 3) and brine (20 mL), dried over sodium sulfate, filtered, and evaporated in vacuo.
  • Example 17 Synthesis of N-(1- ⁇ 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl ⁇ azetidin-3-yl)acetamide (C-30): [0567] Step 1. Synthesis of N-[1-(2-chloro-2-phenylacetyl)azetidin-3-yl]acetamide.
  • Step 2 Synthesis of N-(1- ⁇ 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl ⁇ azetidin-3-yl)acetamide.
  • Ethylbis(propan-2-yl)amine (0.31 g, 2.39 mmol) was added to the solution of 6-chloro-3-ethyl-2-mercaptoquinazolin-4(3H)-one (0.38 g, 1.57 mmol) and N-(1-(2-chloro-2-phenylacetyl)azetidin-3-yl)acetamide (0.43 g, 1.61 mmol) in dry DMSO (10 mL). The reaction mixture was stirred at 50 0 C overnight, cooled to room temperature, diluted with water (30 mL), and extracted with ethylacetate (20 mL x 3).
  • Example 18 Synthesis of 2-(1- ⁇ 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl ⁇ azetidin-3-yl)-N-methylacetamide (C-32): [0570] Step 1. Synthesis of tert-butyl 3-[(methylcarbamoyl)methyl]azetidine-1-carboxylate.
  • Ethylbis(propan-2-yl)amine (4.8 g, 37.1 mmol) was added to the solution of the 2-(1-(tert- butoxycarbonyl)azetidin-3-yl)acetic acid (2.0 g, 9.3 mmol), HOBt (1.5 g, 11.1 mmol), and EDC hydrochloride (2.7 g, 14 mmol) in dry dichloromethane (40 mL). The reaction mixture was stirred at room temperature for 30 min, cooled to 0 oC, and methylamine hydrochloride (0.94 g, 13.9 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then washed twice with water (40 mL).
  • Step 2 Synthesis of 2-(azetidin-3-yl)-N-methylacetamide hydrochloride. A mixture of tert-butyl 3-(2-(methylamino)-2-oxoethyl)azetidine-1-carboxylate (0.9 g, 3.94 mmol) and hydrogen chloride sat.
  • Step 4 Synthesis of 2-(1- ⁇ 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl ⁇ azetidin-3-yl)-N-methylacetamide.
  • Ethylbis(propan-2-yl)amine (0.65 g, 5.02 mmol) was added to a solution of 6-chloro-3-ethyl-2-mercaptoquinazolin-4(3H)-one (0.604 g, 2.51 mmol) and 2-(1-(2-chloro-2-phenylacetyl)azetidin-3-yl)-N-methylacetamide (0.704 g, 2.51 mmol) in dry DMSO (10 mL). The reaction mixture was stirred at 50 0 C overnight, cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (20 mL x 3).
  • Example 19 Synthesis of 3-ethyl-6-methyl-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl ⁇ -3,4-dihydroquinazolin-4-one (C-35): [0575] Step 1. Synthesis of 3-ethyl-6-methyl-2-sulfanyl-3,4-dihydroquinazolin-4-one.
  • Step 2 Synthesis of methyl 2-[(3-ethyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetate.
  • Step 3 Synthesis of give 2-[(3-ethyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetic acid.
  • Step 4 Synthesis of 3-ethyl-6-methyl-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl ⁇ -3,4-dihydroquinazolin-4-one.
  • Example 20 Synthesis of 3-ethyl-4-oxo-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl ⁇ - 3,4-dihydroquinazoline-6-carbonitrile (C-40): [0580] Step 1. Synthesis of 2-amino-5-cyanobenzoate.
  • Step 2 Synthesis of 2-amino-5-cyanobenzoic acid. Sodium hydroxide (2.0 g, 50.0 mmol) solution in water (20 mL) was added to a methyl 2-amino-5-cyanobenzoate (3.0 g, 17.0 mmol) solution in ethanol (100 mL). The reaction mixture was stirred at room temperature overnight.
