Compound comprising a nucleic acid and a half-life extension motif

Abstract

Disclosed herein are compounds including a nucleic acid (A), their preparation, and their use.

Description

COMPOUND COMPRISING A NUCLEIC ACID AND A HALF-LIFE EXTENSION MOTIF CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Patent Application No. 62 / 940,835, filed November 26, 2019, which is incorporated herein in its entirety and for all purposes. REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE

[0002] The Sequence Listing written in file DTX-003-01WO_ST25.TXT, created on November 23, 2020, 1,174 bytes in size, machine format IBM-PC, MS Windows operating system, is hereby incorporated by reference. BACKGROUND Field

[0003] The present disclosure relates to the field of biologically active compounds including a nucleic acid. More specifically, the present disclosure relates to compounds including nucleic acids, their preparation, and their use. Background

[0004] Delivering therapeutic nucleic acids into cells remains a challenging area of research. Thus, there is a need for improved nucleic acid compounds and strategies of introducing such compounds into cells. BRIEF SUMMARY

[0005] Provided herein are, inter alia, compounds, or compounds including a nucleic acid (A) covalently bonded to a half-life extension motif (HLEM).

[0006] In an aspect, provided is a compound having a formula (I) (HLEM)z-A (I). z is an integer from 1 to 5.

[0007] In emodiments, the half-life extension motif has the structure:(III). k is an integer from 1 to 5.

[0008] L1is independently a covalent linker. L2is independently an unsubstituted alkylene.

[0009] In embodiments, the nucleic acid is covalently bonded to an uptake motif (UM).

[0010] In embodiments, the compound has a formula (II): (HLEM)z-A-(UM)t(II). t is an integer from 1 to 5.

[0011] In embodiments, the uptake motif independently has the structure:

[0012] L3and L4are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, - C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)- , -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O- P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, - P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. Each R23, R24and R25is independently hydrogen or unsubstituted C1-C10 alkyl.

[0013] L5is -L5A-L5B-L5C-L5D-L5E-. L6is -L6A-L6B-L6C-L6D-L6E-. L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6Eare independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.

[0014] R1and R2are independently unsubstituted C1-C25alkyl, wherein at least one of R1and R2is unsubstituted C9-C19 alkyl. R3is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0015] In an aspect, provided is a method including contacting a cell with the compound, or the compound including a nucleic acid (A), as described herein.

[0016] In an aspect, provided is a method comprising administering to a subject the compound, or the compound including a nucleic acid (A), as described herein.

[0017] In an aspect, provided is a compound, or the compound including a nucleic acid (A) as described herein, for use in therapy

[0018] In an aspect, provided is a method of introducing a nucleic acid into a cell within a subject. The method includes administering to said subject the compound including a nucleic acid (A) as described herein.

[0019] In an aspect, provided is a cell including the compound including a nucleic acid (A) as described herein.

[0020] In an aspect, provided is a pharmaceutical composition including a pharmaceutically acceptable excipient and the compound including a nucleic acid (A) as described herein.

[0021] Other aspects are disclosed infra. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG.1A shows a structure of DT-000137 according to an exemplary embodiment.

[0023] FIG.1B shows a structure of DT-000146 according to an exemplary embodiment.

[0024] FIG. 1C shows a structure of DT-000347 according to an exemplary embodiment.

[0025] FIG. 1D shows a structure of DT-000155 according to an exemplary embodiment.

[0026] FIG. 1E shows a structure of DT-000156 according to an exemplary embodiment.

[0027] FIG. 1F shows a structure of DT-000157 according to an exemplary embodiment.

[0028] FIG. 1G shows a structure of DT-000272 according to an exemplary embodiment.

[0029] FIG.1H shows a structure of DT-000273 according to an exemplary embodiment.

[0030] FIG. 1I shows a structure of DT-000274 according to an exemplary embodiment.

[0031] FIG.1J shows a structure of DT-000275 according to an exemplary embodiment.

[0032] FIG. 1K shows a structure of DT-000276 according to an exemplary embodiment.

[0033] FIG. 1L shows a structure of DT-000277 according to an exemplary embodiment.

[0034] FIG. 1M shows a structure of DT-000278 according to an exemplary embodiment.

[0035] FIG. 1N shows a structure of DT-000350 according to an exemplary embodiment.

[0036] FIG. 1O shows a structure of DT-000183. DETAILED DESCRIPTION Definitions

[0037] Unless defined otherwise, all technical terms, scientific terms, abbreviations, chemical structures, and chemical formulae used herein have the same meaning as is commonly understood by one of ordinary skill in the art. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least.” When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term “comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0038] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0039] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and / or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and / or one or more double bonds in addition to the one or more triple bonds.

[0040] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w , where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fusedto either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkyl ring systems are a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic cycloalkyl groups include, but are not limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0041] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocycliccycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.

[0042] In embodiments, a heterocycloalkyl is a heterocyclyl. The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within theheterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3 dioxanyl, 1,3 dioxolanyl, 1,3 dithiolanyl, 1,3 dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1 dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3 dihydrobenzofuran 2 yl, 2,3 dihydrobenzofuran 3 yl, indolin 1 yl, indolin 2 yl, indolin 3 yl, 2,3 dihydrobenzothien 2 yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro 1H indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the groupconsisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10- dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0043] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0044] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, S, Si, or P), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2- CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)- CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)- CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / orone or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds.

[0045] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as - C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.

[0046] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0047] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0048] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0049] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1- naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0050] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.

[0051] The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

[0052] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0053] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:.

[0054] An alkylarylene moiety may be substituted (e.g. with a substituent group) on the alkylene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -CF3, - CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 -SO3H, , - OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0055] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0056] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, - SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'- C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', - S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0057] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', -halogen, - SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'- C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', - S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, - CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)- OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present.

[0058] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) inthe structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0059] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure.

[0060] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, - CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, - S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C''R''R''')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0061] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0062] A “substituent group,” as used herein, means a group selected from the following moieties:(A) oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, –CHCl2,–CHBr2, –CHI2, -CH2F,– CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, - SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, - NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, –OCBr3, –OCI3, – OCHF2, –OCHCl2, –OCHBr2, –OCHI2, –OCH2F, –OCH2Cl, –OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: (i) oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, –CHCl2,–CHBr2,–CHI2, -CH2F,– CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, – OCBr3, –OCI3, –OCHF2, –OCHCl2, –OCHBr2, –OCHI2,–OCH2F, –OCH2Cl, – OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:(a) oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, –CHCl2,–CHBr2, –CHI2, -CH2F,– CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, –OCF3, –OCCl3, – OCBr3, –OCI3, –OCHF2, –OCHCl2, –OCHBr2, –OCHI2,–OCH2F, –OCH2Cl, – OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10aryl, C10aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, –CF3, –CCl3, –CBr3, –CI3, –CHF2, – CHCl2,–CHBr2, –CHI2, -CH2F,–CH2Cl, –CH2Br, –CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, −NHNH2, −ONH2, −NHC(O)NHNH2, −NHC(O)NH2, -NHSO2H, -NHC(O)H, - NHC(O)OH, -NHOH, –OCF3, –OCCl3, –OCBr3, –OCI3, –OCHF2, –OCHCl2, – OCHBr2, –OCHI2,–OCH2F, –OCH2Cl, –OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0063] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 memberedheteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0064] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

[0065] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl,substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0066] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

[0067] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0068] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

[0069] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein ifthe substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size- limited substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group is different.

[0070] In embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C20alkyl, each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 3 to 8 membered heterocycloalkyl, each or unsubstituted aryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 10 membered heteroaryl. In embodiments herein, each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C20alkylene, each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C8cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10arylene, and / or each substituted or unsubstitutedheteroarylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 10 membered heteroarylene.

