ULK complex modulators and uses thereof

Abstract

The present disclosure provides recruitment of a ULK initiation complex (e.g., a ULK1 initiation complex) used to induce selective autophagy, a process by which the degradative mechanism is targeted to specific substrates. Chimeric compounds for binding to the ULK initiation complex, comprising a ULK complex binding moiety, a linker, and a target binding moiety, are provided, as well as one or more targets of interest. The present disclosure also provides methods of using such compounds or compositions thereof.

Description

ULK COMPLEX MODULATORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No.63 / 605,380, filed December 1, 2023, the entirety of which is incorporated herein by reference.BACKGROUND

[0002] ULK complexes (e.g. ULK1 and ULK2), 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.SUMMARY

[0003] The therapeutic potential of harnessing cellular degradation systems to direct removal of specific targets has been well appreciated and extensively investigated for more than a decade. See, for example, Bondeson & Crews Annu Rev Pharmacol Toxicol 57: 107-123 (Sept. 6, 2017), and references cited therein. Particular focus has been on development of heterobi functional small molecule agents that recruit an E3 ligase (e.g., the cereblon protein) to a target of interest. Such recruitment leads to ubiquitination of the target, to promote its degradation via the proteosome.

[0004] The present disclosure provides alternative strategies to achieve targeted degradation. Among other things, 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.

[0005] 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 theautophagy 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. Recruitment of the 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. See, for example, Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Ravenhill, et al, Mol. Cell, 74(2): 320-329.e6; Turco, et al., J Mol Biol, 432(1): 123-134 (2020); Johansen & Lamark J Mol Bio 432(1):80-103 (Jan.3, 2020).

[0006] Without being bound by theory, the present disclosure proposes that promoting recruitment and / or assembly of the ULK initiation complex (e.g., a ULK1 initiation complex) represents a particularly useful and / or effective strategy for achieving selective removal of cellular components via the autophagy pathway.

[0007] 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). See, for example, Ravenhill, et al., Mol. Cell, 74(2):320- 329.e6 (2018); Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019). Moreover, one report has described artificially linking a peptide derived from ATG16L to a protein (FKBP) or mitochondrial cargo can trigger autophagic degradataion of the cargo. See Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019).

[0008] 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.

[0009] In certain aspects, the present disclosure provides compounds for binding to the ULK initiation complex and a target of interest. In some embodiments, the present disclosure provides compounds of formula I: A-B-C Ior 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, RAB5A, a peroxisome, a myddosome, MYD88, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes.

[0010] In certain aspects, the present disclosure provides moieties and / or compounds useful for binding to the ULK initiation complex. In some embodiments, the present disclosure provides compounds of formula II:or a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, CR7, S, NR7, S(O), S(O)2, C(O), or O; X2is N, C, or CR9; X3is N, NR9, O, CR9, C(R9)2; X4is N, NR2, CR2, C(R2)2, or C(NR2); X5is N, NR3, CR3, C(R3)2, or C(O);each R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a, or two R1can 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, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a; each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic; or R2and R3can 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; or two R3can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen,or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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 R4is optionally substituted with Z; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7), optionally substituted C1-C12aliphatic-R6, or optionally substituted 5- to 6-membered heteroaryl;R6is Z, -OH, -N(R7)2, -S(O)2-R8, C3-C12cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; or R7and R2, 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 R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, -OH, -O-C1-C12aliphatic, -NH2, -N(H)-C1- C12aliphatic, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and n is 0, 1, or 2.

[0011] In certain aspects, 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) forselective autophagy. In some embodiments, 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. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0014] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, 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. For example, in some cases, 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. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0016] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one ormore 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. For example, an aliphatic group can, in some embodiments, be a bivalent group. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is C1-6alkyl.

[0017] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, 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., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary 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.

[0018] 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. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2)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. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms.

[0019] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, 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 carbonatoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0020] 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.

[0021] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0022] 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.

[0023] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members (e.g., C5-14), 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., C6-12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “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. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include

[0024] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, 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. In some embodiments, carriers are or include one or more solid components.

[0025] Cycloaliphatic: As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8hydrocarbon or a bicyclic C7-10hydrocarbon that is completely saturated or that contains one ormore 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.

[0026] Cycloalkyl: As used herein, the term “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.

[0027] Cycloalkenyl: As used herein, the term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0028] Heteroaliphatic: The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, 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. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwise specified, 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.

[0029] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 12 ring atoms (e.g., 5- to 6- membered monocyclic heteroaryl or 9- to 12-membered bicyclic heteroaryl); having 6, 10, or 14 π-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. 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, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, triazolopyridyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, 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. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0030] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0031] 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. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicalsinclude, 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. The term “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. Exemplary 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.

[0032] Modulator: The term “modulator,” as used herein, refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, 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. For example, a modulator can be an agonist or an antagonist of a particular target, as those terms are defined herein. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0033] 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.

[0034] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other thanenteral 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.

[0035] Partially unsaturated: As used herein, the term “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.

[0036] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, 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. In some embodiments, pharmaceutical 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.

[0037] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, 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.

[0038] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying ortransporting 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. Some examples of 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; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or poly anhydrides; and other nontoxic compatible substances employed in pharmaceutical formulations.

[0039] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds 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). In some embodiments, 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. In some embodiments, 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, palmitate, pamoate,pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, / Moluencsulfonatc, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, 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.

[0040] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0041] Polycyclic’. As used herein, the term “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. For example, in some embodiments, 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.

[0042] Prevent or prevention: As used herein, the terms “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 consideredcomplete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0043] Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g.,refers to at least; andrefers to at leastUnless 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. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0044] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R°, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; – P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O– N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0045] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2, -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, –OSiR●3, -C(O)SR●,–(C1–4straight or branched alkylene)C(O)OR●, or –SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0046] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0047] Suitable substituents on the aliphatic group of R*include halogen, –R●, -(haloR●), -OH, – OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, 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, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] Suitable substituents on the aliphatic group of R†are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD,3 kD, about 2 kD, or about 1 kD. In some embodiments, 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. In some embodiments, 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.

[0051] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, 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.

[0052] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.

[0053] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0054] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroi someric forms. In some embodiments, 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.

[0055] Those of skill in the art will appreciate that 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.

[0056] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;11C,13C or14C for12C;13N or15N for14N;17O or18O for16O;36Cl for35Cl or37Cl;18F for19F;131I for127I; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0057] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, 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.

[0058] In some embodiments, where 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. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, 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.

[0059] Those skilled in the art will appreciate that a bond designated as in a small molecule structure, as used herein, 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. For example, the following structure:is intended to encompass both.

[0060] Those skilled in the art will further appreciate that, in small molecule structures, the symbol and , as used herein, refers to a point of attachment between two atoms.

[0061] 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. Compounds for Binding a ULK Initiation Complex

[0062] In certain aspects the present disclosure provides compounds for binding a ULK initiation complex (e.g., a ULK1 initiation complex or a ULK2 initiation complex). In some embodiments, such compounds comprise a targeting moiety for binding a target, thereby promoting autophagy of said target. In some embodiments, ULK binding is determined described according to methods described herein, for example in Example 52. In some embodiments, 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; andC 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, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes.

[0063] In some embodiments, a ULK complex binding moiety (i.e., moiety A) is a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, CR7, S, NR7, S(O), S(O)2, C(O), or O; X2is N, C, or CR9; X3is N, NR9, O, CR9, C(R9)2; X4is N, NR2, CR2, C(R2)2, or C(NR2); X5is N, NR3, CR3, C(R3)2, or C(O); each R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a, ortwo R1are 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, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a; each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic; or R2and R3are 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; or two R3are taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen, or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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 R4is optionally substituted with Z; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7), optionally substituted C1-C12aliphatic-R6, or optionally substituted 5- to 6-membered heteroaryl; R6is Z, -OH, -N(R7)2, -S(O)2-R8, C3-C12cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-memberedheteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; or R7and R2, 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 R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, -OH, -O-C1-C12aliphatic, -NH2, -N(H)-C1- C12aliphatic, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and n is 0, 1, or 2.

[0064] It is understood that compounds encompassed by genera described herein are those that are chemically feasible and stable, as understood by a person of skill in the art. For example, a compound of formula II is understood to refer to, for example:, wherein X3, X4, and X5are as described herein singly and in combination for chemically feasible compounds, and as valency permits. Moreover, it is understood that embodiments described herein are to be considered both singly and in combination.

[0065] It is also appreciated that, a compound of formula II is, in some embodiments, a moiety A (as part of formula I), and where one of variable R4or R5is replaced with variable B to thereby attach to the rest of the compound of formula I.

[0066] As defined generally herein, X1is C(R7)2, CR7, S, NR7, S(O), S(O)2, C(O), or O. In some embodiments, X1is C(R7)2, S, or NR7. In some embodiments, X1is S or C(R7)2. In some embodiments, X1is S. In some embodiments, X1is C(R7)2. In some embodiments, X1is CH2. In some embodiments, X1is CH(CH3). In some embodiments, X1is:

[0067] In some embodiments, X1is NR7. In some embodiments, X1is NH. In some embodiments, X1is N(CH3). In some embodiments, X1is S(O). In some embodiments, X1is S(O)2. In some embodiments, X1is C(O). In some embodiments, X1is O.

[0068] As defined generally herein, X2is N, C, or CR9. In some embodiments, X2is N or CR9. In some embodiments, X2is N. In some embodiments, X2is C (e.g., when a bond between X1and X2is a double bond). In some embodiments, X2is CR9. In some embodiments, X2is CR9, and R9is H, halo, or C1-C6aliphatic. In some embodiments, X2is CH or C(CH3).

[0069] In some embodiments, a bond between X1and X2is a single bond, and X1is C(R7)2, S, NR7, S(O), S(O)2, C(O), or O, and X2is N or CR9. In some embodiments, a bond between X1and X2is a single bond, and X1is C(R3)2, S, or NR7, and X2is N or CR9. In some embodiments, a bond between X1and X2is a single bond, and X1is C(R7)2, S, or NR7, and X2is N or CR9, and R9is H, halo, or C1-C6aliphatic. In some embodiments, a bond between X1and X2is a single bond, and X1is C(R3)2, S, or NR7, and X2is N or CR9, and R9is H, halo, or CH3. In some embodiments, a bond between X1and X2is a single bond, and X1is C(R7)2, S, or NR7, and X2is N or CH.

[0070] In some embodiments, a bond between X1and X2is a double bond, and X1is CR7, and X2is C.

[0071] As defined generally herein, X3is N, NR9, O, CR9, C(R9)2. In some embodiments, X3is N or CR9. In some embodiments, X3is N. In some embodiments, X3is NR9. In some embodiments, X3is O. In some embodiments, X3is CR9. In some embodiments, X3is CR9, where R9is H or halo. In some embodiments, X3is CH. In some embodiments, X3is C(R9)2.

[0072] As defined generally herein, X4is N, NR2, CR2, C(R2)2, or C(NR2). In some embodiments, when a bond between X4and X5is a single bond, X4is N(R2), C(R2)2, or C(NR2). In some embodiments, X4is NR2or C(R2)2. In some embodiments, X4is NR2or C(R2)2, where each R2is independently selected from H, optionally substituted C1-C6aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X4is NR2. In some embodiments, X4is NR2, where R2is H, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X4is NR2, where R2is optionally substituted C1-C6aliphatic.

[0073] In some embodiments, X4is C(R2)2. In some embodiments, X4is C(R2)2, where each R2is independently selected from H, optionally substituted C1-C6aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic.

[0074] In some embodiments, X4is C(NR2).

[0075] In some embodiments, when a bond between X4and X5is a double bond, X4is N or CR2. In some embodiments, X4is N. In some embodiments, X4is CR2. In some embodiments, X4is CR2, and R2is H, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic.

[0076] As defined generally herein, X5is N, NR3, CR3, C(R3)2, or C(O). In some embodiments, when a bond between X4and X5is a single bond, X5is NR3, C(R3)2or C(O). Insome embodiments, X5is NR3. In some embodiments, X5is C(O). In some embodiments, X5is C(R3)2.

[0077] In some embodiments, when a bond between X4and X5is a double bond, X5is N or CR3. In some embodiments, X5is N. In some embodiments, X5is CR3. In some embodiments, X5is CH.

[0078] As defined generally herein, each R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a. In some embodiments, R1is 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O. In some embodiments, R1is 4- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 4-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is thiophenyl, pyridinyl, pyrazolyl, or imidazolyl, optionally substituted with one or more R1a.

[0079] In some embodiments, R1is 8- to 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 8-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 9-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 10-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 11-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a. In some embodiments, R1is pyrrolopyridinyl, benzimidazolyl, imidazopyridinyl, indolyl, or benzoxazolyl, optionally substituted with one or more R1a.

[0080] In some embodiments, R1is a 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a. In some embodiments, R1is 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. In some embodiments, R1is a 4-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a. In some embodiments, R1is a 5-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a. In some embodiments, R1is a 6-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a.

[0081] In some embodiments, R1is 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. In some embodiments, R1is 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. In some embodiments, R1is a 9- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a. In some embodiments, R1is a 10- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a. In some embodiments, R1is a 11- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a. In some embodiments, R1is a 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a.

[0082] In some embodiments, R1is C6-C12aryl, optionally substituted with one or more R1a. In some embodiments, R1is phenyl, optionally substituted with one or more R1a. In some embodiments, R1is naphthyl optionally substituted with one or more R1a.

[0083] In some embodiments, two R1are 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, C5- C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a.

[0084] In some embodiments, two R1can 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 R1a. In some embodiments, two R1are takentogether 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a.

[0085] In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a.

[0086] In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are takentogether 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 R1a. In some embodiments, two R1are 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 R1a.

[0087] In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a. In some embodiments, two R1are 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 R1a.

[0088] In some embodiments, two R1are taken together with the atoms to which they are attached to form a C5-C12aryl, optionally substituted with one or more R1a. In some embodiments, two R1are taken together with the atoms to which they are attached to form a phenyl ring, optionally substituted with one or more R1a. In some embodiments, two R1are taken together with the atoms to which they are attached to form a naphthyl ring, optionally substituted with one or more R1a.

[0089] In some embodiments, two R1are taken together with the atoms to which they are attached to form a C3-C12cycloaliphatic, optionally substituted with one or more R1a. In some embodiments, two R1are taken together with the atoms to which they are attached to form a monocylic C3-C7cycloaliphatic, optionally substituted with one or more R1a. In some embodiments, two R1are taken together with the atoms to which they are attached to form acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, optionally substituted with one or more R1a.

[0090] In some embodiments, two R1are taken together with the atoms to which they are attached to form a bicyclic C8-C12cycloaliphatic, optionally substituted with one or more R1a.

[0091] As defined generally herein, each R1ais independently halogen, -OH, -CN, -N(R9)2, - NH-S(O)2-R7, -NH-C(O)-NHR7, -NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, 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. In some embodiments, R1ais halogen. In some embodiments, R1ais fluoro, chloro, bromo, or iodo. In some embodiments, R1ais fluoro. In some embodiments, R1ais chloro. In some embodiments, R1ais bromo. In some embodiments, R1ais iodo.

[0092] In some embodiments, R1ais –OH.

[0093] In some embodiments, R1ais –CN.

[0094] In some embodiments, R1ais -NHC(O)-OR7. In some embodiments, R1ais -NHC(O)- O(C1-C6aliphatic). In some embodiments, R1ais -NHC(O)-OC(CH3)3.

[0095] In some embodiments, R1ais -N(R9)2. In some embodiments, R1ais –NH2. In some embodiments, R1ais –NH(R9). In some embodiments, R1ais –NH(C1-C6aliphatic).

[0096] In some embodiments, R1ais -NH-S(O)2-R7. In some embodiments, R1ais -NH-S(O)2- C1-C6aliphatic. In some embodiments, R1ais -NH-S(O)2-CH3. In some embodiments, R1ais - NH-S(O)2-CH2-CH3.

[0097] In some embodiments, R1ais -NH-C(O)-NHR7. In some embodiments, R1ais -NH- C(O)-NH2. In some embodiments, R1ais -NH-C(O)-NHCH3.

[0098] In some embodiments, R1ais -C(O)-NH2.

[0099] In some embodiments, R1ais oxo.

[0100] In some embodiments, R1ais Z.

[0101] In some embodiments, R1ais an optionally substituted group selected from C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, 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.

[0102] In some embodiments, R1ais an optionally substituted C1-C12aliphatic. In some embodiments, R1ais C1-C12aliphatic optionally substituted with –(CH2)0–4R° or –(CH2)0–4OR°. In some embodiments, R1ais C1-C12aliphatic optionally substituted with R° or OR°, where R° is halo, C1-C6aliphatic, 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 C1-C6aliphatic or halo. In some embodiments, R1ais methyl, ethyl, propyl, or butyl.

[0103] In some embodiments, R1ais optionally substituted -O-C1-C12aliphatic. In some embodiments, R1ais O-C1-C12aliphatic optionally substituted with R°. In some embodiments, R1ais -O-CH3.

[0104] In some embodiments, R1ais optionally substituted C3-C12cycloaliphatic.

[0105] In some embodiments, R1ais optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R1ais optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R1ais optionally substituted pyrrolidinyl. In some embodiments, R1ais pyrrolidinyl.

[0106] In some embodiments, R1ais optionally substituted 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.

[0107] In some embodiments, R1ais optionally substituted C6-C12aryl. In some embodiments, R1ais phenyl.

[0108] In some embodiments, each R1ais independently selected from -Br, -Cl, -F, -CH3, - CH2-CH3, -OCH3, -CN, -CF3, -OH, -NH2,.

[0109] 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.

[0110] In some embodiments, R1is substituted with m instances of R1a, e.g., (R1a)m, wherein m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, R1is substituted with 0, 1, 2, 3, 4, 5, or 6 instances of R1a, e.g., R1is substituted with (R1a)m, wherein m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

[0111] In some embodiments, n is 1, and R1is selected from

[0112] In some embodiments, n is 2, and two R1come together to form:

[0113] As defined generally herein, each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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. In some embodiments, R2is H or optionally substituted C1-C6aliphatic.

[0114] In some embodiments, R2is H.

[0115] In some embodiments, R2is optionally substituted C1-C6aliphatic. In some embodiments, R2is C1-C6aliphatic substituted with –(CH2)0–4R° or –(CH2)0–4OR°. In some embodiments, R2is C1-C6aliphatic 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. In some embodiments, R2is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R2is ethyl. In some embodiments, R2is -CF3. In some embodiments, R2is ethyl substituted with halo.

[0116] In some embodiments, R2is optionally substituted -O-C1-C6aliphatic. In some embodiments, R2is –O-CH3or –O-CH2-CH3.

[0117] In some embodiments, R2is optionally substituted C3-C6cycloaliphatic. In some embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0118] In some embodiments, R2is optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, R2is –CH2-CH2-O-CH2-CH2-O-R°.

[0119] In some embodiments, R2is optionally substituted C6-C12aryl. In some embodiments, R2is phenyl.

[0120] In some embodiments, R2is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.

[0121] In some embodiments, R2is optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R2is optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.

[0122] In some embodiments, R2is H, Cl, -CH3, -CH2-CH3, -CH2-CH2-F, -CH2CHF2, - CH2CF3, -O-CH3, -CF3, -O-CH2-CH3, -CH2-CH2-OH, or –CH2-CH2-NH2.

[0123] As defined generally herein, each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, and C3-C6cycloaliphatic. In some embodiments, R3is H. In some embodiments, R3is OH. In some embodiments, R3is halogen. In some embodiments, R3is CN. In some embodiments, R3is -N(R7)2. In some embodiments, R3is –NH2. In some embodiments, R3is –NH(C1-C6aliphatic). In some embodiments, R3is –N(C1-C6aliphatic)2.

[0124] In some embodiments, R3is C1-C6aliphatic. In some embodiments, R3is methyl, ethyl, propyl, butyl, or hexyl.

