Biodegradable lipids and formulations for delivery of mRNA

Abstract

Provided herein are compounds, such as compounds of Formulae (I), (I'), (XI), (XII), and (XIII), and pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, and isotopically labeled derivatives thereof, and compositions, methods, uses, and kits thereof. The compounds provided herein are lipids useful for delivery of agents, including polynucleotides such as mRNA, for the treatment and / or prevention of various diseases and conditions (e.g., genetic diseases, proliferative diseases, hematological diseases, neurological diseases, liver diseases, spleen diseases, lung diseases, painful conditions, psychiatric disorders, musculoskeletal diseases, metabolic disorders, inflammatory diseases, and autoimmune diseases). Also provided herein are methods of synthesis of compounds of Formulae (I'), (XI), (XII), (XIII), and (VIII).

Description

BIODEGRADABLE LIPIDS AND FORMULATIONS FOR DELIVERY OF MRNACROSS-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, U.S.S.N. 63 / 614,873, filed December 26, 2023, titled “Biodegradable Lipids and Formulations for Delivery of mRNA,” which is incorporated herein by reference.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (M123770152WO00-SEQ-CLL.xml; Size: 6,276 bytes; and Date of Creation: December 23, 2024) are herein incorporated by reference in their entirety.BACKGROUND

[0003] mRNA therapeutics have significant potential to treat various diseases through protein replacement, immunomodulation, and gene editing. Non- viral nanoparticles are promising mRNA delivery vehicles to target cells in vivo. For example, mRNA-based vaccines against SARS-CoV-2 has highlighted the utility of lipid nanoparticle formulations for the effective delivery of mRNA. New compounds capable of forming delivery vehicles may be useful for mRNA-based vaccines and chimeric antigen receptor T (CAR-T) cell therapy.

[0004] Provided herein are ionizable lipids and their formulations that are highly efficient for intramuscular (IM) and intravenous (IV) administration of mRNA.SUMMARY OF THE INVENTION

[0005] Provided herein are biodegradable ionizable lipids that, when incorporated in formulations containing mRNA, demonstrate efficient in vivo transfection, for example, via either intramuscular (IM) or intravenous (IV) administration. The lipids provided herein are also suitable for in vitro and ex vivo transfection of mRNA to hard-to-transfect cells.

[0006] In one aspect, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein n, A, B, and R are as defined herein.

[0007] In another aspect, provided herein is a compound of Formula (XI):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R is as defined herein.

[0008] In another aspect, provided herein is a compound of Formula (XII):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R is as defined herein.

[0009] In another aspect, provided herein is a compound of Formula (XIII):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1and R are as defined herein.

[0010] In another aspect, provided herein is a composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and an agent.

[0011] In another aspect, provided herein is a composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, or a composition provided herein, and a pharmaceutically acceptable excipient. In some embodiments, the composition is a pharmaceutical composition.

[0012] In another aspect, provided herein is a method of delivering an agent to a subject, tissue, or a cell, comprising administering to the subject or contacting the tissue or the cell with a composition comprising an agent and a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, provided herein is a method of treating and / or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a composition comprising an agent and a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, provided herein is a method of preparing a compound of Formula (I'):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (VII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein n, A, B, R, R5, and x are as defined herein.

[0015] In another aspect, provided herein is a method of preparing a compound of Formula(XI'):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (XI"):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R, R5, and x are as defined herein.

[0016] In another aspect, provided herein is a method of preparing a compound of Formula (XII'):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (XII''):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R, R5, and x are as defined herein.

[0017] In another aspect, provided herein is a method of preparing a compound of Formula(XIII'):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (XIII''):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R1, R, R5, and x are as defined herein.

[0018] In another aspect, provided herein is a method of preparing a compound of Formula(VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (IX):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a carbodiimide coupling agent, or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and a compound of Formula (X):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein x and R5are as defined herein.

[0019] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. It should be understood that the aspects described herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, provide non-limiting examples of the invention.

[0021] FIGs. 1A-1D show structures of head groups used for the library of ionizable lipids (FIG. 1A), structures of tails from an alkene walking strategy (FIG. IB), the structure of AMG1041 (FIG. 1C), and the structure of AMG1541 (FIG. ID).

[0022] FIGs. 2A-2B show a comparison between in vitro performance of the ionizable lipids screened in HeLa cells (FIG. 2A) and DC2.4 cells (FIG. 2B).

[0023] FIG. 3 shows the Flue expression profile for AMG1041, AMG1241, AMG1541, and AMG1641.

[0024] FIG. 4 shows endpoint titers at day 35 after prime (day 0) and boost (day 21) doses.

[0025] FIG. 5 shows pseudovirus neutralization IC50 values.

[0026] FIGs. 6A-6B show in vitro (FIG. 4A) and in vivo (FIG. 4B) protein expression via intramuscular administration for LNPs made with compounds of the present disclosure.

[0027] FIG. 7 shows total bioluminescent flux in liver.

[0028] FIGs. 8A-8D show evaluation of AMG1541 for intravenous hEPO protein production.

[0029] FIGs. 9A-9D show Cas9 mediated gene editing efficiency using AMG1541 LNPs.

[0030] FIGs. 10A and 10B show structures of additional tails.

[0031] FIGs. 11A-11F show a combinatorial lipid library. FIG. 11A shows a schematic illustrating synthetic scheme for combinatorial lipid library that was screened using batch- based analysis to identify potent ionizable lipids for mRNA delivery. Subsequent, iterative development of hit lipids through medicinal chemistry, computational chemistry, and in vivo screening yielded potent vaccine delivery systems inducing stronger immune response. FIG. 11B shows structures of amine headgroups (Am). FIG. 11C shows structures of ester tails (G) used to synthesize AMG ionizable lipids. FIG. 11D shows results of batch-based analysis where the screen 1 identified potent tail groups (15 μg. n=3). FIG. 11E shows results of batch-based analysis using identified potent smaller batches of headgroups from the tails groups down-selected from the screen 1 (5 μg, n=3). FIG. 11F shows individually tested top lipids (1 μg, n=3) identified from screen 2. All the mice were imaged 24 hours post injection. Statistical significance was analyzed using a two-way analysis of variance with Sidak’s multiple comparisons test with a single pooled variance.

[0032] FIGs. 12A-12F show evaluation of a lipids comprising cyclic head groups. FIG. 12A shows structures of different tails and quantification of Flue protein expression upon intramuscular injection in mice for tail derivatives (5 μg, 24 hours). FIG. 12B shows structures of different headgroups and quantification of Flue protein expression upon intramuscular injection in mice for head group analogues (1 μg, 6 hours). FIG. 12C shows representative images and graph comparing intramuscular Flue protein expression upon intramuscular injection (1 μg, 6 hours) of AMG lipids and to lipid controls (SM-102 and ckk- el2). FIG. 12D shows the structure of AMG1541 ionizable lipid. FIG. 12E shows AMG lipid concentration (nanograms per gram) after IM administration of modified mRNA encoding luciferase in muscles. FIG. 12F shows Flue expression in liver and spleen at 6 hours post-injection (n = 3 per group per time point), showing rapid degradation of AMG1541 with minimal accumulation in liver and spleen. Statistical significance was analyzed using a two- way analysis of variance with Sidak’s multiple comparisons test with a single pooled variance.

[0033] FIGs. 13A-13H show AMG1541 LNPs induce strong humoral and cellular vaccine responses. FIG. 13A shows the vaccination protocol used for all vaccine experiments. The same indicated mRNA dose was used for both vaccine doses. FIG. 13B shows a correlation of firefly luciferase luminescent flux (dose = 1 μg, n = 3) with day 35 binding antibody titers following vaccination with spike mRNA (dose = 1 μg, n = 5). Data are presented as mean ±s.d. A linear best fit line and 95% confidence interval is shown. FIG. 13C shows day 35 binding antibody titers following vaccination with HA mRNA (dose = 1 μg, n = 5). FIG. 13D shows fold-change cytokine levels in the cell culture supernatant of peptide-stimulated splenocytes following vaccination with HA mRNA (dose = 1 μg, n = 5). FIG. 13E BALB / cJ serum cytokines (pg / mL) 6 hrs. after boost with HA mRNA (dose = 1 μg). FIG. 13F shows day 35 female C57B1 / 6J serum binding antibody titers after vaccination with HA mRNA (dose = 1 μg, n = 5). FIG. 13G shows day 35 peptide pool- stimulated splenocyte IFN-γ ELISpot SFU (top) and representative images (bottom) from female C57B1 / 6J mice vaccinated with HA mRNA (dose = 1 μg). FIG. 13H shows day 35 serum neutralizing antibody titers from female BALB / cJ mice vaccinated with HA mRNA (n = 5). Statistical significance was analyzed using a two-way analysis of variance with Sidak’s multiple comparisons test with a single pooled variance. (FIGs. 13C, 13G, and 13H) repeated measures two-way analysis of variance with Tukey’s multiple comparisons test with individual variances (FIGs. 13D and 13E) or an unpaired, two-tailed t-test (FIG. 13F).

[0034] FIGs. 14A-14K shows that AMG1541 enhances mRNA expression in immune cell populations and induces robust germinal center reactions in response to vaccination. FIG. 14A shows representative flow cytometry plots of muscle cells showing Dil-labeled LNP uptake. FIG. 14B shows Dil-labeled LNP uptake in cells isolated from the muscle (n = 5). FIG. 14C shows Dil-labeled LNP uptake in cells isolated from LDLN (n = 5). FIG. 14D shows representative flow cytometry plots of muscle cells showing tdTomato expression. FIG. 14E shows tdTomato mRNA expression in cells isolated from the muscle. FIG. 14F shows tdTomato mRNA expression in cells isolated from the local draining lymph node. FIG. 14G shows IHC images showing tdTomato expression in the muscle following LNP injection. FIG. 14H shows representative flow cytometry plots showing GC B cells (n = 5).FIG. 141 shows representative flow cytometry plots showing number of GCB cells from the LDLN (n = 5). FIG. 14J shows representative flow cytometry plots showing antigen positive GC B cells (n = 5). FIG. 14K shows representative flow cytometry plots showing number of antigen positive GC B cells in the local draining lymph node following vaccination (n = 5). Statistical analysis was performed using a two-way analysis of variance with Tukey’s multiple comparisons test with a single pooled variance (FIGs. 14B, 14C, 14E, and 14F) or a one-way analysis of variance with a Dunnett’s multiple comparisons test with a single pooled variance (FIGs. 141 and 14K).

[0035] FIGs. 15A-15G show how structural features of AMG1541 impact its properties. FIG. 15A shows functional groups present in ionizable lipid AMG1541. FIG. 15B shows TNS measurement of LNP pKa for AMG1541 and SM-102. FIG. 15C shows lipid pKa versus fold increase in mRNA transfection IM at (1 μg, 6 hour) IM for AMG lipids. FIG. 15D shows31P NMR spectra of AMG 1541 lipids showing spectral shift indicating bilayer membrane to hexagonal HIItransformation at acidic pH. FIG. 15E shows in vivo FLuc mRNA transfection of AMG1541 and linear counterpart AMG2041 at 0.1 μg. FIG. 15F shows in vivo FLuc mRNA transfection of AMG1041 and -OH deleted derivative AMG1041OHD at 0.1 μg, 6 hour post IM injection. FIG. 15G shows the structure of -OH deleted derivative AMG1041OHD. Statistical significance was analyzed using a two-way analysis of variance with Sidak’s multiple comparisons test with a single pooled variance (FIGs. 15E, 15F, and 15G).

[0036] FIGs. 16A and 16B show in vitro transfection data for AMG lipid library in C2C12 myoblast cells after treatment with FLuc encapsulating LNPs dosed at 40 ng / well. FIG. 16A shows the data in bar graphs. FIG. 16B shows the data in heat maps. Mean ± s.d., n = 3 wells per group. RLU, relative light unit.

[0037] FIGs. 17A and 17B show the effect of various lipid tails. FIG. 17A shows the structures of different tails. FIG. 17B shows quantification of Flue protein expression upon intramuscular injection in mice for AMG 1541 tail derivatives (0.1 μg, 6 hours).

[0038] FIGs. 18A and 18B show quantification of EPO expression in blood, 6 hours post intravenous administration of EPO encapsulating LNPs. FIG. 18A shows a comparison of AMG1541 and cKK-E12 in a dose response study. FIG. 18B shows a comparison of delivery efficacy with Lipid 5 and LP01. Statistical significance was analyzed using a two-way analysis of variance with Sidak’s multiple comparisons test with a single pooled variance (n=3 per group).

[0039] FIGs. 19A-19E show comparative intramuscular Flue protein expression 6-hour post intramuscular injection. FIG. 19A shows a comparison of AMG1041 and 1041 OHD (0.1 and 1 μg). FIG. 19B shows a comparison of AMG1041, 1041R, and 1041 S (1 μg). FIG. 19C shows a comparison of AMG1541, 1541R, and 1541 S (0.1 μg). FIG. 19D shows a comparison of AMG1541 and its analogue without |3-amino alcohol (AMG1559). FIG. 19E shows the structures of AMG1041OHD and AMG1041. Statistical significance was analyzed using a two-way analysis of variance with Sidak’s multiple comparisons test with a single pooled variance (n=3-5 per group).

[0040] FIGs. 20A-20C show additional vaccine response characterization. FIG. 20A shows day 35 peptide pool- stimulated splenocyte IFN-γ ELISpot SFU (left) and representative images (right) from female BALB / cJ mice vaccinated with HA mRNA (dose = 1 μg, n = 5). FIG. 28B shows day 35 dose-response serum antibody titers in female BALB / cJ mice following H3 HA vaccination (n = 5). FIG. 20C shows serum cytokines 6 hrs. after boosting with HA mRNA in BALB / cJ mice (dose = 1 μg, n = 5). Statistical analysis was performed using an unpaired t test with Welch correction with the two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli (FIG. 20A), an ordinary two-way analysis of variance with Sidak’s multiple comparisons tests (FIG. 20B), or a repeated measurement two-way analysis of variances with the Geisser-Greenhouse correction and Sidak’s multiple comparisons with individual variances for each comparison (FIG. 20C).DEFINITIONSChemical Definitions

[0041] 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.

[0042] 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 invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0043] When a range of values is listed, it is intended to encompass 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 “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3 -4, C4 -6. C4-5, and C5-6alkyl.

[0044] 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.

[0045] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0046] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec -butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hcxyl). 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 C1-12alkyl (such as unsubstituted C1-6alkyl, 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 n-butyl ( n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec -butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-12alkyl (such as substituted C1-6alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0047] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-20alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-12alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-11alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“hctcroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-12alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-12alkyl.

[0048] 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 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1-12alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1-11alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1-10alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9alkenyl”).In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1-4alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1alkenyl”). 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 CIM 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 C1-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), 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 C1-20alkenyl. In certain embodiments, the alkenyl group is a substituted C1-20alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3ormay be in the (E) or (Z)_ configuration.

[0049] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“hetero C1-20alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-12alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-11alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-10alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-9alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-8alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-7alkenyl”). In some embodiments, a heteroalkenyl group has Ito 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-6alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1-5alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“hctcroC1-4alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1-3alkenyl”). In some embodiments, a heteroalkenyl grouphas 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC1-2alkenyl”). In some embodiments, a heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1-6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1-20alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1-20alkenyl.

[0050] 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) (“C1-20alkynyl”). In some embodiments, an alkynyl group has 1 to 10 carbon atoms (“C1-10alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1alkynyl”). 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 C1-4alkynyl 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 C1-6alkenyl groups include the aforementioned C2-4alkynyl groups 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 C1-20alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20alkynyl.

[0051] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refersto a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1-20alkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1-10alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1-9alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1-8alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1-7alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1-6alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1-5alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“hctcroC1-4alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1-3alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC1-2alkynyl”). In some embodiments, a heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC1-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC1-20alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1-20alkynyl.

[0052] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-6carbocyclyl 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 C3-10carbocyclyl groups include the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- l H-indcnyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8carbocyclyl groups include the aforementioned C3-10carbocyclyl groups as well as cycloundecyl (C11), spiro [5.5] undec any 1 (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclo tridecane (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 C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0053] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, acycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl 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 C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0054] 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 certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0055] 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 1-4 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.

