Nucleoside-derived lipids for drug delivery

Abstract

The present disclosure provides compounds of Formula (I) or (II). The compounds may function as ionizable lipids and may facilitate the delivery of pharmaceutical agents to subjects. The present disclosure also provides pharmaceutical compositions and kits comprising the compounds; methods of delivering pharmaceutical agents to subjects; and methods of treating or preventing diseases (e.g., liver diseases) in subjects.

Description

[0001] NUCLEOSIDE-DERIVED LIPIDS FOR DRUG DELIVERY

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 616,449, filed December 29, 2023. The disclosure of the prior application is considered part of and is incorporated by reference in its entirety in the disclosure of this application.

[0004] BACKGROUND

[0005] Pharmaceutical compositions have been used for the delivery of pharmaceutical agents to subjects for the purpose of increasing efficacy and / or reducing toxicity. One of the excipients of the pharmaceutical compositions is an ionizable lipid or cationic lipid. There is a need for improved ionizable lipids or cationic lipids.

[0006] SUMMARY OF THE DISCLOSURE

[0007] In one aspect, the present disclosure provides compounds of Formula I: and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein, among other things: one or more of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Pl:

[0008] -L1-N*(R6)(R6)

[0009] (P1); each nitrogen atom marked with * is attached to a carbon atom of L1; and each carbon atom attached to each nitrogen atom marked with * is an sp3hybridized carbon atom; each instance of R6is independently substituted or unsubstituted alkyl or hydrogen, or two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted heterocyclyl; one or more of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2 or Q3 and optionally with a moiety of Formula Q1: -L2-L3-C(R7)(B1)2-L2-L3-C(B1)3or -L2-L3-C(R7)2(B1)

[0010] (Q2), (Q3), ( Q1); each instance of B1is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and the longest unbranched carbon backbone of each instance of B1is independently C4-10.

[0011] In another aspect, the present disclosure provides compounds of Formula II: and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein:

[0012] R1is hydrogen, -ORa, -SRa, or -L2-L3-CH(R7)X(B1)2.x, wherein Rais hydrogen, - (substituted or unsubstituted, C1-8alkylene)-N(substituted or unsubstituted, C1-5alkyl)2, or - (substituted or unsubstituted, C1-8alkenylene)-N(substituted or unsubstituted, C1-5alkyl)2;

[0013] R2is -L2-L3-CH(R7)x(B1)2,x, -(substituted or unsubstituted, C1-8alkylene)- N(substituted or unsubstituted, C1-5alkyl)2, or -(substituted or unsubstituted, C1-8alkenylene)- N(substituted or unsubstituted, C1-5alkyl)2;

[0014] R3is -L2’-L3-CH(R7’)X(B1’)2-X; and

[0015] R5is hydroxyl, -N(Rb)2, or -L2-L3-CH(R7)X(B1)2-x, wherein each instance of Rbis independently hydrogen or substituted or unsubstituted alkyl; each instance of x is independently 0 or 1 ; each instance of L2is independently a single bond, -(CH2)1-3-(1-yl-1,2,3-triazol-4-yl)- (CH2)1-20-, -(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-, -O-(CH2)1-3-(1-yl-1,2,3-triazol-4-yl)- (CH2)1-20-, or -0-(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-; each instance of L3is independently -O-, -S-, -S-S-, -NRZ-, -C(=O)O-, -C(=NRZ)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRZ-, -C(=NRZ)NRZ-, -S(=O)NRZ-, -S(=O)2NRZ-, -OC(=O)-, -OC(=NRZ)-, -OS(=O)-, -OS(=O)2-, -NRZC(=O)-, -NRZC(=NRZ)-, -NRZS(=O)-, - NRZS(=O)2-, -OC(=O)O-, -OC(=NRZ)O-, -OS(=O)O-, -OS(=O)2O-, -NRZC(=O)O-, - NRZC(=NRZ)O-, -NRZS(=O)O-, -NRZS(=O)2O-, -OC(=O)NRZ-, -OC(=NRZ)NRZ-, - OS(=O)NRZ-, -OS(=O)2NRZ-, -NRZC(=O)NRZ-, -NRZC(=NRZ)NRZ-, -NRZS(=O)NRZ-, - NRZS(=O)2NRZ-, -C(=O)-, -C(=NRZ)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORZ)O-, - SP(=O)(ORZ)O-, -OP(=O)(ORZ)S-, or -OP(=O)(SRz)O-; each instance of Rzis independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; each instance of R7is independently hydrogen, halogen, unsubstituted C1-8alkyl, or C1-8alkyl substituted with one or more instances of halogen; each instance of B1is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and the longest unbranched carbon backbone of each instance of B1is independently C6-30.

[0016] The provided compounds may function as ionizable lipids or cationic lipids. The nitrogen atoms marked with * may be ionizable (e.g., protonated) (e.g., under physiological conditions) to form cations. The B1moieties may be lipophilic. The compounds may be capable of electrostatically binding pharmaceutical agents (e.g., oligonucleotides or polynucleotides) and thus facilitate their delivery to a subject (e.g., a human). The ionizable behavior of the compounds provided herein may improve the intended purposes of a pharmaceutical composition, e.g., by helping with endosomal escape and reducing toxicity as compared with pharmaceutical compositions that do not comprise such compounds. The compounds provided herein may be useful for delivering pharmaceutical agents to a subject. The compounds provided herein may also be useful for treating or preventing a disease in a subject.

[0017] In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein, and a pharmaceutically acceptable excipient.

[0018] In another aspect, the present disclosure provides kits comprising one or more compounds or pharmaceutical composition described herein, and instructions for using the one or more compounds or pharmaceutical composition.

[0019] In another aspect, the present disclosure provides methods for delivering one or more pharmaceutical agents to a subject comprising administering to the subject a pharmaceutical composition described herein.

[0020] In another aspect, the present disclosure provides for the use of a pharmaceutical composition described herein for the manufacture of a medicament for delivering one or more pharmaceutical agents to a subject.

[0021] In another aspect, the present disclosure provides a pharmaceutical composition described herein for use in delivering one or more pharmaceutical agents to a subject.

[0022] In another aspect, the present disclosure provides methods for treating a disease in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition provided herein. In another aspect, the present disclosure provides for the use of a pharmaceutical composition described herein for the manufacture of a medicament for treating a disease in a subject in need thereof.

[0023] In another aspect, the present disclosure provides a pharmaceutical composition described herein for use in treating a disease in a subject in need thereof.

[0024] In another aspect, the present disclosure provides methods for preventing a disease in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition provided herein.

[0025] In another aspect, the present disclosure provides for the use of a pharmaceutical composition described herein for the manufacture of a medicament for preventing a disease in a subject in need thereof.

[0026] In another aspect, the present disclosure provides a pharmaceutical composition described herein for use in preventing a disease in a subject in need thereof.

[0027] It is understood that the embodiments provided herein with respect to preferred variable selections can be taken alone or in combination with one or more embodiments, or other preferred variable selections provided herein, as if each combination were explicitly listed herein.

[0028] It should be appreciated that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying Drawings, which constitute a part of this specification, illustrate embodiments of the disclosure.

[0031] FIG. 1 shows the percent editing ratio at day 1 and day 7 following administration of lipid nanoparticle formulations to mice.

[0032] FIG. 2 shows the average relative hAAT protein following administration of 2.5 mg / kg of each pharmaceutical agent in lipid nanoparticle formulations.

[0033] DEFINITIONS

[0034] 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.

[0035] 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 33:2' T25 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0036] 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. The term “isotopically labeled compound” refers to a derivative of a compound that only structurally differs from the compound in that at least one atom of the derivative includes at least one isotope enriched (e.g., enriched 3-10, 10-100, 100-1,000, or 1,000-10,000-fold, inclusive) above its natural abundance, whereas each atom of the compound includes isotopes at their natural abundances. In certain embodiments, the isotope enriched above its natural abundance is2H (e.g., 1, 2, 3, 4, or 52H atoms). In certain embodiments, the isotope enriched above its natural abundance is13C (e.g., 1, 2, or 313C atoms). In certain embodiments, the isotope enriched above its natural abundance is15N (e.g., 1, 2, or 315N atoms). In certain embodiments, the isotope enriched above its natural abundance is18O (e.g., 1, 2, or 318O atoms).

[0037] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “C1-6alkyl” 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.

[0038] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 100 carbon atoms (“C1-100alkyl”). In some embodiments, an alkyl group has 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 (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). Insome 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- hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as fluorine). 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 (z-Bu)). In certain embodiments, the alkyl group is a substituted C1-12alkyl (such as substituted C 1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0039] 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, sulfur, and phosphorous 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 100 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-100alkyl”). 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 group having 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 (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., -CH3)). In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-12alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-12alkyl. In some embodiments, unsubstituted heteroC1alkyl is -OCH3or -CH2OH. In some embodiments, substituted heteroC1alkyl is -C(=O)NH2. In some embodiments, unsubstituted heteroC2 alkyl is -OCH2CH3, -CH2OCH3, or -CH2CH2OH. The terms “heteroCz1-z2alkyl” and “Cz1-z2heteroalkyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0040] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0041] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0042] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 100 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 100 carbon atoms (“C1-100alkenyl”). In some embodiments, an alkenyl group has at least 2 carbon atoms. 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”). In certain embodiments, an alkenyl group is C2-3alkenyl, C2-4alkenyl, C2-5alkenyl, C2-6alkenyl, C2-7alkenyl, C2-8alkenyl, C2-9alkenyl, C2-10alkenyl, C2-12alkenyl, C2-16alkenyl, C2-20alkenyl, C2-30 alkenyl, C2-40alkenyl, C2-50alkenyl, C2-60alkenyl, C2-70alkenyl, C2-80alkenyl, C2-90alkenyl, or C2-100alkenyl. 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 C1-4alkenyl 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=CHCH3or ) may be in the (E)- or (Z)-configuration.

[0043] 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, sulfur, and phosphorous 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 100 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1-100alkenyl”). In some embodiments, a heteroalkenyl group has at least 2 carbon atoms. 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 (“hetero C1-11alkenyl”). 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 (“hctcro C1-4alkenyl”). 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 group has 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”). In certain embodiments, a heteroalkenyl group is C2-3heteroalkenyl, C2-4 heteroalkenyl, C2-5heteroalkenyl, C2-6heteroalkenyl, C2-7heteroalkenyl, C2-8heteroalkenyl, C2-9heteroalkenyl, C2-10heteroalkenyl, C2-12heteroalkenyl, C2-16heteroalkenyl, C2-20heteroalkenyl, C2-30heteroalkenyl, C2-40heteroalkenyl, C2-50heteroalkenyl, C2-60 heteroalkenyl, C2-70 heteroalkenyl, C2-80heteroalkenyl, C2-90heteroalkenyl, or C2-100heteroalkenyl. 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 (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., -CH3)). In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC1-20alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC1-20alkenyl. In some embodiments, unsubstituted heteroCi alkenyl is -CH=NH or =N-CH3. The terms “heteroCz1-z2alkenyl” and “Czi-z2heteroalkenyl” are used interchangeably, wherein each of zl and z2 is independently an integer.

[0044] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 100 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-100alkynyl”). In some embodiments, an alkynyl group has 1 to 20 carbon atoms (“C1-20alkynyl”). In some embodiments, an alkynyl group has at least 2 carbon atoms. 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”). In certain embodiments, an alkynyl group is C2-3alkynyl, C2-4alkynyl, C2-5alkynyl, C2-6alkynyl, C2-7alkynyl, C2-8alkynyl, C2-9alkynyl, C2-10 alkynyl, C2-12 alkynyl, C2-16alkynyl, C2-20alkynyl, C2-30alkynyl, C2-40alkynyl, C2-50alkynyl, C2-60alkynyl, C2-70alkynyl, C2-80alkynyl, C2-90 alkynyl, or C2-100alkynyl. 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.

[0045] 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, sulfur, and phosphorous 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 refers to a group having from 1 to 100 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1-100alkynyl”). In some embodiments, a heteroalkynyl group has at least 2 carbon atoms. In certain embodiments, a heteroalkynyl group refers to 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”). In certain embodiments, a heteroalkynyl group is C2-3heteroalkynyl, C2-4heteroalkynyl, C2-5heteroalkynyl, C2-6heteroalkynyl, C2-7heteroalkynyl, C2-8heteroalkynyl, C2-9heteroalkynyl, C2-10heteroalkynyl, C2-12heteroalkynyl, C2-16heteroalkynyl, C2-20heteroalkynyl, C2-30heteroalkynyl, C2-40 heteroalkynyl, C2-50heteroalkynyl, C2-60heteroalkynyl, C2-70heteroalkynyl, C2-80heteroalkynyl, C2-90heteroalkynyl, or C2-100heteroalkynyl. 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 (e.g., oxo, substituted or unsubstituted C1-6alkyl (e.g., -CH3)). In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC1-20alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC1-20alkynyl. In some embodiments, unsubstituted heteroCi alkynyl is -C=N. The terms “heteroCz1-z2alkynyl” and “Cz1-z2heteroalkynyl” are used interchangeably, wherein each of z1 and z2 is independently an integer.

[0046] 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 some embodiments, 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- 177- indenyl (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]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14carbocyclyl.

[0047] 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, a cycloalkyl 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 C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6 cycloalkyl 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.

[0048] 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 continues 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 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0049] 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.

[0050] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1 ,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 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- 1H- pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2- b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0051] 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. 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 ring members continues 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.

[0052] 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.

[0053] 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.

[0054] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).

[0055] The term “alkoxy” refers to an -O-alkyl substituent.

[0056] Affixing the suffix “-ene” to a group indicates the resulting group is a polyvalent (e.g., divalent, bivalent, or tetravalent) moiety. For example, alkylene is a polyvalent moiety of alkyl, alkenylene is a polyvalent moiety of alkenyl, alkynylene is a polyvalent moiety of alkynyl, heteroalkylene is a polyvalent moiety of heteroalkyl, heteroalkenylene is a polyvalent moiety of heteroalkenyl, heteroalkynylene is a polyvalent moiety of heteroalkynyl, carbocyclylene is a polyvalent moiety of carbocyclyl, heterocyclylene is a polyvalent moiety of heterocyclyl, arylene is a polyvalent moiety of aryl, and heteroarylene is a polyvalent moiety of heteroaryl. In some embodiments, unsubstituted C1heteroalkylene is -OCH2- or -CH2O-. In some embodiments, substituted C1heteroalkylene is -NHC(=O)- or -C(=O)NH- In some embodiments, unsubstituted C2 heteroalkylene is -OCH2CH2- or -CH2CH2O-. In some embodiments, unsubstituted C4heteroalkylene is -(OCH2CH2)2- or -(OCH2CH2)2- In some embodiments, unsubstituted C6heteroalkylene is -(OCH2CH2)3- or -(OCH2CH2)3- In some embodiments, unsubstituted C8heteroalkylene is -(OCH2CH2)4- or -(OCH2CH2)4-. In some embodiments, unsubstituted C10heteroalkylene is -(OCH2CH2)5- or -(OCH2CH2)5- In some embodiments, unsubstituted C12heteroalkylene is -(OCH2CH2)6- or -(OCH2CH2)6-

[0057] 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 disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0058] 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(=0)Raa, -NRbbC02Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NR^SChR^, -SO2N(Rbb)2, -SChRaa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, — Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORcc)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X-, -P(ORCC)3+X-, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X-, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(RCC)4, -OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), 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, 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; wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; 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, -CO3Raa, -SChRaa, -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)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, 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 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, C1-20perhaloalkyl, 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 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, -ON(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, -OP(=O)(Ree)2, -OP(=O)(ORee)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, C1-10perhaloalkyl, 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(C16alkyl), -NHC(=O)( C1-6alkyl), -N(C1-6alkyl)C(=O)( C1-6alkyl), -NHCO2(CI6alkyl), -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(C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI6alkyl), -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(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)(OC1-6alkyl)2, -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(=O)(OC1-6alkyl)2, C1-10alkyl, C1-10perhaloalkyl, C1-10alkenyl, C1-10alkynyl, heteroC1-10alkyl, heteroC1-10alkenyl, hetero C1-10alkynyl, C3-10carbocyclyl, 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.

[0059] A “counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Etxemplary counterions include halide ions (e.g., F , Cl , Br , I ), NO3, CIO4, OH-, H2PO4, HCO3-, HSO4, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4-, PF4, PF6, AsF6. SbF6, B[3,5-(CF3)2C6H3]4]-, B(C6F5)4-, BPh4, AI(OC(CF3)3)4, and carborane anions (e.g., CB11H12or (HCB11Me5Br6) ). Exemplary counterions which may be multivalent include CO32-, HPO42-, PO43-, B4O72-, SO42-, S2O32-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0060] 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(=0)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).

[0061] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, -C(=0)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(=0)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10alkyl, 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.

[0062] 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(=0)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, C1-10alkyl (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 whereinRaa Rbb,Rccand Rdd are 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.

[0063] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N -b enzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o- nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N - dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N -a ctyl meth ion inc derivatives, o-nitrobenzamide, and o- (benzoyloxymethyl)benzamide.

[0064] 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)fluorenylmethyl 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)-! -methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-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 carbamatet,-buty l 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-nitrobcnzyl carbamate, p-bromobcnzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-bcnzyl thiocarbamate, p-cyanobcnzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p- decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, 1 , 1 -di mcthy l-3-( N,N-dimcthy Icarboxam ido)propy I carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p ’-methoxyphenylazo )benzyl carbamate, 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- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0065] 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),

[0066] 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.

[0067] 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, A-acctyl meth ion inc derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimide, A-dithiasuccinimide (Dts), A-2,3- diphenylmaleimide, A-2,5-di methyl pyrrole, A- 1 , 1 ,4,4-tctramcthyldisilylazacyclopcntanc adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3- dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, N- allylamine, A-[2-(trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l- isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, N- di(4-methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphcnyl methylamine (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, A- 1,1 -dimethylthiomethyleneamine, A-benzylideneamine, A-p- methoxybenzylideneamine, A-diphenylmethyleneamine, A- [(2-pyridyl)mesityl]methyleneamine, A-(A’,A’-dimethylaminomethylene)amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A- 5-chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A- cyclohexylideneamine, A-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, A-borane derivatives, A- diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl] amine, A- copper chelate, A- zinc chelate, A-nitroamine, A-nitrosoamine, amine A-oxide, diphenylphosphinamide (Dpp), dimethylthiopho sphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are A,A’-isopropylidenediamine. In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0068] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or 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 Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or an oxygen protecting group.

[0069] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X-, -P(ORCC)2, -P(ORCC)3+X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X-, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999.

[0070] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxy tetrahydrothiopyranyl S,S-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, l-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxyethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophcnyl, p-mcthoxyphcnyl, 2,4-dinitrophenyl, benzyl (Bn), p-mcthoxybcnzyl (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 N -oxido, diphenylmethyl, p,p ’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'- dimethoxytriphenylmethyl or DMT), a-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-mcthoxyphcnyl)phcnyl methyl, tri(p- methoxyphenyl)methyl, 4-(4’ -bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) Jtrityl 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 ,S'„S’-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldi methyl si ly I (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS)t,-buty lmcthoxyphcnylsilyl (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-buty l carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p- nitrobenzyl 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(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl A^-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0071] 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.

[0072] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-io alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl or a sulfur protecting group.

[0073] 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 -R^, -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.

[0074] 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. 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 the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and 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.

[0075] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0076] 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. In some embodiments, the compounds provided herein are prepared, e.g., in crystalline form. In some embodiments, the compounds provided herein are prepared, e.g., in crystalline form, and are 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. In certain embodiments, the solvate is a hydrate.

[0077] The term “hydrate” refers to a compound, or a salt thereof, that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound, or a salt thereof, is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, in some embodiments, a hydrate of a compound, or a salt thereof, is represented, for example, by the general formula R x H2O, wherein R is the compound, or a salt thereof, and x is a number greater than 0. A given compound, or a salt thereof, 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)). 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 one change 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. In certain embodiments, the tautomer is a tautomer of a nucleobase.

[0078] 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”.

[0079] 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. In some embodiments, an enantiomer is 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”. In certain embodiments, the stereoisomer is a stereoisomer of a compound described herein with respect to the chiral center at the 1'-, 2'-, 3'-, or 4-position.

[0080] 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. In some embodiments, co-crystals are useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein.

[0081] 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. In some embodiments, various polymorphs of a compound (or a salt, hydrate, or solvate thereof) are prepared by crystallization under different conditions.

[0082] The term “prodrug” refers to a compound that may be converted under physiological conditions or by solvolysis to a compound described herein. The prodrug may be a precursor of the compound and may be pharmaceutically acceptable. The prodrug may be inactive when administered to a subject, but at least one of the converted products, e.g., the compound, may be active. Compared to the compound, the prodrug may offer advantages, such as higher solubility, higher permeability, higher absorption, improved distribution, improved metabolism, improved excretion, higher exposure, higher tissue compatibility, slower delivery, more sustained delivery, lower toxicity, and / or wider therapeutic window (see, e.g., Bundgard, H., DESIGN OF PRODRUGS (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The prodrug may be a compound wherein a hydrogen atom of -OH, -NH2, -SH, -C(=O)OH, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O- of the compound is replaced with a protecting group (“PG,” e.g., a carbon- bound moiety, such as substituted or unsubstituted alkyl or substituted or unsubstituted phenyl). The prodrug that comprises -OPG, -NPG2, -SPG, -C(=O)OPG, -OP(=O)(OPG)O-, -SP(=O)(OPG)O-, -OP(=O)(OPG)S-, or -OP(=O)(SPG)O- may be converted under physiological conditions or by solvolysis to form -OH, -NH2, -SH, -C(=O)OH, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-. Examples of prodrugs include, but are not limited to glutathione, acyloxy, thioacyloxy, 2-carboalkoxyethyl, disulfide, thiaminal, and enol ester derivatives of a phosphorus atom-modified nucleic acid. Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., “Prodrugs or phosphonates and phosphates: crossing the membrane” Top. Curr. Chem., 2015, 360:115-160. In certain embodiments, the prodrug is a prodrug of any of the formulae described herein. A “subject” to which administration is contemplated refers to a human (e.g., 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.

[0083] The term “administer, ” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound, pharmaceutical agent, or pharmaceutical composition described herein in or on a subject.

[0084] 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.

[0085] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population of subjects.

[0086] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0087] An “effective amount” of a pharmaceutical agent or pharmaceutical composition described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a pharmaceutical agent or pharmaceutical composition 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 pharmaceutical agent or pharmaceutical composition, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a pharmaceutical agent or pharmaceutical composition described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a pharmaceutical agent or pharmaceutical composition 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).

[0088] A “therapeutically effective amount” of a pharmaceutical agent or pharmaceutical composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more signs and / or symptoms associated with the condition. In certain embodiments, the therapeutically effective amount is 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.

[0089] A “prophylactically effective amount” of a pharmaceutical agent or pharmaceutical composition is an amount sufficient to prevent a condition, or one or more signs and / or symptoms associated with the condition or prevent its recurrence. In certain embodiments, the prophylactically effective amount is an amount that improves overall prophylaxis and / or enhances the prophylactic efficacy of another prophylactic agent.

[0090] The term “composition” means a mixture of substances. The term “pharmaceutical composition” means a composition suitable for administering to a subject.

[0091] The term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than 2,000 g / mol. In certain embodiments, the molecular weight of a small molecule is not more than 1,500 g / mol. In certain embodiments, the molecular weight of a small molecule is not more than 1,000 g / mol, not more than 900 g / mol, not more than 800 g / mol, not more than 700 g / mol, not more than 600 g / mol, not more than 500 g / mol, not more than 400 g / mol, not more than 300 g / mol, not more than 200 g / mol, or not more than 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least 100 g / mol, at least 200 g / mol, at least 300 g / mol, at least 400 g / mol, at least 500 g / mol, at least 600 g / mol, at least 700 g / mol, at least 800 g / mol, or at least 900 g / mol, or at least 1,000 g / mol. Combinations of the above ranges (e.g., at least 200 g / mol and not more than 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589. All listed drugs are considered acceptable for use in accordance with the present disclosure.

[0092] The term “peptide,” “polypeptide,” or “protein” refers to an oligomer or polymer of amino acid residues covalently connected together by peptide bonds. A peptide, polypeptide, or protein may be of any size, structure, and function, and may be an individual peptide, polypeptide, or protein, or a collection (e.g., a complex) of peptides, polypeptides, and proteins, and optionally small molecules and / or metal ions. In certain embodiments, a peptide comprises between 2 and 10, between 11 and 20, between 21 and 30, between 31 and 40, or between 41 and

[0093] 50, inclusive, amino acid residues. In certain embodiments, a polypeptide or protein comprises between 51 and 100, between 101 and 200, between 201 and 300, between 301 and 500, between

[0094] 501 and 1,000, between 1,001 and 3,000, between 3,001 and 10,000, or between 10,001 and

[0095] 30,000, inclusive, amino acid residues. A peptide, polypeptide, or protein may contain only natural amino acids but no non-natural amino acids; only non-natural amino acids but no natural amino acids; or both natural and non-natural amino acids. A peptide, polypeptide, or protein may contain amino acid analogs only or in addition to natural and / or non-natural amino acids. In certain embodiments, the amino acid residues of a peptide, polypeptide, or protein are residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and / or valine, in D and / or L form (e.g., in L form). One or more of the amino acid residues in a peptide, polypeptide, or protein may be alpha amino acid residues or homologs thereof (e.g., beta amino acid residues). One or more of the amino acid residues in a peptide, polypeptide, or protein may be protected or unprotected. One or more (e.g., two) of the termini of a peptide, polypeptide, or protein may be protected (e.g., to form an ester or amide) or unprotected (e.g., as -NH2, -NH3+, -C(=O)OH, or -C(=O)O ). One or more of the amino acid residues in a peptide, polypeptide, or protein may be modified or unmodified. A modification to an amino acid residue in a peptide, polypeptide, or protein may be an addition of a carbohydrate group, a hydroxyl group, a phosphate group, a famesyl group, an isofarnesyl group, a fatty acid group, or a linker for conjugation or functionalization. A peptide, polypeptide, or protein may be naturally occurring, recombinant, synthetic, or a combination thereof. A peptide, polypeptide, or protein may be a fragment of a naturally occurring peptide, polypeptide, or protein.