[0125] In some embodiments, R3is C3-C6cycloaliphatic. In some embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0126] In some embodiments, two R3are taken together with the atom to which they are attached to form a C3-C6spirocycloalkyl. In some embodiments, two R3are taken together to form a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, or spirocyclohexyl.

[0127] In some embodiments, R2and R3are 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. In some embodiments, R2and R3are taken together to form:

[0128] As defined generally herein, R4is hydrogen, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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.

[0129] In some embodiments, R4is hydrogen, or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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 R4is optionally substituted with Z.

[0130] In some embodiments, R4is hydrogen or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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.

[0131] In some embodiments, R4is an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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.

[0132] In some embodiments, R4is hydrogen.

[0133] In some embodiments, R4is optionally substituted C1-C12aliphatic. In some embodiments, R4is optionally substituted C1-C12alkyl. In some embodiments, R4is C1-C12alkyl optionally substituted with –(CH2)0–4R° or –(CH2)0–4OR°. In some embodiments, R4is C1-C12alkyl substituted with –OH or O(C1-C6aliphatic).

[0134] In some embodiments, R4is optionally substituted 2- to 12-membered heteroaliphatic.

[0135] In some embodiments, R4is optionally substituted C3-C12cycloaliphatic. In some embodiments, R4is optionally substituted monocyclic C3-C6cycloaliphatic. In some embodiments, R4is optionally substituted monocyclic C3-C6cycloalkyl. In some embodiments, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0136] In some embodiments, R4is optionally substituted C6-C12aryl. In some embodiments, R4is optionally substituted phenyl.

[0137] In some embodiments, R4is optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted 5- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH2)0–4R°, –(CH2)0–4OR° or –(CH2)0–4C(O)R°. In some embodiments, R4is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –R°, –(CH2)1–4OR° or C(O)R°. In some embodiments, R4is tetrahydropyranyl or piperidinyl optionally substituted with C(O)R°.

[0138] In some embodiments, R4is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted imidazolyl. In some embodiments, R4is imidazolyl substituted with R°.

[0139] In some embodiments, R4is optionally substituted with –(CH2)0–4R°, –(CH2)0–4OR°, - O(CH2)0-4R°, –(CH2)0–4NR°C(O)R°, or –(CH2)0–4C(O)R°. In some embodiments, R4is optionally substituted with Z.

[0140] In some embodiments, a bond between X2and R4is in an (R) stereochemical configuration. In some embodiments, a bond between X2and R4is in an (S) stereochemical configuration.

[0141] In some embodiments, R4is -H, -CH3, -CH2-CH3,

[0142] As defined generally herein, R5is–C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2- R6, -S(O)2N(R6)(R7), -OC(O)-R6, -C(O)OR6, -C(NH)N(R6)(R7), optionally substituted C1-C12aliphatic-R6, or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0143] In some embodiments, R5is –C(O)-R6.

[0144] In some embodiments, R5is -C(O)N(R6)(R7). In some embodiments, R5is - C(O)NH(R7). In some embodiments, R5is -C(O)NH(R6).

[0145] In some embodiments, R5is -N(R7)C(O)-R6. In some embodiments, R5is -NHC(O)- R6.

[0146] In some embodiments, R5is -S(O)2-R6.

[0147] In some embodiments, R5is -S(O)2N(R6)(R7). In some embodiments, R5is - S(O)2NH(R6).

[0148] In some embodiments, R5is -OC(O)-R6.

[0149] In some embodiments, R5is -C(O)OR6.

[0150] In some embodiments, R5is -C(NH)N(R6)(R7). In some embodiments, R5is - C(NH)NH(R6).

[0151] In some embodiments, R5is optionally substituted C1-C12aliphatic-R6. In some embodiments, R5is –CH2-R6.

[0152] In some embodiments, R5is optionally substituted 5- to 6-membered heteroaryl. In some embodiments, R5is oxadiazolyl or imidazolyl.

[0153] As defined generally herein, R6is Z, -OH, -N(R7)2, -S(O)2-R8, C3-C12cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8.

[0154] In some embodiments, R6is Z.

[0155] In some embodiments, R6is –OH.

[0156] In some embodiments, R6is –N(R7)2. In some embodiments, R6is –NHR7. In some embodiments, R6is NH2. In some embodiments, R6is –N(C1-C6aliphatic), wherein C1-C6aliphatic is optionally substituted with R8. In some embodiments, R6is –N(C1-C6aliphatic), wherein C1-C6aliphatic is optionally substituted with Z. In some embodiments, R6is –N(CH3).

[0157] In some embodiments, R6is -S(O)2-R8.

[0158] In some embodiments, R6is C3-C12cycloaliphatic optionally substituted with one or more R8. In some embodiments, R6is C3-C6cycloaliphatic optionally substituted with one or more R8. In some embodiments, R6is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more R8.

[0159] In some embodiments, R6is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. In some embodiments, R6is 3- to 7-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8. In some embodiments, R6is a 3-membered monocyclic heterocyclic having 1 heteroatom selected from N, S, and O, optionally substituted with one or more R8. In some embodiments, R6is a 4-membered monocyclic heterocyclic having1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8. In some embodiments, R6is a 5-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8. In some embodiments, R6is a 6- membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8. In some embodiments, R6is a 7-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8. In some embodiments, R6is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, optionally substituted with one or more R8.

[0160] In some embodiments, R6is 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 R8. In some embodiments, R6is 6-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. In some embodiments, R6is 7-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. In some embodiments, R6is 8-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. In some embodiments, R6is 9-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. In some embodiments, R6is 10-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. In some embodiments, R6is 11-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. In some embodiments, R6is 12-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8.

[0161] As defined generally herein, each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.

[0162] In some embodiments, R7is H.

[0163] In some embodiments, R7is optionally substituted C1-C12aliphatic. In some embodiments, R7is optionally substituted C1-C12alkyl. In some embodiments, R7is optionallysubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R7is C1-C12aliphatic optionally substituted with one or more –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)OR°. In some embodiments, R7is C1-C12aliphatic optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, –(CH2)0–4C(O)NR°2, or –(CH2)0–4C(O)OR°, where R° is H, C1–6aliphatic, 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 –(CH2)0–2R●or –(CH2)0–2OH, 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.

[0164] In some embodiments, R7is optionally substituted C3-C12cycloaliphatic. In some embodiments, R7is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0165] In some embodiments, R7is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R7is 2- to 9- membered heteroaliphatic comprising one or more oxygen atoms. In some embodiments, R7is –(CH2CH2O)2CH2CH2OH, –CH2CH2OCH2CH2CH2OH, - CH2CH2CH2N(CH3)CH2C≡CH.

[0166] In some embodiments, R7is optionally substituted C6-C12aryl. In some embodiments, R7is optionally substituted phenyl.

[0167] In some embodiments, R7is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R7is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0168] In some embodiments, R7and R2, 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.

[0169] As defined generally herein, each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, - C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0170] In some embodiments, R8is –OH.

[0171] In some embodiments, R8is NH2.

[0172] In some embodiments, R8is Z.

[0173] In some embodiments, R8is optionally substituted C1-C12aliphatic. In some embodiments, R8is C1-C12aliphatic optionally substituted with –(CH2)0–4R°, –(CH2)0–4OR°, – (CH2)0–4N(R°)2, –(CH2)0–4C(O)N(R°)2, –(CH2)0–4N(R°)C(O)R°, or –(CH2)0–4N(R°)C(O)OR°. In some embodiments, R8is C1-C12aliphatic optionally substituted with –OH, -NH2, -NH(C1-C6aliphatic), -N(C1-C6aliphatic)2, -NHC(O)(C1-C6aliphatic), -C(O)NH(C1-C6aliphatic), or 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R8is -CH2OH, -CH2CH2C≡CH, -CH2-C≡CH, -C≡CH, .

[0174] In some embodiments, R8is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R82- to 9- membered heteroaliphatic comprising one or more oxygen atoms. In some embodiments, R8is –(CH2CH2O)2CH2CH2OH or –CH2CH2OCH2CH2CH2OH.

[0175] In some embodiments, R8is optionally substituted -O-C1-C12aliphatic. In some embodiments, R8is optionally substituted –O-C1-C12alkyl.

[0176] In some embodiments, R8is optionally substituted -NH-C(O)-C1-C12aliphatic. In some embodiments, R8is -NH-C(O)-C1-C12aliphatic optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4R°, –(CH2)0–4C(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, R8is optionally substituted -C(O)-NH-C1-C12aliphatic. In some embodiments, R8is -C(O)-NH-C1-C12aliphatic optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4N(R°)2, –(CH2)0–4R°, –(CH2)0–4C(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, R8is optionally substituted -C(O)-N(C1-C12aliphatic)2. In some embodiments, R8is -C(O)-N(C1-C12aliphatic)2optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4N(R°)2, –(CH2)0–4R°, –(CH2)0–4C(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, R8is optionally substituted -C(O)O-C1-C12aliphatic. In some embodiments, R8is -C(O)O-C1-C12aliphatic optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4N(R°)2, –(CH2)0–4R°, –(CH2)0–4C(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, R8is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R8is 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH2)0–4R°, –(CH2)0–4N(R°)2, or –(CH2)0–4C(O)R°.

[0181] As defined generally herein, each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic. In some embodiments, R9is H. In some embodiments, R9is halo (e.g., bromo, chloro, iodo, fluoro). In some embodiments, R9is OH. In some embodiments, R9is optionally substituted C1-C12aliphatic. In some embodiments, R9is C1-C12alkyl. In some embodiments, R9is methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl.

[0182] As defined generally herein, Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, - C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, - OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S.

[0183] As defined generally herein, each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic. In some embodiments, RZis H. In some embodiments, RZis C1-C6aliphatic. In some embodiments, RZis C3-C12cycloaliphatic.

[0184] In some embodiments, R5is:,.

[0185] In some embodiments, the present disclosure provides a compound of formula II:or a pharmaceutically acceptable salt thereof, wherein X1is S or NR7; X2is CR9; X3is N or CR9; X4is N, NR2, CR2, C(R2)2, or C(NR2); X5is NR3, C(R3)2, or C(O); a bond between X1and X2is a single bond; a bond between X4and X5is a single bond; n is 2; two R1can 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, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a;each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic ; or R4is an optionally substituted group selected from C3-C12cycloaliphatic, C6-C12aryl, 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; R5is –C(O)-R6; R6is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; and Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic.

[0186] In some embodiments, a compound of formula II is a compound of formula IIa:or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, R1a, R4and R5are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, or 4.

[0187] In certain aspects, the present disclosure provides a compound of formula IIaor a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, S, NR7, S(O), S(O)2, C(O), or O; X2is CR9; X3is N or CR9; X4is NR2, C(R2)2, or C(NR2); X5is C(R3)2or C(O);each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, -NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3-C6cycloaliphatic ; or R2and R3can 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; or two R3can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)- R6, -C(O)OR6, -C(NH)N(R6)(R7) or optionally substituted C1-C12aliphatic-R6; R6is -OH, -N(R7)2, -S(O)2-R8, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)- C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and; m is 0, 1, 2, 3, or 4.

[0188] In some embodiments, a compound of formula II is a compound of formula IIa-1:or a pharmaceutically acceptable salt thereof, wherein X1, X2, R1a, R4and R5are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, or 4.

[0189] In certain aspects, the present disclosure provides a compound of formula IIa-1:or a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, S, NR7, S(O), S(O)2, C(O), or O; X2is CR9;each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, -NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; R4is hydrogen, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12- membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7) or optionally substituted C1-C12aliphatic-R6; R6is -OH, -N(R7)2, -S(O)2-R8, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and m is 0, 1, 2, 3, or 4.

[0190] In some embodiments, a compound of formula II is a compound of formula III:or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, R1a, R4and R5are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, 4, 5, or 6.

[0191] In certain aspects, the present disclosure provides a compound of formula III:or a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, S, NR7, S(O), S(O)2, C(O), or O; X2is CR9; X3is N or CR9; X4is NR2, C(R2)2, or C(NR2); X5is C(R3)2or C(O);each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, -NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3-C6cycloaliphatic ; or R2and R3can 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; or two R3can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)- R6, -C(O)OR6, -C(NH)N(R6)(R7) or optionally substituted C1-C12aliphatic-R6; R6is -OH, -N(R7)2, -S(O)2-R8, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)- C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and m is 0, 1, 2, 3, 4, 5, or 6.

[0192] In some embodiments, a compound of formula II is a compound of formula IIIa:or a pharmaceutically acceptable salt thereof, wherein X1, X2, R1a, R2, R4, R5are as defined in classes and subclasses herein, both singly, and in combination, and m is 0, 1, 2, 3, 4, 5, or 6.

[0193] In certain aspects, the present disclosure provides a compound of formula IIIa:or a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, S, NR7, S(O), S(O)2, C(O), or O; X2is CR9;each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, -NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; R4is hydrogen, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12- membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7) or optionally substituted C1-C12aliphatic-R6; R6is -OH, -N(R7)2, -S(O)2-R8, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and m is 0, 1, 2, 3, 4, 5, or 6.

[0194] In some embodiments, a compound of formula II is a compound of formula IV:or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, R1, R3, R4, and R5are as defined in classes and subclasses herein, both singly, and in combination.

[0195] In certain aspects, the present disclosure provides a compound of formula IVa:or a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, S, NR7, S(O), S(O)2, C(O), or O; X2is N or CR9; X3is N or CR9; X4is NR2, N, CR2, C(R2)2, or C(NR2); R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a;each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; R3is -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3-C6cycloaliphatic ; R4is -H, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12- membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7) or optionally substituted C1-C12aliphatic-R6; R6is -OH, -N(R7)2, -S(O)2-R8, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic;Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic.

[0196] In some embodiments, a compound of formula II is a compound of formula IVb:or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X5, R1, R2, R4, and R5are as defined in classes and subclasses herein, both singly, and in combination.

[0197] In certain aspects, the present disclosure provides a compound of formula IVb:or a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, S, NR7, S(O), S(O)2, C(O), or O; X2is N or CR9; X3is N or CR9; X5is N, CR3, C(R3)2, or C(O);R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a; each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic ; or two R3can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen, Z, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12- membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7) or optionally substituted C1-C12aliphatic-R6; R6is -OH, -N(R7)2, -S(O)2-R8, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; and Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic.

[0198] In some embodiments, a compound of formula II is a compound of formula V:or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, R1, R4, R5, and n are as defined in classes and subclasses herein, both singly, and in combination.

[0199] In some embodiments, a ULK complex binding moiety (i.e., moiety A) is a compound of formula V:or a pharmaceutically acceptable salt thereof, whereinX1is C(R7)2, CR7, S, NR7, S(O), S(O)2, C(O), or O; X2is N, C, or CR9; X3is N, NR9, CR9, or C(R9)2; X4is N, NR2, CR2, C(R2)2, or C(NR2); X5is N, NR3, CR3, C(R3)2, or C(O); each R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a, or two R1can 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, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a; each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic; or R2and R3can 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; or two R3can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen,or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 4- to 12-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, wherein R4is optionally substituted with Z; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7), optionally substituted C1-C12aliphatic-R6, or optionally substituted 5- to 6-membered heteroaryl; R6is Z, -OH, -N(R7)2, -S(O)2-R8, C3-C12cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; or R7and R2, 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 R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, -OH, -O-C1-C12aliphatic, -NH2, -N(H)-C1- C12aliphatic, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and n is 0, 1, or 2.

[0200] As described herein, 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, RAB1B, RAB5A, a peroxisome, a myddosome, MYD88, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes, where, in some embodiments, a ULK complex binding moiety is a compound of formula II-V, as described herein.

[0201] As defined generally herein, A is a compound of formula II, wherein variables R4or R5is replaced with -B-C (i.e., wherein R4or R5are 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.

[0202] As defined generally herein, B is a linker moiety. That is, B is a bivalent moiety covalently bonded to moiety A and moiety C. In some embodiment, B is Z, wherein Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S,5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; and each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic.

[0203] In some embodiments, B is a linker moiety selected from:,where q is an integer from 1 to 25.

[0204] As defined generally herein, 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, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes. Those of skill in the art would understand which target binding moieties are suitable for inclusion in compounds described herein.

[0205] For example, in some embodiments, C is a moiety that binds or associates with mitochondria. In some embodiments, 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. Lett., 21:6314-6318 (2011), Freeman-Cook, et al., J. Med. Chem., 55:935-942 (2012), Takagi, et al., J. Pharmacol. Exp. Ther., 372:256-263 (March 2020), Wu and Huang, Future Med. Chem., 12(6):*1-29 (2020), Harriman, et al., PNAS, E1796-E1805 (Mar.14, 2016), Abu-Elheiga, et al., PNAS, 97(4):1444-1449, Toledo-Sherman, et al., J. Med. Chem., 58:1159-1183 (2015), Walker, et al., J. Med. Chem., 60:3383-3404 (2017), Rover, et al., J. Med. Chem., 40:4378-4385 (1997), Kim, et al., Cell Chemical Biology, 25:425-438 (2018), Osgerby, et al., J. Med. Chem., 60, 3518-3524 (2017), Hertz, et al., Cell, 154:737-747 (2013), Milite, et al., J. Med. Chem., 60:7897-7909 (2017), Damont, et al., J. Med. Chem., 58:7449-7464 (2015), Frantz and Wipf, Environ. Mol. Mutagen., 51(5):462-475(2010), Chaveau, et al., Eur. J. Nucl. Med. Mol. Imaging, 38:509-514 (2011), and Ceccarelli, et al., J. Med. Chem., 54:3109-3152 (2011), each of which is incorporated by reference in its entirety.

[0206] In some embodiments, C is a moiety that binds or associates with a bacterium.

[0207] In some embodiments, C is a moiety that binds or associates with a lipid droplet.

[0208] In some embodiments, C is a moiety that binds or associates with a peroxisome.

[0209] In some embodiments, 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. 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. Chem., 63:13316-13329 (2020), Kargbo, ACS Med. Chem. Lett., 10:1251-1252 (2019), and Chen, et al., ACS Med. Chem. Lett., 12:82-87 (2021), each of which is incorporated herein by reference in its entirety.

[0212] In some embodiments, 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:

[0214] In some embodiments, 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.

[0215] In some embodiments, C is a moiety that binds or associates with NLRP3 inflammasome

[0216] In some embodiments, C is a moiety that binds or associates with NLRP3 inflammasome, and is selected from the table below, whererepresents a point of attachment between moiety C and a compound of formula I:

[0217] In some embodiments, C is a moiety that binds or associates with EGFR. In some embodiments, C is a moiety that binds or associates with EGFR as described in Burslem et al., Cell Chemical Biology, 25: 67–77 (2018), which is incorporated herein by reference in its entirety. In some embodiments, 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 α-synuclein. In some embodiments, C is a moiety that binds or associates with α-synuclein as described in WO 2020 / 041331, Josephson, et al., Molecular Imaging, 17:1-6 (2018), and Hsieh, et al.,

[0220] In some embodiments, C is a moiety that binds or associates with tau. In some embodiments, 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. Imaging, 46:2178-2189 (2019), Rombouts, et al., J. Med. Chem., 62:2974-2987 (2019), Ariza, et al., J. Med. Chem., 58:4365-4382 (2015), Vermeiren, et al., Movement Disorders, 33(2):273-287 (2018), Silva, et al., eLife 8:e45457 (2019), Kolb and Andrés, Cold Spring Harb. Perspect. Biol., 9:a023721 (2017), and US App. Pub. No. US 2018 / 0215731, each of which is incorporated by reference in its entirety.

[0221] In some embodiments, 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, whererepresents a point of attachment between moiety C and a compound of formula I:

[0223] In some embodiments, C is a moiety that binds or associates with estrogen receptor alpha (ER-α).