[0056] 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, tetra- hydrobenzothienyl, 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, l,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, 1,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0057] 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 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; 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 C6.14aryl. In certain embodiments, the aryl group is a substituted C6-14aryl.

[0058] “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0059] 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 π 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 ringmembers 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.

[0060] 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.

[0061] 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 hetero aryl groups containing 4 hetero atoms 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.

[0062] “Hetero aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.

[0063] The term “unsaturated bond” refers to a double or triple bond.

[0064] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0065] 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.

[0066] 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, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, 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.

[0067] 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, heteroalkyl, heteroalkenyl, heteroalkynyl, 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” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “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 invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, 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 invention is not limited in any manner by the exemplary substituents described herein.

[0068] 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, -0C(=0)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbC02Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -0C(=NRbb)Raa, -0C(=NRbb)0Raa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=0)SRaa, -0C(=0)SRaa, -SC(=0)0Raa, -SC(=0)Raa, -P(=0)(Raa)2, -P(=O)(ORCC)2, -0P(=0)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=0)(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(0RCC), C1-20alkyl, C1-20perhaloalkyl, C1-20alkenyl, C1-20alkynyl, heteroC1-20alkyl, heteroC1-20alkenyl, heteroC1-20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 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(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from C1-20alkyl, C1-20perhaloalkyl, C1-20alkenyl, C1-20alkynyl, heteroC1-20alkyl, heteroC1-20alkenyl, heteroC1-20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, heteroalkyl, heteroalkenyl, heteroalkynyl, 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(=O)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, CI 20 alkyl, C1-20perhaloalkyl, C1-20alkenyl, C1-20alkynyl, heteroC1-20alkyl, heteroC1- 2oalkenyl, heteroC1-20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, heteroalkyl, heteroalkenyl, heteroalkynyl, 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, C1-20alkyl, C1- 20 perhaloalkyl, C1-20alkenyl, C1-20alkynyl, heteroC1-20alkyl, heteroC1-20alkenyl, heteroC1-20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, heteroalkyl, heteroalkenyl, heteroalkynyl, 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(ORee)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(=O)N(Rff)2,-C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=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, -0P(=0)(Ree)2, -0P(=0)(0Ree)2, C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3-10carbocyclyl, 3- 10 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 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 C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3- 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 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, C1-10alkyl, C1- io perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 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, heteroalkyl, heteroalkenyl, heteroalkynyl, 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, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3+X“, -NH(C1-6alkyl)2+X-, -NH2(C1-6alkyl)+X“, -NH3+X“, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)( C1-6alkyl), -N(C1-6alkyl)C(=O)( C1-6alkyl), -NHCO2(C1-6alkyl), -NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH(C1-6alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), -OC(=NH)OC1-6alkyl, -C(=NH)N(C1-6alkyl)2, -C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(NH)NH(C1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3-C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=0)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=0)(0C1-6alkyl)2, -P(=0)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -0P(=0)(0C1-6alkyl)2, C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, heteroC1-10alkynyl, C3. io carbocyclyl, C6-10aryl, 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.

[0069] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, -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 atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, -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 C1-10alkyl, 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 C1-10alkyl, 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 C1-6alkyl, -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 C1-10alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, 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 C1-10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0070] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0071] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxyl,” 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 -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X“, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb))2, wherein X-, Raa, Rbb, and Rccare as defined herein.

[0072] 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 -SRaa, -S=SRCC, -SC(=S)SRaa, -SC(=S)ORaa, -SC(=S) N(Rbb)2, - SC(=O)SRaa, -SC(=O)ORaa, -SC(=O)N(Rbb)2, and -SC(=O)Raa, wherein Raaand Rccare as defined herein.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] The term “acyl” refers to a group having the general formula -C(=O)Raa, -C(=O)ORaa, -C(=O)-O-C(=O)Raa, -C(=O)SRaa, -C(=O)N(Rbb)2, -C(=S)Raa, -C(=S)N(Rbb)2, and -C(=S)S(Raa), -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)SRaa, and -C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0078] 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.

[0079] 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, -SORaa, -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, C1-20alkyl, C1-20perhaloalkyl, C1-20alkenyl, C1-20alkynyl, hetero C1-20alkyl, hetero C1-20alkenyl, hetero C1-20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0080] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, 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 C1-10alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protectinggroup, wherein R3ilis hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, 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 C1-10alkyl, 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 C1-6alkyl or a nitrogen protecting group.

[0081] 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, -SO2R33, -C(=NRCC)Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -S0Raa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, CI-IO alkyl (e.g., aralkyl, heteroaralkyl), C1-20alkenyl, C1-20alkynyl, hetero C1-20alkyl, hetero C1-20alkenyl, hetero C1-20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 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.

[0082] 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(=0)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, Wbenzoylphenylalanyl derivatives, benzamide, -phenyIbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (W-dithiobcnzyloxyacylamino)acctamidc, 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, Wacctylmcthioninc derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0083] 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), 1,1- dimethyl-2-haloethyl 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'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, / -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), -methoxybenzyl carbamate (Moz), p- nitobenzyl carbamate, -bromobcnzyl carbamate, -chlorobcnzyl 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- dimethyl-2-cyanoethyl 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, / -amyl carbamate, 5-bcnzyl thiocarbamate, -cyanobcnzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, -decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A,A-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(A,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 )benzylcarbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1- cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl- l-(p-phenylazophenyl)ethyl carbamate, 1 -methyl- 1 -phenylethyl carbamate, 1 -methyl- 1 -(4- pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6- tri butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0084] 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.

[0085] 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, A’-phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, N- acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthal imide, N- dithiasuccinimide (Dts), A-2,3-diphenylmaleimide, N-2,5-di methyl pyrrole, N- 1,1, 4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl- 1,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,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), N- [(4-methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7- dichloro-9-fluorenylmethyleneamine, A-ferrocenylmethylamino (Fem), A-2-picolylamino N’-oxide, N- 1,1 -dimethylthiomethyleneamine, N-bcnzylidcncaminc, N-p- methoxybenzylideneamine, N-di phenyl mcthylcncam inc, N-[(2- pyridyl)mesityl] methyleneamine, N(AF,AF-dimethylaminomethylene)amine, N-p- nitrobenzylideneamine, N-salicylidcncaminc, iV-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohcxylidcncaminc, N-(5,5-dimcthyl-3-oxo- 1 - cyclohexenyl)amine, N-boranc derivatives, AMiphcnylborinic acid derivatives, N- [phenyl(pentaacylchromium- or tungsten)acyl] amine, N-coppcr chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxidc, diphenylphosphinamide (Dpp), dimethylthiopho sphinamide (Mpt), diphenylthiopho sphinamide (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 N,N’-isopropylidenediamine.

[0086] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0087] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, 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 C1-10alkyl, 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 C1-6alkyl or an oxygen protecting group.

[0088] 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. Oxygenprotecting 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.

[0089] 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 methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), / -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 -methoxycyclohexyl, 4- methoxy tetrahydropyranyl (MTHP), 4-methoxy tetrahydrothiopyranyl, 4- methoxy tetrahydrothiopyranyl WS'-diox ide, 1 - [(2-chloro-4-methyl)phenyl] -4- methoxypiperidin-4-yl (CTMP), l,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, 1- (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, a- naphthyldiphenylmethyl, p-methoxyphenyldiphenyl methyl, d i ( / ?- methoxyphenyl)phenylmethyl, tri(p-methoxy phenyl) 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, l,3-benzodithiolan-2-yl, benzisothiazolyl WS'-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, / -butyldi methyl si lyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 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, -mcthoxybcnzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, -nitrobcnzyl carbonate, S-bcnzyl 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- (1,1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1 , 1 -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o- (methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0090] 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.

[0091] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, -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 C1-10alkyl, -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 C1-10alkyl, 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 C1-10alkyl, 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 C1-6alkyl or a sulfur protecting group.

[0092] 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, -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 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.

[0093] 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.

[0094] 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.

[0095] The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents. Additional terms may be defined in other sections of this disclosure.Other Definitions

[0096] 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 this invention 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 N+(C1-4alkyl)4salts. 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.

[0097] 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 this invention 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+(C1-4alkyl)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.

[0098] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0099] The term “stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent molecules are an integral part of the crystal lattice, in which they interact strongly with the compound and each other. The removal of the solvent molecules will cause instability of the crystal network, which subsequently collapses into an amorphous phase or recrystallizes as a new crystalline form with reduced solvent content.

[0100] The term “non-stoichiometric solvate” refers to a solvate, which comprises a compound (e.g., a compound disclosed herein) and a solvent, wherein the solvent content may vary without major changes in the crystal structure. The amount of solvent in the crystal lattice only depends on the partial pressure of solvent in the surrounding atmosphere. In the fully solvated state, non-stoichiometric solvates may, but not necessarily have to, show an integer molar ratio of solvent to the compound. During drying of a non-stoichiometric solvate, a portion of the solvent may be removed without significantly disturbing the crystal network, and the resulting solvate can subsequently be resolvated to give the initial crystalline form. Unlike stoichiometric solvates, the desolvation and resolvation of non-stoichiometric solvates is not accompanied by a phase transition, and all solvation states represent the same crystal form.

[0101] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R O.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0102] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0103] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.

[0104] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least onechange in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0105] 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”.

[0106] 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 (i.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”.

[0107] The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0108] 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.

[0109] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, aryl, C7-C12substituted aryl, and C7-C12arylalkyl esters of the compounds described herein may be preferred.

[0110] As used herein, “lipophilic” refers to the ability of a group to dissolve in fats, oils, lipids, and lipophilic non-polar solvents such as hexane or toluene. In general, a lipophilic group refers to an unsubstituted n-alkyl or unsubstituted n-alkenyl group having 6 to 50 carbon atoms, e.g., 6 to 40, 6 to 30, 6 to 20, 8 to 20, 8 to 19, 8 to 18, 8 to 17, 8 to 16, or 8 to 15 carbon atoms.

[0111] The terms “phosphorylethanolamine” and “phosphoethanolamine” are used interchangeably.

[0112] The term “sterol” refers to a subgroup of steroids also known as steroid alcohols, i.e., a steroid containing at least one hydroxyl group. Sterols are usually divided into two classes: (1) plant sterols also known as “phytosterols,” and (2) animal sterols also known as “zoosterols.” The term “sterol” includes, but is not limited to, cholesterol, sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, pollinastasterol, and all natural or synthesized forms and derivatives thereof, including isomers.

[0113] As used here, the term “PEG-lipid” refers to a PEGylated lipid.

[0114] An “amino acid” refers to natural and unnatural D / L alpha- amino acids, as well as natural and unnatural beta- and gamma- amino acids. A “peptide” refers to two amino acids joined by a peptide bond. A “polypeptide” refers to three or more amino acids joined by peptide bonds. An “amino acid side chain” refers to the group(s) pended to the alpha carbon (if an alpha amino acid), alpha and beta carbon (if a beta amino acid), or the alpha, beta, and gamma carbon (if a gamma amino acid). Exemplary amino acid side chains are depicted herein.

[0115] A “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds. The term, as used herein, 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 (i.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 famesyl 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.

[0116] The term “apolipoprotein” refers to a protein that binds a lipid (e.g., triacylglycerol or cholesterol) to form a lipoprotein. Apolipoproteins also serve as enzyme cofactors, receptor ligands, and lipid transfer carriers that regulate the metabolism of lipoproteins and their uptake in tissues. Major types of apolipoproteins include integral and non-integral apolipoproteins. Exemplary apolipoproteins include apoA (e.g., apoA-I, apoA-II, apoA-IV, and apoA-V); apoB (e.g., apoB48 and apoB 100); apoC (e.g., apoC-I, apoC-II, apoC-III, and apoC-IV); apoD; apoE; apoH; and apoJ.

[0117] The term “gene” refers to a nucleic acid fragment that expresses a specific protein, including regulatory sequences preceding (5’ non-coding sequences) and following (3’ non- coding sequences) the coding sequence. “Native gene” refers to a gene as found in nature with its own regulatory sequences. “Chimeric gene” or “chimeric construct” refers to any gene or a construct, not a native gene, comprising regulatory and coding sequences that are not found together in nature. Accordingly, a chimeric gene or chimeric construct may comprise regulatory sequences and coding sequences that are derived from different sources, or regulatory sequences and coding sequences derived from the same source, but arranged in a manner different than that found in nature. “Endogenous gene” refers to a native gene in its natural location in the genome of an organism. A “foreign” gene refers to a gene not normally found in the host organism, but which is introduced into the host organism by gene transfer. Foreign genes can comprise native genes inserted into a non-native organism, or chimeric genes. A “transgene” is a gene that has been introduced into the genome by a transformation procedure.

[0118] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, its hybridization parameters, etc. The oligonucleotide may comprise a modified base moiety which is selected from the group including, but not limited to, 5- fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4- acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2- thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2- dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5- methylcytosine, N6-adenine, 7- methylguanine, 5-methylaminomethyluracil, 5- methoxy aminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5’-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6- isopentenyladenine, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2- thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil- 5-oxy acetic acid methylester, uracil- 5 -oxy acetic acid, 5-methyl-2- thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, a thio-guanine, and 2,6-diaminopurine. The oligonucleotide may comprise one or more locked nucleic acid (LNA) moieties. A nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single-stranded genomic and cDNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double- stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA- RNA hybrids, as well as “protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids. Exemplary DNAs include single-stranded DNA (ssDNA), double- stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), micro satellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), a provirus, a lysogen, repetitive DNA, satellite DNA, and viral DNA. Exemplary RNAs include single- stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA),precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non- coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), a polyinosinic acid, a ribozyme, a flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA.

[0119] Polynucleotides described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as those that are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al., Nucl. Acids Res., 16, 3209, (1988), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. U.S.A. 85, 7448-7451, (1988)). A number of methods have been developed for delivering antisense DNA or RNA to cells, e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systemically. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines. However, it is often difficult to achieve intracellular concentrations of the antisense sufficient to suppress translation of endogenous mRNAs. Therefore a preferred approach utilizes a recombinant DNA construct in which the antisense oligonucleotide is placed under the control of a strong promoter. The use of such a construct to transfect target cells in the patient will result in the transcription of sufficient amounts of single stranded RNAs that will form complementary base pairs with the endogenous target gene transcripts and thereby prevent translation of the target gene mRNA. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an antisense RNA. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, orothers known in the art, used for replication and expression in mammalian cells. Expression of the sequence encoding the antisense RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Such promoters include, but are not limited to: the SV40 early promoter region (Bernoist et al., Nature, 290, 304-310, (1981); Yamamoto et al., Cell, 22, 787-797, (1980); Wagner et al., Proc. Natl. Acad. Sci. U.S.A. 78, 1441-1445, (1981); Brinster et al., Nature 296, 39-42, (1982)). Any type of plasmid, cosmid, yeast artificial chromosome, or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site. Alternatively, viral vectors can be used which selectively infect the desired tissue, in which case administration may be accomplished by another route (e.g., systemically).

[0120] The polynucleotides may be flanked by natural regulatory (expression control) sequences, or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5'- and 3 '-non- coding regions, and the like. The nucleic acids may also be modified by many means known in the art. Non-limiting examples of such modifications include methylation, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, and intemucleotide modifications such as, for example, those with uncharged linkages (e.g.. methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.) and with charged linkages (e.g.. phosphorothioates, phosphorodithioates, etc.). Polynucleotides may contain one or more additional covalently linked moieties, such as, for example, proteins e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators. The polynucleotides may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage. Furthermore, the polynucleotides herein may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, biotin, and the like.