[0096] The term “nucleic acid” refers to compounds composed of linked monomeric nucleotides or nucleosides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single- stranded nucleic acids, and double- stranded nucleic acids.

[0097] The term “DNA” refers to a polymer comprising an oligomeric strand of deoxyribonucleotides. DNA is often double-stranded and comprises two such oligomeric strands that are complementary to one another and coil around each other to form a double helix. DNA molecules typically carry genetic instructions and can be translated into RNA. 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), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA.

[0098] The term “RNA” refers to a polymer comprising an oligomeric strand of ribonucleotides. RNA can be single-stranded or double- stranded. Some RNAs act as a template for the production of proteins, (e.g., messenger RNAs), while other RNAs are non-coding and are capable of independently performing other biological functions (e.g., in gene regulation). 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), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA. The term “oligomeric compound” or “oligomer” means a compound that consists of a small number of linked (e.g., covalently linked) subunits. With reference to a protein, peptide, polypeptide, or antibody, “subunit” refers to an amino acid (e.g., protected or unprotected amino acid) or peptide bond. With reference to an oligonucleotide, “subunit” refers to a nucleotide, nucleoside, nucleobase, intemucleosidic linker, or sugar, or a modified nucleotide, nucleoside, nucleobase, intemucleosidic linker, or sugar, or a combination thereof (e.g., a combination of nucleobase, intemucleosidic linker, or sugar, each of which may be modified or unmodified). The small number may be between 6 and 100, inclusive. In some embodiments, the small number is between 6 and 9, between 10 and 13, between 14 and 18, between 19 and 23, between 24 and

[0099] 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between

[0100] 81 and 100, inclusive.

[0101] The term “oligonucleotide” means an oligomer of linked (e.g., covalently linked) nucleotides and / or nucleosides (e.g., nucleic acid, oligomer of nucleotides), each of which can be modified or unmodified, independent from one another. Without limitation, an oligonucleotide may be comprised of ribonucleic acids (e.g., comprised of ribonucleosides), deoxyribonucleic acids (e.g., comprised of deoxyribonucleosides), modified nucleic acids (e.g., comprised of modified nucleobases, sugars, and / or phosphate groups), or a combination thereof. Oligonucleotides may comprise one or more loops in their structure (e.g., a stem loop, hairpin loop, or internal loop in the structure of an RNA). Oligonucleotides may be single-stranded or double-stranded and may be RNA, DNA, or a hybrid thereof. Oligonucleotides may include single- stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), chloroplast DNA (ctDNA or cpDNA), micro satellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, viral DNA, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), messenger RNA (mRNA), precursor messenger RNA (pre- mRNA), transfer RNA (tRNA), 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), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, antisense oligonucleotides (e.g., antisense DNA and antisense RNA), interfering RNA compounds (RNAi compounds), circular RNA (circRNA) compounds, microRNA (miRNA) targeting oligonucleotides, miRNA mimics, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds) and editing compounds (e.g., ADAR recruiting compounds, ADAR targeting compounds, single-stranded guide nucleic acids, or a combination thereof). RNAi compounds include double-stranded compounds (e.g., short- interfering RNA (siRNA) and double- stranded RNA (dsRNA)) and single- stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics). RNAi compounds work at least in part through the RNA- induced silencing complex (RISC) pathway resulting in sequence specific degradation and / or sequestration of a target nucleic acid through a process known as RNA interference (RNAi). The term “RNAi compound” is meant to be equivalent to other terms used to describe nucleic acid compounds that are capable of mediating sequence-specific RNA interference, for example, interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, short interfering RNA, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, and others. Additionally, the term “RNAi” is meant to be equivalent to other terms used to describe sequence- specific RNA interference. In some embodiments, an oligonucleotide comprises 6-100 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 10-50 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 14-30 nucleotides and nucleosides. In some embodiments, an oligonucleotide comprises 20-23 nucleotides and nucleosides. In certain embodiments, an oligonucleotide comprises 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides and nucleosides.

[0102] The term “nucleoside” means a compound comprising a nucleobase and a sugar moiety.

[0103] The nucleobase and sugar moiety are each, independently, unmodified or modified. The nucleoside may an unmodified or modified nucleoside. “Modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase and optionally include a non- nucleobase moiety at the corresponding position (e.g., l position).

[0104] The term “target nucleic acid,” “target RNA,” and “nucleic acid target” all mean a nucleic acid capable of being targeted by an oligonucleotide (e.g., an siRNA).

[0105] The terms “small interfering RNA,” “short interfering RNA,” and “siRNA,” as may be used interchangeably herein, refer to RNA compounds that present as non-coding single- stranded RNA or double-stranded RNA (dsRNA) compounds having a strand or strands of about 20 to about 24 nucleotides in length and are useful in RNA interference (RNAi). siRNAs are often found with phosphorylated 5' ends and hydroxylated 3' ends, which 3' ends typically have a 2- nucleotide overhang beyond the 5' end of the anti-parallel strand (e.g., complementary strand of the dsRNA compound). siRNAs can interfere with the expression of specific genes through binding of target sequences (e.g., target nucleic acid sequences) to which they are complementary and promoting (e.g., facilitating, triggering, initiating) degradation of the mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. RNAi act, at least in part, through an RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNaseH, to modulate a target nucleic acid and / or protein encoded by a target nucleic acid. After integration and separation into the RISC complex, siRNAs base-pair (e.g., full complementarity) to their target mRNA and cleave it, thereby preventing it from being used as a translation template. As discussed herein above, also part of the RNAi pathway, a miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity (e.g., partial complementarity) .

[0106] 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.

[0107] 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, 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 certain embodiments, the particle is a nanoparticle. In certain embodiments, the particle is a microparticle.

[0108] The term “nanoparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 nanometer (nm) and about 1 micrometer (μm) (e.g., between about 1 nm and about 300 nm, between about 1 nm and about 100 nm, between about 1 nm and about 30 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 3 nm), inclusive.

[0109] The term “microparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 micrometer (μm) and about 1 millimeter (mm) (e.g., between about 1 μm and about 100 μm, between about 1 μm and about 30 μm, between about 1 μm and about 10 μm, or between about 1 μm and about 3 pm), inclusive. The term “helper lipid” refers to any lipid that can be used to improve the properties of lipid nanoparticles (LNPs), e.g., by enhancing their stability, fluidity, delivery efficacy, tolerability, and / or biodistribution. Helper lipids may enhance LNP stability by modulating membrane integrity and rigidity and may also help with endosomal release. Helper lipids include, for example, glycerophospholipids, sterol lipids, and polymer-conjugated lipids, further examples of each of which are provided herein. More specifically, helper lipids with cone-shaped geometry (e.g., dioleoylphosphatidylethanolamine (DOPE)) can promote endosomal release of the LNP contents. Cylindrical- shaped lipids (e.g., phosphatidylcholines) may help provide greater stability to the LNP lipid bilayer. Cholesterol and related compounds may be used as helper lipids to increase LNP stability and intracellular delivery of LNPs. Inclusion of polymer-conjugated lipids (e.g., PEG conjugated lipids) in LNPs may also help enhance stability. The use of helper lipids in LNPs is described further, for example, in Cheng et al., Adv. Drug Deliv. Rev. 2016, 99, 129-137, which is incorporated herein by reference.

[0110] “Glycerophospholipids” are amphipathic molecules (containing both hydrophobic and hydrophilic regions) that contain a glycerol core linked to two fatty acid-derived tails by ester linkages and to one head group by a phosphate ester linkage. They are the main component of biological membranes in eukaryotic cells. Examples of glycerophospholipids include, but are not limited to, phosphatidylcholines, phosphatidylethanolamines, and phosphatidylserines. Further examples of glycerophospholipids are provided herein.

[0111] The term “sterol lipid” refers to a class of amphipathic lipids that regulate biological processes and play an important role in cell membrane stability. Examples of sterol lipids include cholesterol molecules, tocopherol molecules, and derivatives thereof. Further examples of sterol lipids are provided herein.

[0112] The term “polymer-conjugated lipid” refers to any lipid that is conjugated to a molecule comprising repeating units of one or more monomers. In some embodiments, a polymer- conjugated lipid is a polyethylene glycol (PEG)-conjugated lipid. Further examples of polymer- conjugated lipids (including PEG-conjugated lipids) are provided herein.

[0113] A “targeting ligand” refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biological molecule and facilitates the targeting of another substance to a particular cell type or region of the body (e.g., a target tissue or particular organ). In some embodiments, a targeting ligand is selected from the group consisting of small molecules; saccharines; oligosaccharides; polysaccharides; biological macromolecules, e.g., peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; an extract made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; and naturally occurring or synthetic compositions. In some embodiments, a targeting ligand is a small molecule. In some embodiments, a targeting ligand binds to a protein (e.g., a receptor). In some embodiments, a targeting ligand is capable of targeting a substance (e.g., a pharmaceutical composition described herein) to the liver of a subject. In certain embodiments, a targeting ligand is acetylgalactosamine (GalNAc).

[0114] “LNPxx” and “LNP-xx” refer to the same compound, wherein xx is an integer between 3 and 56, inclusive.

[0115] DETAILED DESCRIPTION OF CERTAIN EMBODIMDENTS OF THE DISCLOSURE

[0116] In one aspect, the present disclosure provides compounds that may facilitate the delivery of pharmaceutical agents, e.g., in a pharmaceutical composition. The present disclosure also provides pharmaceutical compositions and kits comprising any of the compounds described herein. The present disclosure also provides methods of delivering any of the pharmaceutical compositions described herein to a subject, methods of treating a disease in a subject in need thereof using any of the pharmaceutical compositions described herein, and methods of preventing a disease in a subject in need thereof using any of the pharmaceutical compositions described herein. In certain embodiments, the disease is a liver disease.

[0117] Compounds

[0118] In one aspect, the present disclosure provides compounds of Formula I: and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein:

[0119] R1is substituted or unsubstituted heteroaryl or substituted or unsubstituted, partially unsaturated heterocyclyl; each of R2A, R2B, R3A, and R3B, when present, is independently hydrogen, halogen, 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, substituted or unsubstituted heteroaryl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -NO, -N(Ra)2, - NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)SRa, -C(=O)N(Ra)2, -S(=O)Ra, -S(=O)ORa, -S(=O)SRa, - S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2SRa, -S(=O)2N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)SRa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)SRa, -OS(=O)N(Ra)2, - OS(=O)2Ra, -OS(=O)2ORa, -OS(=O)2SRa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, - SC(=O)ORa, -SC(=O)SRa, -SC(=O)N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)SRa, - NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)SRa, -NRaS(=O)N(Ra)2, - NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2SRa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa, - Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3; each instance of Rais independently hydrogen, 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, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattached to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring;

[0120] R5, when present, is -ORb, -SRb, -SSRb, -N(Rb)2, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)SRb, -OC(=O)N(Rb)2, -OS(=O)Rb, -OS(=O)ORb, -OS(=O)SRb, -OS(=O)N(Rb)2, - OS(=O)2Rb, -OS(=O)2ORb, -OS(=O)2SRb, -OS(=O)2N(Rb)2, -ON(Rb)2, -SC(=O)Rb, - SC(=O)ORb, -SC(=O)SRb, -SC(=O)N(Rb)2, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)SRb, - NRbC(=O)N(Rb)2, -NRbS(=O)Rb, -NRbS(=O)ORb, -NRbS(=O)SRb, -NRbS(=O)N(Rb)2, - NRbS(=O)2Rb, -NRbS(=O)2ORb, -NRbS(=O)2SRb, -NRbS(=O)2N(Rb)2, -OSi(Rb)3, - OSi(Rb)2ORb, -OSi(Rb)(ORb)2,-OSi(ORbb)3hydrogen, or halogen; each instance of Rbis independently hydrogen, 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, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; provided that one or more of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Pl:

[0121] -L1-N*(R6)(R6)

[0122] (Pi); wherein: each instance of L1is independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene, wherein optionally one or more unbranched backbone carbon atoms of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; each instance of R6is independently substituted or unsubstituted alkyl or hydrogen, or two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted heterocyclyl; each nitrogen atom marked with * is attached to a carbon atom of L1; and each carbon atom attached to each nitrogen atom marked with * is an sp3hybridized carbon atom; and provided that one or more of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2 or Q3 and optionally with a moiety of Formula Q1:

[0123] -L2-L3-C(R7)(B1)2L2-L3-C(B1)3 or -L2-L3-C(R7)2(B1)

[0124] (Q2), (Q3), (QD; wherein: each instance of L2is independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein optionally one or more unbranched backbone carbon atoms of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted hetero arylene; each instance of L3is independently -O-, -S-, -S-S-, -NRZ-, -C(=O)O-, - C(=NRZ)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRZ-, -C(=NRZ)NRZ-, -S(=O)NRZ-, - S(=O)2NRZ-, -OC(=O)-, -OC(=NRZ)-, -OS(=O)-, -OS(=O)2-, -NRZC(=O)-, - NRZC(=NRZ)-, -NRZS(=O)-, -NRZS(=O)2-, -OC(=O)O-, -OC(=NRZ)O-, -OS(=O)O-, - OS(=O)2O-, -NRZC(=O)O-, -NRZC(=NRZ)O-, -NRZS(=O)O-, -NRZS(=O)2O-, - OC(=O)NRZ-, -OC(=NRZ)NRZ-, -OS(=O)NRZ-, -OS(=O)2NRZ-, -NRZC(=O)NRZ-, - NRZC(=NRZ)NRZ-, -NRZS(=O)NRZ-, -NRZS(=O)2NRZ-, -C(=O)-, -C(=NRZ)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORZ)O-, -SP(=O)(ORZ)O-, -OP(=O)(ORZ)S-, or -OP(=O)(SRZ)O-; each instance of Rzis independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; each instance of R7is independently hydrogen, halogen, unsubstituted C1-3alkyl, or C1-3alkyl substituted with one or more instances of halogen; each instance of B1is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and the longest unbranched carbon backbone of each instance of B1is independently C4-10.

[0125] When Formula I includes two or more instances of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from each other. When Formula II includes two or more instances of a moiety, unless otherwise provided, any two instances of the moiety may be the same or different from each other. In certain embodiments, at least one instance is one instance. In certain embodiments, at least one instance is two, three, four, five, or six instances. In certain embodiments, at least one instance is each instance.

[0126] In certain embodiments, R1is substituted or unsubstituted heteroaryl. In certain embodiments, R1is substituted or unsubstituted, monocyclic, 5- or 6-membered heteroaryl or substituted or unsubstituted, bicyclic, 9- or 10-membered heteroaryl. In certain embodiments, R1is pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each of which is independently substituted or unsubstituted. In certain embodiments, R1is substituted or unsubstituted triazolyl. In certain embodiments, R1is substituted or unsubstituted 1,2,3-triazol-4-yl or substituted or unsubstituted 1,2,3-triazol-l-yl.

[0127] In certain embodiments, R1is substituted or unsubstituted, partially unsaturated heterocyclyl. In certain embodiments, R1is substituted or unsubstituted, monocyclic, partially unsaturated heterocyclyl. In certain embodiments, R1is substituted or unsubstituted, bicyclic, partially unsaturated heterocyclyl. In certain embodiments, R1is substituted or unsubstituted, monocyclic, 5- or 6-membered, partially unsaturated heterocyclyl or substituted or unsubstituted, bicyclic, 9- or 10-membered, partially unsaturated heterocyclyl. In certain embodiments, R1is substituted or unsubstituted, monocyclic, partially unsaturated heterocyclyl fused with substituted or unsubstituted, monocyclic heterocyclyl, substituted or unsubstituted phenyl, or substituted or unsubstituted, monocyclic heteroaryl, wherein the point of attachment is at the monocyclic, partially unsaturated heterocyclyl. In certain embodiments, R1is substituted or unsubstituted, partially unsaturated heterocyclyl comprising nitrogen atoms (e.g., 1, 2, 3, or 4 nitrogen atoms) as the only heteroatoms in the heterocyclic ring system. In certain embodiments, R1is partially unsaturated heterocyclyl substituted at least with oxo.

[0128] In certain embodiments, R1is a substituted or unsubstituted radical of a nucleobase.

[0129] In certain embodiments, the nucleobase is a canonical nucleobase. In certain embodiments, the nucleobase is a pyrimidine nucleobase. In certain embodiments, the nucleobase is a purine nucleobase. In certain embodiments, the nucleobase is thymine, uracil, or cytosine, the 1 -position of each of which is attached to the 1 '-position; or the nucleobase is adenine, guanine, xanthine, or hypoxanthine, the 9-position of each of which is attached to the I '-position. In certain embodiments, the nucleobase is uracil.

[0130] In certain embodiments, the nucleobase is a modified nucleobase. In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6- azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2- aminopropyladenine, 5- hydroxymethyl cytosine, 5-methylcytosine, xanthine, hypoxanthine, 2- aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2- thiothymine and 2-thiocytosine, 5-propynyl (C=C-CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8- thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly, 5- bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as l,3-diazaphenoxazine-2-one, l,3-diazaphenothiazine-2- one, and 9-(2-aminoethoxy)-l,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example, 7-deaza- adenine, 7-deazaguanosine, and 2- aminopyridine and 2-pyridone.

[0131] In certain embodiments, a modified nucleobase is xanthine, allyaminouracil, allyaminothymidine, hypoxanthine, digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurineriboside, N6-methyladenine, methylpseudouracil, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-dihydrouracil, 5-[(3-Indolyl)propionamide-N-allyl]uracil, 5- aminoallylcytosine, 5-aminoallyluracil, 5-bromouracil, 5-bromocytosine, 5-carboxycytosine, 5- carboxymethylesteruracil, 5-carboxyuracil, 5-fluoro uracil, 5-formylcytosine, 5-formyluracil, 5- hydroxycytosine, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, 5-hydroxyuracil, 5- iodocytosine, 5-iodouracil, 5-methoxycytosine, 5-methoxyuracil, 5-methylcytosine, 5- methyluracil, 5-propargylaminocytosine, 5-propargylaminouracil, 5-propynylcytosine, 5- propynyluracil, 6-azacytosine, 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deazaadenine, 7- deazaguanine, 7-deaza-7 -propargylaminoadenine, 7-deaza-7-propargylaminoguanine, 8- azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine, aracytosine, araguanine, arauracil, biotin- 16-7-deaza-7-propargylaminoguanine, biotin- 16- aminoallylcytosine, biotin- 16-aminoallyluracil, cyanine 3-5-propargylaminocytosine, cyanine 3- 6-propargylaminouracil, cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6- propargylaminocytosine, cyanine 5-6-propargylaminouracil, cyanine 5-aminoallylcytosine, cyanine 5-aminoallyluracil, cyanine 7-aminoallyluracil, dabcyl-5-3-aminoallyluracil, desthiobiotin-16-aminoallyl-uracil, desthiobiotin-6-aminoallylcytosine, isoguanine, Nl- ethylpseudouracil, N1 -methoxymethylpseudouracil, N1 -methyladenine, N1 -methylpseudouracil, N1 -propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6- methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6- daminoguanine, 5-carboxamide-uracil, 5-ethynyluracil, N6-isopentenyladenine (i6A), 2-methyl- thio-N6-isopentenyladenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis- hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2- methylthio-N6-threonyl carbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalyl carbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

[0132] Further nucleobases include those disclosed in U.S. Patent Do. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859; Kroschwitz, J.L., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, dsRNA Research and Applications, pages 289- 302; Antisense Research and Applications, Crooke, S.T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S.T., Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15).

[0133] Publications that teach the preparation of certain of the above noted modified nucleobases, as well as other modified nucleobases, include without limitation, U.S. Patent

[0134] Application Publication Dos. 2003 / 0158403 and 2003 / 0175906; U.S. Patent Dos. 4,845,205;

[0135] 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,434,257; 5,457,187; 5,459,255;

[0136] 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617;

[0137] 5,645,985; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588;

[0138] 5,830,653; 5,808,027; 6,005,096. 6,015,886; 6,147,200; 6,166,197; 6,166,199; 6,222,025;

[0139] 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088.

[0140] In certain embodiments, the compound comprises one substituted or unsubstituted radical of a nucleobase.

[0141] In certain embodiments In certain embodiments, . In certain embodiments, R1 In certain embodiments, R1is

[0142]

[0143] 6 In certain 1 embodiments, R1 is . In certain embodiments, R1is

[0144] In certain embodiments, one hydrogen atom of R1is replaced with a moiety of Formula Pl. In certain embodiments, two hydrogen atoms of R1are independently replaced with a moiety of Formula Pl. In certain embodiments, one hydrogen atom of R1is replaced with a moiety of Formula Q2, Q3, or Q1. In certain embodiments, two hydrogen atoms of R1are independently replaced with a moiety of Formula Q2, Q3, or Q1. In certain embodiments, one hydrogen atom of R1is replaced with a moiety of Formula Q2. In certain embodiments, two hydrogen atoms of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, R2A, when present, is -ORa, halogen, hydrogen, -CN, or -N3. In certain embodiments, R2A, when present, is -O(substituted or unsubstituted alkyl), -OH, halogen, or hydrogen. In certain embodiments, R2A, when present, is -OCH3, -OH, fluoro, or hydrogen. In certain embodiments, R2A, when present, is hydrogen. In certain embodiments, R2A, when present, is halogen (e.g., fluoro). In certain embodiments, R2A, when present, is substituted or unsubstituted alkyl. In certain embodiments, R2A, when present, is substituted or unsubstituted, C1-6alkyl. In certain embodiments, R2A, when present, is alkyl substituted at least with oxo. In certain embodiments, R2A, when present, is alkyl substituted with one or more halogen (e.g., fluoro). In certain embodiments, R2A, when present, is unsubstituted, C1-6alkyl (e.g., Me). In certain embodiments, R2A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -NO, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -

[0145] C(=O)SRa, -C(=O)N(Ra)2, -S(=O)Ra, -S(=O)ORa, -S(=O)SRa, -S(=O)N(Ra)2, -S(=O)2Ra,

[0146] S(=O)2ORa, -S(=O)2SRa, -S(=O)2N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)SRa,

[0147] OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)SRa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0148] OS(=O)2ORa, -OS(=O)2SRa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa,

[0149] SC(=O)SRa, -SC(=O)N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)SRa,

[0150] NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)SRa, -NRaS(=O)N(Ra)2,

[0151] NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2SRa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0152] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R2A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0153] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0154] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0155] OS(=O)2ORa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa, -SC(=O)N(Ra)2,

[0156] NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa,

[0157] NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0158] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R2A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0159] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0160] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0161] OS(=O)2ORa, -OS(=O)2N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2,

[0162] NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, or -

[0163] NRaS(=O)2N(Ra)2. In certain embodiments, R2A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, - C(=O)ORa, -C(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)N(Ra)2, -NRaC(=O)Ra, - NRaC(=O)ORa, or -NRaC(=O)N(Ra)2.

[0164] In certain embodiments, at least one instance of Rais hydrogen. In certain embodiments, each instance of Rais hydrogen. In certain embodiments, at least one instance of Rais not hydrogen. In certain embodiments, no instance of Rais hydrogen.

[0165] In certain embodiments, at least one instance of Rais substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., fluoro)). In certain embodiments, at least one instance of Rais unsubstituted alkyl. In certain embodiments, at least one instance of Rais unsubstituted C1-6alkyl. In certain embodiments, at least one instance of Rais Me. In certain embodiments, at least one instance of Rais Et, Pr, or Bu. In certain embodiments, at least one instance of Rais substituted C1-6alkyl. In certain embodiments, at least one instance of Rais substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of Rais substituted ethyl, substituted propyl, or substituted butyl.

[0166] In certain embodiments, at least one instance of Rais substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of Rais substituted or unsubstituted, C2-6alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl).

[0167] In certain embodiments, at least one instance of Rais substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of Rais substituted or unsubstituted, C2-6alkynyl (e.g., substituted or unsubstituted ethynyl).

[0168] In certain embodiments, at least one instance of Rais substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of Rais substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of Rais saturated carbocyclyl. In certain embodiments, at least one instance of Rais partially unsaturated carbocyclyl (e.g., comprising one C=C bond in the carbocyclic ring system).

[0169] In certain embodiments, at least one instance of Rais substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of Rais substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of Rais saturated heterocyclyl. In certain embodiments, at least one instance of Rais partially unsaturated heterocyclyl (e.g., comprising one C=C bond in the heterocyclic ring system).

[0170] In certain embodiments, at least one instance of Rais substituted or unsubstituted aryl. In certain embodiments, at least one instance of Rais substituted or unsubstituted phenyl. In certain embodiments, at least one instance of Rais unsubstituted phenyl. In certain embodiments, at least one instance of Rais 2-mono-substituted phenyl. In certain embodiments, at least one instance of Rais 3-mono-substituted phenyl. In certain embodiments, at least one instance of Rais 4-mono- substituted phenyl. In certain embodiments, Rais di-substituted phenyl. In certain embodiments, at least one instance of Rais substituted or unsubstituted naphthyl.

[0171] In certain embodiments, at least one instance of Rais substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of Rais substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of Rais substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of Rais substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of Rais substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of Rais substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0172] In certain embodiments, at least one instance of Rais a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of Rais 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. In certain embodiments, at least one instance of Rais 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.

[0173] In certain embodiments, two instances of Raattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of Raattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl). In certain embodiments, R2Ais replaced with a moiety of Formula Q2, Q3, or Q1. In certain embodiments, R2Ais replaced with a moiety of Formula Q2. In certain embodiments, R2Ais replaced with a moiety of Formula Pl.