[0224] In some embodiments, C is a moiety that binds or associates with an androgen receptor (AR). In some embodiments, C is a moiety that binds or associates with AR as described in Scott, et al., ACS Med. Chem. Lett., 11:1539-1547 (2020). In some embodiments, C is a moiety that binds or associates with tau, and is represented by the structure below, whererepresents a point of attachment between moiety C and a compound of formula I:

[0225] In some embodiments, C is a moiety that binds or associates with acetyl coenzyme A2 (ACC2). In some embodiments, C is a moiety that binds or associates with ACC2 as described inW02013 / 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.

[0226] In some embodiments, C is a moiety that binds or associates with ACC2, and is a compound, or derived from a compound, of the following structure:

[0227] In some embodiments, C is a moiety that binds or associates with ACC2, and is selected from the table below, whererepresents a point of attachment between moiety C and a compound of formula I:

[0228] In some embodiments, 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:

[0229] In some embodiments, C is a moiety that binds or associates with KMO, and is selected from the table below, whererepresents 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 (2018). In some embodiments, 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, whererepresents 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. In some embodiments, 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. Chem., 63:13316-13329 (2020), Kargbo, ACS Med. Chem. Lett., 10:1251-1252 (2019), and Chen, et al., ACS Med. Chem. Lett., 12:82-87 (2021), each of which is incorporated herein by reference in its entirety.

[0234] In some embodiments, 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. Chem., 59(10):4526-4538 (2016), Le Fur, et al., Life Sciences, 32(16):1849-1856 (1983), Camins, et al., Immunopharmacology, 29(2):159-166 (1995), and Damont, et al., J. Med. Chem., 58(18):7449-7464 (2015), each of which is incorporated herein by reference in its entirety.

[0235] In some embodiments, C is a moiety that binds or associates with TSPO, and is a compound, or derived from a compound, from the table below: ,.

[0236] In some embodiments, C is a moiety that binds or associates with TSPO, and is selected from the table below, whererepresents 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 .

[0241] In some embodiments, C is a moiety that binds or associates with huntingtin. In some embodiments, 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.

[0242] In some embodiments, C is a moiety that binds or associates with huntington and is a compound, or derived from a compound, of the following structure;

[0243] In some embodiments, C is a moiety that binds or associates with huntington, and is selected from the table below, whererepresents a point of attachment between moiety C and a compound of formula I:

[0244] In some embodiments, C is a moiety that binds or associates with TDP43.

[0245] In some embodiments, C is a moiety that binds or associates with HSP90.

[0246] In some embodiments, C is a moiety that binds or associates with Hap40.

[0247] In some embodiments, C is a moiety that binds or associates with RNA.

[0248] In some embodiments, C is a moiety that binds or associates with NLRP3.

[0249] In some embodiments, C is a moiety that binds or associates with MCL1.

[0250] In some embodiments, 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.

[0257] In some embodiments, C is a moiety that binds or associates with MAOA.

[0258] In some embodiments, C is a moiety that binds or associates with MAOB.

[0259] In some embodiments, C is a moiety that binds or associates with VDAC1 / 2.

[0260] In some embodiments, C is a moiety that binds or associates with CISD1.

[0261] In some embodiments, C is a moiety that binds or associates with MTARC1.

[0262] In some embodiments, C is a moiety that binds or associates with ACSL1.

[0263] In some embodiments, C is a moiety that binds or associates with BAK1.

[0264] In some embodiments, C is a moiety that binds or associates with BAX.

[0265] In some embodiments, C is a moiety that binds or associates with HK1 / 2.

[0266] In some embodiments, C is a moiety that binds or associates with GPAM.

[0267] In some embodiments, C is a moiety that binds or associates with a virus.

[0268] In some embodiments, C is a moiety that binds or associates with PNLPA2.

[0269] In some embodiments, C is a moiety that binds or associates with PNPLA3.

[0270] In some embodiments, C is a moiety that binds or associates with ABHD5.

[0271] In some embodiments, 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.

[0277] In some embodiments, 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.

[0284] In some embodiments, 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.

[0290] In some embodiments, 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.

[0296] In some embodiments, 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.

[0302] In some embodiments, 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.

[0308] In some embodiments, 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

[0314] In some embodiments, C is a moiety selected from Table 1B, whererepresents a point of attachment between moiety C and the remainder of a compound of formula I: Table 1B

[0315] In some embodiments, a compound of formula I is a compound of formula la, lb, lc, or Idor a pharmaceutically acceptable salt thereof, wherein X1’is C(R7’)2, CR7’, S, NR7’, S(O), S(O)2, C(O), or O; X2’is N, C, or CR9’X3’is N, NR9’, O, CR9’, C(R9’)2; X4’is N, NR2’, CR2’, C(R2’)2, or C(NR2’); X5’is N, NR3’, CR3’, C(R3’)2, or C(O); each R1’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 C6-C12aryl, wherein each R1’is optionally substituted with one or more R1a’, or two R1’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, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a’;each R1a’is independently halogen, -OH, -CN, -N(R9’)2, -NH-S(O)2-R7’, -NH-C(O)-NHR7’, - NHC(O)-OR7’, -C(O)-NH2, oxo, or an optionally substituted group selected from, C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2’is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3’is independently selected from -H, -OH, -N(R7’)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic; or R2’and R3’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; or two R3’are taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4’is hydrogen, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12- membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5’is –C(O)-R6’, -C(O)N(R6’)(R7’), -N(R7’)C(O)-R6’, -S(O)2-R6’, -S(O)2N(R6’)(R7’), -OC(O)- R6’, -C(O)OR6’, -C(NH)N(R6’)(R7’), optionally substituted C1-C12aliphatic-R6’, or optionally substituted 5- to 6-membered heteroaryl; R6’is -OH, -N(R7’)2, -S(O)2-R8’, C3-C12cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8’; each R7’is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; orR7’and R2’, 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 R8’is independently -OH, -NH2, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9’is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; and n’ is 0, 1, or 2.

[0316] As defined generally herein, X1’is C(R7’)2, CR7’, S, NR7’, S(O), S(O)2, C(O), or O. In some embodiments, X1’is C(R7’)2, S, or NR7’. In some embodiments, X1’is S or C(R7’)2. In some embodiments, X1’is S. In some embodiments, X1’is C(R7’)2. In some embodiments, X1’is CH2. In some embodiments, X1’is CH(CH3). In some embodiments, X1’is:

[0317] In some embodiments, X1’is NR7’. In some embodiments, X1’is NH. In some embodiments, X1’is N(CH3). In some embodiments, X1’is S(O). In some embodiments, X1’is S(O)2. In some embodiments, X1’is C(O). In some embodiments, X1’is O.

[0318] As defined generally herein, X2’is N, C, or CR9’. In some embodiments, X2’is N or CR9’. In some embodiments, X2’is N. In some embodiments, X2’is C (e.g., when a bond between X1’and X2’is a double bond). In some embodiments, X2’is CR9. In some embodiments, X2’is CR9’, and R9’is H, halo, or C1-C6aliphatic. In some embodiments, X2’is CH or C(CH3).

[0319] In some embodiments, a bond between X1’and X2’is a single bond, and X1’is C(R3’)2, S, NR7’, S(O), S(O)2, C(O), or O, and X2’is N or CR9’. In some embodiments, a bond between X1’and X2’is a single bond, and X1’is C(R7’)2, S, or NR7’, and X2’is N or CR9’. In some embodiments, a bond between X1’and X2’is a single bond, and X1’is C(R7’)2, S, or NR7’, and X2’is N or CR9’, and R9’is H, halo, or C1-C6aliphatic. In some embodiments, a bond between X1’and X2’is a single bond, and X1’is C(R7’)2, S, or NR7’, and X2’is N or CR9’, and R9’is H, halo, or CH3. In some embodiments, a bond between X1’and X2’is a single bond, and X1’is C(R7’)2, S, or NR7’, and X2’is N or CH.

[0320] In some embodiments, a bond between X1’and X2’is a double bond, and X1’is CR7’, and X2’is C.

[0321] As defined generally herein, X3’is N, NR9’, O, CR9’, C(R9’)2. In some embodiments, X3’is N or CR9’. In some embodiments, X3’is N. In some embodiments, X3’is O. In some embodiments, X3’is CR9. In some embodiments, X3’is CR9’, where R9’is H or halo. In some embodiments, X3’is CH.

[0322] As defined generally herein, X4’is N, NR2’, CR2’, C(R2’)2, or C(NR2’). In some embodiments, when a bond between X4’and X5’is a single bond, X4’is NR2’, C(R2’)2, or C(NR2’). In some embodiments, X4’is NR2’or C(R2’)2. In some embodiments, X4’is NR2’or C(R2’)2, where each R2’is independently selected from H, optionally substituted C1-C6aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X4’is NR2’. In some embodiments, X4’is NR2’, where R2’is H, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, X4’is NR2’, where R2’is optionally substituted C1-C6aliphatic.

[0323] In some embodiments, X4’is C(R2’)2. In some embodiments, X4’is C(R2’)2, where each R2’is independently selected from H, optionally substituted C1-C6aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic.

[0324] In some embodiments, X4’is C(NR2).

[0325] In some embodiments, when a bond between X4’and X5’is a double bond, X4’is N or CR2’. In some embodiments, X4’is N. In some embodiments, X4’is CR2’. In some embodiments, X4’is CR2’, and R2’is H, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic.

[0326] As defined generally herein, X5’is N, NR3’, CR3’, C(R3’)2, or C(O). In some embodiments, when a bond between X4’and X5’is a single bond, X5’is NR3’, C(R3’)2or C(O). In some embodiments, X5’is NR3’. In some embodiments, X5’is C(O). In some embodiments, X5’is C(R3’)2.

[0327] In some embodiments, when a bond between X4’and X5’is a double bond, X5’is N or CR3’. In some embodiments, X5’is N. In some embodiments, X5’is CR3’. In some embodiments, X5’is CH.

[0328] As defined generally herein, each R1’is independently selected from 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 4- to 12- memberedheterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and C6-C12aryl, wherein each R1’is optionally substituted with one or more R1a’. In some embodiments, R1’is 4- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O. In some embodiments, R1’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’. In some embodiments, R1’is 4-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is thiophenyl, pyridinyl, pyrazolyl, or imidazolyl, optionally substituted with one or more R1a’.

[0329] In some embodiments, R1’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’. In some embodiments, R1’is 8-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is 9-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is 10-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is 11-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is 12-membered bicyclic heteroaryl having 1 to 6 heteroatoms selected from N, S, and O optionally substituted with one or more R1a’. In some embodiments, R1’is pyrrolopyridinyl, benzimidazolyl, imidazopyridinyl, indolyl, or benzoxazolyl, optionally substituted with one or more R1a’.

[0330] In some embodiments, R1’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’. In some embodiments, R1’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’. In some embodiments, R1’is a 4-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’. In some embodiments, R1’is a 5-membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’. In some embodiments, R1’is a 6-membered monocyclicheterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’.

[0331] In some embodiments, R1’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’. In some embodiments, R1’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’. In some embodiments, R1’is a 9- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’. In some embodiments, R1’is a 10- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’. In some embodiments, R1’is a 11- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’. In some embodiments, R1’is a 12- membered bicyclic heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’.

[0332] In some embodiments, R1’is C6-C12aryl, optionally substituted with one or more R1a’. In some embodiments, R1’is phenyl, optionally substituted with one or more R1a’. In some embodiments, R1’is naphthyl optionally substituted with one or more R1a’.

[0333] In some embodiments, two R1’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, C5- C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a’.

[0334] In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’are taken together with the atoms to which they are attached toform a 5- membered monocylic heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a’.

[0335] In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’.

[0336] In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’.

[0337] In some embodiments, two R1’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 R1a’. In some embodiments, two R1’aretaken 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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’. In some embodiments, two R1’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 R1a’.

[0338] In some embodiments, two R1’are taken together with the atoms to which they are attached to form a C5-C12aryl, optionally substituted with one or more R1a’. In some embodiments, two R1’are taken together with the atoms to which they are attached to form a phenyl ring, optionally substituted with one or more R1a’. In some embodiments, two R1’are taken together with the atoms to which they are attached to form a naphthyl ring, optionally substituted with one or more R1a’.

[0339] In some embodiments, two R1’are taken together with the atoms to which they are attached to form a C3-C12cycloaliphatic, optionally substituted with one or more R1a’. In some embodiments, two R1’are taken together with the atoms to which they are attached to form a monocylic C3-C7cycloaliphatic, optionally substituted with one or more R1a’. In some embodiments, two R1’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 R1a’.

[0340] In some embodiments, two R1’are taken together with the atoms to which they are attached to form a bicyclic C8-C12cycloaliphatic, optionally substituted with one or more R1a’.

[0341] As defined generally herein, each R1a’is independently halogen, -OH, -CN, -N(R9’)2, - NH-S(O)2-R7’, -NH-C(O)-NHR7’, -NHC(O)-OR7’, -C(O)-NH2, oxo, or an optionally substituted group selected from C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, 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. In some embodiments, R1a’is halogen. In some embodiments, R1a’is fluoro, chloro, bromo, or iodo. In some embodiments, R1a’is fluoro. In some embodiments, R1a’is chloro. In some embodiments, R1a’is bromo. In some embodiments, R1a’is iodo.

[0342] In some embodiments, R1a’is –OH.

[0343] In some embodiments, R1a’is –CN.

[0344] In some embodiments, R1a’is -NHC(O)-OR7’. In some embodiments, R1a’is -NHC(O)- O(C1-C6aliphatic). In some embodiments, R1a’is -NHC(O)-OC(CH3)3.

[0345] In some embodiments, R1a’is -N(R9’)2. In some embodiments, R1a’is –NH2. In some embodiments, R1a’is –NH(R9’). In some embodiments, R1a’is –NH(C1-C6aliphatic).

[0346] In some embodiments, R1a’is -NH-S(O)2-R7’. In some embodiments, R1a’is -NH- S(O)2-C1-C6aliphatic. In some embodiments, R1a’is -NH-S(O)2-CH3. In some embodiments, R1a’is -NH-S(O)2-CH2-CH3.

[0347] In some embodiments, R1a’is -NH-C(O)-NHR7’. In some embodiments, R1a’is -NH- C(O)-NH2. In some embodiments, R1a’is -NH-C(O)-NHCH3.

[0348] In some embodiments, R1a’is -C(O)-NH2.

[0349] In some embodiments, R1a’is oxo.

[0350] In some embodiments, R1a’is an optionally substituted group selected from C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, 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.

[0351] In some embodiments, R1a’is an optionally substituted C1-C12aliphatic. In some embodiments, R1a’is C1-C12aliphatic optionally substituted with –(CH2)0–4R° or –(CH2)0–4OR°. In some embodiments, R1a’is C1-C12aliphatic optionally substituted with R° or OR°, where R° is halo, C1-C6aliphatic, 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 C1-C6aliphatic or halo. In some embodiments, R1a’is methyl, ethyl, propyl, or butyl.

[0352] In some embodiments, R1a’is optionally substituted -O-C1-C12aliphatic. In some embodiments, R1a’is O-C1-C12aliphatic optionally substituted with R°. In some embodiments, R1a’is -O-CH3.

[0353] In some embodiments, R1a’is optionally substituted C3-C12cycloaliphatic.

[0354] In some embodiments, R1a’is optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R1a’is optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R1a’is optionally substituted pyrrolidinyl. In some embodiments, R1a’is pyrrolidinyl.

[0355] In some embodiments, R1a’is optionally substituted 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.

[0356] In some embodiments, R1a’is optionally substituted C6-C12aryl. In some embodiments, R1a’is phenyl.

[0357] In some embodiments, each R1a’is independently selected from -Br, -Cl, -F, -CH3, - CH2-CH3, -OCH3, -CN, -CF3, -OH, -NH2,

[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, R1’is substituted with m instances of R1a’, e.g., (R1a’)m. In some embodiments, R1’is substituted with 0, 1, 2, 3, 4, 5, or 6 instances of R1a’, e.g., R1’is substituted with (R1a’)m’, wherein m’ is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m’ is 0. In some embodiments, m’ is 1. In some embodiments, m’ is 2. In some embodiments, m’ is 3. In some embodiments, m’ is 4. In some embodiments, m’ is 5. In some embodiments, m’ is 6.

[0360] In some embodiments, n’ is 1, and R1’is selected from

[0361] In some embodiments, n’ is 2, and two R1’come together to form:

[0362] As defined generally herein, each R2’is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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. In some embodiments, R2’is H or optionally substituted C1-C6aliphatic.

[0363] In some embodiments, R2’is H.

[0364] In some embodiments, R2’is optionally substituted C1-C6aliphatic. In some embodiments, R2’is C1-C6aliphatic substituted with –(CH2)0–4R° or –(CH2)0–4OR°. In some embodiments, R2’is C1-C6aliphatic 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. In some embodiments, R2’is methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R2’is ethyl. In some embodiments, R2’is -CF3. In some embodiments, R2’is ethyl substituted with halo.

[0365] In some embodiments, R2’is optionally substituted -O-C1-C6aliphatic. In some embodiments, R2’is –O-CH3or –O-CH2-CH3.

[0366] In some embodiments, R2’is optionally substituted C3-C6cycloaliphatic. In some embodiments, R2’is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0367] In some embodiments, R2’is optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, R2’is –CH2-CH2-O-CH2-CH2-O-R°.

[0368] In some embodiments, R2’is optionally substituted C6-C12aryl. In some embodiments, R2’is phenyl.

[0369] In some embodiments, R2’is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.

[0370] In some embodiments, R2’is optionally substituted 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R2’is optionally substituted 3- to 6- membered monocyclic heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O.

[0371] In some embodiments, R2’is H, Cl, -CH3, -CH2-CH3, -CH2-CH2-F, -CH2CHF2, - CH2CF3, -O-CH3, -CF3, -O-CH2-CH3, -CH2CH2OH, or -CH2CH2NH2.

[0372] As defined generally herein, each R3’is independently selected from -H, -OH, -N(R7’)2, halogen, CN, C1-C6aliphatic, and C3-C6cycloaliphatic. In some embodiments, R3’is H. In some embodiments, R3’is OH. In some embodiments, R3’is halogen. In some embodiments, R3’is CN. In some embodiments, R3’is -N(R7’)2. In some embodiments, R3’is –NH2. In some embodiments, R3’is –NH(C1-C6aliphatic). In some embodiments, R3’is –N(C1-C6aliphatic)2.

[0373] In some embodiments, R3’is C1-C6aliphatic. In some embodiments, R3’is methyl, ethyl, propyl, butyl, or hexyl.

[0374] In some embodiments, R3’is C3-C6cycloaliphatic. In some embodiments, R3’is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0375] In some embodiments, two R3’can be taken together with the atom to which they are attached to form a C3-C6spirocycloalkyl. In some embodiments, two R3’are taken together to form a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, or spirocyclohexyl.

[0376] In some embodiments, R2’and R3’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. In some embodiments, R2’and R3’are taken together to form:

[0377] As defined generally herein, R4’is hydrogen, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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.

[0378] In some embodiments, R4’is hydrogen, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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.

[0379] In some embodiments, R4’is hydrogen or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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.

[0380] In some embodiments, R4’is an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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.

[0381] In some embodiments, R4’is hydrogen.

[0382] In some embodiments, R4’is optionally substituted C1-C12aliphatic. In some embodiments, R4’is optionally substituted C1-C12alkyl. In some embodiments, R4’is C1-C12alkyl optionally substituted with –(CH2)0–4R° or –(CH2)0–4OR°. In some embodiments, R4’is C1-C12alkyl substituted with –OH or –O-(C1-C6aliphatic).

[0383] In some embodiments, R4’is optionally substituted 2- to 12-membered heteroaliphatic.

[0384] In some embodiments, R4’is optionally substituted C3-C12cycloaliphatic. In some embodiments, R4’is optionally substituted monocyclic C3-C6cycloaliphatic. In some embodiments, R4’is optionally substituted monocyclic C3-C6cycloalkyl. In some embodiments, R4’is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0385] In some embodiments, R4’is optionally substituted C6-C12aryl. In some embodiments, R4’is optionally substituted phenyl.