[0121] A “recombinant nucleic acid molecule” is a nucleic acid molecule that has undergone a molecular biological manipulation, i.e., non-naturally occurring nucleic acid molecule or genetically engineered nucleic acid molecule. Furthermore, the term “recombinant DNA molecule” refers to a nucleic acid sequence which is not naturally occurring, or can be made by the artificial combination of two otherwise separated segmentsof nucleic acid sequence, i.e., by ligating together pieces of DNA that are not normally continuous. By “recombinantly produced” is meant artificial combination often accomplished by either chemical synthesis means, or by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques using restriction enzymes, ligases, and similar recombinant techniques as described by, for example, Sambrook et al., Molecular Cloning, second edition, Cold Spring Harbor Laboratory, Plainview, N.Y.; (1989), or Ausubel et al., Current Protocols in Molecular Biology, Current Protocols (1989), and DNA Cloning: A Practical Approach, Volumes I and II (ed. D. N. Glover) IREL Press, Oxford, (1985); each of which is incorporated herein by reference.

[0122] Such manipulation may be done to replace a codon with a redundant codon encoding the same or a conservative amino acid, while typically introducing or removing a sequence recognition site. Alternatively, it may be performed to join together nucleic acid segments of desired functions to generate a single genetic entity comprising a desired combination of functions not found in nature. Restriction enzyme recognition sites are often the target of such artificial manipulations, but other site specific targets, e.g., promoters, DNA replication sites, regulation sequences, control sequences, open reading frames, or other useful features may be incorporated by design. Examples of recombinant nucleic acid molecule include recombinant vectors, such as cloning or expression vectors which contain DNA sequences encoding Ror family proteins or immunoglobulin proteins which are in a 5' to 3' (sense) orientation or in a 3' to 5' (antisense) orientation.

[0123] The term “pDNA,” “plasmid DNA,” or “plasmid” refers to a small DNA molecule that is physically separate from, and can replicate independently of, chromosomal DNA within a cell. Plasmids can be found in all three major domains: Archaea, Bacteria, and Eukarya. In nature, plasmids carry genes that may benefit survival of the subject e.g., antibiotic resistance) and can frequently be transmitted from one bacterium to another (even of another species) via horizontal gene transfer. Artificial plasmids are widely used as vectors in molecular cloning, serving to drive the replication of recombinant DNA sequences within host subjects. Plasmid sizes may vary from 1 to over 1,000 kbp. Plasmids are considered replicons, capable of replicating autonomously within a suitable host.

[0124] ‘ ‘RNA transcript” refers to the product resulting from RNA polymerase-catalyzed transcription of a DNA sequence. When the RNA transcript is a complementary copy of the DNA sequence, it is referred to as the primary transcript or it may be an RNA sequence derived from post-transcriptional processing of the primary transcript and is referred to asthe mature RNA. “Messenger RNA (mRNA)” refers to the RNA that is without introns and can be translated into polypeptides by the cell. “cRNA” refers to complementary RNA, transcribed from a recombinant cDNA template. “cDNA” refers to DNA that is complementary to and derived from an mRNA template. The cDNA can be single- stranded or converted to double-stranded form using, for example, the Klenow fragment of DNA polymerase I.

[0125] A sequence “complementary” to a portion of an RNA, refers to a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double-stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with an RNA it may contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

[0126] The terms “nucleic acid” or “nucleic acid sequence”, “nucleic acid molecule”, “nucleic acid fragment” or “polynucleotide” may be used interchangeably with “gene”, “mRNA encoded by a gene” and “cDNA”.

[0127] The term “mRNA” or “mRNA molecule” refers to messenger RNA, or the RNA that serves as a template for protein synthesis in a cell. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA comprising a sequence coding for the protein to be synthesized.

[0128] The term “siRNA” or “siRNA molecule” refers to small inhibitory RNA duplexes that induce the RNA interference (RNAi) pathway, where the siRNA interferes with the expression of specific genes with a complementary nucleotide sequence. siRNA molecules can vary in length (e.g., between 18-30 or 20-25 basepairs) and contain varying degrees of complementarity to their target mRNA in the antisense strand. Some siRNA have unpaired overhanging bases on the 5’ or 3’ end of the sense strand and / or the antisense strand. The term siRNA includes duplexes of two separate strands, as well as single strands that can form hairpin structures comprising a duplex region.

[0129] The term “gene silencing” refers to an epigenetic process of gene regulation where a gene is “switched off’ by a mechanism other than genetic modification. That is, a gene which would be expressed (i.e., “turned on”) under normal circumstances is switched off by machinery in the cell. Gene silencing occurs when RNA is unable to make a protein duringtranslation. Genes are regulated at either the transcriptional or post-transcriptional level. Transcriptional gene silencing is the result of histone modifications, creating an environment of heterochromatin around a gene that makes it inaccessible to transcriptional machinery (e.g., RNA polymerase and transcription factors). Post-transcriptional gene silencing is the result of mRNA of a particular gene being destroyed or blocked. The destruction of the mRNA prevents translation and thus the formation of a gene product (e.g., a protein). A common mechanism of post-transcriptional gene silencing is RNAi.

[0130] As used herein, a “chimeric receptor” or “chimeric antigen receptor” refers to a non- naturally occurring molecule that can be expressed on the surface of a host cell and comprises binding domain that provides specificity of the chimeric receptor (e.g., an antigen-binding fragment that binds to an epitope of a cell surface protein). In general, chimeric receptors comprise at least two domains that are derived from different molecules. In addition to the epitope-binding fragment described herein, the chimeric receptor may further comprise one or more of the following: a hinge domain, a transmembrane domain, a co- stimulatory domain, a cytoplasmic signaling domain, and combinations thereof. In some embodiments, the chimeric receptor comprises from N terminus to C terminus, an antigen-binding fragment that binds to a cell surface protein, a hinge domain, a transmembrane domain, and a cytoplasmic signaling domain. In some embodiments, the chimeric receptor further comprises at least one co- stimulatory domain. See, e.g., Marin- Acevedo et al. J. Hematol. Oncol.(2018)11:8.

[0131] In some embodiments, the chimeric receptors described herein comprise one or more hinge domain(s). In some embodiments, the hinge domain may be located between the antigen-binding fragment and a transmembrane domain. A hinge domain is an amino acid segment that is generally found between two domains of a protein and may allow for flexibility of the protein and movement of one or both of the domains relative to one another. Any amino acid sequence that provides such flexibility and movement of the antigen-binding fragment relative to another domain of the chimeric receptor can be used.

[0132] In some embodiments, the chimeric receptors described herein may comprise one or more transmembrane domain(s). The transmembrane domain for use in the chimeric receptors can be in any form known in the art. As used herein, a “transmembrane domain” refers to any protein structure that is thermodynamically stable in a cell membrane, preferably a eukaryotic cell membrane. Transmembrane domains compatible for use in the chimeric receptors used herein may be obtained from a naturally occurring protein. Alternatively, thetransmembrane domain may be a synthetic, non-naturally occurring protein segment, e.g., a hydrophobic protein segment that is thermodynamically stable in a cell membrane.

[0133] In some embodiments, the chimeric receptors described herein comprise one or more costimulatory signaling domains. The term “co- stimulatory signaling domain,” as used herein, refers to at least a portion of a protein that mediates signal transduction within a cell to induce an immune response, such as an effector function. The co-stimulatory signaling domain of the chimeric receptor described herein can be a cytoplasmic signaling domain from a co-stimulatory protein, which transduces a signal and modulates responses mediated by immune cells, such as T cells, NK cells, macrophages, neutrophils, or eosinophils.

[0134] The term “particle” refers to a small object, fragment, or piece of a substance that may be a single element, inorganic material, organic material, or mixture thereof. Examples of particles include polymeric particles, single-emulsion particles, double-emulsion particles, coacervates, liposomes, microparticles, nanoparticles (e.g., lipid nanoparticles), macroscopic particles, pellets, crystals, aggregates, composites, pulverized, milled or otherwise disrupted matrices, and cross-linked protein or polysaccharide particles, each of which have an average characteristic dimension of about less than about 1 mm and at least 1 nm, where the characteristic dimension, or “critical dimension,” of the particle is the smallest cross-sectional dimension of the particle. A particle may be composed of a single substance or multiple substances. In certain embodiments, the particle is not a viral particle. In other embodiments, the particle is not a liposome. In certain embodiments, the particle is not a micelle. In certain embodiments, the particle is substantially solid throughout. In certain embodiments, the particle is a nanoparticle. In certain embodiments, the particle is a microparticle.

[0135] The terms “composition” and “formulation” are used interchangeably.

[0136] A “subject” to which administration is contemplated refers to a human (i.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.

[0137] 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 as samples 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.

[0138] The term “target tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the invention is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher- than- normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A “non-target tissue” is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is not a target tissue.

[0139] 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.

[0140] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0141] 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.

[0142] 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 orwho 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.

[0143] An “effective amount” of a compound or agent described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound or agent 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 or agent, 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 prophy tactically effective amount. In certain embodiments, an effective amount is the amount of a compound or agent described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound or agent 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).

[0144] 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 about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0145] In certain embodiments, the compounds of the invention may be 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.

[0146] 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 beadministered 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.

[0147] A “therapeutically effective amount” of a compound or agent 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 or agent 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 delivering an agent to a subject or a cell. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering mRNA to a subject or a cell. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering an agent to a subject or a cell and treating a disease, disorder, or condition. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell and treating a disease, disorder, or condition. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering mRNA to a subject or a cell and treating a disease, disorder, or condition. In certain embodiments, a therapeutically effective amount is an amount effective for chimeric antigen receptor T cell therapy.

[0148] A “prophylactically effective amount” of a compound or agent 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 or agent 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 delivering an agent to a subject or a cell. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell. In certainembodiments, a prophylactically effective amount is an amount sufficient for delivering mRNA to a subject or a cell. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering an agent to a subject or a cell and preventing a disease, disorder, or condition. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering a polynucleotide to a subject or a cell and preventing a disease, disorder, or condition. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering mRNA to a subject or a cell and preventing a disease, disorder, or condition. In certain embodiments, a prophylactically effective amount is an amount effective for chimeric antigen receptor T cell therapy.

[0149] The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and / or RNAs of the subject. In such cases, the genetic disease will be heritable if it occurs in the germline. Exemplary genetic diseases include, but are not limited to, Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno-leukodystrophy, albinism, ablepharon- macrostomia syndrome, alagille syndrome, alkaptonuria, alpha- 1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler-Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers -Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia,hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper- IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, and Zellweger syndrome.

[0150] 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. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0151] 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 oftumors 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.

[0152] 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.

[0153] 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 (i.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; immunocyticamyloidosis; 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).

[0154] A “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and / or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectiousmononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm’s tumor, Ewing’s sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism.

[0155] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; bbrain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebralatrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy- induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt- Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTEV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune- mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg- Welander disease; kuru; Eafora disease; Eambert-Eaton myasthenic syndrome; Eandau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Eeigh’s disease; Eennox-Gastaut syndrome; Eesch-Nyhan syndrome; leukodystrophy; Eewy body dementia; lissencephaly; locked-in syndrome; Eou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor neuropathy; multiplesclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0156] The term “liver disease” or “hepatic disease” refers to damage to or a disease of the liver. Non-limiting examples of liver disease include intrahepatic cholestasis (e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (i.e., Wilson's disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic jaundice), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis, chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced chronic hepatitis), toxic hepatitis, viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, varices, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (e.g., hepatic encephalopathy, acute liver failure), angiomyolipoma, calcified liver metastases, cystic liver metastases, fibrolamellar hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g., Simple cysts, Polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst), mesenchymal tumors (mesenchymal hamartoma, infantile hemangioendothelioma, hemangioma, peliosis hepatis, lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile duct hamartoma, bile duct adenoma), focal nodular hyperplasia, nodular regenerative hyperplasia, hepatoblastoma, hepatocellular carcinoma, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi's sarcoma, hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma, peliosis hepatis, erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome.

[0157] The term “spleen disease” refers to a disease of the spleen. Example of spleen diseases include, but are not limited to, splenomegaly, spleen cancer, asplenia, spleen trauma, idiopathic purpura, Felty’s syndrome, Hodgkin’s disease, and immune-mediated destruction of the spleen.

[0158] The term “lung disease” or “pulmonary disease” refers to a disease of the lung. Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratory distress syndrome (ARDS), severe acute respiratorysyndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma).

[0159] A “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post-operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre-operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, bum pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawl symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculoskeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g., nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0160] In certain embodiments, the painful condition is neuropathic pain. The term “neuropathic pain” refers to pain resulting from injury to a nerve. Neuropathic pain is distinguished from nociceptive pain, which is the pain caused by acute tissue injury involving small cutaneous nerves or small nerves in muscle or connective tissue. Neuropathic pain typically is long-lasting or chronic and often develops days or months following an initial acute tissue injury. Neuropathic pain can involve persistent, spontaneous pain as well asallodynia, which is a painful response to a stimulus that normally is not painful. Neuropathic pain also can be characterized by hyperalgesia, in which there is an accentuated response to a painful stimulus that usually is trivial, such as a pin prick. Neuropathic pain conditions can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain conditions include, but are not limited to, diabetic neuropathy (e.g., peripheral diabetic neuropathy); sciatica; non-specific lower back pain; multiple sclerosis pain; carpal tunnel syndrome, fibromyalgia; HIV-related neuropathy; neuralgia (e.g., post-herpetic neuralgia, trigeminal neuralgia); pain resulting from physical trauma (e.g., amputation; surgery, invasive medical procedures, toxins, burns, infection), pain resulting from cancer or chemotherapy (e.g., chemotherapy- induced pain such as chemotherapy- induced peripheral neuropathy), and pain resulting from an inflammatory condition (e.g., a chronic inflammatory condition). Neuropathic pain can result from a peripheral nerve disorder such as neuroma; nerve compression; nerve crush, nerve stretch or incomplete nerve transsection; mononeuropathy or polyneuropathy. Neuropathic pain can also result from a disorder such as dorsal root ganglion compression; inflammation of the spinal cord; contusion, tumor or hemisection of the spinal cord; tumors of the brainstem, thalamus or cortex; or trauma to the brainstem, thalamus or cortex.

[0161] The symptoms of neuropathic pain are heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as “pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

[0449] In certain embodiments, the painful condition is non-inflammatory pain. The types of non-inflammatory pain include, without limitation, peripheral neuropathic pain (e.g., pain caused by a lesion or dysfunction in the peripheral nervous system), central pain (e.g., pain caused by a lesion or dysfunction of the central nervous system), deafferentation pain (e.g. , pain due to loss of sensory input to the central nervous system), chronic nociceptive pain (e.g., certain types of cancer pain), noxious stimulus of nociceptive receptors (e.g., pain felt in response to tissue damage or impending tissue damage), phantom pain (e.g., pain felt in a part of the body that no longer exists, such as a limb that has been amputated), pain felt by psychiatric subjects (e.g., pain where nophysical cause may exist), and wandering pain (e.g., wherein the pain repeatedly changes location in the body).

[0162] The term “psychiatric disorder” refers to a disease of the mind and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV), published by the American Psychiatric Association, Washington D. C. (1994). Psychiatric disorders include, but are not limited to, anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, and specific phobia), childhood disorders, (e.g., attention-deficit / hyperactivity disorder, conduct disorder, and oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age- related memory loss), and Tourette’s disorder.