[0071] In embodiments, each substituted or unsubstituted alkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C7cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 9 membered heteroaryl. In embodiments, each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C1-C8alkylene, each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted 5 to 9 membered heteroarylene. In embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0072] Certain compounds provided herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometricisomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of provided herein do not include those that are known in art to be too unstable to synthesize and / or isolate. Compounds provided herein include those in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0073] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0074] The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0075] It will be apparent to one skilled in the art that certain compounds provided herein may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0076] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the (R) and (S) configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds, generally recognized as stable by those skilled in the art, are within the scope of the present disclosure.

[0077] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by adeuterium or tritium, replacement of fluoride by18F, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0078] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds provided herein, whether radioactive or not, are inlcuded within the present disclosure.

[0079] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0080] “Analog,” or “analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.

[0081] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0082] Where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman decimal symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13substituents are present, each R13substituent may be distinguished as R13.1, R13.2, R13.3, R13.4, etc., wherein each of R13.1, R13.2, R13.3, R13.4, etc. is defined within the scope of the definition of R13and optionally differently. The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls.

[0083] Description of compounds of provided herein is limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0084] The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0085] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds, biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. For example, contacting includes the process of allowing a compound to become sufficiently proximal to a cell to bind to a cell-surface receptor.

[0086] As used herein, “contacting a cell” refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell.

[0087] As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like mean negatively affecting (e.g. decreasing) activity or function relative to the activity or function in the absence of the inhibitor. In embodiments inhibition means negatively affecting (e.g. decreasing) the concentration or levels of a biomolecule, such as a protein or mRNA, relative to the concentration or level of the biomolecule in the absence of the inhibitor. For example, inhibition includes decreasing the level of mRNA expression in a cell. In embodiments, inhibition refers to a reduction in the activity of a particular biomolecule target, such as a protein target or an mRNA target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a biomolecule. In embodiments, inhibition refers to a reduction of activity of a target biomolecule resulting from a direct interaction (e.g. an inhibitor binds to a target protein). In embodiments, inhibition refers to a reduction of activity of a target biomolecule from an indirect interaction (e.g. an inhibitor binds to a protein that activates a target protein, thereby preventing target protein activation).

[0088] The term “inhibitor” also refers to a compound, composition, or substance capable of detectably decreasing the expression or activity of a given gene or protein. For example, an inhibitor may decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%or more in comparison to a control in the absence of the inhibitor. Inhibitors include, for example, synthetic or biological molecules, such as oligonucleotides.

[0089] The terms "expression" and “gene expression” as used herein refer to the steps involved in the translation of a nucleic acid into a protein, including mRNA expression and protein expression. Expression can be detected using conventional techniques for detecting nucleic acids or proteins (e.g., PCR, ELISA, Southern blotting, Western blotting, flow cytometry, FISH, immunofluorescence, immunohistochemistry).

[0090] An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist.

[0091] The term “in vivo” used herein means a process that takes place within a subject’s body.

[0092] The term “subject” used herein means a human or non-human animal selected for treatment or therapy. In embodiments, a subject is a human.

[0093] The term “ex vivo” used herein means a process that takes place in vitro in isolated tissue or cells where the treated tissue or cells comprise primary cells. As is known in the art, any medium used in this process can be aqueous and non-toxic so as not to render the tissue or cells non-viable. In embodiments, the ex vivo process takes place in vitro using primary cells.

[0094] The term “administration” means providing a pharmaceutical agent or composition to a subject, and includes administration performed by a medical professional and self-administration.

[0095] The term “therapy” means the application of one or more specific procedures used for the amelioration of at least one indicator or a disease or condition. In embodiments, the specific procedure is the administration of one or more pharmaceutical agents.

[0096] The term “modulate” is used herein in its ordinary sense as understood by a person of ordinary skill in the art, and thus refers to the act of changing or varying one or more properties. For example, in the context of a modulator’s effects on a target molecule, to modulate means tochange by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. A modulator of a disease decreases a symptom, cause, or characteristic of the targeted disease.

[0097] The terms “nucleic acid” means compounds containing at least two nucleotide monomers covalently linked together. Nucleic acids include polynucleotides and oligonucleotides, including double-stranded oligonucleotides and single-stranded oligonucleotides, and modified versions thereof.

[0098] The term “polynucleotide” means a longer length nucleic acid, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, or 10,000 nucleotides in length. Non-limiting examples of polynucleotides include a gene, a gene fragment, an exon, an intron, intergenic DNA (including, without limitation, heterochromatic DNA), messenger RNA (mRNA), a long non-coding RNA, transfer RNA, ribosomal RNA, a ribozyme, cDNA, a recombinant polynucleotide, a branched polynucleotide, a plasmid, a vector, isolated DNA of a sequence, and an isolated RNA of a sequence. Polynucleotides useful in the methods of the disclosure may include natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or a combination of such sequences.

[0099] The term“oligonucleotide” means a shorter length nucleic acid, e.g. of less than 100 nucleotides in length. Oligonucleotides may be single-stranded or double-stranded. An oligonucleotide may comprise naturally occurring ribonucleotides, naturally occurring deoxyribonucleotides, and / or nucleotides having one or more modifications to a naturally occurring terminus, sugar, nucleobase, and / or internucleotide linkage. Non-limiting examples of oligonucleotides include double-stranded oligonucleotides, single-stranded oligonucleotides, antisense oligonucleotides, small interfering RNA (siRNA), microRNA mimics, short hairpin RNAs (shRNA), single-strand small interfering RNA (ssRNAi), RNaseH oligonucleotides, anti- microRNA oligonucleotides, steric blocking oligonucleotides, exon-skipping oligonucleotides, CRISPR guide RNAs, and aptamers.

[0100] The term “double-stranded oligonucleotide” means an oligonucleotide that is substantially in a duplex form. Double-stranded oligonucleotides may comprise structures where the duplex region is formed between two anti-parallel oligonucleotides that are not covalently linked, as in an siRNA or microRNA mimic. Such double-stranded oligonucleotides may have a short nucleotide overhang at one or both ends of the duplex structure. Double-strandedoligonucleotides may also include a single oligonucleotide with sufficient length and self- complementarity to form a duplex structure, as in an shRNA. Such double-stranded oligonucleotides include stem-loop structures. A double-stranded nucleic acid may include one or more modifications relative to a naturally occurring terminus, sugar, nucleobase, and / or phosphate group. Non-limiting exanmples of double-stranded oligonucleotides include small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA mimics.

[0101] The term “small interfering RNA” or “siRNA” means a double-stranded oligonucleotide formed from separate antisense and sense strands, which interferes with the expression of genes in a sequence-specific manner by facilitating mRNA degradation before translation through the RNA interference pathway. The antisense and sense strands of an siRNA are not covalently linked.

[0102] The term “microRNA mimic” means a synthetic version of a naturally occurring microRNA. A microRNA mimic comprises a antisense strand, which is complementary to one or more target mRNAs, and a sense strand which is complementary to the antisense strand. In naturally occurring microRNAs, the antisense strand is typically only partially complementary to its target mRNA(s), and the sense strand is only partially complementary to the antisense strand. A microRNA mimic may comprise nucleobase sequences having 100% identity to the naturally occurring microRNA or may comprise a nucleobase sequences less than 100% identical to the naturally occurring microRNA. For example, a microRNA mimic may comprise a sense strand that is 100% complementary to the antisense strand.

[0103] The term “single-strand RNA interfering” or “ssRNAi” means a single-stranded oligonucleotide which interferes with the expression of genes in a sequence-specific manner by facilitating mRNA degradation before translation through the RNA interference pathway.