[0386] In some embodiments, R4’is optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is optionally substituted 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is optionally substituted 4-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is optionally substituted 5- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is optionally substituted 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH2)0–4R°, –(CH2)0–4OR° or –(CH2)0–4C(O)R°. In some embodiments, R4’is 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –R°, –(CH2)1–4OR° or C(O)R°. In some embodiments, R4’is tetrahydropyranyl or piperidinyl optionally substituted with C(O)R°.

[0387] In some embodiments, R4’is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is optionally substituted 5-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is optionally substituted 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4’is optionally substituted imidazolyl. In some embodiments, R4’is imidazolyl substituted with R°.

[0388] In some embodiments, R4’is optionally substituted with –(CH2)0–4R°, –(CH2)0–4OR°, - O(CH2)0-4R°, –(CH2)0–4NR°C(O)R°, or –(CH2)0–4C(O)R°.

[0389] As defined generally herein, R5’is C(O)-R6’, -C(O)N(R6’)(R7’), -N(R7’)C(O)-R6’, - S(O)2-R6’, -S(O)2N(R6’)(R7’), -OC(O)-R6’, -C(O)OR6’, -C(NH)N(R6’)(R7’), optionally substituted C1-C12aliphatic-R6’, or optionally substituted 5- to 6-membered heteroaryl. In some embodiments,

[0390] In some embodiments, R5’is -N(R7’)C(O)-R6’. In some embodiments, R5’is -NHC(O)- R6’.

[0391] In some embodiments, R5’is -S(O)2-R6’.

[0392] In some embodiments, R5’is -S(O)2N(R6’)(R7’). In some embodiments, R5’is - S(O)2NH(R6’).

[0393] In some embodiments, R5’is -OC(O)-R6’,

[0394] In some embodiments, R5’is -C(O)OR6’.

[0395] In some embodiments, R5’is -C(NH)N(R6’)(R7’). In some embodiments, R5’is - C(NH)NH(R6’).

[0396] In some embodiments, R5’is optionally substituted C1-C12aliphatic-R6’. In some embodiments, R5’is –CH2-R6’.

[0397] In some embodiments, R5’is optionally substituted 5- to 6-membered heteroaryl. In some embodiments, R5’is oxadiazolyl or imidazolyl.

[0398] As defined generally herein, R6’is -OH, -N(R7’)2, -S(O)2-R8’, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8’.

[0399] In some embodiments, R6’is –OH.

[0400] In some embodiments, R6’is –N(R7’)2. In some embodiments, R6’is –NHR7’. In some embodiments, R6’is NH2. In some embodiments, R6’is –N(C1-C6aliphatic), wherein C1-C6aliphatic is optionally substituted with R8’. In some embodiments, R6’is –N(CH3).

[0401] In some embodiments, R6’is -S(O)2-R8’.

[0402] In some embodiments, R6’is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8’. In some embodiments, R6’is 3- to 7-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8’. In some embodiments, R6’is a 3- membered monocyclic heterocyclic having 1 heteroatom selected from N, S, and O, optionally substituted with one or more R8’. In some embodiments, R6’is a 4-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8’. In some embodiments, R6’is a 5-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8’. In some embodiments, R6’is a 6-membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8’. In some embodiments, R6’is a 7- membered monocyclic heterocyclic having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R8’. In some embodiments, R6’is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, optionally substituted with one or more R8’.

[0403] In some embodiments, R6’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 R8’. In some embodiments, R6’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 R8’. In some embodiments, R6’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 R8’. In some embodiments, R6’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 R8’. In some embodiments, R6’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 R8’. In some embodiments, R6’is 10-membered fused bicyclic or spirocyclic heterocyclic having 1 to 3heteroatoms selected from N, S, and O optionally substituted with one or more R8’. In some embodiments, R6’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 R8’. In some embodiments, R6’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 R8’.

[0404] As defined generally herein, each R7’is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O.

[0405] In some embodiments, R7’is H.

[0406] In some embodiments, R7’is optionally substituted C1-C12aliphatic. In some embodiments, R7’is optionally substituted C1-C12alkyl. In some embodiments, R7’is optionally substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R7’is C1-C12aliphatic optionally substituted with one or more –(CH2)0–4R°, –(CH2)0–4OR°, or –(CH2)0–4C(O)OR°. In some embodiments, R7’is C1-C12aliphatic optionally substituted with one or more of halogen, –(CH2)0–4R°, –(CH2)0–4OR°, –(CH2)0–4C(O)NR°2, or –(CH2)0–4C(O)OR°, where R° is H, C1–6aliphatic, 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 –(CH2)0–2R●or –(CH2)0–2OH, 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.

[0407] In some embodiments, R7’is optionally substituted C3-C12cycloaliphatic. In some embodiments, R7’is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0408] In some embodiments, R7’is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R7’is 2- to 9- membered heteroaliphatic comprising one or more oxygen atoms. In some embodiments, R7’is –(CH2CH2O)2CH2CH2OH, –CH2CH2OCH2CH2CH2OH, - CH2CH2CH2N(CH3)CH2C≡CH.

[0409] In some embodiments, R7’is optionally substituted C6-C12aryl. In some embodiments, R7’is optionally substituted phenyl.

[0410] In some embodiments, R7’is optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O. In some embodiments, R7’is optionally substituted pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0411] In some embodiments, R7’and R2’, 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.

[0412] As defined generally herein, each R8’is independently -OH, -NH2, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, - C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0413] In some embodiments, R8’is –OH.

[0414] In some embodiments, R8’is NH2.

[0415] In some embodiments, R8’is optionally substituted C1-C12aliphatic. In some embodiments, R8’is C1-C12aliphatic optionally substituted with –(CH2)0–4R°, –(CH2)0–4OR°, – (CH2)0–4N(R°)2, –(CH2)0–4C(O)N(R°)2, –(CH2)0–4N(R°)C(O)R°, or –(CH2)0–4N(R°)C(O)OR°. In some embodiments, R8’is C1-C12aliphatic optionally substituted with –OH, -NH2, -NH(C1-C6aliphatic), -N(C1-C6aliphatic)2, -NHC(O)(C1-C6aliphatic), -C(O)NH(C1-C6aliphatic), or 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R8’is -CH2OH, - CH2CH2C≡CH, -CH2-C≡CH, -C≡CH, .

[0416] In some embodiments, R8’is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R8’2- to 9- membered heteroaliphatic comprising one or more oxygen atoms. In some embodiments, R8’is –(CH2CH2O)2CH2CH2OH or –CH2CH2OCH2CH2CH2OH.

[0417] In some embodiments, R8’is optionally substituted -O-C1-C12aliphatic. In some embodiments, R8’is optionally substituted –O-C1-C12alkyl.

[0418] In some embodiments, R8’is optionally substituted -NH-C(O)-C1-C12aliphatic. In some embodiments, R8’is -NH-C(O)-C1-C12aliphatic optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4R°, –(CH2)0–4C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0419] In some embodiments, R8’is optionally substituted -C(O)-NH-C1-C12aliphatic. In some embodiments, R8’is -C(O)-NH-C1-C12aliphatic optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4N(R°)2, –(CH2)0–4R°, –(CH2)0–4C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0420] In some embodiments, R8’is optionally substituted -C(O)-N(C1-C12aliphatic)2. In some embodiments, R8’is -C(O)-N(C1-C12aliphatic)2optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4N(R°)2, –(CH2)0–4R°, –(CH2)0–4C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0421] In some embodiments, R8’is optionally substituted -C(O)O-C1-C12aliphatic. In some embodiments, R8’is -C(O)O-C1-C12aliphatic optionally substituted with –(CH2)0–4N(R°)C(O)R°, –(CH2)0–4N(R°)2, –(CH2)0–4R°, –(CH2)0–4C(O)R° or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0422] In some embodiments, R8’is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R8’is 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with –(CH2)0–4R°, –(CH2)0–4N(R°)2, or –(CH2)0–4C(O)R°.

[0423] As defined generally herein, each R9’is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic. In some embodiments, R9’is H. In some embodiments, R9’is halo (e.g., bromo, chloro, iodo, fluoro). In some embodiments, R9’is OH. In some embodiments, R9’is optionally substituted C1-C12aliphatic. In some embodiments, R9’is C1-C12alkyl. In some embodiments, R9’is methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl.

[0424] In some embodiments, a compound of formula I is a compound of formula Ia:or a pharmaceutically acceptable salt thereof, wherein X1’, X2’, X3’, X4’, X5’, R1’, R4’, R5’, n’, B and C are as defined herein.

[0425] In some embodiments, a compound of formula I is a compound of formula Ib:or a pharmaceutically acceptable salt thereof, wherein X1’, X2’, X3’, X4’, X5’, R1’, R4’, R5’, n’, B and C are as defined herein.

[0426] In some embodiments, a compound of formula I is a compound of formula Ic: 'or a pharmaceutically acceptable salt thereof, wherein X1’, X2’, X3’, X4’, X5’, R1’, R4’, R5’, n’, B and C are as defined herein.

[0427] In some embodiments, a compound of formula I is a compound of formula Id:or a pharmaceutically acceptable salt thereof, wherein X1’, X2’, X3’, X4’, X5’, R1’, R4’, R5’, n’, B and C are as defined herein.

[0428] In some embodiments, a compound described herein (e.g., a compound of formula II) is provided in Table 2A Table 2A

[0429] In some embodiments, a compound described herein (e.g., a compound of formula II) is provided in Table 2B:Table 2B

[0430] In some embodiments, a compound described herein (e g., a compound of formula II) is provided in Table 3A:Table 3A

[0431] In some embodiments, a compound described herein (e g., a compound of formula II) is provided in Table 3B:Table 3B

[0432] In some embodiments, a compound described herein (e.g., a compound of formula II) is provided in Table 4A: Table 4A

[0433] In some embodiments, a compound described herein (e.g., a compound of formula II) is provided in Table 4B:Table 4B

[0434] In some embodiments, a compound described herein (e.g., a compound of formula I) is provided in Table 5A:Table 5A

[0435] In some embodiments, a compound described herein (e.g., a compound of formula I) is provided in Table 5B: Table 5B

[0436] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.Uses, Formulation, and AdministrationPharmaceutically Acceptable Compositions

[0437] According to another embodiment, 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. In certain embodiments, 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. In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.

[0438] 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 describedherein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

[0439] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternallyor via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously.

[0440] 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0441] For this purpose, 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.

[0442] 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.

[0443] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate ofdissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, 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.

[0444] In some embodiments, 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.

[0445] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants suchas talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0446] 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.

[0447] 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0448] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0449] Alternatively, pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These 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. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0450] 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.

[0451] Pharmaceutically acceptable 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.

[0452] 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.

[0453] For topical applications, provided pharmaceutically acceptable 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. Alternatively, 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, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyl dodecanol, benzyl alcohol and water.

[0454] For ophthalmic use, provided pharmaceutically acceptable 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. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0455] Pharmaceutically acceptable 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.

[0456] 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. Additionally, 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.Uses of Compounds and Pharmaceutically Acceptable CompositionsA ULK Initiation Complex

[0457] Cellular degradation of large objects such as molecular aggregates, organelles, and intracellular pathogens is accomplished by the autophagy pathway. In this process, the autophagy machinery initiates and grows a double membrane phagophore around a cargo of interest. The double membrane phagophore ultimately fuses with itself to encapsulate the cargo in a double membrane autophagosome. Nakatogawa, Nat. Rev. Mol. Cell. Biology, 21:439-458 (2020). Theautophagosome membrane, which has encompassed the cargo then fuses with a lysosome to degrade the inner membrane and cargo contents, resulting in degradation of the encapsulated materials and release of metabolic byproducts such as amino acids. See Rabinowitz and White, Science, 330(6009):1344-1348 (2010).

[0458] The present disclosure provides an insight that recruitment of a ULK initiation complex (e.g., a ULK1 initiation complex and / or a ULK2 initiation complex) can be used to induce selective autophagy, a process by which the degradative mechanism is targeted to specific substrates. 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. Recruitment of a 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. See, for example, Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Ravenhill, et al, Mol. Cell, 74(2): 320-329.e6; Turco, et al., J Mol Biol, 432(1): 123-134 (2020); Johansen & Lamark J Mol Bio 432(1):80-103 (Jan.3, 2020).

[0459] Without being bound by theory, the present disclosure proposes that promoting recruitment and / or assembly of a ULK initiation complex (e.g., a ULK1 initiation complex and / or a ULK2 initiation complex) represents a particularly useful and / or effective strategy for achieving selective removal of cellular components via the autophagy pathway.

[0460] 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.

[0461] 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 / ormutagenesis of interacting components). See, for example, Ravenhill, et al., Mol. Cell, 74(2):320- 329.e6 (2018); Turco, et al., Mol. Cell, 74(2):330-346.e6 (2019); Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019). Moreover, one report has described artificially linking a peptide derived from ATG16L to a protein (FKBP) or mitochondrial cargo can trigger autophagic degradataion of the cargo. Vargas, et al., Mol. Cell, 74(2):347-326.e6 (2019); Turco, et al., Mol. Cell, 74(2):330- 346.e6 (2019); Ravenhill, et al., Mol. Cell, 74(2):320-329.e6 (2018).

[0462] The present disclosure surprisingly demonstrates that small molecule agents can be developed that target a ULK initiation complex and can be used to recruit the complex to cargo, and / or to initiate its assembly thereon. Without being bound by theory, it is understood that small molecule compounds can recruit a ULK initiation complex to the target of interest. 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.

[0463] In some embodiments, compounds and compositions described herein target a ULK1 initiation complex. In some embodiments, 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. In some embodiments, 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 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 and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupus erythematosus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.

[0465] In some embodiments, a particular target binding moiety (e.g, moiety C in formula I, above) 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:

[0466] In some embodiments, a target is a lipid droplet, and a disease, disorder or condition to be treated is selected from NASH and NAFLD.

[0467] In some embodiments, a target is COP9, and a disease, disorder or condition is cancer.

[0468] In some embodiments, a target is MYC, and a disease, disorder or condition is Burkitt lymphoma, cervical cancer, colon cancer, breast cancer, lung cancer, or stomach cancer.

[0469] In some embodiments, a target is myddosome, and 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.

[0470] In some embodiments, a target is inflammasome, and 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.

[0471] In some embodiments, a target is KRAS, and a disease, disorder or condition is colorectal cancer, lung cancer, leukemia, or pancreatic cancer.

[0472] In some embodiments, a target is α-synuclein, and a disease, disorder or condition is Parkinson’s disease, dementia with Lewy bodies, multiple systems atrophy, or neuroaxonal dystrophies.

[0473] In some embodiments, a target is tau, and 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.

[0474] In some embodiments, a target is estrogen receptor-α, and a disease, disorder or condition is breast cancer.

[0475] In some embodiments, 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.

[0476] In some embodiments, a target is KSR1, and a disease, disorder or condition is cancer.

[0477] In some embodiments, a target is islet amyloid polypeptide (IAPP), and a disease, disorder or condition is type-II diabetes.

[0478] In some embodiments, a target is IRAK4, and a disease, disorder or condition is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or psoriasis.

[0479] In some embodiments, a target is PINK1, and a disease, disorder or condition is Parkinson’s disease, Huntingtin’s disease, or spinocerebellar ataxia.

[0480] In some embodiments, a target is TDP43, and a disease, disorder or condition is familial amylotrophic lateral sclerosis or frontotemporal dementia (FTLD-TDP). Exemplary Embodiments

[0481] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the disclosure: Embodiment 1. A compound of formula IIor a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, CR7, S, NR7, S(O), S(O)2, C(O), or O; X2is N, C, or CR9; X3is N, O, or CR9; X4is NR2, N, CR2, C(R2)2, or C(NR2); X5is N, NR3, CR3, C(R3)2, or C(O); each R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a, or two R1can 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, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a; each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from, C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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;each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic; or R2and R3can 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; or two R3can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen,or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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 R4is optionally substituted with Z; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7), optionally substituted C1-C12aliphatic-R6, or optionally substituted 5- to 6-membered heteroaryl; R6is Z, -OH, -N(R7)2, -S(O)2-R8, C3-C12cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; or R7and R2, 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 R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, -OH, -O-C1-C12aliphatic, -NH2, -N(H)-C1- C12aliphatic, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and n is 0, 1, or 2. Embodiment 2. The compound of Embodiment 1, wherein the bond between X4and X5is a single bond. Embodiment 3. The compound of Embodiments 1 or 2, wherein X3is N. Embodiment 4. The compound of any one of Embodiments 1-3, wherein X1is S. Embodiment 5. The compound of any one of Embodiments 1-4, wherein a bond between X1and X2is a single bond. Embodiment 6. The compound of any one of Embodiments 1-5, wherein n is 2, and two R1are taken together with the atoms to which they are attached to form a 5- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 5- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a. Embodiment 7. The compound of any one of Embodiments 1-6, wherein n is 2, and two R1are taken together with the atoms to which they are attached to form a C6aryl (e.g., phenyl) optionally substituted with one or more R1a. Embodiment 8. The compound of any one of Embodiments 1-6, wherein n is 2, and two R1are taken together with the atoms to which they are attached to form a C12aryl (e.g., naphthyl) optionally substituted with one or more R1a.Embodiment 9. The compound of any one of Embodiments 1-8, wherein each R1ais independently selected from -Br, -Cl, -F, -CH3, -CH2-CH3, -OCH3, -CN, -CF3, OH, NH2, ZEmbodiment 10. The compound of any one of Embodiments 1-9, where R4is 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 X2is CH. Embodiment 12. The compound of any one of Embodiments 1-11, wherein R2is optionally substituted C1-C12aliphatic. Embodiment 13. The compound of any one of Embodiments 1-12, wherein a bond between X4and X5is a single bond, and X4is NR2. Embodiment 14. The compound of any one of Embodiments 1-13, wherein a bond between X4and X5is a single bond, and X5is C(O). Embodiment 15. The compound of any one of Embodiments 1-14, wherein R5is -C(O)-R6. Embodiment 16. The compound of any one of Embodiments 1-15, wherein R6is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8. Embodiment 17. The compound of any one of Embodiments 1-16, wherein R6is azetidinyl, pyrrolidinyl, or piperidinyl, optionally substituted with one or more R8.Embodiment 18. The compound of Embodiment 1, wherein n is 2, and two R1come together to form:Embodiment 19. The compound of Embodiment 1, wherein n is 1. Embodiment 20. The compound of Embodiment 19, wherein R1is 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 R1is selected from:Embodiment 22. The compound of Embodiment 1, wherein R2is H, Cl, -CH3, -CH2-CH3, - CH2-CH2-F, -CH2CHF2, -CH2CF3, -O-CH3, -CF3, -O-CH2-CH3, -CH2-CH2-OH, or –CH2- CH2-NH2. Embodiment 23. The compound of Embodiment 1, wherein R4is -H, -CH3, -CH2-CH3,Embodiment 24. The compound of Embodiment 1, wherein R5is:Embodiment 25. The compound of Embodiment 1, wherein the compound is of formula Ilaor 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 formulaIIa-1:or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.Embodiment 27. The compound of Embodiment 1, wherein the compound is of formula IIIor a pharmaceutically acceptable salt thereof, wherein m is 0-6.Embodiment 28. The compound of Embodiment 1, wherein the compound is of formulaIllaor a pharmaceutically acceptable salt thereof, wherein m is 0-6.Embodiment 29. The compound of Embodiment 1, wherein the compound is of formulaIVaor a pharmaceutically acceptable salt thereof. Embodiment 30. The compound of Embodiment 1, wherein the compound is of formula IVbor 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. 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; andC 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, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes. 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 Idor a pharmaceutically acceptable salt thereof, wherein X1’is C(R7’)2, CR7’, S, NR7’, S(O), S(O)2, C(O), or O; X2’is N, NR9’, C, CR9’, or C(R9’)2X3’is N, O, or CR9’; X4’is N, NR2’, CR2’, C(R2’)2, or C(NR2’); X5’is N, NR3’, CR3’, C(R3’)2, or C(O); each R1’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 C6-C12aryl, wherein each R1’is optionally substituted with one or more R1a’, or two R1’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, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a’; each R1a’is independently halogen, -OH, -CN, -N(R9’)2, -NH-S(O)2-R7’, -NH-C(O)-NHR7’, - NHC(O)-OR7’, -C(O)-NH2, oxo, or an optionally substituted group selected from, C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2’is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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;each R3’is independently selected from -H, -OH, -N(R7’)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic ; or R2’and R3’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; or two R3’can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4’is hydrogen,or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; R5’is –C(O)-R6’, -C(O)N(R6’)(R7’), -N(R7’)C(O)-R6’, -S(O)2-R6’, -S(O)2N(R6’)(R7’), -OC(O)- R6’, -C(O)OR6’, -C(NH)N(R6’)(R7’), optionally substituted C1-C12aliphatic-R6’, or optionally substituted 5- to 6-membered heteroaryl; R6’is -OH, -N(R7’)2, -S(O)2-R8’, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8’; each R7’is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; or R7’and R2’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 R8’is independently -OH, -NH2, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9’is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; and n’ is 0, 1, or 2.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 C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O) N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered bivalent heteroaryl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl, and each RZis independently H, C1-C6aliphatic, or C3-C6aliphatic . Embodiment 38. The compound of Embodiment 33, wherein the linker is selected from:where q is an integer from 1 to 25. 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. The method of 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, 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 and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupus erythematosus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.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. EXAMPLES

[0482] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Table of Abbreviations ACN: acetonitrile CDI: 1,1'-carbonyldiimidazole DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene DCM: dichloromethane DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEA: diethanolamine DIAD: diisopropyl azodicarboxylate DIEA, DIPEA: N,N-diisopropylethylamine DMF: dimethylformamide DMSO: dimethyl sulfoxide dppf: 1,1′-bis(diphenylphosphino)ferrocene EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HEP: heptane HOBt: hydroxybenzotriazole HPLC: high performance liquid chromatography IPA: isopropyl alcohol LDA: lithium diisopropylamide LCMS: liquid chromatography mass spectrometry LiHDMS: lithium bis(trimethylsilyl)amide m-CPBA: meta-chloroperbenzoic acid MTBE: methyl tert-butyl ether NMP: N-methyl-2-pyrrolidone NMR: nuclear magnetic resonance PE: petroleum ether RT: room temperature TBAB: tetrabutylazanium bromide TBAF: tetrabutylammonium fluorideTEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: thin-layer chromatography TMSOTf: trimethylsilyl trifluoromethanesulfonate T3P: propylphosphonic anhydride TSTU: N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate Xphos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Analytical Instrumentation and Purification:

[0483] NMR Instrument Details: : Varian 400MHz, Probe-1: Auto XID Probe 2: ATB.