  • Trimethylsilyl trifluoromethanesulfonate (0.3 g, 1.33 mmol) solution in dichloromethane (10 mL) was added dropwise to a solution of tert-butyl 4-(2-((8-bromo-6-cyano-3-ethyl-4-oxo-3,4-dihydroquinazolin- 2-yl)thio)-2-phenylacetyl)piperazine-1-carboxylate (0.6 g, 1.12 mmol) solution in dichloromethane (20 mL) at 0 oC.
  • the reaction mixture was stirred at the same temperature for 1 h, and then washed with aq. saturated solution of sodium bicarbonate (30 mL).
  • Example 21 Synthesis of 3-ethyl-2-( ⁇ 2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxo-1- phenylethyl ⁇ sulfanyl)-6-(trifluoromethyl)-3,4-dihydroquinazolin-4-one, (C-41): [0585] Step 1. Synthesis of 3-ethyl-2-mercapto-6-(trifluoromethyl)quinazolin-4(3H)-one.
  • Step 3 Synthesis of 3-ethyl-2-( ⁇ 2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxo-1- phenylethyl ⁇ sulfanyl)-6-(trifluoromethyl)-3,4-dihydroquinazolin-4-one.
  • Ethylbis(propan-2- yl)amine (0.52 g, 4.02 mmol) was added to a solution of 3-ethyl-2-mercapto-6- (trifluoromethyl)quinazolin-4(3H)-one (0.73 g, 2.66 mmol) and 2-chloro-1-((S)-3- hydroxypyrrolidin-1-yl)-2-phenylethan-1-one (0.64 g, 2.67 mmol) in dry DMSO (20 mL). The reaction mixture was stirred at 50 oC overnight, cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (20 mL x 3).
  • Example 22 Synthesis of 2-((6-chloro-3-ethyl-4-oxo-3, 4-dihydroquinazolin-2-yl)thio)-N,N- dimethyl-2-phenylacetamide (C-42): [0588] Step 1. Synthesis of 2-hydroxy-N,N-dimethyl-2-phenylacetamide. To a solution of benzaldehyde (3.1 g, 29.2 mmol) and N,N-dimethylformamide (2.13 g, 29.2 mmol) in THF (20 mL) was added lithium diisopropylamide (3.11 g, 29.0 mmol) at -70 °C.
  • Example 23 2-((3-ethyl-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)thio)-N,N-dimethyl-2- phenylacetamide (C-43): [0592] Step 1. Synthesis of methyl 4-amino-[1,1'-biphenyl]-3-carboxylate.
  • Step 3 Synthesis of 2-[(3-ethyl-4-oxo-6-phenyl-3,4-dihydroquinazolin-2-yl)sulfanyl]- N,N-dimethyl-2-phenylacetamide.
  • Example 24 Synthesis of N-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-N- phenylpiperidine-4-carboxamide (C-46): [0596] Step 1. Synthesis of tert-butyl 4-(phenylcarbamoyl)piperidine-1-carboxylate. To a solution of 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (500 mg, 2.18 mmol) in DMF (5 mL) were added aniline (304 mg, 3.27 mmol), HATU (991 mg, 2.61 mmol), and DIEA (845 mg, 6.54 mmol).
  • Step 3 Synthesis of 2-(bromomethyl)-6-chloro-3-ethylquinazolin-4(3H)-one.
  • acetic acid 15 mL
  • reaction mixture was stirred at 0 °C for 4 h. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with EtOAc (50 mL ⁇ 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.
  • Example 25 Synthesis of 6-chloro-3-ethyl-2-(2-oxo-1-phenyl-2-(piperazin-1-yl)- ethoxy)quinazolin-4(3H)-one (C-47): [0601] Step 1. Synthesis of 6-chloro-3-ethyl-2-sulfanylidene-1,2,3,4-tetrahydroquinazolin-4- one.
  • Isothiocyanatoethane (5.57 g, 64.0 mmol) was added to a mixture of 2-amino-5-chlorobenzoic acid (10 g, 58.2 mmol) and triethylamine (12.9 g, 128 mmol) in anhydrous ethanol (500 mL). The reaction mixture was refluxed at 85 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature.