[0163] The term “musculoskeletal disease” or “MSD” refers to an injury and / or pain in a subject’s joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck, and back. In certain embodiments, an MSD is a degenerative disease. In certain embodiments, an MSD includes an inflammatory condition. Body parts of a subject that may be associated with MSDs include upper and lower back, neck, shoulders, and extremities (arms, legs, feet, and hands). In certain embodiments, an MSD is a bone disease, such as achondroplasia, acromegaly, bone callus, bone demineralization, bone fracture, bone marrow disease, bone marrow neoplasm, dyskeratosis congenita, leukemia (e.g., hairy cell leukemia, lymphocytic leukemia, myeloid leukemia, Philadelphia chromosome-positive leukemia, plasma cell leukemia, stem cell leukemia), systemic mastocytosis, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, myeloid sarcoma, myeloproliferativedisorders, multiple myeloma, polycythemia vera, pearson marrow-pancreas syndrome, bone neoplasm, bone marrow neoplasm, Ewing sarcoma, osteochondroma, osteoclastoma, osteosarcoma, brachydactyly, Camurati-Engelmann syndrome, Craniosynostosis, Crouzon craniofacial dysostosis, dwarfism, achondroplasia, bloom syndrome, Cockayne syndrome, Ellis-van Creveld syndrome, Seckel syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, Werner syndrome, hyperostosis, osteophyte, Klippel-Trenaunay-Weber syndrome, Marfan syndrome, McCune- Albright syndrome, osteitis, osteoarthritis, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, Leri- Weill dyschondrosteosis, osteochondrosis, osteodystrophy, osteogenesis imperfecta, osteolysis, Gorham-Stout syndrome, osteomalacia, osteomyelitis, osteonecrosis, osteopenia, osteopetrosis, osteoporosis, osteosclerosis, otospondylomegaepiphyseal dysplasia, pachydermoperiostosis, Paget disease of bone, Polydactyly, Meckel syndrome, rickets, Rothmund- Thomson syndrome, Sotos syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, syndactyly, Apert syndrome, syndactyly type II, or Werner syndrome. In certain embodiments, an MSD is a cartilage disease, such as cartilage neoplasm, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, or Leri-Weill dyschondrosteosis. In certain embodiments, an MSD is hernia, such as intervertebral disk hernia. In certain embodiments, an MSD is a joint disease, such as arthralgia, arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), Lyme disease, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, Eelty syndrome, synovitis, Blau syndrome, nail-patella syndrome, spondyloarthropathy, reactive arthritis, Stickler syndrome, synovial membrane disease, synovitis, or Blau syndrome. In certain embodiments, an MSD is Langer- Giedion syndrome. In certain embodiments, an MSD is a muscle disease, such as Barth syndrome, mitochondrial encephalomyopathy, MELAS syndrome, MERRE syndrome, MNGIE syndrome, mitochondrial myopathy, Kearns-Sayre syndrome, myalgia, fibromyalgia, polymyalgia rheumatica, myoma, myositis, dermatomyositis, neuromuscular disease, Kearns-Sayre syndrome, muscular dystrophy, myasthenia, congenital myasthenic syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, myotonia, myotonia congenita, spinal muscular atrophy, tetany, ophthalmoplegia, or rhabdomyolysis. In certain embodiments, an MSD is Proteus syndrome. In certain embodiments, an MSD is a rheumatic diseases, such as arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan lyme disease)), osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, Felty syndrome, synovitis, Blau syndrome, gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), polymyalgiarheumatica, rheumatic fever, rheumatic heart disease, or Sjogren syndrome. In certain embodiments, an MSD is Schwartz- Jampel syndrome. In certain embodiments, an MSD is a skeleton disease, such as Leri-Weill dyschondrosteosis, skeleton malformations, Melnick- Needles syndrome, pachydermoperiostosis, Rieger syndrome, spinal column disease, intervertebral disk hernia, scoliosis, spina bifida, spondylitis, ankylosing spondylitis, spondyloarthropathy, reactive arthritis, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, or spondylosis.

[0164] The term “metabolic disorder” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0002] In certain embodiments, the metabolic disorder is a wasting condition. A “wasting condition” includes but is not limited to, anorexia and cachexias of various natures (e.g., weight loss associated with cancer, weight loss associated with other general medical conditions, weight loss associated with failure to thrive, and the like). In certain embodiments, the metabolic disorder is an obesity-related condition or a complication thereof. An “obesity-related condition” includes, but is not limited to, obesity, undesired weight gain (e.g., from medication-induced weight gain, from cessation of smoking) and an over-eating disorder (e.g. , binge eating, bulimia, compulsive eating, or a lack of appetite control each of which can optionally lead to undesired weight gain or obesity). “Obesity” and “obese” refers to class I obesity, class II obesity, class III obesity and pre-obesity (e.g., being “over- weight”) as defined by the World Health Organization.

[0165] Reduction of storage fat is expected to provide various primary and / or secondary benefits in a subject (e.g., in a subject diagnosed with a complication associated with obesity) such as, for example, an increased insulin responsiveness (e.g., in a subject diagnosed with Type II diabetes mellitus); a reduction in elevated blood pressure; a reduction in elevated cholesterol levels; and / or a reduction (or a reduced risk or progression) of ischemic heart disease, arterial vascular disease, angina, myocardial infarction, stroke, migraines, congestiveheart failure, deep vein thrombosis, pulmonary embolism, gall stones, gastroesophagael reflux disease, obstructive sleep apnea, obesity hypoventilation syndrome, asthma, gout, poor mobility, back pain, erectile dysfunction, urinary incontinence, liver injury (e.g., fatty liver disease, liver cirrhosis, alcoholic cirrhosis, endotoxin mediated liver injury) or chronic renal failure.

[0166] The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’sgranulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host- versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0167] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, bums, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocyticcolitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, bums, physical injury), vasculitis, vitiligo and Wegener's granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatistis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease).

[0168] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0169] In certain embodiments, the inflammatory disorder and / or the immune disorder is a gastrointestinal disorder. In some embodiments, the gastrointestinal disorder is selected fromgastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)). In certain embodiments, the gastrointestinal disorder is inflammatory bowel disease (IBD).

[0170] In certain embodiments, the inflammatory condition and / or immune disorder is a skin condition. In some embodiments, the skin condition is pruritus (itch), psoriasis, eczema, bums or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is pruritis.

[0171] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, or more typically, within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0172] Unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0173] Provided herein are compounds (e.g., compounds of Formula (I), (XI), (XII), and (XIII)), and pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, and isotopically labeled derivatives thereof, and compositions and kits thereof. The compounds provided herein can form particles and may therefore be used to deliver agents (e.g., a polynucleotide) to a subject, tissue, or cell. Also provided herein are methods of delivery and methods of treating a disease, disorder, or condition, comprising administering to the subject a composition comprising a compound provided herein (e.g., a compound of Formula (I), (XI), (XII), or (XIII)), or a pharmaceutically acceptable salt thereof.Compounds

[0174] Provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: n is 1, 2, or 3;A and B are independently optionally substituted saturated or unsaturated aliphatic; orA and B combine to form optionally substituted C2-C6alkylene; each R is independently hydrogen, a nitrogen protecting group, or a group of theFormula (i), (ii), (iii), (iv) or (v): wherein one of R6and R7is hydrogen, and the other is wherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

[0175] In a particular embodiment, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0176] Also provided herein is a compound of the formula:or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3;A and B are independently optionally substituted saturated or unsaturated aliphatic; orA and B combine to form optionally substituted C2-C6alkylene; each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (i), (ii), (iii), (iv) or (v):wherein one of R6and R7is hydrogen, and the other iswherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

[0177] In some embodiments of Formula (I), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (i), provided that at least one R is of formula (i).

[0178] In some embodiments of Formula (I), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (ii), provided that at least one R is of Formula(ii).

[0179] In some embodiments of Formula (I), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iii), provided that at least one R is of Formula(iii).

[0180] In some embodiments of Formula (I), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iv), provided that at least one R is of Formula(iv).

[0181] In some embodiments of Formula (I), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (v), provided that at least one R is of Formula(v).

[0182] Also provided herein is a compound of Formula (I'):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: n is 1, 2, or 3;A and B are independently optionally substituted saturated or unsaturated aliphatic; orA and B combine to form optionally substituted C2-C6alkylene; each R is independently hydrogen, a nitrogen protecting group, orwherein one of R6and R7is hydrogen, and the other iseach instance of R5is independently optionally substituted, C4-C35saturated or unsaturated aliphatic or optionally substituted, C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is

[0183] In a particular embodiment, provided herein is a compound of Formula (I'), or a pharmaceutically acceptable salt thereof.

[0184] Also provided herein is a compound of the formula:or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3;A and B are independently optionally substituted saturated or unsaturated aliphatic; or A and B combine to form optionally substituted C2-C6alkylene; each R is independently hydrogen, a nitrogen protecting group, orwherein one of R6and R7is hydrogen, and the other iseach instance of R5is independently optionally substituted, C4-C35saturated or unsaturated aliphatic or optionally substituted, C4-C35saturated or unsaturated heteroaliphatic; andeach x independently is an integer from 1 to 10, inclusive; provided that at least one R is

[0185] Provided herein is a compound of Formula (XI):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v): , wherein one of R6and R7is hydrogen, and the other iswherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

[0186] In a particular embodiment, provided herein is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments of Formula (XI), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (i), provided that at least one R is of formula (i).

[0188] In some embodiments of Formula (XI), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (ii), provided that at least one R is of Formula(ii).

[0189] In some embodiments of Formula (XI), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iii), provided that at least one R is of Formula(iii).

[0190] In some embodiments of Formula (XI), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iv), provided that at least one R is of Formula(iv).

[0191] In some embodiments of Formula (XI), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (v), provided that at least one R is of Formula(v).

[0192] Provided herein is a compound of Formula (XII):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v): , wherein one of R6and R7is hydrogen, and the other is, wherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

[0193] In a particular embodiment, provided herein is a compound of Formula (XII), or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments of Formula (XII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (i), provided that at least one R is of formula (i).

[0195] In some embodiments of Formula (XII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (ii), provided that at least one R is of Formula (ii).

[0196] In some embodiments of Formula (XII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iii), provided that at least one R is of Formula (iii).

[0197] In some embodiments of Formula (XII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iv), provided that at least one R is of Formula (iv).

[0198] In some embodiments of Formula (XII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (v), provided that at least one R is of Formula (v).

[0199] Provided herein is a compound of Formula (XIII):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:R1is hydrogen, -ORA, -SRA, or -N(RA)2, each instance of RAis independently -H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or wherein two instances of RAattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v):, wherein one of R6and R7is hydrogen, and the other is, wherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

[0200] In a particular embodiment, provided herein is a compound of Formula (XIII), or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments of Formula (XIII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (i), provided that at least one R is of formula (i).

[0202] In some embodiments of Formula (XIII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (ii), provided that at least one R is of Formula (ii).

[0203] In some embodiments of Formula (XIII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iii), provided that at least one R is of Formula (iii).

[0204] In some embodiments of Formula (XIII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iv), provided that at least one R is of Formula (iv).

[0205] In some embodiments of Formula (XIII), each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (v), provided that at least one R is of Formula (v).

[0206] As defined herein, R1is hydrogen, -ORA, -SRA, or -N(RA)2. In some embodiments, R1is hydrogen or -ORA. In some embodiments, R1is hydrogen or -OH. In some embodiments, R1is hydrogen or -SRA. In some embodiments, R1is hydrogen or -SH. In some embodiments, R1is hydrogen or -N(RA)2. In some embodiments, R1is hydrogen or -NH2. Insome embodiments, R1is hydrogen, -ORA, or -SRA. In some embodiments, R1is hydrogen, - OH, or -SH. In some embodiments, R1is -ORA, -SRA, or -N(RA)2. In some embodiments, R1is hydrogen. In some embodiments, R1is -ORA. In some embodiments, R1is -OH. In some embodiments, R1is -SRA. In some embodiments, R1is -SH. In some embodiments, R1is - N(RA)2. In some embodiments, R1is -NH2.

[0207] As defined herein, each instance of RAis independently -H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or wherein two instances of RAattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In some embodiments, RAis -H. In some embodiments, RAis optionally substituted C1-10aliphatic. In some embodiments, RAis optionally substituted C1-10alkyl. In some embodiments, RAis optionally substituted C1-10alkenyl. In some embodiments, RAis optionally substituted C1-10alkynyl. In some embodiments, RAis optionally substituted C1-10heteroaliphatic. In some embodiments, RAis optionally substituted C1-10heteroalkyl. In some embodiments, RAis optionally substituted C1-10 heteroalkenyl. In some embodiments, RAis optionally substituted C1-10heteroalkynyl. In some embodiments, RAis optionally substituted acyl. In some embodiments, RAis optionally substituted aryl. In some embodiments, RAis optionally substituted phenyl. In some embodiments, RAis optionally substituted heteroaryl. In some embodiments, RAis optionally substituted 5- or 6-membered heteroaryl. In some embodiments, RAis optionally substituted carbocyclyl. In some embodiments, RAis optionally substituted 3- to 8-membered carbocyclyl. In some embodiments, RAis optionally substituted heterocyclyl. In some embodiments, RAis optionally substituted 3- to 8-membered heterocyclyl. In some embodiments, RAis an oxygen protecting group. In some embodiments, RAis a sulfur protecting group. In some embodiments, RAis a nitrogen protecting group. In some embodiments, two instances of RAattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl. In some embodiments, two instances of RAattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heteroaryl.

[0208] As defined herein, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0209] As defined herein, A and B are independently optionally substituted saturated or unsaturated aliphatic; or A and B combine to form optionally substituted C2-C6alkylene. In some embodiments, A and B are the same. In some embodiments, A and B are independently optionally substituted saturated or unsaturated aliphatic. In some embodiments, A and B are independently substituted saturated or unsaturated aliphatic. In some embodiments, A and B are independently substituted saturated aliphatic. In some embodiments, A and B are independently substituted unsaturated aliphatic. In some embodiments, A and B are independently unsubstituted saturated or unsaturated aliphatic. In some embodiments, A and B are independently unsubstituted saturated aliphatic. In some embodiments, A and B are independently unsubstituted unsaturated aliphatic.

[0210] In some embodiments, A and B are independently optionally substituted C1-C20saturated or unsaturated aliphatic. In some embodiments, A and B are independently substituted C1-C20saturated or unsaturated aliphatic. In some embodiments, A and B are independently substituted C1-C20saturated aliphatic. In some embodiments, A and B are independently substituted C1-C20unsaturated aliphatic. In some embodiments, A and B are independently unsubstituted C1-C20saturated or unsaturated aliphatic. In some embodiments, A and B are independently unsubstituted C1-C20saturated aliphatic. In some embodiments, A and B are independently unsubstituted C1-C20unsaturated aliphatic.

[0211] In some embodiments, A and B are independently optionally substituted C1-C6saturated or unsaturated aliphatic. In some embodiments, A and B are independently substituted C1-C6saturated or unsaturated aliphatic. In some embodiments, A and B are independently substituted C1- C6saturated aliphatic. In some embodiments, A and B are independently substituted C1-C6unsaturated aliphatic. In some embodiments, A and B are independently unsubstituted C1-C6saturated or unsaturated aliphatic. In some embodiments, A and B are independently unsubstituted C1-C6saturated aliphatic. In some embodiments, A and B are independently unsubstituted C1-C6unsaturated aliphatic.

[0212] In some embodiments, A and B are independently optionally substituted alkyl. In some embodiments, A and B are independently substituted alkyl. In some embodiments, A and B are independently unsubstituted alkyl. In some embodiments, A and B are independently optionally substituted C1-C20alkyl. In some embodiments, A and B are independently substituted C1-C20alkyl. In some embodiments, A and B are independentlyunsubstituted C1-C20alkyl. In some embodiments, A and B are independently optionally substituted C1-C6alkyl. In some embodiments, A and B are independently substituted C1-C6alkyl. In some embodiments, A and B are independently unsubstituted C1-C6alkyl. In some embodiments, A and B are independently -CH3.

[0213] In some embodiments, A and B are independently optionally substituted alkenyl. In some embodiments, A and B are independently substituted alkenyl. In some embodiments, A and B are independently unsubstituted alkenyl. In some embodiments, A and B are independently optionally substituted C1-C20alkenyl. In some embodiments, A and B are independently substituted C1-C20alkenyl. In some embodiments, A and B are independently unsubstituted C1-C20alkenyl. In some embodiments, A and B are independently optionally substituted C1-C6alkenyl. In some embodiments, A and B are independently substituted C1- C6alkenyl. In some embodiments, A and B are independently unsubstituted C1-C6alkenyl.

[0214] In some embodiments, A is optionally substituted saturated or unsaturated aliphatic. In some embodiments, A is substituted saturated or unsaturated aliphatic. In some embodiments, A is substituted saturated aliphatic. In some embodiments, A is substituted unsaturated aliphatic. In some embodiments, A is unsubstituted saturated or unsaturated aliphatic. In some embodiments, A is unsubstituted saturated aliphatic. In some embodiments, A is unsubstituted unsaturated aliphatic.