[0104] The term “antisense strand” means an oligonucleotide of an siRNA or a ssRNAi that is complementary to the target mRNA and is incorporated into the RNA-induced silencing complex (RISC) to direct gene silencing in a sequence-specific manner through the RNA interference pathway. An antisense strand may also be referred to as the “guide strand.”

[0105] The term “sense strand” means an oligonucleotide that is complementary to the antisense strand of a double-stranded oligonucleotide. The sense strand is typically degraded following incorporation of the antisense strand into RISC. The sense strand may also be referred to as the “passenger strand.”

[0106] The term “duplex region” means a structure formed through nucleotide base-pairing of complementary oligonucleotide sequences. A duplex region may be formed from portions of complementary sequences, or from full lengths of complementary sequences.

[0107] The term “short hairpin RNA” or “shRNA” means a double-stranded oligonucleotide containing a loop structure that is processed in a cell to an siRNA which interferes with the expression of genes in a sequence-specific manner, by facilitating mRNA degradation before translation through the RNA interference pathway.

[0108] The term “nucleotide overhang” means contiguous single-stranded nucleotides at the end of an oligonucleotide in a double-stranded oligonucleotide.

[0109] The term “single-stranded oligonucleotide” means an oligonucleotide that is not hybridized to a complementary strand. Non-limiting examples of single-stranded oligonucleotides include single-strand small interfering RNA (ssRNAi), RNaseH oligonucleotides (oligonucleotides chemically modified to elicit RNaseH-mediated degradation of a target RNA), anti-microRNA oligonucleotides (oligonucleotides complementary to microRNAs), steric blocking oligonucleotides (oligonucleotides that interfere with target RNA activity without degrading the target RNA), exon-skipping oligonucleotides (oligonucleotides that hybridized to an exon annealing site and alter splicing), CRISPR guide RNAs, and aptamers.

[0110] The term “hybridize” means the annealing of one nucleic acid to another nucleic acid based on nucleobase sequence complementarity. In embodiments, an antisense strand is hybridized to a sense strand. In embodiments, an antisense strand hybridizes to a target mRNA sequence.

[0111] The term “complementary” means nucleobases having the capacity to pair non- covalently via hydrogen bonding.

[0112] The term “fully complementary” means each nucleobase of a first nucleic acid is complementary to each nucleobase of a second nucleic acid. In embodiments, an antisense strand is fully complementary to its target mRNA. In embodiments, a sense strand and an antisense strand of a double-stranded oligonucleotide are fully complementary over their entire lengths. In embodiments, a sense strand and an antisense strand of double-stranded oligonucleotide are fully complementary over the entire length of the double-stranded region of the siRNA, and one or both termini of either strand comprises single-stranded nucleotides.

[0113] The term “nucleoside” means a monomer of a nucleobase and a pentofuranosyl sugar (e.g., either ribose or deoxyribose). Nucleosides may be modified at the nucleobase and / or and the sugar. In embodiments, a nucleoside is a deoxyribonucleoside. In embodiments, a nucleoside is a ribonucleoside.

[0114] The term “nucleotide” means a nucleoside covalently linked to a phosphate group at the 5’-carbon of the pentafuranosyl sugar. Nucleotides may be modified at one or more of the nucleobase, sugar, or phosphate group. A nucleotide may have a ligand attached, either directly or through a linker. In embodiments, a nucleotide is a deoxyribonucleotide. In embodiments, a nucleotide is a ribonucleotide.

[0115] The term “nucleobase” means the heterocyclic base moiety of a nucleoside or nucleotide. Non-limiting examples of nucleobases includes cytosine or a derivative thereof (e.g., cytosine analogue), guanine or a derivative thereof (e.g., guanine analogue), adenine or a derivative thereof (e.g., adenine analogue), thymine or a derivative thereof (e.g., thymine analogue), uracil or a derivative thereof (e.g., uracil analogue), hypoxanthine or a derivative thereof (e.g,. hypoxanthine analogue), xanthine or a derivative thereof (e.g., xanthine analogue), 7-methylguanine or a derivative thereof (e.g., 7-methylguanine analogue) , deaza-adenine or a derivative thereof (e.g., deaza-adenine analogue), deaza-guanine or a derivative thereof (e.g., deaza-guanine), deaza-hypoxanthine or a derivative thereof, 5,6-dihydrouracil or a derivative thereof (e.g., 5,6-dihydrouracil analogue), 5-methylcytosine or a derivative thereof (e.g., 5- methylcytosine analogue), or 5-hydroxymethylcytosine or a derivative thereof (e.g., 5- hydroxymethylcytosine analogue) moieties. In embodiments, the nucleobase is adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, or isoguanine, which may be optionally substituted or modified. In embodiments, the nucleobase, which may be optionally substituted or modified.

[0116] The term “modified nucleotide” means a nucleotide having one or more modifications relative to a naturally occurring nucleotide. A modification may be present in an internucleoside linkage, a nucleobase, and / or a sugar moiety of the nucleotide. A modified nucleotide may be selected over an unmodified form because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for other oligonucleotides or nucleic acid targets, increased stability in the presence of nucleases, and / or reduced immune stimulation. A modified nucleotide may have a modified sugar moiety and an unmodified phosphate group. A modified nucleotide may have an unmodified sugar moiety and a modified phosphate group. A modified nucleotide may have a modified sugar moiety and an unmodified nucleobase. A modified nucleotide may have a modified sugar moiety and a modified phosphate group. Nucleic acids, polynucleotides and oligonucleotides may comprise one or more modified nucleotides.

[0117] The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[0118] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that participate in nucleobase-pairing (i.e.,about 60% complementarity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher complementarity over a specified region).

[0119] “Hybridize” shall mean the annealing of one single-stranded nucleic acid (such as a primer) to another nucleic acid based on the well-understood principle of sequence complementarity. In an embodiment the other nucleic acid is a single-stranded nucleic acid. The propensity for hybridization between nucleic acids depends on the temperature and ionic strength of their miliu, the length of the nucleic acids and the degree of complementarity. The effect of these parameters on hybridization is described in, for example, Sambrook J, Fritsch EF, Maniatis T., Molecular cloning: a laboratory manual, Cold Spring Harbor Laboratory Press, New York (1989). As used herein, hybridization of a primer, or of a DNA extension product, respectively, is extendable by creation of a phosphodiester bond with an available nucleotide or nucleotide analogue capable of forming a phosphodiester bond, therewith.

[0120] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., at least 60% identity, or at least 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% ,94%, 95%, 96%, 97%, 98%, 99%, or within a range defined by any of two of the preceding values, identity over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site or the like). This definition also refers to, or may be applied to, the complement of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps, insertions and the like. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared can be determined by known methods.Compounds

[0121] Provided are, inter alia, compounds including a nucleic acid (A) that is covalently bonded to one or more half-life extension motifs (HLEMs). For example, the compound includes a nucleic acid (A) covalently bonded to one half-life extension motif (HLEM), two half-life extension motifs (HLEMs), three half-life extension motifs (HLEMs), four half-life extension motifs (HLEMs), or five half-life extension motifs (HLEMs).

[0122] In an aspect, the compound has a formula (I) (HLEM)z-A (I), wherein z is an integer from 1 to 5.

[0123] In embodiments, z is 1. In embodiments, z is 2. In embodiments, z is 3. In embodiments, z is 4. In embodiments, z is 5.

[0124] In an aspect, the nucleic acid is covalently bonded to one or more uptake motifs (UMs). For example, the nucleic acid is covalently bonded to one uptake motif (UM), two uptake motifs (UMs), three uptake motifs (UMs), four uptake motifs (UMs), or five uptake motifs (UMs).