  • Example 26 Synthesis of 7-chloro-2-ethyl-3-( ⁇ 2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxo-1- phenylethyl ⁇ sulfanyl)-1,2-dihydroisoquinolin-1-one (C-48): [0607] Step 1. Synthesis of 7-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinoline-1,3-dione. 2-(4- chlorophenyl)acetic acid (5 g, 29.3 mmol) was dissolved in DCM (150 mL) at RT under N 2 atmosphere.
  • Step 4 Synthesis of 7 ethyl 2-[(7-chloro-2-ethyl-1-oxo-1,2-dihydroisoquinolin-3- yl)sulfanyl]-2-phenylacetate.
  • reaction mixture was concentrated under reduced pressure to give a residue.
  • the crude product was more purified by prep-HPLC (ACN/H 2 O/0.1% NH 4 HCO 3 ) to give the desired product 7-chloro-2-ethyl-3-( ⁇ 2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxo-1- phenylethyl ⁇ sulfanyl)-1,2-dihydroisoquinolin-1-one (125 mg, 0.2839 mmol) as a light-yellow solid (C-48).
  • Example 27 Synthesis of (R)-6-chloro-3-ethyl-2-(methyl(2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl)amino)quinazolin-4(3H)-one (C-50): [0614] Step 1. Synthesis of tert-butyl (R)-4-(2-(((benzyloxy)carbonyl)amino)-2- phenylacetyl)piperazine-1-carboxylate.
  • Step 4 Synthesis of tert-butyl (R)-4-(2-((6-chloro-3-ethyl-4-oxo-3,4- dihydroquinazolin-2-yl)(methyl)amino)-2-phenylacetyl)piperazine-1-carboxylate.
  • Example 28 6,7-dichloro-3-ethyl-2- ⁇ [2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl ⁇ -3,4- dihydroquinazolin-4-one (C-52): [0620] Step 1. Synthesis of 6,7-dichloro-3-ethyl-2-sulfanyl-3,4-dihydroquinazolin-4-one.
  • Step 2 Synthesis of ethyl 2-[(6,7-dichloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetate.
  • Example 29 Synthesis of (3S)-1- ⁇ 2-[(6-chloro-3-methoxyquinoxalin-2-yl)sulfanyl]-2- phenylacetyl ⁇ -N-methylpyrrolidine-3-carboxamide (C-53): [0624]
  • Step-1 Synthesis of 2,6-dichloro-3-methoxyquinoxaline.
  • Sodium methanolate (98.3 mg, 1.82 mmol) was diluted with methanol (3 mL) and added over a 10 min period to a solution of 2,3,6-trichloroquinoxaline (350 mg, 1.49 mmol) in methanol (3 mL) at 50 °C.
  • Step 6 Synthesis of (3S)-1- ⁇ 2-[(6-chloro-3-methoxyquinoxalin-2-yl)sulfanyl]-2- phenylacetyl ⁇ -N-methylpyrrolidine-3-carboxamide.
  • methanamine hydrochloride 110 mg, 1.63 mmol was added at RT.
  • the reaction mixture was stirred at 50 °C for 5 h.
  • the reaction mixture was cooled to RT and quenched by addition of water.
  • the aqueous layer was separated and extracted with EtOAc (3 ⁇ 50 mL).
  • the combined organic layers were washed with brine (2 ⁇ 50 mL).
  • the organics were then separated and dried over sodium sulfate before concentration to dryness.
  • Example 30 Synthesis of 2-[(3,6-dichloroquinoxalin-2-yl)sulfanyl]-2-phenyl-1-(piperazin-1- yl)ethan-1-one (C-58): [0632] Step 1. Synthesis of 2-bromo-2-phenylacetyl chloride. To the solution of 2-bromo-2- phenylacetic acid (1 g, 4.65 mmol) in dichloromethane (30 mL) was added thionyl chloride (5.53 g, 46.5 mmol).
  • Step 2 Synthesis of tert-butyl 4-(2-bromo-2-phenylacetyl)piperazine-1-carboxylate. To a solution of the compound of the previous step in dichloromethane (20 mL) was added triethylamine (1.39 g, 13.8 mmol) and tert-butyl piperazine-1-carboxylate (1.08 g, 4.62 mmol). The reaction mixture was stirred at RT for 2 h.