[0215] In some embodiments, A is optionally substituted C1-C20saturated or unsaturated aliphatic. In some embodiments, A is substituted C1-C20saturated or unsaturated aliphatic. In some embodiments, A is substituted C1-C20saturated aliphatic. In some embodiments, A is substituted C1-C20unsaturated aliphatic. In some embodiments, A is unsubstituted C1-C20saturated or unsaturated aliphatic. In some embodiments, A is unsubstituted C1-C20saturated aliphatic. In some embodiments, A is unsubstituted C1-C20unsaturated aliphatic.

[0216] In some embodiments, A is optionally substituted C1-C6saturated or unsaturated aliphatic. In some embodiments, A is substituted C1-C6saturated or unsaturated aliphatic. In some embodiments, A is substituted C1-C6saturated aliphatic. In some embodiments, A is substituted C1-C6unsaturated aliphatic. In some embodiments, A is unsubstituted C1-C6saturated or unsaturated aliphatic. In some embodiments, A is unsubstituted C1-C6saturated aliphatic. In some embodiments, A is unsubstituted C1-C6unsaturated aliphatic.

[0217] In some embodiments, A is optionally substituted alkyl. In some embodiments, A is substituted alkyl. In some embodiments, A is unsubstituted alkyl. In some embodiments, A is optionally substituted C1-C20alkyl. In some embodiments, A is substituted C1-C20alkyl. In some embodiments, A is unsubstituted C1-C20alkyl. In some embodiments, A is optionallysubstituted C1-C6alkyl. In some embodiments, A is substituted C1-C6alkyl. In some embodiments, A is unsubstituted C1-C6alkyl. In some embodiments, A is -CH3.

[0218] In some embodiments, A is optionally substituted alkenyl. In some embodiments, A is substituted alkenyl. In some embodiments, A is unsubstituted alkenyl. In some embodiments, A is optionally substituted C1-C20alkenyl. In some embodiments, A is substituted C1-C20alkenyl. In some embodiments, A is unsubstituted C1-C20alkenyl. In some embodiments, A is optionally substituted C1-C6alkenyl. In some embodiments, A is substituted C1-C6alkenyl. In some embodiments, A is unsubstituted C1-C6alkenyl.

[0219] In some embodiments, A is optionally substituted alkynyl. In some embodiments, A is substituted alkynyl. In some embodiments, A is unsubstituted alkynyl. In some embodiments, A is optionally substituted C1-C20alkynyl. In some embodiments, A is substituted C1-C20alkynyl. In some embodiments, A is unsubstituted C1-C20alkynyl. In some embodiments, A is optionally substituted C1-C6alkynyl. In some embodiments, A is substituted C1-C6alkynyl. In some embodiments, A is unsubstituted C1-C6alkynyl.

[0220] In some embodiments, B is optionally substituted saturated or unsaturated aliphatic. In some embodiments, B is substituted saturated or unsaturated aliphatic. In some embodiments, B is substituted saturated aliphatic. In some embodiments, B is substituted unsaturated aliphatic. In some embodiments, B is unsubstituted saturated or unsaturated aliphatic. In some embodiments, B is unsubstituted saturated aliphatic. In some embodiments, B is unsubstituted unsaturated aliphatic.

[0221] In some embodiments, B is optionally substituted C1-C20saturated or unsaturated aliphatic. In some embodiments, B is substituted C1-C20saturated or unsaturated aliphatic. In some embodiments, B is substituted C1-C20saturated aliphatic. In some embodiments, B is substituted C1-C20unsaturated aliphatic. In some embodiments, B is unsubstituted C1-C20saturated or unsaturated aliphatic. In some embodiments, B is unsubstituted C1-C20saturatefR5d aliphatic. In some embodiments, B is unsubstituted C1-C20unsaturated aliphatic.

[0222] In some embodiments, B is optionally substituted C1-C6saturated or unsaturated aliphatic. In some embodiments, B is substituted C1-C6saturated or unsaturated aliphatic. In some embodiments, B is substituted C1-C6saturated aliphatic. In some embodiments, B is substituted C1-C6unsaturated aliphatic. In some embodiments, B is unsubstituted C1-C6saturated or unsaturated aliphatic. In some embodiments, B is unsubstituted C1-C6saturated aliphatic. In some embodiments, B is unsubstituted C1-C6unsaturated aliphatic.

[0223] In some embodiments, B is optionally substituted alkyl. In some embodiments, B is substituted alkyl. In some embodiments, B is unsubstituted alkyl. In some embodiments, B isoptionally substituted C1-C20alkyl. In some embodiments, B is substituted C1-C20alkyl. In some embodiments, B is unsubstituted C1-C20alkyl. In some embodiments, B is optionally substituted C1-C6alkyl. In some embodiments, B is substituted C1-C6alkyl. In some embodiments, B is unsubstituted C1-C6alkyl. In some embodiments, B is -CH3.

[0224] In some embodiments, B is optionally substituted alkenyl. In some embodiments, B is substituted alkenyl. In some embodiments, B is unsubstituted alkenyl. In some embodiments, B is optionally substituted C1-C20alkenyl. In some embodiments, B is substituted C1-C20alkenyl. In some embodiments, B is unsubstituted C1-C20alkenyl. In some embodiments, B is optionally substituted C1-C6alkenyl. In some embodiments, B is substituted C1-C6alkenyl. In some embodiments, B is unsubstituted C1-C6alkenyl.

[0225] In some embodiments, A and B are independently optionally substituted saturated or unsaturated aliphatic, and n is 1. In some embodiments, A and B are independently optionally substituted C1-C6saturated or unsaturated aliphatic, and n is 1. In some embodiments, A and B are independently unsubstituted C1-C6saturated or unsaturated aliphatic, and n is 1. In some embodiments, A and B are independently optionally substituted alkyl, and n is 1. In some embodiments, A and B are independently optionally substituted C1-C6alkyl, and n is 1. In some embodiments, A and B are independently unsubstituted C1-C6alkyl, and n is 1. In some embodiments, A and B are independently -CH3, and n is 1.

[0226] In some embodiments, A and B are independently optionally substituted saturated or unsaturated aliphatic, and n is 2. In some embodiments, A and B are independently optionally substituted C1-C6saturated or unsaturated aliphatic, and n is 2. In some embodiments, A and B are independently unsubstituted C1-C6saturated or unsaturated aliphatic, and n is 2. In some embodiments, A and B are independently optionally substituted alkyl, and n is 2. In some embodiments, A and B are independently optionally substituted C1-C6alkyl, and n is 2. In some embodiments, A and B are independently unsubstituted C1-C6alkyl, and n is 2. In some embodiments, A and B are independently -CH3, and n is 2.

[0227] In some embodiments, A and B are independently optionally substituted saturated or unsaturated aliphatic, and n is 3. In some embodiments, A and B are independently optionally substituted C1-C6saturated or unsaturated aliphatic, and n is 3. In some embodiments, A and B are independently unsubstituted C1-C6saturated or unsaturated aliphatic, and n is 3. In some embodiments, A and B are independently optionally substituted alkyl, and n is 3. In some embodiments, A and B are independently optionally substituted C1-C6alkyl, and n is 3. In some embodiments, A and B are independently unsubstituted C1-C6alkyl, and n is 3. In some embodiments, A and B are independently -CH3, and n is 3.

[0228] In some embodiments, A and B combine to form optionally substituted C2-C6alkylene. In some embodiments, A and B combine to form optionally substituted branched C2-C6alkylene. In some embodiments, A and B combine to form optionally substituted unbranched C2-C6alkylene. In some embodiments, A and B combine to form optionally substituted ethylene. In some embodiments, A and B combine to form optionally substituted n-propylcnc. In some embodiments, A and B combine to form optionally substituted n- butylene. In some embodiments, A and B combine to form optionally substituted n- pentylene. In some embodiments, A and B combine to form optionally substituted n- hexylene.

[0229] In some embodiments, A and B combine to form substituted C2-C6alkylene. In some embodiments, A and B combine to form substituted branched C2-C6alkylene. In some embodiments, A and B combine to form substituted unbranched C2-C6alkylene. In some embodiments, A and B combine to form unsubstituted C2-C6alkylene. In some embodiments, A and B combine to form unsubstituted branched C2-C6alkylene. In some embodiments, A and B combine to form unsubstituted unbranched C2-C6alkylene. In some embodiments, A and B combine to form ethylene. In some embodiments, A and B combine to form n- propylene. In some embodiments, A and B combine to form n-butylcnc. In some embodiments, A and B combine to form n-pcntylcnc. In some embodiments, A and B combine to form n-hexylene.

[0230] In some embodiments, A and B combine to form optionally substituted C2-C6alkylene, and n is 1. In some embodiments, A and B combine to form optionally substituted unbranched C2-C6alkylene, and n is 1. In some embodiments, A and B combine to form unsubstituted C2-C6alkylene, and n is 1. In some embodiments, A and B combine to form unsubstituted unbranched C2-C6alkylene, and n is 1. In some embodiments, A and B combine to form ethylene, and n is i.

[0231] In some embodiments, A and B combine to form optionally substituted C2-C6alkylene, and n is 2. In some embodiments, A and B combine to form optionally substituted unbranched C2-C6alkylene, and n is 2. In some embodiments, A and B combine to form unsubstituted C2-C6alkylene, and n is 2. In some embodiments, A and B combine to form unsubstituted unbranched C2-C6alkylene, and n is 2. In some embodiments, A and B combine to form ethylene, and n is 2.

[0232] In some embodiments, A and B combine to form optionally substituted C2-C6alkylene, and n is 3. In some embodiments, A and B combine to form optionally substituted unbranched C2-C6alkylene, and n is 3. In some embodiments, A and B combine to formunsubstituted C2-C6alkylene, and n is 3. In some embodiments, A and B combine to form unsubstituted unbranched C2-C6alkylene, and n is 3. In some embodiments, A and B combine to form ethylene, and n is 3.

[0233] As defined herein, each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v): wherein one of R6and R7is hydrogen, and the other iswherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

[0234] In some embodiments, each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (i), provided that at least one R is of Formula (i). In some embodiments, each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (ii), provided that at least one R is of Formula (ii). In some embodiments, each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iii),provided that at least one R is of Formula (iii). In some embodiments, each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (iv), provided that at least one R is of Formula (iv). In some embodiments, each R is independently hydrogen, a nitrogen protecting group, or a group of the Formula (v), provided that at least one R is of Formula (v).

[0235] In some embodiments, each R is independently hydrogen, a nitrogen protecting group, wherein one of R and R7is hydrogen, and the other isprovided that at least one R isIn some embodiments, at least one R is. In some embodiments, at least two R are independently. In some embodiments, at least three R are independently. In some embodiments, at least four R are independently. In some embodiments, at least five R are independently. In some embodiments, at least six R are independentlyIn some embodiments, at least seven R are independently. In some embodiments, at least eight R are independently

[0236] In some embodiments, each R isIn some embodiments, one R isIn some embodiments, two R are independently. In some embodiments, three R are independently. In some embodiments, four R are independently. In some embodiments, five R are independentlyIn some embodiments, six R are independently. In some embodiments, seven R are independently. In some embodiments, eight R are independently

[0237] In some embodiments, at least one R is hydrogen or a nitrogen protecting group. In some embodiments, at least one R is hydrogen or. In some embodiments, at least one R is a nitrogen protecting group or. In some embodiments, at least one R is hydrogen. In some embodiments, at least one R is a nitrogen protecting group. In some embodiments, at least one R is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0238] As defined herein, for each moietyindividually, one of R6and R7is hydrogen, and the other is; or for each moietyindividually, one of R6and R7is hydrogen, and the other isIn some embodiments, for each moietyindividually, one of R6and R7is hydrogen, and the other issomeembodiments, R6is hydrogen. In some embodiments, R7is hydrogen.In some embodiments, R6is. In some embodiments, R7is. In some embodiments, at least one moiety

[0239] In some embodiments, each R6is hydrogen. In some embodiments, each R7is hydrogen. In some embodiments, each R6is. In some embodiments, each R7is

[0240] In some embodiments, each moiety in someembodiments, each R is. In some embodiments, one R is. In some embodiments, two R are independently . In some embodiments, three R are independently . In some embodiments, four R are independently . In some embodiments, five R are independently . In some embodiments, six R are independently . In some embodiments, seven R are independently . In some embodiments, eight R are independently

[0241] As defined herein, each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic.

[0242] In some embodiments, each instance of R5is different. In some embodiments, two instances of R5are the same. In some embodiments, at least two instances of R5are the same. In some embodiments, three instances of R5are the same. In some embodiments, at least three instances of R5are the same. In some embodiments, four instances of R5are the same. In some embodiments, at least four instances of R5are the same. In some embodiments, fiveinstances of R5are the same. In some embodiments, at least five instances of R5are the same. In some embodiments, six instances of R5are the same. In some embodiments, at least six instances of R5are the same. In some embodiments, seven instances of R5are the same. In some embodiments, at least seven instances of R5are the same. In some embodiments, eight instances of R5are the same. In some embodiments, at least eight instances of R5are the same. In some embodiments, each instance of R5is the same.

[0243] In some embodiments, each instance of R5is independently optionally substituted C4- C35saturated aliphatic or optionally substituted C4-C35saturated hetero aliphatic. In some embodiments, each instance of R5is independently optionally substituted C4-C35unsaturated aliphatic or optionally substituted C4-C35unsaturated heteroaliphatic.

[0244] In some embodiments, each instance of R5is independently optionally substituted C4- C35saturated or unsaturated aliphatic. In some embodiments, each instance of R5is independently optionally substituted C4-C12saturated or unsaturated aliphatic. In some embodiments, each instance of R5is independently optionally substituted C10-C20saturated or unsaturated aliphatic. In some embodiments, each instance of R5is independently optionally substituted C12-C25saturated or unsaturated aliphatic.

[0245] In some embodiments, each R5is independently optionally substituted C4-C35alkyl or optionally substituted C4-C35alkenyl. In some embodiments, each R5is independently optionally substituted C4-C10alkyl or optionally substituted C4-C10alkenyl. In some embodiments, each R5is independently optionally substituted C10-C20alkyl or optionally substituted C10-C20alkenyl. In some embodiments, each R5is independently optionally substituted C12-C25alkyl or optionally substituted C12-C25alkenyl.

[0246] In some embodiments, each R5is independently optionally substituted C4-C35alkyl or optionally substituted C4-C35alkynyl. In some embodiments, each R5is independently optionally substituted C4-C10alkyl or optionally substituted C4-C10alkynyl. In some embodiments, each R5is independently optionally substituted C10-C20alkyl or optionally substituted C10-C20alkynyl. In some embodiments, each R5is independently optionally substituted C12-C25alkyl or optionally substituted C12-C25alkynyl.

[0247] In some embodiments, each R5is independently optionally substituted C4-C35alkynyl or optionally substituted C4-C35alkenyl. In some embodiments, each R5is independently optionally substituted C4-C10alkynyl or optionally substituted C4-C10alkenyl. In some embodiments, each R5is independently optionally substituted C10-C20alkynyl or optionally substituted C10-C20alkenyl. In some embodiments, each R5is independently optionally substituted C12-C25alkynyl or optionally substituted C12-C25alkenyl.

[0248] In some embodiments, each R5is independently branched C4-C35alkyl. In some embodiments, each R5is independently branched C4-C12alkyl. In some embodiments, each R5is independently branched C10-C20alkyl. In some embodiments, each R5is independently branched C12-C25alkyl. In some embodiments, each R5is independently unbranched C4-C35alkyl. In some embodiments, each R5is independently unbranched C4-C12alkyl. In some embodiments, each R5is independently unbranched C10-C20alkyl. In some embodiments, each R5is independently unbranched C12-C25alkyl.

[0249] In some embodiments, each R5is independently branched C4-C35alkenyl. In some embodiments, each R5is independently branched C4-C35alkenyl comprising a single double bond. In some embodiments, each R5is independently branched C4-C35alkenyl comprising a single (Z) double bond. In some embodiments, each R5is independently branched C4-C12alkenyl. In some embodiments, each R5is independently branched C10-C20alkenyl. In some embodiments, each R5is independently branched C12-C25alkenyl.

