Mettl3 / mettl14 degraders and uses thereof

Abstract

The present disclosure provides compounds of the formulae herein (e.g., Formula (I), Formula (II), Formula (III), Formula (VI), Formula (VII)), and pharmaceutically acceptable salts thereof, and compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, which are useful for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14). The present disclosure also provides methods of treating or preventing diseases (e.g., diseases associated with a METTL protein) by administering the compounds, or pharmaceutically acceptable salts thereof, or compositions thereof, to a subject in need thereof.

Description

METTL3 / METTL14 DEGRADERS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 625,801, filed January 26, 2024, titled METTL3 / METTL14 DEGRADERS AND USES THEREOF, the contents of which are incorporated herewith by reference in their entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under Grant Numbers CA257923, GM136583, CA259576, and CA266659, awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION

[0003] N6-methyladenosine (m6A) is the most abundant mRNA modification in mammalian cells and is crucial for RNA metabolism and maintaining proper RNA functions such as nuclear export, processing, splicing, and translation. The m6A modification is reversible, allowing for precise regulation of altered RNA and the downstream effects. Three classes of proteins are involved in m6A modification effects: the ‘writer’ proteins install the modification; ‘reader’ proteins recognize the methylation and recruit other proteins for more specific effects; and ‘eraser’ proteins remove the modification, restoring the RNA to its original form. The methyltransferase-like protein 3 (METTL3), in complex with METTL14, functions as the catalytic ‘writer’ unit of the m6A methyltransferase complex (MTC), accounting for almost all m6A modifications on mRNA (Liu et al., 2014; Wang P et al., 2016). The METTL3 / METTL14 heterodimer catalyzes the methylation of mRNA using S- adenosylmethionine (SAM) as the donor molecule, with METTL3 functioning as the catalytic unit and METTL14 required for RNA binding and m6A deposition (Wang X et al., 2016). In some instances, METTL3 seems to act as a tumor suppressor. However, numerous studies indicate its role as an oncogene in many cancers (He et al., 2018). Further studies on human cancer cell lines and mouse models have established METTL3 as a potential novel anticancer target (Fiorentino et al., 2023). Several METTL3 / METTL14 small molecule inhibitors have been reported (Dolbois et al., 2021; Yankova et al., 2021; Fiorentino et al., 2023; W02020201773; WO2021079196;WG2021081211; WO2021111124; WO2022074379; WO2022081739; WO2022243333; WO2023104209; WO2023129933).

[0004] Aside from the catalytic responsibility of METTL3 to methylate N6-adenosine, METTL3 has been shown to have a role in the promotion of translation for a subset of mRNAs (Choe et al., 2018). Recent studies have also identified the METTL3- / m6A-independent roles of METTL14 (Dou et al., 2023; Mu et al., 2023).SUMMARY OF THE INVENTION

[0005] The bifunctional compounds of the present disclosure are designed and optimized to bind both METTL3 / METTL14 and a ubiquitin E3 ligase (e.g., VHL and CRBN). Without wishing to be bound by theory, compounds of the present disclosure recruit the E3 ligase to the vicinity of METTL3 / METTL14 for polyubiquitination and subsequent proteasomal degradation. The event- driven pharmacology of these bifunctional compounds is particularly suited to overcome competition from endogenous ligands (SAM / SAH in this case). Thus, compounds of the present disclosure differ from METTL3 / METTL14 small molecule inhibitors through their ability to remove non-enzymatic function of METTL3 and METTL14 through complete protein degradation.

[0006] Accordingly, in one aspect, the present disclosure provides compounds of Formula (I):or pharmaceutically acceptable salts thereof, wherein Z, L1, and Y are as defined herein.

[0007] In another aspect, the present disclosure provides compounds of Formula (VI):or pharmaceutically acceptable salts thereof, wherein Z, L1, and Y are as defined herein.

[0008] In another aspect, the present disclosure provides compounds of Formula (VII):or pharmaceutically acceptable salts thereof, wherein Z, E1, E5, L6, and X are as defined herein.

[0009] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein. In some embodiments, the pharmaceutical composition comprises an excipient.

[0010] In another aspect, the present disclosure provides methods of degrading a METTL protein in a subject or in a cell, tissue, or biological sample, the methods comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.

[0011] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, the methods comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound or pharmaceutical composition.

[0012] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use.

[0013] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparentfrom the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows Western blots showing the levels of the METTL3 protein in MV4.11, M0LM13 and NB4 cells treated with different concentrations of Degrader 24 for 24 hours. METTL3 band intensity was normalized against ACTIN in each sample and DC50 (the drug concentration causing 50% protein degradation) concentration was calculated.

[0015] FIGs. 2A-2D show immunoblot analyses. FIG. 2A shows a representative immunoblot analysis of METTL3 in MV4.11 cells after they were treated with 1 μM Degrader 24 for various durations as indicated. FIG. 2B shows analysis of METTL3 expression by immunoblot in MV4.11 cells treated with Degrader 24 for 12 h followed by drug withdrawal and then cultured without Degrader 24 for 0 to 24 h as indicated. FIG. 2C shows a representative immunoblot analysis of METTL3 in HEK293T cells after they were either left untreated or pretreated with proteasome inhibitor MG132 (1 μM) or Bortezomib (0.1 μM) or VHL ligand (10 μM) for 1 h, and then treated with or without Degrader 24 (5 μM) for 24 h. FIG. 2D shows a representative immunoblot analysis of METTL3, METTL14 and RBM15 in NB4 cells after treated with 1 μM Degrader 24 for 24 h.

[0016] FIG. 3 shows the synthesis of ZW27941 (Degrader 24) and ZW27941NC (negative control). Reagents and conditions: (a) DIPEA, isopropanol, 80 °C, microwave irradiation, 3 h; (b) DIPEA, isopropanol, H2O, 130 °C, microwave irradiation, 5 h; (c) HATU, DMF, DIPEA, room temperature, 2 h. DIPEA, diisopropylethylamine; DMF, dimethylformamide; HATU, hexafluorophosphate azabenzotriazole tetramethyl uronium.

[0017] FIGs. 4A-4E show structure-activity relationship and proteasomal degradation of METTL3 via VHL. FIG. 4A shows selection of linkage points (yellow circle) on targeted protein ligands. The left is the crystal structure of UZH2-bound METTL3 (PDB ID 7O2F) and the right is the crystal structure of a VHL ligand bound to the VCB E3 ligase complex (PDB ID 4W9H). FIG. 4B shows the chemical structure of ZW27941 and ZW27941NC. FIG. 4C shows Western blot analysis of METTL3 in MV4.11 cells. The cells were treated with 1 μM of UZH2, ZW27941 , and ZW27941NC for 24 h before being assayed. FIG. 4D shows M0LM13 cells were transfected with nontargeting shRNA control (SC) or VHL shRNA (shVHL), and VHL protein levels were analyzed by western blot. FIG. 4E shows transfected cells were treated with DMSO or 1 μM ZW27941 for 24 h, and METTL3 levels were analyzed by western blot.

[0018] FIGs. 5A-5G show ZW27941 (Degrader 24) reduces cell viability and degrades METTL3 in a dose- and time-dependent manner. FIG. 5A shows viability of M0LM13 and MV4.11 cells after they were treated with increasing concentrations of ZW27941 for 72 h. EC50 values are the average of three independent experiments. EC50 values were calculated based on the percentage of viable cells, normalized to control, as determined by CCK8 assay. FIG. 5B shows Western blot analysis ofMETTL3, METTL14, METTL16, WTAP, and RBM15 in NB4 cells after treated with 1 μM ZW27941 for 24 h. FIG. 5C shows the effect of UZH2 or ZW27941 (1 μM) treatment on global mRNA m6A levels in M0LM13 cells detected by dot-blot assay. FIG. 5D shows quantification of m6A levels on polyA mRNA following 24 h treatment of M0LM13 cells with UZH2 or ZW27941 (1 μM). Data shown were mean ± standard deviation of triplicate experiments; ***p < 0.001, ****P < 0.0001. FIG. 5E shows cellular thermal shift assay (CETSA) was conducted with M0LM13 cell lysate to monitor cellular target engagement. The cell lysate was incubated with either vehicle (DMSO) or ZW27941 (100 μM) for 30 min before melting at the indicated temperatures. The assay was performed in duplicate and western blots of METTL3 are shown. FIG. 5F shows densitometric analysis of METTL3 expression for FIG. 2A as the mean of two independent experiments. FIG. 5G shows analysis of METTL3 expression for FIG. 2B.

[0019] FIGs. 6A-6C show METTL3 inhibition affects the proliferation and survival of human acute myeloid leukemia cell lines. FIG. 6A shows cell proliferation of leukemia cell lines treated with DMSO, STM2457, UZH2, or ZW27941 (5 μM) determined by trypan blue exclusion. FIG. 6B shows colony formation assays used the indicated cell lines to expose to DMSO or ZW27941 at the indicated concentrations. Representative images are shown in the left panel, and the quantification of three independent experiments is shown in the right panel as bar graphs. Data shown were mean ± standard deviation of triplicate experiments; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. FIG. 6C shows analysis of METTL3 protein levels by immunoblot in M0LM13 and MV4.11 cells plated in methylcellulose medium and treated with DMSO, 1 μM ZW27941, and 5 μM ZW27941 for 7 days parallel to colony formation assay.

[0020] FIGs. 7A-7D show ZW27941 is highly potent in cell cycle progression and inducing apoptosis. FIG. 7A shows flow cytometric analysis of the cell cycle of M0LM13 cells treated with DMSO, STM2457, UZH2, or ZW27941 (1 μM) for 24 h. The gating strategy is shown in the left panel. Cells were stained with BrdU (to determine the S phase) and DAPI (to determine the DNA content). FIG. 7B shows flow cytometric analysis of the apoptosis of M0LM13 cells in vitro. The gating strategy is shown in the left panel. Cells were stained with annexin V and DAPI.AnnexinV+DAPI- and Annexin V+DAPI+cells represent early and late apoptotic cells, respectively. All data are representative of two to three independent experiments. FIG. 7C shows real-time PCR analysis of MOLM-13 cells treated with ZW27941 (1 μM) assessed for relative mRNA expression of several genes. FIG. 7D shows Western blot analysis showed that the c-Myc protein levels were down- regulated in M0LM13 cells after treatment with different concentrations of ZW27941. Data shown were mean ± standard deviation of triplicate experiments; *P < 0.05, **P < 0.01, ***P < 0.001, ****p < 0.0001.

[0021] FIGs. 8A-8C show differential expression analysis of M0LM13 cells after being treated with DMSO or ZW27941. FIG. 8A shows a volcano plot for M0LM13 cells treated with 1 μM ZW27941 versus DMSO samples after 24 h of treatment, showing significantly dysregulated genes (P <0.05). FIG. 8B shows Gene ontology (GO) analysis of the differentially expressed genes post- treatment with 1 μM ZW27941 in MOLM-13 cells. FIG. 8C shows KEGG pathway analysis of differentially expressed genes between DMSO and ZW27941 treated cells. Size is proportional to the number of differential expressed genes. Red to blue colors represent different adjusted P values.

[0022] FIGs. 9A-9B show ZW27941 enhanced the efficacy of other therapeutic agents used for acute myeloid leukemia treatment. Drug dose matrix and synergy landscapes of human MV4.11 (FIG. 9A) and M0LM13 (FIG. 9B) cells treated with increasing concentrations of ZW27941, venetoclax, or their combinations for 72 h. Cell viability was evaluated using the CCK-8 assay. The presented results are representative of three independent experiments. The matrix illustrates the percentage of inhibition of treated cells versus vehicle controls. Drug combination landscapes were built using the bioconductor package “synergyfinder”.DEFINITIONS

[0023] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0024] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0025] In a formula, the bond is a single bond, the dashed line - is a single bond or absent, and the bond =-=-= or = is a single or double bond.

[0026] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0027] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C24, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0028] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^t alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., zz-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n- pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C61 (e.g., n-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z'-Bu)). In certain embodiments, the alkyl group is a substituted C1-12 alkyl (such as substituted C1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0029] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“Ci-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1-4 alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of Ci 4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C24 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or) may be in the (E)- or(Z) -configuration.

[0030] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1 -20 alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1- 10 - alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“Ci-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“CM alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2- butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C24 alkynylgroups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl.

[0031] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3 -14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3 -13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3 -11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3 -10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3 -7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5 -10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl(C8 ), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3 -s carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0032] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3 -10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0033] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certainembodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1 , 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0034] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 -A ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0035] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5 -membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6- membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5 ,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H- furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0036] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ctu aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is a substituted Ce u aryl.

[0037] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5 -indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0038] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0039] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0040] The term “unsaturated bond” refers to a double or triple bond.

[0041] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0042] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0043] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0044] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0045] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X“,-P(ORCC)3+X-, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci20alkyl, Ci20perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X“ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, and 5- 14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=0)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CI2Oalkyl, Ci20perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, and 5- 14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-io carbocyclyl, 3-14 membered heterocyclyl, G> i4aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X“, -N(0Ree)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -0C(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-10 alkyl, C1-10perhaloalkyl, C1-10 alkenyl, C1-10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S; wherein X“ is a counterion; each instance of Reeis, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C1-10 alkenyl, C1-10 alkynyl, C3-10 carbocyclyl, Ce 10 aryl, 3-10 membered heterocyclyl, and 3- 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C1-10 alkenyl, C1-10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, G> 10 aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, — ON(C1-6 alkyl)2, -N(C1-6 alkyl)2, -N(C1-6 alkyl)3+X“, -NH(C1-6 alkyl)2+X“, -NH2(C1-6 alkyl)+X“, -NH3+X“, -N(OCiGalkyl)(C1-6 alkyl), -N(OH)(C1-6 alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SSlCiGalkyl), -C(=O)(C1-6 alkyl), -CO2H, — CChlCi alkyl), -OC(=O)(C1-6 alkyl), -OCO2(C1-6 alkyl), -C(=O)NH2, -C(=O)N(C1-6 alkyl)2, -OC(=O)NH(C1-6 alkyl), -NHC(=O)( CM, alkyl), -N(C1-6 alkyl)C(=O)( Cwalkyl), -NHCO2(C1-6 alkyl), -NHC(=O)N(C1-6 alkyl)2, -NHC(=O)NH(Ci^> alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6 alkyl), -OC(=NH)(C1-6 alkyl), — C)C(=NH)C)Ci <, alkyl, -C(=NH)N(CI_6alkyl)2, -C(=NH)NH(C1-6 alkyl), -C(=NH)NH2, — OC(=NH)N(C1-6 alkyl)2, -OC(NH)NH(C,_ 6 alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6 alkyl), -SO2N(CI -6 alkyl)2, -SO2NH(CIGalkyl), -SO2NH2, -SO2C1Galkyl, -SO2OC1Galkyl, -OSO2CiGalkyl, -SOCiGalkyl, -Si(C1-6 alkyl)3, -OSilCiGalkyl)3-C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, -C(=O)S(C1-6 alkyl), -C(=S)SC1-6 alkyl, -SC(=S)SCi. _6alkyl, -P(=O)(OC« alkyl)2, -P(=O)(C1-6 alkyl)2, -OP(=O)(C« alkyl)2, -OP(=O)(OC« alkyl)2, C1-10 alkyl, C1-10 perhaloalkyl, C1-10 alkenyl, C1-10 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; and each X" is a counterion.