[0125] In an aspect, the compound has a formula (II): (HLEM)z-A-(UM)t(II), wherein t is an integer from 1 to 5.

[0126] In embodiments, t is 1. In embodiments, t is 2. In embodiments, t is 3. In embodiments, t is 4. In embodiments, t is 5.

[0127] In embodiments, the half-life extension motif has the structure:integer from 1 to 5.

[0128] L1is independently a covalent linker. L2is independently an unsubstituted alkylene.

[0129] In embodiments, k is 1. In embodiments, k is 2. In embodiments, k is 3. In embodiments, k is 4. In embodiments, k is 5. In embodiments, k is an integer from 1 to 3. In embodiments, k is an integer from 1 to 2.

[0130] In embodiments, one or more L2may be attached to one or more atoms in L1. In embodiments, one or more L2may be attached to one or more atoms in L1and the one or moreatoms may be the same or different. In embodiments, the one or more L2are attached to the same atom. In embodiments, the one or more L2are attached to the different atoms. In embodiments, the one or more L2are attached to the same or different atoms.

[0131] In embodiments, one or more L2may be independently attached to L1A, L1B, L1C, L1D, or L1E. In embodiments, L2may be independently attached to L1A. In embodiments, one L2may be independently attached to L1B. In embodiments, one L2may be independently attached to L1C. In embodiments, one L2may be independently attached to L1D. In embodiments, one L2may be independently attached to L1E.

[0132] In embodiments, L1A, L1B, L1C, L1D, and L1Eare independently a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, - O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, - P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. Each R20, R21and R22is independently hydrogen or unsubstituted C1-C10alkyl.

[0133] In embodiments, one or more L2may be independently attached to L1A, L1B, L1C, L1D, or L1E. In embodiments, one or more L2may be independently attached to L1A. In embodiments, one or more L2may be independently attached to L1B. In embodiments, one or more L2may be independently attached to L1C. In embodiments, one or more L2may be independently attached to L1D. In embodiments, one or more L2may be independently attached to L1E.

[0134] In embodiments, at least one L2may be independently attached to L1A. In embodiments, at least one L2may be independently attached to L1B. In embodiments, at least one L2may be independently attached to L1C. In embodiments, at least one L2may be independently attached to L1D. In embodiments, at least one L2may be independently attached to L1E.

[0135] In embodiments, one L2may be independently attached to L1A. In embodiments, one L2may be independently attached to L1B. In embodiments, one L2may be independently attachedto L1C. In embodiments, one L2may be independently attached to L1D. In embodiments, one L2may be independently attached to L1E.

[0136] In embodiments, L1Ais a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, - O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, - P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0137] In embodiments, L1Ais a bond. In embodiments, L1Ais -N(R20)-. In embodiments, L1Ais -O- or -S-. In embodiments, L1Ais -C(O)-. In embodiments, L1Ais -N(R20)C(O)- or - C(O)N(R21)-. In embodiments, L1Ais -N(R20)C(O)N(R21)-. In embodiments, L1Ais -C(O)O- or -OC(O)-. In embodiments, L1Ais -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1Ais -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(O)(NR20R21)-N-, or O- P(O)(NR20R21)-O-. In embodiments, L1Ais -P(O)(NR20R21)-N-,-P(S)(NR20R21)-N-, - P(O)(NR20R21)-O- or -P(S)(NR20R21)-O-. In embodiments, L1Ais -S-S-.

[0138] In embodiments, L1Ais independently substituted or unsubstituted alkylene (e.g., C1- C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Ais independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Ais independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Ais independently substituted or unsubstituted C1-C20alkylene. In embodiments, L1Ais independently substituted C1-C20 alkylene. In embodiments, L1Ais independently unsubstituted C1-C20alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1Ais independently substituted C1-C12 alkylene. In embodiments, L1Ais independently unsubstituted C1-C12alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1Ais independently substituted C1-C8alkylene. In embodiments, L1Ais independently unsubstituted C1-C8 alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1Ais independently substituted C1-C6 alkylene. In embodiments, L1Ais independently unsubstituted C1-C6 alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1Ais independently substitutedC1-C4 alkylene. In embodiments, L1Ais independently unsubstituted C1-C4 alkylene. In embodiments, L1Ais independently substituted or unsubstituted ethylene. In embodiments, L1Ais independently substituted ethylene. In embodiments, L1Ais independently unsubstituted ethylene. In embodiments, L1Ais independently substituted or unsubstituted methylene. In embodiments, L1Ais independently substituted methylene. In embodiments, L1Ais independently unsubstituted methylene.

[0139] In embodiments, L1Ais independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Ais independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Ais independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Ais independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Ais independently substituted 2 to 20 membered heteroalkylene. In embodiments, L1Ais independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Ais independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Ais independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Ais independently substituted 2 to 6 membered heteroalkylene. In embodiments, L1Ais independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Ais independently substituted 4 to 6 membered heteroalkylene. In embodiments, L1Ais independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Ais independently substituted 2 to 3 membered heteroalkylene. In embodiments, L1Ais independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L1Ais independently substituted 4 to 5 membered heteroalkylene. In embodiments, L1Ais independently unsubstituted 4 to 5 membered heteroalkylene.

[0140] In embodiments, L1Bis a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, - O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, - P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0141] In embodiments, L1Bis a bond. In embodiments, L1Bis -N(R20)-. In embodiments, L1Bis -O- or -S-. In embodiments, L1Bis -C(O)-. In embodiments, L1Bis -N(R20)C(O)- or - C(O)N(R21)-. In embodiments, L1Bis -N(R20)C(O)N(R21)-. In embodiments, L1Bis -C(O)O- or -OC(O)-. In embodiments, L1Bis -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1Bis -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(O)(NR20R21)-N-, or O- P(O)(NR20R21)-O-. In embodiments, L1Bis -P(O)(NR20R21)-N-,-P(S)(NR20R21)-N-, - P(O)(NR20R21)-O- or -P(S)(NR20R21)-O-. In embodiments, L1Bis -S-S-.

[0142] In embodiments, L1Bis independently substituted or unsubstituted alkylene (e.g., C1- C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Bis independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Bis independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Bis independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1Bis independently substituted C1-C20alkylene. In embodiments, L1Bis independently unsubstituted C1-C20 alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1Bis independently substituted C1-C12 alkylene. In embodiments, L1Bis independently unsubstituted C1-C12 alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1Bis independently substituted C1-C8alkylene. In embodiments, L1Bis independently unsubstituted C1-C8 alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1Bis independently substituted C1-C6alkylene. In embodiments, L1Bis independently unsubstituted C1-C6 alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C4alkylene. In embodiments, L1Bis independently substituted C1-C4 alkylene. In embodiments, L1Bis independently unsubstituted C1-C4 alkylene. In embodiments, L1Bis independently substituted or unsubstituted ethylene. In embodiments, L1Bis independently substituted ethylene. In embodiments, L1Bis independently unsubstituted ethylene. In embodiments, L1Bis independently substituted or unsubstituted methylene. In embodiments, L1Bis independently substituted methylene. In embodiments, L1Bis independently unsubstituted methylene.

[0143] In embodiments, L1Bis independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Bis independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Bis independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Bis independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Bis independently substituted 2 to 20 membered heteroalkylene. In embodiments, L1Bis independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Bis independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Bis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Bis independently substituted 2 to 6 membered heteroalkylene. In embodiments, L1Bis independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Bis independently substituted 4 to 6 membered heteroalkylene. In embodiments, L1Bis independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Bis independently substituted 2 to 3 membered heteroalkylene. In embodiments, L1Bis independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L1Bis independently substituted 4 to 5 membered heteroalkylene. In embodiments, L1Bis independently unsubstituted 4 to 5 membered heteroalkylene.