[0174] In certain embodiments, R2B, when present, is -ORa, halogen, hydrogen, -CN, or -N3. In certain embodiments, R2B, when present, is -O(substituted or unsubstituted alkyl), -OH, halogen, or hydrogen. In certain embodiments, R2B, when present, is -OCH3, -OH, fluoro, or hydrogen. In certain embodiments, R2B, when present, is hydrogen. In certain embodiments, R2B, when present, is halogen (e.g., fluoro). In certain embodiments, R2B, when present, is substituted or unsubstituted alkyl. In certain embodiments, R2B, when present, is substituted or unsubstituted, C1-6alkyl. In certain embodiments, R2B, when present, is alkyl substituted at least with oxo. In certain embodiments, R2B, when present, is alkyl substituted with one or more halogen (e.g., fluoro). In certain embodiments, R2B, when present, is unsubstituted, C1-6alkyl (e.g., Me). In certain embodiments, R2B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -NO, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -

[0175] C(=O)SRa, -C(=O)N(Ra)2, -S(=O)Ra, -S(=O)ORa, -S(=O)SRa, -S(=O)N(Ra)2, -S(=O)2Ra,

[0176] S(=O)2ORa, -S(=O)2SRa, -S(=O)2N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)SRa,

[0177] OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)SRa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0178] OS(=O)2ORa, -OS(=O)2SRa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa,

[0179] SC(=O)SRa, -SC(=O)N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)SRa,

[0180] NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)SRa, -NRaS(=O)N(Ra)2,

[0181] NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2SRa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0182] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R2B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0183] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0184] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0185] OS(=O)2ORa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa, -SC(=O)N(Ra)2,

[0186] NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa,

[0187] NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0188] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R2B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0189] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0190] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra, OS(=O)2ORa, -OS(=O)2N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2,

[0191] NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, or - NRaS(=O)2N(Ra)2. In certain embodiments, R2B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, - C(=O)ORa, -C(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)N(Ra)2, -NRaC(=O)Ra, -

[0192] NRaC(=O)ORa, or -NRaC(=O)N(Ra)2.

[0193] In certain embodiments, R2Bis replaced with a moiety of Formula Q2, Q3, or Q1. In certain embodiments, R2Bis replaced with a moiety of Formula Q2. In certain embodiments, R2Bis replaced with a moiety of Formula Pl.

[0194] In certain embodiments, R3A, when present, is -ORa, halogen, hydrogen, -CN, or -N3. In certain embodiments, R3A, when present, is -O(substituted or unsubstituted alkyl), -OH, halogen, or hydrogen. In certain embodiments, R3A, when present, is -OCH3, -OH, fluoro, or hydrogen. In certain embodiments, R3A, when present, is hydrogen. In certain embodiments, R3A, when present, is halogen (e.g., fluoro). In certain embodiments, R3A, when present, is substituted or unsubstituted alkyl. In certain embodiments, R3A, when present, is substituted or unsubstituted, C1-6alkyl. In certain embodiments, R3A, when present, is alkyl substituted at least with oxo. In certain embodiments, R3A, when present, is alkyl substituted with one or more halogen (e.g., fluoro). In certain embodiments, R3A, when present, is unsubstituted, C1-6alkyl (e.g., Me). In certain embodiments, R3A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -NO, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -

[0195] C(=O)SRa, -C(=O)N(Ra)2, -S(=O)Ra, -S(=O)ORa, -S(=O)SRa, -S(=O)N(Ra)2, -S(=O)2Ra,

[0196] S(=O)2ORa, -S(=O)2SRa, -S(=O)2N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)SRa,

[0197] OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)SRa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0198] OS(=O)2ORa, -OS(=O)2SRa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa,

[0199] SC(=O)SRa, -SC(=O)N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)SRa,

[0200] NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)SRa, -NRaS(=O)N(Ra)2,

[0201] NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2SRa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0202] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R3A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0203] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0204] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0205] OS(=O)2ORa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa, -SC(=O)N(Ra)2,

[0206] NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa, NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0207] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R3A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0208] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0209] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0210] OS(=O)2ORa, -OS(=O)2N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2,

[0211] NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, or - NRaS(=O)2N(Ra)2. In certain embodiments, R3A, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, - C(=O)ORa, -C(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)N(Ra)2, -NRaC(=O)Ra, -

[0212] NRaC(=O)ORa, or -NRaC(=O)N(Ra)2.

[0213] In certain embodiments, R3Ais replaced with a moiety of Formula Q2, Q3, or Q1. In certain embodiments, R3Ais replaced with a moiety of Formula Q2. In certain embodiments, R3Ais replaced with a moiety of Formula Pl.

[0214] In certain embodiments, R3B, when present, is -ORa, halogen, hydrogen, -CN, or -Na. In certain embodiments, R3B, when present, is -O(substituted or unsubstituted alkyl), -OH, halogen, or hydrogen. In certain embodiments, R3B, when present, is -OCH3, -OH, fluoro, or hydrogen. In certain embodiments, R3B, when present, is hydrogen. In certain embodiments, R3B, when present, is halogen (e.g., fluoro). In certain embodiments, R3B, when present, is substituted or unsubstituted alkyl. In certain embodiments, R3B, when present, is substituted or unsubstituted, C1-6alkyl. In certain embodiments, R3B, when present, is alkyl substituted at least with oxo. In certain embodiments, R3B, when present, is alkyl substituted with one or more halogen (e.g., fluoro). In certain embodiments, R3B, when present, is unsubstituted, C1-6alkyl (e.g., Me). In certain embodiments, R3B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -NO, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -

[0215] C(=O)SRa, -C(=O)N(Ra)2, -S(=O)Ra, -S(=O)ORa, -S(=O)SRa, -S(=O)N(Ra)2, -S(=O)2Ra,

[0216] S(=O)2ORa, -S(=O)2SRa, -S(=O)2N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)SRa,

[0217] OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)SRa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0218] OS(=O)2ORa, -OS(=O)2SRa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa,

[0219] SC(=O)SRa, -SC(=O)N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)SRa,

[0220] NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)SRa, -NRaS(=O)N(Ra)2,

[0221] NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2SRa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0222] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R3B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0223] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0224] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0225] OS(=O)2ORa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, -SC(=O)ORa, -SC(=O)N(Ra)2,

[0226] NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa,

[0227] NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa,

[0228] Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3. In certain embodiments, R3B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)N(Ra)2, -

[0229] S(=O)Ra, -S(=O)ORa, -S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -OC(=O)Ra,

[0230] OC(=O)ORa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)N(Ra)2, -OS(=O)2Ra,

[0231] OS(=O)2ORa, -OS(=O)2N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)N(Ra)2,

[0232] NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)N(Ra)2, -NRaS(=O)2Ra, -NRaS(=O)2ORa, or - NRaS(=O)2N(Ra)2. In certain embodiments, R3B, when present, is hydrogen, halogen, substituted or unsubstituted alkyl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -N(Ra)2, -NO2, -C(=O)Ra, - C(=O)ORa, -C(=O)N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)N(Ra)2, -NRaC(=O)Ra, -

[0233] NRaC(=O)ORa, or -NRaC(=O)N(Ra)2.

[0234] In certain embodiments, R3Bis replaced with a moiety of Formula Q2, Q3, or Q1. In certain embodiments, R3Bis replaced with a moiety of Formula Q2. In certain embodiments, R3Bis replaced with a moiety of Formula Pl.

[0235] In certain embodiments, each of R2Band R3B, when present, is hydrogen.

[0236] In certain embodiments, R5, when present, is -ORb, -SRb, or -N(Rb)2. In certain embodiments, R5, when present, is -ORb. In certain embodiments, R5, when present, is -OH. In certain embodiments, R5, when present, is -O(substituted or unsubstituted alkyl). In certain embodiments, R5, when present, is -O(substituted or unsubstituted, C1-6alkyl). In certain embodiments, R5, when present, is -O(unsubstituted, C1-6alkyl) (e.g., -OMe). In certain embodiments, R5, when present, is -SRb. In certain embodiments, R5, when present, is -SH. In certain embodiments, R5, when present, is -S(substituted or unsubstituted alkyl). In certain embodiments, R5, when present, is -S(substituted or unsubstituted, C1-6alkyl). In certain embodiments, R5, when present, is -S(unsubstituted, C1-6alkyl) (e.g., -SMe). In certain embodiments, R5, when present, is -OH, -O(unsubstituted C1-3alkyl), or -O( C1-3alkyl substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted C1-3alkyl)). In certain embodiments, R5, when present, is hydrogen. In certain embodiments, R5, when present, is halogen (e.g., fluoro). In certain embodiments, R5, when present, is -ORb, -SRb, -SSRb, -N(Rb)2, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)N(Rb)2, -OS(=O)Rb, -OS(=O)ORb, -OS(=O)N(Rb)2, -OS(=O)2Rb, -OS(=O)2ORb, - OS(=O)2N(Rb)2, -ON(Rb)2, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)N(Rb)2, -NRbS(=O)Rb, -NRbS(=O)ORb, -NRbS(=O)N(Rb)2, -NRbS(=O)2Rb, -NRbS(=O)2ORb, -NRbS(=O)2N(Rb)2, - OSi(Rbb)3-OSi(Rb)2ORb, -OSi(Rb)(ORb)2,-OSi(ORbb)3hydrogen, or halogen. In certain embodiments, R5, when present, is -ORb, -SRb, -SSRb, -N(Rb)2, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)N(Rb)2, -OS(=O)Rb, -OS(=O)ORb, -OS(=O)N(Rb)2, -OS(=O)2Rb, -OS(=O)2ORb, - OS(=O)2N(Rb)2, -ON(Rb)2, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)N(Rb)2, -NRbS(=O)Rb, -NRbS(=O)ORb, -NRbS(=O)N(Rb)2, -NRbS(=O)2Rb, -NRbS(=O)2ORb, -NRbS(=O)2N(Rb)2, hydrogen, or halogen. In certain embodiments, R5, when present, is -ORb, -SRb, -SSRb, -N(Rb)2, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)N(Rb)2, -ON(Rb)2, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)N(Rb)2, hydrogen, or halogen.

[0237] In certain embodiments, R5is replaced with a moiety of Formula Q2, Q3, or Q1. In certain embodiments, R5is replaced with a moiety of Formula Q2. In certain embodiments, R5is replaced with a moiety of Formula Pl.

[0238] In certain embodiments . In certain embodiments, .s

[0239] In certain embodiments, at least one instance of Rbis hydrogen. In certain embodiments, each instance of Rbis hydrogen. In certain embodiments, at least one instance of Rbis not hydrogen. In certain embodiments, no instance of Rbis hydrogen.

[0240] In certain embodiments, at least one instance of Rbis substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., fluoro)). In certain embodiments, at least one instance of Rbis unsubstituted alkyl. In certain embodiments, at least one instance of Rbis unsubstituted C1-6alkyl. In certain embodiments, at least one instance of Rbis Me. In certain embodiments, at least one instance of Rbis Et, Pr, or Bu. In certain embodiments, at least one instance of Rbis substituted C1-6alkyl. In certain embodiments, at least one instance of Rbis substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of Rbis substituted ethyl, substituted propyl, or substituted butyl.

[0241] In certain embodiments, at least one instance of Rbis substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted, C2-6alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of Rbis substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted, C2-6alkynyl (e.g., substituted or unsubstituted ethynyl).

[0242] In certain embodiments, at least one instance of Rbis substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl). In certain embodiments, at least one instance of Rbis substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of Rbis saturated carbocyclyl. In certain embodiments, at least one instance of Rbis partially unsaturated carbocyclyl (e.g., comprising one C=C bond in the carbocyclic ring system).

[0243] In certain embodiments, at least one instance of Rbis substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of Rbis substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of Rbis saturated heterocyclyl. In certain embodiments, at least one instance of Rbis partially unsaturated heterocyclyl (e.g., comprising one C=C bond in the heterocyclic ring system).

[0244] In certain embodiments, at least one instance of Rbis substituted or unsubstituted aryl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted phenyl. In certain embodiments, at least one instance of Rbis unsubstituted phenyl. In certain embodiments, at least one instance of Rbis 2-mono-substituted phenyl. In certain embodiments, at least one instance of Rbis 3-mono-substituted phenyl. In certain embodiments, at least one instance of Rbis 4-mono- substituted phenyl. In certain embodiments, Rbis di-substituted phenyl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted naphthyl.

[0245] In certain embodiments, at least one instance of Rbis substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of Rbis substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of Rbis substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.

[0246] In certain embodiments, at least one instance of Rbis a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In certain embodiments, at least one instance of Rbis 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. In certain embodiments, at least one instance of R bbi ;s 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.

[0247] In certain embodiments, two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).

[0248] In certain embodiments, one of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R 4s replaced with a moiety of Formula Pl. In certain embodiments, two of R2A, R2B, R3A, R 3B R5 and hydrogen atoms of R1are independently replaced with a moiety of Formula Pl.

[0249] In certain embodiments, one or more instances of L1are a single bond. In certain embodiments, one or more instances of E1are independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, optionally wherein one or more unbranched backbone carbon atoms of the alkylene or heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0250] In certain embodiments, one or more instances of L1are independently substituted or unsubstituted, C1-6alkylene or substituted or unsubstituted, C1-12heteroalkylene, optionally wherein one or two unbranched backbone carbon atoms of the alkylene or heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0251] In certain embodiments, one or more instances of L1are independently substituted or unsubstituted, C1-6alkylene or substituted or unsubstituted, C1-12heteroalkylene, optionally wherein one or two unbranched backbone carbon atoms of the alkylene or heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted phenylene, or substituted or unsubstituted heteroarylene.

[0252] In certain embodiments, one or more instances of L1are independently substituted or unsubstituted heteroalkylene. In certain embodiments, one or more instances of L1are independently substituted or unsubstituted, C1-12heteroalkylene. In certain embodiments, one or more instances of L1are independently C1-12heteroalkylene independently optionally substituted with one or more oxo.

[0253] In certain embodiments, one or more instances of L1are independently a combination of - CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, and -NHC(=O)-, provided that: the numbers of backbone atoms of the one or more instances of L1are independently between 1 and 10, inclusive; and the one or more instances of L1do not comprise O-O, O-N, N-O, or N-N.

[0254] In certain embodiments, one or more instances of L1are independently a combination of - CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=0)NH-, -NHC(=0)-, -NH-, or -N(unsubstituted C1-3alkyl)-, provided that: the numbers of backbone atoms of the one or more instances of L1are independently between 1 and 10, inclusive; and the one or more instances of L1do not comprise O-O, O-N, N-O, or N-N.

[0255] In certain embodiments, one or more instances of L1are independently -NRx-(substituted or unsubstituted alkylene)-C3or -O-(substituted or unsubstituted alkylene)-C3, and each bond C3 is attached to the nitrogen atom marked with *, wherein each instance of Rxis independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

[0256] In certain embodiments, at least one instance of Rxis hydrogen. In certain embodiments, each instance of Rxis hydrogen. In certain embodiments, at least one instance of Rxis not hydrogen. In certain embodiments, no instance of Rxis hydrogen.

[0257] In certain embodiments, at least one instance of Rxis substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., fluoro)). In certain embodiments, at least one instance of Rxis unsubstituted alkyl. In certain embodiments, at least one instance of Rxis unsubstituted C1-6alkyl. In certain embodiments, at least one instance of Rxis Me. In certain embodiments, at least one instance of Rxis Et, Pr, or Bu. In certain embodiments, at least one instance of Rxis substituted C1-6alkyl. In certain embodiments, at least one instance of Rxis substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of Rxis substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of Rxis a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0258] In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one or more unbranched backbone carbon atoms is independently of the formula: k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl); and Rgis hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl).

[0259] The substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one or more unbranched backbone carbon atoms may be attached at either direction.

[0260] In certain embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one or more unbranched backbone carbon atoms is of the formula: In certain embodiments, the substituted or unsubstituted heteroarylene that replaces one or more unbranched backbone carbon atoms is of the formula:

[0261] . Each moiety described in this paragraph can be attached in any direction.

[0262] In certain embodiments, one or more instances of R6are independently substituted or unsubstituted alkyl. In certain embodiments, one or more instances of R6are independently substituted or unsubstituted, C1-6alkyl. In certain embodiments, one or more instances of R6are independently unsubstituted C1-6alkyl or C1-6alkyl substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -O(unsubstituted C1-3alkyl), and -O( C1-3alkyl substituted with one or more instances of halogen). In certain embodiments, one or more instances of R6are independently unsubstituted C1-6alkyl. In certain embodiments, one or more instances of R6are independently -(CH2)1-6OH. In certain embodiments, one or more instances of R6are -CH3or -C2H5. In certain embodiments, two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted heterocyclyl. In certain embodiments, two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted, monocyclic, 4- to 7-membered heterocyclyl. In certain embodiments, two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted azepanyl. In certain embodiments, two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted piperidinyl.

[0263] In certain embodiments, one or more instances of -N*(R6)(R6) are independently - N*(substituted or unsubstituted, C1-6alkyl)(substituted or unsubstituted, C1-6alkyl). In certain embodiments, one or more instances of -N*(R6)(R6) are independently -N*(unsubstituted, C1-6alkyl)(substituted or unsubstituted, C1-6alkyl). In certain embodiments, one or more instances of -N*(R6)(R6) are independently -N*(unsubstituted, C1-6alkyl)(unsubstituted, C1-6alkyl).

[0264] In certain embodiments, one of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1is replaced with a moiety of Formula Q2 or Q3. In certain embodiments, two or three of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, two of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, one of R2A, R2B, R3A, R3B, and hydrogen atoms of R1is replaced with a moiety of Formula Q2. In certain embodiments, two of R2A, R2B, R3A, R3B, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, three of R2A, R2B, R3A, R3B, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, four of R2A, R2B, R3A, R3B, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, one of R2Aand R2Band one of R3Aand R3Bare independently replaced with a moiety of Formula Q2. In certain embodiments, one of R2Aand R2Band one hydrogen atom of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, one of R3Aand R3Band one hydrogen atom of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, R2Aand R3Aare independently replaced with a moiety of Formula Q2. In certain embodiments, R2Aand one hydrogen atom of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, R3Aand one hydrogen atom of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, one of R2Aand R2B, one of R3Aand R3B, and one hydrogen atom of R1are independently replaced with a moiety of Formula Q2. In certain embodiments, R2A, R3A, and one hydrogen atom of R1are independently replaced with a moiety of Formula Q2.

[0265] In certain embodiments, none of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are replaced with a moiety of Formula Q1. In certain embodiments, none of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are replaced with a moiety of Formula Q3.

[0266] In certain embodiments, at least the last four consecutive carbon atoms of at least one instance of B1counted from the attachment point are unbranched and unsubstituted. In certain embodiments, at least the last five consecutive carbon atoms of at least one instance of B1counted from the attachment point are unbranched and unsubstituted. In certain embodiments, at least the last six consecutive carbon atoms of at least one instance of B1counted from the attachment point are unbranched and unsubstituted.

[0267] In certain embodiments, each instance of B1independently comprises unsubstituted n- butyl, unbranched unsubstituted C4alkenyl, or unbranched unsubstituted C4alkynyl. In certain embodiments, each instance of B1independently comprises unsubstituted butyl n or- unbranched unsubstituted C4alkenyl. In certain embodiments, each instance of B1independently comprises unsubstituted np-entyl or unbranched unsubstituted C5 alkenyl. In certain embodiments, each instance of B1independently comprises unsubstituted hex ny-l or unbranched unsubstituted C6alkenyl. In certain embodiments, each instance of B1independently comprises unsubstituted n- butyl. In certain embodiments, each instance of B1independently comprises unsubstituted n- pentyl. In certain embodiments, each instance of B1independently comprises unsubstituted n- hexyl.

[0268] In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C4-10alkyl, unbranched unsubstituted C4-10alkenyl, or unbranched unsubstituted C4-10 alkynyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C6-10alkyl, unbranched unsubstituted C6-10alkenyl, or unbranched unsubstituted C6-10 alkynyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C6-8alkyl, unbranched unsubstituted C6-8alkenyl, or unbranched unsubstituted C6-8alkynyl.

[0269] In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C4-10alkyl or unbranched unsubstituted C4-10alkenyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C6-10alkyl or unbranched unsubstituted C6-10alkenyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C6-8alkyl or unbranched unsubstituted C6-8alkenyl.

[0270] In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C4-10alkyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C6-10alkyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C6-8alkyl.

[0271] In certain embodiments, at least one instance of B1is unbranched unsubstituted C5-9alkyl or unbranched unsubstituted C5-9alkenyl. In certain embodiments, at least one instance of B1is unbranched unsubstituted C5-9alkyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C5-9alkyl or unbranched unsubstituted C5-9alkenyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C5-9alkyl.

[0272] In certain embodiments, each instance of B1is independently unbranched unsubstituted C4-10alkyl, unbranched unsubstituted C4-10alkenyl, or unbranched unsubstituted C4-10alkynyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C6-10alkyl, unbranched unsubstituted C6-10alkenyl, or unbranched unsubstituted C6-10alkynyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C6-8alkyl, unbranched unsubstituted C6-8alkenyl, or unbranched unsubstituted C6-8alkynyl.

[0273] In certain embodiments, each instance of B1is independently unbranched unsubstituted C4-10alkyl or unbranched unsubstituted C4-10alkenyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C6-10alkyl or unbranched unsubstituted C6-10alkenyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C5-9alkyl or unbranched unsubstituted C5-9alkenyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C6-8alkyl or unbranched unsubstituted C6-8alkenyl.

[0274] In certain embodiments, each instance of B1is independently unbranched unsubstituted C4-10alkyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C6-10alkyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C5-9alkyl. In certain embodiments, each instance of B1is independently unbranched unsubstituted C6-8alkyl.

[0275] In certain embodiments, each instance of B1independently comprises 0, 1, or 2 carbon- carbon unsaturated bonds. In certain embodiments, each instance of B1independently comprises 0, 1, or 2 C=C bonds. In certain embodiments, no instance of B1comprises C=C bonds.

[0276] In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C4-10. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C4-8. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C6-10. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C6-8.

[0277] In certain embodiments, the longest unbranched carbon backbone of each instance of B1is not substituted with oxo.

[0278] In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently unsubstituted or substituted independently with one or more substituents selected from the group consisting of fluoro, unsubstituted alkyl, alkyl substituted with one or more fluoro, unsubstituted alkenyl, alkenyl substituted with one or more fluoro, unsubstituted alkynyl, and alkynyl substituted with one or more fluoro. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently unsubstituted or substituted independently with one or more substituents selected from the group consisting of fluoro, unsubstituted C1-3alkyl, or C1-3alkyl substituted with one or more fluoro. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently unsubstituted or substituted independently with one or more fluoro.

[0279] In certain embodiments, at least one instance of -C(R7)(B1)2is nbranched unsubstituted C6_8alkyl or unbranched unsubstituted C6_8alkenyl)

[0280] (unbranched unsubstituted C6_8alkyl or unbranched unsubstituted C6_8alkenyl) . In certain embodiments, at least one instance of -C(R7)(B1)2is

[0281] (unbranched unsubstituted C6.8alkyl or unbranched unsubstituted C6.8alkenyl)

[0282] (unbranched unsubstituted C6.8alkyl or unbranched unsubstituted C6.8alkenyl)

[0283] In certain embodiments, at least one instance of -C(R7)(B1)2is nbranched unsubstituted C6alkyl or unbranched unsubstituted C6alkenyl)

[0284] (unbranched unsubstituted C6_8alkyl or unbranched unsubstituted C6_8alkenyl) . In certain embodiments, at least one instance of -C(R7)(B1)2is unbranched unsubstituted C6alkyl or unbranched unsubstituted C6alkenyl)

[0285] (unbranched unsubstituted C6.8alkyl or unbranched unsubstituted C6.8alkenyl)

[0286] In certain embodiments, one or more instances of L2are a single bond. In certain embodiments, one or more instances of L2are independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, optionally wherein one or more unbranched backbone carbon atoms of the alkylene or heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0287] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted, C1-6alkylene or substituted or unsubstituted, C1-12heteroalkylene, optionally wherein one or two unbranched backbone carbon atoms of the alkylene or heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0288] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted, C1-6alkylene or substituted or unsubstituted, C1-12heteroalkylene, optionally wherein one or two unbranched backbone carbon atoms of the alkylene or heteroalkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted phenylene, or substituted or unsubstituted heteroarylene.

[0289] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, wherein one, two, or three unbranched backbone carbon atoms of the alkylene or hetero alkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0290] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted, C1-6alkylene or substituted or unsubstituted, C1-12heteroalkylene, wherein one or two unbranched backbone carbon atoms of the alkylene or hetero alkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0291] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted, C1-6alkylene or substituted or unsubstituted, C1-12heteroalkylene, wherein one or two unbranched backbone carbon atoms of the alkylene or hetero alkylene are independently replaced with substituted or unsubstituted heterocyclylene, substituted or unsubstituted phenylene, or substituted or unsubstituted heteroarylene.

[0292] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted heteroalkylene. In certain embodiments, one or more instances of L2are independently substituted or unsubstituted, C1-12heteroalkylene. In certain embodiments, one or more instances of L2are independently C1-12heteroalkylene independently optionally substituted with one or more oxo.

[0293] In certain embodiments, one or more instances of L2are independently a combination of - CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, and -NHC(=O)-, provided that: the numbers of backbone atoms of the one or more instances of L2are independently between 1 and 10, inclusive; and the one or more instances of L2do not comprise O-O, O-N, N-O, or N-N.

[0294] In certain embodiments, one or more instances of L2are independently a combination of - CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene; provided that: the numbers of backbone atoms of the one or more instances of L2are independently between 1 and 20, inclusive; the one or more instances of L2do not comprise O-O, O-N, N-O, or N-■; and the combined numbers of the substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene of the one or more instances of L2are independently 1, 2, or 3.

[0295] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted alkylene or -©-(substituted or unsubstituted alkylene)-C1; one, two, or three unbranched backbone carbon atoms of the alkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and each bond Cl is attached to L3.

[0296] In certain embodiments, one or more instances of L2are independently -(CH2)1-3-(l-yl-

[0297] 1.2.3-triazol-4-yl)-(CH2)1-20-, -(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-, -O-(CH2)1-3-(l-yl-

[0298] 1.2.3-triazol-4-yl)-(CH2)1-20-cl, or -O-(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-c1, and each bond Cl is attached to L3.