[0484] LCMS Instrument Details: Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and ELS detectors. Softa model 400.

[0485] LCMS Method 1 - Acidic conditions Column: X-Select C18 CSH (3.0*50) mm 2.5µ; Make: Waters Mobile Phase A: 0.05% formic acid in water: Acetonitrile ( 95:5); pH= 3.5 Mobile Phase B: 0.05% formic acid in Acetonitrile Column oven temperature: 50 C Flow rate: 1.2 ml / minute PDA: 210nm Maxplot Gradient program :MS Parameters Mode: Dual (+ / -) Detector voltage: 1.5KV Scan rang: 80-2000amu Scan speed: 2000

[0486] LCMS Method 2 - Basic conditions Column: X-Select C18 CSH (3.0*50) mm 2.5µm ; Make: Waters Mobile Phase A : 5mM Ammonium Bicarb; pH= 8.8 Mobile Phase B: Acetonitrile Column oven temperature: 50 C Flow rate: 1.2 ml / minute PDA: 210nm Maxplot Gradient program :MS Parameters Mode: Dual (+ / -) Detector voltage: 1.5KV Scan rang: 80-2000amu Scan speed: 2000

[0487] HPLC Method 1 – Acidic Conditions Column : X-Select CSH C18 (4.6*150) mm; 5µ; Make: Waters Mobile Phase: A - 0.1% Formic acid in water : Acetonitrile(95:05) ; pH=3.5 B - Acetonitrile Flow Rate: 1.0. mL / minute PDA : 210nm maxplot Gradient program :

[0488] HPLC Method 2 – Basic Conditions Column : Xbridge C18 (4.6*150) mm, 5µ; Make: Waters Mobile Phase A - 0.1% NH3 in water; pH=9.5 B – Acetonitrile Flow Rate: 1.2. mL / minute PDA : 210nm maxplot Gradient program :Example 1: Synthesis of 3-ethyl-2-{[2-(3-hydroxyazetidin-1-yl)-2-oxo-1- phenylethyl]sulfanyl}-3H,4H-benzo[g]quinazolin-4-one (A-1)Scheme 1. Synthesis of 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2- phenylacetic acid:

[0489] Step 1. Synthesis of 3-ethyl-2-sulfanylbenzo[g]quinazolin-4(3H)-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. The formed precipitate was filtered and washed with cold ethanol (100 mL x 2) to give 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin- 4-one (23.0 g, 89.7 mmol, 100% by LCMS, 84.8% yield).

[0490] Step 2. Synthesis of methyl 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl}sulfanyl)-2-phenylacetate. Ethylbis(propan-2-yl)amine (1.13 g, 8.78 mmol) was added to the solution of 3-ethyl-2-sulfanylbenzo[g]quinazolin-4(3H)-one (1.5 g, 5.85 mmol) and methyl 2- chloro-2-phenylacetate (1.19 g, 6.44 mmol) in dry DMSO (20 mL). The reaction mixture was stirred at 500C overnight, cooled to room temperature and diluted with distilled water (50 mL). The formed solid was filtered, washed with distilled water (50 mL x 3), and dried at room temperature to afford methyl 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2- phenylacetate (2.3 g, 5.68 mmol, 95% purity, 83.8% yield).

[0491] Step 3. Synthesis of 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2- phenylacetic acid. A solution of LiOH∙H2O (0.49 g, 11.67 mmol) in water (20 mL) was added to 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetate (2.3 g, 5.834 mmol) in ethanol (80 mL). The reaction mixture was stirred at 50 ºC until of formation of a transparent solution, and it was then stirred at room temperature overnight. After, the reaction mixture was diluted with distilled water (25 mL) and sat. NaHSO4aq. solution was added dropwise until pH =3. The formed solid was filtered off, washed with water (25 mL x 2), and dried at room temperature to afford 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2- phenylacetic acid. Yield: 1900 mg, 78.4%; Appearance: Yellow solid;1H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.39 (dt, J = 13.5, 7.2 Hz, 3H), 5.65 (d, J = 2.9 Hz, 1H), 4.12 – 3.95 (m, 2H), 1.34 – 1.18 (m, 3H); HPLC purity: 93.92%; LCMS Calculated for C22H20N2O2S: 390.46; Observed: 391.2[M+H]+. Scheme 2. Synthesis of 3-ethyl-2-{[2-(3-hydroxyazetidin-1-yl)-2-oxo-1-phenylethyl]sulfanyl}- 3H,4H-benzo[g]quinazolin-4-one (A-1):

[0492] The vial was charged with amine (1.2 equiv.), acid (1 equiv.), and ethylbis(propan-2- yl)amine (25-55 equiv depending on amine form (base or hydrochloride)) in DMSO (1 mL).Then HATU (1.25 eq.) was added in one portion. The reaction mixture was stirred at room temperature for 2 h and at 80 ºC overnight. After, the mixture was cooled to room temperature and subjected to HPLC purification (deionized water / HPLC-grade methanol) to give 3-ethyl-2-{[2-(3- hydroxyazetidin-1-yl)-2-oxo-1-phenylethyl]sulfanyl}-3H,4H-benzo[g]quinazolin-4-one (A-1). Yield: 10.8 mg, 13.9%; Appearance: Light-brown solid;1H NMR (600 MHz, DMSO-d6) δ 8.79 (d, J = 4.0 Hz, 1H), 8.58 – 7.92 (m, 3H), 7.65 (t, J = 7.6 Hz, 1H), 7.60 (dd, J = 11.8, 7.5 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.36 – 7.31 (m, 1H), 6.13 – 5.62 (m, 2H), 4.96 – 4.08 (m, 4H), 4.09 – 4.01 (m, 2H), 3.86 – 3.53 (m, 1H), 1.26 (q, J = 7.4 Hz, 3H); LCMS Calculated for C25H23N3O3S: 445.53; Observed: 446.1[M+H]+.

[0493] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example (A-1). Analytical data is given in the table below: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. The reaction mixture was stirred at room temperature for 2 h and at 80 ºC overnight. After, the mixture was cooled to room temperature and evaporated to dryness. The residue was dissolved in dichloromethane (1.5 mL), followed by addition of TFA (1 mL). The mixture was stirred at room temperature for 3 h and evaporated to dryness. The residue was subjected to HPLC purification (deionized water / HPLC-grade methanol, ammonia) to give 3-ethyl-2-{[2-oxo-1-phenyl-2- (piperazin-1-yl)ethyl]sulfanyl}-3H,4H-benzo[g]quinazolin-4-one (A-44). Yield: 3.2 mg, 4.17%. Appearance: Light brown oil;1H NMR (600 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.68 – 7.61 (m, 3H), 7.54 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 6.33 (s, 1H), 4.12 – 4.03 (m, 2H), 3.69 (ddd, J = 11.0, 7.8, 3.0 Hz, 1H), 3.56 – 3.48 (m, 2H), 3.37 – 3.32 (m, 1H), 2.80 (ddd, J = 12.5, 6.2, 3.1 Hz, 1H),2.67 (ddd, J = 12.4, 6.2, 3.3 Hz, 1H), 2.27 (ddd, J = 11.5, 7.6, 3.0 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H); LCMS Calculated for C26H26N4O2S: 458.58; Observed: 459.2[M+H]+. 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 LiAlH4(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. The mixture was stirred for 30 minutes, then filtered. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified on column chromatography (hexane / MTBE) to afford 2-chloro-2- phenylethan-1-ol (0.95 g, 6.06 mmol, 95% purity, 53.3% yield).

[0496] Step 2. Synthesis of 3-ethyl-2-[(2-hydroxy-1-phenylethyl)sulfanyl]-3H,4H- benzo[g]quinazolin-4-one. Ethylbis(propan-2-yl)amine (0.0816 g, 0.631 mmol, 0.11 mL) and 2- chloro-2-phenylethan-1-ol (0.075 g, 0.478 mmol) were added to a solution of 3-ethyl-2-sulfanyl- 3H,4H-benzo[g]quinazolin-4-one (0.1 g, 0.39 mmol) in dry DMSO (2 mL). The reaction mixture was stirred at 80 ºС overnight, cooled to room temperature, diluted with water (10 mL). The formed precipitate was filtered, washed with water (10 mL x 3), and subjected to HPLC purification (deionized water / HPLC-grade methanol, ammonia) to afford 3-ethyl-2-[(2-hydroxy- 1-phenylethyl)sulfanyl]-3H,4H-benzo[g]quinazolin-4-one (A-45). Yield: 15.2 mg, 6.75%; Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.24(t, J = 7.4 Hz, 1H), 5.30 (t, J = 5.5 Hz, 1H), 5.23 (t, J = 6.4 Hz, 1H), 4.13 – 4.03 (m, 2H), 4.03 – 3.93 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); LCMS Calculated for C22H20N2O2S: 376.47; Observed: 377.2[M+H]+. 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. 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin-4-one (1.25 g, 4.87 mmol) and triethylamine (0.98 g, 9.68 mmol) were added to a stirred solution of 3-bromooxolan- 2-one (1 g, 6.06 mmol) in DMF (15 mL). The reaction mixture was stirred at 60 °C for 12 h. After cooling, the mixture was poured into water (100 mL) and filtered. The solid was washed with water (20 mL x 2) to give 3-ethyl-2-[(2-oxooxolan-3-yl)sulfanyl]-3H,4H-benzo[g]quinazolin-4- one (0.850 g, 2.49 mmol, 100% purity, 41.2% yield).

[0498] Step 2. Synthesis of 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-4- hydroxy-N,N-dimethylbutanamide. A mixture of a solution of 3-ethyl-2-[(2-oxooxolan-3- yl)sulfanyl]-3H,4H-benzo[g]quinazolin-4-one (0.3 g, 0.881 mmol) in methanol (15 mL) and a 40% solution of dimethylamine in water (0.495 g, 4.40 mmol) was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was subjected to HPLC purification (deionized water / HPLC-grade acetonitrile) that afforded 2- ({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-4-hydroxy-N,N-dimethylbutanamide (A-46).. Yield: 116 mg, 32.4%; Appearance: Beige solid;1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.12 (dd, J = 33.5, 8.4 Hz, 2H), 7.99 (s, 1H), 7.67 – 7.49 (m, 2H), 5.28 (t, J = 7.2 Hz, 1H), 4.79 (t, J = 5.1 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.67 – 3.46 (m, 2H), 2.92 (s, 3H), 2.16 –1.92 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H); LCMS Calculated for C20H23N3O3S: 385.48; Observed: 386.2[M+H]+. Example 5: Synthesis of 2-{[3-(2-hydroxyethyl)-4-oxo-3H,4H-benzo[g]quinazolin-2- yl]sulfanyl}-N,N-dimethyl-2-phenylacetamide (A-47):

[0499] 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 ℃. The reaction mixture was stirred for 5 h at -70 ℃. After the reaction was complete, the reaction mixture was quenched with MeOH (10 mL). The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash chromatography (EtOAc / PE =0-50%) to afford the product 2-hydroxy-N,N-dimethyl-2-phenylacetamide (2.30 g, 12.8 mmol, 62% purity, 44% yield) as a white solid.

[0500] Step 2. Synthesis of 2-chloro-N,N-dimethyl-2-phenylacetamide. To a solution of 2- hydroxy-N,N-dimethyl-2-phenylacetamide (2.97 g, 16.5 mmol) in DCM (30 mL) was added thionyl chloride (3.92 g, 33 mmol) at 0 ℃. The reaction mixture was stirred for 30 min at 25 ℃. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to afford the crude product 2-chloro-N,N-dimethyl-2-phenylacetamide (2.30 g, 12.8 mmol, 93% purity, 92% yield). The crude product was used in the next step directly without purification.

[0501] Step 3. Synthesis of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2-sulfanyl-3H,4H- benzo[g]quinazolin-4-one. To a solution of 3-aminonaphthalene-2-carboxylic acid (186 mg, 998 µmol), tert-butyl(2-isothiocyanatoethoxy)dimethylsilane (217 mg, 998 µmol) in EtOH (3 mL) was added Et3N (5 mL) at RT. The reaction mixture was stirred for 2 h at 90 ℃. After the reaction was complete, the reaction mixture was cooled to RT and filtered to give 3-{2-[(tert- butyldimethylsilyl)oxy]ethyl}-2-sulfanyl-3H,4H-benzo[g]quinazolin-4-one (214 mg, 553 µmol, 100% purity, 55% yield) as a light yellow solid.

[0502] Step 4. Synthesis of 3-(2-hydroxyethyl)-2-sulfanyl-3H,4H-benzo[g]quinazolin-4-one. To a solution of 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2-sulfanyl-3H,4H-benzo[g]quinazolin- 4-one (500 mg, 1.29 mmol) in THF (10 mL) was added TBAF (1.01 g, 3.87 mmol) at RT. The reaction mixture was stirred for 2 h at 50 ℃. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give residue, which was dissolved in ACN (10 mL) and stirred for 1 h at RT. The mixture was filtered to get 3-(2-hydroxyethyl)-2-sulfanyl-3H,4H- benzo[g]quinazolin-4-one (323 mg, 1.18 mmol, 100% purity, 92% yield) as a yellow solid.

[0503] Step 5. Synthesis of 2-{[3-(2-hydroxyethyl)-4-oxo-3H,4H-benzo[g]quinazolin-2- yl]sulfanyl}-N,N-dimethyl-2-phenylacetamide. To a solution of 3-(2-hydroxyethyl)-2-sulfanyl- 3H,4H-benzo[g]quinazolin-4-one (100 mg, 367 µmol) and Et3N (111 mg, 1.10 mmol) in DMF (5 mL) was added 2-chloro-N,N-dimethyl-2-phenylacetamide (72.5 mg, 367 µmol) at RT. The reaction mixture was stirred for 2 h at 50 ℃. Water (10 mL) was added, and the reaction mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by prep- HPLC(ACN / H2O / 0.1% NH4OH) to 2-{[3-(2-hydroxyethyl)-4-oxo-3H,4H-benzo[g]quinazolin-2-yl]sulfanyl}-N,N-dimethyl-2-phenylacetamide (A-47). Yield: 86.0 mg, 54%; Appearance: White solid;1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 7.72 – 7.64 (m, 3H), 7.59 – 7.53 (m, 1H), 7.44 – 7.38 (m, 2H), 7.38 – 7.32 (m, 1H), 6.28 (s, 1H), 5.01 (t, J = 6.0 Hz, 1H), 4.19 – 4.07 (m, 2H), 3.69 – 3.62 (m, 2H), 3.28 (s, 3H), 2.91 (s, 3H); LCMS Calculated for C24H23N3O3S: 433.53; Observed: 434.4 [M+H]+.

[0504] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below: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. Isothiocyanatoethane (5.57 g, 64.0 mmol) was added to a mixture of 3-aminonaphthalene-2- carboxylic acid (10 g, 53.4 mmol) and TEA (5.66 g, 53.4 mmol) in anhydrous EtOH (50 mL) at 80 ℃. The mixture was refluxed until the starting material was consumed and cooled to RT. The formed precipitate was filtered and washed with cold ethanol (100 mL × 2) to give the 3-ethyl-2- sulfanyl-3H,4H-benzo[g]quinazolin-4-one (13.0 g, 50.7 mmol, 100% purity, 95% yield) as a yellow solid.

[0506] Step 2. Synthesis of ethyl 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl}sulfanyl)-2-phenylacetate. To a solution of 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin-4- one (1.84 g, 7.17 mmol) and 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 ℃, and the reaction mixture was stirred for 16 h. After the reaction was complete, the reaction was quenched by addition ofwater (30 mL). The mixture was filtered and the filter cake was washed with water (20 mL) and dried under vacuum to give the desired product ethyl 2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetate (2.10 g, 5.01 mmol, 100% purity, 70% yield) as a yellow solid.

[0507] Step 3. Synthesis of 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2- phenylacetic acid. To a mixture of methyl 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl}sulfanyl)-2-phenylacetate (7.9 g, 19.5 mmol) in THF (80 mL) was added lithium hydroxide (818 mg, 19.5 mmol). The reaction mixture was stirred at 25 ℃ for 16 h. After the reaction was complete, the mixture was diluted with distilled water (25 mL) and acidified with HCl (1 M) until the pH value reached 3. The formed solid was filtered off and washed with water (25 mL × 2) to afford 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetic acid (6.70 g, 17.1 mmol, 87.0% purity, 88% yield) as a yellow solid that was used for next step without further purification.