[0046] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atomsubstituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1-10 alkyl, -OR311, -SRaa, -N(Rbb)2, - CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine- sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0047] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0048] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxy,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -OR33, -ON(Rbb)2, -0C(=0)SR33, -0C(=0)R33, -OCO2R33, -OC(=O)N(Rbb)2, -0C(=NRbb)R33, -0C(=NRbb)0R33, -OC(=NRbb)N(Rbb)2, -0S(=0)R33, -OSO2R33, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(=O)(R33)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb))2, wherein X“, R33, Rbb, and Rccare as defined herein.

[0049] The term “thiol” or “thio” refers to the group -SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from - SR33, -S=SRCC, -SC(=S)SRaa, -SC(=S)0R33, -SC(=S) N(Rbb)2, -SC(=0)SR33, -SC(=0)0R33, - SC(=O)N(Rbb)2, and -SC(=0)R33, wherein R33and Rccare as defined herein.

[0050] The term “amino” refers to the group -NH2. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.

[0051] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2Raa, -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group -NH(Rbb) is not hydrogen.

[0052] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0053] The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(Rbb)3and -N(Rbb)3+X“, wherein Rbband X“ are as defined herein.

[0054] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (-C(=O)Raa), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-CO2Raa, - C(=O)SRaa, -C(=S)SRaa), amides (-C(=O)N(Rbb)2, -C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (-C(=NRbb)Raa, -C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0055] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOFT. -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, C1-20 alkyl, C 1-20 perhaloalkyl, C 1-20 alkenyl, C1-20 alkynyl, hetero C 1-20 alkyl, hetero C 1-20 alkenyl, hetero Ci- 20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6 -14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein R“ Rbb, Rccand Rddare as defined above.

[0056] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atomsubstituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0057] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C 1-20 alkenyl, C1-20 alkynyl, heteroC1-20 alkyl, hetero C1-20 alkenyl, hetero C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6- 14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0058] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3- methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0059] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), I J -dimcthyl-2-halocthyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-py ricly l)cthy 1 carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1 -dime thyl-2-cy anoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m- nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6- nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A,2V-dimethylcarboxamido)benzyl carbamate, I , I -dimcthylA-fW.A / - dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1- (3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0060] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4 / ,8 / -dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0061] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimidc, A-dithiasuccinimide (Dts), A-2,3-diphcnylmalcimidc, A-2,5-dimethylpyrrole, A-l , 1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1, 3 -dibenzyl- 1,3,5 - triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, A-allylamine, A-[2- (trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo- 3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4- methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), A-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7-dichloro-9- fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), A-2-picolylamino A’-oxide, A- 1,1- dimethylthiomethyleneamine, A-benzylideneamine, A-p-methoxybenzylideneamine, A- diphenylmethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’,A’- dime thylaminome thy lene) amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5- chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A- cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivatives, A- diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl]amine, A-copper chelate, A-zinc chelate, A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2- nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are A,A’-isopropylidenediamine.

[0062] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0063] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -C(=O)Raa, -CCER”, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atomsubstituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=0)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group.

[0064] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X’, -P(ORCC)2, -P(ORCC)3+X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein X“, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0065] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl .S'..S'-dioxidc, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8- trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1- methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3- methyl-2-picolyl A-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT), a- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p- methoxyphenyl)methyl, 4-(4’ -bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4, 4', 4"- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr-OR),4,4’-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), 1 ,l-bis(4- methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1.3-benzodithiolan-2-yl, benzisothiazolyl .S'.S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri- p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, triphenylmethoxy acetate, phenoxy acetate, p-chlorophenoxy acetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o- nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l , 1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl iV-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl2.4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0066] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0067] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.

[0068] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -SiCR^s, -P(RCC)2, -P(RCC)3+X“, -P(ORCC)2, -P(ORCC)3+X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0069] In certain embodiments, the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0070] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F", CP, Br , I"), NO3", CIO4 , OH , H2PO4 , HCOf, HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5- sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4~, PEp, PFe", AsFe", SbFe", B[3,5-(CF3)2CeH3]4] , B(C6F5)4~, BPh4 , A1(OC(CF3)3)4", and carborane anions (e.g., CBHHI2- or (HCBi iMesBre) ). Exemplary counterions which may be multivalent include CO32-, HPO42-, PO43-. B4O72-, SO42-, S2O32-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0071] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0072] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0073] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.

[0074] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts 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, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, 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, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and NACi 4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0075] The term “pharmaceutically acceptable salt” refers to those 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, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts 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, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate, 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, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0076] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0077] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0078] The terms “composition” and “formulation” are used interchangeably.

[0079] A “subject” to which administration is contemplated refers to a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non- human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0080] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such assamples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0081] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0082] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0083] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0084] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0085] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0086] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0087] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0088] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a cancer (e.g., a cancer associated with a methyltransferase-like (METTL) protein (e.g., glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer)). In certain embodiments, a therapeutically effective amount is an amount sufficient for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14) and treating cancer (e.g., a cancer associated with a methyltransferase-like (METTL) protein (e.g., glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer)).

[0089] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading amethyltransferase-like (METTL) protein (e.g., METTL3, METTL14). In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a cancer (e.g., a cancer associated with a methyltransferase-like (METTL) protein (e.g., glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer)). In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14) and treating cancer (e.g., a cancer associated with a methyltransferase- like (METTL) protein (e.g., glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer)).

[0090] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0091] As used herein, the term “degrade” or “degradation” in the context of proteins, for example, in the context of degrading a METTL protein (e.g., METTL3, METTL 14), refers to a reduction in the amount of the protein. In some embodiments, the term refers to a reduction of the amount of protein, e.g., a METTL protein (e.g., METTL3, METTL 14), to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of amount of the protein. In some embodiments, the term refers to a reduction of the amount of protein, e.g., a METTL protein (e.g., METTL3, METTL14), to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of the amount of protein.

[0092] The term “about X,” where X is a number or percentage, refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.

[0093] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplaryproliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0094] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0095] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0096] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia,1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non- Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (z.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T- cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer(NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0097] Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.

[0098] Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon y), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and / or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g., HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).

[0099] Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), anti-androgens (e.g., flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, andvinorelbine), taxoids (e.g., paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., ’2’ -paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5 -fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g., actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI- 272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF- 02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ- 26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM- 121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin,porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine.

[0100] A “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds. The term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein will be at least three amino acids long. A protein may refer to an individual protein or a collection of proteins. Inventive proteins preferably contain only natural amino acids, although non-natural amino acids (z.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and / or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. A protein may also be a single molecule or may be a multi- molecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination of these.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0101] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.Compounds

[0102] In one aspect, the present disclosure provides a compound of Formula (I):Z - L1- Y (I), or a pharmaceutically acceptable salt thereof, wherein:each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl;each instance of R2and R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3;R4is optionally substituted aryl or optionally substituted heteroaryl;L1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is optionally substituted arylene or optionally substituted heteroarylene;L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene; each of ml, nl, m2, and n2 is independently 1, 2, or 3; each of pl and p2 is independently 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl; andY is a moiety capable of binding to an E3 ubiquitin ligase.

[0103] In some embodiments, the compound of Formula (I) is of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl; each instance of R2is independently -F, -Cl, -CHF2, -CH2F, or -CF3;L1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is optionally substituted arylene or optionally substituted heteroarylene; each of ml and nl is independently 1, 2, or 3; pl is 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl; andY is a moiety capable of binding to an E3 ubiquitin ligase.

[0104] In some embodiments, the compound of Formula (I) is of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: each instance of R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3;R4is optionally substituted aryl or optionally substituted heteroaryl;F1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substitutedheterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene; each of m2 and n2 is independently 1, 2, or 3; p2 is 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl; andY is a moiety capable of binding to an E3 ubiquitin ligase.

[0105] In another aspect, the present disclosure provides a compound of Formula (VI):Z - L1- Y (VI), or a pharmaceutically acceptable salt thereof, wherein:each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl; each instance of R2and R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3;R4is optionally substituted aryl or optionally substituted heteroaryl;F1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is optionally substituted arylene or optionally substituted heteroarylene;L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene; each of ml, nl, m2, and n2 is independently 1, 2, or 3; each of pl and p2 is independently 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl; andY is of Formulae (IV-a), (IV-b), or (IV-c):wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl; andR10is optionally substituted alkyl or optionally substituted cycloalkyl.

[0106] In another aspect, the present disclosure provides a compound of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein:each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl; each instance of R2and R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3;R4is optionally substituted aryl or optionally substituted heteroaryl;L1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is optionally substituted arylene or optionally substituted heteroarylene;L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene; each of ml, nl, m2, and n2 is independently 1, 2, or 3; each of pl and p2 is independently 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; andL6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof.

[0107] As generally described herein, Z is of formula:a). In some embodiments, Z is of formula:Rla, Rlb, R2, pl, ml, nl, L2, and L3

[0109] As generally described herein, each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl.

[0110] In some embodiments, at least one of Rlaand Rlbis hydrogen.

[0111] In some embodiments, at least one of Rlaand Rlbis optionally substituted alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted Cm alkyl, optionally substituted Ci- ii alkyl, optionally substituted C1-10 alkyl, optionally substituted C1-9 alkyl, optionally substituted Ci-8 alkyl, optionally substituted C1-7 alkyl, optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted CM alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl.

[0112] In some embodiments, at least one of Rlaand Rlbis optionally substituted Ci-12 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted Cm alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C1-10 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C1-9 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted Ci-8 alkyl. In some embodiments, at least one of Rlaand Rlbis optionallysubstituted C1-7 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C1-6 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C1-5 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted CM alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C1-3 alkyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C1-2 alkyl.

[0113] In some embodiments, at least one of Rlaand Rlbis substituted alkyl. In some embodiments, at least one of Rlaand Rlbis substituted Ci-12 alkyl, substituted CMI alkyl, substituted Ci-10 alkyl, substituted C1-9 alkyl, substituted Ci-8 alkyl, substituted C1-7 alkyl, substituted C1-6 alkyl, substituted C1-5 alkyl, substituted CM alkyl, substituted C1-3 alkyl, or substituted C1-2 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-6 alkyl, substituted C1-5 alkyl, substituted CM alkyl, substituted C1-3 alkyl, or substituted C1-2 alkyl.

[0114] In some embodiments, at least one of Rlaand Rlbis substituted Ci-12 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted Crn alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-10 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-9 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted CM alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-7 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-6 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-5 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-4 alkyl. In some embodiments, at least one of Rlaand Rlbis substituted Cm alkyl. In some embodiments, at least one of Rlaand Rlbis substituted C1-2 alkyl.

[0115] In some embodiments, at least one of Rlaand Rlbis CM alkyl, C1-5 alkyl, CM alkyl, Cm alkyl, or C1-2 alkyl substituted with halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -ORA, -SCN, -SRA, - SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, - C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, - OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, - OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, - NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, - NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, - NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, - NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, - OSi(RA)(ORA)2, -OSi(ORA)a, and / or -B(ORA)2, wherein each instance of RAis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0116] In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or C1-2 alkyl substituted with halogen and / or optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl substituted with halogen and / or optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-5 alkyl substituted with halogen and / or optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis CM alkyl substituted with halogen and / or optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-3 alkyl substituted with halogen and / or optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-2 alkyl substituted with halogen and / or optionally substituted carbocyclyl.

[0117] In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or C1-2 alkyl substituted with halogen. In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl substituted with halogen. In some embodiments, at least one of Rlaand Rlbis C1-5 alkyl substituted with halogen. In some embodiments, at least one of Rlaand Rlbis CM alkyl substituted with halogen. In some embodiments, at least one of Rlaand Rlbis C1-3 alkyl substituted with halogen. In some embodiments, at least one of Rlaand Rlbis C1-2 alkyl substituted with halogen.

[0118] In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or C1-2 alkyl substituted with optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl substituted with optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-5 alkyl substituted with optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis CM alkyl substituted with optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-3 alkyl substituted with optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-2 alkyl substituted with optionally substituted carbocyclyl.

[0119] In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or C1-2 alkyl substituted with -F and / or optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl substituted with -F and / or optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-5 alkyl substituted with -F and / or optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis CM alkyl substituted with -F and / or optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-3 alkyl substituted with -F and / or optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-2 alkyl substituted with -F and / or optionally substituted C3-6 carbocyclyl.

[0120] In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or C1-2 alkyl substituted with -F. In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl substituted with -F. In some embodiments, at least one of Rlaand Rlbis C1-5 alkyl substituted with -F. In some embodiments, at least one of Rlaand Rlbis CM alkyl substituted with -F. In some embodiments, at least one of Rlaand Rlbis C1-3 alkyl substituted with -F. In some embodiments, at least one of Rlaand Rlbis C1-2 alkyl substituted with -F.

[0121] In some embodiments, at least one of Rlaand Rlbis methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertamyl, or / z-hcxyl substituted with -F. In some embodiments,

[0122] In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or Ci-2 alkyl substituted with optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-6 alkyl substituted with optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-5 alkyl substituted with optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis CM alkyl substituted with optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-3 alkyl substituted with optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis C1-2 alkyl substituted with optionally substituted C3-6 carbocyclyl.

[0123] In some embodiments, at least one of Rlaand Rlbis methyl substituted with optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis methyl substituted with C3-6 carbocyclyl, wherein the C3-6 carbocyclyl is substituted with halogen or optionally substituted alkyl.

[0124] In some embodiments, at least one of Rlaand Rlbis methyl substituted with C3-6 carbocyclyl, wherein the C3-6 carbocyclyl is substituted with halogen. In some embodiments, at least one of Rlaand Rlbis methyl substituted with C3-6 carbocyclyl, wherein the C3-6 carbocyclyl is substituted with -F. In some embodiments, at least one of Rlaand Rlbis methyl substituted with C3-6 carbocyclyl, wherein the C3-6 carbocyclyl is substituted with optionally substituted alkyl. In some embodiments, at least one of Rlaand Rlbis methyl substituted with C3-6 carbocyclyl, wherein the C3-6 carbocyclyl is substituted with optionally substituted C1-3 alkyl. In some embodiments, at least one of Rlaand Rlbis methyl substituted with C3-6 carbocyclyl, wherein the C3-6 carbocyclyl is substituted with -CH3. In some

[0125] In some embodiments, at least one of Rlaand Rlbis methyl substituted with unsubstituted C3-6carbocyclyl. In some embodiments,

[0126] In some embodiments, at least one of Rlaand Rlbis unsubstituted alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted Ci-12 alkyl, unsubstituted Ci-11 alkyl, unsubstituted C1-10 alkyl, unsubstituted C1-9 alkyl, unsubstituted Ci-8 alkyl, unsubstituted C1-7 alkyl, unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted C1-4 alkyl, unsubstituted Cm alkyl, or unsubstituted C1-2 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted CM alkyl, unsubstituted C1-3 alkyl, or unsubstituted C1-2 alkyl.