[0144] In embodiments, L1Cis a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, -O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, - P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0145] In embodiments, L1Cis a bond. In embodiments, L1Cis -N(R20)-. In embodiments, L1Cis -O- or -S-. In embodiments, L1Cis -C(O)-. In embodiments, L1Cis -N(R20)C(O)- or - C(O)N(R21)-. In embodiments, L1Cis -N(R20)C(O)N(R21)-. In embodiments, L1Cis -C(O)O- or -OC(O)-. In embodiments, L1Cis -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1Cis -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(O)(NR20R21)-N-, or O- P(O)(NR20R21)-O-. In embodiments, L1Cis -P(O)(NR20R21)-N-,-P(S)(NR20R21)-N-, - P(O)(NR20R21)-O- or -P(S)(NR20R21)-O-. In embodiments, L1Cis -S-S-.

[0146] In embodiments, L1Cis independently substituted or unsubstituted alkylene (e.g., C1- C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Cis independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Cis independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Cis independently substituted or unsubstituted C1-C20alkylene. In embodiments, L1Cis independently substituted C1-C20 alkylene. In embodiments, L1Cis independently unsubstituted C1-C20alkylene. In embodiments, L1Cis independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1Cis independently substituted C1-C12 alkylene. In embodiments, L1Cis independently unsubstituted C1-C12alkylene. In embodiments, L1Cis independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1Cis independently substituted C1-C8 alkylene. In embodiments, L1Cis independently unsubstituted C1-C8 alkylene. In embodiments, L1Cis independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1Cis independently substituted C1-C6 alkylene. In embodiments, L1Cis independently unsubstituted C1-C6alkylene. In embodiments, L1Cis independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1Cis independently substituted C1-C4alkylene. In embodiments, L1Cis independently unsubstituted C1-C4alkylene. In embodiments, L1Cis independently substituted or unsubstituted ethylene. In embodiments, L1Cis independently substituted ethylene. In embodiments, L1Cis independently unsubstituted ethylene. In embodiments, L1Cis independently substituted or unsubstituted methylene. Inembodiments, L1Cis independently substituted methylene. In embodiments, L1Cis independently unsubstituted methylene.

[0147] In embodiments, L1Cis independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Cis independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Cis independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Cis independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Cis independently substituted 2 to 20 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Cis independently substituted 2 to 6 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Cis independently substituted 4 to 6 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Cis independently substituted 2 to 3 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L1Cis independently substituted 4 to 5 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 4 to 5 membered heteroalkylene.

[0148] In embodiments, L1Dis a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, - O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, - P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0149] In embodiments, L1Dis a bond. In embodiments, L1Dis -N(R20)-. In embodiments, L1Dis -O- or -S-. In embodiments, L1Dis -C(O)-. In embodiments, L1Dis -N(R20)C(O)- or - C(O)N(R21)-. In embodiments, L1Dis -N(R20)C(O)N(R21)-. In embodiments, L1Dis -C(O)O- or -OC(O)-. In embodiments, L1Dis -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1Dis -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(O)(NR20R21)-N-, or O- P(O)(NR20R21)-O-. In embodiments, L1Dis -P(O)(NR20R21)-N-,-P(S)(NR20R21)-N-, - P(O)(NR20R21)-O- or -P(S)(NR20R21)-O-. In embodiments, L1Dis -S-S-.

[0150] In embodiments, L1Dis independently substituted or unsubstituted alkylene (e.g., C1- C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Dis independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Dis independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Dis independently substituted or unsubstituted C1-C20alkylene. In embodiments, L1Dis independently substituted C1-C20 alkylene. In embodiments, L1Dis independently unsubstituted C1-C20alkylene. In embodiments, L1Dis independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1Dis independently substituted C1-C12 alkylene. In embodiments, L1Dis independently unsubstituted C1-C12alkylene. In embodiments, L1Dis independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1Dis independently substituted C1-C8alkylene. In embodiments, L1Dis independently unsubstituted C1-C8 alkylene. In embodiments, L1Dis independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1Dis independently substituted C1-C6 alkylene. In embodiments, L1Dis independently unsubstituted C1-C6 alkylene. In embodiments, L1Dis independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1Dis independently substituted C1-C4alkylene. In embodiments, L1Dis independently unsubstituted C1-C4alkylene. In embodiments, L1Dis independently substituted or unsubstituted ethylene. In embodiments, L1Dis independently substituted ethylene. In embodiments, L1Dis independently unsubstituted ethylene. In embodiments, L1Dis independently substituted or unsubstituted methylene. In embodiments, L1Dis independently substituted methylene. In embodiments, L1Dis independently unsubstituted methylene.

[0151] In embodiments, L1Dis independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Dis independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Dis independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Dis independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Dis independently substituted 2 to 20 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Dis independently substituted 2 to 6 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Dis independently substituted 4 to 6 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Dis independently substituted 2 to 3 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L1Dis independently substituted 4 to 5 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 4 to 5 membered heteroalkylene.

[0152] In embodiments, L1Eis a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, - O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, - P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted orunsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0153] In embodiments, L1Eis a bond. In embodiments, L1Eis -N(R20)-. In embodiments, L1Eis -O- or -S-. In embodiments, L1Eis -C(O)-. In embodiments, L1Eis -N(R20)C(O)- or - C(O)N(R21)-. In embodiments, L1Eis -N(R20)C(O)N(R21)-. In embodiments, L1Eis -C(O)O- or -OC(O)-. In embodiments, L1Eis -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1Eis -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(O)(NR20R21)-N-, or O- P(O)(NR20R21)-O-. In embodiments, L1Eis -P(O)(NR20R21)-N-,-P(S)(NR20R21)-N-, - P(O)(NR20R21)-O- or -P(S)(NR20R21)-O-. In embodiments, L1Eis -S-S-.

[0154] In embodiments, L1Eis independently substituted or unsubstituted alkylene (e.g., C1- C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Eis independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Eis independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1Eis independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1Eis independently substituted C1-C20alkylene. In embodiments, L1Eis independently unsubstituted C1-C20 alkylene. In embodiments, L1Eis independently substituted or unsubstituted C1-C12alkylene. In embodiments, L1Eis independently substituted C1-C12alkylene. In embodiments, L1Eis independently unsubstituted C1-C12 alkylene. In embodiments, L1Eis independently substituted or unsubstituted C1-C8alkylene. In embodiments, L1Eis independently substituted C1-C8 alkylene. In embodiments, L1Eis independently unsubstituted C1-C8alkylene. In embodiments, L1Eis independently substituted or unsubstituted C1-C6alkylene. In embodiments, L1Eis independently substituted C1-C6 alkylene. In embodiments, L1Eis independently unsubstituted C1-C6 alkylene. In embodiments, L1Eis independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1Eis independently substituted C1-C4 alkylene. In embodiments, L1Eis independently unsubstituted C1-C4 alkylene. In embodiments, L1Eis independently substituted or unsubstituted ethylene. In embodiments, L1Eis independently substituted ethylene. In embodiments, L1Eis independently unsubstituted ethylene. In embodiments, L1Eis independently substituted or unsubstituted methylene. In embodiments, L1Eis independently substituted methylene. In embodiments, L1Eis independently unsubstituted methylene.

[0155] In embodiments, L1Eis independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Eis independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Eis independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L1Eis independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Eis independently substituted 2 to 20 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Eis independently substituted 2 to 6 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Eis independently substituted 4 to 6 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Eis independently substituted 2 to 3 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L1Eis independently substituted 4 to 5 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 4 to 5 membered heteroalkylene.