[0508] Step 4. Synthesis of 3-ethyl-2-{[2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}- 3H,4H-benzo[g]quinazolin-4-one. To a solution of 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin- 2-yl}sulfanyl)-2-phenylacetic acid (500 mg, 1.28 mmol), piperazine (551 mg, 6.40 mmol), and HATU (730 mg, 1.92 mmol) in DMF (5 mL) was added DIPEA (496 mg, 3.84 mmol) at RT. The reaction mixture was stirred for 12 h at 45 ℃. After the reaction was complete, water was added (20 mL), and the reaction mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by flash chromatography (EtOAc / PE = 0-50%) to give 3-ethyl-2-{[2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3H,4H-benzo[g]quinazolin- 4-one (425 mg, 926 µmol, 94.1% purity, 72% yield) as a light yellow solid

[0509] Step 5. Synthesis of 3-ethyl-2-{[(1R)-2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl}-3H,4H-benzo[g]quinazolin-4-one and Synthesis of 3-ethyl-2-{[(1S)-2-oxo-1- phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3H,4H-benzo[g]quinazolin-4-one. The racemate of 3- ethyl-2-{[2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3H,4H-benzo[g]quinazolin-4-one (40 mg, 87.2 µmol) was purified by chiral prep-HPLC (HEP : IPA (0.1% DEA) = 65:35) to afford 3- ethyl-2-{[(1R)-2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3H,4H-benzo[g]quinazolin-4- one and 3-ethyl-2-{[(1S)-2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3H,4H- benzo[g]quinazolin-4-one.

[0510] 3-ethyl-2-{[(1R)-2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3H,4H- benzo[g]quinazolin-4-one (A-50). Yield: 2.62 mg, 7%; Appearance: White solid;1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.70 – 7.64 (m, 3H), 7.59 – 7.54 (m, 1H), 7.44 – 7.38 (m, 2H), 7.37 – 7.32 (m, 1H), 6.37 (s, 1H), 4.14 – 4.05 (m, 2H), 3.77 – 3.68 (m, 1H), 3.59 – 3.49 (m, 2H), 3.41 – 3.33 (m, 2H), 2.90 – 2.80 (m, 1H), 2.76 – 2.67 (m, 1H), 2.38 – 2.27 (m, 1H), 1.28 (t, J = 7.0 Hz, 3H); LCMS Calculated for C26H26N4O2S: 458.58; Observed: 459.2 [M+H]+;

[0511] 3-ethyl-2-{[(1S)-2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3H,4H- benzo[g]quinazolin-4-one (A-51). Yield: 4.7 mg, 11%; Appearance: White solid;1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.70 – 7.64 (m, 3H), 7.59 – 7.54 (m, 1H), 7.44 – 7.38 (m, 2H), 7.37 – 7.32 (m, 1H), 6.37 (s, 1H), 4.14 – 4.05 (m, 2H), 3.77 – 3.68 (m, 1H), 3.59 – 3.49 (m, 2H), 3.41 – 3.33 (m, 2H), 2.90 – 2.80 (m, 1H), 2.76 – 2.67 (m, 1H), 2.38 – 2.27 (m, 1H), 1.28 (t, J = 7.0 Hz, 3H); LCMS Calculated for C26H26N4O2S: 458.58; Observed: 459.2 [M+H]+.

[0512] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation (Step 1 to Step 4) of the previous example as indicated in the table below.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. To a mixture of activated Raney nickel (10.5 g of 50% slurry in water on aluminum; 180 mmol, 17 eq.) and 3-aminonaphthalene-2-carboxylic acid (2.0 g, 10.6 mmol) in 80 mL of a 1 : 1 mixture of isopropyl alcohol (40 mL) and water (40 mL) at 95 ℃ was added 1% aqueous NaOH (40 mL) over 1 h. The reaction mixture was stirred for 24 h at 95 ℃. The mixture was filtered and the filtrate was concentrated to 50 mL of water and brought to pH = 3 with the addition of HCl (1 M) to precipitate the product. The aqueous layer was separated and extracted with EtOAc (5 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (EtOAc / PE = 20-50%) to give 3-amino-5,6,7,8-tetrahydronaphthalene-2- carboxylic acid (1.77 g, 9.25 mmol, 100% purity, 88% yield) as a light-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.39 (s, 1H), 6.42 (s, 1H), 2.60 – 2.56 (m, 4H), 1.73 – 1.59 (m, 4H).

[0514] Step 2. Synthesis of 3-ethyl-2-sulfanyl-3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin- 4-one. 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. The formed precipitate was filtered and washed with cold ethanol (50 mL × 3) to give 3-ethyl- 2-sulfanyl-3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-4-one (1.50 g, 5.76 mmol, 100% purity, 87 % yield) as a white solid.

[0515] Step 3. Synthesis of ethyl 2-({3-ethyl-4-oxo-3H,4H,6H,7H,8H,9H- cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetate. Dipotassium carbonate (1.19 g, 8.63 mmol) was added to the solution of 3-ethyl-2-sulfanyl-3H,4H,6H,7H,8H,9H- cyclohexa[g]quinazolin-4-one (1.50 g, 5.76 mmol) and ethyl 2-bromo-2-phenylacetate (1.40 g, 5.76 mmol) in dry DMF (20 mL). The reaction mixture was stirred for 16 h at RT. The mixture was diluted with distilled water (100 mL). The aqueous layer was separated and extracted with EtOAc (5 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (EtOAc / DCM = 0-3%) to give ethyl 2-({3-ethyl-4-oxo- 3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetate (1.38 g, 3.28 mmol, 77.7% purity, 73% yield) as a light-yellow solid.

[0516] Step 4. Synthesis of 2-({3-ethyl-4-oxo-3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin- 2-yl}sulfanyl)-2-phenylacetic acid. To a solution of ethyl 2-({3-ethyl-4-oxo- 3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetate (1.78 g, 4.21 mmol) in THF (20 mL) was added aqueous lithium hydroxide (2 M, 20 mL, 40 mmol) at RT. The reaction mixture was stirred for 16 h. The reaction mixture was concentrated to remove organic solvents under reduced pressure. To the residue was added HCl (2 M) to adjust to pH=3 ~ 4. The formed precipitate was filtered and washed with PE (30 mL × 3) to give 2-({3-ethyl-4-oxo- 3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetic acid (1.63 g, 3.22 mmol, 60.5% purity, 98% yield) as an off-white solid, which was used in the next step without further purification.

[0517] Step 5. Synthesis of tert-butyl 4-[2-({3-ethyl-4-oxo-3H,4H,6H,7H,8H,9H- cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]piperazine-1-carboxylate. The mixture of 2-({3-ethyl-4-oxo-3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetic acid (260 mg, 0.659 mmol), HATU (300 mg, 0.790 mmol), and DIEA (254 mg, 1.97 mmol) was stirred in DMF (5 mL) at RT for 5 min. Then, tert-butyl piperazine-1-carboxylate (134 mg, 0.724 mmol) was added at RT. The reaction mixture was stirred at 50 ℃ for 4 h. The reaction was 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), dried over sodium sulfate, filtered and concentrated to afford the crude, which was purified by prep-HPLC (ACN / H2O / 0.1% NH4OH) to give the desired product tert-butyl 4-[2-({3-ethyl-4-oxo- 3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]piperazine-1- carboxylate (182.9 mg, 0.323 mmol, 99.6% purity, 49% yield ) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.65 – 7.58 (m, 2H), 7.44 – 7.38 (m, 2H), 7.37 – 7.32 (m, 1H), 7.25 (s, 1H), 6.27 (s, 1H), 4.03 (q, J = 8.0 Hz, 2H), 3.83 – 3.77 (m, 1H), 3.60 – 3.46 (m, 5H), 3.23 – 3.14 (m, 1H), 3.00 – 2.95 (m, 1H), 2.91 – 2.82 (m, 4H), 1.80 – 1.73 (m, 4H), 1.40 (s, 9H), 1.22 (t, J = 8.0 Hz, 3H); LCMS Calculated for C31H38N4O4S: 562.73; Observed: 563.2 [M+H]+.

[0518] 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. To a solution of tert-butyl 4-[2-({3-ethyl-4- oxo-3H,4H,6H,7H,8H,9H-cyclohexa[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]piperazine-1- carboxylate (130 mg, 0.231 mmol) in DCM (10 mL) was added trifluoroacetic acid (1 mL, 13.4 mmol) at RT. The reaction mixture was stirred for 4 h. To the reaction mixture was added NH4OH to adjust pH= 8 ~ 9, and then the mixture was concentrated to give a crude, which was purified by prep-HPLC (ACN / H2O / 0.1% NH4OH) to give 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). Yield: 51.1 mg, 48%; Appearance: White solid;1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.65 – 7.57 (m, 2H), 7.42 – 7.29 (m, 4H), 6.27 (s, 1H), 4.03 (q, J = 8.0 Hz, 2H), 3.66 – 3.61 (m, 1H), 3.52 – 3.45 (m, 2H), 3.31 – 3.19 (m, 1H), 2.95 – 2.80 (m, 4H), 2.78 – 2.73 (m, 1H), 2.69 – 2.63 (m, 1H), 2.46 – 2.32 (m, 1H), 2.30 – 2.19 (m, 1H), 1.82 – 1.73 (m, 4H), 1.21 (t, J = 8.0 Hz, 3H); LCMS Calculated for C26H30N4O2S: 462.61; Observed: 463.2 [M+H]+.

[0519] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.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. To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol (298 mg, 1.99 mmol) and sodium carbonate (252 mg, 2.38 mmol) in THF (3 mL) and water (1 mL) was added benzyl carbonochloridate (406 mg, 2.38 mmol). The reaction was stirred for 2 h at RT. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography(EtOAc / PE = 0- 80%) to afford the desired product benzyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (500 mg, 1.76 mmol, 100% purity, 88% yield) as a colorless oil.

[0521] Step 2. Synthesis of benzyl N-{2-[2-(2-bromoethoxy)ethoxy]ethyl}carbamate. To a solution of benzyl N-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (4.54 g, 16.0 mmol) in THF (50 mL) was added PPh3(8.39 g, 32.0 mmol) and CBr4(10.6 g, 32.0 mmol). The reaction mixture was stirred at 80 ℃ for 16 h. The reaction was poured into water (20 ml) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (EtOAc / PE = 0-5%) to afford the desired product benzyl N-{2-[2-(2- bromoethoxy)ethoxy]ethyl}carbamate (3.20 g, 9.24 mmol, 63% purity, 58% yield) as a yellow oil.

[0522] Step 3. Synthesis of methyl 2-(4-{2-[2-(2- {[(benzyloxy)carbonyl]amino}ethoxy)ethoxy]ethoxy} phenyl)acetate. Benzyl N-{2-[2-(2- bromoethoxy)ethoxy]ethyl}carbamate (100 mg, 288 µmol) and methyl 2-(4- hydroxyphenyl)acetate (72 mg, 432 µmol) were added to potassium carbonate (119 mg, 864 µmol) in DMF (5 mL). The reaction mixture was stirred at 60 ℃ for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (EtOAc / PE = 0-20%) to afford methyl 2-(4-{2- [2-(2-{[(benzyloxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)acetate (74 mg, 171 µmol, 85% purity, 60% yield) as a yellow oil.

[0523] Step 4. Synthesis of methyl 2-(4-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}phenyl)acetate. Pd / C (83 mg, 786 µmol) was added to methyl 2-(4-{2-[2-(2- {[(benzyloxy)carbonyl]amino}ethoxy) ethoxy]ethoxy}phenyl)acetate (1.7 g, 3.93 mmol) in MeOH (20 mL) under H2atmosphere. The reaction mixture was stirred at 25 ℃ for 2 h. Theorganic layer was condensed to afford the desired product methyl 2-(4-{2-[2-(2- aminoethoxy)ethoxy]ethoxy}phenyl)acetate (crude, 86% purity) that was used in the next step without further purification.

[0524] Step 5. Synthesis of methyl 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy} phenyl)acetate. (Boc)2O (82 mg, 376 µmol) was added to a solution of methyl 2-(4-{2-[2-(2-aminoethoxy) ethoxy]ethoxy}phenyl)acetate (56 mg, 188 µmol) in DCM (5 mL). The reaction mixture was stirred at 25 ℃ for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduce pressure to give a residue. The residue was purified by flash chromatography (EtOAc / PE = 0-20%) to afford the desired product methyl 2-(4-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy} phenyl) acetate (50 mg, 125 µmol, 67% purity, 67% yield) as a yellow oil.

[0525] Step 6. Synthesis of methyl 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-diazoacetate. To a solution of DBU (1.03 g, 6.77 mmol) and methyl 2-(4-{2-[2-(2-{[(tert-butoxy)carbonyl]amino} ethoxy)ethoxy]ethoxy}phenyl)acetate (900 mg, 2.26 mmol) in ACN (50 mL) was added 4- acetamidobenzene-1-sulfonyl azide (812 mg, 3.38 mmol). The reaction mixture was stirred at RT for 16 h. It was then added to water (20 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product methyl 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy} phenyl)-2-diazoacetate(crude, 64% purity), which was used in the next step without further purification.

[0526] Step 7. Synthesis of 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)acetate. To a solution of rhodium(II) acetate dimer (937 mg, 2.12 mmol) in 1,4-dioxane (5 mL) were added methyl 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-diazoacetate (900 mg, 2.12 mmol) and 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin-4-one (543 mg, 2.12 mmol) under N2atmosphere. After the reaction mixture was stirred at RT for 16 h, the mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (EtOAc / PE= 0-30%) to give compound methyl 2-(4-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-({3-ethyl-4-oxo- 3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)acetate (600 mg, 920 µmol, 67.0% purity, 43% yield) as a yellow oil.

[0527] Step 8. Synthesis of 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)acetic acid. To a solution of methyl 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)acetate (600 mg, 920 µmol) in THF (20 mL) and water (5 mL) was added lithium hydroxide monohydrate (193 mg, 4.60 mmol). The reaction mixture was stirred at RT for 2 h, then diluted with distilled water (25 mL). The mixture was acidified with 1 N HCl until the pH value reached 3. The organic layer was extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (EtOAc / PE= 0- 50%) to give 2-(4-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-({3- ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)acetic acid (300 mg, 470 µmol, 95% purity, 51% yield) as a yellow oil.

[0528] Step 9. Synthesis of tert-butyl N-{2-[2-(2-{4-[1-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-2- oxoethyl]phenoxy}ethoxy)ethoxy]ethyl}carbamate (A-60). DIEA (150 mg, 1.17 mmol) and (3S)- pyrrolidin-3-ol (41 mg, 470 µmol) was added to 2-(4-{2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethoxy}phenyl)-2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)acetic acid (250 mg, 392 µmol) and HATU (223 mg, 588 µmol) in DMF (15 mL). The reaction mixture was stirred at 45 ℃ for 2h, which was cooled to RT. The mixture was added with water (20 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The crude product was purified by flash chromatography (100% EtOAc) to give compound tert-butyl N-{2-[2-(2-{4-[1-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl}sulfanyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-2- oxoethyl]phenoxy}ethoxy)ethoxy]ethyl}carbamate (A-60) (150 mg, 212 µmol, 100% purity, 54% yield) as a yellow oil.

[0529] 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). A solution of tert-butyl N-{2-[2-(2-{4-[1-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl}sulfanyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-2- oxoethyl]phenoxy}ethoxy)ethoxy]ethyl}carbamate (70 mg, 99.0 µmol) in 1,1,1,3,3,3-hexafluoro- 2-propanol (5 mL) was stirred at 125 ℃ under microwave until the reaction was complete. The reaction was then concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (ACN / water / 0.1% FA) to afford 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). Yield: 18.0 mg, 30%; Appearance: White solid;1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.4 Hz, 1H), 8.42 – 8.36 (m, 1H), 8.22 – 8.16 (m, 1H), 7.96 (d, J = 6.8 Hz, 1H), 7.71 – 7.61 (m, 1H), 7.61 – 7.43 (m, 3H), 7.03 – 6.93 (m, 2H), 6.07 – 5.87 (m, 1H), 4.59 – 4.28 (m, 2H), 4.21 – 4.01 (m, 5H), 3.77 – 3.70 (m, 3H), 3.63 – 3.58 (m, 4H), 3.57 – 3.52 (m, 6H), 2.80 (t, J = 5.1 Hz, 2H), 2.30 – 1.71 (m, 2H), 1.40 – 1.18 (m, 3H); LCMS Calculated for C32H38N4O6S: 606.74; Observed: 607.3 [M+H]+. 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. To a solution of tert-butyl (2R)-2-formylpyrrolidine-1- carboxylate (400 mg, 2.00 mmol) in methanol (10 mL) were added 1,4-dioxa-8- azaspiro[4.5]decane (286 mg, 2.00 mmol) and sodium cyanoborohydride (628 mg, 10.00 mmol). The reaction mixture was stirred at RT for 16 h. After the reaction was complete, water was added to the solution and extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated under reduced pressure and purified by flash chromatography (MeOH / DCM = 0- 10%) to give tert-butyl (2R)-2-({1,4-dioxa-8-azaspiro[4.5]decan-8-yl}methyl)pyrrolidine-1- carboxylate (600 mg, 1.84 mmol, 100% purity, 92% yield) as a white solid.

[0531] Step 2. Synthesis of (R)-8-(pyrrolidin-2-ylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane. A mixture of tert-butyl (2R)-2-({1,4-dioxa-8-azaspiro[4.5]decan-8-yl}methyl)pyrrolidine-1- carboxylate (600 mg, 1.84 mmol) in hydrochloric acid (10 mL) and H2O (10 mL) was stirred at 100 ℃ for 2 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give (R)-8-(pyrrolidin-2-ylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (crude) as yellow oil, which was used directly for the next step without further purification.

[0532] Step 3. 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. To a solution of 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetic acid (100 mg, 0.256 mmol) in dichloromethane (10 mL) were added HATU (116 mg, 0.307 mmol) and N,N-diisopropylethylamine (165 mg, 1.28 mmol). The mixture was stirred for 10 min. (R)-8- (pyrrolidin-2-ylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (115 mg, 0.5122 mmol) was added, and the reaction mixture was stirred at 50 ℃ for 3 h. After the reaction was complete, water was added to the solution, and the reaction mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were concentrated under reduced pressure and purified by prep-HPLC (ACN / H2O / 0.5% NH4HCO3) to give 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). Yield: 14.9 mg, 10%; Appearance: White solid;1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.13 – 8.06 (m, 1H), 7.98 (s, 1H), 7.73 – 7.64 (m, 3H), 7.61 – 7.53 (m, 1H), 7.45 – 7.28 (m, 3H), 6.37 – 5.94 (m, 1H), 4.15 – 4.05 (m, 3H), 3.85 – 3.78 (m, 3H), 3.69 – 3.55 (m, 1H), 3.47 – 3.39 (m, 1H), 3.31 – 3.25 (m, 1H), 2.70 – 2.57 (m, 1H), 2.47 – 2.38 (m, 1H), 2.36 – 2.24 (m, 2H), 2.20 – 2.07 (m, 1H), 2.08 – 1.84 (m, 3H), 1.67 – 1.40(m, 5H), 1.32 – 1.21 (m, 4H); LCMS Calculated for C34H38N4O4S: 598.76; Observed: 599.6 [M+H]+.

[0533] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.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. The formed precipitate was filtered and washed with cold ethanol (100 mL x 2) to give 3-ethyl-2-sulfanyl-3H,4H-benzo[g]quinazolin- 4-one (23.0 g, 89.7 mmol, 100% by LCMS, 84.8% yield).

[0535] Step 2. Synthesis of methyl 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2- yl}sulfanyl)-3-phenylpropanoate. Methyl 2-bromo-3-phenylpropanoate (0.43 g, 1.76 mmol) and dipotassium carbonate (0.344 g, 2.48 mmol) were added to a stirred solution of 3-ethyl-2-sulfanyl- 3H,4H-benzo[g]quinazolin-4-one (0.4 g, 1.56 mmol) in DMF (15 mL). The reaction mixture wasstirred at 100 °C for 12 h. After cooling, the mixture was diluted with water (100 mL) and filtered. The solid was washed with water (20 mL x 2) to give methyl 2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-3-phenylpropanoate (0.555 g, 1.32 mmol, 100% purity, 85.1% yield).

[0536] Step 3. Synthesis of 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-3- phenylpropanoic acid. Methyl 2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-3- phenylpropanoate (0.555 g, 1.32 mmol) was dissolved in THF (7 mL). Lithium(1+) hydrate hydroxide (0.200 g, 6.60 mmol) solution in water (2 mL) was then added. The reaction mixture was stirred at 450C overnight. Tetrahydrofuran was then removed under reduced pressure, and the residue was diluted with water (10 mL) and acidified with citric acid aq. solution. The resulting solid was filtered off and washed with water (20 mL x 2)to give 2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-3-phenylpropanoic acid (0.480 g, 1.18 mmol, 100% purity, 90% yield).