[0299] In certain embodiments, one or more instances of L2are independently substituted or unsubstituted alkylene or -©-(substituted or unsubstituted alkylene)-C1, and each bond Cl is attached to L3. In certain embodiments, one or more instances of L2are independently substituted or unsubstituted, C1-6alkylene or -©-(substituted or unsubstituted, C1-6alkylene)-C1, and each bond C1is attached to L3. In certain embodiments, one or more instances of L2are independently -(CH2)1-3- or -O-(CH2)1-3-C1, and each bond C1is attached to L3. In certain embodiments, one or more instances of L3areC2-C(=O)O-, wherein each bond C2 is attached to L2. In certain embodiments, one or more instances of L3areC2-OC(=O)-, wherein each bond C2 is attached to L2. In certain embodiments, one or more instances of L3are -SS-. In certain embodiments, one or more instances of L3are independently -S(=O)O-, - S(=O)2O-, -OS(=O)-, -OS(=O)2-, -OC(=O)O-, -OS(=O)O-, -OS(=O)2O-, -OP(=O)(ORZ)O-, -SP(=O)(ORZ)O-, -OP(=O)(ORZ)S-, or -OP(=O)(SRZ)O-.

[0300] In certain embodiments, one or more instances of -L2-L 33- are cleavable under physiological conditions. In certain embodiments, one or more instances of -L2-L3- are hydrolysable under physiological conditions. In certain embodiments, one or more instances of - L2-L3- independently comprise -C(=O)O- or -OC(=O)-. In certain embodiments, one or more instances of -L2-L3- comprise -SS-. In certain embodiments, one or more instances of -L2-L3- independently comprise -S(=O)O-, -S(=O)2O-, -OS(=O)-, -OS(=O)2-, -OC(=O)O-, - OS(=O)O-, -OS(=O)2O-, -OP(=O)(ORZ)O-, -SP(=O)(ORZ)O-, -OP(=O)(ORZ)S-, or - OP(=O)(SRZ)O-.

[0301] In certain embodiments, at least one instance of Rzis hydrogen. In certain embodiments, each instance of Rzis hydrogen. In certain embodiments, at least one instance of Rzis not hydrogen. In certain embodiments, no instance of Rzis hydrogen.

[0302] In certain embodiments, at least one instance of Rzis substituted alkyl (e.g., alkyl substituted with one or more instances of halogen (e.g., fluoro)). In certain embodiments, at least one instance of Rzis unsubstituted alkyl. In certain embodiments, at least one instance of Rzis unsubstituted C1-6alkyl. In certain embodiments, at least one instance of Rzis Me. In certain embodiments, at least one instance of Rzis Et, Pr, or Bu. In certain embodiments, at least one instance of Rzis substituted C1-6alkyl. In certain embodiments, at least one instance of Rzis substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of Rzis substituted ethyl, substituted propyl, or substituted butyl.

[0303] In certain embodiments, at least one instance of Rzis a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0304] In certain embodiments, one or more instances of R7are independently hydrogen, fluoro, or unsubstituted C1-3alkyl. In certain embodiments, one or more instances of R7are hydrogen. In certain embodiments, each instance of R7is hydrogen.

[0305] In certain embodiments, the compound is of the formula:

[0306] In certain embodiments, the compound is of the formula:

[0307] In certain embodiments, the compound is of the formula:

[0308] In certain embodiments, the compound is of the formula:

[0309] In certain embodiments, the compound is of the formula: 0 In certain embodiments, the compound is of the formula:

[0310] In certain embodiments, the compound is of the formula:

[0311] In certain embodiments, the compound is of the formula:

[0312] In certain embodiments, the compound is of the formula:

[0313] In certain embodiments, the compound is of the formula:

[0314] In certain embodiments, the compound is of the formula:

[0315] In certain embodiments, the compound is of the formula:

[0316] In certain embodiments, the compound is of the formula:

[0317] In certain embodiments, the compound is of the formula:

[0318] In certain embodiments, the compound is of the formula:

[0319] In certain embodiments, the compound is of the formula:

[0320] In certain embodiments, the compound is of the formula:

[0321] In certain embodiments, the compound is of the formula:

[0322]

[0323] In certain embodiments, the compound is of the formula:

[0324]

[0325] In certain embodiments, the compound is of the formula:

[0326]

[0327] In certain embodiments, the compound is of the formula:

[0328] In certain embodiments, the compound is of the formula:

[0329]

[0330] In certain embodiments, the compound is of the formula:

[0331]

[0332] In certain embodiments, the compound is of the formula:

[0333] In certain embodiments, the compound is of the formula:

[0334] In certain embodiments, the compound is of the formula:

[0335]

[0336] In certain embodiments, the compound is of the formula:

[0337] In certain embodiments, the compound is of the formula:

[0338] In certain embodiments, the compound is of the formula:

[0339]

[0340] In certain embodiments, the compound is of the formula:

[0341] In certain embodiments, the compound is of the formula:

[0342] In certain embodiments, the compound is of the formula:

[0343]

[0344] In certain embodiments, the compound is of the formula:

[0345] In certain embodiments, the compound is of the formula:

[0346] In certain embodiments, the compound is of the formula:

[0347]

[0348] In certain embodiments, the compound is of the formula:

[0349] In certain embodiments, the compound is of the formula:

[0350] In certain embodiments, the compound is of the formula:

[0351]

[0352] In certain embodiments, the compound is of the formula:

[0353] In certain embodiments the compound is of the formula:

[0354] In certain embodiments, the compound is of the formula:

[0355]

[0356] In certain embodiments, the compound is of the formula:

[0357] In certain embodiments, the compound is of the formula:

[0358] In certain embodiments, the compound is of the formula:

[0359]

[0360] In certain embodiments, the compound is of the formula:

[0361] / JD

[0362] In certain embodiments, the compound is of the formula:

[0363] In certain embodiments, the compound is of the formula: (LNP-13).

[0364] In another aspect, the present disclosure provides compounds of Formula II: and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof, wherein:

[0365] R1is hydrogen, -ORa, -SRa, or -L2-L3-CH(R7)X(B1)2-x, wherein Rais hydrogen, - (substituted or unsubstituted, C1-8alkylene)-N(substituted or unsubstituted, C1-5alkyl)2, or - (substituted or unsubstituted, C1-8alkenylene)-N(substituted or unsubstituted, C1-5alkylh;

[0366] R2is -L2-L3-CH(R7)X(B1)2-x, -(substituted or unsubstituted, C1-8alkylene)- N(substituted or unsubstituted, C1-5alkyl)2, or -(substituted or unsubstituted, C1-8alkenylene)- N(substituted or unsubstituted, C1-5alkyl)2;

[0367] R3is -L2’-L3-CH(R7’)X(B1’ )2-x; and

[0368] R5is hydroxyl, -N(Rb)2, or -L2-L3-CH(R7)X(B1)2-x,wherein each instance of Rbis independently hydrogen or substituted or unsubstituted alkyl; each instance of x is independently 0 or 1 ; each instance of L2is independently a single bond, -(CH2)1-3-(l-yI-l,2,3-triazol-4-yl)- (CH2)1-20-, -(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-, -O-(CH2)1-3-(l-yI-l,2,3-triazol-4-yl)- (CH2)1-20-, or -O-(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-; each instance of L3is independently -O-, -S-, -S-S-, -NRZ-, -C(=O)O-, -C(=NRZ)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRZ- -C(=NRZ)NRZ- -S(=O)NRZ- -S(=O)2NRZ- -OC(=O)-, -OC(=NRZ)-, -OS(=O)-, -OS(=O)2-, -NRZC(=O)-, -NRZC(=NRZ)-, -NRZS(=O)-, - NRZS(=O)2-, -OC(=O)O-, -OC(=NRZ)O-, -OS(=O)O-, -OS(=O)2O-, -NRZC(=O)O-, - NRZC(=NRZ)O-, -NRZS(=O)O-, -NRZS(=O)2O-, -OC(=O)NRZ-, -OC(=NRZ)NRZ-, - OS(=O)NRZ-, -OS(=O)2NRZ-, -NRZC(=O)NRZ-, -NRZC(=NRZ)NRZ-, -NRZS(=O)NRZ-, - NRZS(=O)2NRZ-, -C(=O)-, -C(=NRZ)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORZ)O-, - SP(=O)(ORZ)O-, -OP(=O)(ORZ)S-, or -OP(=O)(SRZ)O-; each instance of Rzis independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; each instance of R7is independently hydrogen, halogen, unsubstituted C1-8alkyl, or C1-8alkyl substituted with one or more instances of halogen; each instance of B1is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and the longest unbranched carbon backbone of each instance of B1is independently Ce-30.

[0369] In certain embodiments, R1is hydrogen. In certain embodiments, R1is -S-(CH2)2-6-

[0370] N(unsubstituted C1-3alkyl)2. In certain embodiments, R1is -S-(CH2)3-N(unsubstituted methyl)2.

[0371] In certain embodiments, R1is -O-(CH2)2-6-N(unsubstituted C1-3alkyl)2. In certain embodiments, R1is -O-(CH2)3-N(unsubstituted methyl)2.

[0372] In certain embodiments

[0373] In certain embodiments, R2is -(CH2)i-6-N(unsubstituted C1-3alkyl)2. In certain embodiments, R2is -(CH2)2-N(unsubstituted methyl)2. In certain embodiments, R2is - (unsubstituted C2-6alkyenylene)-N(unsubstituted C1-3alkyl)2. In certain embodiments, R is - (CH2CH=CHCH2)-N(unsubstituted methyl)2.

[0374] In certain embodiments, at least one instance of L2is a single bond. In certain embodiments, at least one instance of L2is -0-(CH2)1-3-(l-yl-1,2,3-triazol-4-yl)-(CH2)i-io- or 0-(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)i-io-

[0375] In certain embodiments,

[0376] In certain embodiments,

[0377] In certain embodiments, R5is hydroxyl. In certain embodiments, R is -N(unsubstituted C1-3alkyl)2. In certain embodiments, R5is -N(unsubstituted methyl)2.

[0378] In Formula II, L3and Rzare as described in Formula I. In certain embodiments, at least one instance of L3is -OC(=O)-. In certain embodiments, at least one instance of L3is - C(=O)O- In certain embodiments, at least one instance of L3is -OC(=O)O- In certain embodiments, each instance of R7is hydrogen.

[0379] In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C6-10. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C11-15. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C16-20. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C21-25. In certain embodiments, the longest unbranched carbon backbone of each instance of B1is independently C26-30.

[0380] In certain embodiments, at least the last six consecutive carbon atoms of at least one instance of B1counted from the attachment point are unbranched and unsubstituted. In certain embodiments, at least the last seven consecutive carbon atoms of at least one instance of B1counted from the attachment point are unbranched and unsubstituted. In certain embodiments, at least the last eight consecutive carbon atoms of at least one instance of B1counted from the attachment point are unbranched and unsubstituted.

[0381] In certain embodiments, each instance of B1independently comprises unsubstituted n- hexyl or unbranched unsubstituted C6alkenyl. In certain embodiments, each instance of B1independently comprises unsubstituted n -heptyl or unbranched unsubstituted C7alkenyl. In certain embodiments, each instance of B1independently comprises unsubstituted octyl o nr- unbranched unsubstituted C8alkenyl.

[0382] In certain embodiments, at least one instance of B1is unbranched unsubstituted C6-10alkyl or unbranched unsubstituted C6-10alkenyl. In certain embodiments, at least one instance of B1is unbranched unsubstituted C11-15alkyl or unbranched unsubstituted C11-15alkenyl. In certain embodiments, at least one instance of B1is unbranched unsubstituted C16-20alkyl or unbranched unsubstituted C16-20alkenyl. In certain embodiments, at least one instance of B1is unbranched unsubstituted C21-25alkyl or unbranched unsubstituted C21-25alkenyl. In certain embodiments, at least one instance of B1is unbranched unsubstituted C26-30alkyl or unbranched unsubstituted C26-30alkenyl.

[0383] In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C6-10alkyl or unbranched unsubstituted C6-10alkenyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C11-15alkyl or unbranched unsubstituted C11-15alkenyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C16-20alkyl or unbranched unsubstituted C16-20alkenyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C21-25alkyl or unbranched unsubstituted C21-25alkenyl. In certain embodiments, at least two instances of B1are independently unbranched unsubstituted C26-30alkyl or unbranched unsubstituted C26-30alkenyl.

[0384] In certain embodiments, at least three instances of B1are independently unbranched unsubstituted C6-10alkyl or unbranched unsubstituted C6-10alkenyl. In certain embodiments, at least three instances of B1are independently unbranched unsubstituted C11-15alkyl or unbranched unsubstituted C11-15alkenyl. In certain embodiments, at least three instances of B1are independently unbranched unsubstituted C16-20alkyl or unbranched unsubstituted C16-20alkenyl. In certain embodiments, at least three instances of B1are independently unbranched unsubstituted C21-25alkyl or unbranched unsubstituted C21-25alkenyl. In certain embodiments, at least three instances of B1are independently unbranched unsubstituted C26-30alkyl or unbranched unsubstituted C26-30alkenyl.

[0385] In certain embodiments, at least four instances of B1are independently unbranched unsubstituted C6-10alkyl or unbranched unsubstituted C6-10alkenyl. In certain embodiments, at least four instances of B1are independently unbranched unsubstituted C11-15alkyl or unbranched unsubstituted C11-15alkenyl. In certain embodiments, at least four instances of B1are independently unbranched unsubstituted C16-20alkyl or unbranched unsubstituted C16-20alkenyl. In certain embodiments, at least four instances of B1are independently unbranched unsubstituted C21-25alkyl or unbranched unsubstituted C21-25alkenyl. In certain embodiments, at least four instances of B1are independently unbranched unsubstituted C26-30alkyl or unbranched unsubstituted C26-30alkenyl.

[0386] In certain embodiments, each instance of B1independently comprises 0, 1, or 2 carbon- carbon unsaturated bonds. In certain embodiments, each instance of B1independently comprises 0, 1, or 2 C=C bonds. In certain embodiments, no instance of B1comprises C=C bonds.

[0387] In certain embodiments, Formula II comprises two instances of B1. In certain embodiments, Formula II comprises three instances of B1. In certain embodiments, Formula II comprises four instances of B1. In certain embodiments, Formula II comprises five instances of B1. In certain embodiments, Formula II comprises six instances of B1.

[0388] In certain embodiments, the compound is of the formula: In certain embodiments, a provided compound (a compound provided herein or a compound of the present disclosure) is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound (a compound provided herein or a compound of the present disclosure) is a compound of Formula II, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof.

[0389] In certain embodiments, the molecular weight of a compound of Formula I is lower than 500, between 500 and 600, between 600 and 800, between 800 and 1000, between 1000 and

[0390] 1200, between 1200 and 1500, or between 1500 and 2000, inclusive, g / mol. In certain embodiments, the molecular weight of a compound of Formula II is lower than 500, between 500 and 600, between 600 and 800, between 800 and 1000, between 1000 and 1200, between 1200 and 1500, or between 1500 and 2000, inclusive, g / mol.

[0391] Pharmaceutical Compositions, Administration, and Kits

[0392] In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and one or more pharmaceutically acceptable excipients. The one or more compounds provided herein may act as ionizable lipids in the presently described pharmaceutical compositions. Such compounds may be capable of electrostatically binding one or more pharmaceutical agents, e.g., oligonucleotides or polynucleotides. In some embodiments, the one or more compounds provided herein are associated with one or more pharmaceutical agents, e.g., by forming complexes with the one or more pharmaceutical agents, or by forming vesicles in which the one or more pharmaceutical agents are enclosed or encapsulated. In some embodiments, the pharmaceutical composition is in the form of particles (e.g., nanoparticles or microparticles). In some embodiments, the one or more compounds provided herein are ionized and have a net positive charge. The one or more compounds provided herein may thus be capable of binding negatively charged pharmaceutical agents (e.g., oligonucleotides or polynucleotides) by electrostatic interaction. In certain embodiments, the one or more compounds provided herein have a net positive charge only at a lower pH (e.g., lower than physiological pH, e.g., acidic pH). In certain embodiments, the one or more compounds provided herein have no net positive charge (e.g., no charge at all (i.e., are neutral)) at a higher pH (e.g., physiological pH or higher). This ionizable behavior of the one or more compounds provided herein may improve the intended purposes of the pharmaceutical compositions, e.g., by helping with endosomal escape and reducing toxicity as compared with pharmaceutical compositions that comprise compounds not ionizable at a lower pH (e.g., lower than physiological pH) and / or remaining cationic at a higher pH (e.g., physiological pH or higher). In some embodiments, the one or more of the nitrogen atoms marked with * are positively charged or capable of being protonated and becoming positively charged (e.g., at lower than physiological pH, e.g., acidic pH). In some embodiments, the one or more nitrogen atoms marked with * are hydrophilic. In some embodiments, the one or more B1moieties are lipophilic.

[0393] In certain embodiments, the pharmaceutical compositions are useful for treating a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the pharmaceutical compositions are useful for preventing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the pharmaceutical compositions are useful for reducing the risk of developing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the pharmaceutical compositions are useful for diagnosing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the pharmaceutical compositions are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein (e.g., an asialoglycoprotein receptor) in a subject, cell, tissue, or biological sample.

[0394] In some embodiments, the combined concentration of the one or more compounds provided herein in the pharmaceutical composition is about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%,

[0395] 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%,

[0396] 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%,

[0397] 74%, 75%, 76%, 77%, 78%, 79%, or 80% mokmol. In some embodiments, the combined concentration of the one or more compounds provided herein in the pharmaceutical composition is between 20% and 40%, between 40% and 60%, or between 60% and 80%, inclusive, mokmol.

[0398] In certain embodiments, the combined concentration of the one or more compounds provided herein in the pharmaceutical composition is between 40% and 60%, inclusive, mokmol.

[0399] In certain embodiments, a concentration described herein is the concentration in the pharmaceutical composition without including any solvent.

[0400] In some embodiments, the pharmaceutical composition further comprises one or more helper lipids. The inclusion of a helper lipid may, for example, increase the stability and / or the fluidity of the pharmaceutical composition.

[0401] In some embodiments, at least one helper lipid is a glycerophospholipid. In certain embodiments, at least one glycerophospholipid is a phosphatidylcholine, a phosphatidylethanolamine, or a phosphatidylserine. In some embodiments, at least one glycerophospholipid is distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricos anoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl- phosphatidy lethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), 1,2-di-O- octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), l -hcxadccyl-.sn--glyccro-3- phosphocholine (C16 Lyso PC), palmitoyloleoyl-phosphatidylethanolamine (POPE), dioleoyl- phosphatidy lethanolamine 4-(N-maleimidomethyl)-cyclohexane-l carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), dilauroyl-phosphatidylethanolamine (DLPE), diphytanoyl-phosphatidylethanolamine (DPyPE), 16-O-monomethyl phosphatidylethanolamine, 16-O-dimethyl phosphatidylethanolamine, 18-1trans phosphatidylethanolamine, l-stearoyl-2- olcoyl-.s77-glyccro-3-phosphocholinc (SOPC), l-stearioyl-2-oleoylphosphatidyethanol amine (SOPE), and l,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (transDOPE). In certain embodiments, at least one glycerophospholipid is distearoylphosphatidylcholine (DSPC). In some embodiments, the combined concentration of the glycerophospholipids in the pharmaceutical compositions is about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% mokmol. In some embodiments, the combined concentration of the glycerophospholipids in the pharmaceutical compositions is between 3% and 7%, between 7% and 10%, between 10% and 15%, or between 15% and 25%, inclusive, mokmol. In certain embodiments, the combined concentration of the glycerophospholipids in the pharmaceutical compositions is between 7% and 15%, inclusive, mokmol.

[0402] In some embodiments, at least one helper lipid is a sterol lipid. In some embodiments, at least one sterol lipid is a sterol, steroid, tocopherol, secosteroid, bile acid, or steroid conjugate. In some embodiments, at least one helper lipid is cholesterol, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4 '-hydroxybutyl ether, stigmastanol, β-sitosterol, brassicasterol, calcipotriol, campesterol, 9,11 -dehydroergosterol, ergosterol, fucosterol, Vitamin D2, Vitamin D3, and Vitamin E. In certain embodiments, at least one sterol lipid is cholesterol.

[0403] In some embodiments, the combined concentration of the sterol lipids in the pharmaceutical compositions is about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,

[0404] 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%,

[0405] 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% mokmol. In some embodiments, the combined concentration of the sterol lipids in the pharmaceutical compositions is between 20% and 30%, between 30% and 40%, between 40% and 50%, or between 50% and 70%, inclusive, mokmol. In certain embodiments, the combined concentration of the sterol lipids in the pharmaceutical compositions is between 30% and 50%, inclusive, mokmol.

[0406] In some embodiments, the pharmaceutical compositions further comprise one or more polymer-conjugated lipids. In some embodiments, at least one polymer-conjugated lipid is a polyethylene glycol (PEG) lipid. In some embodiments, at least one PEG lipid comprises 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, 91-100, 101-110, 111-120, 121-130,

[0407] 131-140, 141-150, 151-160, 161-170, 171-180, 181-190, or 191-200 PEG units. In some embodiments, at least one PEG lipid comprises 30-60 (e.g., 40-55) PEG units. In certain embodiments, each PEG unit is of the formula: In some embodiments, at least one PEG lipid is of the formula: wherein: each instance of R11is independently substituted or unsubstituted alkyl or hydrogen; each instance of ml is independently an integer between 10 and 200, inclusive; and each instance of R12and R13is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, optionally wherein one or more longest unbranched backbone carbon atoms are independently replaced with - C(=O)O- or -OC(=O)-.

[0408] In some embodiments, each instance of R11is independently substituted or unsubstituted alkyl. In some embodiments, each instance of R11is independently substituted or unsubstituted C1-6alkyl. In certain embodiments, each instance of R11is independently unsubstituted C1-6alkyl. In some embodiments, each instance of R11is independently substituted or unsubstituted C1-3alkyl. In certain embodiments, each instance of R11is independently unsubstituted C1-3alkyl. In certain embodiments, each instance of R11is Me.

[0409] In some embodiments, each instance of ml is independently 30, 31, 32, 33, 34, 35, 36,

[0410] 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60. In certain embodiments, each instance of ml is independently an integer between 30 and 60, inclusive. In certain embodiments, each instance of ml is independently an integer between 40 and 55, inclusive.

[0411] In some embodiments, each instance of R12and R13is independently substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl. In some embodiments, each instance of R12and R13is independently substituted or unsubstituted C10-30alkyl or substituted or unsubstituted C10-30alkenyl. In certain embodiments, each instance of R12and R13is independently unsubstituted C10-30alkyl or unsubstituted C10-30alkenyl. In certain embodiments, each instance of R12and R13is independently unsubstituted unbranched C10-30alkyl or unsubstituted unbranched C10-30alkenyl. In some embodiments, each instance of R12and R13is independently substituted or unsubstituted C12-16alkyl or substituted or unsubstituted C12-16alkenyl. In some embodiments, each instance of R12and R13is independently unsubstituted C12-16alkyl or unsubstituted C12-16alkenyl. In some embodiments, each instance of R12and R13is independently unsubstituted unbranched C12-16alkyl or unsubstituted unbranched C12-16alkenyl. In certain embodiments, each instance of R12and R13is independently unsubstituted unbranched C12-16alkyl. In certain embodiments, the longest unbranched carbon backbone of each instance of R12and R13independently comprises 0, 1, or 2 C=C bonds.

[0412] In certain embodiments, each instance of R11is independently unsubstituted C1-6alkyl; each instance of ml is independently an integer between 30 and 60, inclusive; and each instance of R12and R13is independently unsubstituted C10-30alkyl or unsubstituted C10-30alkenyl. In certain embodiments, each instance of R11is independently unsubstituted C1-3alkyl; each instance of ml is independently an integer between 40 and 55, inclusive; and each instance of R12and R13is independently unsubstituted unbranched C12-16alkyl.

[0413] In certain embodiments, at least one polymer-conjugated lipid is of the formula:

[0414] In some embodiments, at least one PEG lipid is mPEG-DMG, mPEG-c-DOMG, mPEG- DOPE, mPEG-DLPE, mPEG-DPPE, mPEG-DMPE, mPEG-DPPC, mPEG-DSPE, mPEG-CLS, mPEG-palmitic acid, and mPEG-N,Nitctradccylacctamidc. DMG refers to dimyristoyl glyceride. DOMG refers to dimyristoyloxy glyceride. CLS refers to cholesterol. In this paragraph, m refers to methyl. In some embodiments, the number average molecular weight of the PEG moiety of at least one PEG lipid (e.g., as determined by gel permeation chromatography) is between 500 and 1000, between 1000 and 1500, between 1500 and 2000, between 2000 and 3000, or between 3000 and 4000, inclusive, g / mol. In certain embodiments, the number average molecular weight of the PEG moiety of at least one PEG lipid (e.g., as determined by gel permeation chromatography) is between 1500 and 3000, inclusive, g / mol. In certain embodiments, the number average molecular weight of the PEG moiety of at least one PEG lipid (e.g., as determined by gel permeation chromatography) is between 1500 and 2500, inclusive, g / mol.

[0415] In some embodiments, the combined concentration of the polymer-conjugated lipids in the pharmaceutical compositions is about 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%,

[0416] 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%,

[0417] 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5.0% mokmol. In some embodiments, the combined concentration of the polymer-conjugated lipids in the pharmaceutical compositions is between 0.2% and 0.5%, between 0.5% and 1%, between 1% and 2.5%, or between 2.5% and 5%, inclusive, mokmol. In certain embodiments, the combined concentration of the polymer-conjugated lipids in the pharmaceutical compositions is between 0.5% and 2.5%, inclusive, mokmol.