[0127] In some embodiments, at least one of Rlaand Rlbis unsubstituted Ci-12 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted CHI alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-10 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-9 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted Ci-8 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-7 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-6 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-5 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted CM alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-3 alkyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C1-2 alkyl.

[0128] In some embodiments, at least one of Rlaand Rlbis methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl, or / 7-hcxyl. In some embodiments, at least one of Rlaand Rlbis methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. In some embodiments, at least one of Rlaand Rlbis methyl, ethyl, or n-propyl. In some embodiments, at least one of Rlaand Rlbis methyl (-CH3).

[0129] In some embodiments,

[0130] In some embodiments, at least one of Rlaand Rlbis optionally substituted carbocyclyl. In some embodiments, at least one of Rlaand Rlbis optionally substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis substituted C3-6 carbocyclyl. In some embodiments, at least one of Rlaand Rlbis unsubstituted C3-6 carbocyclyl.

[0131] In some embodiments, Rlaand Rlbare taken together to form optionally substituted heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form optionally substituted 3-10 membered heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form optionally substituted 3-6 membered monocyclic heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form optionally substituted 6-10 membered bicyclic heterocyclyl.

[0132] In some embodiments, Rlaand Rlbare taken together to form substituted heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form substituted 3-10 membered heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form substituted 3-6 membered monocyclic heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -OH, and / or -©(optionally substituted alkyl). In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with halogen, optionally substituted alkyl, and / or -OH. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with halogen. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with optionally substituted alkyl.

[0133] In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with -F, optionally substituted C1-6 alkyl, and / or -OH. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with -F, optionally substituted Cm alkyl, and / or -OH. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with -F. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with optionally substituted C1-6 alkyl. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with optionally substituted Cm alkyl. In some embodiments, Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl substituted with -OH. In

[0134] In some embodiments, Rlaand Rlbare taken together to form substituted 6-10 membered bicyclic heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl substituted with halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -OH, and / or -©(optionally substituted alkyl). In some embodiments, Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl substituted with optionally substituted alkyl and / or optionally substituted carbocyclyl.

[0135] In some embodiments, Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl substituted with optionally substituted Cm alkyl and / or optionally substituted C3-6 carbocyclyl. In some embodiments, Rlaand Rlbare taken together to form 6-10 membered bicyclicheterocyclyl substituted with optionally substituted C1-3 alkyl. In some embodiments, Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl substituted with unsubstituted C1-3 alkyl. In some embodiments, Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl substituted with optionally substituted C3-6 carbocyclyl. In some embodiments, Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl substituted with unsubstituted C3-6 carbocyclyl.

[0136] In some embodiments, Rlaand Rlbare taken together to form unsubstituted heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form unsubstituted 3-10 membered heterocyclyl. In some embodiments, Rlaand Rlbare taken together to form unsubstituted 3-6 membered monocyclic heterocyclyl. In some embodiments,embodiments, Rlaand Rlbare taken together to form unsubstituted 6-10 membered bicyclic

[0137] In some embodiments, each of Rlaand Rlbis independently hydrogen or optionally substituted alkyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis optionally substituted alkyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis optionally substituted alkyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis optionally substituted C1-6 alkyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis optionally substituted C1-3 alkyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis substituted C1-6 alkyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis substituted C1-3 alkyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis unsubstituted C1-6 alkyl. In some embodiments, one of Rlaand Rlbis hydrogen, and the other of Rlaand Rlbis unsubstituted C1-3 alkyl.,

[0139] As generally described herein, each instance of R2is independently -F, -Cl, -CHF2, -CH2F, or -CF3.

[0140] In some embodiments, at least one instance of R2is -F, -Cl, -CHF2, -CH2F, or -CF3.

[0141] In some embodiments, at least one instance of R2is -Cl, -CHF2, -CH2F, or -CF3. In some embodiments, at least one instance of R2is -F, -CHF2, -CH2F, or -CF3. In some embodiments, at least one instance of R2is -F, -Cl, -CH2F, or -CF3. In some embodiments, at least one instance of R2is -F, -Cl, -CHF2, or -CF3. In some embodiments, at least one instance of R2is -F, -Cl, -CHF2, or-CH2F.

[0142] In some embodiments, at least one instance of R2is -CHF2, -CH2F, or -CF3. In some embodiments, at least one instance of R2is -Cl, -CH2F, or -CF3. In some embodiments, at least one instance of R2is -Cl, -CHF2, or -CF3. In some embodiments, at least one instance of R2is -Cl, -CHF2, or -CH2F. In some embodiments, at least one instance of R2is -F, -CH2F, or -CF3. In some embodiments, at least one instance of R2is -F, -CHF2, or -CF3. In some embodiments, at least oneinstance of R2is -F, -CHF2, or -CH2F. In some embodiments, at least one instance of R2is -F, -Cl, or -CF3. In some embodiments, at least one instance of R2is -F, -Cl, or -CH2F. In some embodiments, at least one instance of R2is -F, -Cl, or -CHF2.

[0143] In some embodiments, at least one instance of R2is -F or -Cl. In some embodiments, at least one instance of R2is -F or -CHF2. In some embodiments, at least one instance of R2is -F or -CH2F. In some embodiments, at least one instance of R2is -F or -CF3. In some embodiments, at least one instance of R2is -Cl or -CHF2. In some embodiments, at least one instance of R2is -Cl or -CH2F. In some embodiments, at least one instance of R2is -Cl or -CF3. In some embodiments, at least one instance of R2is -CHF2 or -CH2F. In some embodiments, at least one instance of R2is -CHF2 or - CF3. In some embodiments, at least one instance of R2is -CH2F or -CF3.

[0144] In some embodiments, at least one instance of R2is -F. In some embodiments, at least one instance of R2is -Cl. In some embodiments, at least one instance of R2is -CHF2. In some embodiments, at least one instance of R2is -CH2F. In some embodiments, at least one instance of R2is -CF3.

[0145] As generally described herein, pl is 0, 1, 2, 3, or 4.

[0146] In some embodiments, pl is 0, 1, 2, or 3. In some embodiments, pl is 0, 1, or 2. In some embodiments, pl is 0 or 1. In some embodiments, pl is 0. In some embodiments, pl is 1. In some embodiments, pl is 2. In some embodiments, pl is 3. In some embodiments, pl is 4.

[0147] In some embodiments, at least two instances of R2are independently -F. In some embodiments, at least two instances of R2are independently -Cl. In some embodiments, at least two instances of R2are independently -CHF2. In some embodiments, at least two instances of R2are independently -CH2F. In some embodiments, at least two instances of R2are independently -CF3.

[0149] As generally described herein, ml is 1, 2, or 3.

[0150] In some embodiments, ml is 1 or 2. In some embodiments, ml is 1. In some embodiments, ml is 2. In some embodiments, ml is 3.

[0151] As generally described herein, nl is 1, 2, or 3.

[0152] In some embodiments, nl is 1 or 2. In some embodiments, nl is 1. In some embodiments, nl is 2. In some embodiments, nl is 3.

[0153] In some embodiments, ml is the same as nl. In some embodiments, ml and nl are each 1. In some embodiments, ml and nl are each 2. In some embodiments, ml and nl are each 3.

[0154] In some embodiments, ml is different from nl. In some embodiments, ml is 1, and nl is 2. In some embodiments, ml is 1, and nl is 3. In some embodiments, ml is 2, and nl is 1. In some embodiments, ml is 2, and nl is 3. In some embodiments, ml is 3, and nl is 1. In some embodiments, ml is 3, and nl is 2.

[0155] As generally described herein, L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, - S(=O)2- — C(=O)— , optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0156] In some embodiments, L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-io alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0157] In some embodiments, L2is a bond.

[0158] In some embodiments, L2comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with — O— , -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C1-6 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprisesoptionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted Cm alkylene, wherein one backbone carbon atom in the optionally substituted Cm alkylene is replaced with -O- or -NR5-.

[0159] In some embodiments, L2comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -NR5-, -O-,wherein: each instance of R5is independently hydrogen or optionally substituted alkyl; each instance of X is independentlyCH or N; and each of m3 and n3 is independently 1, 2, or 3.

[0160] In some embodiments, L2comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independentlycomprises -CH2-. In some embodiments, L2is -CH2-.

[0161] In some embodiments, L2comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-io alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O- or -NR5-. In some embodiments, L2comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR2-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independentlyreplaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L2comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms.

[0162] In some embodiments, L2comprises formula:, wherein each instance of X is independently CH or N; and each of m3 and n3 is independently 1, 2, or 3. In some embodiments, L2

[0163] In some embodiments, L2comprises optionally substituted arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted arylene are independently replaced with — O— , -NR5-, — S— , -S(=O)-, -S(=O)2-, or -C(=O)-. In some embodiments, L2comprises optionally substituted arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted arylene are independently replaced with -O- or -NR5-. In some embodiments, L2

[0164] In some embodiments, L2comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-. In some embodiments, L2comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with -O- or -NR5-. In some embodiments, L2comprises optionally substituted heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L2comprises optionally substituted heteroarylene containing at least 1 ring N atom. In some embodiments, L2comprises optionally substituted heteroarylene containing atleast 2 ring N atoms. In some embodiments, L2comprises optionally substituted heteroarylene containing at least 3 ring N atoms. In some embodiments, L2comprises

[0165] In some embodiments, L2comprises optionally substituted C1-10 alkylene and optionally substituted heterocyclylene, optionally substituted C1-10 alkylene and optionally substituted arylene, optionally substituted C1-10 alkylene and optionally substituted heteroarylene, optionally substituted heterocyclylene and optionally substituted arylene, optionally substituted heterocyclylene and optionally substituted heteroarylene, or optionally substituted arylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- — C(=O)— , optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0166] In some embodiments, L2comprises optionally substituted C1-10 alkylene and optionally substituted heterocyclylene, optionally substituted C1-10 alkylene and optionally substituted arylene, or optionally substituted C1-10 alkylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C1-10 alkylene and optionally substituted heterocyclylene, optionally substituted C1-10 alkylene and optionally substituted arylene, or optionally substituted Ci-io alkylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted C1-10 alkylene and optionally substituted heterocyclylene, optionally substituted C1-10 alkylene and optionally substituted arylene, or optionally substituted C1-10 alkylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O- or -NR5-.

[0167] In some embodiments, L2comprises optionally substituted Cm alkylene and optionally substituted heterocyclylene, optionally substituted Cm alkylene and optionally substituted arylene, or optionally substituted Cm alkylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted Cm alkylene and optionally substituted heterocyclylene, optionallysubstituted C1-3 alkylene and optionally substituted arylene, or optionally substituted Cm alkylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2comprises optionally substituted Cm alkylene and optionally substituted heterocyclylene, optionally substituted Cm alkylene and optionally substituted arylene, or optionally substituted Cm alkylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with -O- or -NR5-.

[0168] In some embodiments, L2comprises -CH2- and optionally substituted heterocyclylene, -CH2- and optionally substituted arylene, or -CH2- and optionally substituted heteroarylene. In some embodiments, L2comprises -CH2- and optionally substituted heterocyclylene, -CH2- and optionally substituted arylene, or -CH2- and optionally substituted heteroarylene. In some embodiments, L2comprises -CH2- and optionally substituted heterocyclylene, -CH2- and optionally substituted arylene, or -CH2- and optionally substituted heteroarylene.^*N^n3

[0169] In some embodiments, L2is of formula: -NR5-, -O-, -C(R5)2-, » ,wherein: each instance of R5is independently hydrogen or optionally substituted alkyl; each instance of X is independently CH or N; and each of m3 and n3 is independently 1, 2, or 3.embodiments, L2is -NH-, -O-, or -CH:-. In some embodiments, L2is -NH- or -O-. In some

[0171] As generally described herein, L3is optionally substituted arylene or optionally substituted heteroarylene.

[0172] In some embodiments, L3is optionally substituted arylene. In some embodiments, L3is optionally substituted phenylene. In some embodiments, L3is unsubstituted phenylene. In some embodiments, L3is substituted phenylene.

[0173] In some embodiments, L3is of formula:, wherein each instance of R6is independentlyhalogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -Ns, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2, wherein each instance of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0174] In some embodiments, L3is optionally substituted heteroarylene. In some embodiments, L3is optionally substituted heteroarylene containing 1 , 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, L3is optionally substituted heteroarylene containing at least 1 ring O atom. In some embodiments, L3is optionally substituted heteroarylene containing at least 1 ring N atom. In some embodiments, L3is optionally substituted heteroarylene containing at least 1 ring S atom.

[0175] In some embodiments, L3is optionally substituted heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L3is optionally substituted heteroarylene containing 1 or 2 ring N atoms. In some embodiments, L3is optionally substituted heteroarylene containing 1 ring N atom. In some embodiments, L3is optionally substituted heteroarylene containing 2 ring N atoms. In some embodiments, L3is optionally substituted heteroarylene containing 3 ring N atoms.

[0176] In some embodiments, L3is optionally substituted monocyclic heteroarylene. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing 1, 2, or 3 ringheteroatoms independently selected from O, N, and S. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing at least 1 ring O atom. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing at least 1 ring N atom. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing at least 1 ring S atom.

[0177] In some embodiments, L3is optionally substituted monocyclic heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing 1 or 2 ring N atoms. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing 1 ring N atom. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing 2 ring N atoms. In some embodiments, L3is optionally substituted monocyclic heteroarylene containing 3 ring N atoms.

[0178] In some embodiments, L3is substituted monocyclic heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L3is substituted monocyclic heteroarylene containing 1 or 2 ring N atoms. In some embodiments, L3is substituted monocyclic heteroarylene containing 1 ring N atom. In some embodiments, L3is substituted monocyclic heteroarylene containing 2 ring N atoms.

[0179] In some embodiments, L3is unsubstituted monocyclic heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L3is unsubstituted monocyclic heteroarylene containing 1 or 2 ring N atoms. In some embodiments, L3is unsubstituted monocyclic heteroarylene containing 1 ring N atom. In some embodiments, L3is unsubstituted monocyclic heteroarylene containing 2 ring N atoms.wherein each instance of R6is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2, wherein each instance of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.R3, p2, R4, m2, n2, and L4

[0182] As generally described herein, each instance of R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3.

[0183] In some embodiments, at least one instance of R3is -F, -Cl, -CHF2, -CH2F, or -CF3.

[0184] In some embodiments, at least one instance of R3is -Cl, -CHF2, -CH2F, or -CF3. In some embodiments, at least one instance of R3is -F, -CHF2, -CH2F, or -CF3. In some embodiments, at least one instance of R3is -F, -Cl, -CH2F, or -CF3. In some embodiments, at least one instance of R3is -F, -Cl, -CHF2, or -CF3. In some embodiments, at least one instance of R3is -F, -Cl, -CHF2, or -CH2F.