[0537] Step 4. Synthesis of 2‐({3‐ethyl‐4‐oxo‐3H,4H‐benzo[g]quinazolin‐2‐yl}sulfanyl)‐ N,N‐dimethyl‐3‐phenylpropanamide. 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-3λ⁵-[1,2,3]triazolo[5,4- b]pyridin-3-ylium-2-ide; hexafluoro-λ⁵-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. After the reaction reached completion (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the residue was subjected to HPLC purification (deionized water / HPLC-grade acetonitrile) that afforded 2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-N,N-dimethyl-3-phenylpropanamide (A-64). Yield: 23.7 mg, 14.1 %; Appearance: Yellow solid;1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.10 (s, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.39 – 7.29 (m, 4H), 7.23 (t, J = 7.0 Hz, 1H), 5.37 (dd, J = 9.1, 6.1 Hz, 1H), 4.09 (q, J = 7.6 Hz, 2H), 3.31 – 3.17 (m, 2H), 2.98 – 2.87 (m, 3H), 2.85 – 2.76 (m, 3H), 1.28 (t, J = 7.0 Hz, 3H); LCMS Calculated for C25H25N3O2S: 431.55; Observed: 432.2[M+H]+.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. To a solution of 2, 4, 6-trichloroquinazoline (220 mg, 942 µmol) and 2-aminoethan-1-ol (62.9 mg, 1.03 mmol) in ethanol (10 mL) was added N,N-diisopropylethylamine (121 mg, 942 µmol). The reaction was stirred at 25 ℃ until the reaction reached completion (TLC control, 3 h). The reaction mixture was concentrated under the reduced pressure to obtained the product 2-[(2, 6-dichloroquinazolin-4- yl)amino]ethan-1-ol (130 mg, 507 µmol, 77% purity, 53% yield) that was used in next step without further purification.

[0539] Step 2. Synthesis of 5, 9-dichloro-2H,3H-imidazo[1,2-c]quinazoline. To a solution of 2-[(2,6-dichloroquinazolin-4-yl)amino]ethan-1-ol (170 mg, 658 µmol) in dichloromethane (6 mL) was added thionyl chloride (78.2 mg, 658 µmol) and triethylamine (67 mg, 658 µmol). Themixture was stirred at 25 ℃ until the reaction reached completion (LCMS control, 3 h). The reaction mixture was then concentrated under reduced pressure. The mixture was diluted with water (30 mL), then neutralized with sodium bicarbonate aqueous solution until it reached pH – 8. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (EtOAc / PE = 0-50%) to afford the desire product 5, 9-dichloro-2H,3H- imidazo[1, 2-c]quinazoline (92.0 mg, 383 µmol, 92% purity, 59% yield) as a brown solid.

[0540] Step 3. Synthesis of 9-chloro-2H, 3H-imidazo[1,2-c]quinazoline-5-thiol. To a solution of 5, 9-dichloro-2H,3H-imidazo[1,2-c]quinazoline (140 mg, 583 µmol) in dimethyl sulfoxide (8 mL) was added sodium sulfocyanate (94 mg, 1.16 mmol). The reaction mixture was stirred at 80 ℃ until the reaction reached completion (LC-MS control, 3 h). The reaction mixture was used in the next step directly without further work-up.

[0541] Step 4. Synthesis of 2-({9-chloro-2H,3H-imidazo[1,2-c]quinazolin-5-yl}sulfanyl)-2- phenylacetate. To a solution of 9-chloro-2H,3H-imidazo[1,2-c]quinazoline-5-thiol (140 mg, 588 µmol) and ethyl 2-bromo-2-phenylacetate (171 mg, 705 µmol) in dimethyl sulfoxide (10 mL) was added N,N-diisopropylethylamine (227 mg, 1.76 mmol). The reaction was stirred for 2 h at 50 ℃. After the reaction was complete, water (20 mL) was added to it, and the aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (EtOAc / PE = 0-35%) to afford the desire product ethyl 2-({9-chloro-2H,3H-imidazo[1,2-c]quinazolin-5-yl}sulfanyl)-2- phenylacetate (120 mg, 588 µmol, 100% purity, 51% yield) as yellow solid.

[0542] Step 5. Synthesis of 2-({9-chloro-2H,3H-imidazo[1,2-c]quinazolin-5-yl}sulfanyl)-2- phenylacetic acid. To a solution of ethyl 2-({9-chloro-2H,3H-imidazo[1,2-c]quinazolin-5- yl}sulfanyl)-2-phenylacetate (105 mg, 262 µmol) in tetrahydrofuran (6 mL) was added lithium hydroxide (13 mg, 524 µmol) and H2O (0.5 mL). The reaction was stirred for 2 h at 25 ℃. The reaction mixture was concentrated under reduced pressure to obtained the crude product 2-({9- chloro-2H,3H-imidazo[1,2-c]quinazolin-5-yl}sulfanyl)-2-phenylacetic acid (89.3 mg, 240 µmol, 94% purity, 92% yield) as a white solid.

[0543] Step 6. Synthesis of 2-({9-chloro-2H,3H-imidazo[1,2-c]quinazolin-5-yl}sulfanyl)-2- phenyl-1-(piperazin-1-yl)ethan-1-one. To a solution of 2-({9-chloro-2H,3H-imidazo[1,2- c]quinazolin-5-yl}sulfanyl)-2-phenylacetic acid (100 mg, 268 µmol) in DMF (5 mL) wasadded N,N-diisopropylethylamine (173 mg, 1.34 mmol), HATU (152 mg, 402 µmol), and piperazine (28 mg, 321 µmol). The reaction mixture was stirred at 50 ℃ until the reaction reached completion (LC-MS control, 3 h). Water (20 mL) was added to the reaction, and the aqueous phase was then extracted with EtOAc (30 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (EtOAc / PE = 0-50%) to afford the desire product, which was further purified by prep-HPLC to give 2-({9-chloro-2H,3H-imidazo[1,2-c]quinazolin-5-yl}sulfanyl)-2-phenyl-1- (piperazin-1-yl)ethan-1-one (37.4 mg, 84.0 µmol) as white solid. (A-65). Yield: 37.4 mg, 32%; Appearance: White solid;1H NMR (400 MHz, DMSO-d6) δ 7.75 – 7.71 (m, 1H), 7.63 (dd, J = 8.7, 2.5 Hz, 1H), 7.59 – 7.55 (m, 2H), 7.45 – 7.29 (m, 4H), 6.25 (s, 1H), 4.02 – 3.87 (m, 4H), 3.65 – 3.55 (m, 1H), 3.49 – 3.35 (m, 3H), 3.30 (s, 1H), 2.77 – 2.69 (m, 1H), 2.65 – 2.57 (m, 1H), 2.53 – 2.51 (m, 1H), 2.30 – 2.20 (m, 1H); LCMS Calculated for C22H22ClN5OS: 439.96; Observed: 430.4 [M+H]+.

[0544] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous examples as indicated in the table below.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. Isothiocyanatoethane (11.6 g, 133 mmol) was added to a mixture of 2-amino-5- chlorobenzenecarboxylic acid (20.8 g, 121 mmol) and triethylamine (26.9 g, 267 mmol) in anhydrous ethanol (400 mL). The mixture was refluxed for 16 h and cooled to room temperature. The formed precipitate was filtered and washed with cold ethanol (100 mL x 2) to give 6-chloro- 3-ethyl-2-mercaptoquinazolin-4(3H)-one (20.0 g, 83 mmol, 100% purity, 68.7% yield).

[0546] Step 2. Synthesis of methyl 2-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)thio)-2-phenylacetate. Ethylbis(propan-2-yl)amine (9.4 g, 72.7 mmol) was added to the solution of 6-chloro-3-ethyl-2-mercaptoquinazolin-4(3H)-one (11.7.0 g, 48.6 mmol) and methyl 2-bromo- 2-phenylacetate (12.3 g, 53.6 mmol) in dry DMSO (150 mL). The reaction mixture was stirred at 500C overnight, cooled to room temperature, and diluted with distilled water (250 mL). The formed solid was filtered, washed with distilled water (50 mL x 3), and dried at room temperature to give methyl 2-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-2-phenylacetate (14.4 g, 37 mmol, 100% purity, 76.5% yield).

[0547] Step 3. Synthesis of 2-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-2- phenylacetic acid. A solution of LiOH*H2O (3.1 g, 74 mmol) in water (50 mL) was added to methyl 2-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-2-phenylacetate (14.4 g, 37 mmol) in ethanol (300 mL). The reaction mixture was stirred at 500C until of formation of a transparent solution (for 30 min), which was stirred at room temperature overnight. Afterwards, the reaction mixture was diluted with distilled water (300 mL) and 20% HCl aq. solution wasadded dropwise until pH =3 was reached. The formed solid was filtered off, washed with water, and dried at room temperature to give 2-((6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)thio)-2-phenylacetic acid, Yield: 9700 mg, 65.3%; Appearance: Yellow solid;1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.7, 2.5 Hz, 1H), 7.58 – 7.47 (m, 3H), 7.41 – 7.32 (m, 3H), 5.58 (s, 1H), 4.01 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H); HPLC purity: 96.68%; LCMS Calculated for C18H15ClN2O3S: 274.84; Observed: 375.0[M+H]+. Scheme 2: Synthesis of 6-chloro-3-ethyl-2-{[2-oxo-1-phenyl-2-(pyrrolidin-1- yl)ethyl]sulfanyl}-3,4-dihydroquinazolin-4-one (C-1):

[0548] A vial was charged with amine (1.2 eq.), acid (1 eq.) and ethylbis(propan-2-yl)amine (2.5 eq.) in DMSO (1 mL). Then, HATU (1.25 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 subjected to HPLC purification (deionized water / HPLC-grade methanol) to give 6-chloro-3-ethyl-2-{[2-oxo-1-phenyl-2-(pyrrolidin-1-yl)ethyl]sulfanyl}-3,4- dihydroquinazolin-4-one (C-1). Yield: 17.7 mg, 25.8%; Appearance: Light brown solid;1H NMR (600 MHz, DMSO-d6) δ 7.99 (d, J = 2.6 Hz, 1H), 7.84 (dd, J = 8.7, 2.6 Hz, 1H), 7.65 – 7.59 (m, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.36 – 7.28 (m, 1H), 5.95 (s, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.99 (dt, J = 10.2, 7.1 Hz, 1H), 3.39 – 3.32 (m, 2H), 3.27 – 3.22 (m, 1H), 2.01 (dq, J = 13.1, 6.8 Hz, 1H), 1.90 – 1.83 (m, 1H), 1.83 – 1.77 (m, 1H), 1.73 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H); LCMS Calculated for C22H22ClN3O2S: 427.14; Observed: 428.0[M+H]+.

[0549] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.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. The residue was dissolved in dichloromethane (1.5 mL), followed by addition of TFA (1 mL). The mixture was stirred at room temperature for 3 h and evaporated to dryness. The residue was subjected to HPLC purification (deionized water / HPLC-grade methanol, ammonia) to give 6-chloro-3-ethyl-2-{[2-oxo-1-phenyl-2- (piperazin-1-yl)ethyl]sulfanyl}-3,4-dihydroquinazolin-4-one, (C-12). Yield: 7 mg, 9.56%;Appearance: Yellow solid;1H NMR (600 MHz, DMSO-d6) δ 7.97 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 8.7, 2.6 Hz, 1H), 7.66 – 7.56 (m, 3H), 7.36 (dd, J = 8.3, 6.8 Hz, 2H), 7.34 – 7.27 (m, 1H), 6.24 (s, 1H), 4.07 – 3.98 (m, 2H), 3.64 – 3.60 (m, 1H), 3.47 – 3.41 (m, 2H), 3.14 (d, J = 5.1 Hz, 1H), 2.77 – 2.70 (m, 1H), 2.66 – 2.60 (m, 1H), 2.44 (d, J = 3.0 Hz, 1H), 2.29 – 2.23 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); LCMS Calculated for C22H23ClN4O2S: 442,15; Observed: 443.0[M+H]+.

[0551] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.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. Synthesis of tert-butyl 4-{2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl}piperazine-1-carboxylate. Solution of 2-[(6-chloro-3-ethyl-4-oxo- 3,4-dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetic acid (0.5 g, 1.33 mmol), tert-butyl piperazine-1-carboxylate (0.271 g, 1.46 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5- b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ5-phosphanuide (0.577 g, 1.52 mmol), and ethylbis(propan-2-yl)amine (0.257 g, 1.99 mmol) in dimethylformamide (15 mL) was stirred at 80 °C for 16 h. The obtained mixture was diluted with water (40 mL) and extracted with ethyl acetate (20mL x 3). The combined organic layers were washed with water (30 mL x 3) and brine (20 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure affording tert-butyl 4-{2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)sulfanyl]-2- phenylacetyl}pipera-zine-1-carboxylate (0.55 g, 1.01 mmol, 90% purity, 68.5% yield) that was used in next step without further purification.

[0553] Step 2. Synthesis of rel-6-chloro-3-ethyl-2-{[(1R)-2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl}-3,4-dihydroquinazolin-4-one and rel-6-chloro-3-ethyl-2-{[(1S)-2-oxo-1- phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3,4-dihydroquinazolin-4-one. A solution of trimethylsilyl trifluoromethanesulfonate (0.202 g, 0.910 mmol) in dichloromethane (5 mL) was added to a stirred solution of tert-butyl 4-{2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl}piperazine-1-carboxylate (0.45 g, 0.828 mmol) in dichloromethane (15 mL) at 0 °C . The reaction mixture was stirred at 0 °C for 2 h and then poured into a sat. aq. solution of NaHCO3(10 mL). The organic layer was separated and washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified with HPLC (deionized water / HPLC-grade methanol, ammonia) to afford 6-chloro-3-ethyl-2-{[2-oxo- 1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3,4-dihydroquinazolin-4-one (C-12) (0.128 g, 0.290 mmol, 34.9 % yield.) Chiral separation of racemic 6-chloro-3-ethyl-2-{[2-oxo-1-phenyl-2- (piperazin-1-yl)ethyl]sulfanyl}-3,4-dihydroquinazolin-4-one (0.1 g, 0.225 mmol) with the use of Chiralpak AD-H (250*4.6, 5mkm) column in system hexane / IPA / MeOH=50 / 25 / 25 resulted in rel-6-chloro-3-ethyl-2-{[(1R)-2-oxo-1-phenyl-2-(piperazin-1-yl)ethyl]sulfanyl}-3,4- dihydroquinazolin-4-one, Enantiomer-1, (C-14). Yield: 44.6 mg, 40.6 %; Appearance: Light brown oil;1H NMR (600 MHz, DMSO-d6) δ 7.99 (d, J = 2.6 Hz, 1H), 7.84 (dd, J = 8.7, 2.6 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.61 – 7.58 (m, 2H) , 7.38 (t, J = 7.5 Hz, 2H), 7.36 – 7.27 (m, 1H), 6.26 (s, 1H), 4.04 (t, J = 7.2, 2H), 3.66 – 3.59 (m, 1H), 3.49 – 3.40 (m, 2H), 2.76 – 2.61 (m, 2H),2.29 – 2.22 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H); LCMS Calculated for C22H23ClN4O2S: 442.96; Observed: 443.2[M+H]+and rel-6-chloro-3-ethyl-2-{[(1S)-2-oxo-1-phenyl-2-(piperazin-1- yl)ethyl]sulfanyl}-3,4-dihydroquinazolin-4-one as light brown oil (0.0441 g, 0.995 mmol, 99.26% EE, 40.2% yield), Enantiomer-2, (C-15). Yield: 44.1 mg, 40.2%; Appearance: Light brown oil; 1H NMR (600 MHz, DMSO-d6) δ 7.99 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 8.7, 2.6 Hz, 1H), 7.67 – 7.57 (m, 3H), 7.38 (t, J = 7.6 Hz, 2H), 7.36 – 7.29 (m, 1H), 6.26 (s, 1H), 4.04 (t, J = 6.0 Hz, 2H), 3.66 – 3.59 (m, 1H), 3.45 (s, 2H), 2.76 – 2.61 (m, 2H), 2.29 – 2.22 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H) ); LCMS Calculated for C22H23ClN4O2S: 442.96; Observed: 443.2[M+H]+

[0554] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.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. The obtained mixture was stirred for 14 h and evaporated in vacuo. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford N-[(3R)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4- dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetyl}pyrrolidin-3-yl]acetamide (C-25). Yield: 5.8 mg, 36.7%; Appearance: Light brown oil;1H NMR (600 MHz, DMSO-d6) δ 7.99 (q, J = 3.4, 2.9 Hz, 1H), 7.86 – 7.78 (m, 1H), 7.67 – 7.52 (m, 3H), 7.43 – 7.30 (m, 3H), 5.99 – 5.90 (m, 1H), 4.40 – 4.27 (m, 1H), 4.24 – 4.13 (m, 1H), 4.03 (q, J = 7.1, 6.5 Hz, 2H), 3.74 – 3.60 (m, 1H), 3.51 – 3.35 (m, 2H), 3.08 (s, 1H), 2.08 – 2.01 (m, 1H), 1.98 – 1.90 (m, 1H), 1.85 – 1.70 (m, 3H), 1.22 (t, J = 7.0 Hz, 3H); LCMS Calculated for C24H25ClN4O3S: 484.16; Observed: 485.2[M+H]+.

[0556] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example. Analytical data is given in the table below.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. Synthesis of tert-butyl N-[(3S)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4- dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetyl}pyrrolidin-3-yl]carbamate. A solution of 2-[(6- chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetic acid (0.15 g, 0.400 mmol), tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (0.0745 g, 0.400 mmol), (dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ5-phosphanuide (0.174 g, 0.459 mmol), and ethylbis(propan-2-yl)amine (0.129 g, 1 mmol) in DMF (10mL) was stirred at 80 °C for 16 h. The obtained mixture was diluted with water (25mL) 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 under reduced pressure affording tert-butyl N-[(3S)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4- dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetyl}pyrrolidin-3-yl]carbamate (0.22 g, 0.213 mmol, 52.6% purity, 52.9 % yield) that was used in the next step without further purification.

[0558] 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. A solution of trimethylsilyl trifluoromethanesulfonate (0.107 g, 0.485 mmol) in dichloromethane (2 mL) was added to a stirred solution of tert-butyl N-[(3S)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl}pyrrolidin-3-yl]carbamate (0.22 g, 0.405 mmol) in dichloromethane(10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then poured into NaHCO3sat. aq. solution (10 mL). The organic layer was separated and washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to afford 2-({2-[(3S)-3- aminopyrrolidin-1-yl]-2-oxo-1-phenylethyl}sulfanyl)-6-chloro-3-ethyl-3,4-dihydroquinazolin-4- one (0.13 g, 0.176 mmol, 60% purity, 43.5% yield) that was used in the next step without further purification.