[0418] In some embodiments, the pharmaceutical compositions further comprise one or more targeting ligands. In some embodiments, at least one targeting ligand is attached to another component of the pharmaceutical composition. In certain embodiments, “attached” refers to “covalently attached.” In some embodiments, at least one targeting ligand is attached to at least one helper lipid. In some embodiments, at least one targeting ligand is attached to at least one glycophospholipid. In some embodiments, at least one targeting ligand is not attached to another component of the pharmaceutical composition. In certain embodiments, at least one targeting ligand is an asialoglycoprotein receptor ligand. In certain embodiments, at least one asialoglycoprotein receptor ligand is an N-acetylgalactosamine (GalNAc). In some embodiments, a helper lipid comprises more than one (e.g., two, three, four, or five) targeting ligand (e.g., GalNAc) attached thereto, for example, two, three, four, or five GalNAcs.

[0419] In some embodiments, the pharmaceutical compositions further comprise one or more pharmaceutical agents. In some embodiments, at least one pharmaceutical agent is a therapeutic agent. In some embodiments, at least one pharmaceutical agent is a prophylactic agent or diagnostic agent. In some embodiments, at least one prophylactic agent is a vaccine. In certain embodiments, at least one diagnostic agent is an imaging agent or contrast agent. In some embodiments, at least one pharmaceutical agent is a small molecule, peptide, protein, carbohydrate, monosaccharide, oligosaccharide, polysaccharide, nucleoprotein, mucoprotein, lipoprotein, synthetic peptide, synthetic protein, (small molecule)-peptide conjugate, (small molecule)-protein conjugate, glycoprotein, steroid, nucleotide, nucleoside, oligonucleotide, polynucleotide, (small molecule) -oligonucleotide conjugate, (small molecule) -polynucleotide conjugate, lipid, hormone, vitamin, or cell. In some embodiments, at least one pharmaceutical agent is an antibody (e.g., monoclonal antibody or polyclonal antibody). In some embodiments, at least one pharmaceutical agent is an oligonucleotide or polynucleotide. In some embodiments, at least one pharmaceutical agent is an RNA or DNA. In certain embodiments, at least one pharmaceutical agent is an siRNA or mRNA. In some embodiments, at least one pharmaceutical agent is a small molecule, peptide, or protein. In some embodiments, the molar ratio of the one or more compounds provided herein to the one or more pharmaceutical agents is between 2: 1 and 3:1, between 3:1 and 4:1, between 4:1 and 5:1, between 5:1 and 6:1, between 6:1 and 7:1, between 7:1 and 8:1, between 8:1 and 10:1, or between 10:1 and 15:1, inclusive. In certain embodiments, the molar ratio of the one or more compounds provided herein to the one or more pharmaceutical agents is between 4:1 and 8:1, inclusive. In some embodiments, the combined concentration of the one or more pharmaceutical agents in the pharmaceutical compositions is between 2% and 5%, between 5% and 8%, between 8% and 12%, between 12% and 16%, or between 16% and 20%, inclusive, mokmol. In certain embodiments, the combined concentration of the one or more pharmaceutical agents in the pharmaceutical compositions is between 5% and 12%, inclusive, mokmol.

[0420] In certain embodiments, a pharmaceutical composition comprises one or more compounds described herein; one or more glycerophospholipids; one or more sterol lipids; one or more polymer-conjugated lipids; and one or more pharmaceutical agents.

[0421] In certain embodiments, a pharmaceutical composition comprises between 40% and 60%, inclusive, mokmol, of one or more compounds described herein (where 40% to 60%, inclusive, mokmol is the combined concentration of the one or more compounds described herein); between 7% and 15%, inclusive, mokmol, of one or more glycerophospholipids (where 7% to 15%, inclusive, mokmol is the combined concentration of the one or more glycerophospholipids); between 30% and 50%, inclusive, mokmol, of one or more sterol lipids (where 30% to 50%, inclusive, mokmol is the combined concentration of the one or more sterol lipids); between 0.5% and 2.5%, inclusive, mokmol, of one or more polymer-conjugated lipids (where 0.5% to 2.5%, inclusive, mokmol is the combined concentration of the one or more polymer-conjugated lipids); and between 5% and 12%, inclusive, mokmol, of one or more pharmaceutical agents (where 5% to 12%, inclusive, mokmol is the combined concentration of the one or more pharmaceutical agents).

[0422] The total combined concentrations of all components described herein (e.g., one or more compounds described herein, one or more glycerophospholipids, one or more sterol lipids, one or more polymer-conjugated lipids, one or more pharmaceutical agents, and one or more targeting ligands when not attached to another component in the pharmaceutical composition) of the pharmaceutical composition does not exceed 100% mokmol.

[0423] In certain embodiments, a pharmaceutical composition comprises one or more compounds described herein; distearoylphosphatidylcholine (DSPC); cholesterol; one or more polyethylene glycol (PEG) lipids, wherein the number average molecular weights of the PEG moieties of the PEG lipids (e.g., as determined by gel permeation chromatography) are independently between 1500 and 3000, inclusive, g / mol; and one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

[0424] In certain embodiments, a pharmaceutical composition comprises between 40% and 60%, inclusive, mokmol, of one or more compounds described herein; between 7% and 15%, inclusive, mokmol, of distearoylphosphatidylcholine (DSPC); between 30% and 50%, inclusive, mokmol, of cholesterol; between 0.5% and 2.5%, inclusive, mokmol, of a polyethylene glycol (PEG) lipid, wherein the number average molecular weight of the PEG moiety of the PEG lipid (e.g., as determined by gel permeation chromatography) is between 1500 and 3000 g / mol; and between 5% and 12%, inclusive, mokmol, of one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

[0425] In certain embodiments, a pharmaceutical composition comprises one or more compounds described herein; one or more glycerophospholipids; one or more sterol lipids; one or more targeting ligands; one or more polymer-conjugated lipids; and one or more pharmaceutical agents.

[0426] In certain embodiments, a pharmaceutical composition comprises one or more compounds described herein; one or more glycerophospholipids; one or more sterol lipids; one or more targeting ligands, optionally wherein the targeting ligands are independently attached to the glycerophospholipid or sterol lipids; one or more polymer-conjugated lipids; and one or more pharmaceutical agents.

[0427] In certain embodiments, a pharmaceutical composition comprises one or more compounds described herein; one or more glycerophospholipids; one or more sterol lipids; one or more targeting ligands, wherein the targeting ligands are independently attached to the glycerophospholipid or sterol lipids; one or more polymer-conjugated lipids; and one or more pharmaceutical agents.

[0428] In certain embodiments, a pharmaceutical composition comprises one or more compounds described herein; distearoylphosphatidylcholine (DSPC); cholesterol; one or more N- acetylgalactos amine (GalNAc) moieties; one or more polyethylene glycol (PEG) lipids, wherein the number average molecular weights of the PEG moieties of the PEG lipids (e.g., as determined by gel permeation chromatography) are independently between 1500 and 3000, inclusive, g / mol; and one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

[0429] In certain embodiments, a pharmaceutical composition comprises one or more compounds described herein; distearoylphosphatidylcholine (DSPC); cholesterol; one or more N- acetylgalactos amine (GalNAc) moieties, wherein the GalNAc moieties are independently attached to the DSPC or the cholesterol; one or more polyethylene glycol (PEG) lipids, wherein the number average molecular weights of the PEG moieties of the PEG lipids (e.g., as determined by gel permeation chromatography) are independently between 1500 and 3000, inclusive, g / mol; and one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

[0430] The pharmaceutical composition can also be administered in combination with one or more additional pharmaceutical agents. In some embodiments, at least one additional pharmaceutical agent is a therapeutic agent. In some embodiments, at least one additional pharmaceutical agent is a prophylactic agent. In some embodiments, at least one additional pharmaceutical agent is a diagnostic agent. The one or more additional pharmaceutical agents may improve the intended purposes of the pharmaceutical compositions (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and / or in reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject, cell, tissue, or biological sample. The combination may achieve an improvement for the same desired effect, and / or it may achieve different desired effects. In certain embodiments, the combination exhibits a synergistic effect that is absent in a pharmaceutical composition that does not include the one or more additional pharmaceutical agents.

[0431] The pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combinations. In certain embodiments, at least one additional pharmaceutical agent is a drug approved for human or veterinary use by the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. Each additional pharmaceutical agent may also be administered together with each other and / or with the pharmaceutical composition in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the pharmaceutical composition with the one or more additional pharmaceutical agents and / or the desired effect (e.g., therapeutic and / or prophylactic effect) to be achieved. In general, it is expected that the one or more additional pharmaceutical agents in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0432] In some embodiments, the amount of the one or more compounds provided herein in the pharmaceutical compositions is an effective amount. In some embodiments, the combined amount of the one or more compounds provided herein and the one or more additional pharmaceutical agents in the pharmaceutical compositions is an effective amount. In some embodiments, the pharmaceutical composition is suitable for administration to a subject. In certain embodiments, the pharmaceutical composition provides sustained delivery of the one or more compounds provided herein and / or the one or more additional pharmaceutical agents to a subject (e.g., for 12-24 hours, 24-36 hours, 36-48 hours, 48 hours-1 week, 1-2 weeks, 2-3 weeks, 3-4 weeks, or 4-6 weeks, inclusive) after the administration.

[0433] Actual dosage levels and time course of administration of the active ingredients (e.g., the one or more compounds provided herein and / or the one or more additional pharmaceutical agents) in the pharmaceutical compositions of the disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, pharmaceutical composition, and mode of administration, while being acceptably tolerant to the subject.

[0434] In one embodiment, the pharmaceutical composition is administered acutely. The pharmaceutical composition may therefore be administered for a short course, such as for about 1 day to about 1 week. In another embodiment, the pharmaceutical composition may be administered over a longer period of time, such as, for example, for about one week to several months. In certain embodiments, the time period over which the pharmaceutical composition is administered depends upon the condition to be treated or prevented. In certain embodiments, the pharmaceutical composition is administered in a single dose or multiple doses. In certain embodiments, when multiple doses are administered, any two doses of the multiple doses include different or substantially the same amounts of the one or more compounds described herein. In certain embodiments, when multiple doses are administered, the frequency of administering the multiple doses is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses is one dose per day. In certain embodiments, the frequency of administering the multiple doses is two doses per day. In certain embodiments, the frequency of administering the multiple doses is three doses per day. In certain embodiments, when multiple doses are administered, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.

[0435] The pharmaceutical composition may be administered in any convenient manner, such as by intrathecal, intravenous, intramuscular, subcutaneous, oral, or intra-cerebroventricular injection routes, or by topical application, such as in creams or gels. Depending on the route of administration, the active ingredients may be required to be coated in a material to protect the active ingredients from the action of enzymes, acids, and other natural conditions that may inactivate or otherwise degrade the active ingredient. In order to administer a pharmaceutical composition by a mode other than parenteral administration, the active ingredient can be coated by, or administered with, a material to prevent inactivation. The pharmaceutical composition may be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.

[0436] Some examples of substances that can serve as pharmaceutical excipients are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethycellulose, ethylcellulose, and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil, corn oil, and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acids; pyrogen-free water; isotonic saline; and phosphate buffer solution; skim milk powder; as well as other non-toxic compatible substances used in pharmaceutical formulations, such as Vitamin C, estrogen, and echinacea, for example. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, anti-oxidants, and preservatives, can also be present. Solubilizing agents, including, for example, cremaphore, and beta-cyclodextrins, can also be used in the pharmaceutical compositions.

[0437] The pharmaceutical compositions can be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable excipients, which facilitate processing of the pharmaceutical agents into preparations that can be used pharmaceutically. The pharmaceutical compositions can be made by combining (e.g., contacting, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing) a pharmaceutical agent delineated herein with one or more suitable excipients, including those described herein (e.g., for pharmaceutical, agricultural, or veterinary use).

[0438] The pharmaceutical compositions (e.g., in the form of nanoparticles (e.g., lipid nanoparticles, e.g., in which one or more pharmaceutical agents are encapsulated in a lipid bilayer)) may be formed by any method known in the art including, but not limited to, a continuous mixing method or a direct dilution process. In order to investigate safe and efficacious pharmaceutical compositions for use in the delivery of one or more pharmaceutical agents, a range of nanoparticle formulations can be prepared and tested. Specifically, the particular elements and ratio of the lipid components of a nanoparticle can be optimized.

[0439] Lipid nanoparticles may be produced via a continuous mixing method, that includes providing an aqueous solution comprising one or more pharmaceutical agents in a first reservoir, providing an organic lipid solution in a second reservoir, and mixing the aqueous solution with the organic lipid solution such that the organic lipid solution mixes with the aqueous solution so as to substantially instantaneously produce a liposome encapsulating the one or more pharmaceutical agents; see for example, U.S. Patent Publication No. 20040142025, the disclosure of which is herein incorporated by reference in its entirety. In some instances, the action of continuously introducing lipid and buffer solutions into a mixing environment, such as in a mixing chamber, causes a continuous dilution of the lipid solution with the buffer solution, thereby producing a liposome substantially instantaneously upon mixing. The phrase “continuously diluting a lipid solution with a buffer solution” (and variations) generally means that the lipid solution is diluted sufficiently rapidly in a hydration process with sufficient force to effectuate vesicle generation. By mixing the aqueous solution with the organic lipid solution, the organic lipid solution undergoes a continuous stepwise dilution in the presence of the aqueous solution to produce an pharmaceutical agent-lipid particle.

[0440] Lipid nanoparticles may also be produced via a direct dilution process, that includes forming a liposome solution and immediately and directly introducing the liposome solution into a collection vessel containing a controlled amount of dilution buffer. The collection vessel may include one or more elements configured to stir the contents of the collection vessel to facilitate dilution. In certain embodiments, the amount of dilution buffer present in the collection vessel is substantially equal to the volume of liposome solution introduced thereto.

[0441] In some instances, lipid nanoparticles are produced via a direct dilution process in which a third reservoir containing dilution buffer is fluidly coupled to a second mixing region. In this instance, the liposome solution formed in a first mixing region is immediately and directly mixed with dilution buffer in the second mixing region. The second mixing region may include a T- connector arranged so that the liposome solution and the dilution buffer flows meet as opposing 180° flows; however, connectors providing shallower angles can be used. In some instances, a pump mechanism delivers a controllable flow of buffer to the second mixing region. The flow rate of dilution buffer provided to the second mixing region is controlled to be substantially equal to the flow rate of liposome solution introduced thereto from the first mixing region. This allows for more control of the flow of dilution buffer mixing with the liposome solution in the second mixing region, and therefore also the concentration of liposome solution in buffer throughout the second mixing process. Such processes and the apparatuses for carrying them out are described in U.S. Patent Publication No. 20070042031, the disclosure of which is herein incorporated by reference in its entirety.

[0442] Particle size distribution can be monitored, for example, by conventional laser-beam particle size discrimination, or QELS or using a ZetaSizer apparatus. Lipid nanoparticles may be sized by any of the methods available for sizing liposomes. The sizing may be conducted to achieve a desired size range and / or relatively narrow distribution of particle sizes. Several techniques are available for sizing the particles to a desired size; see for example, U.S. Pat. No. 4,737,323, the disclosure of which is herein incorporated by reference in its entirety.

[0443] In some instances, sonicating a particle suspension produces a size reduction down to particles of less than about 50 nm. Homogenization is another method which fragments larger particles into smaller ones. In a typical homogenization procedure, particles are recirculated through a standard emulsion homogenizer until the desired particle sizes are obtained. Extrusion of the particles through a small-pore polycarbonate membrane or an asymmetric ceramic membrane is also an effective method for reducing particle sizes to a relatively well-defined size distribution. In certain embodiments, the suspension is cycled through the membrane one or more times until the desired particle size distribution is achieved. The particles may be extruded through successively smaller-pore membranes, to achieve a gradual reduction in size.

[0444] The pharmaceutical compositions can take a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, and the like, or a form suitable for administration by inhalation or insufflation.

[0445] In certain embodiments, the pharmaceutical composition is suitable for parenteral administration. In certain embodiments, the pharmaceutical composition is suitable for intravenous, subcutaneous, or intramuscular administration.

[0446] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0447] Useful injectable preparations include sterile suspensions, solutions, or emulsions of the pharmaceutical agent(s) in aqueous or oily vehicles. The pharmaceutical compositions may also contain formulating agents, such as suspending, stabilizing, and / or dispersing agents. The formulations for injection can be presented in unit dosage form (e.g., in ampules or in multidose containers) and can contain added preservatives. Alternatively, the injectable formulation can be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen free water, buffer, dextrose solution, and the like, before use. To this end, the pharmaceutical agent(s) can be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0448] For prolonged delivery, the pharmaceutical agent(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The pharmaceutical agent(s) can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0449] Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the pharmaceutical agent(s). Certain organic solvents such as dimethyl sulfoxide (DMSO) also can be employed. In certain embodiments, the pharmaceutical composition further comprises a solvent. In certain embodiments, the solvent of is one single solvent. In certain embodiments, the solvent is a mixture of two or more (e.g., three) solvents. In certain embodiments, the solvent is an inorganic solvent. In certain embodiments, the solvent is water. In certain embodiments, the solvent is an organic solvent. In certain embodiments, the solvent is a combination of water and an organic solvent. In certain embodiments, the solvent is an alcohol solvent. In certain embodiments, the solvent is ethanol, pr no-panol, z-propanol, or / -butanol, or a mixture thereof. In certain embodiments, the solvent is a combination of water and an alcohol solvent. In certain embodiments, the solvent is an aprotic solvent. In certain embodiments, the solvent is a chlorinated hydrocarbon solvent. In certain embodiments, the solvent is dichloromethane, chloroform, or 1,2-dichloroethane, or a mixture thereof. In certain embodiments, the solvent is an ether solvent. In certain embodiments, the solvent is a di(unsubstituted CM alkyl) ether. In certain embodiments, the solvent is diethyl ether, methyl tert-butyl ether, tetrahydrofuran, or 2- methyltetrahydrofuran, or a mixture thereof. In certain embodiments, the solvent is a ketone solvent. In certain embodiments, the solvent is acetone, methyl ethyl ketone, acetonitrile, or ethyl acetate, or a mixture thereof. In certain embodiments, the solvent is DMSO. In certain embodiments, the solvent is a combination of water and DMSO. In certain embodiments, the solvent is an amide solvent. In certain embodiments, the solvent is MA^-di methyl formamide or MA-di methyl acetamide, or a mixture thereof. In certain embodiments, the boiling point of the solvent at about 1 atm is between 30 and 50, between 50 and 70, between 70 and 100, between

[0450] 100 and 130, between 130 and 160, or between 160 and 190 °C, inclusive. The pharmaceutical compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the pharmaceutical agent(s). The pack can, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration.

[0451] The pharmaceutical compositions will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. The pharmaceutical compositions can be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disease being treated and / or eradication or amelioration of one or more of the symptoms associated with the underlying disease such that the patient reports an improvement in feeling or condition, notwithstanding that the patient can still be afflicted with the underlying disease. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0452] For prophylactic administration, the pharmaceutical compositions can be administered to a subject at risk of developing one of the previously described diseases. A subject at risk of developing a disease can be a subject having characteristics placing the subject in a designated group of at-risk subjects, as defined by an appropriate medical professional or group. A subject at risk may also be a subject that is commonly or routinely in a setting where development of the underlying disease could occur. In other words, an at-risk subject is one who is commonly or routinely exposed to the disease or illness causing conditions or may be acutely exposed for a limited time. Alternatively, prophylactic administration can be applied to avoid the onset of symptoms in a subject diagnosed with the underlying disease.

[0453] The amount of the pharmaceutical compositions administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated, the age and weight of the subject, the bioavailability of the pharmaceutical compositions, and the like. Determination of an effective dosage is well within the capabilities of those skilled in the art.

[0454] Effective dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of the pharmaceutical agent(s) that is at or above an IC50 of the particular pharmaceutical agent(s) as measured in an in vitro assay, such as an in vitro fungal MIC or MFC, and other in vitro assays. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular pharmaceutical agent(s) is well within the capabilities of skilled artisans. For guidance, see “General Principles,” In: Goodman and Gilman’s The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. I"112, 13th ed., McGraw-Hill, and the references cited therein.

[0455] Initial dosages also can be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of pharmaceutical compositions to treat or prevent the various diseases described above are well-known in the art.

[0456] Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg / kg / day to about 100 mg / kg / day, but can be higher or lower, depending upon, among other factors, the activity of the pharmaceutical composition, its bioavailability, the mode of administration, and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the pharmaceutical compositions that are sufficient to maintain therapeutic or prophylactic effect. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active pharmaceutical agents cannot be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation. In certain embodiments, a dose (e.g., a single dose) described herein includes independently between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 10 mg, between 10 mg and 100 mg, between 100 mg and 1,000 mg, between 1 g and 10 g, or between 10 g and 100 g, inclusive, of the one or more compounds described herein. In certain embodiments, a dose (e.g., a single dose) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 10 mg, between 10 mg and 100 mg, or between 100 mg and 1,000 mg, inclusive, of the one or more compounds described herein, per kg of the body weight of a human per day.

[0457] The pharmaceutical compositions may provide an intended (e.g., therapeutic or prophylactic) benefit and will have acceptable tolerability. Tolerability of the pharmaceutical compositions can be determined using standard pharmaceutical procedures. The dose ratio between non-tolerable and therapeutic (or prophylactic) effect is the therapeutic index. Pharmaceutical compositions that exhibit high therapeutic indices are preferred.

[0458] In another aspect, provided are kits comprising one or more compounds provided herein or pharmaceutical composition. In some embodiments, the kits comprise an effective amount of the one or more compounds provided herein. In some embodiments, the kits comprise the one or more compounds provided herein or pharmaceutical composition in unit dosage form. In some embodiments, the kits further comprise instructions for using the one or more compounds provided herein or pharmaceutical composition. The kits may further comprise a first container. In some embodiments, the first container contains the one or more compounds provided herein or pharmaceutical composition. In some embodiments, provided kits may optionally further include a second container. In some embodiments, the second container contains a pharmaceutical excipient. In some embodiments, the pharmaceutical excipient is suitable for dilution or suspension of a pharmaceutical composition or the one or more compounds described herein. In some embodiments, the pharmaceutical compositions or compounds described herein are combined to form one unit dosage form. In certain embodiments, each container is independently a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container.

[0459] In certain embodiments, the kits are useful for treating a disease in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the kits are useful for diagnosing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein (e.g., an asialoglycoprotein receptor) in a subject, cell, tissue, or biological sample.

[0460] In certain embodiments, the kit further includes instructions for using the one or more compounds provided herein or pharmaceutical composition thereof. The kit may also include information as required by a regulatory agency such as the FDA or EMA. In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for diagnosing a disease (e.g., a liver disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for modulating the activity (e.g., inhibiting increased activity or enhancing decreased activity) of a protein (e.g., an asialoglycoprotein receptor) in a subject, cell, tissue, or biological sample. The kits may include one or more additional pharmaceutical agents. In some embodiments, the kits further include additional containers. In some embodiments, the additional containers contain the one or more additional pharmaceutical agents. Methods of Use and Uses

[0461] In another aspect, provided are methods for delivering one or more pharmaceutical agents to a subject comprising administering to the subject a pharmaceutical composition described herein.

[0462] In another aspect, provided are uses of a pharmaceutical composition described herein for the manufacture of a medicament for delivering one or more pharmaceutical agents to a subject.

[0463] In another aspect, a pharmaceutical composition described herein is provided for use in delivering one or more pharmaceutical agents to a subject.

[0464] In some embodiments, the one or more pharmaceutical agents are delivered to a target organ or target tissue of the subject. In some embodiments, the one or more pharmaceutical agents are delivered to the liver of the subject. In some embodiments, the delivery of the one or more pharmaceutical agents to the liver of the subject is higher (e.g., 10-30%, 30-100%, 1-3 fold, 3-10 fold, 10-30 fold, 30-100 fold, 100-300 fold, 300-1000 fold, or greater than 1000 fold higher) than the delivery of the one or more pharmaceutical agents to a non-target organ or non-target tissue. In some embodiments, the delivery is determined by the definite integral of the concentration of the one or more pharmaceutical agents in the organ (e.g., target organ or non- target organ) or tissue (e.g., target tissue or non-target tissue) as a function of time.

[0465] In another aspect, provided are methods for treating a disease in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition described herein.

[0466] In another aspect, provided are uses of a pharmaceutical composition described herein for the manufacture of a medicament for treating a disease in a subject in need thereof.

[0467] In another aspect, a pharmaceutical composition described herein is for use in treating a disease in a subject in need thereof.

[0468] In another aspect, the present disclosure provides methods for preventing a disease in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition described herein.

[0469] In another aspect, provided are uses of a pharmaceutical composition described herein for the manufacture of a medicament for preventing a disease in a subject in need thereof.

[0470] In another aspect, a pharmaceutical composition described herein is for use in preventing a disease in a subject in need thereof.

[0471] In certain embodiments, the disease is associated with the over-production of an asialoglycoprotein receptor. In some embodiments, the disease is a liver disease. In certain embodiments, the disease is viral hepatitis, liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), obesity, hemochromatosis, thalassemia, liver injury, alcoholic liver disease, or liver genetic disease.

[0472] In certain embodiments, the pharmaceutical composition is administered to the subject parenterally. In some embodiments, the pharmaceutical composition is administered to the subject intravenously, subcutaneously, or intramuscularly. In some embodiments, the pharmaceutical composition is administered to the subject orally. In some embodiments, the pharmaceutical composition is administered to the subject topically.

[0473] The subject in the methods and uses provided herein may be a mammal, for example, a primate, such as a human or non-human primate. In certain embodiments, the subject is a human. In some embodiments, the subject is a human younger than 2 years. In some embodiments, the subject is a human aged 2-6 years, inclusive. In some embodiments, the subject is a human aged 6-18 years, inclusive. In certain embodiments, the subject is a human aged 18 years and older. In some embodiments, the subject is a male. In some embodiments, the subject is a female. In certain embodiments, the subject is a non-human animal (e.g., a non-human mammal).

[0474] In some embodiments, any of the pharmaceutical compositions provided herein are administered alone or in combination with one or more additional pharmaceutical agents. In certain embodiments, at least one pharmaceutical agent is as described herein. In certain embodiments, the additional pharmaceutical agent is an agent for treating a liver disease.

[0475] In another aspect, the present disclosure provides for veterinary uses of the pharmaceutical compositions provided herein (e.g., in a non-human subject as described herein).