[0185] In some embodiments, at least one instance of R3is -CHF2, -CH2F, or -CF3. In some embodiments, at least one instance of R3is -Cl, -CH2F, or -CF3. In some embodiments, at least one instance of R3is -Cl, -CHF2, or -CF3. In some embodiments, at least one instance of R3is -Cl, -CHF2, or -CH2F. In some embodiments, at least one instance of R3is -F, -CH2F, or -CF3. In some embodiments, at least one instance of R3is -F, -CHF2, or -CF3. In some embodiments, at least one instance of R3is -F, -CHF2, or -CH2F. In some embodiments, at least one instance of R3is -F, -Cl, or -CF3. In some embodiments, at least one instance of R3is -F, -Cl, or -CH2F. In some embodiments, at least one instance of R3is -F, -Cl, or -CHF2.

[0186] In some embodiments, at least one instance of R3is -F or -Cl. In some embodiments, at least one instance of R3is -F or -CHF2. In some embodiments, at least one instance of R3is -F or -CH2F. In some embodiments, at least one instance of R3is -F or -CF3. In some embodiments, at least one instance of R3is -Cl or -CHF2. In some embodiments, at least one instance of R3is -Cl or -CH2F. In some embodiments, at least one instance of R3is -Cl or -CF3. In some embodiments, at least one instance of R3is -CHF2 or -CH2F. In some embodiments, at least one instance of R3is -CHF2 or - CF3. In some embodiments, at least one instance of R3is -CH2F or -CF3.

[0187] In some embodiments, at least one instance of R3is -F. In some embodiments, at least one instance of R3is -Cl. In some embodiments, at least one instance of R3is -CHF2. In some embodiments, at least one instance of R3is -CH2F. In some embodiments, at least one instance of R3is -CF3.

[0188] As generally described herein, p2 is 0, 1, 2, 3, or 4.

[0189] In some embodiments, p2 is 0, 1, 2, or 3. In some embodiments, p2 is 0, 1, or 2. In some embodiments, p2 is 0 or 1. In some embodiments, p2 is 0. In some embodiments, p2 is 1. In some embodiments, p2 is 2. In some embodiments, p2 is 3. In some embodiments, p2 is 4.

[0190] In some embodiments, at least two instances of R3are independently -F. In some embodiments, at least two instances of R3are independently -Cl. In some embodiments, at least two instances of R3are independently -CHF2. In some embodiments, at least two instances of R3are independently -CH2F. In some embodiments, at least two instances of R3are independently -CF3.,

[0192] As generally described herein, R4is optionally substituted aryl or optionally substituted heteroaryl.

[0193] In some embodiments, R4is optionally substituted aryl. In some embodiments, R4is optionally substituted phenyl. In some embodiments, R4is unsubstituted phenyl. In some embodiments, R4is substituted phenyl., wnerein eacn K™ is independently nalogen, optionally substituted alKyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionallysubstituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, and / or -B(ORA)2, wherein each instance of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0195] In some embodiments, R4is optionally substituted heteroaryl. In some embodiments, R4is optionally substituted heteroaryl containing 1 , 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, R4is optionally substituted heteroaryl containing at least 1 ring O atom. In some embodiments, R4is optionally substituted heteroaryl containing at least 1 ring N atom. In some embodiments, R4is optionally substituted heteroaryl containing at least 1 ring S atom.

[0196] In some embodiments, R4is optionally substituted heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R4is optionally substituted heteroaryl containing 1 or 2 ring N atoms. In some embodiments, R4is optionally substituted heteroaryl containing 1 ring N atom. In some embodiments, R4is optionally substituted heteroaryl containing 2 ring N atoms. In some embodiments, R4is optionally substituted heteroaryl containing 3 ring N atoms.

[0197] In some embodiments, R4is optionally substituted monocyclic heteroaryl. In some embodiments, R4is optionally substituted monocyclic heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, N, and S. In some embodiments, R4is optionally substituted monocyclic heteroaryl containing at least 1 ring O atom. In some embodiments, R4isoptionally substituted monocyclic heteroaryl containing at least 1 ring N atom. In some embodiments, R4is optionally substituted monocyclic heteroaryl containing at least 1 ring S atom.

[0198] In some embodiments, R4is optionally substituted monocyclic heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R4is optionally substituted monocyclic heteroaryl containing 1 or 2 ring N atoms. In some embodiments, R4is optionally substituted monocyclic heteroaryl containing 1 ring N atom. In some embodiments, R4is optionally substituted monocyclic heteroaryl containing 2 ring N atoms. In some embodiments, R4is optionally substituted monocyclic heteroaryl containing 3 ring N atoms.

[0199] In some embodiments, R4is substituted monocyclic heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R4is substituted monocyclic heteroaryl containing 1 or 2 ring N atoms. In some embodiments, R4is substituted monocyclic heteroaryl containing 1 ring N atom. In some embodiments, R4is substituted monocyclic heteroaryl containing 2 ring N atoms.

[0200] In some embodiments, R4is unsubstituted monocyclic heteroaryl containing 1, 2, or 3 ring N atoms. In some embodiments, R4is unsubstituted monocyclic heteroaryl containing 1 or 2 ring N atoms. In some embodiments, R4is unsubstituted monocyclic heteroaryl containing 1 ring N atom. In some embodiments, R4is unsubstituted monocyclic heteroaryl containing 2 ring N atoms.independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -ORA, -SCN, -SRA, -SSRA, -Ns, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, -OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, -OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, -NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, -NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, -NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, -NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, -OSi(RA)(ORA)2, -OSi(ORA)3, or -B(ORA)2, wherein each instance of RAis independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring. In some embodiments,some embodiments,some embodiments,someembodiments,

[0202] As generally described herein, m2 is 1, 2, or 3.

[0203] In some embodiments, m2 is 1 or 2. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 3.

[0204] As generally described herein, n2 is 1, 2, or 3.

[0205] In some embodiments, n2 is 1 or 2. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3.

[0206] In some embodiments, m2 is the same as n2. In some embodiments, m2 and n2 are each 1. In some embodiments, m2 and n2 are each 2. In some embodiments, m2 and n2 are each 3.

[0207] In some embodiments, m2 is different from n2. In some embodiments, m2 is 1, and n2 is 2. In some embodiments, m2 is 1, and n2 is 3. In some embodiments, m2 is 2, and n2 is 1. In some embodiments, m2 is 2, and n2 is 3. In some embodiments, m2 is 3, and n2 is 1. In some embodiments, m2 is 3, and n2 is 2.

[0208] As generally described herein, L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- - C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

[0209] In some embodiments, L4comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprises optionally substituted C1-6 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprises optionally substituted C1-6 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -O-, -NR5-, or -C(=O)-.

[0210] In some embodiments, L4comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently, p y independently 1, 2, or 3; and each R6is hydrogen, optionally substituted alkyl, or halogen. In some embodiments, L4comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with

[0211] In some embodiments, L4comprises optionally substituted carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprises optionally substituted carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted carbocyclylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprises optionally substituted C4-6 carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C4-6 carbocyclylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprises optionally substituted C4-6 carbocyclylene. In some embodiments, L4comprises

[0212] In some embodiments, L4comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprisesoptionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, or -C(=O)-.independently 1, 2, or 3; and each R6is hydrogen, optionally substituted alkyl, or halogen. In some

[0214] In some embodiments, L4comprises optionally substituted C1-10 alkylene and optionally substituted carbocyclylene, optionally substituted C1-10 alkylene and optionally substituted heterocyclylene, optionally substituted C1-10 alkylene and optionally substituted arylene, optionally substituted C1-10 alkylene and optionally substituted heteroarylene, optionally substituted carbocyclylene and optionally substituted heterocyclylene, optionally substituted carbocyclylene and optionally substituted arylene, optionally substituted carbocyclylene and optionally substituted heteroarylene, optionally substituted heterocyclylene and optionally substituted arylene, optionally substituted heterocyclylene and optionally substituted heteroarylene, and optionally substituted arylene and optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

[0215] In some embodiments, L4comprises optionally substituted C1-10 alkylene and optionally substituted carbocyclylene, or optionally substituted C1-10 alkylene and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substitutedcarbocyclylene, or optionally substituted heterocyclylene. In some embodiments, L4comprises optionally substituted C1-6 alkylene and optionally substituted carbocyclylene, or optionally substituted C1-6 alkylene and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -O-, -NR5-, — C(— O)— , optionally substituted carbocyclylene, or optionally substituted heterocyclylene.wherein: each instance of X is independentlyCH or N; each of m3 and n3 is independently 1, 2, or 3; and each R6is hydrogen, optionallyembodiments, L4is of formula:

[0218] In some embodiments, L4comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR5-, - C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

[0219] In some embodiments, L4comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms.wherein: each instance of X is independently CH or N; each of m3 and n3 is independently 1, 2, or 3; and each R6is hydrogen, optionally substituted alkyl, or halogen.embodiments, L4is of formula:

[0223] In some embodiments, L4comprises optionally substituted arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted arylene are independently replaced with -O-, or -NR5-. In some embodiments, L4comprises optionally substituted phenylene. In some embodiments, L4comprises substituted phenylene. In some embodiments, L4comprises phenylene. In some embodiments, L4comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with -O-, or -NR5-. In some embodiments, L4comprises substituted heteroarylene. In some embodiments, L4comprises unsubstituted heteroarylene.

[0224] In some embodiments, L4is of formula:wherein: each instance of X is independently CH or N; each of m3 and n3 is independently 1, 2, or 3; and each R6is hydrogen, optionally substituted alkyl, or halogen.L1and R5

[0227] As generally described herein, L1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0228] In some embodiments, L1comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR5-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionallysubstituted heteroarylene. In some embodiments, L1comprises optionally substituted Ci-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0229] In some embodiments, L1comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted Ci-12 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-12 alkylene are independently replaced with - O— , -NR5-, — C(— O)— , or optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted Cn- 20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cn-20 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, or optionally substituted heterocyclylene.

[0230] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR5-, — C(— O)— , or optionally substituted heterocyclylene.

[0231] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-. In some embodiments, L1comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -O-. In some embodiments, L1comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with -O-. In some embodiments, L1comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -O-.

[0232] In some embodiments, L1comprises -O-. In some embodiments, L1comprisesO , or O . In some embodiments, L1comprises

[0233] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with - NR5-. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-. In some embodiments, L1comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with - NR5-. In some embodiments, L1comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -NH-.In some embodiments, L1comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with -NH-.In some embodiments, L1comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -NH-.

[0234] In some embodiments, L1comprises -NH-. In some embodiments, L1comprises, wherein each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each r is independently 1, 2, 3, 4, or 5. In some embodiments, L1comprises. In some embodiments, L1comprises

[0235] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-. In some embodiments, L1comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with-C(=0)-. In some embodiments, L1comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with -C(=O)-. In some embodiments, L1comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -C(=O)-.

[0236] In some embodiments, L1comprises -C(=O)-. In some embodiments, L1comprisesAA / qy f ,, wherein each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; andeach r is independently 1, 2, 3, 4, or 5. In some embodiments, L1comprises 0 ,

[0237] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted Ci- 20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises optionally substituted straight-chain Ci-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain Ci-20 alkylene is replaced with optionally substituted 3-10 membered heterocyclylene. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene. In some embodiments, L1comprises optionally substituted Ci-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene comprising 1 or 2 ring N atoms. In some embodiments, L1comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene comprising 1 or 2 ring N atoms. In some embodiments, L1comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6membered heterocyclylene comprising 1 or 2 ring N atoms. In some embodiments, L1comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene comprising 1 or 2 ring N atoms.O O, wherein each instance of X is independently CH or N. In somecomprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are replaced with -O-, -NR5-, — C(— O)— , or optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-. In some embodiments, L1comprises

[0240] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR5-. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-. In some

[0241] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted Ci-20 alkylene is replaced with -C(=O)-. In

[0242] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene.

[0243] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR5-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-. In someinstance of X is independently CH or N; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0244] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR5-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted Ci-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted Ci- 20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene. In somewherein: each instance of X is independently CH or N; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each r is independently 1, 2, 3, 4, or 5. In some embodiments, L1comprises

[0245] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with-C(=O)-. In some embodiments, L1comprises, wherein: each instance of X is independently CH or N; and each r is independently 1, 2, 3, 4, or 5. In some embodiments, L1comprises

[0246] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted Ci-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene. In some embodiments, L1wherein each instance of X is independently CH or N.

[0247] In some embodiments, L1comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted Ci-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted Ci-20 alkylene are independently replaced with optionally substituted 5-6 membered heterocyclylene. In some, wherein each instance of X is independently CH or N. In some embodiments, L1comprises

[0248] In some embodiments, L1comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0249] In some embodiments, L1comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L1comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR5-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted 5-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 5-6 membered heterocyclylene are independently replaced with -O-, -NR5-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L1comprises optionally substituted 5-6 memberedheterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, some embodiments, L1comprisesindependently CH or N.

[0250] In some embodiments, L1is of formula:wherein: each instance of X is independently CH or N; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0252] As generally described herein, each instance of R5is independently hydrogen or optionally substituted alkyl.

[0253] In some embodiments, at least one instance of R5is hydrogen.

[0254] In some embodiments, at least one instance of R5is optionally substituted alkyl. In some embodiments, at least one instance of R5is optionally substituted Ci-i2alkyl, optionally substituted Ci- 11 alkyl, optionally substituted C1-10 alkyl, optionally substituted C1-9 alkyl, optionally substituted Ci-8 alkyl, optionally substituted C1-7 alkyl, optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted CM alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl. In some embodiments, at least one instance of R5is optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted CM alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl.

[0255] In some embodiments, at least one instance of R5is substituted alkyl. In some embodiments, at least one instance of R5is substituted CM2alkyl, substituted Cm alkyl, substituted CMO alkyl, substituted C1-9 alkyl, substituted CM alkyl, substituted C1-7 alkyl, substituted C1-6 alkyl, substituted C1-5 alkyl, substituted CM alkyl, substituted C1-3 alkyl, or substituted C1-2 alkyl. In some embodiments, at least one instance of R5is substituted C1-6 alkyl, substituted C1-5 alkyl, substituted CM alkyl, substituted C1-3 alkyl, or substituted C1-2 alkyl.

[0256] In some embodiments, at least one instance of R5is C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or C1-2 alkyl substituted with halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -ORA, -SCN, -SRA, - SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, - C(=NRA)RA, -C(=NRA)0RA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -0C(=NRA)RA, -0C(=NRA)0RA, -OC(=NRA)SRA, - 0C(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, - OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -0N(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, - NRAC(=0)RA, -NRAC(=0)0RA, -NRAC(=O)SRA, -NRAC(=0)N(RA)2, -NRAC(=NRA)RA, - NRAC(=NRA)0RA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, - NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, - NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, - OSi(RA)(ORA)2, -OSi(ORA)a, and / or -B(ORA)2, wherein each instance of RAis independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of RAare joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.

[0257] In some embodiments, at least one instance of R5is unsubstituted alkyl. In some embodiments, at least one instance of R5is unsubstituted Cm alkyl, unsubstituted C1-11 alkyl, unsubstituted C1-10 alkyl, unsubstituted C1-9 alkyl, unsubstituted C1-8 alkyl, unsubstituted C1-7 alkyl, unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted C1-4 alkyl, unsubstituted Cm alkyl, or unsubstituted C1-2 alkyl. In some embodiments, at least one instance of R5is unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted CM alkyl, unsubstituted C1-3 alkyl, or unsubstituted C1-2 alkyl.