  • Step 7 Synthesis of tert-butyl 4- ⁇ 2-[(3,6-dichloroquinoxalin-2-yl)sulfanyl]-2- phenylacetyl ⁇ piperazine-1-carboxylate.
  • Example 31 Synthesis of 2-[(6-chloro-3-methylquinoxalin-2-yl)sulfanyl]-2-phenyl-1- (piperazin-1-yl)ethan-1-one (C-59): [0640] Step 1. Synthesis of 2-bromo-2-phenylacetyl chloride. To a solution of 2-bromo-2- phenylacetic acid (1 g, 4.65 mmol) in dichloromethane (30 mL) was added thionyl chloride (5.53 g, 46.5 mmol). The reaction mixture was stirred at 40 °C for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure and used for the next step directly without work-up and further purification.
  • Step-2 Synthesis of tert-butyl 4-(2-bromo-2-phenylacetyl)piperazine-1-carboxylate.
  • dichloromethane 20 mL
  • triethylamine 1.39 g, 13.8 mmol
  • tert-butyl piperazine-1-carboxylate 1.08 g, 4.62 mmol.
  • the reaction mixture was stirred at RT for 2 h. After the reaction was complete, water was added, and the solution was extracted with EtOAc (20 mL ⁇ 3).
  • Step 8 Synthesis of tert-butyl 4- ⁇ 2-[(6-chloro-3-methylquinoxalin-2-yl)sulfanyl]-2- phenylacetyl ⁇ piperazine-1-carboxylate.
  • Example 32 Synthesis of 2-((6-chloro-3-methoxyquinolin-2-yl)thio)-1-((S)- 3(((methylamino)oxy) carbonyl) pyrrolidin-1-yl)-2-phenylethan-1-one (C-64): [0650] Step 1. Synthesis of 3-bromo-6-chloroquinoline. NBS (2.4 g, 13.4 mmol) was added to a solution of 6-chloroquinoline (2.0 g, 12.2 mmol) in acetic acid (15 mL). The mixture was stirred at 115 °C for 2 h. The mixture solution was concentrated to remove acetic acid under reduced pressure.
  • Step 2 Synthesis of 6-chloro-3-methoxyquinoline. Methoxysodium (2.56 g, 47.4 mmol) and CuI (270 mg, 1.42 mmol) were added to a solution of 3-bromo-6-chloroquinoline (2.3 g 948 mmol) in NMP (20 mL) and MeOH (5 mL) The mixture was stirred at 140 °C for 16 h under N 2 .
  • Step 6 Synthesis of ethyl 2-((6-chloro-3-methoxyquinolin-2-yl)thio)-2-phenylacetate.
  • DMSO dimethyl sulfoxide
  • DIEA dimethyl sulfoxide
  • ethyl2-bromo-2-phenylacetate 295 mg, 1.22 mmol.
  • the mixture solution was stirred at 50 °C for 2 h. Water was added to the mixture. The aqueous solution was extracted with EtOAc (3 ⁇ 10 mL).
  • Step 8 Synthesis of methyl (3S)-1-(2-((6-chloro-3-methoxyquinolin-2-yl)thio)-2- phenylacetyl) pyrrolidine-3-carboxylate.
  • Example 33 Synthesis of 2-[(6-chloro-3- methylquinolin-2-yl)sulfanyl]-2-phenyl-1-(piperazin- 1-yl)ethan-1-one (C-65): [0660] Step 1. Synthesis of N-(4-chlorophenyl)propanamide. To a solution of 4-chloroaniline (900 mg, 7.0 mmol) in DCM (5 mL) were added TEA (213.6 mg, 2.1 mmol) and propanoyl propanoate (1.3 g, 10.5 mmol) at RT. The reaction mixture was stirred for 1.5 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2 Synthesis of 2,6-dichloro-3-methylquinoline. To a mixture of POCl 3 (1.7 g, 10.8 mmol) was slowly added DMF (878 mg, 5.88 mmol) at 0 °C, and the mixture was stirred at this temperature for 15 min. To the mixture was added N-(4-chlorophenyl)propanamide (1 g, 5.4 mmol), and the mixture was stirred at 70 °C for 2.5 h.