[0250] In some embodiments, each R5is independently unbranched C4-C35alkenyl. In some embodiments, each R5is independently unbranched C4-C35alkenyl comprising a single double bond. In some embodiments, each R5is independently unbranched C4-C35alkenyl comprising a single (Z) double bond. In some embodiments, each R5is independently unbranched C4-C35alkenyl comprising two double bonds. In some embodiments, each R5is independently unbranched C4-C35alkenyl comprising two (Z) double bonds. In some embodiments, each R5is independently unbranched C4-C35alkenyl comprisingIn some embodiments, each R5is independently unbranched C4-C35alkenyl comprising three double bonds. In some embodiments, each R5is independently unbranched C4-C35alkenyl comprising three (Z) double bonds. In some embodiments, each R5is independently unbranched C4-C35alkenyl comprising only (Z) double bonds.

[0251] In some embodiments, each R5is independently unbranched C4-C12alkenyl. In some embodiments, each R5is independently unbranched C4-C12alkenyl comprising a single double bond. In some embodiments, each R5is independently unbranched C4-C12alkenyl comprising a single (Z) double bond. In some embodiments, each R5is independently unbranched C4-C12alkenyl comprising two double bonds. In some embodiments, each R5is independently unbranched C4-C12alkenyl comprising two (Z) double bonds. In some embodiments, each R5is independently unbranched C4-C12alkenyl comprisingIn some embodiments, each R5is independently unbranched C4-C12alkenyl comprising three double bonds. In some embodiments, each R5is independently unbranched C4-C12alkenyl comprising three (Z) double bonds. In some embodiments, each R5is independently unbranched C4-C12alkenyl comprising only (Z) double bonds.

[0252] In some embodiments, each R5is independently unbranched C10-C20alkenyl. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising a single double bond. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising a single (Z) double bond. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising two double bonds. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising two (Z) double bonds. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising three double bonds. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising three (Z) double bonds. In some embodiments, each R5is independently unbranched C10-C20alkenyl comprising only (Z) double bonds.

[0253] In some embodiments, each R5is independently unbranched C12-C25alkenyl. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising a single double bond. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising a single (Z) double bond. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising two double bonds. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising two (Z) double bonds. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising three double bonds. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising three (Z) double bonds. In some embodiments, each R5is independently unbranched C12-C25alkenyl comprising only (Z) double bonds.

[0254] In some embodiments, each R5is independently unbranched C11alkenyl. In some embodiments, each R5is independently unbranched C11alkenyl comprising a single double bond. In some embodiments, each R5is independently unbranched C11alkenyl comprising a single (Z) double bond. In some embodiments, each R5is independently unbranched C11alkenyl comprising two double bonds. In some embodiments, each R5is independentlyunbranched C11alkenyl comprising two (Z) double bonds. In some embodiments, each R5is independently unbranched C11alkenyl comprising. in some embodiments, eachR5is independently unbranched C11alkenyl comprising three double bonds. In some embodiments, each R5is independently unbranched C11alkenyl comprising three (Z) double bonds. In some embodiments, each R5is independently unbranched C11alkenyl comprising only (Z) double bonds.

[0255] In some embodiments, each R5is independently branched C4-C35alkynyl. In some embodiments, each R5is independently branched C4-C12alkynyl. In some embodiments, R5is independently branched C10-C20alkynyl. In some embodiments, each R5is independently branched C12-C25alkynyl. In some embodiments, each R5is independently unbranched C4- C35alkynyl. In some embodiments, each R5is independently unbranched C4-C12alkynyl. In some embodiments, each R5is independently unbranched C10-C20alkynyl. In some embodiments, each R5is independently unbranched C12-C25alkynyl.

[0256] In some embodiments, each instance of R5is independently optionally substituted C4- C35saturated or unsaturated hetero aliphatic. In some embodiments, each instance of R5is independently optionally substituted C4-C35saturated or unsaturated heteroaliphatic comprising at least one O, N, or S atom. In some embodiments, each instance of R5is independently optionally substituted C4-C35saturated or unsaturated heteroaliphatic comprising at least one O or S atom. In some embodiments, each instance of R5is independently optionally substituted C4-C12saturated or unsaturated heteroaliphatic. In some embodiments, each instance of R5is independently optionally substituted C4-C12saturated or unsaturated heteroaliphatic comprising at least one O, N, or S atom. In some embodiments, each instance of R5is independently optionally substituted C4-C12saturated or unsaturated heteroaliphatic comprising at least one O or S atom. In some embodiments, each instance of R5is independently optionally substituted C10-C20saturated or unsaturated heteroaliphatic. In some embodiments, each instance of R5is independently optionally substituted C10-C20saturated or unsaturated heteroaliphatic comprising at least one O, N, or S atom. In some embodiments, each instance of R5is independently optionally substituted C10-C20saturated or unsaturated heteroaliphatic comprising at least one O or S atom. In some embodiments, each instance of R5is independently optionally substituted C12-C25saturated or unsaturated heteroaliphatic. In some embodiments, each instance of R5is independently optionally substituted C12-C25saturated or unsaturated heteroaliphatic comprising at least one O, N, or Satom. In some embodiments, each instance of R5is independently optionally substituted C12- C25saturated or unsaturated hetero aliphatic comprising at least one O or S atom.

[0257] In some embodiments, each R5is independently optionally substituted C4-C35heteroalkyl or optionally substituted C4-C35heteroalkenyl. In some embodiments, each R5is independently optionally substituted C4-C10heteroalkyl or optionally substituted C4-C10heteroalkenyl. In some embodiments, each R5is independently optionally substituted C10-C20heteroalkyl or optionally substituted C10-C20heteroalkenyl. In some embodiments, each R5is independently optionally substituted C12-C25heteroalkyl or optionally substituted C12-C25heteroalkenyl.

[0258] In some embodiments, each R5is independently optionally substituted C4-C35heteroalkyl or optionally substituted C4-C35heteroalkynyl. In some embodiments, each R5is independently optionally substituted C4-C10heteroalkyl or optionally substituted C4-C10heteroalkynyl. In some embodiments, each R5is independently optionally substituted C10-C20heteroalkyl or optionally substituted C10-C20heteroalkynyl. In some embodiments, each R5is independently optionally substituted C12-C25heteroalkyl or optionally substituted C12-C25heteroalkynyl.

[0259] In some embodiments, each R5is independently optionally substituted C4-C35heteroalkynyl or optionally substituted C4-C35heteroalkenyl. In some embodiments, each R5is independently optionally substituted C4-C10heteroalkynyl or optionally substituted C4-C10heteroalkenyl. In some embodiments, each R5is independently optionally substituted C10-C20heteroalkynyl or optionally substituted C10-C20heteroalkenyl. In some embodiments, each R5is independently optionally substituted C12-C25heteroalkynyl or optionally substituted C12- C25heteroalkenyl.

[0260] In some embodiments, each R5is independently branched C4-C35heteroalkyl. In some embodiments, R5is independently branched C4-C12heteroalkyl. In some embodiments, each R5is independently branched C10-C20heteroalkyl. In some embodiments, each R5is independently branched C12-C25heteroalkyl. In some embodiments, each R5is independently unbranched C4-C35heteroalkyl. In some embodiments, each R5is independently unbranched C4-C12heteroalkyl. In some embodiments, each R5is independently unbranched C10-C20heteroalkyl. In some embodiments, each R5is independently unbranched C12-C25heteroalkyl.

[0261] In some embodiments, each R5is independently branched C4-C35heteroalkenyl. In some embodiments, each R5is independently branched C4-C12heteroalkenyl. In some embodiments, each R5is independently branched C10-C20heteroalkenyl. In some embodiments, each R5is independently branched C12-C25heteroalkenyl. In someembodiments, each R5is independently unbranched C4-C35heteroalkenyl. In some embodiments, each R5is independently unbranched C4-C12heteroalkenyl. In some embodiments, each R5is independently unbranched C10-C20heteroalkenyl. In some embodiments, each R5is independently unbranched C12-C25heteroalkenyl.

[0262] In some embodiments, each R5is independently branched C4-C35heteroalkynyl. In some embodiments, each R5is independently branched C4-C12heteroalkynyl. In some embodiments, each R5is independently branched C10-C20heteroalkynyl. In some embodiments, each R5is independently branched C12-C25heteroalkynyl. In some embodiments, each R5is independently unbranched C4-C35heteroalkynyl. In some embodiments, each R5is independently unbranched C4-C12heteroalkynyl. In some embodiments, each R5is independently unbranched C10-C20heteroalkynyl. In some embodiments, each R5is independently unbranched C12-C25heteroalkynyl.

[0263] In some embodiments, each R5is independently selected from the group consisting of:

[0264] In some embodiments, each R5is independently selected from the group consisting of:In some embodiments, each R5is independently selected from the group consisting of:

[0265] In some embodiments, each R5is independently selected from the group consisting of:. In some embodiments, each R5is independently selected from the group consisting of:

[0266] In some embodiments, each R5is independently selected from the group consisting of:. In some embodiments,R5is(G41). In some embodiments, each R5is independently selected from the group consisting of:

[0267] In some embodiments, each R5is independently selected from the group consisting of:embodiments, each R5is independently selected from the group consisting of:

[0268] In some embodiments, each R5is independently selected from the group consisting of:

[0269] In some embodiments, each R5is independently selected from the group consisting of:

[0270] In some embodiments, at least one instance of R5is optionally substituted C4-C35saturated aliphatic or optionally substituted C4-C35saturated heteroaliphatic. In some embodiments, at least one instance of R5is optionally substituted C4-C35unsaturated aliphatic or optionally substituted C4-C35unsaturated heteroaliphatic.

[0271] In some embodiments, at least one instance of R5is optionally substituted C4-C35saturated or unsaturated aliphatic. In some embodiments, at least one instance of R5isoptionally substituted C4-C12saturated or unsaturated aliphatic. In some embodiments, at least one instance of R5is optionally substituted C10-C20saturated or unsaturated aliphatic. In some embodiments, at least one instance of R5is optionally substituted C12-C25saturated or unsaturated aliphatic.

[0272] In some embodiments, at least one instance of R5is optionally substituted C4-C35alkyl or optionally substituted C4-C35alkenyl. In some embodiments, at least one instance of R5is optionally substituted C4-C10alkyl or optionally substituted C4-C10alkenyl. In some embodiments, at least one instance of R5is optionally substituted C10-C20alkyl or optionally substituted C10-C20alkenyl. In some embodiments, at least one instance of R5is optionally substituted C12-C25alkyl or optionally substituted C12-C25alkenyl.

[0273] In some embodiments, at least one instance of R5is optionally substituted C4-C35alkyl or optionally substituted C4-C35alkynyl. In some embodiments, at least one instance of R5is optionally substituted C4-C10alkyl or optionally substituted C4-C10alkynyl. In some embodiments, at least one instance of R5is optionally substituted C10-C20alkyl or optionally substituted C10-C20alkynyl. In some embodiments, at least one instance of R5is optionally substituted C12-C25alkyl or optionally substituted C12-C25alkynyl.

[0274] In some embodiments, at least one instance of R5is optionally substituted C4-C35alkynyl or optionally substituted C4-C35alkenyl. In some embodiments, at least one instance of R5is optionally substituted C4-C10alkynyl or optionally substituted C4-C10alkenyl. In some embodiments, at least one instance of R5is optionally substituted C10-C20alkynyl or optionally substituted C10-C20alkenyl. In some embodiments, at least one instance of R5is optionally substituted C12-C25alkynyl or optionally substituted C12-C25alkenyl.

[0275] In some embodiments, at least one instance of R5is branched C4-C35alkyl. In some embodiments, at least one instance of R5is branched C4-C12alkyl. In some embodiments, at least one instance of R5is branched C10-C20alkyl. In some embodiments, at least one instance of R5is branched C12-C25alkyl. In some embodiments, at least one instance of R5is unbranched C4-C35alkyl. In some embodiments, at least one instance of R5is unbranched C4- C12alkyl. In some embodiments, at least one instance of R5is unbranched C10-C20alkyl. In some embodiments, at least one instance of R5is unbranched C12-C25alkyl.

[0276] In some embodiments, at least one instance of R5is branched C4-C35alkenyl. In some embodiments, at least one instance of R5is branched C4-C35alkenyl comprising a single double bond. In some embodiments, at least one instance of R5is branched C4-C35alkenyl comprising a single (Z) double bond. In some embodiments, at least one instance of R5isbranched C4-C12alkenyl. In some embodiments, at least one instance of R5is branched C10- C20alkenyl. In some embodiments, at least one instance of R5is branched C12-C25alkenyl.

[0277] In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising a single double bond. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising a single (Z) double bond. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising two double bonds. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising two (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising three double bonds. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising three (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C4-C35alkenyl comprising only (Z) double bonds.

[0278] In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising a single double bond. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising a single (Z) double bond. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising two double bonds. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising two (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising three double bonds. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising three (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C4-C12alkenyl comprising only (Z) double bonds.

[0279] In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising a single double bond. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising a single (Z) double bond. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising two double bonds. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising two (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising three double bonds. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising three (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C10-C20alkenyl comprising only (Z) double bonds.

[0280] In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising a single double bond. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising a single (Z) double bond. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising two double bonds. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising two (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising three double bonds. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising three (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C12-C25alkenyl comprising only (Z) double bonds.

[0281] In some embodiments, at least one instance of R5is unbranched C11alkenyl. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising a single double bond. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising a single (Z) double bond. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising two double bonds. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising two (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising three double bonds. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising three (Z) double bonds. In some embodiments, at least one instance of R5is unbranched C11alkenyl comprising only (Z) double bonds.

[0282] In some embodiments, at least one instance of R5is branched C4-C35alkynyl. In some embodiments, at least one instance of R5is branched C4-C12alkynyl. In some embodiments, R5is branched C10-C20alkynyl. In some embodiments, at least one instance of R5is branched C12-C25alkynyl. In some embodiments, at least one instance of R5is unbranched C4-C35alkynyl. In some embodiments, at least one instance of R5is unbranched C4-C12alkynyl. In some embodiments, at least one instance of R5is unbranched C10-C20alkynyl. In some embodiments, at least one instance of R5is unbranched C12-C25alkynyl.

[0283] In some embodiments, at least one instance of R5is optionally substituted C4-C35saturated or unsaturated heteroaliphatic. In some embodiments, at least one instance of R5is optionally substituted C4-C35saturated or unsaturated hetero aliphatic comprising at least one O, N, or S atom. In some embodiments, at least one instance of R5is optionally substituted C4-C35saturated or unsaturated heteroaliphatic comprising at least one O or S atom. In some embodiments, at least one instance of R5is optionally substituted C4-C12saturated or unsaturated heteroaliphatic. In some embodiments, at least one instance of R5is optionally substituted C4-C12saturated or unsaturated heteroaliphatic comprising at least one O, N, or S atom. In some embodiments, at least one instance of R5is optionally substituted C4-C12saturated or unsaturated heteroaliphatic comprising at least one O or S atom. In some embodiments, at least one instance of R5is optionally substituted C10-C20saturated or unsaturated heteroaliphatic. In some embodiments, at least one instance of R5is optionally substituted C10-C20saturated or unsaturated heteroaliphatic comprising at least one O, N, or S atom. In some embodiments, at least one instance of R5is optionally substituted C10-C20saturated or unsaturated heteroaliphatic comprising at least one O or S atom. In some embodiments, at least one instance of R5is optionally substituted C12-C25saturated or unsaturated heteroaliphatic. In some embodiments, at least one instance of R5is optionally substituted C12-C25saturated or unsaturated heteroaliphatic comprising at least one O, N, or S atom. In some embodiments, at least one instance of R5is optionally substituted C12-C25saturated or unsaturated heteroaliphatic comprising at least one O or S atom.