[0258] In some embodiments, at least one instance of R5is methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl, or / 7-hcxyl. In some embodiments, at least one instance of R5is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. In some embodiments, at least one instance of R5is methyl, ethyl, or n-propyl. In some embodiments, at least one instance of R5is methyl (-CH3).Y, R8, R9, R10, L5, and L6

[0259] As generally described herein, Y is a moiety capable of binding to an E3 ubiquitin ligase.

[0260] In some embodiments, Y is a moiety capable of binding to an E3 ubiquitin ligase as described in Ishida T. and Ciulli A., SIAS Discov. 2021, 26(4), 484-502, doi: 10.1177 / 2472555220965528, or Bricelj, A. et al., Front. Chem. 2021, 9, Article 707317, doi: 10.3389 / fchem.2021.707317, the contents of each of which are incorporated by reference.

[0261] In some embodiments, Y is of Formula (IV-a):wherein R8is hydrogen or optionally substituted alkyl.

[0262] In some embodiments, R8is hydrogen. In some embodiments, R8is optionally substituted Cm alkyl. In some embodiments, R8is -CH3. In some embodiments, R8is hydrogen or -CH3.

[0263] In some embodiments, Y is of Formula (IV-b):wherein R9is optionally substituted alkyl or optionally substituted cycloalkyl.

[0264] In some embodiments, R9is optionally substituted Cm alkyl. In some embodiments, R9is -CH3. In some embodiments, R9is optionally substituted C3-4 cycloalkyl. In some embodiments, R9is cyclopropyl optionally substituted with halogen or -CN. In some embodiments, R9is cyclopropyl optionally substituted with -F or -CN. In some embodiments, R9is -CH3,

[0265] In some embodiments, Y is of Formula (IV-c):wherein R10is optionally substituted alkyl or optionally substituted cycloalkyl.

[0266] In some embodiments, R10is optionally substituted C1-3 alkyl. In some embodiments, R10is -CH3. In some embodiments, R10is optionally substituted C3-4 cycloalkyl. In some embodiments, R10is cyclopropyl optionally substituted with halogen or -CN. In some embodiments, R10is cyclopropyl optionally substituted with -F or -CN. In some embodiments, R10is -CH3,wherein:X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0269] In some embodiments, X is CH. In some embodiments, X is N.

[0270] In some embodiments, Y is of Formula (V-a):

[0271] In some embodiments, Y is of Formula (V-b):

[0272] As generally described herein, L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0273] In some embodiments, L5is optionally substituted heterocyclylene. In some embodiments, L5is substituted heterocyclylene. In some embodiments, L5is optionally substituted heterocyclylene containing 1, 2, or 3 ring N atoms. In some embodiments, L5is optionally substituted heterocyclylene containing 1 ring N atom. In some embodiments, L5is optionally substituted heterocyclylene containing 2 ring N atom. In some embodiments, L5is substituted heterocyclylene containing 1, 2, or 3 ring N atoms. In some embodiments, L5is substituted heterocyclylene containing 1 ring N atom. In some embodiments, L5is optionally substituted arylene. In some embodiments, L5is optionally substituted phenylene. In some embodiments, L5is substituted phenylene. In some embodiments, L5is unsubstituted phenylene. In some embodiments, L5is optionally substituted heteroarylene. In some embodiments, L5is optionally substituted heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L5is optionally substituted heteroarylene containing 1 ring N atom. In some embodiments, L5is optionally substituted heteroarylene containing 2 ring N atoms.

[0275] As generally described herein, L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0276] In some embodiments, L6is a bond. In some embodiments, L6is -C(R5)2- In some embodiments, L6is -CHR5-. In some embodiments, L6is -CH2-. In some embodiments, L6is -NR5-. In some embodiments, L6is -NH-. In some embodiments, L6is -C(=O)-. In some embodiments, L6is -C(=O)NR5-. In some embodiments, L6is -C(=O)NH-.

[0278] In some embodiments, Y is of Formulae (IV-a), (IV-b), (IV-c), or (V). In some embodiments, Y is of Formulae (IV-a), (IV-b), (IV-c), (V-a), or (V-b).Subgeneric Embodiments

[0280] In some embodiments, the compound of Formula (II) is of Formula (II-a):or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the compound of Formula (II) is of Formulae (II-a-1), (II-a-2), (II-a-3), or (II-a-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0282] In some embodiments, the compound of Formula (II) is of Formulae (II-a-1). In some embodiments, the compound of Formula (II) is of Formulae (II-a-2). In some embodiments, the compound of Formula (II) is of Formulae (II-a-3). In some embodiments, the compound of Formula (II) is of Formulae (II-a-4).

[0283] In some embodiments, the compound of Formula (II-a-4) is of Formulae (II-a-4-i) or (II-a-4- ii):or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the compound of Formula (II-a-4) is of Formulae (II-a-4-i). In some embodiments, the compound of Formula (II-a-4) is of Formulae (II-a-4-ii).

[0285] In some embodiments, the compound of Formula (II) is of Formula (Il-b):or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the compound of Formula (II) is of Formulae (II-b-1), (II-b-2), (Il-b- 3), or (II-b-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0287] In some embodiments, the compound of Formula (II) is of Formulae (II-b-1). In some embodiments, the compound of Formula (II) is of Formulae (II-b-2). In some embodiments, the compound of Formula (II) is of Formulae (II-b-3). In some embodiments, the compound of Formula (II) is of Formulae (II-b-4).

[0288] In some embodiments, the compound of Formula (II-b-4) is of Formulae (II-b-4-i) or (II-b-4- ii):or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the compound of Formula (II-b-4) is of Formulae (II-b-4-i). In some embodiments, the compound of Formula (II-b-4) is of Formulae (II-b-4-ii).

[0290] In some embodiments, the compound of Formula (II) is of Formula (II-c):or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the compound of Formula (II) is of Formulae (II-c-1), (II-c-2), (II-c-3), or (II-c-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0292] In some embodiments, the compound of Formula (II) is of Formulae (II-c-1). In some embodiments, the compound of Formula (II) is of Formulae (II-c-2). In some embodiments, the compound of Formula (II) is of Formulae (II-c-3). In some embodiments, the compound of Formula (II) is of Formulae (II-c-4).

[0293] In some embodiments, the compound of Formula (II-c-4) is of Formulae (II-c-4-i) or (II-c-4- ii):or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the compound of Formula (II-c-4) is of Formulae (II-c-4-i). In some embodiments, the compound of Formula (II-c-4) is of Formulae (II-c-4-ii).

[0295] In some embodiments, the compound of Formula (II) is of Formula (Il-d):or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the compound of Formula (II) is of Formulae (II-d-1), (II-d-2), (Il-d- 3), or (II-d-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0297] In some embodiments, the compound of Formula (II) is of Formulae (II-d-1). In some embodiments, the compound of Formula (II) is of Formulae (II-d-2). In some embodiments, the compound of Formula (II) is of Formulae (II-d-3). In some embodiments, the compound of Formula (II) is of Formulae (II-d-4).

[0298] In some embodiments, the compound of Formula (II-d-4) is of Formulae (II-d-4-i) or (II-d-4-or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the compound of Formula (II-d-4) is of Formulae (II-d-4-i). In some embodiments, the compound of Formula (II-d-4) is of Formulae (II-d-4-ii).

[0300] In some embodiments, the compound of Formula (II) is of Formula (Il-e):or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the compound of Formula (II) is of Formulae (II-e-1), (II-e-2), (II-e-3), or (II-e-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0302] In some embodiments, the compound of Formula (II) is of Formulae (II-e-1). In some embodiments, the compound of Formula (II) is of Formulae (II-e-2). In some embodiments, the compound of Formula (II) is of Formulae (II-e-3). In some embodiments, the compound of Formula (II) is of Formulae (II-e-4).

[0303] In some embodiments, the compound of Formula (II-e-4) is of Formulae (II-e-4-i) or (II-e-4- ii):or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the compound of Formula (II-e-4) is of Formulae (II-e-4-i). In some embodiments, the compound of Formula (II-e-4) is of Formulae (II-e-4-ii).

[0305] In some embodiments, the compound of Formula (III) is of Formula (III-a):or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the compound of Formula (III) is of Formulae (III-a-1), (III-a-2), (III- a-3), or (III-a-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0307] In some embodiments, the compound of Formula (III) is of Formulae (III-a-1). In some embodiments, the compound of Formula (III) is of Formulae (III-a-2). In some embodiments, the compound of Formula (III) is of Formulae (III-a-3). In some embodiments, the compound of Formula (III) is of Formulae (III-a-4).

[0308] In some embodiments, the compound of Formula (III-a-4) is of Formulae (III-a-4-i) or (Ill-a- 4-ii):or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the compound of Formula (III-a-4) is of Formulae (III-a-4-i). In some embodiments, the compound of Formula (III-a-4) is of Formulae (III-a-4-ii).

[0310] In some embodiments, the compound of Formula (III) is of Formula (Ill-b):or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of Formula (III) is of Formulae (III-b-1), (III-b-2), (III- b-3), or (III-b-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0312] In some embodiments, the compound of Formula (III) is of Formulae (III-b-1). In some embodiments, the compound of Formula (III) is of Formulae (III-b-2). In some embodiments, the compound of Formula (III) is of Formulae (III-b-3). In some embodiments, the compound of Formula (III) is of Formulae (III-b-4).

[0313] In some embodiments, the compound of Formula (III-b-4) is of Formulae (III-b-4-i) or (Ill-b-4-ii):or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the compound of Formula (III-b-4) is of Formulae (III-b-4-i). In some embodiments, the compound of Formula (III-b-4) is of Formulae (III-b-4-ii).

[0315] In some embodiments, the compound of Formula (III) is of Formula (III-c):or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the compound of Formula (III) is of Formulae (III-c-1), (III-c-2), (III- c-3), or (III-c-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0317] In some embodiments, the compound of Formula (III) is of Formulae (III-c-1). In some embodiments, the compound of Formula (III) is of Formulae (III-c-2). In some embodiments, the compound of Formula (III) is of Formulae (III-c-3). In some embodiments, the compound of Formula (III) is of Formulae (III-c-4).

[0318] In some embodiments, the compound of Formula (III-c-4) is of Formulae (III-c-4-i) or (III-c- 4-ii):or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the compound of Formula (III-c-4) is of Formulae (III-c-4-i). In some embodiments, the compound of Formula (III-c-4) is of Formulae (III-c-4-ii).

[0320] In some embodiments, the compound of Formula (III) is of Formula (Ill-d):or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the compound of Formula (III) is of Formulae (III-d-1), (III-d-2), (III- d-3), or (III-d-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=0)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0322] In some embodiments, the compound of Formula (III) is of Formulae (III-d-1). In some embodiments, the compound of Formula (III) is of Formulae (III-d-2). In some embodiments, the compound of Formula (III) is of Formulae (III-d-3). In some embodiments, the compound of Formula (III) is of Formulae (III-d-4).

[0323] In some embodiments, the compound of Formula (III-d-4) is of Formulae (III-d-4-i) or (Ill-d- 4-ii):or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the compound of Formula (III-d-4) is of Formulae (III-d-4-i). In some embodiments, the compound of Formula (III-d-4) is of Formulae (III-d-4-ii).

[0325] In some embodiments, the compound of Formula (III) is of Formula (Ill-e):or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the compound of Formula (III) is of Formulae (III-e-1), (III-e-2), (III- e-3), or (III-e-4):or a pharmaceutically acceptable salt thereof, wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl;R10is optionally substituted alkyl or optionally substituted cycloalkyl;X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

[0327] In some embodiments, the compound of Formula (III) is of Formulae (III-e-1). In some embodiments, the compound of Formula (III) is of Formulae (III-e-2). In some embodiments, the compound of Formula (III) is of Formulae (III-e-3). In some embodiments, the compound of Formula (III) is of Formulae (III-e-4).

[0328] In some embodiments, the compound of Formula (III-e-4) is of Formulae (III-e-4-i) or (Ill-e- 4-ii):or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the compound of Formula (III-e-4) is of Formulae (III-e-4-i). In some embodiments, the compound of Formula (III-e-4) is of Formulae (III-e-4-ii).

[0330] In some embodiments, the compound of Formula (VI) is of Formulae (Vl-a), (Vl-b), (VI-c), (Vl-d), (Vl-e), or (Vl-f):or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the compound of Formula (VI) is of Formula (Vl-a). In some embodiments, the compound of Formula (VI) is of Formula (Vl-b). In some embodiments, the compound of Formula (VI) is of Formula (VI-c). In some embodiments, the compound of Formula (VI) is of Formula (Vl-d). In some embodiments, the compound of Formula (VI) is of Formula (Vl-e). In some embodiments, the compound of Formula (VI) is of Formula (VI- f).

[0332] In some embodiments, the compound of Formula (I) is of Formula (VI). In some embodiments, the compound of Formula (I) is of Formulae (Vl-a), (Vl-b), (VI-c), (Vl-d), (Vl-e), or (Vl-f). In some embodiments, the compound of Formula (I) is of Formula (Vl-a). In some embodiments, the compound of Formula (I) is of Formula (Vl-b). In some embodiments, the compound of Formula (I) is of Formula (VI-c). In some embodiments, the compound of Formula (I) is of Formula (Vl-d). In some embodiments, the compound of Formula (I) is of Formula (Vl-e). In some embodiments, the compound of Formula (I) is of Formula (Vl-f).

[0333] In some embodiments, the compound of Formula (VII) is of Formulae (Vll-a), (Vll-b), (VII- c), or (Vll-d):or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, the compound of Formula (VII) is of Formula (Vll-a). In some embodiments, the compound of Formula (VII) is of Formula (Vll-b). In some embodiments, the compound of Formula (VII) is of Formula (VII-c). In some embodiments, the compound of Formula (VII) is of Formula (Vll-d).

[0335] In some embodiments, the compound of Formula (I) is of Formula (VII). In some embodiments, the compound of Formula (I) is of Formulae (Vll-a), (Vll-b), (VII-c), or (Vll-d). In some embodiments, the compound of Formula (I) is of Formula (Vll-a). In some embodiments, the compound of Formula (I) is of Formula (Vll-b). In some embodiments, the compound of Formula (I) is of Formula (VII-c). In some embodiments, the compound of Formula (I) is of Formula (Vll-d).

[0336] In some embodiments, the compound of Formula (I) is selected from those in Table 1, and pharmaceutically acceptable salts thereof.Table 1. Exemplary degraders of the present disclosure.

[0337] In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I)), or a salt thereof. In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I)).Pharmaceutical Compositions and Kits

[0338] The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0339] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophy tactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a in a painful condition subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a painful condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a metabolic disorder in a subject in need thereof. Incertain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14) in a subject or cell.

[0340] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0341] In certain embodiments, the cell is present in vitro. In certain embodiments, the cell is present in vivo.