[0559] Step 3. 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. Solution of 4- oxo-4-(pyrrolidin-1-yl)butanoic acid (0.0301 g, 0.176 mmol), [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ5- phosphanuide (0.0768 g, 0.202 mmol), and ethylbis(propan-2-yl)amine (0.0568 g, 0.440 mmol) in DMF (10 mL) was stirred at room temperature for 10 min, and a solution of 2-({2-[(3S)-3- aminopyrrolidin-1-yl]-2-oxo-1-phenylethyl}sulfanyl)-6-chloro-3-ethyl-3,4-dihydroquinazolin-4- one (0.13 g, 0.176 mmol, 60% purity) in DMF (2 mL) was added. The obtained mixture was stirred at room temperature for 14 h and evaporated in vacuo. The residue was purified with HPLC (deionized water / HPLC-grade acetonitrile) to afford 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). Yield: 9.9 mg, 8.56%; Appearance: Yellow oil;1H NMR (600 MHz, DMSO-d6) δ 8.28 – 7.94 (m, 2H), 7.87 – 7.78 (m, 1H), 7.67 – 7.50 (m, 3H), 7.42 – 7.35 (m, 2H), 7.35 – 7.30 (m, 1H), 6.02 – 5.85 (m, 1H), 4.53 – 4.06 (m, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.76 – 3.34 (m, 4H), 3.25 – 3.18 (m, 2H), 2.43 – 2.22 (m, 4H), 2.07 – 1.90 (m, 1H), 1.88 – 1.79 (m, 2H), 1.77 – 1.69 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); LCMS Calculated for C30H34ClN5O4S: 596.14; Observed: 596.0 [M+H]+.Example 15: Synthesis of N-{[(2R)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl}pyrrolidin-2-yl]methyl}-4-oxo-4-(pyrrolidin-1-yl)butanamide (C- 28):

[0560] Step 1. Synthesis of tert-butyl N-{[(2R)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4- dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetyl}pyrrolidin-2-yl]methyl}carbamate. A solution of 2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetic acid (0.15 g, 0.400 mmol), tert-butyl N-{[(2R)-pyrrolidin-2-yl]methyl}carbamate (0.0801 g, 0.400 mmol), [(dimethyl-amino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium, hexafluoro-λ⁵-phosphanuide (0.174 g, 0.459 mmol), and ethylbis(propan-2-yl)amine (0.129 g, 1 mmol) in DMF (10 mL) was stirred at 80 °C for 16 h. 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 under reduced pressure affording tert-butyl N-{[(2R)-1-{2-[(6-chloro-3-ethyl-4-oxo- 3,4-dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetyl}pyrrolidin-2-yl]methyl}carbamate (0.19 g, 0.341 mmol, 76% purity, 64.8% yield) that was used in the next step without further purification.

[0561] 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. A solution of trimethylsilyl trifluoromethanesulfonate (0.091 g, 0.409 mmol) in dichloromethane (2 mL) was added to a stirred solution of tert-butyl N-{[(2R)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydro-quinazolin-2- yl)sulfanyl]-2-phenylacetyl}pyrrolidin-2-yl]methyl}carbamate (0.19 g, 0.341 mmol) in dichloromethane (10 mL) at 0 °C . The reaction mixture was stirred at 0 °C for 2 h and then pouredinto NaHCO3saturated aqueous solution (10 mL). The organic layer was separated and washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to afford 2-({2-[(2R)-2-(aminomethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}sulfanyl)-6-chloro-3-ethyl- 3,4-dihydroquinazolin-4-one as yellow solid (0.13 g, 0.284 mmol, 67% purity, 56.1% yield) that was used in the next step without further purification.

[0562] Step 3. Synthesis of 4-oxo-4-(pyrrolidin-1-yl)butanoic acid. Triethylamine (13.9 g, 137 mmol) was added to a stirred solution of pyrrolidine (4.9 g, 68.8 mmol) and oxolane-2,5-dione (7.24 g, 72.3 mmol) in dichloromethane (500 mL) at room temperature. The obtained mixture was stirred overnight, then washed with water (100 mL), saturated citric acid solution (80 mL), and brine (100 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford 4-oxo-4- (pyrrolidin-1-yl)butanoic acid (4.80 g, 28.0 mmol, 100% purity, 41% yield).

[0563] Step 4. Synthesis of N-{[(2R)-1-{2-[(6-chloro-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)sulfanyl]-2-phenylacetyl}pyrrolidin-2-yl]methyl}-4-oxo-4-(pyrrolidin-1-yl)butanamide. A solution of 4-oxo-4-(pyrrolidin-1-yl)butanoic acid (0.325 g, 0.190 mmol) , [(dimethylamino)({3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵- phosphanuide (0.0828 g, 0.218 mmol), and ethylbis(propan-2-yl)amine (0.0612 g, 0.474 mmol) in DMF (10 mL) was stirred at room temperature for 10 min, and a solution of 2-({2-[(2R)-2- (aminomethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}sulfanyl)-6-chloro-3-ethyl-3,4- dihydroquinazolin-4-one (0.13 g, 0.190 mmol) in DMF (2 mL) was added. The obtained mixture was stirred at room temperature for 14 h and evaporated in vacuo. The residue was purified by HPLC (deionized water / HPLC-grade acetonitrile) to afford N-{[(2R)-1-{2-[(6-chloro-3-ethyl-4- oxo-3,4-dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetyl}pyrrolidin-2-yl]methyl}-4-oxo-4- (pyrrolidin-1-yl)butanamide (C-28). Yield: 42 mg, 32.8%; Appearance: Yellow solid;1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 6.2, 2.3 Hz, 1H), 7.66 – 7.54 (m, 3H), 7.45 – 7.29 (m, 4H), 5.88 (d, J = 10.5 Hz, 1H), 4.34 – 3.95 (m, 4H), 3.53 –3.20 (m, 8H), 2.61 – 1.82 (m, 15H), 1.41 – 1.23 (m, 4H); LCMS Calculated for C31H36ClN5O4S: 610.17; Observed: 611.2[M+H]+.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. A solution of 3-amino-1-(4-methylpiperazin-1- yl)propan-1-one (0.3 g, 1.75 mmol), (3S)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-carboxylic acid (0.413 g, 1.92 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3- yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (0.764 g, 2.01 mmol), and ethylbis(propan-2-yl)amine (0.760 mL, 4.37 mmol) in DMF (8 mL) was stirred at 80 °C for 16 h. The obtained mixture was cooled to room temperature, 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 under reduced pressure, affording tert-butyl (3S)-3-{[3-(4-methylpiperazin-1-yl)-3-oxopropyl]carbamoyl}pyrrolidine-1- carboxylate (1.1 g, 1.49 mmol, 50% purity, 85.4% yield) that was used in the next step without further purification.

[0565] Step 2. Synthesis of (3S)-N-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]pyrrolidine-3- carboxamide; bis(trifluoroacetic acid). Trifluoroacetic acid (25 mL, 326 mmol) was added to astirred solution of tert-butyl (3S)-3-{[3-(4-methylpiperazin-1-yl)-3- oxopropyl]carbamoyl}pyrrolidine-1-carboxylate (1.1 g, 1.49 mmol, 50% purity) in dichloromethane (25 mL). The resulting mixture was stirred at room temperature for 4 h, then evaporated to dryness in vacuo to give(3S)-N-[3-(4-methylpiperazin-1-yl)-3- oxopropyl]pyrrolidine-3-carboxamide; bis(trifluoroacetic acid) (1.06 g, 1.35 mmol, 45% purity, 91.3% yield) that was used in the next step without further purification.

[0566] Step 3. 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. A solution of (3S)-N-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]pyrrolidine-3- carboxamide; bis(trifluoroacetic acid) (1.06 g, 1.35 mmol, 45% purity), 2-[(6-chloro-3-ethyl-4- oxo-3,4-dihydroquinazolin-2-yl)sulfanyl]-2-phenylacetic acid (0.200 g, 0.533 mmol), [(dimethylamino)({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy})methylidene]dimethylazanium; hexafluoro-λ⁵-phosphanuide (0.234 g, 0.615 mmol), and ethylbis(propan-2-yl)amine (0.47 mL, 2.69 mmol) in DMF (8mL) was stirred at 80 °C for 16 h. 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. The residue was purified by HPLC (deionized water / HPLC-grade acetonitrile, ammonia) to give .(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 as brown solid (0.043 g, 0.0687 mmol, 90% purity, 11.5% yield) (C-29). Yield: 43 mg, 11.5%; Appearance: Brown solid;1H NMR (600 MHz, DMSO-d6) δ 8.13 – 7.97 (m, 2H), 7.87 – 7.78 (m, 1H), 7.69 – 7.47 (m, 3H), 7.41 – 7.31 (m, 3H), 5.99 – 5.81 (m, 1H), 4.24 – 4.10 (m, 1H), 4.03 (q, J = 7.2 Hz, 2H), 3.62 – 3.36 (m, 5H), 3.27 – 3.12 (m, 2H), 3.02 – 2.81 (m, 1H), 2.40 (dd, J = 11.3, 6.3 Hz, 1H), 2.27 – 2.17 (m, 4H), 2.16 – 2.11 (m, 3H), 2.07 – 1.73 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); LCMS Calculated for C31H37ClN6O4S: 624.27; Observed: 625.2[M+H]+.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. A mixture of N-(azetidin-3-yl)acetamide hydrochloride (0.3 g, 1.99 mmol), 2-chloro-2-phenylacetyl chloride (0.41 g, 2.16 mmol), and triethylamine (0.50 g, 4.94 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give N-[1-(2-chloro-2- phenylacetyl)azetidin-3-yl]acetamide (0.43 g, 1.61 mmol, 90.52% purity, 73.3% yield).

[0568] 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...

Claims

CLAIMS 1. A compound of formula IIor a pharmaceutically acceptable salt thereof, wherein X1is C(R7)2, CR7, S, NR7, S(O), S(O)2, C(O), or O; X2is N, C, or CR9; X3is N, O, or CR9; X4is NR2, N, CR2, C(R2)2, or C(NR2); X5is N, NR3, CR3, C(R3)2, or C(O); each R1is 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 C6-C12aryl, wherein each R1is optionally substituted with one or more R1a, or two R1can 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, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a; each R1ais independently halogen, -OH, -CN, -N(R9)2, -NH-S(O)2-R7, -NH-C(O)-NHR7, - NHC(O)-OR7, -C(O)-NH2, oxo, Z, or an optionally substituted group selected from C1- C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, and 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O;each R2is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3is independently selected from -H, -OH, -N(R7)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic; or R2and R3can 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; or two R3can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4is hydrogen,or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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 R4is optionally substituted with Z; R5is –C(O)-R6, -C(O)N(R6)(R7), -N(R7)C(O)-R6, -S(O)2-R6, -S(O)2N(R6)(R7), -OC(O)-R6, - C(O)OR6, -C(NH)N(R6)(R7), optionally substituted C1-C12aliphatic-R6, or optionally substituted 5- to 6-membered heteroaryl; R6is Z, -OH, -N(R7)2, -S(O)2-R8, C3-C12cycloaliphatic, or 3- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8; each R7is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; or R7and R2, 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 R8is independently -OH, -NH2, Z, or an optionally substituted group selected from C1- C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9is independently selected from H, halo, -OH, -O-C1-C12aliphatic, -NH2, -N(H)-C1- C12aliphatic, and optionally substituted C1-C12aliphatic; Z is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, - N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent C3-C6cycloaliphatic, 5- to 6-membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, S, 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from N, O, S; each RZis independently H, C1-C6aliphatic, or C3-C12cycloaliphatic; and n is 0, 1, or 2.

2. The compound of claim 1, wherein the bond between X4and X5is a single bond.

3. The compound of claims 1 or 2, wherein X3is N.

4. The compound of any one of claims 1-3, wherein X1is S.

5. The compound of any one of claims 1-4, wherein a bond between X1and X2is a single bond.

6. The compound of any one of claims 1-5, wherein n is 2, and two R1are taken together with the atoms to which they are attached to form a 5- to 12- membered heteroaryl having 1 to 6 heteroatoms selected from N, S, and O, 5- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a.

7. The compound of any one of claims 1-6, wherein n is 2, and two R1are taken together with the atoms to which they are attached to form a C6aryl (e.g., phenyl) optionally substituted with one or more R1a.

8. The compound of any one of claims 1-6, wherein n is 2, and two R1are taken together with the atoms to which they are attached to form a C12aryl (e.g., naphthyl) optionally substituted with one or more R1a.

9. The compound of any one of claims 1-8, wherein each R1ais independently selected from -Br, -Cl, -F, -CH3, -CH2-CH3, -OCH3, -CN, -CF3, OH, NH2, Z.

10. The compound of any one of claims 1-9, where R4is phenyl or 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

11. The compound of any one of claims 1-10, wherein X2is CH.

12. The compound of any one of claims 1-11, wherein R2is optionally substituted C1-C12aliphatic.

13. The compound of any one of claims 1-12, wherein a bond between X4and X5is a single bond, and X4is NR2.

14. The compound of any one of claims 1-13, wherein a bond between X4and X5is a single bond, and X5is C(O).

15. The compound of any one of claims 1-14, wherein R5is -C(O)-R6.

16. The compound of any one of claims 1-15, wherein R6is 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O optionally substituted with one or more R8.

17. The compound of any one of claims 1-16, wherein R6is azetidinyl, pyrrolidinyl, or piperidinyl, optionally substituted with one or more R8.

18. The compound of claim 1, wherein n is 2, and two R1come together to form:

19. The compound of claim 1, wherein n is 1.

20. The compound of claim 19, wherein R1is 5- to 12- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with one or more R1a.

21. The compound of claim 1, wherein n is 1, and R1is selected from:

22. The compound of claim 1, wherein R2is H, Cl, -CH3, -CH2-CH3, -CH2-CH2-F, - CH2CHF2, -CH2CF3, -O-CH3, -CF3, -O-CH2-CH3, -CH2-CH2-OH, or –CH2-CH2-NH2.

23. The compound of claim 1, wherein R4is -H, -CH3, -CH2-CH3,24. The compound of claim 1, wherein R5is:

25. The compound of claim 1, wherein the compound is of formula Ilaor a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

26. The compound of claim 1, wherein the compound is of formula IIa-1:or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

27. The compound of claim 1, wherein the compound is of formula IIIor a pharmaceutically acceptable salt thereof, wherein m is 0-6.

28. The compound of claim 1, wherein the compound is of formula Illaor a pharmaceutically acceptable salt thereof, wherein m is 0-6.

29. The compound of claim 1, wherein the compound is of formula IVaor a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein the compound is of formula IVbor a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound is selected from Table 2A, Table 3A, or Table 4A.

32. The compound of claim 1, wherein the compound is selected from Table 2B, Table 3B, or Table 4B.

33. 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, RAB5A, a peroxisome, a myddosome, MYD88, IRAK1 / 2 / 4, an inflammasome, NLRP3, ASC, an endosome, receptor tyrosine kinases, EGFR, cMet, LRP5 / 6, frizzled, oncogenic signaling complexes, RAF, RAS, COP9, MYC, ER-α, AR, KSR1, α-synuclein, tau, huntingtin, TDP43, polyQ / CAG repeat proteins, IAPP, rubicon, FKBP12, HSP90, Hap40, RNA, Hsp90, autophagy cargo adapter proteins, p62, NBR1, OPTN, TAX1BP1, NDP52, liquid-liquid phase separation condensates, Shp2, endoplasmic reticulum, AXTN3, FLCN, FNIP, mTOR, ABHD6, and damaged lysosomes.

34. The compound of claim 33, wherein the ULK complex binding moiety is a compound of any one of claims 1-32.

35. The compound of claim 33, wherein A-B-C is a compound of formula Ia, Ib, Ic, or Id or apharmaceutically acceptable salt thereof, whereinX1’is C(R7’)2, CR7’, S, NR7’, S(O), S(O)2, C(O), or O; X2’is N, NR9’, C, CR9’, or C(R9’)2X3’is N, O, or CR9’; X4’is N, NR2’, CR2’, C(R2’)2, or C(NR2’); X5’is N, NR3’, CR3’, C(R3’)2, or C(O); each R1’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 C6-C12aryl, wherein each R1’is optionally substituted with one or more R1a’, or two R1’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, 4- to 12- membered heterocyclyl having 1 to 6 heteroatoms selected from N, S, and O, C5-C12aryl, or C3-C12cycloaliphatic, each optionally substituted with one or more R1a’; each R1a’is independently halogen, -OH, -CN, -N(R9’)2, -NH-S(O)2-R7’, -NH-C(O)-NHR7’, - NHC(O)-OR7’, -C(O)-NH2, oxo, or an optionally substituted group selected from, C1-C12aliphatic, -O-C1-C12aliphatic, C3-C12cycloaliphatic, C6-C12aryl, 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; each R2’is independently hydrogen, halogen, or an optionally substituted group selected from C1-C6aliphatic, -O-C1-C6aliphatic, C3-C6cycloaliphatic, 2- to 6-membered heteroaliphatic, C6-C12aryl, 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; each R3’is independently selected from -H, -OH, -N(R7’)2, halogen, CN, C1-C6aliphatic, C3- C6cycloaliphatic ; or R2’and R3’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; or two R3’can be taken together with the atom to which they attach to form a C3-C6spirocycloalkyl; R4’is hydrogen,or a group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, C3-C12cycloaliphatic, C6-C12aryl, 4- to 12-membered heterocyclyl comprising 1 to 3heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; R5’is –C(O)-R6’, -C(O)N(R6’)(R7’), -N(R7’)C(O)-R6’, -S(O)2-R6’, -S(O)2N(R6’)(R7’), -OC(O)- R6’, -C(O)OR6’, -C(NH)N(R6’)(R7’), optionally substituted C1-C12aliphatic-R6’, or optionally substituted 5- to 6-membered heteroaryl; R6’is -OH, -N(R7’)2, -S(O)2-R8’, or 3- to 12- membered heterocyclyl having 1 to 3 heteroatoms selected from N, S, and O, each optionally substituted with one or more R8’; each R7’is independently selected from H, optionally substituted C1-C12aliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 2- to 12-membered heteroaliphatic, optionally substituted C6-C12aryl, and optionally substituted 5- to 6- membered heteroaryl having 1 to 3 heteroatoms selected from N, S, and O; or R7’and R2’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 R8’is independently -OH, -NH2, or an optionally substituted group selected from C1-C12aliphatic, 2- to 12-membered heteroaliphatic, -O-C1-C12aliphatic, -NH-C(O)-C1-C12aliphatic, -C(O)-NH-C1-C12aliphatic, -C(O)-N(C1-C12aliphatic)2, -C(O)O-C1-C12aliphatic, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each R9’is independently selected from H, halo, OH, and optionally substituted C1-C12aliphatic; and n’ is 0, 1, or 2.

36. The compound of any one of claims 33-35, wherein the ULK complex binding moiety is a ULK1 complex binding moiety.

37. The compound of any one of claims 33-36, wherein the linker is an optionally substituted C2-30aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, - N(RZ)C(O) N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-8 membered bivalent heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8membered bivalent heteroaryl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted C3-C6cycloalkyl, or an optionally substituted C6-C12aryl, and each RZis independently H, C1-C6aliphatic, or C3-C6aliphatic .

38. The compound of claim 33, wherein the linker is selected from:,where q is an integer from 1 to 25.

39. The compound of claim 33, wherein the target binding moiety is selected from Table 1B.

40. The compound of claim 33, wherein C is a moiety that binds or associates with autophagy cargo adapter proteins.

41. The compound of claim 33, wherein the compound is selected from Table 5A.

42. A pharmaceutical composition comprising a compound of any one of claims 1-41, and a pharmaceutically acceptable excipient.

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 claims 33-41.

44. The method of claim 43, wherein the biological sample comprises a ULK initiation complex.

45. The method of claim 44, wherein the biological sample comprises a ULK1 initiation complex.

46. A method of treating a disease, disorder, or condition in a patient, comprising administering a compound of claim 33.

47. The method of claim 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, primaryage-related tauopathy (PART) dementia, chronic traumatic encephalopathy, 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 and gangliocytoma, Meningioangiomatosis, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis (SSPE), Lead encephalopathy, Tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, Lipofuscinosis, Spinal and bulbar muscular atrophy (SBMA) / Kennedy’s disease, rheumatoid arthritis, psoriasis, Systemic lupus erythematosus, Huntington’s disease, Spinocerebellar ataxia, Familial amylotrophic lateral sclerosis, Frontotemporal dementia (FTLD-TDP), and Amyotrophic lateral sclerosis.

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.

49. The method of claim 48, wherein the ULK complex is a ULK1 initiation complex.

50. The method of claim 48, wherein the agent is a compound of any one of claims 33-41.