[0476] EXAMPLES

[0477] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, uses, and methods provided herein and are not to be construed in any way as limiting their scope.

[0478] Example 1: Exemplary synthesis of the compounds

[0479] General scheme for preparation of certain intermediates:

[0480] Preparation of bromoacetate-lipid and azido acetate-lipid intermediates

[0481] Preparation of pentadecan-7-yl 2-bromoacetate

[0482] To a solution of pentadecan-7-ol (3 g, 13.13 mmol) in DCM (65 mL), bromoacetyl bromide (1.37 ml, 15.76 mmol) was added dropwise at 0°C. The reaction mixture was stirred overnight at RT. Saturated NaHCO3solution (50 mL) was added, and the resulting mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were washed several times with 5% NaHCO3solution, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography using 0-50% EtOAc in hexane to obtain the title compound 3.4 g (74% yield) as a clear oil. Preparation of pentadecan-7 -yl 2-azidoacetate

[0483] To a solution of pentadecan-7-yl 2-bromo acetate (3.1 g, 8.87 mmol) in DMF (35 mL), sodium azide (1.73 g, 26.62 mmol) was added, and the mixture heated at 50°C overnight. Saturated NaHCO3(aq) solution (25 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over sodium sulphate, filtered, concentrated, and purified by flash chromatography using 0-70% EtOAc in hexane to obtain the title compound (2.10 g, 76% yield) as a clear oil.

[0484] Preparation of LNP-03:

[0485] Di(heptadecan-9-yl) 8,8'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(3-((l-(8-(heptadecan-

[0486] 9-yloxy)-8-oxooctyl)-lH-1,2,3-triazol-4-yl)methyl)-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)tetrahydrofuran-3,4-diyl)bis(oxy))bis(methylene))bis(lH-1,2,3-triazole-4,l-diyl))dioctanoate

[0487] Step 1: Heptadecan-9-yl 8-azidooctanoate

[0488] To a solution of heptadecan-9-yl 8-bromooctanoate (0.9 g, 1.95 mmol) in DMF (8 mL), sodium azide (0.38 g, 5.85 mmol) was added, and the mixture heated at 50°C overnight. Saturated NaHCO3(aq) solution (25 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography using 0-60% EtOAc in hexane to obtain the title compound (0.75 g, 91% yield) as a clear oil.

[0489] Step 2: l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4-bis(prop-2-yn- l-yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione

[0490] To a solution of l-((2R,3R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)- 3,4-dihydroxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (5.00 g, 9.16 mmol) in anhydrous DMF (40 mL), NaH (1.32 g, 33.0 mmol) was added all at once at 0°C and the resulting mixture was stirred at 0°C for 30 min. Propargyl bromide (4.77 g, 32.1 mmol) was added dropwise, and the mixture was stirred for 1 h at 0°C and then at RT for another 1 h. The reaction was quenched by adding saturated NH4CI solution (30 mL) at 0°C. The resulting mixture was extracted with DCM (3 x 30 mL), and the combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified via flash column chromatography with eluent of 0-40% EtOAc in hexane, to obtain the title compound (5.25 g, 87 % yield) as an off-white solid.

[0491] Step 3: l-((2R,3R,4R,5R)-5-(hydroxymethyl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)-3- (prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione

[0492] To a solution of l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)- 3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (5.25 g, 7.95 mmol) in DCM (70 mL), TFA (2.72 g, 23.9 mmol) was added, and the resulting solution was stirred for 2 h at rt. The reaction mixture was then neutralized with saturated

[0493] NaHCCE solution and extracted with DCM (2 x 25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as light-yellow oil, which was purified via flash column chromatography with eluent of 0-60 % EtOAc in hexane to obtain the title compound (2.04 g, 72 % yield) as an off-white syrup.

[0494] Step 4: ((2R,3R,4R,5R)-5-(2,4-dioxo-3-(prop-2-yn-l-yl)-3,4-dihydropyrimidin-l(2H)-yl)-3,4- bis(prop-2-yn- 1 -yloxy)tetrahydrofuran-2-yl)methyl methane sulfonate

[0495] To a solution of l-((2R,3R,4R,5R)-5-(hydroxymethyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (2.04 g, 5.70 mmol) and TEA (1.15 g, 11.4 mmol) in DCM (60 mL), methanesulfonyl chloride (780 mg, 6.84 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2h. Saturated NaHCO3solution

[0496] (50 mL) was added, and the resulting mixture extracted with DCM (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as an off-white solid (2.40 g, 97 % yield), which was used in the next step without further purification.

[0497] Step 5: l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran- 2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione

[0498] To a solution of ((2R,3R,4R,5R)-5-(2,4-dioxo-3-(prop-2-yn-l-yl)-3,4-dihydropyrimidin- l(2H)-yl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)methyl methanesulfonate (1.00 g, 2.29 mmol) in acetonitrile (25 mL), dimethylamine hydrochloride (940 mg, 11.5 mmol), TEA (695 mg, 6.88 mmol), Nal (35.0 mg, 0.235 mmol), and potassium carbonate (949 mg, 6.88 mmol) were added and heated overnight at 65°C. The reaction mixture was cooled to rt, filtered, and the residue washed with EtOAc. The filtrate was concentrated to obtain the crude product as light- yellow oil, which was purified via flash column chromatography with eluent of 0-60 % EtOAc in hexane to obtain the title compound (593 mg, 67 % yield) as a colorless oil.

[0499] Step 6: Di(heptadecan-9-yl) 8,8'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(3-((l-(8- (heptadecan-9-yloxy)-8-oxooctyl)-lH-l,2,3-triazol-4-yl)methyl)-2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)tetrahydrofuran-3,4-diyl)bis(oxy))bis(methylene))bis(lH-l,2,3-triazole-4,l- diyl))dioctanoate, LNP-03

[0500] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (50 mg, 0.13 mmol) and heptadecan-9-yl 8-azidooctanoate (0.19 g, 0.454 mmol) in THF:DMF (V / V =1:2, 3 mL) was added a solution of CuSO4-5H2O (32 mg, 0.13 mmol) in water (0.4 mL) and a solution of sodium ascorbate (26 mg, 0.13 mmol) in water (0.4 mL). The reaction mixture was stirred at 40°C overnight and then quenched with saturated NaHCO3solution (8 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a yellow oil, which was purified via flash column chromatography with eluent of 0-30% MeOH in DCM to obtain the title compound (60 mg, 35% yield) as a colorless oil. MS (ESI): m / z = 1657.6 [M+H]+. NMR (499 MHz, DMSO-d6) δ 7.81 (s, 3H), 5.81 (s, 2H), 4.68 (s, 4H), 4.34 - 4.23 (m, 4H), 4.02-3.84 (m, 6H), 2.30-2.17 (m, 2H), 2.13-1.90 (m, 2H), 2.17 (m, 6H), 1.84 - 1.60 (m, 6H), 1.41 (bs, 18H), 1.17 (bs, 99H), 0.74 (s, 18H). Preparation of LNP-04:

[0501] (((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(3-((l-(8-((2-hexyldecanoyl)oxy)octyl)-lH- 1,2,3-triazol-4-yl)methyl)-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl)bis(oxy))bis(methylene))bis(lH-1,2,3-triazole-4,l-diyl))bis(octane-8,l-diyl) bis(2- hexyldecanoate)

[0502] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (50 mg, 0.13 mmol) and 8-azidooctyl 2-hexyldecanoate (0.19 g, 0.45 mmol) in THF:DMF (V / V =1:2, 3 mL) was added a solution of CuSO4-5H2O (32 mg, 0.13 mmol) in water (0.4 mL) and a solution of sodium ascorbate (26 mg, 0.13 mmol) in water (0.4 mL). The reaction was stirred at 40°C overnight and then quenched with saturated NaHCO3solution (8 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a yellow oil, which was purified via flash column chromatography with eluent of 0-30% MeOH in DCM to obtain the title compound (72 mg, 34 % yield) as a colorless oil. MS (ESI): m / z = 1614.6 [M+H]+. NMR (499 MHz, DMSO-d6) δ 7.83 (s, 3H), 5.83 (s, 2H), 5.03 (s, 1H), 4.47 (s, 1H), 4.68 (s, 4H), 4.34 - 4.23 (m, 9H), 4.03-3.82 (m, 6H), 2.30-2.19 (m, 2H), 2.11-1.94 (m, 2H), 2.17 (m, 6H), 1.84 - 1.60 (m, 6H), 1.57-1.29 (m, 18H), 1.17 (m, 86H), 0.91 - 0.64 (m, 18H). Preparation of LNP-05:

[0503] Di(pentadecan-7-yl) 2,2'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(2,4-dioxo-3-((l-(2- oxo-2-(pentadecan-7-yloxy)ethyl)-lH-1,2,3-triazol-4-yl)methyl)-3,4-dihydropyrimidin-l(2H)- yl)tetrahydrofuran-3,4-diyl)bis(oxy))bis(methylene))bis(lH-1,2,3-triazole-4,l-diyl))diacetate

[0504] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (200 mg, 0.52 mmol) and pentadec an-7-yl 2-azidoacetate (565 mg, 1.82 mmol) in THF:DMF (V / V =1:2, 6 mL) was added a solution of CuSO4-5H2O (130 mg, 0.519 mmol) in water (0.8 mL) and a solution of sodium ascorbate (102 mg, 0.519 mmol) in water (0.8 mL). The reaction was stirred at 40°C overnight and then quenched with saturated NaHCO3solution (8 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a yellow oil, which was purified via flash column chromatography with eluent of 0-30 % MeOH in DCM to obtain the title compound (491 mg, 72% yield) as a colorless oil. MS (ESI): m / z = 1320.0 [M+H]+. NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 9.5 Hz, 2H), 7.98 (d, J = 28.0 Hz, 3H), 7.75 (d, J = 8.2 Hz, 1H), 5.91 (d, J = 3.8 Hz, 1H), 5.83 (d, J = 8.2 Hz, 1H), 5.41 - 5.29 (m, 6H), 5.11 - 5.01 (m, 2H), 4.88 - 4.78 (m, 3H), 4.77 - 4.69 (m, 2H), 4.62 - 4.53 (m, 2H), 4.31 (t, J = 4.4 Hz, 1H), 4.06 - 4.01 (m, 2H), 2.21 (s, 6H), 1.20 (s, 72H), 0.88 - 0.81 (m, 18H). Preparation of LNP-06:

[0505] Di(heptadecan-9-yl) 8,8'-(((((2R,3R,4S)-2-((dimethylamino)methyl)tetrahydrofuran-3,4- diyl)bis(oxy))bis(methylene))bis(lH-1 23-triazole-4 l-diyl))dioctanoate

[0506] Step 1: (2R,3S,4S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)tetrahydrofuran-3,4-diol

[0507] To a stirred solution of (2R,3S,4S)-2-(hydroxymethyl)tetrahydrofuran-3,4-diol (1 g, 7.45 mmol) in pyridine (38 mL), DMT-C1 (3 g, 8.94 mmol) was added and stirred at room temperature for 24h. The reaction mixture was concentrated and diluted with ethyl acetate (60 mL). The resulting solution was washed with 10% citric acid (30 mL), water (25 mL), and brine solution. The organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography using 0-40% EtOAc in hexane to obtain the product (2.7 g, 83% yield) as a white solid. MS(ESI) m / z= 459.5 [M+Na]+.

[0508] Step 2: (2R,3S,4S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4-bis(prop-2-yn-l- yloxy )tetrahydrofuran

[0509] (2R,3S,4S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)tetrahydrofuran-3,4-diol (2.70 g, 6.19 mmol) was dissolved in anhydrous DMF (30 mL) and cooled to 0 °C. Sodium hydride (0.77 g, 60% dispersion in mineral oil, 19.18 mmol) was added all at once and stirred for 1 h. Propargyl bromide (1.20 mL, 16 mmol) was added drop wise and stirring was continued for 1 h at RT. Reaction was quenched with saturated ammonium chloride (aq) solution and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-50% EtOAc in hexane) to obtain the titled compound (2.60 g, 82% yield) as a white solid. MS(ESI) m / z= 536 [M+Na]+.

[0510] Step 3: ((2R,3R,4S)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)methanol

[0511] To a solution of (2R,3S,4S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4- bis(prop-2-yn-l-yloxy)tetrahydrofuran (2.60 g, 5.07 mmol) in DCM (21 mL), TEA (1.2 mL, 15.21 mmol) was added dropwise and stirred overnight. The reaction mixture was neutralized by adding saturated NaHCCL (aq) solution dropwise at 0 °C and extracted with DCM (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography using 0-100% ethyl acetate in hexane as an eluent to obtain the desired product (1 g, 90% yield) as a white solid.

[0512] Step 4: Di(heptadecan-9-yi) 8,8'-(((((2R,3R,4S)-2-(hydroxymethyl)tetrahydrofuran-3,4- diyl )bis( oxy ) )bis( methylene ) )bis( lH-l,2,3-triazole-4, 1 -diyl ) )dioctanoate

[0513] To a solution of ((2R,3R,4S)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)methanol (0.18 g, 0.86 mmol) and heptadecan-9-yl 8-azidooctanoate (0.87 g, 2.05 mmol) in THF:DMF (1:2, 3 mL), a solution of CuSO4-5H2O (65 mg, 0.26 mmol) in water (0.4 mL) and a solution of sodium ascorbate (68 mg, 0.34 mmol) in water (0.4 mL) were added. The reaction was stirred overnight at 40 °C. The reaction was quenched with saturated ammonium chloride solution. The resulting mixture was extracted with EtOAc (2 x 5 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated to obtain the crude product (0.50 g, 55% yield) as a light-yellow oil.

[0514] Preparation of LNP-07

[0515] Pentadecan-7-yl 2-(4-((3-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3-methoxy-4-((l-(2-oxo-

[0516] 2-(pentadecan-7-yloxy)ethyl)-lH-1,2,3-triazol-4-yl)methoxy)tetrahydrofuran-2-yl)-2,6-dioxo-

[0517] 3 ,6-dihydropyrimidin- 1 (2H)-yl)methyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)acetate

[0518] Step 1: l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-methoxy-4-(prop- 2-yn- 1 -yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn- 1 -yl)pyrimidine-2,4( lH,3H)-dione

[0519] To a solution of 3-benzoyl-l-((2R,3R,4R,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxy-3-methoxytetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione (3.5 g, 6.24 mmol) in anhydrous DMF (30 mL), NaH (0.65 g, 16.23 mmol) was added all at once at 0°C, and the resulting mixture stirred at 0°C for 30 min. Propargyl bromide (1.13 mL, 14.98 mmol) was added dropwise, and the mixture was stirred for 1 h at 0°C and then at rt for another 1 h. The reaction was quenched by adding saturated NH4CI solution (30 mL) at 0°C and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified via flash column chromatography with eluent of 0-47% EtOAc in hexane to obtain the title compound (3.30 g, 83% yield) as an off-white solid. Step 2: l-((2R,3R,4R,5R)-5-(hydroxymethyl)-3-methoxy-4-(prop-2-yn-l-yloxy)tetrahydrofuran-2- yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione

[0520] To a solution of l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3- methoxy-4-(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)- dione (3.30 g, 5.18 mmol) in DCM (24 mL), TFA (1 mL, 12.95 mmol) was added, and the resulting solution stirred for 2 h at rt. The reaction mixture was then neutralized with saturated NaHCO3solution and extracted with DCM (2 x 25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as light-yellow oil, which was purified via flash column chromatography with an eluent of 0-100% EtOAc in hexane to obtain the title compound (0.80 g, 43 % yield) as an off-white solid.

[0521] Step 3: ((2R,3R,4R,5R)-5-(2,4-dioxo-3-(prop-2-yn-l-yl)-3,4-dihydropyrimidin-l(2H)-yl)-4- methoxy-3-(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)methyl methane sulfonate

[0522] To a solution of l-((2R,3R,4R,5R)-5-(hydroxymethyl)-3-methoxy-4-(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (0.80 g, 2.39 mmol) and TEA (0.66 mL , 4.79 mmol) in DCM (10 mL), methanesulfonyl chloride (0.22 mL, 2.87 mmol) was added at 0°C and the reaction mixture stirred at 0°C for 2h. Saturated NaHCO3solution (30 mL) was added, and the resulting mixture was extracted with DCM (3 x 50 mL).

[0523] The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as an off-white solid which was used in the next step without purification.

[0524] Step 4: 1 -(( 2R,3R,4R,5R)-5-( ( dimethylamino )methyl)-3-methoxy-4-(prop-2-yn-l - yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione

[0525] To a solution of ((2R,3R,4R,5R)-5-(2,4-dioxo-3-(prop-2-yn-l-yl)-3,4-dihydropyrimidin- l(2H)-yl)-4-methoxy-3-(prop-2-yn- l-yloxy)tetrahydrofuran-2-yl)methyl methanesulfonate (0.90 g, 2.18 mmol) in acetonitrile (11 mL), dimethylamine hydrochloride (0.89 g, 10.9 mmol), TEA (0.91 mL, 6.54 mmol), and potassium carbonate (0.90 g, 6.54 mmol) were added and heated overnight at 65°C. The reaction mixture was cooled to rt and filtered, and the filtrate was washed with EtOAc. The filtrate was concentrated, and the resulting residue was purified by column chromatography (0-100 % ethyl acetate in hexane followed by 0-25% MeOH in DCM) to obtain the title compound (0.35 g, 44% yield) as a colorless oil. Step 5: Pentadecan-7 -yl 2-(4-((3-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3-methoxy-4-((l-(2- oxo-2-(pentadecan-7-yloxy)ethyl)-lH-l,2,3-triazol-4-yl)methoxy)tetrahydrofuran-2-yl)-2,6- dioxo-3,6-dihydropyrimidin-l(2H)-yl)methyl)-lH-l,2,3-triazol-l-yl)acetate, LNP-07

[0526] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3-methoxy-4-(prop-2-yn- l-yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (50 mg, 0.14 mmol) and pentadec an-7-yl 2-azidoacetate (99 mg, 0.32 mmol) in THF:DMF (V / V=l:2, 3 mL) was added a solution of CuSO4-5H2O (26 mg, 0.10 mmol) in water (0.4 mL) and a solution of sodium ascorbate (21 mg, 0.10 mmol) in water (0.4 mL) and the mixture stirred overnight at 40°C. The reaction was quenched with saturated NaHCO3solution and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a light-yellow oil, which was purified via flash column chromatography with eluent of 0-30% MeOH in DCM to obtain the title compound (80 mg, 60% yield) as a colorless oil. MS (ESI): m / z = 984.9 [M+H]+.

[0527] Preparation of LNP-08: di((6Z,15Z)-henicosa-6,15-dien-l l-yl) 2,2'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(3- (( 1 -(2-(((6Z, 15Z)-henicosa-6, 15-dien- 11 -yl)oxy)-2-oxoethyl)- 1H- 1 ,2,3-triazol-4-yl)methyl)-2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4-diyl)bis(oxy))bis(methylene))bis(lH- 1 2 3-triazole-4 1 -diyl))diacetate

[0528] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (48 mg, 0.13 mmol) and (6Z,15Z)-henicosa-6,15-dien-l l-yl 2-azidoacetate (161 mg, 0.411 mmol) in THF:DMF (V / V 1:2, 3 mL) was added a solution of CuSO4-5H2O (31 mg, 0.13 mmol) in water (0.4 mL) and a solution of sodium ascorbate (25 mg, 0.13 mmol) in water (0.4 mL). The reaction was stirred at 40 °C overnight, quenched with saturated NaHCO3solution, and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a light-yellow oil, which was purified via flash column chromatography with eluent of 0-30 % MeOH in DCM to obtain the title compound (52 mg, 27% yield) as a colorless oil. MS (ESI): m / z = 1560.3 [M+H]+. NMR (499 MHz, DMSO-d6) δ 8.08 (d, J = 10.2 Hz, 3H), 8.01 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 5.91 (d, J = 3.8 Hz, 2H), 5.83 (d, J = 8.1 Hz, 2H), 5.44 - 5.23 (m, 12H), 5.12 - 5.02 (m, 4H), 4.90 - 4.78 (m, 6H), 4.77 - 4.71 (m, 4H), 4.63 - 4.50 (m, 4H), 4.31 (s, 4H), 4.10 (q, J = 5.2 Hz, 3H), 4.01 (d, J = 21.0 Hz, 4H), 2.19 (s, 6H), 2.04 - 1.88 (m, 24H), 1.50 (s, 12H), 1.40 - 1.11 (m, 36H), 0.85 (td, J = 7.0, 1.1 Hz, 18H).

[0529] Preparation of LNP-09:

[0530] (6Z,15Z)-henicosa-6,15-dien-l l-yl 2-(4-((3-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-4-((l-

[0531] (2-(((6Z,15Z)-henicosa-6,15-dien-l l-yl)oxy)-2-oxoethyl)-lH-1,2,3-triazol-4-yl)methoxy)-3- methoxytetrahydrofuran-2-yl)-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)methyl)-lH-l,2,3- triazol- 1 -yl) acetate

[0532] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3-methoxy-4-(prop-2-yn- l-yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (48 mg, 0.13 mmol) and (6Z,15Z)-henicosa-6,15-dien-l l-yl 2-bromoacetate (0.12 g, 0.31 mmol) in THF:DMF (V / V =1:2, 3 mL) was added a solution of CuSO4-5H2O (26mg ,0.10m mmol) in water (0.4 mL) and a solution of sodium ascorbate (21 mg, 0.10 mmol) in water (0.4 mL). The reaction was stirred at 40°C overnight, quenched with saturated NaHCO3solution, and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a light-yellow oil, which was purified via flash column chromatography with eluent of 0-30% MeOH in DCM to obtain the title compound (64 mg, 42% yield) as a colorless oil. MS (ESI): m / z = 1145.1 [M+H]+.

[0533] Preparation of LNP-10:

[0534] Di(pentadecan-7-yl) 2,2'-(((((2R,3R,4R,5R)-2-(((3-(dimethylamino)propyl)(methyl) amino)methyl)-5-(2,4-dioxo-3-((l-(2-oxo-2-(pentadecan-7-yloxy)ethyl)-lH-1,2,3-triazol-4- yl)methyl)-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl)bis(oxy))bis(methylene))bis(lH-1,2,3-triazole-4,l-diyl))diacetate

[0535] Step 1: 1 -(( 2R,3R,4R,5R)-5-( ((3-( dimethylamino )propyl)( methyl)amino )methyl)-3,4-bis(prop-2- yn-l-yloxy)tetrahydrofuran-2-yl)-3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione

[0536] To a solution of ((2R,3R,4R,5R)-5-(2,4-dioxo-3-(prop-2-yn-l-yl)-3,4-dihydropyrimidin- l(2H)-yl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)methyl methanesulfonate (0.21 g, 0.48 mmol) in acetonitrile (2.5 mL), trimethylpropane- 1,3-diamine (0.19 g, 1.68 mmol), triethylamine (0.13 ml, 0.96 mmol), and potassium carbonate (0.13 g, 0.96 mmol) were added and heated overnight at 70-75°C. The reaction mixture was filtered and washed with EtOAc. The filtrate was concentrated, and the resulting residue was purified by column chromatography (0-25% MeOH in DCM) to obtain the title compound (70 mg, 32% yield) as a white solid. MS (ESI): m / z = 457.2 [M+H]+. Step 2: Di(pentadecan-7-yl) 2,2'-(((((2R,3R,4R,5R)-2-(((3- (dimethylamino)propyl)(methyl)amino)methyl)-5-(2,4-dioxo-3-((l-(2-oxo-2-(pentadecan-7- yloxy)ethyl)-lH-l,2,3-triazol-4-yl)methyl)-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl )bis( oxy ) )bis( methylene ) )bis( lH-l,2,3-triazole-4, 1 -diyl ) )diacetate

[0537] To a solution of l-((2R,3R,4R,5R)-5-(((3- (dimethylamino)propyl)(methyl)amino)methyl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)- 3-(prop-2-yn-l-yl)pyrimidine-2,4(lH,3H)-dione (70 mg, 0.15 mmol) and pentadecan-7-yl 2- azidoacetate (0.17 g, 0.54 mmol) in THF:DMF (V / V =1:2, 3 mL) was added a solution of CuSO4-5H2O (57 mg, 0.23 mmol) in water (0.4 mL) and a solution of sodium ascorbate (46 mg, 0.23 mmol) in water (0.4 mL). The reaction was stirred at 40°C overnight, quenched with saturated NaHCO3solution, and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a light- yellow oil, which was purified via flash column chromatography with eluent of 0-30% MeOH in DCM to obtain the title compound (21 mg, 10% yield) as a colorless oil. MS (ESI): m / z = 1391.2 [M+H]+.

[0538] Preparation of LNP-11:

[0539] Di(pentadecan-7-yl) 2,2'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(3-((2- methoxyethoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl)bis(oxy))bis(methylene))bis(lH-1,2,3-triazole-4,l-diyl))diacetate.

[0540]

[0541] Step 1: 1 -(( 6aR,8R,9R,9aS )-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[ 3,2- f][l,3,5,2,4] lrioxadisilocin-8-yl)-3-((2-inelhoxyelhoxy)inelhyl)pyriinidine-2,4(1 H,3H)-dione

[0542] To a stirred solution of l-((6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-

[0543] 6H-furo[3,2-f][l,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(lH,3H)-dione (2 g, 4.11 mmol) in

[0544] DCM (20 mL), TEA (1.14 ml, 8.22 mmol) and 2-methoxyethoxymethyl chloride (0.66 g, 5.34 mmol) were added and stirred at RT for 6 h. The reaction was quenched with water, and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified via flash column chromatography with eluent of 0-60%

[0545] EtOAc in hexane to obtain the title compound (1.70 g, 73% yield) as a white solid. MS (ESI): m / z = 597 [M+Na]+. Step 2: l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-((2- methoxyethoxy) methyl)pyrimidine-2,4( lH,3H)-dione

[0546] To a solution of l-((6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H- furo[3,2-f][l,3,5,2,4] trioxadisilocin-8-yl)-3-((2-methoxyethoxy)methyl)pyrimidine-2,4(lH,3H)- dione (1.3 g, 2.26 mmol) in THE (15 ml), TBAF (IM in THE, 5 mL, 5 mmol) was added and stirred at RT for 2 h. The reaction mixture was concentrated, and the residue obtained was purified by silica gel column chromatography using a gradient 80-100% EtOAc in hexane followed by 0-15% MeOH in DCM to obtain the title compound (0.63 g 84% yield) as a clear oil. MS (ESI): m / z = 355 [M+Na]+.