[0284] In some embodiments, at least one instance of R5is optionally substituted C4-C35heteroalkyl or optionally substituted C4-C35heteroalkenyl. In some embodiments, at least one instance of R5is optionally substituted C4-C10heteroalkyl or optionally substituted C4- C10heteroalkenyl. In some embodiments, at least one instance of R5is optionally substituted C10-C20heteroalkyl or optionally substituted C10-C20heteroalkenyl. In some embodiments, at least one instance of R5is optionally substituted C12-C25heteroalkyl or optionally substituted C12-C25heteroalkenyl.

[0285] In some embodiments, at least one instance of R5is optionally substituted C4-C35heteroalkyl or optionally substituted C4-C35heteroalkynyl. In some embodiments, at least one instance of R5is optionally substituted C4-C10heteroalkyl or optionally substituted C4- C10heteroalkynyl. In some embodiments, at least one instance of R5is optionally substitutedC10-C20heteroalkyl or optionally substituted C10-C20heteroalkynyl. In some embodiments, at least one instance of R5is optionally substituted C12-C25heteroalkyl or optionally substituted C12-C25heteroalkynyl.

[0286] In some embodiments, at least one instance of R5is optionally substituted C4-C35heteroalkynyl or optionally substituted C4-C35heteroalkenyl. In some embodiments, at least one instance of R5is optionally substituted C4-C10heteroalkynyl or optionally substituted C4- C10heteroalkenyl. In some embodiments, at least one instance of R5is optionally substituted C10-C20heteroalkynyl or optionally substituted C10-C20heteroalkenyl. In some embodiments, at least one instance of R5is optionally substituted C12-C25heteroalkynyl or optionally substituted C12-C25heteroalkenyl.

[0287] In some embodiments, at least one instance of R5is branched C4-C35heteroalkyl. In some embodiments, R5is branched C4-C12heteroalkyl. In some embodiments, at least one instance of R5is branched C10-C20heteroalkyl. In some embodiments, at least one instance of R5is branched C12-C25heteroalkyl. In some embodiments, at least one instance of R5is unbranched C4-C35heteroalkyl. In some embodiments, at least one instance of R5is unbranched C4-C12heteroalkyl. In some embodiments, at least one instance of R5is unbranched C10-C20heteroalkyl. In some embodiments, at least one instance of R5is unbranched C12-C25heteroalkyl.

[0288] In some embodiments, at least one instance of R5is branched C4-C35heteroalkenyl. In some embodiments, at least one instance of R5is branched C4-C12heteroalkenyl. In some embodiments, at least one instance of R5is branched C10-C20heteroalkenyl. In some embodiments, at least one instance of R5is branched C12-C25heteroalkenyl. In some embodiments, at least one instance of R5is unbranched C4-C35heteroalkenyl. In some embodiments, at least one instance of R5is unbranched C4-C12heteroalkenyl. In some embodiments, at least one instance of R5is unbranched C10-C20heteroalkenyl. In some embodiments, at least one instance of R5is unbranched C12-C25heteroalkenyl.

[0289] In some embodiments, at least one instance of R5is branched C4-C35heteroalkynyl. In some embodiments, at least one instance of R5is branched C4-C12heteroalkynyl. In some embodiments, at least one instance of R5is branched C10-C20heteroalkynyl. In some embodiments, at least one instance of R5is branched C12-C25heteroalkynyl. In some embodiments, at least one instance of R5is unbranched C4-C35heteroalkynyl. In some embodiments, at least one instance of R5is unbranched C4-C12heteroalkynyl. In some embodiments, at least one instance of R5is unbranched C10-C20heteroalkynyl. In some embodiments, at least one instance of R5is unbranched C12-C25heteroalkynyl.

[0290] In some embodiments, at least one instance of R5is selected from the group consisting. In some embodiments, at least one instance of R5is selected from the group consisting of:

[0291] In some embodiments, at least one instance of R5is selected from the group consistingIn some embodiments, at least one instance of R5is selected from the group consisting of:

[0292] In some embodiments, at least one instance of R5is selected from the group consisting. In someembodiments, at least one instance of R5is selected from the group consisting of:R5is(G41). In some embodiments, at least one instance of R5is selected from the group consisting of:

[0293] In some embodiments, at least one instance of R5is selected from the group consistingIn some embodiments, at least one instance of R5is selected from the group consisting of:embodiments, at least one instance of R5is selected from the group consisting of:

[0294] In some embodiments, at least one instance of R5is selected from the group consisting

[0295] In some embodiments, at least one instance of R5is selected from the group consisting

[0296] In a particular embodiment, R5is G41. In a particular embodiment, R5is G45. In a particular embodiment, R5is G46. In a particular embodiment, R5is G47. In a particular embodiment, R5is G48. In a particular embodiment, R5is G49. In a particular embodiment, R5is G50. In a particular embodiment, R5is G51. In a particular embodiment, R5is G52. In a particular embodiment, R5is G53. In a particular embodiment, R5is G54. In a particular embodiment, R5is G55. In a particular embodiment, R5is G56. In a particular embodiment, R5is G57. In a particular embodiment, R5is G58. In a particular embodiment, R5is G62. In a particular embodiment, R5is G63. In a particular embodiment, R5is G64. In a particular embodiment, R5is G65. In a particular embodiment, R5is G66. In a particular embodiment,R5is G67. In a particular embodiment, R5is G68. In a particular embodiment, R5is GC12. In a particular embodiment, R5is GC14. In a particular embodiment, R5is GC16. In a particular embodiment, R5is GC18. In a particular embodiment, R5is G42. In a particular embodiment, R5is G43. In a particular embodiment, R5is G44. In a particular embodiment, R5is Gl. In a particular embodiment, R5is G2. In a particular embodiment, R5is G3. In a particular embodiment, R5is G4. In a particular embodiment, R5is G5. In a particular embodiment, R5is G6. In a particular embodiment, R5is G7. In a particular embodiment, R5is G8. In a particular embodiment, R5is G9. In a particular embodiment, R5is GIO. In a particularembodiment, R5is

[0297] In any of the embodiments of R5described herein, one or more carbon atoms may be replaced with a heteroatom, e.g., to form a chemical functional group such as an ester. In some embodiments, R5comprises a functional group that is biodegradable. In some embodiments, the biodegradable functional group is an ester.

[0298] As defined herein, each x independently is an integer from 1 to 10, inclusive. In some embodiments, each x independently is an integer from 1 to 9, inclusive. In some embodiments, each x independently is an integer from 1 to 8, inclusive. In some embodiments, each x independently is an integer from 1 to 7, inclusive. In some embodiments, each x independently is an integer from 1 to 6, inclusive. In some embodiments, each x independently is an integer from 1 to 5, inclusive. In some embodiments, each x independently is an integer from 1 to 4, inclusive. In some embodiments, each x independently is an integer from 1 to 3, inclusive. In some embodiments, each x independently is an integer from 1 to 2, inclusive.

[0299] In some embodiments, each x is the same. In some embodiments, at least two instances of x are the same. In some embodiments, at least three instances of x are the same. In some embodiments, at least four instances of x are the same. In some embodiments, at least five instances of x are the same. In some embodiments, at least six instances of x are thesame. In some embodiments, at least seven instances of x are the same. In some embodiments, at least eight instances of x are the same. In some embodiments, six instances of x are the same. In some embodiments, seven instances of x are the same. In some embodiments, eight instances of x are the same.

[0300] In some embodiments, at least one x is 1. In some embodiments, at least one x is 2. In some embodiments, at least one x is 3. In some embodiments, at least one x is 4. In some embodiments, at least one x is 5. In some embodiments, at least one x is 6. In some embodiments, at least one x is 7. In some embodiments, at least one x is 8. In some embodiments, at least one x is 9. In some embodiments, at least one x is 10.

[0301] In some embodiments, each x is 1. In some embodiments, each x is 2. In some embodiments, each x is 3. In some embodiments, each x is 4. In some embodiments, each x is 5. In some embodiments, each x is 6. In some embodiments, each x is 7. In some embodiments, each x is 8. In some embodiments, each x is 9. In some embodiments, each x is 10.

[0302] In some embodiments, one x is 1. In some embodiments, two x are 1. In some embodiments, three x are 1. In some embodiments, four x are 1. In some embodiments, five x are 1. In some embodiments, six x are 1. In some embodiments, seven x are 1. In some embodiments, eight x are 1.

[0303] In some embodiments, the compound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each R is . In some embodiments, thecompound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each R. In some embodiments, thecompound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each R . In some embodiments, thecompound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each R is In some embodiments,the compound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein eachR is. In some embodiments, the compound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein eachthe compound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each. In some embodiments, the compound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each R is . In some embodiments, thecompound is of Formula (XI), or a pharmaceutically acceptable salt thereof, wherein each R

[0304] In some embodiments, the compound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, thecompound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R is In some embodiments, thecompound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R. In some embodiments, the compound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R. In some embodiments, the compound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R is . In some embodiments,the compound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R is). In some embodiments, the compound is of Formula (XII), or a pharmaceutically acceptable saltIn some embodiments, the compound is of Formula (XII), or a pharmaceutically acceptablesalt thereof, wherein each R isIn some embodiments, the compound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R is). In some embodiments, the compound is of Formula (XII), or a pharmaceutically acceptable salt thereof, wherein each R is

[0305] In some embodiments, the compound of Formula (XIII) is of Formula (XIII- A):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

[0306] In some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R isIn some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R isIn some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R is In someembodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable saltthereof, wherein R1is hydrogen and each R is . In some embodiments, thecompound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R is Insome embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R is In some embodiments, thecompound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1issome embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R is . In some embodiments, thecompound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R is. In some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen and each R is

[0307] In some embodiments, the compound of Formula (XIII) is of Formula (XIII- A):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

[0308] In some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is . In some embodiments, thecompound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is - OH and each R is. In some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is. In some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is(AMG84). In some embodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is . In some embodiments, thecompound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is In someembodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R iscompound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is In someembodiments, the compound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is . In some embodiments, thecompound is of Formula (XIII), or a pharmaceutically acceptable salt thereof, wherein R1is -OH and each R is

[0309] In some embodiments, the compound of Formula (I) is of Formula (II):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In some embodiments, the compound of Formula (I) is of Formula (II), or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the compound is of the formula:or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of Formula (I) is of Formula (III):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is In some embodiments, thecompound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is . In someembodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein eachR isIn some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is In someembodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound ofFormula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R . In some embodiments, the compoundof Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein eachR is In some embodiments, thecompound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is

[0313] In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5iseach R5is(AMG1546); each R5is ; each R5iseach R5is(AMG1568).

[0314] In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R isand wherein each R5is In some embodiments, the compound of Formula(I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is . In some embodiments, the compound ofFormula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R isand wherein each R5isIn some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, wherein each R is,and wherein each R5is

[0315] In some embodiments, the compound of Formula (I) is AMG1541, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1541, wherein each chiral center has ( S) configuration. In some embodiments, the compound of Formula (I) is AMG1545, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1545, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1546, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1546, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1547, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1547, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1548, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1548, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1549, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1549, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1550, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1550, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1551, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1551, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1552, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1552, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1553, wherein each chiral center has (R) configuration. In some embodiments, the compound ofFormula (I) is AMG1553, wherein each chiral center has ( S) configuration. In some embodiments, the compound of Formula (I) is AMG1554, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1554, wherein each chiral center has ( S ) configuration. In some embodiments, the compound of Formula (I) is AMG1555, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1555, wherein each chiral center has ( S) configuration. In some embodiments, the compound of Formula (I) is AMG1556, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1556, wherein each chiral center has (S) configuration. In some embodiments, the compound of Formula (I) is AMG1557, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1557, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1558, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1558, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1559, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1559, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1560, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1560, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1561, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1561, wherein each chiral center has ( S ) configuration. In some embodiments, the compound of Formula (I) is AMG1562, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1562, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1563, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1563, wherein each chiral center has ( S ) configuration. In some embodiments, the compound of Formula (I) is AMG1564, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1564, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1565, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1565, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1566, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1566, wherein each chiral centerhas (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1567, wherein each chiral center has (R) configuration. In some embodiments, the compound ofFormula (I) is AMG1567, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1568, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1568, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG15C12, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG15C12, wherein each chiral center has (S ) configuration.

[0316] In some embodiments, the compound of Formula (I) is of Formula (IV):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein eachR is In some embodiments, thecompound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound ofFormula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each

[0318] In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is; each R5is(AMG1746); each R5is; each R5is each R5is(AMG1768).

[0319] In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is. In some embodiments, the compound of Formula(I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is . In some embodiments, the compound ofFormula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5isIn some embodiments, the compound of Formula (I) is of Formula (IV), or apharmaceutically acceptable salt thereof, wherein each R is?and wherein each R5is .

[0320] In some embodiments, the compound of Formula (I) is AMG1741, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1741, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1745, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1745, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1746, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1746, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1747, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1747, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1748, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1748, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1749, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1749, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1750, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1750, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1751, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1751, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1752, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1752, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1753, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1753, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1754, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1754, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I)is AMG1755, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1755, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1756, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1756, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1757, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1757, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1758, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1758, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1759, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1759, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1760, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1760, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1761, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1761, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1762, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1762, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1763, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1763, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1764, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1764, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1765, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1765, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1766, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1766, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1767, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1767, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1768, wherein each chiral center has (R )configuration. In some embodiments, the compound of Formula (I) is AMG1768, wherein each chiral center has (S ) configuration.

[0321] In some embodiments, the compound of Formula (I) is of Formula (V):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is . In some embodiments, thecompound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is.In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is(AMG1949). In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is . In some embodiments, the compoundof Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein eachR is . In some embodiments, thecompound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is

[0323] In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R isand wherein each R5iseach R5is(AMG1946); each R5is(AMG1952); each R5is(AMG1965); each R5is(AMG1966); each R5is(AMG1967); or each R5is(AMG1968).

[0324] In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is. In some embodiments, the compound of Formula(I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is. In some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is. In some embodiments, the compound ofFormula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R, and wherein each R5isIn some embodiments, the compound of Formula (I) is of Formula (V), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is

[0325] In some embodiments, the compound of Formula (I) is AMG1941, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG1941, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1945, wherein each chiral center has (R) configuration. Insome embodiments, the compound of Formula (I) is AMG1945, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1946, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1946, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1947, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1947, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1948, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1948, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1949, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1949, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1950, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1950, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1951, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1951, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1952, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1952, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1953, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1953, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1954, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1954, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1955, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1955, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1956, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1956, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1957, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1957, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1958, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I)is AMG1958, wherein each chiral center has (S) configuration. In some embodiments, the compound of Formula (I) is AMG1959, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1959, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1960, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1960, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1961, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1961, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1962, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1962, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1963, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1963, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1964, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1964, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1965, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1965, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1966, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1966, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1967, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1967, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG1968, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG1968, wherein each chiral center has (S ) configuration.

[0326] In some embodiments, the compound of Formula (I) is of Formula (VI):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof. In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof.

[0327] In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is . In some embodiments, the compoundof Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each. In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is. In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound of Formula (I) is of Formula (VI), or apharmaceutically acceptable salt thereof, wherein each R isIn some embodiments, the compound ofFormula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is . In some embodiments, the compoundof Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein eachR is

[0328] In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is( ); each R5is(AMG2046); each R5is(AMG2052); each R5is(AMG2057); each R5is(AMG2068).

[0329] In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is. In some embodiments, the compound of Formula(I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R is, and wherein each R5is(AMG2058). In some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R isand wherein each R5is(AMG2059). In some embodiments, the compound ofFormula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R, and wherein each R5isIn some embodiments, the compound of Formula (I) is of Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each R isand wherein each R5is

[0330] In some embodiments, the compound of Formula (I) is AMG2041, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2041, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2045, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2045, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2046, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2046, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2047, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2047, whereineach chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2048, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2048, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2049, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2049, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2050, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2050, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2051, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2051, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2052, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2052, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2053, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2053, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2054, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2054, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2055, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2055, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2056, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2056, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2057, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2057, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2058, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2058, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2059, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2059, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2060, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2060, wherein each chiral center has (S ) configuration. In someembodiments, the compound of Formula (I) is AMG2061, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2061, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2062, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2062, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2063, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2063, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2064, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2064, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2065, wherein each chiral center has (R) configuration. In some embodiments, the compound of Formula (I) is AMG2065, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2066, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2066, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2067, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2067, wherein each chiral center has (S ) configuration. In some embodiments, the compound of Formula (I) is AMG2068, wherein each chiral center has (R ) configuration. In some embodiments, the compound of Formula (I) is AMG2068, wherein each chiral center has (S ) configuration.