[0156] In embodiments, each R20, R21and R22is independently hydrogen or unsubstituted C1- C10alkyl.

[0157] In embodiments, R20is independently hydrogen or unsubstituted C1-C10alkyl. In embodiments, R20is independently hydrogen. In embodiments, R20is unsubstituted C1-C10 alkyl. In embodiments, R20is unsubstituted C1-C8alkyl. In embodiments, R20is unsubstituted C1-C6alkyl. In embodiments, R20is unsubstituted C1-C5 alkyl. In embodiments, R20is unsubstituted C1-C4alkyl. In embodiments, R20is unsubstituted C1-C3alkyl. In embodiments, R20isunsubstituted methyl. In embodiments, R20is unsubstituted ethyl. In embodiments, R20is unsubstituted propyl. In embodiments, R20is unsubstituted isopropyl. In embodiments, R20is unsubstituted n-butyl. In embodiments, R20is unsubstituted t-butyl. In embodiments, R20is unsubstituted 2-butyl. In embodiments, R20is unsubstituted isobutyl.

[0158] In embodiments, R21is independently hydrogen or unsubstituted C1-C10alkyl. In embodiments, R21is independently hydrogen. In embodiments, R21is unsubstituted C1-C10 alkyl. In embodiments, R21is unsubstituted C1-C8alkyl. In embodiments, R21is unsubstituted C1-C6alkyl. In embodiments, R21is unsubstituted C1-C5 alkyl. In embodiments, R21is unsubstituted C1-C4alkyl. In embodiments, R21is unsubstituted C1-C3alkyl. In embodiments, R21is unsubstituted methyl. In embodiments, R21is unsubstituted ethyl. In embodiments, R21is unsubstituted propyl. In embodiments, R21is unsubstituted isopropyl. In embodiments, R21is unsubstituted n-butyl. In embodiments, R21is unsubstituted t-butyl. In embodiments, R21is unsubstituted 2-butyl. In embodiments, R21is unsubstituted isobutyl.

[0159] In embodiments, R22is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R22is independently hydrogen. In embodiments, R22is unsubstituted C1-C10alkyl. In embodiments, R22is unsubstituted C1-C8 alkyl. In embodiments, R22is unsubstituted C1-C6 alkyl. In embodiments, R22is unsubstituted C1-C5alkyl. In embodiments, R22is unsubstituted C1-C4 alkyl. In embodiments, R22is unsubstituted C1-C3 alkyl. In embodiments, R22is unsubstituted methyl. In embodiments, R22is unsubstituted ethyl. In embodiments, R22is unsubstituted propyl. In embodiments, R22is unsubstituted isopropyl. In embodiments, R22is unsubstituted n-butyl. In embodiments, R22is unsubstituted t-butyl. In embodiments, R22is unsubstituted 2-butyl. In embodiments, R22is unsubstituted isobutyl.

[0160] In embodiments, each of R20, R21and R22is independently hydrogen or unsubstituted C1- C3 alkyl. In embodiments, R20is hydrogen and each R21and R22is independently unsubstituted C1-C3 alkyl. In embodiments, R21is hydrogen and each R20and R22is independently unsubstituted C1-C3 alkyl. In embodiments, R22is hydrogen and each R20and R21is independently unsubstituted C1-C3alkyl. In embodiments, R20, R21and R22are hydrogen. In embodiments, R20is unsubstituted C1-C3 alkyl and R21and R22hydrogen. In embodiments, R21is unsubstituted C1-C3alkyl and R20and R22hydrogen. In embodiments, R22is unsubstituted C1-C3alkyl and R20and R21hydrogen. In embodiments, each of R20, R21and R22are independently unsubstituted C1-C3alkyl.

[0161] In embodiments, L2is independently an unsubstituted C2-C24 alkylene. In embodiments, L2is independently an unsubstituted C2-C22alkylene. In embodiments, L2is independently an unsubstituted C5-C22 alkylene. In embodiments, L2is independently an unsubstituted C10-C22alkylene. In embodiments, L2is independently an unsubstituted C12-C22alkylene. In embodiments, L2is independently an unsubstituted C10-C20 alkylene. In embodiments, L2is independently an unsubstituted C12-C20alkylene. In embodiments, L2is independently an unsubstituted C10-C18 alkylene. In embodiments, L2is independently an unsubstituted C12-C18alkylene. In embodiments, L2is independently an unsubstituted C10-C16alkylene. In embodiments, L2is independently an unsubstituted C12-C16 alkylene. In embodiments, L2is independently an unsubstituted C14-C16 alkylene. In embodiments, L2is independently an unsubstituted C14-C15alkylene. In embodiments, L2is independently an unsubstituted C14 alkylene. In embodiments, L2is independently an unsubstituted C15 alkylene. In embodiments, L2is independently an unsubstituted C16alkylene.

[0162] In embodiments, L2is independently an unsubstitued unbranched C2-C24alkylene. In embodiments, L2is independently an unsubstitued unbranched C2-C22 alkylene. In embodiments, L2is independently an unsubstitued unbranched C5-C22alkylene. In embodiments, L2is independently an unsubstitued unbranched C10-C22 alkylene. In embodiments, L2is independently an unsubstitued unbranched C12-C22alkylene. In embodiments, L2is independently an unsubstitued unbranched C10-C20 alkylene. In embodiments, L2is independently an unsubstitued unbranched C12-C20alkylene. In embodiments, L2is independently an unsubstitued unbranched C10-C18 alkylene. In embodiments, L2is independently an unsubstitued unbranched C12-C18 alkylene. In embodiments, L2is independently an unsubstitued unbranched C10-C16 alkylene. In embodiments, L2is independently an unsubstitued unbranched C12-C16 alkylene. In embodiments, L2is independently an unsubstitued unbranched C14-C16 alkylene. In embodiments, L2is independently an unsubstitued unbranched C14-C15 alkylene. In embodiments, L2is independently an unsubstitued unbranched C14alkylene. In embodiments, L2is independently an unsubstitued unbranched C15 alkylene. In embodiments, L2is independently an unsubstitued unbranched C16alkylene.

[0163] In embodiments, L2is independently an unsubstitued ununbranched saturated C2-C24alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C2-C22 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C5-C22alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C10-C22 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C12-C22alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C10-C20 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C12-C20alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C10-C18 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C12-C18alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C10-C16 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C12-C16alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C14-C16 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C14-C15 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C14alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C15 alkylene. In embodiments, L2is independently an unsubstitued ununbranched saturated C16alkylene.

[0164] In embodiments, L2is independently an unsubstitued ununbranched unsaturated C2-C24 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C2- C22 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C5-C22alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C10-C22 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C12-C22alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C10-C20 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C12-C20 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C10-C18 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C12-C18 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C10-C16 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C12-C16 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C14-C16alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C14- C15alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C14 alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C15alkylene. In embodiments, L2is independently an unsubstitued ununbranched unsaturated C16 alkylene.

[0165] In embodiments, the largest dimension of L1is less than 200 angstroms. In embodiments, the largest dimension of L1is less than 190 angstroms. In embodiments, the largest dimension of L1is less than 180 angstroms. In embodiments, the largest dimension of L1is less than 170 angstroms. In embodiments, the largest dimension of L1is less than 160 angstroms. In embodiments, the largest dimension of L1is less than 150 angstroms. In embodiments, the largest dimension of L1is less than 140 angstroms. In embodiments, the largest dimension of L1is less than 130 angstroms. In embodiments, the largest dimension of L1is less than 120 angstroms. In embodiments, the largest dimension of L1is less than 110 angstroms. In embodiments, the largest dimension of L1is less than 100 angstroms. In embodiments, the largest dimension of L1is less than 90 angstroms. In embodiments, the largest dimension of L1is less than 80 angstroms. In embodiments, the largest dimension of L1is less than 70 angstroms. In embodiments, the largest dimension of L1is less than 60 angstroms. In embodiments, the largest dimension of L1is less than 50 angstroms. In embodiments, the largest dimension of L1is less than 40 angstroms. In embodiments, the largest dimension of L1is less than 30 angstroms. In embodiments, the largest dimension of L1is less than 20 angstroms. In embodiments, the largest dimension of L1is less than 10 angstroms.