[0547] Step 3: 1 -(( 2R,3R,4S, 5R)-5-( (bis(4-m elhoxyphenyl)(phenyl )methoxy )methyl)-3,4-dihydroxy tetrahydrofuran-2-yl)-3-((2-methoxyethoxy)methyl)pyrimidine-2,4(lH,3H)-dione

[0548] To a solution of l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-3-((2-methoxyethoxy) methyl)pyrimidine-2,4(lH,3H)-dione (0.63 g, 1.90 mmol) in pyridine (10 mL), DMT-C1 (0.93 g, 2.46 mmol) was added and stirred for 18h at room temperature. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with 10% citric acid (20 mL) and brine solution (20 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified by flash chromatography using 0-100% EtOAc in hexane to obtain the title compound (0.83 g, 69% yield) as a white solid. MS (ESI): m / z = 657 [M+Na]+.

[0549] Step 4: l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4-bis(prop-2-yn- 1 -yloxy )tetrahydrofuran-2-yl)-3-( (2 -methoxy ethoxy )methyl ) pyrimidine -2, 4( 1H, 3H)-dione l-((2R,3R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4-dihydroxy tetrahydrofuran-2-yl)-3-((2-methoxyethoxy)methyl)pyrimidine-2,4(lH,3H)-dione (0.83 g, 1.31 mmol) was dissolved in anhydrous DMF (7 mL) and cooled to 0°C. Sodium hydride (0.14 g, 60% dispersion in mineral oil, 3.4 mmol) was added all at once and stirred for 1 h. Propargyl bromide (0.23 mL, 3.13 mmol) was added dropwise and stirring was continued for 1 h at RT. The reaction was quenched with saturated ammonium chloride (aq) solution and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product (0.80 g, 87% yield) as an off-white solid. Step 5: l-((2R,3R,4R,5R)-5-(hydroxymethyl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)-3- ( (2-methoxyethoxy)methyl)pyrimidine-2,4( lH,3H)-dione

[0550] To a solution of l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)- 3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)-3-((2-methoxyethoxy)methyl)pyrimidine- 2,4(lH,3H)-dione (0.80 g, 1.13 mmol) in DCM (5 ml), TEA (0.22 mL, 2.81 mmol) was added and stirred for 2h. The reaction mixture was neutralized by adding saturated NaHCO3(aq) solution drop wise at 0°C and then extracted with DCM (2 x 15 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using 0-100% ethyl acetate in hexane as an eluent to obtain the title compound (0.40 g, 88% yield) as a white solid.

[0551] Step 6: ((2R,3R,4R,5R)-5-(3-( (2-methoxyethoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)methyl methanesulfonate

[0552] To a solution of l-((2R,3R,4R,5R)-5-(hydroxymethyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-((2-methoxyethoxy)methyl)pyrimidine-2,4( lH,3H)-dione (0.40 g, 0.98 mmol) and triethylamine (0.27 mL, 1.96 mmol) in DCM (10 mL), methanesulfonyl chloride (0.10 mL, 1.17 mmol) was added dropwise at 0°C and stirred for 2h. Saturated NaHCO3(aq) solution was added and the mixture was extracted with DCM (3 x 15 mL). The combined organic extracts were dried over sodium sulphate, filtered, and concentrated to obtain the title compound as an off-white solid which was used in the next step without purification.

[0553] Step 7: l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran- 2-yl)-3-(( 2 -methoxy ethoxy )methyl ) pyrimidine -2, 4( 1H, 3H)-dione

[0554] To a solution of ((2R,3R,4R,5R)-5-(3-((2-methoxyethoxy)methyl)-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-3,4-bis(prop-2-yn-l-yloxy)tetrahydrofuran-2-yl)methyl methanesulfonate (0.42 g, 0.86 mmol) in acetonitrile (7 mL), dimethylamine hydrochloride (0.35 g, 4.31 mmol), triethylamine (0.36 ml, 2.59 mmol), and potassium carbonate (0.35 g, 2.59 mmol) were added and heated at 70-75°C overnight. The reaction mixture was filtered and washed with EtOAc. The filtrate was concentrated, and the resulting residue was purified by column chromatography (0-100 % ethyl acetate in hexane followed by 0-25% MeOH in DCM) to obtain the title compound (0.30 g, 80% yield) as a white solid. MS (ESI): m / z = 436.2 [M+H]+. Step 8: Di(pentadecan-7-yl) 2,2'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(3-((2- methoxyethoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl )bis( oxy ) )bis( methylene ) )bis( lH-l,2,3-triazole-4, 1 -diyl ) )diacetate, LNP-11

[0555] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-((2-methoxyethoxy)methyl)pyrimidine-2,4( lH,3H)-dione (50 mg, 0.12 mmol) and pentadecan-7-yl 2-azidoacetate (0.09 g, 0.27 mmol) in THF:DMF (V / V =1:2, 3 mL) was added a solution of CuSO4-5H2O (24 mg, 0.10 mmol) in water (0.4 mL) and a solution of sodium ascorbate (19 mg, 0.10 mmol) in water (0.4 mL). The reaction was stirred at 40°C overnight and then quenched with saturated NaHCO3solution and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a light-yellow oil, which was purified via flash column chromatography with eluent of 0-30% DCM in MeOH to obtain the title compound (62 mg, 51% yield) as a colorless oil. MS (ESI): m / z = 1058.8 [M+H]+.

[0556] Preparation of LNP-12:

[0557] Di((6Z,15Z)-henicosa-6,15-dien-l l-yl) 2,2'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(3-

[0558] ((2-methoxyethoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl)bis(oxy))bis(methylene))bis(lH-1,2,3-triazole-4 l-diyl))diacetate

[0559] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-((2-methoxyethoxy)methyl)pyrimidine-2,4( lH,3H)-dione (50 mg, 0.12 mmol) and (6Z,15Z)-henicosa-6,15-dien-l l-yl 2-azidoacetate (0.10 g, 0.26 mmol) in THF:DMF (V / V =1:2, 3 mL) was added a solution of CuSO4-5H2O (24 mg, 0.10 mmol) in water (0.4 mL) and a solution of sodium ascorbate (19 mg, 0.10 mmol) in water (0.4 mL). The reaction was stirred overnight at 40°C and then quenched with saturated NaHCO3solution and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain the crude product as a light-yellow oil, which was purified via flash column chromatography with eluent of 0-30% MeOH in DCM to obtain the title compound (62 mg, 44% yield) as a colorless oil. MS (ESI): m / z = 1219 [M+H]+.

[0560] Preparation of LNP-13:

[0561] Pentadecan-7-yl 2-(3-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3-methoxy-4-(2-oxo-2- (pentadecan-7-yloxy)ethoxy)tetrahydrofuran-2-yl)-2,6-dioxo-3,6-dihydropyrimidin-l(2H)- yl)acetate

[0562] Step 1: 1 -(( 2R,3R,4R,5R)-5-((bis( 4-methoxyphenyl)(phenyl)methoxy)methyl )-4-( ( tert- butyldimethylsilyl ) oxy)-3 -methoxytetrahydrofuran-2 -yl )pyrimidine-2,4( 1H, 3H)-dione

[0563] To a solution of 5'-O-(4,4'-dimethoxytrityl)-2'-O-methyluridine (10.0 g, 17.8 mmol) in DMF (71 mL), DMAP (430 mg, 3.5 mmol), imidazole (3.0 g, 44.57 mmol), and tert- butyldimethylsilyl chloride (4.0 g, 27 mmol) were added under nitrogen at 0°C. The reaction mixture was stirred overnight, quenched with water at room temperature, and extracted with EtOAc (3x50 mF). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to obtain the title compound which was used in the next step without purification. MS (ESI): m / z = 675.4 [M+H]+.

[0564] Step 2: 1 -(( 2R,3R,4R,5R)-4-( ( tert-butyldimethylsilyl)oxy )- 5 -(hydroxymethyl )-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione

[0565] To a solution of l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4- ((tert-butyldimethylsilyl) oxy)-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (2.30 g, 3.41 mmol) in DCM (17 mL), TFA (0.65 g, 8.18 mmol) was added dropwise and stirred overnight. The reaction mixture was neutralized by dropwise addition of saturated NaHCO3(aq) solution at 0°C and then extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using 0-100 % ethyl acetate in hexane as an eluent to obtain the title product (0.90 g, 71%) as a yellow oil. MS (ESI): m / z = 373.3 [M+H]+.

[0566] Step 3: ((2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4-dihydropyrimidin- 1 ( 2H)-yl)-4-methoxytetrahydrofuran-2-yl )methyl methane sulfonate

[0567] To a solution of l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (2.9 g, 7.785 mmol) and triethylamine (1.7 mL, 12.46 mmol) in DCM (38 mL), methanesulfonyl chloride (0.70 mL, 8.95 mmol) was added dropwise and stirred for 2h. Saturated NaHCO3(aq) solution was added, and the mixture was extracted with DCM (3 x 25 mL). The combined organic extracts were dried over sodium sulphate, filtered, and concentrated to obtain the title compound which was used in the next step without purification. MS (ESI): m / z = 451.2 [M+H]+.

[0568] Step 4: 1 -(( 2R,3R,4R,5R)-4-( ( tert-butyldimethylsilyl)oxy )-5-( ( dimethylamino )methyl)-3- methoxytetra- hydrofuran-2-yl)pyrimidine-2,4( lH,3H)-dione

[0569] To a solution of ((2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4- dihydro- pyrimidin-l(2H)-yl)-4-methoxytetrahydrofuran-2-yl)methyl methanesulfonate (2.8 g, 6.2 mmol) in acetonitrile (31 mL), dimethylamine hydrochloride (1.1 g, 13 mmol), triethylamine (1.3 ml, 9.4 mmol), and potassium carbonate (1.29 g, 9.36 mmol) were added, and the mixture was heated overnight at 70-75°C. The reaction mixture was filtered and washed with EtOAc. The filtrate was concentrated, and the resulting residue was purified by column chromatography (0- 100 % ethyl acetate in hexane followed by 0-25% MeOH in DCM) to obtain the title compound (1.78 g, 73 % yield) as a yellow oil. MS (ESI): m / z = 400.2 [M+H]+. Step 5: l-(( 2R,3R,4R,5R)-5-( ( dimethylamino )methyl)-4-hydroxy-3 -methoxytetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione

[0570] To a solution of l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-((dimethylamino)- methyl)-3-methoxytetra- hydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (0.56 g, 1.40 mmol) in THF (7 mL), TBAF (1 M in THF, 1.68 mL, 1.68 mmol) was added dropwise and stirred for 2 h. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (0-40% MeOH in DCM) to obtain the title compound (0.25 g, 63 % yield) as a white solid. MS (ESI): m / z = 285.9 [M+H]+.

[0571] Step 6: Pentadecan-7 -yl 2-(3-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3-methoxy-4-(2-oxo-2- (penta- decan-7 -yloxy)ethoxy )tetrahydrofuran-2-yl)-2,6-dioxo-3,6-dihydropyrimidin-l(2H)- yl)acetate, LNP-13 l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-4-hydroxy-3-methoxytetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione (0.50 g, 1.75 mmol) was dissolved in anhydrous DMF (9 mL) and cooled to 0°C. Sodium hydride (0.17 g, 60% dispersion in mineral oil, 4.38 mmol) was added all at once and stirred for 1 h. Pentadecan-7-yl 2-bromoacetate (1.47 g, 4.21 mmol) was added dropwise, and stirring was continued for 1 h at 0°C and another 3h at rt. The reaction was quenched with saturated ammonium chloride (aq) solution and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (0-100% EtOAc) in hexane to obtain the title compound (0.44 g, 31 % yield) as a clear oil. MS (ESI): m / z = 822.5 [M+H]+1H NMR (500 MHz, DMSO- d6) NMR (499 MHz, DMSO-d6) δ 7.82 (d, J = 8.2 Hz, 1H), 5.88 (d, J = 8.2 Hz, 1H), 5.83 (d, J = 4.8 Hz, 1H), 4.87 (q, J = 6.5 Hz, 1H), 4.80 (q, J = 5.8 Hz, 1H), 4.52 (d, J = 4.7 Hz, 2H), 4.22 (d, J = 4.8 Hz, 2H), 4.11 (t, J = 5.0 Hz, 1H), 4.09 - 4.03 (m, 1H), 4.03 - 3.97 (m, 1H), 3.39 (s, 3H), 2.63 (dd, J = 13.2, 5.4 Hz, 1H), 2.43 (dd, J = 13.3, 6.5 Hz, 1H), 2.20 (s, 6H), 1.56 (s, 8H), 1.23 (s, 40H), 0.85 (td, J = 7.0, 1.4 Hz, 12H). Preparation of LNP-14:

[0572] Di(pentadecan-7-yl) 2,2'-(((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(2,4-dioxo-3-(2-oxo-2-

[0573] (pentadecan-7-yloxy)ethyl)-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl)bis(oxy))diacetate

[0574] Step 1: ((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2,2- dimethyltetrahydrofuro[3 ,4-d ][1,3 ]dioxol-4-yl )methyl methane sulfonate

[0575] To a solution of l-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)pyrimidine-2,4(lH,3H)-dione (11.60 g, 40.98 mmol) and TEA (8.28 g, 11.3 mmol) in DCM (200 mL), methanesulfonyl chloride (5.61 mg, 49.2 mmol) was added at 0°C. The reaction mixture was stirred at rt for 2h. Saturated NaHCO3solution (100 mL) was added, and the resulting mixture was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford the crude product as a white solid (14.83 g, 100 % yield), which was used in the next step without further purification.

[0576] Step 2: I -((3aR,4R,6R,6aR)-6-((diinethylainino)inethyl)-2,2-diinethyltetrahydrojuro[3,4- d][l,3 ]dioxol-4-yl)pyrimidine-2,4( lH,3H)-dione

[0577] To a solution of ((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methyl methanesulfonate (14.83 g, 40.98 mmol) in acetonitrile (200 mL), dimethylamine hydrochloride (16.59 g, 204.9 mmol), TEA (12.42 mg, 122.9 mmol), Nal (611 mg, 4.10 mmol), and potassium carbonate (16.97 g, 122.9 mmol) were added and stirred at 65 °C overnight. The reaction mixture was cooled to rt, filtered, and the residue was washed with EtOAc. The filtrate was concentrated to obtain the crude product as a yellow oil, which was purified via flash column chromatography with eluent of 0-100 % EtOAc in hexane to obtain the title compound (3.98 g, 31 % yield) as a yellow solid.

[0578] Step 3: l-(( 2R,3R,4S,5R)-5-( ( dimethylamino )methyl)-3,4-dihydroxytetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione

[0579] To a solution of l-((3aR,4R,6R,6aR)-6-((dimethylamino)methyl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)pyrimidine-2,4(lH,3H)-dione (200 mg, 0.643 mmol) was added 4M HC1 solution in dioxane (4 mL) and H2O (cat.) at rt, and the resulting solution was stirred at rt for 3 h. The solvent was evaporated to dryness under reduced pressure and co-evaporated twice with EtOH (2x1 mL) to afford the crude product as a yellow oil, which was purified via flash column chromatography with eluent of 0-20% 7M NH4OH in MeOH / DCM to obtain the title compound (136 mg, 78 % yield) as a colorless oil.

[0580] Step 4: Di(pentadecan-7-yl) 2,2'-(((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(2,4-dioxo-3-(2- oxo-2-(pentadecan-7-yloxy)ethyl)-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4- diyl )bis( oxy ) )diacetate, LNP-14

[0581] To a solution of l-((2R,3R,4S,5R)-5-((dimethylamino)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (40 mg, 0.14 mmol) in anhydrous DMF (2 mL) was added NaH (26 mg, 0.64 mmol) all at once at 0°C, and the resulting solution stirred at 0°C for 30 min. Pentadecan-7-yl 2-bromoacetate (182 mg, 0.521 mmol) was added dropwise and the resulting solution stirred at rt for 1 h. Saturated NH4CI solution was added at 0°C, and the resulting solution was extracted with DCM (3 x 3 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford the crude product as a yellow oil, which was purified by column chromatography on silica gel using 0-40% EtOAc in hexane to obtain the title compound (46 mg, 28 % yield) as a colorless oil. MS (ESI): m / z = 1077.3 [M+H]+. NMR (499 MHz, DMSO-d6) δ 7.83 (d, J= 8.2 Hz, 1H), 5.91 - 5.79 (m, 2H), 4.86 (s, 4H), 4.49 (d, J = 11.3 Hz, 6H), 4.37 - 4.23 (m, 6H), 2.68 (d, J = 5.4 Hz, 6H), 2.64-2.61 (m, 2H), 2.37-2.34 (m, 2H), 2.21 (s, 6H), 1.47 (s, 12H), 1.21 (d, J = 19.5 Hz, 48H), 0.89 - 0.79 (m, 18H). Preparation of LNP-15:

[0582] Di(pentadecan-7-yl) 2,2'-(((((2R,3R,4R,5R)-2-((dimethylamino)methyl)-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4-diyl)bis(oxy))bis(methylene))bis(lH- 1,2,3- triazole-4, 1 -diyl))diacetate

[0583] Step 1: 1 -(( 2R,3R,4R,5R)-5-( ( dimethylamino )methyl)-3,4-bis(prop-2-yn-l -yloxy)tetrahydrofuran- 2-yl)pyrimidine-2,4(lH,3H)-dione

[0584] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)-3-((2-methoxyethoxy)methyl)pyrimidine-2,4(lH,3H)-dione (0.12 g, 0.28 mmol) in DCM (2 mL), 2-bromobenzo[d][l,3,2]dioxaborole (0.16 g, 0.83 mmol) was added and stirred at rt for 5h. The reaction was quenched with saturated NaHCO3solution and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (0-30% MeOH in DCM) to obtain the desired product (60 mg, 57% yield) as an off-white solid. MS (ESI): m / z = 348.2 [M+H]+.

[0585] Step 2: di(pentadecan-7-yl) 2,2'-(((((2R,3R,4R,5R)-2-((diinethylainino)inethyl)-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)tetrahydrofuran-3,4-diyl)bis( oxy))bis(methyiene))bis( 1H- 1,2,3 - triaz.ole-4, 1 -diyl))diacetate, LNP-15

[0586] To a solution of l-((2R,3R,4R,5R)-5-((dimethylamino)methyl)-3,4-bis(prop-2-yn-l- yloxy)tetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (50 mg, 0.14 mmol) and pentadecan-7- yl 2-azidoacetate (0.10 g, 0.33 mmol) in THF:DMF (V...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein:R1is substituted or unsubstituted heteroaryl or substituted or unsubstituted, partially unsaturated heterocyclyl; each of R2A, R2B, R3A, and R3B, when present, is independently hydrogen, halogen, 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, substituted or unsubstituted heteroaryl, -CN, -ORa, -SCN, -SRa, -SSRa, -N3, -NO, -N(Ra)2, - NO2, -C(=O)Ra, -C(=O)ORa, -C(=O)SRa, -C(=O)N(Ra)2, -S(=O)Ra, -S(=O)ORa, -S(=O)SRa, - S(=O)N(Ra)2, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2SRa, -S(=O)2N(Ra)2, -OC(=O)Ra, -OC(=O)ORa, -OC(=O)SRa, -OC(=O)N(Ra)2, -OS(=O)Ra, -OS(=O)ORa, -OS(=O)SRa, -OS(=O)N(Ra)2, - OS(=O)2Ra, -OS(=O)2ORa, -OS(=O)2SRa, -OS(=O)2N(Ra)2, -ON(Ra)2, -SC(=O)Ra, - SC(=O)ORa, -SC(=O)SRa, -SC(=O)N(Ra)2, -NRaC(=O)Ra, -NRaC(=O)ORa, -NRaC(=O)SRa, - NRaC(=O)N(Ra)2, -NRaS(=O)Ra, -NRaS(=O)ORa, -NRaS(=O)SRa, -NRaS(=O)N(Ra)2, - NRaS(=O)2Ra, -NRaS(=O)2ORa, -NRaS(=O)2SRa, -NRaS(=O)2N(Ra)2, -Si(Ra)3, -Si(Ra)2ORa, - Si(Ra)(ORa)2, -Si(ORa)3, -OSi(Ra)3, -OSi(Ra)2ORa, -OSi(Ra)(ORa)2, or -OSi(ORa)3; each instance of Rais independently hydrogen, 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, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Raattachedto the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring;R5, when present, is -ORb, -SRb, -SSRb, -N(Rb)2, -OC(=O)Rb, -OC(=O)ORb, - OC(=O)SRb, -OC(=O)N(Rb)2, -OS(=O)Rb, -OS(=O)ORb, -OS(=O)SRb, -OS(=O)N(Rb)2, - OS(=O)2Rb, -OS(=O)2ORb, -OS(=O)2SRb, -OS(=O)2N(Rb)2, -ON(Rb)2, -SC(=O)Rb, - SC(=O)ORb, -SC(=O)SRb, -SC(=O)N(Rb)2, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)SRb, - NRbC(=O)N(Rb)2, -NRbS(=O)Rb, -NRbS(=O)ORb, -NRbS(=O)SRb, -NRbS(=O)N(Rb)2, - NRbS(=O)2Rb, -NRbS(=O)2ORb, -NRbS(=O)2SRb, -NRbS(=O)2N(Rb)2, -OSi(Rb)3, - OSi(Rb)2ORb, -OSi(Rb)(ORb)2,-OSi(ORb)3, hydrogen, or halogen; each instance of Rbis independently hydrogen, 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, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of Rbattached to the same intervening atom are joined together with the intervening atom to form an substituted or unsubstituted, monocyclic, heterocyclic or heteroaryl ring; provided that one or more of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Pl:-L1-N*(R6)(R6)(Pi); wherein: each instance of L1is independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene, wherein optionally one or more unbranched backbone carbon atoms of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;each instance of R6is independently substituted or unsubstituted alkyl or hydrogen, or two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted heterocyclyl; each nitrogen atom marked with * is attached to a carbon atom of L1; and each carbon atom attached to each nitrogen atom marked with * is an sp3hybridized carbon atom; and provided that one or more of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2 or Q3 and optionally with a moiety of Formula Q1:-L2-L3-C(R7)(B1)2L2-L3-C(B1)3 or -L2-L3-C(R7)2(B1)(Q2), (Q3), (QD; wherein: each instance of L2is independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, wherein optionally one or more unbranched backbone carbon atoms of the alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted hetero arylene; each instance of L3is independently -O-, -S-, -S-S-, -NRZ-, -C(=O)O-, - C(=NRZ)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRZ-, -C(=NRZ)NRZ-, -S(=O)NRZ-, - S(=O)2NRZ-, -OC(=O)-, -OC(=NRZ)-, -OS(=O)-, -OS(=O)2-, -NRZC(=O)-, - NRZC(=NRZ)-, -NRZS(=O)-, -NRZS(=O)2-, -OC(=O)O-, -OC(=NRZ)O-, -OS(=O)O-, - OS(=O)2O-, -NRZC(=O)O-, -NRZC(=NRZ)O-, -NRZS(=O)O-, -NRZS(=O)2O-, - OC(=O)NRZ-, -OC(=NRZ)NRZ-, -OS(=O)NRZ-, -OS(=O)2NRZ-, -NRZC(=O)NRZ-, - NRZC(=NRZ)NRZ-, -NRZS(=O)NRZ-, -NRZS(=O)2NRZ-, -C(=O)-, -C(=NRZ)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORZ)O-, -SP(=O)(ORZ)O-, -OP(=O)(ORZ)S-, or -OP(=O)(SRZ)O-; each instance of Rzis independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; each instance of R7is independently hydrogen, halogen, unsubstituted C1-3alkyl, or C1-3alkyl substituted with one or more instances of halogen;each instance of B1is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and the longest unbranched carbon backbone of each instance of B1is independently C4-10.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

13. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

14. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

16. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

18. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

19. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

20. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: the compound is of the formula:provided that one of R2A, R2B, R3AR3B, and R5is replaced with a moiety of Formula Pl; and optionally provided that one or more of the remaining R2A, R2B, R , R3B, and R5are independently replaced with a moiety of Formula Q2, Q3, or Q1.

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

22. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

23. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

24. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

25. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

26. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

27. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

28. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

29. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

30. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

31. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

32. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

33. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

34. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein two or three of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are independently replaced with a moiety of Formula Q2.

35. The compound of any one of claims 1 and 34, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein none of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1are replaced with a moiety of Formula Q1.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least the last four consecutive carbon atoms of at least one instance of B1counted from the attachment point are unbranched and unsubstituted.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of B1independently comprises unsubstituted n -butyl, unbranched unsubstituted C4alkenyl, or unbranched unsubstituted C4alkynyl.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least two instances of B1are independently unbranched unsubstituted C4-10alkyl, unbranched unsubstituted C4-10alkenyl, or unbranched unsubstituted C4-10alkynyl.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least two instances of B1are independently unbranched unsubstituted C6-8alkyl or unbranched unsubstituted C6-8alkenyl.

40. The compound of claim 39, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein three, four, five, or six instances of B1are independently unbranched unsubstituted C6-8alkyl or unbranched unsubstituted C6-8alkenyl.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of B1independently comprises 0, 1, or 2 carbon-carbon unsaturated bonds.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the longest unbranched carbon backbone of each instance of B1is not substituted with oxo.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the longest unbranched carbon backbone of each instance of B1is independently unsubstituted or substituted independently with one or more substituents selected from the group consisting of fluoro, unsubstituted alkyl, alkyl substituted with one or more fluoro, unsubstituted alkenyl, alkenyl substituted with one or more fluoro, unsubstituted alkynyl, and alkynyl substituted with one or more fluoro.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of -C(R7)(B1)2is nbranched unsubstituted C6_8alkyl or unbranched unsubstituted C6_8alkenyl)(unbranched unsubstituted C6_8alkyl or unbranched unsubstituted C6_8alkenyl)45. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of B1is unbranched unsubstituted C5-9alkyl or unbranched unsubstituted C5-9alkenyl.