  • Example 34 Synthesis of (3S)-1- ⁇ 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylpropanoyl ⁇ -N-methylpyrrolidine-3-carboxamide (C-68): [0667] Step 1. Synthesis of 6-chloro-3-ethyl-2-sulfanylidene-1,2,3,4-tetrahydroquinazolin-4- one.
  • Step 2 Synthesis of ethyl 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetate.
  • 6-chloro-3-ethyl-2-sulfanyl-3,4-dihydroquinazolin- 4-one 8.0 g, 33.2 mmol
  • ethyl 2-bromo-2-phenylacetate 8.87 g, 36.5 mmol
  • dry DMSO 50 mL
  • reaction mixture was stirred at 55 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature and diluted with distilled water (150 mL) and EtOAc (200 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude.
  • Step 3 Synthesis of ethyl 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2- phenylpropanoate.
  • Example 35 Synthesis of 6-chloro-3-ethyl-2-((2-oxo-1-phenyl-2-((S)-3-(3-(2-(piperazin-1- yl)ethyl)-1H-1,2,4-triazol-5-yl)pyrrolidin-1-yl)ethyl)thio)quinazolin-4(3H)-one (C-70): [0675] Step 1. Synthesis of tert-butyl 4-(2-cyanoethyl)piperazine-1-carboxylate.
  • Step 4 Synthesis of tert-butyl (S)-4-(2-(5-(1-((benzyloxy)carbonyl)pyrrolidin-3-yl)- 1H-1,2,4-triazol-3-yl)ethyl)piperazine-1-carboxylate.
  • Step 7 Synthesis of 6-chloro-3-ethyl-2-((2-oxo-1-phenyl-2-((S)-3-(3-(2-(piperazin-1- yl)ethyl)-1H-1,2,4-triazol-5-yl)pyrrolidin-1-yl)ethyl)thio)quinazolin-4(3H)-one.
  • Example 36 Synthesis of 2-[(5-bromo-3-methylpyridin-2-yl)sulfanyl]-1-[(3S)-3- hydroxypyrrolidin-1-yl]-2-phenylethan-1-one: [0684] Step-1. Synthesis of 5-bromo-3-methylpyridine-2-thiol [0685] 2,5-dibromo-3-methylpyridine (7.5 g, 29.8 mmol) was added to a stirred solution of thiourea (6.80 g, 89.4 mmol) in HCl 20% aq solution (150 mL). The reaction mixture was stirred at reflux for 8 h.
  • reaction mixture was stirred at room temperature for 16 h, after completion of reaction (monitored by TLC) the reaction mixture was poured into water (200 mL). The organic layer was separated, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Obtained crude product was purified by column chromatography (silica gel, acetonitrile/chloroform) to give 2-[(5-bromo-3-methylpyridin-2-yl)sulfanyl]-1-[(3S)-3-hydroxypyrrolidin-1-yl]-2-phenylethan-1- one (4.37 g, 10.7 mmol, 95% purity, 46.8% yield).
  • Example 37 Synthesis of 5-[6-( ⁇ 2-[(3S)-3-hydroxypyrrolidin-1-yl]-2-oxo-1- phenylethyl ⁇ sulfanyl)-5-methylpyridin-3-yl]thiophene-2-carboxamide, (I-1) [0690] 2-[(5-bromo-3-methylpyridin-2-yl)sulfanyl]-1-[(3S)-3-hydroxypyrrolidin-1-yl]-2- phenylethan-1-one (1 eq.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2- carboxamide (1.5 eq.) were mixed in dry dioxane (1 mL) followed by XPhos Pd G3 (0.05 eq.) and disodium carbonate (2.5 eq.) addition in one portion in an inert atmosphere.
  • XPhos Pd G3 0.05 eq.
  • Example 38 Synthesis of 1-[(3S)-3-hydroxypyrrolidin-1-yl]-2-[(3-methyl-5- ⁇ 1H-pyrrolo[2,3- b]pyridin-3-yl ⁇ pyridin-2-yl)sulfanyl]-2-phenylethan-1-one (I-20): [0692] Step-1.