[0166] In embodiments, the largest dimension of each of L1A, L1B, L1C, L1D, and L1Eis independently less than 50 angstroms. In embodiments, the largest dimension of each of L1A, L1B, L1C, L1D, and L1Eis independently less than 40 angstroms. In embodiments, the largest dimension of each of L1A, L1B, L1C, L1D, and L1Eis independently less than 30 angstroms. In embodiments, the largest dimension of each of L1A, L1B, L1C, L1D, and L1Eis independently less than 20 angstroms. In embodiments, the largest dimension of each of L1A, L1B, L1C, L1D, and L1Eis independently less than 10 angstroms.

[0167] In embodiments, the largest dimension of L1Ais independently less than 50 angstroms. In embodiments, the largest dimension of L1Ais independently less than 40 angstroms. In embodiments, the largest dimension of L1Ais independently less than 30 angstroms. In embodiments, the largest dimension of L1Ais independently less than 20 angstroms. In embodiments, the largest dimension of L1Ais independently less than 10 angstroms.

[0168] In embodiments, the largest dimension of L1Bis independently less than 50 angstroms. In embodiments, the largest dimension of L1Bis independently less than 40 angstroms. In embodiments, the largest dimension of L1Bis independently less than 30 angstroms. Inembodiments, the largest dimension of L1Bis independently less than 20 angstroms. In embodiments, the largest dimension of L1Bis independently less than 10 angstroms.

[0169] In embodiments, the largest dimension of L1Cis independently less than 50 angstroms. In embodiments, the largest dimension of L1Cis independently less than 40 angstroms. In embodiments, the largest dimension of L1Cis independently less than 30 angstroms. In embodiments, the largest dimension of L1Cis independently less than 20 angstroms. In embodiments, the largest dimension of L1Cis independently less than 10 angstroms.

[0170] In embodiments, the largest dimension of L1Dis independently less than 50 angstroms. In embodiments, the largest dimension of L1Dis independently less than 40 angstroms. In embodiments, the largest dimension of L1Dis independently less than 30 angstroms. In embodiments, the largest dimension of L1Dis independently less than 20 angstroms. In embodiments, the largest dimension of L1Dis independently less than 10 angstroms.

[0171] In embodiments, the largest dimension of L1Eis independently less than 50 angstroms. In embodiments, the largest dimension of L1Eis independently less than 40 angstroms. In embodiments, the largest dimension of L1Eis independently less than 30 angstroms. In embodiments, the largest dimension of L1Eis independently less than 20 angstroms. In embodiments, the largest dimension of L1Eis independently less than 10 angstroms.

[0172] In embodiments, the nucleic acid (A) is an oligonucleotide. In embodiments, one L1Ais attached to a 3’ carbon of the oligonucleotide. In embodiments, one L1Ais attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, one L1Ais attached to a 5’ carbon of the oligonucleotide. In embodiments, one L1Ais attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, one L1Ais attached to a 2’ carbon of the oligonucleotide. In embodiments, one L1Ais attached to a nucleobase of the oligonucleotide.

[0173] In embodiments, at least one L1Ais attached to a 3’ carbon of the oligonucleotide at a 3’ end. In embodiments, at least one L1Ais attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at its 3’ end. In embodiments, at least one L1Ais attached to a 5’ carbon of the oligonucleotide at its 5’ end. In embodiments, at least one L1Ais attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at its 5’ end.

[0174] In embodiments, the nucleic acid (A) is a double-stranded oligonucleotide. In embodiments, one L1Ais attached to a 3’ carbon of the double-stranded oligonucleotide. In embodiments, one L1Ais attached to a 3’ carbon of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, one L1Ais attached to a 3’ carbon of the double-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, one L1Ais attached to a 3’ carbon of the double-stranded oligonucleotide at the 3’end of its sense strand.

[0175] In embodiments, one L1Ais attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at either of its 3’ ends. In embodiments, one L1Ais attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at the 3’end of its antisense strand. In embodiments, one L1Ais attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at the 3’end of its sense strand.

[0176] In embodiments, one L1Ais attached to a 5’ carbon of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, one L1Ais attached to a 5’ carbon of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, one L1Ais attached to a 5’ carbon of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0177] In embodiments, one L1Ais attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at either of its 5’ ends. In embodiments, one L1Ais attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at the 5’ end of its antisense strand. In embodiments, one L1Ais attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at the 5’ end of its sense strand.

[0178] In embodiments, one L1Ais attached to a 2’ carbon of the double-stranded oligonucleotide. In embodiments, one L1Ais attached to a 2’ carbon of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, one L1Ais attached to a 2’ carbon at the 5’ end of the sense strand. In embodiments, one L1Ais attached to a 2’ carbon at the 5’ end of the antisense strand. In embodiments, one L1Ais attached to a 2’ carbon of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, one L1Ais attached to a 2’ carbon at the 3’ end of the sense strand. In embodiments, one L1Ais attached to a 2’ carbon at the 3’ end of the antisense strand.

[0179] In embodiments, one L1Ais attached to a nucleobase of the double-stranded oligonucleotide. In embodiments, one L1Ais attached to a nucleobase of the sense strand of the double-stranded oligonucleotide. In embodiments, one L1Ais attached to a nucleobase of the antisense strand of the double-stranded oligonucleotide. In embodiments, one L1Ais attached to a nucleobase of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, one L1Ais attached to a nucleobase of the double-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, one L1Ais attached to a nucleobase of the double-stranded oligonucleotide at the 3’end of its sense strand. In embodiments, one L1Ais attached to a nucleobase of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, one L1Ais attached to a nucleobase of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, one L1Ais attached to a nucleobase of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0180] In embodiments, the nucleic acid (A) is a single-stranded oligonucleotide. In embodiments, one L1Ais attached to a 3’ carbon of the single-stranded oligonucleotide at the 3’ end.

[0181] In embodiments, one L1Ais attached to a 3’ nitrogen of the single-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at the 3’ end of the single-stranded oligonucleotide.

[0182] In embodiments, one L1Ais attached to a 5’ carbon of the single-stranded oligonucleotide at the 5’ end.

[0183] In embodiments, one L1Ais attached to a 6’ carbon of the single-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at the 5’ end.

[0184] In embodiments, one L1Ais attached to a 2’ carbon of the single-stranded oligonucleotide. In embodiments, on L1Ais attached to a 2’ carbon of the single-stranded oligonucleotide at its 5’ end. In embodiments, one L1A is attached to a 2’ carbon of the single- stranded oligonucleotide at its 3’ end.

[0185] In embodiments, one L1Ais attached to a nucleobase of the single-stranded oligonucleotide. In embodiments, one L1Ais attached to a nucleobase of the single-stranded oligonucleotide at the of 3’ end. In embodiments, one L1Ais attached to a nucleobase of the single-stranded oligonucleotide at the 5’ end.