[0342] In certain embodiments, the effective amount is an amount effective for degrading a protein by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14) by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL 14) by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0343] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0344] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would beadministered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0345] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0346] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0347] Exemplary diluents or fillers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, starches (such as dry starch, cornstarch), sugars (such as powdered sugar), calcium trisulfate, carboxymethylcellulose calcium, dextrate, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium, maltitol, maltodextrin, maltose, sucrose, glucose, mannitol, silicic acid, xylitol, and mixtures thereof.

[0348] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0349] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly (vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0350] Exemplary disintegrating agents or disintegrants include agar, algin, alginic acid, sodium alginate, silicates, sodium carbonate, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, rubber, magnesium silicate, methylcellulose, potassium krillin, hydroxypropylcellulose (e.g., low substituted Hydroxypropylcellulose), crosslinked polyvinylpyrrolidone, hydroxypropylcellulose, and starch (e.g., sodium glycolate starch, potato or tapioca starch).

[0351] Exemplary binding agents include starch (e.g., glycolate starch, cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0352] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0353] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0354] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.

[0355] Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0356] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0357] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0358] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0359] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®.

[0360] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0361] Exemplary lubricating agents include agar, ethyl oleate, ethyl laurate, glycerin, blyceryl palmitostearate, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium stearyl, sorbitol, zinc stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0362] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0363] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise 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 (e.g., 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 include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0364] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0365] In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a ready-to-use (“RTU”) preparation that can be directly administered to a subject. In some embodiments, the RTU preparation is a suspension. In some embodiments, the RTU preparation is a solution. In some embodiments, the RTU preparation is an emulsion. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a solid that is reconstituted prior to administration. In some embodiments, the solid is a lyophilized solid. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.

[0366] In some embodiments, the pharmaceutical compositions disclosed herein comprise a bulking agent. Bulking agents can be used, e.g., to improve the appearance of a solid composition, to providevisible “bulk” to demonstrate product quality or to facilitate preparation, e.g., of a solid composition prepared for reconstitution prior to administration. Bulking agents can be used for low dose (high potency) drugs that do not have the necessary bulk to support their own structure or provide a visible composition in a unit dosage form. Bulking agents are used in lyophilized formulations. Bulking agents provide a desirable structure for a lyophilized cake comprising pores that provide the means for vapor to escape from the product during lyophilization cycles, and facilitate dissolution on reconstitution. In some embodiments, the bulking agent is mannitol, lactose, sucrose, dextran, trehalose, povidone, dextran, glycine, isoleucine, methionine, or a cyclodextrin (e.g., (2- hydroxypropyl)-P-cyclodextrin).

[0367] The injectable formulations can be sterilized, for example, by filtration 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.

[0368] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0369] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates 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 ingredient.

[0370] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient 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, 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 (i) lubricants such as 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 include a buffering agent.

[0371] Solid compositions of a similar type can 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 polyethyleneglycols 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 art of pharmacology. They may optionally comprise opacifying agents and can 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 encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can 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.

[0372] The active ingredient can be in a 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 ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may 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 comprise buffering agents. They may optionally comprise opacifying agents and can 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 encapsulating agents which can be used include polymeric substances and waxes.

[0373] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0374] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0375] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0376] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self- propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0377] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0378] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0379] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable forintranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0380] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0381] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0382] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0383] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0384] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0385] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, theduration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0386] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0387] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and / or in degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14) in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0388] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drugcompounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0389] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol- lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti- proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HD AC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all- trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g.,stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

[0390] In some embodiments, the pharmaceutical composition further comprises an additional pharmaceutical agent (e.g., an anti-cancer agent (e.g., an alkylating agent, an anti-metabolite, an anti- tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent)). In some embodiments, the additional pharmaceutical agent is an anti-cancer agent (e.g., an alkylating agent, an anti-metabolite, an anti- tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent). In some embodiments, the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof. In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the anti-cancer agent is an anti-metabolite. In some embodiments, the anti-cancer agent is an anti-tumor antibiotic. In some embodiments, the anti-cancer agent is an anti-cytoskeletal agent. In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the anti-cancer agent is an anti-hormonal agent. In some embodiments, the anti-cancer agent is a targeted therapeutic agent. In some embodiments, the anti- cancer agent is a photodynamic therapeutic agent.

[0391] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0392] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Incertain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14) in a subject or cell.

[0393] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for degrading a methyltransferase-like (METTL) protein (e.g., METTL3, METTL14) in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.Methods of Degrading a METTL Protein and Methods of Treatment or Prevention

[0394] In another aspect, the present disclosure provides a method of degrading a methyltransferase- like (METTL) protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of degrading a methyltransferase-like (METTL) protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0395] In another aspect, the present disclosure provides a method of degrading a methyltransferase- like (METTL) protein in a subject, the method comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of degrading a methyltransferase-like (METTL) protein in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0396] In another aspect, the present disclosure provides a method of degrading a methyltransferase- like (METTL) protein in a cell, tissue, or biological sample, the method comprising contacting thecell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of degrading a methyltransferase-like (METTL) protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0397] In some embodiments, the METTL protein is METTL3 and / or METTL14. In some embodiments, the METTL protein is METTL3. In some embodiments, the METTL protein is METTL14. In some embodiments, the METTL protein is METTL3 and METTL14. In some embodiments, the METTL protein is a complex of METTL3 and METTL14. In some embodiments, the cell, tissue, or biological sample is in vitro. In some embodiments, the cell, tissue, or biological sample is in vivo. In some embodiments, the cell is a cancer cell.

[0398] In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the treatment or prevention of a disease in a subject in need thereof. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for the treatment or prevention of a disease in a subject in need thereof. In some embodiments, the disease is a proliferative disease. In some embodiments, the disease is a cancer (e.g., glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer).

[0399] In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease in a subject in need thereof. In some embodiments, the disease is a proliferative disease. In some embodiments, the disease is a cancer (e.g., glioblastoma, liver cancer, ovarian cancer).

[0400] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a provided compound or pharmaceutical composition for use in the treatment of cancer in a subject in need thereof. In another aspect, the present disclosure provides aprovided compound or pharmaceutical composition for use in the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

[0401] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer in a subject in need thereof. In another aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

[0402] In some embodiments, the cancer is associated with a methyltransferase-like (METTL) protein (e.g., glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer). In some embodiments, the cancer is associated with METTL3 and / or METTL14. In some embodiments, the cancer is associated with METTL3. In some embodiments, the cancer is associated with METTL14. In some embodiments, the cancer is associated with METTL3 and METTL14. In some embodiments, the cancer is associated with a complex of METTL3 and METTL14.

[0403] In some embodiments, the cancer is glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, or lung cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is hematopoietic cancer (e.g., acute myeloid leukemia). In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is lung cancer.

[0404] In some embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In some embodiments, the subject described herein is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In some embodiments, the animal is a genetically engineered animal. In someembodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In some embodiments, the subject is a fish or reptile.EXAMPLES

[0405] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

[0406] The synthesis of ZW27941 (Degrader 24) and the negative control ZW27941NC is depicted in FIG. 3. First, a SNAT reaction between the spiro ring starting material 1 and 4,6-difluoropyrimdine afforded the fluoride intermediate 2 in quantitative yield. Intermediate 2 then underwent another SNAT reaction with 8-aminooctanoic acid in isopropanol and H2O to give the acid intermediate 3 after trituration in methanol and dichloromethane. Finally, hexafluorophosphate azabenzotriazole tetramethyl uronium-mediated amide coupling of VHL ligand 4 or its corresponding negative ligand 5 with 3 in dimethylformamide yielded ZW27941 and ZW27941NC, respectively.Example 1: Preparation of Intermediates

[0407] Intermediate AIntermediate A

[0408] Step 1. Synthesis of tert-butyl 4-amino-4-(nitromethyl)piperidine-l-carboxylate. To a stirred solution of McNCh (3.5 mL, 65 mmol) in NH3 (29 mL, 7 N in MeOH, 200 mmol) was added tert-butyl 4-oxopiperidine-l -carboxylate (10 g, 50 mmol) in portions. After the addition was completed, the resulting mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na^SO-i. filtered, and concentrated to give the desired product (13 g, 100% yield) as a yellow oil, which was used in the next step without further purification. 1H-NMR (600 MHz, Chloroform-d ): δ 4.34 (s, 2H), 3.79 (br s, 2H), 3.27 (t, J= 12.3 Hz, 2H), 1.63 - 1.57 (m, 2H), 1.51 - 1.47 (m, 2H), 1.45 (s, 9H) ppm.

[0409] Step 2. Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(nitromethyl)piperidine-l-carboxylate. To a stirred solution of tert-butyl 4-amino-4-(nitromethyl)piperidine-l -carboxylate (13 g, 50 mmol) in DCM (75 mL) was added a solution of K2CO3 (13.80 g, 100 mmol) in H2O (75 mL). The resulting mixture was cooled to 0 °C, and CbzCl (9.40 g, 55 mmol) was added dropwise. After addition was completed, the resulting mixture was stirred vigorously at room temperature for 2 days. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. filtered, and concentrated. The oil residue was purified by flash column chromatography (EtOAc in hexane 0-20%) to give the desired product (16.1 g, 82% yield) as an oil. 1H-NMR (600 MHz, Chloroform-d ): δ5 7.39 - 7.33 (m, 5H), 5.14 (s, 2H), 4.78 (s, 2H), 3.90 (br s, 2H), 3.06 (br s, 2H), 2.14 (d, J= 13.2 Hz, 2H), 1.68 - 1.63 (m, 2H), 1.47 (s, 9H) ppm.

[0410] Step 3. tert-butyl 4-(aminomethyl)-4-(((benzyloxy)carbonyl)amino)piperidine-l- carboxylate. To a stirred solution of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4- (nitromethyl)piperidine-l -carboxylate (16.10 g, 41 mmol) and NiC12-6H2O (9.80 g, 41 mmol) in MeOH (160 mL) was added NaBH4 (7.80 g, 205 mmol) in portions at 0 °C under a nitrogen atmosphere. Caution should be taken when adding NaBH4 because the reaction was highly exothermic and produced hydrogen gas. After the addition of NaBH4 was completed, the resulting mixture was stirred at room temperature for 1 hour and the reaction was quenched by adding a saturated aqueous NaHCCL solution. The precipitated black solids were filtered off through a pad of Celite, washed with MeOH, and the filtrate was concentrated under reduced pressure to remove MeOH. The aqueous residue was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (MeOH in DCM 0-8%) to give the crude product as a semi-solid. Trituration with DCM / hexane (1:4) followed by filtration gave the desired product (13.6 g, 91% yield) as a white solid. 1H-NMR (600 MHz, Chloroform-d ): δ 7.40 - 7.33 (m, 5H), 5.08 (s, 2H), 4.67 (s, 1H), 3.81 (br s, 2H), 3.07 (t, J = 10.8 Hz, 2H), 2.91 (s, 2H), 2.04 (br s, 2H), 1.53 - 1.47 (m, 2H), 1.47 (s, 9H) ppm. ESI-MS m / z [M+H]+: calculated, 364.2; found, 364.3.

[0411] Step 4. Synthesis of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(((2-ethoxy-2- oxoethyl)amino)methyl)piperidine-l-carboxylate. To a stirred solution of tert-butyl 4- (aminomethyl)-4-(((benzyloxy)carbonyl)amino)piperidine-l-carboxylate (13.60 g, 37 mmol) and TEA (5.2 mL, 37 mmol) in dry DCM (100 mL) was added a solution of ethyl 2-bromoacetate (6.70 g, 37 mmol) in dry DCM (20 mL) dropwise at 0 °C. After the addition was completed, the resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to remove the solvent and TEA. The oil residue was partitioned between EtOAc and saturated aqueous NaHCOi solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the desired product (13 g) as an oil, which was used in the next step without further purification.

[0412] Step 5. Synthesis of tert-butyl 2-oxo-l,4,9-triazaspiro[5.5]undecane-9-carboxylate (Intermediate A). To a solution of tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(((2-ethoxy-2- oxoethyl)amino)methyl)piperidine-l -carboxylate (13 g, 29 mmol) in IPA (250 mL) was added Pd / C (1.3 g, 10% wt) and ammonium formate (11.4 g, 180 mmol) in portions under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 4 hours, cooled to room temperature, and filtered through a pad of Celite. The filtrate was concentrated and the residue was partitioned between DCM and saturated aqueous NaHCCh solution. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4,. filtered, and concentrated to give a solid residue. Trituration with hexane / EtOAc (10:1) followed by filtration gave the desired product (first batch, 1.1 g) as a white powder. The filtrate was concentrated and the residue was purified by flash column chromatography (MeOH in DCM 0-10%) to give the product (second batch, 0.9 g, 20% yield over two steps) as a white solid. ‘H-NMR (600 MHz, Chloroform-tf): δ 6.39 (s, 1H), 3.49 (s, 2H), 3.45 (t, J = 5.8 Hz, 4H), 2.89 (s, 2H), 1.73 - 1.64 (m, 4H), 1.45 (s, 9H) ppm. ESI-MS m / z [2M+H]+: calculated 539.3, found 539.2.

[0413] Intermediate BIntermediate B

[0414] Step 1. Synthesis of (4-bromo-2,5-difluorophenyl)methanol. To a solution of 4-bromo-2,5- difluorobenzoic acid (950 mg, 4.0 mmol) in dry THF (10 mL) was added BH3'Me2S (610 mg, 8.0 mmol) dropwise at 0 °C under nitrogen atmosphere. After the addition was completed, the resulting mixture was stirred at room temperature for 24 hours. The reaction was quenched by the addition of saturated aqueous NaiCCL solution at 0 °C. The organic layer was separated and the aqueous layer was extracted by EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SO-i. filtered, and concentrated to give the desired product (812 mg, 91% yield) as a white solid. ‘H-NMR (600 MHz, Chloroform-d ): 5 7.29 - 7.26 (m, 2H), 4.74 (d, J= 5.4 Hz, 2H), 1.92 (t, J= 5.4 Hz, 1H) ppm.

[0415] Step 2. Synthesis of l-bromo-4-(chloromethyl)-2,5-difluorobenzene. To a stirred solution of (4-bromo-2,5-difluorophenyl)methanol (812 mg, 3.6 mmol) in dry DCM (5 mL) and DMF (1 drop) was added SOCL (0.4 mL, 5.5 mmol) dropwise at 0 °C. After the addition was completed, the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the crude product (870 mg, 100% yield), which was used in the next step without further purification.

[0416] Step 3. Synthesis of l-(4-bromo-2,5-difluorobenzyl)-4,4-dimethylpiperidine. To a solution of l-bromo-4-(chloromethyl)-2,5-difluorobenzene (870 mg, 3.6 mmol) in dry DMF (6 mL) was added 4,4-dimethylpiperidine hydrochloride (545 mg, 3.6 mmol) and solid K2CO3 (1.0 g, 7.3 mmol). The resulting mixture was stirred at 50 °C for 12 hours and cooled down to room temperature. Thereaction mixture was partitioned between water (60 mL) and EtOAc (60 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (EtOAc in hexane 0-25%) to give the desired product (1.0 g, 88% yield over two steps) as a clear oil. 1H-NMR (600 MHz, Chloroform-d): δ 7.25 - 7.21 (m, 2H), 3.49 (d, J= 1.5 Hz, 2H), 2.41 (t, J = 5.6 Hz, 4H), 1.40 (t, 7= 5.6 Hz, 4H), 0.91 (s, 6H) ppm. ESI- MS m / z [M+H]+: calculated, 318.1; found, 318.1.