  • Step-7 Synthesis of 2-((3-ethyl-5-(1H-pyrrolo[3,2-c]pyridin-3-yl)pyridin-2-yl)thio)-1- ((S)-3-hydroxypyrrolidin-1-yl)-2-phenylethan-1-one [0715] To a solution of 2-((5-bromo-3-ethylpyridin-2-yl)thio)-1-((S)-3-hydroxypyrrolidin-1- yl)-2-phenylethan-1-one (100 mg, 0.238 mmol) in 1,4-dioxane (2 mL) was added with KOAc (46 mg, 0.476 mmol), Pd(dppf)Cl 2 (17.4 mg, 0.024 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (66.5 mg, 0.262 m
  • the mixture was stirred at 110 °C for 6 h under a N 2 atmosphere. After the reaction was completed, the mixture was cooled to 25 °C.3-bromo-1H- pyrrolo[3,2-c]pyridine (70 mg, 0.357 mmol), K 2 CO 3 (98 mg, 0.714 mmol), XPhos (17 mg, 0.036 mmol), Pd(dppf)Cl 2 (17 mg, 0.024 mmol) and water (0.5 mL) was added to the mixture. The mixture was irradiated in a microwave reactor at 120 °C for 4 h under a N 2 atmosphere. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure.
  • Example 40 Synthesis of (3S)-N-methyl-1- ⁇ 2-[(3-methyl-5- ⁇ 1H-pyrrolo[3,2-c]pyridin-3- yl ⁇ pyridin-2-yl)sulfanyl]-2-phenylacetyl ⁇ pyrrolidine-3-carboxamide (I-22): [0716] Step-1. Synthesis of ethyl 2-((5-bromo-3-methylpyridin-2-yl)thio)-2-phenylacetate [0717] NaSH (4.33 g, 52.6 mmol) was added to a solution of 5-bromo-2-fluoro-3- methylpyridine (5.00 g, 26.3 mmol) in DMSO (50 mL).
  • the mixture was irradiated in a microwave reactor at 150 °C for 10 h under a N 2 atmosphere.
  • the reaction was quenched by water (40 mL).
  • the aqueous layer was extracted with ethyl acetate (3 ⁇ 50 mL).
  • the combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated to afford the crude.
  • Example 42 Synthesis of N 1 -(2-(2-((4-(3-(difluoromethyl)-4-(2-(2-((2,2,2- trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)benzyl)amino) ethoxy)ethoxy)ethyl)-N 4 -(((2R)-1-(2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)- 2-phenylacetyl)pyrrolidin-2-yl)methyl)succinamide (B-5):
  • Step 1 Synthesis of tert-butyl N- ⁇ [(2R)-1-[2-( ⁇ 3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl ⁇ sulfanyl)-2-phenylacetyl]pyrrolidin-2-yl]methyl ⁇ carbamate.
  • Step 6 Synthesis of N 1 -(2-(2-(2-aminoethoxy)ethoxy)ethyl)-N 4 -(((2R)-1-(2-((3-ethyl- 4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2-phenylacetyl)pyrrolidin-2- yl)methyl)succinamide.
  • reaction mixture was stirred for 16 h at RT. After the reaction was complete, water (30 mL) was added. The mixture was extracted with EtOAc (50 mL ⁇ 3). Then, the combined organic layers were washed with brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • Step 10 Synthesis of N 1 -(2-(2-((4-(3-(difluoromethyl)-4-(2-(2-((2,2,2- trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)benzyl)amino) ethoxy)ethoxy)ethyl)-N 4 -(((2R)-1-(2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)- 2-phenylacetyl)pyrrolidin-2-yl)methyl)succinamide.
  • Example 43 Synthesis of tert-butyl N-[4-(4- ⁇ [3-(difluoromethyl)-1- ⁇ 4-[(2- ⁇ 2-[2-(3- ⁇ [(3S)-1-[2- ( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl ⁇ sulfanyl)-2phenylacetyl]pyrrolidin-3- yl]carbamoyl ⁇ propanamido)ethoxy]ethoxy ⁇ ethyl)c-arbamoyl]phenyl ⁇ -1H-pyrazol-4- yl]carbamoyl ⁇ -1,3-oxazol-2-yl)pyridin-2-yl]-N-(2,2,2-trifluor-oethyl)carbamate (B-7) and N'
  • Step 1 Synthesis of tert-butyl ((3S)-1-(2-((3-ethyl-4-oxo-3,4- dihydrobenzo[g]quinazolin-2-yl)thio)-2-phenylacetyl)pyrrolidin-3-yl)carbamate.