46. The compound of any one of claims 1-35 and 45, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of B1is independently unbranched unsubstituted C4-10alkyl, unbranched unsubstituted C4-10alkenyl, or unbranched unsubstituted C4-10alkynyl.

47. The compound of claim 46, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each instance of B1is independently unbranched unsubstituted C6-8alkyl or unbranched unsubstituted C6-8alkenyl, e.g., unbranched unsubstituted C6-8alkyl.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, optionally wherein one or more unbranched backbone carbon atoms of the alkylene or hetero alkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently a combination of -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, and -NHC(=O)-, provided that:the numbers of backbone atoms of the one or more instances of L2are independently between 1 and 20, inclusive; and the one or more instances of L2do not comprise O-O, O-N, N-O, or N-N.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently substituted or unsubstituted alkylene or -O-(substituted or unsubstituted alkylene)-C1, and each bond Cl is attached to L3.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently -(CH2)I-3- or -O- (CH2)I-3-C1, and each bond Cl is attached to L3.

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, wherein one, two, or three unbranched backbone carbon atoms of the alkylene or hetero alkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently a combination of -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene; provided that: the numbers of backbone atoms of the one or more instances of L2are independently between 1 and 20, inclusive; the one or more instances of L2do not comprise O-O, O-N, N-O, or N-N; andthe combined numbers of the substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene of the one or more instances of L2are independently 1, 2, or 3.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: one or more instances of L2are independently substituted or unsubstituted alkylene or - O-(substituted or unsubstituted alkylene)-C1; one, two, or three unbranched backbone carbon atoms of the alkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and each bond Cl is attached to L3.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L2are independently -(CH2)1-3-(l-yl- 1,2,3- triazol-4-yl)-(CH2) 1-20-, -(CH2) 1-3— (4-yl- 1 ,2,3-triazol- 1 -yl)-(CH2)1-20-, -O-(CH2)I-3-( 1 -yl- 1 ,2,3- triazol-4-yl)-(CH2)1-20-cl, or -O-(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-cl, and each bond Cl is attached to L3.

57. The compound of any one of claims 1-21, 24-27, and 30-56, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L3are CC22-C(=O)O-, wherein each bond C2 is attached to L2.

58. The compound of any one of claims 1-21, 24-27, and 30-57, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L3are CC22-OC(=O)-, wherein each bond C2 is attached to L2.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, orprodrug thereof, wherein one or more instances of -L2-L3- are cleavable under physiological conditions.

60. The compound of claim 59, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of -L2-L3- are hydrolysable under physiological conditions.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of -L2-L3- independently comprise -C(=O)O- or -OC(=O)-.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of -L2-L3- comprise -SS-.

63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of R7are independently hydrogen, fluoro, or unsubstituted C1-3alkyl.

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of R7are hydrogen.

65. The compound of any one of claims 1 and 34-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one of R2A, R2B, R3A, R3B, R5, and hydrogen atoms of R1is replaced with a moiety of Formula Pl.

66. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R5is replaced with a moiety of Formula Pl.

67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L1are a single bond.

68. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L1are independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, optionally wherein one or more unbranched backbone carbon atoms of the alkylene or hetero alkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L1are independently substituted or unsubstituted heteroalkylene.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L1are independently a combination of -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, and -NHC(=O)-, provided that: the numbers of backbone atoms of the one or more instances of L1are independently between 1 and 10, inclusive; and the one or more instances of L1do not comprise O-O, O-N, N-O, or N-N.

71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of L1are independently -NRx-(substituted or unsubstituted alkylene)-C3or -O-(substituted or unsubstituted alkylene)-C3, and each bond C3 is attached to the nitrogen atom marked with *, wherein each instance of Rxis independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one or more unbranched backbone carbon atoms is independently of the formula:k21 is 0, 1, 2, 3, or 4; each instance of Rd, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl); k22 is 0, 1, 2, 3, or 4; each instance of Re, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl); k23 is an integer between 0 and 11, inclusive; each instance of Rf, if present, is independently halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl); andRgis hydrogen, halogen, substituted or unsubstituted, C1-6alkyl, or -O-(substituted or unsubstituted, C1-6alkyl).

73. The compound of claim 72, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the substituted or unsubstituted heteroarylene that replaces one or more unbranched backbone carbon atoms is of the formula:

74. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of R6are independently substituted or unsubstituted alkyl.

75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of R6are independently substituted or unsubstituted, C1-6alkyl.

76. The compound of any one of claims 1-75, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of R6are independently unsubstituted C1-6alkyl or C1-6alkyl substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -O(unsubstituted C1-3alkyl), and -O(C1-3alkyl substituted with one or more instances of halogen).

77. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein one or more instances of R6are -CH3or -C2H5.

78. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, orprodrug thereof, wherein two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted heterocyclyl.

79. The compound of claim 78, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein two instances of R6attached to a same nitrogen atom are taken together with the same nitrogen atom to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted azepanyl.

80. The compound of any one of claims 1-3, 5, 7-11, 13, 15-17, 19, 22-25, 28-31, and 34-79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted heteroaryl.

81. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted, monocyclic, 5- or 6-membered heteroaryl or substituted or unsubstituted, bicyclic, 9- or 10-membered heteroaryl.

82. The compound of any one of claims 1-3, 5, 7-11, 13, 15-17, 19, 22-25, 28-31, and 34-79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted, partially unsaturated heterocyclyl.

83. The compound of claim 82, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is substituted or unsubstituted, monocyclic, 5- or 6-membered, partially unsaturated heterocyclyl or substituted or unsubstituted, bicyclic, 9- or 10-membered, partially unsaturated heterocyclyl.

84. The compound of any one of claims 1-3, 5, 7-11, 13, 15-17, 19, 22-25, 28-31, and 34-79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein:R1is a substituted or unsubstituted radical of a nucleobase; and the nucleobase is thymine, uracil, or cytosine, the 1 -position of each of which is attached to the l'-position; or the nucleobase is adenine, guanine, xanthine, or hypoxanthine, the 9- position of each of which is attached to the I '-position.

85. The compound of claim 84, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the nucleobase is uracil.

86. The compound of any one of claims 1-85, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound comprises one substituted or unsubstituted radical of a nucleobase.

87. The compound of any one of claims 2-3, 5, 11, 13, 17, 19, 24-25, 30-31, and 34-79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein88. The compound of any one of claims 2-3, 5, 11, 13, 17, 19, 24-25, 30-31, and 34-79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein489. The compound of any one of claims 34-79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal tautomer stereoisomer isotopically labeled compound, or prodrug thereof, wherein R1i90. The compound of any one of claims 34-79, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1is:

91. The compound of any one of claims 1-90, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein92. The compound of any one of claims 1 and 34-91, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2Ais replaced with a moiety of Formula Q2, Q3, or Q1.

93. The compound of claim 92, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2Ais replaced with a moiety of Formula Q2.

94. The compound of any one of claims 1 and 34-91, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2A, when present, is -ORa, halogen, hydrogen, -CN, or -N3.

95. The compound of claim 94, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2A, when present, is -O(substituted or unsubstituted alkyl), -OH, halogen, or hydrogen.

96. The compound of claim 94, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2A, when present, is -OCH3, -OH, fluoro, or hydrogen.

97. The compound of any one of claims 1 and 34-96, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2Bis replaced with a moiety of Formula Q2, Q3, or Q1.

98. The compound of claim 97, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2Bis replaced with a moiety of Formula Q2.

99. The compound of any one of claims 1 and 34-96, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2B, when present, is -ORa, halogen, hydrogen, -CN, or -N3.

100. The compound of claim 99, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2B, when present, is hydrogen.

101. The compound of any one of claims 1 and 34-100, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3Ais replaced with a moiety of Formula Q2, Q3, or Q1.

102. The compound of claim 101, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3Ais replaced with a moiety of Formula Q2.

103. The compound of any one of claims 1 and 34-100, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3A, when present, is -ORa, halogen, hydrogen, -CN, or -N3.

104. The compound of claim 103, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3A, when present, is -O(substituted or unsubstituted alkyl), -OH, halogen, or hydrogen.

105. The compound of claim 103, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3A, when present, is -OCH3, -OH, fluoro, or hydrogen.

106. The compound of any one of claims 1 and 34-105, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3Bis replaced with a moiety of Formula Q2, Q3, or Q1.

107. The compound of claim 106, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3Bis replaced with a moiety of Formula Q2.

108. The compound of any one of claims 1 and 34-105, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3B, when present, is -ORa, halogen, hydrogen, -CN, or -N3.

109. The compound of claim 108, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3B, when present, is hydrogen.

110. The compound of any one of claims 1, 34-96, and 101-105, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein each of R2Band R3B, when present, is hydrogen.

111. The compound of any one of claims 34-110, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R5, when present, is -ORb, -SRb, or -N(Rb)2.

112. The compound of claim 111, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R5, when present, is -ORb.

113. The compound of claim 112, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R5, when present, is -OH, -O(unsubstituted C1-3alkyl), or -O(C1-3alkyl substituted with one or more substituents independently selected from the group consisting of halogen, -OH, and -O(unsubstituted C1-3alkyl)).

114. The compound of any one of claims 1-113, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal tautomer stereoisomer isotopically labeled compound, or prodrug thereof, wherein115. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

116. The compound of claim 115, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula:

117. A compound of Formula II:or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein:R1is hydrogen, -ORa, -SRa, or -L2-L3-CH(R7)X(B1)2-x, wherein Rais hydrogen, - (substituted or unsubstituted, C1-8alkylene)-N(substituted or unsubstituted, C1-5alkyl)2, or - (substituted or unsubstituted, C1-8alkenylene)-N(substituted or unsubstituted, C1-5alkyl )2;R2is -L2-L3-CH(R7)X(B1)2-X, -(substituted or unsubstituted, C1-8alkylene)- N(substituted or unsubstituted, C1-5alkyl)2, or -(substituted or unsubstituted, C1-8alkenylene) N(substituted or unsubstituted, C1-5alkyl)2;R3is -L2’-L3-CH(R7’)X(B1’)2-X; andR5is hydroxyl, -N(Rb)2, or -L2-L3-CH(R7)X(B1)2-x, wherein each instance of Rbis independently hydrogen or substituted or unsubstituted alkyl; each instance of x is independently 0 or 1 ; each instance of L2is independently a single bond, -(CH2)1-3-(l-yI-l,2,3-triazol-4-yl)- (CH2)1-20-, -(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-, -O-(CH2)1-3-(l-yI-l,2,3-triazol-4-yl)- (CH2)1-20-, or -O-(CH2)1-3-(4-yl-1,2,3-triazol-l-yl)-(CH2)1-20-; each instance of L3is independently -O-, -S-, -S-S-, -NRZ-, -C(=O)O-, -C(=NRZ)O-, -S(=O)O-, -S(=O)2O-, -C(=O)NRZ-, -C(=NRZ)NRZ-, -S(=O)NRZ-, -S(=O)2NRZ-, -OC(=O)-,OC(=NRZ)-, -OS(=O)-, -OS(=O)2-, -NRZC(=O)-, -NRZC(=NRZ)-, -NRZS(=O)-,NRZS(=O)2-, -OC(=O)O-, -OC(=NRZ)O-, -OS(=O)O-, -OS(=O)2O-, -NRZC(=O)O-NRZC(=NRZ)O-, -NRZS(=O)O-, -NRZS(=O)2O-, -OC(=O)NRZ-, -OC(=NRZ)NRZ-OS(=O)NRZ-, -OS(=O)2NRZ-, -NRZC(=O)NRZ-, -NRZC(=NRZ)NRZ-, -NRZS(=O)NRZ-NRZS(=O)2NRZ-, -C(=O)-, -C(=NRZ)-, -S(=O)-, -S(=O)2-, -OP(=O)(ORZ)O-SP(=O)(ORZ)O-, -OP(=O)(ORZ)S-, or -OP(=O)(SRz)O-; each instance of Rzis independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; each instance of R7is independently hydrogen, halogen, unsubstituted C1-8alkyl, or C1-8alkyl substituted with one or more instances of halogen; each instance of B1is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; andthe longest unbranched carbon backbone of each instance of B1is independently C6-30; preferably the compound is of the formula:

118. The compound of any one of claims 1-116, or a pharmaceutically acceptable salt or stereoisomer thereof; preferably a pharmaceutically acceptable salt thereof.

119. A pharmaceutical composition comprising one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and one or more pharmaceutically acceptable excipients.

120. The pharmaceutical composition of claim 119 comprising: one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; one or more glycerophospholipids; one or more sterol lipids; one or more polymer-conjugated lipids; and one or more pharmaceutical agents.

121. The pharmaceutical composition of claim 119 comprising: between 40% and 60%, inclusive, mokmol, of one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; between 7% and 15%, inclusive, mokmol, of one or more glycerophospholipids; between 30% and 50%, inclusive, mokmol, of one or more sterol lipids; between 0.5% and 2.5%, inclusive, mokmol, of one or more polymer-conjugated lipids; and between 5% and 12%, inclusive, mokmol, of one or more pharmaceutical agents.

122. The pharmaceutical composition of claim 119 comprising: one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; distearoylphosphatidylcholine (DSPC); cholesterol;one or more polyethylene glycol (PEG) lipids, wherein the number average molecular weights of the PEG moieties of the PEG lipids as determined by gel permeation chromatography are independently between 1500 and 3000, inclusive, g / mol; and one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

123. The pharmaceutical composition of claim 119 comprising: between 40% and 60%, inclusive, mokmol, of one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; between 7% and 15%, inclusive, mokmol, of distearoylphosphatidylcholine (DSPC); between 30% and 50%, inclusive, mokmol, of cholesterol; between 0.5% and 2.5%, inclusive, mokmol, of a polyethylene glycol (PEG) lipid, wherein the number average molecular weight of the PEG moiety of the PEG lipid as determined by gel permeation chromatography is between 1500 and 3000 g / mol; and between 5% and 12%, inclusive, mokmol, of one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

124. The pharmaceutical composition of claim 119 comprising: one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; one or more glycerophospholipids; one or more sterol lipids; one or more targeting ligands; one or more polymer-conjugated lipids; and one or more pharmaceutical agents.

125. The pharmaceutical composition of claim 119 comprising: one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; one or more glycerophospholipid; one or more sterol lipids;one or more targeting ligands, wherein the targeting ligands are independently attached to the glycerophospholipid or sterol lipids; one or more polymer-conjugated lipids; and one or more pharmaceutical agents.

126. The pharmaceutical composition of claim 119 comprising: one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; distearoylphosphatidylcholine (DSPC); cholesterol; one or more N- acetylgalactosamine (GalNAc) moieties; one or more polyethylene glycol (PEG) lipids, wherein the number average molecular weights of the PEG moieties of the PEG lipids as determined by gel permeation chromatography are independently between 1500 and 3000, inclusive, g / mol; and one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

127. The pharmaceutical composition of claim 119 comprising: one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof; distearoylphosphatidylcholine (DSPC); cholesterol; one or more A-acetylgalactosamine (GalNAc) moieties, wherein the GalNAc moieties are independently attached to the DSPC or the cholesterol; one or more polyethylene glycol (PEG) lipids, wherein the number average molecular weights of the PEG moieties of the PEG lipids as determined by gel permeation chromatography are independently between 1500 and 3000, inclusive, g / mol; and one or more oligonucleotide therapeutic agents and / or polynucleotide therapeutic agents.

128. The pharmaceutical composition of any one of claims 119-120, 122, and 124-127, wherein the combined concentration of the one or more compounds, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled compounds, or prodrugs thereof, in the pharmaceutical composition is between 20% and 40%, between 40% and 60%, or between 60% and 80%, inclusive, mokmol.

129. The pharmaceutical composition of claim 128, wherein the combined concentration of the one or more compounds, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, in the pharmaceutical composition is between 40% and 60%, inclusive, mokmol.

130. The pharmaceutical composition of any one of claims 119-129 further comprising one or more helper lipids.

131. The pharmaceutical composition of claim 130, wherein at least one helper lipid is a glycerophospholipid.

132. The pharmaceutical composition of any one of claims 120-121, 124-125, and 131, wherein at least one glycerophospholipid is a phosphatidylcholine, a phosphatidylethanolamine, or a phosphatidylserine.

133. The pharmaceutical composition of any one of claims 120-121, 124-125, and 131, wherein at least one glycerophospholipid is distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricos anoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), 1 ,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), l-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), palmitoyloleoyl- phosphatidy lethanolamine (POPE), dioleoyl-phosphatidy lethanolamine 4-(N-maleimidomethyl)- cyclohexane- 1 carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), dilauroyl-phosphatidy lethanolamine (DLPE), diphy tanoyl-phosphatidy lethanolamine (DPyPE), 16-O-monomethyl phosphatidylethanolamine, 16-O-dimethyl phosphatidylethanolamine, 18-1-trans phosphatidylethanolamine, l-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), 1- stearioyl-2-oleoylphosphatidyethanol amine (SOPE), or l,2-dielaidoyl-sn-glycero-3- phosphoethanolamine (transDOPE).

134. The pharmaceutical composition of claim 133, wherein at least one glycerophospholipid is distearoylphosphatidylcholine (DSPC).

135. The pharmaceutical composition of any one of claims 120, 124-125, and 131-134, wherein the combined concentration of the glycerophospholipids in the pharmaceutical composition is between 3% and 7%, between 7% and 10%, between 10% and 15%, or between 15% and 25%, inclusive, mokmol.

136. The pharmaceutical composition of claim 135, wherein the combined concentration of the glycerophospholipids in the pharmaceutical composition is between 7% and 15%, inclusive, mokmol.

137. The pharmaceutical composition of any one of claims 130-136, wherein at least one helper lipid is a sterol lipid.

138. The pharmaceutical composition of any one of claims 120-121, 124-125, and 137, wherein at least one sterol lipid is a sterol, steroid, tocopherol, secosteroid, bile acid, or steroid conjugate.

139. The pharmaceutical composition of any one of claims 120-121, 124-125, and 137, wherein at least one sterol lipid is cholesterol, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2 '-hydroxy ethyl ether, cholesteryl-4'-hydroxybutyl ether, stigmastanol, β-sitosterol, brassicasterol, calcipotriol, campesterol, 9, 11 -dehydroergosterol, ergosterol, fucosterol, Vitamin D2, Vitamin D3, or Vitamin E.

140. The pharmaceutical composition of claim 139, wherein at least one sterol lipid is cholesterol.

141. The pharmaceutical composition of any one of claims 120, 124-125, and 137-140, wherein the combined concentration of the sterol lipids in the pharmaceutical composition isbetween 20% and 30%, between 30% and 40%, between 40% and 50%, or between 50% and70%, inclusive, mokmol.

142. The pharmaceutical composition of claim 141, wherein the combined concentration of the sterol lipids in the pharmaceutical composition is between 30% and 50%, inclusive, mokmol.

143. The pharmaceutical composition of any one of claims 119-142 further comprising one or more polymer-conjugated lipids.

144. The pharmaceutical composition of any one of claims 120-121, 124-125, and 143, wherein at least one polymer-conjugated lipid is a polyethylene glycol (PEG) lipid.

145. The pharmaceutical composition of claim 144, wherein at least one PEG lipid is of the formula:wherein: each instance of R11is independently substituted or unsubstituted alkyl or hydrogen; each instance of ml is independently an integer between 10 and 200, inclusive; and each instance of R12and R13is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, optionally wherein one or more longest unbranched backbone carbon atoms are independently replaced with - C(=O)O- or -OC(=O)-.

146. The pharmaceutical composition of claim 145, wherein: each instance of R11is independently unsubstituted C1-6alkyl; each instance of ml is independently an integer between 30 and 60, inclusive; and each instance of R12and R13is independently unsubstituted C10-30alkyl or unsubstituted C10-30alkenyl.

147. The pharmaceutical composition of claim 146, wherein: each instance of R11is independently unsubstituted C1-3alkyl; each instance of ml is independently an integer between 40 and 55, inclusive; andeach instance of R12and R13is independently unsubstituted unbranched C12-16alkyl.

148. The pharmaceutical composition of claim 147, wherein at least one polymer-conjugated lipid is of the formula:

149. The pharmaceutical composition of any one of claims 144-148, wherein at least one PEG lipid is mPEG-DMG, mPEG-c-DOMG, mPEG-DOPE, mPEG-DLPE, mPEG-DPPE, mPEG- DMPE, mPEG-DPPC, mPEG-DSPE, mPEG-CLS, mPEG-palmitic acid, or mPEG- N,N- ditetradecy lacetamide .

150. The pharmaceutical composition of any one of claims 144-145 and 149, wherein the number average molecular weight of the PEG moiety of at least one PEG lipid as determined by gel permeation chromatography is between 500 and 1000, between 1000 and 1500, between 1500 and 2000, between 2000 and 3000, or between 3000 and 4000, inclusive, g / mol.

151. The pharmaceutical composition of claim 150, wherein the number average molecular weight of the PEG moiety of at least one PEG lipid as determined by gel permeation chromatography is between 1500 and 3000, inclusive, g / mol.

152. The pharmaceutical composition of any one of claims 120-121, 124-125, and 143-151, wherein the combined concentration of the polymer-conjugated lipids in the pharmaceutical composition is between 0.2% and 0.5%, between 0.5% and 1%, between 1% and 2.5%, or between 2.5% and 5%, inclusive, mokmol.

153. The pharmaceutical composition of claim 152, wherein the combined concentration of the polymer-conjugated lipids in the pharmaceutical composition is between 0.5% and 2.5%, inclusive, mokmol.

154. The pharmaceutical composition of any one of claims 119 and 128-153 further comprising one or more pharmaceutical agents.

155. The pharmaceutical composition of any one of claims 120-121, 124-125, and 154, wherein at least one pharmaceutical agent is a therapeutic agent.

156. The pharmaceutical composition of any one of claims 120-121, 124-125, and 154-155, wherein at least one pharmaceutical agent is a prophylactic agent or diagnostic agent.

157. The pharmaceutical composition of any one of claims 120-121, 124-125, and 154-156, wherein at least one pharmaceutical agent is an oligonucleotide or polynucleotide.

158. The pharmaceutical composition of claim 157, wherein at least one pharmaceutical agent is an RNA or DNA.

159. The pharmaceutical composition of claim 158, wherein at least one pharmaceutical agent is an siRNA or mRNA.

160. The pharmaceutical composition of any one of claims 120-121, 124-125, and 154-159, wherein at least one pharmaceutical agent is a small molecule, peptide, or protein.

161. The pharmaceutical composition of any one of claims 120-121, 124-125, and 154-160, wherein the molar ratio of the one or more compounds, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, to the pharmaceutical agents is between 3:1 and 4:1, between 4:1 and 5:1, between 5:1 and 6:1, between 6:1 and 7:1, between 7:1 and 8:1, or between 8:1 and10:1, inclusive.

162. The pharmaceutical composition of claim 161, wherein the molar ratio of the one or more compounds, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, to the pharmaceutical agents is between 5:1 and 7:1, inclusive.

163. The pharmaceutical composition of any one of claims 119-162 further comprising one or more targeting ligands.

164. The pharmaceutical composition of any one of claims 124 and 163, wherein at least one targeting ligand is attached to at least one helper lipid.

165. The pharmaceutical composition of any one of claims 124-125 and 163-164, wherein at least one targeting ligand is an asialoglycoprotein receptor ligand.

166. The pharmaceutical composition of claim 165, wherein at least one asialoglycoprotein receptor ligand is an N- acetylgalactosamine (GalNAc).

167. A kit comprising: one or more compounds of any one of claims 1-116, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, or the pharmaceutical composition of any one of claims 119- 166; and instructions for using the one or more compounds, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, prodrugs, or pharmaceutical composition.

168. A method for delivering one or more pharmaceutical agents to a subject comprising administering to the subject the pharmaceutical composition of any one of claims 119-166.

169. Use of the pharmaceutical composition of any one of claims 119-166, for the manufacture of a medicament for delivering one or more pharmaceutical agents to a subject.

170. The pharmaceutical composition of any one of claims 119-166, for use in delivering one or more pharmaceutical agents to a subject.

171. The method of claim 168, the use of claim 169, or the pharmaceutical composition for use of claim 170, wherein the one or more pharmaceutical agents are delivered to the liver of the subject.

172. A method for treating a disease in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 119-166.

173. Use of the pharmaceutical composition of any one of claims 119-166 for the manufacture of a medicament for treating a disease in a subject in need thereof.

174. The pharmaceutical composition of any one of claims 119-166 for use in treating a disease in a subject in need thereof.

175. A method for preventing a disease in a subject in need thereof comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 119- 166.

176. Use of the pharmaceutical composition of any one of claims 119-166 for the manufacture of a medicament for preventing a disease in a subject in need thereof.

177. The pharmaceutical composition of any one of claims 119-166 for use in preventing a disease in a subject in need thereof.

178. The method of any one of claims 172 and 175, the use of any one of claims 173 and 176, or the pharmaceutical composition for use of any one of claims 174 and 177, wherein the disease is a liver disease.

179. The method, use, or pharmaceutical composition for use of claim 178, wherein the liver disease is viral hepatitis, liver fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFUD), obesity, hemochromatosis, thalassemia, liver injury, alcoholic liver disease, or liver genetic disease.

180. The method of any one of claims 172, 175, and 178-179, the use of any one of claims 173, 176, and 178-179, or the pharmaceutical composition for use of any one of claims 174 and 177-179, wherein the pharmaceutical composition, is administered to the subject parenterally.

181. The method, use, or pharmaceutical composition for use of claim 180, wherein the pharmaceutical composition, is administered to the subject intravenously, subcutaneously, or intramuscularly.

182. The method of any one of claims 172, 175, and 178-181, the use of any one of claims 173, 176, and 178-181, or the pharmaceutical composition for use of any one of claims 174 and 177-181, wherein the subject is a human.

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