[0417] Intermediate C

[0418] Step 1. Synthesis of tert-butyl 4-(4-((4,4-dimethylpiperidin-l-yl)methyl)-2,5- difluorophenyl)-2-oxo-l,4,9-triazaspiro[5.5]undecane-9-carboxylate. To a suspension of tert-butyl 2-oxo-l,4,9-triazaspiro[5.5]undecane-9-carboxylate (Intermediate A, 270 mg, 1.0 mmol) and l-(4- bromo-2,5-difluorobenzyl)-4,4-dimethylpiperidine (318 mg, 1.0 mmol) in dry 1,4-dioxane (2 mL) was added RuPhos-Pd-G4 (85 mg, 0.1 mmol), RuPhos (47 mg, 0.1 mmol) and CS2CO3 (390 mg, 1.2 mmol). The resulting mixture was stirred at 115 °C for 24 hours under an atmosphere of nitrogen. The reaction mixture was cooled down to room temperature, filtered through a pad of Celite, and the inorganic cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by flash column chromatography (MeOH in DCM 0-8%) to give the desired product (348 mg, 69% yield) as an off-white solid. 1H-NMR (600 MHz, Chloroform--d ): δ 7.15 (br s, 1H), 6.61 - 6.58 (m, 1H), 6.46 (s, 1H), 3.74 (s, 2H), 3.59 - 3.45 (m, 6H), 3.26 (br s, 2H), 2.44 (br s, 4H), 1.93 - 1.87 (m, 2H), 1.78 - 1.72 (m, 2H), 1.49 (s, 9H), 1.42 (br s, 4H), 0.93 (s, 6H) ppm. ESI-MS m / z [M+H]+: calculated, 507.3; found, 507.4.

[0419] Step 2. Synthesis of 4-(4-((4,4-dimethylpiperidin-l-yl)methyl)-2,5-difluorophenyl )- 1,4,9- triazaspiro[5.5]undecan- 2-one hydrochloride. To a solution of tert-butyl 4-(4-((4,4- dimethylpiperidin-l-yl)methyl)-2,5-difluorophenyl)-2-oxo-l,4,9-triazaspiro[5.5]undecane-9- carboxylate (348 mg, 0.7 mmol) in MeOH (4 mL) was added concentrated aqueous HCI solution (37%, 1.2 mL, 14 mmol) dropwise at 0 °C. After the addition was completed, the resulting slurry was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed withcold MeOH (1 mL), and dried under vacuum to give the desired product (240 mg, 66% yield) as an off-white solid. ESI-MS m / z [M+H]+: calculated, 406.3; found, 406.3.

[0420] Step 3. Synthesis of 4-(4-((4,4-dimethylpiperidin-l-yl)methyl)-2,5-difluorophenyl)-9-(6- fluoropyrimidin-4-yl)-l,4,9-triazaspiro[5.5Jundecan-2-one (Intermediate C). To a microwave reaction tube containing a suspension of 4-(4-((4,4-dimethylpiperidin-l-yl)methyl)-2,5- difluorophenyl)-l,4,9-triazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 0.2 mmol) and 4,6- difluoropyrimidine (92 mg, 0.8 mmol) in IPA (1 mL) was added DIPEA (260 mg, 2.0 mmol). The resulting mixture was purged with nitrogen and stirred at 80 °C under microwave irradiation for 3 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and saturated aqueous NH4CI solution. The organic layer was washed with water and brine, dried over anhydrousNa2SO4. filtered, and concentrated. The residue was purified by flash column chromatography (MeOH in DCM 0-8%) to give the desired product (98 mg, 100% yield) as an off- white solid. 1H-NMR (600 MHz, Chloroform-d ): δ 8.33 (d, J = 2.7 Hz, 1H), 7.75 (s, 1H), 7.13 (dd, J = 12.8, 6.5 Hz, 1H), 6.57 (dd, 7 = 10.8, 7.1 Hz, 1H), 6.03 (s, 1H), 3.87 - 3.79 (m, 2H), 3.78 - 3.72 (m, 2H), 3.71 (s, 2H), 3.50 (s, 2H), 3.27 (s, 2H), 2.42 (s, 4H), 2.00 - 1.92 (m, 2H), 1.92 - 1.85 (m, 2H), 1.40 (t, J = 5.6 Hz, 4H), 0.90 (s, 6H) ppm. ESI-MS m / z [M+H]+: calculated, 503.3; found, 503.2.

[0421] Intermediates D1-D10

[0422] General procedure. To a microwave tube containing a suspension of 4-(4-((4,4- dimethylpiperidin-l-yl)methyl)-2,5-difluorophenyl)-9-(6-fluoropyriinidin-4-yl)-l,4,9- triazaspiro[5.5]undecan-2-one (Intermediate C, 20 mg, 0.04 mmol) in IPA (0.2 mL) was added co- aminocarboxylic acid (0.4 mmol, 10 eq.), DIPEA (52 mg, 0.4 mmol) and water (0.2 mL). The resulting mixture was stirred at 120 °C under microwave irradiation for 2.5 hours. The reaction mixture was diluted with MeOH (1 mL) and filtered through a short pad of anhydrous Na2SO4- The filtrate was concentrated, the residue was triturated with MeOH (2 mL), and the solid was filtered off. The filtrate with concentrated, the residue was triturated with DCM / MeOH (10 / 1, 2 mL), and the solid was filtered off. The filtrate was concentrated to give the desired product (quantitative yield) as a pale-yellow foam, which was used in the next step without further purification.Table 2. Intermediates of the present disclosure.

[0423] Intermediate E

[0424] Synthesis of 4-(4-((4,4-dimethylpiperidin-l-yl)methyl)-2,5-difluorophenyl)-9-(6-(prop-2- yn-l-ylamino)pyrimidin-4-yl)-l,4,9-triazaspiro[5.5Jundecan-2-one (Intermediate E). A suspension of 4-(4-((4,4-dimethylpiperidin- 1 -yl)methyl)-2,5-difluorophenyl)-9-(6-fluoropyrimidin-4- yl)-l,4,9-triazaspiro[5.5]undecan-2-one (Intermediate C, 100 mg, 0.2 mmol) in propargylamine (0.5 mL) was stirred at 130 °C under microwave irradiation and nitrogen atmosphere for 1 hour. The reaction was cooled down to room temperature and sonicated for 2 minutes. The precipitated solid was collected by filtration, washed with acetone (1 mL) and dried under vacuum to give the desiredproduct (80 mg, 75% yield) as an off-white powder. 1H-NMR (600 MHz, CDCh) δ 8.22 (d, J = 0.9 Hz, 1H), 7.12 (dd, J= 12.5, 6.3 Hz, 1H), 6.59 (dd, J= 10.8, 7.1 Hz, 1H), 6.26 (s, 1H), 5.57 (d, J= 1.1 Hz, 1H), 4.84 (t, 7= 5.8 Hz, 1H), 4.09 (dd, J= 5.8, 2.5 Hz, 2H), 3.77 - 3.69 (m, 4H), 3.66 - 3.59 (m, 2H), 3.48 (s, 2H), 3.29 (s, 2H), 2.41 (s, 4H), 2.26 (t, 7= 2.5 Hz, 1H), 2.02 - 1.95 (m, 2H), 1.86 - 1.78 (m, 2H), 1.39 (t, 7 = 5.7 Hz, 4H), 0.91 (s, 6H) ppm. ESI-MS m / z [M+H]+: calculated, 538.3; found, 538.3.

[0425] Intermediate F

[0426] Step 1. Synthesis of ethyl 4-methylpiperidine-4-carboxylate hydrochloride. To a flask containing ethyl A-Boc-4-methylpiperidine-4-carboxylate (2.0 g, 7.5 mmol) was added HC1 solution in dioxane (4 M, 9.4 mL, 37.5 mmol). The resulting solution was stirred at room temperature overnight and concentrated to dryness. The residue was triturated with tert-butyl methyl ether, and the solid was collected by filtration to give the desired product (1.5 g, 94.5% yield) as a white solid.1H- NMR (600 MHz, DMSO-d6-d ): 9.01 (s, 1H), 4.14 (q, 7= 7.1 Hz, 2H), 3.16 (dt, 7 = 12.5, 4.0 Hz, 2H), 2.82 (t, 7= 10.9 Hz, 2H), 2.08 (dt, 7 = 14.4, 3.5 Hz, 2H), 1.65 (ddd, 7 = 14.5, 10.7, 3.9 Hz, 2H), 1.21 (t, 7= 7.1 Hz, 3H), 1.19 (s, 3H) ppm. ESI-MS m / z [M+H]+: calculated, 172.1; found, 172.1.

[0427] Step 2. Synthesis of ethyl l-(4-bromo-2,5-difluorobenzyl)-4-methylpiperidine-4- carboxylate. To a solution of l-bromo-4-(chloromethyl)-2,5-difluorobenzene (Intermediate B, 1.9 g, 8.9 mmol) in dry DMF (25 mL) was added ethyl 4-methylpiperidine-4-carboxylate hydrochloride (2.2 g, 8.9 mmol) and K2CO3 (3.7 g, 26.8 mmol). The resulting mixture was at 50 °C for 18 hours, then cooled to room temperature. The reaction mixture was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc three times. The combined EtOAc phases were washed with water and brine, dried over anhydrous Na^SO-i. filtered, and concentrated. The residue was purified by flash column chromatography (EtOAc in hexane 0-20%) to give the desired product (1.8 g, 81% yield) as a clear oil. 1H-NMR (600 MHz, Chloroform-d7): δ 7.23 (dd, 7= 8.6, 6.0 Hz, 2H), 4.16 (q, 7 = 7.1 Hz, 2H), 3.46 (s, 2H), 2.69 - 2.59 (m, 2H), 2.19 (t, 7= 10.9 Hz, 2H), 2.16 - 2.10 (m, 2H), 1.50(ddd, J= 13.8, 10.6, 3.6 Hz, 2H), 1.26 (t, J= 7.1 Hz, 3H), 1.19 (s, 3H) ppm. ESI-MS m / z [M+H]+: calculated, 376.1; found, 375.9.

[0428] Step 3. Synthesis of tert-butyl 4-(4-((4-ethoxycarbonyl)-4-methylpiperidin-l-yl)methyl)- 2,5-difluorophenyl)-2-oxo- l,4,9-triazaspiro[5.5Jundecane-9-carboxylate. To a suspension of tert- butyl 2-oxo-l,4,9-triazaspiro[5.5]undecane-9-carboxylate (Intermediate A, 270 mg, 1.0 mmol) and ethyl l-(4-bromo-2,5-difluorobenzyl)-4-methylpiperidine-4-carboxylate (377 mg, 1.0 mmol) in dry 1,4-dioxane (2 mL) was added RuPhos-Pd-G4 (85 mg, 0.1 mmol), RuPhos (47 mg, 0.1 mmol) and CS2CO3 (390 mg, 1.2 mmol). The resulting mixture was stirred at 115 °C for 24 hours under an atmosphere of nitrogen. The reaction mixture was cooled down to room temperature, filtered through a pad of Celite, and the inorganic cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by flash column chromatography (MeOH in DCM 0-8%) to give the desired product (396 mg, 70% yield) as an off-white solid. 1H-NMR (599 MHz, Chloroform-d): δ 7.12 (s, 1H), 7.09 (dd, J = 12.9, 6.6 Hz, 1H), 6.58 (dd, J= 10.8, 7.2 Hz, 1H), 4.15 (q, J= 7.1 Hz, 2H), 3.71 (s, 2H), 3.61 - 3.55 (m, 2H), 3.49 - 3.45 (m, 2H), 3.44 (s, 2H), 3.24 (s, 2H), 2.66 - 2.60 (m, 2H), 2.17 - 2.09 (m, 4H), 1.87 (ddd, 7 = 11.5, 7.3, 3.9 Hz, 2H), 1.76 (ddd, 7 = 12.9, 7.8, 4.0 Hz, 2H), 1.52 - 1.48 (m, 2H), 1.48 (s, 9H), 1.25 (t, 7= 7.1 Hz, 3H), 1.18 (s, 3H). ESI-MS m / z [M+H]+: calculated, 565.3; found, 565.2.

[0429] Step 4. Synthesis of ethyl l-(2,5-difluoro-4-(2-oxo-l,4,9-triazaspiro[5.5]undecane-4- yl)benzyl)-4-methylpiperidine-4-carboxylate hydrochloride. To a solution of tert-butyl 4-(4-((4- ethoxycarbonyl)-4-methylpiperidin- 1 -yl)methyl)-2,5-difluorophenyl)-2-oxo- 1 ,4,9- triazaspiro[5.5]undecane-9-carboxylate (572 mg, 1 mmol) in MeOH (4 mL) was added concentrated aqueous HC1 (0.4 mL, 5 mmol) dropwise at 0 °C. After the addition was completed, the resulting slurry was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with cold MeOH (1 mL), and dried under vacuum to give the desired product (500 mg, quantitative yield) as an off-white solid. ESI-MS m / z [M+H]+: calculated, 465.3; found, 465.3.

[0430] Step 5. Synthesis of ethyl l-(2,5-difhioro-4-(9-(6-fhioropyrimidin-4-yl)-2-oxo-l,4>9- triazaspiro[5.5]undecane-4-yl)benzyl)-4-methylpiperidine-4-carboxylate. To a 5 mL microwave reaction tube containing ethyl l-(2,5-difluoro-4-(2-oxo-l,4,9-triazaspiro[5.5]undecane-4-yl)benzyl)-4- methylpiperidine-4-carboxylate hydrochloride (0.7 g, 1.4 mmol) was added DIPEA (1.20 mL, 6.9 mmol), 4,6-difluoropyrimidine (0.24 mL, 2.8 mmol) and isopropanol (3 mL). The resulting mixture was stirred at 80 °C under microwave irradiation and nitrogen atmosphere for 3 hours and cooled down to room temperature. The reaction mixture was concentrated to dryness and the residue was purified flash column chromatography (MeOH in DCM 0-10%) to give the desired product (0.36 g, 46% yield) as a yellow solid. 1H-NMR (600 MHz, Chloroform-d ): δ 8.38 (d, 7= 2.4 Hz, 1H), 7.13 (dd, 7= 12.9, 6.6 Hz, 1H), 6.61 (dd, 7= 10.7, 7.2 Hz, 1H), 6.27 (s, 1H), 6.08 (s, 1H), 4.17 (q, 7= 7.1 Hz, 2H), 3.89 - 3.80 (m, 2H), 3.76 (s, 2H), 3.75 - 3.69 (m, 2H), 3.46 (s, 2H), 3.33 (s, 2H), 2.67 - 2.61 (m, 2H), 2.25 - 2.11 (m, 4H), 2.05 (ddd, 7= 11.4, 7.1, 3.8 Hz, 2H), 1.87 (ddd, 7 = 12.9, 8.0, 3.9 Hz,2H), 1.50 (ddd, J = 13.8, 10.5, 3.7 Hz, 2H), 1.27 (t, 7= 7.1 Hz, 3H), 1.20 (s, 3H) ppm. ESI-MS m / z [M+H]+: calculated, 561.3; found, 561.2.