  • Step 3 Synthesis of ethyl 3- ⁇ [(3S)-1-[2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl ⁇ sulfanyl)-2-phenylacetyl]pyrrolidin-3-yl]carbamoyl ⁇ propanoate.
  • Step 4 Synthesis of 3- ⁇ [(3S)-1-[2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl ⁇ sulfanyl)-2-phenylacetyl]pyrrolidin-3-yl]carbamoyl ⁇ propanoic acid.
  • Step 8 Synthesis of N'-(2- ⁇ 2-[2-( ⁇ 4-[3-(difluoromethyl)-4-(2- ⁇ 2-[(2,2,2- trifluoroethyl)amino]pyridin-4-yl ⁇ -1,3-oxazole-4-amido)-1H-pyrazol-1- yl]phenyl ⁇ formamido)ethoxy]ethoxy ⁇ ethyl)-N-[(3S)-1-[2-( ⁇ 3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl ⁇ sulfan-yl)-2-phenylacetyl]pyrrolidin-3-yl]butanediamide.
  • reaction was quenched with saturated aqueous sodium bicarbonate and extracted with DCM (3 ⁇ 20 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to dryness.
  • Step 1 Synthesis of (E)-4-((6-methoxybenzo[d]thiazol-2-yl)diazenyl)-N,N- dimethylaniline.
  • the mixture of 6-methoxy-1,3-benzothiazol-2-amine (6.0 g, 33.2 mmol) was mixed with glacial acetic acid (20 mL) and cooled to 0 °C in an ice bath. Concentrated sulfuri (95 %, 7.0 mL) was added. Then, a solution of NaNO 2 (2.74 g, 39.8 mmol) in deionized water (10 mL) was added dropwise to the mixture. The mixture was stirred at 0 °C for 2 h.
  • Step 2 Synthesis of (E)-2-((4-(dimethylamino)phenyl)diazenyl)benzo[d]thiazol-6-ol.
  • Step 3 Synthesis of 4-[(1E)-2- ⁇ 6-[2-(2-bromoethoxy)ethoxy]-1,3-benzothiazol-2- yl ⁇ diazen-1-yl]-N,N-dimethylaniline.
  • Step 5 Synthesis of 3-( ⁇ [(2R)-1-[2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl ⁇ sulfanyl)-2-phenylacetyl]pyrrolidin-2-yl]methyl ⁇ carbamoyl)propanoic acid.
  • Step 7 Synthesis of N- ⁇ [(2R)-1-[2-( ⁇ 3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl ⁇ sulfanyl)-2-phenylacetyl]pyrrolidin-2-yl]methyl ⁇ -4-oxo-4-(piperazin-1-yl)butanamide.

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Abstract

La présente invention concerne le recrutement d'un complexe d'initiation ULK (par exemple, un complexe d'initiation ULK1) utilisé pour induire une autophagie sélective, un procédé par lequel le mécanisme de dégradation est ciblé sur des substrats spécifiques. Il est divulgué des composés chimériques pour la liaison au complexe d'initiation ULK, comprenant une fraction de liaison de complexe ULK, un lieur et une fraction de liaison cible, ainsi qu'une cible d'intérêt.
PCT/US2024/057958 2023-12-01 2024-11-29 Modulateurs du complexe ulk et leurs utilisations Pending WO2025117886A1 (fr)

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WO2024236326A1 (fr) * 2023-05-18 2024-11-21 Ucl Business Ltd Molécule chimère

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US20190248806A1 (en) * 2014-08-25 2019-08-15 Salk Institute For Biological Studies Novel ulk1 inhibitors and methods using same
US20230039712A1 (en) * 2019-05-10 2023-02-09 Deciphera Pharmaceuticals, Llc Phenylaminopyrimidine amide autophagy inhibitors and methods of use thereof
WO2024236326A1 (fr) * 2023-05-18 2024-11-21 Ucl Business Ltd Molécule chimère

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