[0331] In some embodiments, the compound of Formula (I) is:or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.

[0332] In some embodiments, the compound of Formula (I) is:or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof.Pharmaceutical Compositions and Administration

[0333] The present disclosure provides compositions comprising a compound provided herein (e.g., a compound of Formula (I), (XI), (XII), (XIII)), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and an agent.The present disclosure also provides compositions comprising a compound provided herein (e.g., a compound of Formula (I), (XI), (XII), (XIII)), or a pharmaceutically acceptable salt thereof, and an agent.

[0334] The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising a compound provided herein (e.g., a compound of Formula (I), (XI), (XII), (XIII)), or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a composition provided herein and an excipient (e.g., a pharmaceutically acceptable excipient). The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising a compound provided herein (e.g., a compound of Formula (I), (XI), (XII), (XIII)), or a pharmaceutically acceptable salt thereof, or a composition provided herein and an excipient (e.g., a pharmaceutically acceptable excipient). In one aspect, the composition is a pharmaceutical composition. In one aspect, the composition is a pharmaceutical composition, and the excipient is a pharmaceutically acceptable excipient.

[0335] In some embodiments, the composition further comprises an agent.

[0336] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is an amount effective for delivering an agent to a subject or cell. In certain embodiments, the effective amount is an amount effective for delivering a polynucleotide to a subject or cell. In certain embodiments, the effective amount is an amount effective for delivering mRNA to a subject or cell. In certain embodiments, the effective amount is an amount effective for chimeric antigen receptor T cell therapy.

[0337] In certain embodiments, the composition further comprises one or more of a PEG- lipid, sterol, or a phospholipid. In certain embodiments, the composition comprises a PEG- lipid. In some embodiments, the composition comprises a sterol. In certain embodiments, the composition comprises a phospholipid. In certain embodiments, the composition further comprises a PEG-lipid and a sterol. In certain embodiments, the composition further comprises a PEG-lipid and a phospholipid. In certain embodiments, the composition further comprises a sterol and a phospholipid. In certain embodiments, the composition comprises one or more of a PEG-lipid, sterol, or a phospholipid and is formulated as a particle. In some embodiments, the composition comprises one or more of a PEG-lipid, sterol, or a phospholipid and is formulated as a nanoparticle or microparticle. In certain embodiments, the composition comprises one or more of a PEG-lipid, sterol, or a phospholipid and is formulated as a lipid nanoparticle. In certain embodiments, the composition comprises oneor more of a PEG-lipid, sterol, or a phospholipid and is formulated as a micelle, liposome, or lipoplex.

[0338] In some embodiments, the composition comprises approximately 20-70 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 25-65 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 20-60 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 30-60 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 35-60 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 40-60 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 45-60 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 50-60 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 55-60 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 20-30 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 20-35 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 20-40 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 20-45 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 20-50 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 20-55 molar % of the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 55, or approximately 60 molar % of the compound, or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the composition comprises approximately 0-75 molar % of a sterol. In some embod...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: n is 1, 2, or 3;A and B are independently optionally substituted saturate or unsaturated aliphatic; orA and B combine to form optionally substituted C2-C6alkylene; each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v):wherein one of R6and R7is hydrogen, and the other is wherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

2. The compound of claim 1, of Formula (II):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, of Formula (III), Formula (IV), or Formula (V):or a pharmaceutically acceptable salt thereof.

4. A compound of Formula (XI):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v):wherein one of R6and R7is hydrogen, and the other iswherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

5. A compound of Formula (XII):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v):wherein one of R6and R7is hydrogen, and the other iswherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

6. A compound of Formula (XIII):or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:R1is hydrogen, -ORA, -SRA, or -N(RA)2, each instance of RAis independently -H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or wherein two instances of RAattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each R is independently hydrogen, a nitrogen protecting group, or a group of the formula (i), (ii), (iii), (iv) or (v): wherein one of R6and R7is hydrogen, and the other iswherein one of R6and R7is hydrogen, and the other iswherein each instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is of Formula (i), (ii), (iii), (iv), or (v).

7. The compound of claim 6, wherein R1is hydrogen or -OH.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R iswherein one of R6and R7is hydrogen, and the other9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R iswherein one of R6and R7is hydrogen, and the otheris10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R6is hydrogen.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each R7is hydrogen.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein each x is 1.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein each x is 8.

14. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R is15. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R is16. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R is17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each R5is independently optionally substituted C4-C35alkyl or optionally substituted C4-C35alkenyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein each R5is independently branched C4-C35alkyl.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein each R5is independently unbranched C4-C35alkenyl.

20. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each R5is independently optionally substituted C4-C35heteroalkyl or optionally substituted C4-C35heteroalkenyl.

21. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each R5is independently optionally substituted C4-C35saturated or unsaturated heteroaliphatic comprising at least one O or S atom.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from the group consisting of:

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein each R5is24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein each instance of R5is the same.

25. The compound of claim 1, of Formula (III):or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein each R iseach R iseach R iseach R iseach R is27. The compound of claim 1, of Formula (IV):or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein each R is each R iseach R iseach R is29. The compound of claim 1, of Formula (V):or a pharmaceutically acceptable salt thereof.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein; each R is31. The compound of any one of claims 1 or 8-24, or a pharmaceutically acceptable salt thereof, wherein A and B are independently optionally substituted saturated or unsaturated aliphatic.

32. The compound of any one of claims 1, 8-24, or 31, or a pharmaceutically acceptable salt thereof, wherein A and B are independently unsubstituted C1-C6alkyl.

33. The compound of claim 1, of Formula (VI):or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein35. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein each36. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein each37. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1isOH hydrogen, and wherein: each R is(AMG31); each R is38. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1is-OH, and wherein: each R iseach R is39. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

41. A composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and an agent.

42. The composition of claim 41, wherein the agent is an organic molecule, inorganic molecule, polynucleotide, protein, peptide, polynucleotide, targeting agent, an isotopicallylabeled chemical compound, vaccine, an immunological agent, or an agent useful in bioprocessing.

43. The composition of claim 41 or 42, wherein the agent is a polynucleotide.

44. The composition of claim 43, wherein the polynucleotide is an RNA.

45. The composition of claim 44, wherein the RNA is coding RNA or non-coding RNA.

46. The composition of claim 45, wherein the coding RNA is messenger RNA (mRNA).

47. The composition of claim 44, wherein the RNA is precursor messenger RNA.

48. The composition of claim 45, wherein the non-coding RNA is double- stranded RNA, short hairpin RNA, microRNA, guide RNA, transfer RNA, antisense RNA, long non-coding RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA, ribosomal RNA, Piwi-interacting RNA, small nucleolar RNA, or spliced leader RNA.

49. The composition of claim 45, wherein the non-coding RNA is small interfering RNA.

50. The composition of claim 41 or 42, wherein the agent is ribozyme or flexizyme.

51. The composition of claim 44, wherein the RNA is single- stranded RNA, heterogeneous nuclear RNA, satellite RNA, viral RNA, or viral satellite RNA.

52. The composition of claim 43, wherein the polynucleotide is a DNA.

53. The composition of claim 52, wherein the DNA is a plasmid DNA (pDNA).

54. The composition of any one of claims 41-53, wherein the composition further comprises one or more of a PEG-lipid, sterol, or phospholipid.

55. The composition of claim 54, wherein the PEG-lipid is 1,2-dimyristoyl-sn-Glycero-3- Phosphoethanolamine-polyethylene glycol (DMPE-PEG).

56. The composition of claim 54 or 55, wherein the sterol is cholesterol.

57. The composition of any one of claims 54-56, wherein the phospholipid is 1,2- dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or distearoylphosphatidylcholine (DSPC).

58. The composition of any one of claims 54-57, wherein the composition comprises approximately 30-40% of the compound, or a pharmaceutically acceptable salt thereof, approximately 11-21% of the phospholipid, approximately 41.5-51.5% of the sterol, and approximately 1-4% of the PEG-lipid.

59. The composition of any one of claims 54-58, wherein the composition comprises approximately 35% of the compound, or a pharmaceutically acceptable salt thereof, approximately 16% of DOPE, approximately 46.5% of cholesterol, and approximately 2.5% of DMPE-PEG.

60. The composition of any one of claims 41-59, wherein the agent and the compound, or the pharmaceutically acceptable salt thereof, are not covalently attached.

61. The composition of any one of claims 41-60, wherein the composition is in the form of a particle.

62. The composition of claim 61, wherein the particle is a nanoparticle or microparticle.

63. The composition of claim 61, wherein the particle is a micelle, liposome, or lipoplex.

64. The composition of claim 61, wherein the particle encapsulates the agent.

65. A composition comprising a compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-64, and a pharmaceutically acceptable excipient.

66. The composition of claim 65, wherein the composition is a pharmaceutical composition.

67. A method of delivering an agent to a subject, tissue, or a cell, comprising administering to the subject or contacting the cell with a composition comprising an agent and a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-66.

68. The method of claim 67, wherein the agent is an organic molecule, inorganic molecule, polynucleotide, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, an immunological agent, or an agent useful in bioprocessing.

69. The method of claim 67 or 68, wherein the agent is a polynucleotide.

70. The method of claim 69, wherein the polynucleotide is an RNA.

71. The method of claim 70, wherein the RNA is coding RNA or non-coding RNA.

72. The method of claim 71, wherein the coding RNA is messenger RNA (mRNA).

73. The method of claim 72, wherein the mRNA encodes for the SARS-CoV-2 B.1.617.2 spike protein.

74. The method of claim 72, wherein the mRNA encodes for the SARS-CoV-2 B.1.617.2 spike protein with 984P and 985P mutations.

75. The method of claim 72, wherein the mRNA encodes for the H3 protein of influenza virus.

76. The method of claim 70, wherein the RNA is precursor messenger RNA.

77. The method of claim 71, wherein the non-coding RNA is double-stranded RNA, short hairpin RNA, microRNA, guide RNA, transfer RNA, antisense RNA, long non-coding RNA,signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA, ribosomal RNA, Piwi-interacting RNA, small nucleolar RNA, or spliced leader RNA.

78. The method of claim 71, wherein the non-coding RNA is small interfering RNA.

79. The method of claim 67 or 68, wherein the agent is ribozyme or flexizyme.

80. The method of claim 70, wherein the RNA is single-stranded RNA, heterogeneous nuclear RNA, satellite RNA, viral RNA, or viral satellite RNA.

81. The method of claim 69, wherein the polynucleotide is a DNA.

82. The method of claim 81, wherein the DNA is a plasmid DNA (pDNA).

83. The method of any one of claims 67-82, wherein the polynucleotide is delivered to the liver or spleen of the subject.

84. The method of any one of claims 67-83, wherein the composition is administered intravenously.

85. The method of any one of claims 67-83, wherein the composition is administered intramuscularly.

86. A compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-66 for use in delivering an agent to a subject, tissue, or a cell.

87. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-66 in the manufacture of a medicament for delivering an agent to a subject, tissue, or a cell.

88. A method of treating and / or preventing a disease, disorder, or condition in a subject, comprising administering to the subject a composition comprising an agent and a compoundof any one of claims 1-40, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-66.

89. The method of claim 88, wherein the disease, disorder, or condition is a genetic disease, proliferative disease, hematological disease, neurological disease, liver disease, spleen disease, lung disease, painful condition, psychiatric disorder, musculoskeletal disease, a metabolic disorder, inflammatory disease, or autoimmune disease.

90. The method of claim 88 or 89, wherein the disease, disorder, or condition is a liver disease or spleen disease.

91. A compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-66 for use in treating and / or preventing a disease, disorder, or condition in a subject.

92. Use of a compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-66 in the manufacture of a medicament for treating and / or preventing a disease, disorder, or condition in a subject.

93. A method of preparing a compound of Formula (!'):or a salt thereof, the method comprising reacting a compound of Formula (VII):or a salt thereof, with a compound of Formula (VIII):or a salt thereof, wherein: n is 1, 2, or 3;A and B are independently optionally substituted saturated or unsaturated aliphatic; or A and B combine to form optionally substituted C2-C6alkylene; each R is independently hydrogen, a nitrogen protecting group, or, 7 wherein one of R and R is hydrogen, and the other iseach instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated hetero aliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is94. The method of claim 93, wherein the compound of Formula (VII) is of Formula (VII- a):or a salt thereof.

95. The method of claim 93, wherein the compound of Formula (VII) is of Formula (VII- b), Formula (VII-c), or Formula (Vll-d):or a salt thereof.

96. A method of preparing a compound of Formula (XI'):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (XI"):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: each R is independently hydrogen, a nitrogen protecting group, orwherein one of R and R is hydrogen, and the other iseach instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is97. A method of preparing a compound of Formula (XII'):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (XII"):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein: each R is independently hydrogen, a nitrogen protecting group, orwherein one of R6and R7is hydrogen, and the other iseach instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is98. A method of preparing a compound of Formula (XIII'):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, the method comprising reacting a compound of Formula (XIII"):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, with a compound of Formula (VIII):or a salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:R1is hydrogen, -ORA, -SRA, or -N(RA)2, each instance of RAis independently -H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or wherein two instances of RAattached to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;OH each R is independently hydrogen, a nitrogen protecting group, orwherein one of R and R is hydrogen, and the other iseach instance of R5is independently optionally substituted C4-C35saturated or unsaturated aliphatic or optionally substituted C4-C35saturated or unsaturated heteroaliphatic; and each x independently is an integer from 1 to 10, inclusive; provided that at least one R is99. The method of claim 98, wherein R1is hydrogen or -OH.OH100. The method of any one of claims 93-99, wherein each R is101. The method of any one of claims 93-100, wherein each R5is independently optionally substituted C4-C35alkyl or optionally substituted C4-C35alkenyl.

102. The method of any one of claims 93-101, wherein each R5is independently branched C4-C35alkyl.

103. The method of any one of claims 93-101, wherein each R5is independently unbranched C4-C35alkenyl.

104. The method of any one of claims 93-99, wherein each R5is independently optionally substituted C4-C35heteroalkyl or optionally substituted C4-C35heteroalkenyl.

105. The method of any one of claims 93-99, wherein each R5is independently optionally substituted C4-C35saturated or unsaturated heteroaliphatic comprising at least one O or S atom.

106. The method of any one of claims 93-99, wherein each R5is independently selected from the group consisting of:

107. The method of any one of claims 93-106, wherein each R5is108. A method of preparing a compound of Formula (VIII):or a salt thereof, the method comprising reacting a compound of Formula (IX):or a salt thereof, with a carbodiimide coupling agent, or a salt thereof, and a compound of Formula (X):or a salt thereof, wherein: x is an integer from 1 to 10, inclusive; andR5is optionally substituted C4-C35unsaturated aliphatic or optionally substituted C4- C35unsaturated hetero aliphatic.

109. The method of claim 108, wherein the carbodiimide coupling agent is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride.

110. The method of claim 108 or 109, wherein x is 1.

111. The method of claim 108 or 109, wherein x is 8.

112. The method of any one of claims 108-111, wherein R5is optionally substituted C4-C35alkenyl.

113. The method of any one of claims 108-112, wherein R5is unbranched C4-C35alkenyl.

114. The method of any one of claims 108-113, wherein R5is unbranched C4-C35alkenyl comprising at least one (Z) alkene.

115. The method of any one of claims 108-111, wherein R5is optionally substituted C4-C35heteroalkenyl.

116. The method of any one of claims 108-111 or 115, wherein R5is optionally substituted C4-C35heteroalkenyl comprising at least one O or S atom.

117. The method of any one of claims 108-116, wherein R5is selected from the group consisting of:

118. The method of claim 117, wherein R5is119. A kit comprising: a compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 41-66; and instructions for using the compound, or pharmaceutically acceptable salt thereof, or composition.