[0431] Step 6. Synthesis of ethyl l-(2,5-difluoro-4-(9-(6-(methylamino)pyrimidin-4-yl)-2-oxo- l,4,9-triazaspiro[5.5]undecan-4-yl)benzyl)-4-methylpiperidine-4-carboxylate. To 10 mL microwave reaction tube containing ethyl l-(2,5-difhroro-4-(9-(6-fluoropyrimidin-4-yl)-2-oxo-l,4,9- triazaspiro[5.5]undecane-4-yl)benzyl)-4-methylpiperidine-4-carboxylate (0.29 g, 0.5 mmol) was added methylamine solution (2.0 M in methanol, 5 mL, 10 mmol). The resulting mixture was stirred at 130 °C under microwave irradiation for 1 hour and cooled down to room temperature. The reaction mixture was concentrated and the residue was purified by flash column chromatography (MeOH in DCM 0-10%) to give the desired product (0.22 g, 76% yield) as a light-yellow solid. 1H-NMR (600 MHz, Chloroform-d ): δ 8.14 (s, 1H), 7.09 (dd, J = 12.8, 6.6 Hz, 1H), 6.83 (s, 1H), 6.58 (dd, J = 10.8, 7.2 Hz, 1H), 5.43 (s, 1H), 4.91 (d, J = 4.4 Hz, 1H), 4.14 (q, J= 7.1 Hz, 2H), 3.78 - 3.72 (m, 2H), 3.72 (s, 2H), 3.67 - 3.58 (m, 2H), 3.43 (s, 2H), 3.28 (s, 2H), 2.88 (d, J = 5.2 Hz, 3H), 2.75 - 2.57 (m, 2H), 2.17 (t, J= 11.1 Hz, 2H), 2.13 - 2.08 (m, 2H), 1.97 (ddd, 7= 11.7, 7.5, 3.8 Hz, 2H), 1.83 (ddd, 7 = 12.9, 7.9, 4.0 Hz, 2H), 1.48 (ddd, 7= 13.6, 10.7, 3.5 Hz, 2H), 1.24 (t, 7= 7.1 Hz, 3H), 1.17 (s, 3H) ppm. ESI-MS m / z [M+H]+: calculated, 572.3; found, 572.2.

[0432] Step 7. Synthesis of l-(2,5-difluoro-4-(9-(6-(methylamino)pyrimidin-4-yl)-2-oxo-l,4,9- triazaspiro[5.5]undecane-4-yl)benzyl)-4-methylpiperidine-4-carboxylic acid (Intermediate F). To a solution of ethyl l-(2,5-difluoro-4-(9-(6-(methylamino)pyrimidin-4-yl)-2-oxo-l,4,9- triazaspiro[5.5]undecan-4-yl)benzyl)-4-methylpiperidine-4-carboxylate (109 mg, 0.19 mmol) in THF / MeOH (1:1, 0.5 mL of each solvent) was added aqueous NaOH solution (2.0 M, 1 mL, 2 mmol). The resulting mixture was stirred at 70 °C overnight an...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :Z - L1- Y (I), or a pharmaceutically acceptable salt thereof, wherein:each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl; each instance of R2and R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3;R4is optionally substituted aryl or optionally substituted heteroaryl;L1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is optionally substituted arylene or optionally substituted heteroarylene;L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionallysubstituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene; each of ml, nl, m2, and n2 is independently 1, 2, or 3; each of pl and p2 is independently 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl; andY is a moiety capable of binding to an E3 ubiquitin ligase.

2. A compound of Formula (VI):Z - L1- Y (VI), or a pharmaceutically acceptable salt thereof, wherein:each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl; each instance of R2and R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3;R4is optionally substituted aryl or optionally substituted heteroaryl;L1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-,optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is optionally substituted arylene or optionally substituted heteroarylene;L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene; each of ml, nl, m2, and n2 is independently 1, 2, or 3; each of pl and p2 is independently 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl; andY is of Formulae (IV-a), (IV-b), or (IV-c):wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl; and R10is optionally substituted alkyl or optionally substituted cycloalkyl.

3. A compound of Formula (VII) :or a pharmaceutically acceptable salt thereof, wherein:each of Rlaand Rlbis independently hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl; each instance of R2and R3is independently -F, -Cl, -CHF2, -CH2F, or -CF3;R4is optionally substituted aryl or optionally substituted heteroaryl;L1is optionally substituted C1-20 alkylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with - O-, -NR5-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L2is bond, optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L3is optionally substituted arylene or optionally substituted heteroarylene;L4is optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene; each of ml, nl, m2, and n2 is independently 1, 2, or 3;each of pl and p2 is independently 0, 1, 2, 3, or 4; each instance of R5is independently hydrogen or optionally substituted alkyl;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; andL6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof.

4. The compound of any one of claims 1-3, wherein the compound is of Formula (II)or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4, wherein each of Rlaand Rlbis independently hydrogen or optionally substituted alkyl, or Rlaand Rlbare taken together to form optionally substituted heterocyclyl.

6. The compound of any one of claims 1-5, wherein at least one of Rlaand Rlbis optionally substituted C1-6 alkyl.

7. The compound of any one of claims 1-6, wherein at least one of Rlaand Rlbis unsubstituted C1-6 alkyl.

8. The compound of any one of claims 1-7, wherein at least one of Rlaand Rlbis C1-6 alkyl substituted with halogen and / or optionally substituted carbocyclyl.

9. The compound of any one of claims 1-8, wherein at least one of Rlaand Rlbis C1-6 alkyl substituted with -F and / or optionally substituted C3-6 carbocyclyl.

10. The compound of any one of claims 1-5, wherein Rlaand Rlbare taken together to form optionally substituted heterocyclyl.

11. The compound of any one of claims 1-5 or 10, wherein Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl optionally substituted with halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -OH, and / or - □(optionally substituted alkyl).

12. The compound of any one of claims 1-5, 10, or 11, wherein Rlaand Rlbare taken together to form 3-6 membered monocyclic heterocyclyl optionally substituted with -F, optionally substituted Ci- 3 alkyl, and / or -OH.

13. The compound of any one of claims 1-5 or 10, wherein Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl optionally substituted with halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, -OH, and / or -©(optionally substituted alkyl).

14. The compound of any one of claims 1-5, 10, or 13, wherein Rlaand Rlbare taken together to form 6-10 membered bicyclic heterocyclyl optionally substituted with optionally substituted Cm alkyl and / or optionally substituted C3-6 carbocyclyl.

16. The compound of any one of claims 1-15, wherein pl is 0, 1, or 2.

17. The compound of any one of claims 1-16, wherein pl is 2.

18. The compound of any one of claims 1-17, wherein at least one instance of R2is -F.

19. The compound of any one of claims 1-18, wherein20. The compound of any one of claims 1-19, wherein ml and nl are each 2.

21. The compound of any one of claims 1-20, wherein the compound is of Formula (Il-a)or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1-21, wherein L3is optionally substituted phenylene.

23. The compound of any one of claims 1-21, wherein L3is optionally substituted heteroarylene.

24. The compound of any one of claims 1-21 or 23, wherein L3is optionally substituted monocyclic heteroarylene containing 1, 2, or 3 ring N atoms.

25. The compound of any one of claims 1-21, 23, or 24, wherein L3is,26. The compound of any one of claims 1-21 or 23-25, wherein L3is27. The compound of any one of claims 1-5, 11, 12, 15-21, or 23-26, wherein the compound is of Formula (Il-e)or a pharmaceutically acceptable salt thereof.

28. The compound of any one of claims 1-27, wherein L2is bond, optionally substituted Ci-io alkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

29. The compound of any one of claims 1-28, wherein L2is bond.

30. The compound of any one of claims 1-28, wherein L2comprises optionally substituted Ci-io alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Ci-ioalkylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

31. The compound of any one of claims 1-28 or 30, wherein L2comprises optionally substituted Ci-3 alkylene, wherein one backbone carbon atom in the optionally substituted Cm alkylene is replaced with -O- or -NR5-.

32. The compound of any one of claims 1-28, 30, or 31, wherein L2comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

33. The compound of any one of claims 1-28 or 30-32, wherein L2comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms.

34. The compound of any one of claims 1-28 or 30-33, wherein L2comprises optionally substituted arylene, optionally wherein one or more backbone carbon atoms in the optionally substituted arylene are independently replaced with -O- or -NR5-.

35. The compound of any one of claims 1-28 or 30-34, wherein L2comprises optionally substituted phenylene.

36. The compound of any one of claims 1-28 or 30-35, wherein L2comprises optionally substituted heteroarylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heteroarylene are independently replaced with -O- or -NR5-.

37. The compound of any one of claims 1-28 or 30-36, wherein L2comprises optionally substituted heteroarylene containing 1, 2, or 3 ring N atoms.

38. The compound of any one of claims 1-28 or 30-37, wherein L2is of formula: -NR5-, -O-, -wherein: each instance of X is independently CH or N; and each of m3 and n3 is independently 1, 2, or 3.

39. The compound of any one of claims 1-28 or 30-38, wherein L2is -NH-, -O-, -CH2-,40. The compound of any one of claims 1-3, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 1-3 or 40, wherein p2 is 0, 1, or 2.

42. The compound of any one of claims 1-3, 40, or 41, wherein at least one instance of R3is -F.The compound of any one of claims 1-3 or 40-42, wherein44. The compound of any one of claims 1-3 or 40-43, wherein ml and nl are each 2.

45. The compound of any one of claims 1-3 or 40-44, wherein the compound is of Formula (III-or a pharmaceutically acceptable salt thereof.

46. The compound of any one of claims 1-3 or 40-45, wherein R4is optionally substituted heteroaryl.

47. The compound of any one of claims 1-3 or 40-46, wherein R4is optionally substituted monocyclic heteroaryl containing 1, 2, or 3 ring N atoms.

48. The compound of any one of claims 1-3 or 40-47, wherein49. The compound of any one of claims 1-3 or 40-48, wherein the compound is of Formula (HI- c):or a pharmaceutically acceptable salt thereof.

50. The compound of any one of claims 1-3 or 40-49, wherein L4comprises optionally substituted C1-10 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

51. The compound of any one of claims 1-3 or 40-50, wherein L4comprises optionally substituted C1-6 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

52. The compound of any one of claims 1-3 or 40-51, wherein L4comprises optionally substituted C1-6 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-6 alkylene are independently replaced with -O-, -NR5-, or -C(=O)-.

53. The compound of any one of claims 1-3 or 40-52, wherein L4comprises optionally substituted carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionallysubstituted carbocyclylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

54. The compound of any one of claims 1-3 or 40-53, wherein L4comprises optionally substituted C4-6 carbocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C4-6 carbocyclylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

55. The compound of any one of claims 1-3 or 40-54, wherein L4comprises optionally substituted C4-6 carbocyclylene.

56. The compound of any one of claims 1-3 or 40-55, wherein L4comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

57. The compound of any one of claims 1-3 or 40-56, wherein L4comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR5-, -C(=O)-, optionally substituted carbocyclylene, or optionally substituted heterocyclylene.

58. The compound of any one of claims 1-3 or 40-57, wherein L4comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms.

59. The compound of any one of claims 1-3 or 40-58, wherein L4is of formula:wherein:each instance of X is independently CH or N; each of m3 and n3 is independently 1, 2, or 3; and each R6is hydrogen, optionally substituted alkyl, or halogen.

60. The compound of any one of claims 1-3 or 40-59, wherein L4is of formula:

61. The compound of any one of claims 1-3 or 40-60, wherein L4is of formula:

62. The compound of any one of claims 1-3 or 40-61, wherein the compound is of Formula (Ill- e):or a pharmaceutically acceptable salt thereof.

63. The compound of any one of claims 1-3 or 40-62, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with - O-, -NR5-, — S— , -S(=O)-, -S(=O)2-, — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

64. The compound of any one of claims 1-3 or 40-63, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted Cm alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted Cm alkylene are independently replaced with - O- , -NR5-, — C(— O)— , or optionally substituted heterocyclylene.

65. The compound of any one of claims 1-3 or 40-64, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR5-, -S-, -S(=O)-, - S(=O)2- — C(=O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

66. The compound of any one of claims 1-3 or 40-65, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR5-, -C(=O)-, or optionally substituted heterocyclylene.

67. The compound of any one of claims 1-3 or 40-66, or a pharmaceutically acceptable salt4X0' 2V / 'otyN \ 4 / -N Hy thereof, wherein L1is of formula:wherein: each instance of X is independently CH or N; each q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each r is independently 1, 2, 3, 4, or 5;68. The compound of any one of claims 1-3 or 40-67, or a pharmaceutically acceptable salt69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, wherein Y is of Formulae (IV-a), (IV-b), or (IV-c):wherein:R8is hydrogen or optionally substituted alkyl;R9is optionally substituted alkyl or optionally substituted cycloalkyl; and R10is optionally substituted alkyl or optionally substituted cycloalkyl.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt thereof,71. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, wherein Y is of Formula (V):wherein:X is CH or N;L5is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;L6is a bond, -C(R5)2-, -NR5-, -C(=O)-, or a combination thereof; and each instance of R5is independently hydrogen or optionally substituted alkyl.

72. The compound of any one of claims 1-68 or 71, or a pharmaceutically acceptable salt thereof,73. The compound of any one of claims 1-72, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

74. A pharmaceutical composition comprising the compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

75. The pharmaceutical composition of claim 74 further comprising an additional pharmaceutical agent.

76. The pharmaceutical composition of claim 75, wherein the additional pharmaceutical agent is an anti-cancer agent.

77. The pharmaceutical composition of claim 76, wherein the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof.

78. A method of degrading a methyltransferase-like (METTL) protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of the compound of any one of claims 1-73, or apharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 74- 77.

79. The method of claim 78, wherein the METTL protein is METTL3 and / or METTL14.

80. The method of any one of claims 78 or 79, wherein the cell, tissue, or biological sample is in vitro.

81. The method of any one of claims 78 or 79, wherein the cell, tissue, or biological sample is in vivo.

82. The method of any one of claims 78-81, wherein the cell is a cancer cell.

83. A method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 74-77.

84. The method of claim 83, wherein the disease is a cancer.

85. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-73, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 74-77.

86. The method of any one of claims 84 or 85, wherein the cancer is associated with a methyltransferase-like (METTL) protein.

87. The method of any one of claims 84-86, wherein the cancer is associated with METTL3 and / or METTL14.

88. The method of any one of claims 84-87, wherein the cancer is glioblastoma, liver cancer, ovarian cancer, hematopoietic cancer (e.g., acute myeloid leukemia), breast cancer, bladder cancer, gastric cancer, prostate cancer, colorectal cancer, or lung cancer.

89. The method of any one of claims 78-88, wherein the subject is a mammal.

90. The method of any one of claims 78-89, wherein the subject is a human.