[0186] In embodiments, L1Ais independently -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)- N-, -O-P(S)(N(CH3)2)-O-, -P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, - P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1Ais independently -O-, -C(O)-, -C(O)O- or -OC(O)-. In embodiments, L1Ais independently -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, or -O- P(S)(CH3)-O-. In embodiments, L1Ais independently -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)- O-, -O-P(S)(N(CH3)2)-N-, or -O-P(S)(N(CH3)2)-O-. In embodiments, L1Ais independently - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, or -P(S)(N(CH3)2)-O-.

[0187] In embodiments, L1Ais independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C8alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C4alkylene. In embodiments, L1Ais independently substituted or unsubstituted C1-C2 alkylene.

[0188] In embodiments, L1Ais independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 16 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L1Ais independently substituted or unsubstituted 2 to 3 membered heteroalkylene.

[0189] In embodiments, L1Ais independently. In embodiments, L1Ais independently -OPO2-O-. In embodiments, L1Ais independently -O-P(O)(S)-O-. In embodiments, L1Ais independently -O-. In embodiments, L1Ais independently –S-.

[0190] ). In embodiments, L1Ais attached to the 3’nitrogen of a morpholino moiety. In embodiments, L1Ais independently –C(O)-. In embodiments, L1Ais attached to the 6’ carbon ofa morpholino moiety. In embodiments, L1Ais independently -O-P(O)(N(CH3)2)-N-. In embodiments, L1Ais independently -O-P(O)(N(CH3)2)-O-. In embodiments, L1Ais independently -P(O)(N(CH3)2)-N-. In embodiments, L1Ais independently -P(O)(N(CH3)2)-O-.

[0191] In embodiments, L1Bis independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C12alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C6alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C4alkylene. In embodiments, L1Bis independently substituted or unsubstituted C1-C2 alkylene.

[0192] In embodiments, L1Bis independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 16 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L1Bis independently substituted or unsubstituted 2 to 3 membered heteroalkylene.

[0193] In embodiments, L1Bis independently –L10-NH-C(O)- or –L10-C(O)-NH-. L10is substituted or unsubstituted alkylene.

[0194] In embodiments, L10is independently substituted or unsubstituted alkylene (e.g., C1- C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10is independently substituted or unsubstituted C1-C20alkylene. In embodiments, L10is independently substituted C1-C20 alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1-C20alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C20 alkylene. In embodiments, L10is independently unsubstituted C1-C20alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C12alkylene. In embodiments, L10is independently substituted C1-C12 alkylene. In embodiments,L10is independently hydroxy(OH)-substituted C1-C12 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C12alkylene. In embodiments, L10is independently unsubstituted C1-C12 alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C8alkylene. In embodiments, L10is independently substituted C1-C8alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C8alkylene. In embodiments, L10is independently unsubstituted C1-C8 alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C6alkylene. In embodiments, L10is independently substituted C1-C6 alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1-C6 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C6 alkylene. In embodiments, L10is independently unsubstituted C1-C6alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L10is independently substituted C1-C4alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1- C4 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C4 alkylene. In embodiments, L10is independently unsubstituted C1-C4alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L10is independently substituted C1-C2alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1- C2 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C2 alkylene. In embodiments, L10is independently unsubstituted C1-C2alkylene.

[0195] In embodiments, L1Bis independentlyIn embodiments, L1Bis independently

[0196] In embodiments, L1Bis independently. w1 is an integer from 0 to 10. w2 is an integer from 0 to 5. w3 is an integer from 0 to 5. w4 is an integer from 0 to 5.

[0197] In embodiments, L1Bis independently,w1, w2, w3, and w4 are as describedabove.

[0198] In embodiments, w1 is 0. In embodiments, w1 is 1. In embodiments, w1 is 2. In embodiments, w1 is 3. In embodiments, w1 is 4. In embodiments, w1 is 5. In embodiments, w1 is 6. In embodiments, w1 is 7. In embodiments, w1 is 8. In embodiments, w1 is 9. In embodiments, w1 is 10. In embodiments, w2 is 0. In embodiments, w2 is 1. In embodiments, w2 is 2. In embodiments, w2 is 3. In embodiments, w2 is 4. In embodiments, w2 is 5. In embodiments, w3 is 0. In embodiments, w3 is 1. In embodiments, w3 is 2. In embodiments, w3 is 3. In embodiments, w3 is 4. In embodiments, w3 is 5. In embodiments, w4 is 0. In embodiments, w4 is 1. In embodiments, w4 is 2. In embodiments, w4 is 3. In embodiments, w4 is 4. In embodiments, w4 is 5.

[0199] In embodiments, L1Bis independently

[0200] In embodiments, L1Bis independently Inembodiments, L1Bis independently In embodiments, w4 is0. In embodiments, w1 is 1. In embodiments, w1 is 2. In embodiments, w2 is 3. In embodiments, w4 is 0 and w1 is 2. In embodiments, w4 is 0 and w1 is 3. In embodiments, w4 is 0 and w1 is 4.

[0201] In embodiments, L1Bis independently In embodiments,L1Bis independently

[0202] In embodiments, –L1A-L1B- is independently –O-L10-NH-C(O)- or –O-L10-C(O)-NH-. L10is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene. In embodiments, –L1A-L1B- is independently –O-L10-NH-C(O)-. In embodiments, –L1A-L1B- is independently –O-L10-C(O)- NH-.

[0203] In embodiments, L10is independently substituted or unsubstituted alkylene (e.g., C1- C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L10is independently substituted C1-C20alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1-C20 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C20alkylene. In embodiments, L10is independently unsubstituted C1-C20 alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L10is independently substituted C1-C12alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1-C12 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C12alkylene. In embodiments, L10is independently unsubstituted C1-C12 alkylene. In embodiments, L10is independently substitutedor unsubstituted C1-C8 alkylene. In embodiments, L10is independently substituted C1-C8 alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1-C8alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L10is independently unsubstituted C1-C8alkylene. In embodiments, L10is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, L10is independently substituted C5-C8alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C5-C8alkylene. In embodiments, L10is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, L10is independently unsubstituted C5-C8alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L10is independently substituted C1-C6 alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1- C6alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C6alkylene. In embodiments, L10is independently unsubstituted C1-C6 alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C4alkylene. In embodiments, L10is independently substituted C1-C4 alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1- C4alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C4alkylene. In embodiments, L10is independently unsubstituted C1-C4 alkylene. In embodiments, L10is independently substituted or unsubstituted C1-C2alkylene. In embodiments, L10is independently substituted C1-C2 alkylene. In embodiments, L10is independently hydroxy(OH)-substituted C1- C2alkylene. In embodiments, L10is independently hydroxymethyl-substituted C1-C2alkylene. In embodiments, L10is independently unsubstituted C1-C2 alkylene.

[0204] In embodiments, –L1A-L1B- is independentlyIn embodi1Aments, –L - L1B- is independently In embodiments, –L1A-L1B- is independentlyIn embodiments, –L1A-L1B- is independently

[0205] In embodiments, –L1A-L1B- is independently -OPO2-O-L10-NH-C(O)- , -OP(O)(S)-O-L10-NH-C(O)-, -OPO2-O-L10-C(O)-NH-or -OP(O)(S)-O-L10-C(O)-NH-. In embodiments, L10is independently substituted or unsubstituted alkylene. In embodiments, –L1A- L1B- is independently -OPO2-O-L10-NH-C(O)- or -OP(O)(S)-O-L10-NH-C(O)-. In embodiments, –L1A-L1B- is independently -OPO2-O-L10-C(O)-NH-or -OP(O)(S)-O-L10-C(O)-NH-. In embodiments, L10is independently substituted or unsubstituted alkylene. In embodiments, L10is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, L10is independently substituted C5-C8alkylene. In embodiments, L10is independently hydroxy (OH)- substituted C5-C8 alkylene. In embodiments, L10is independently hydroxymethyl-substituted C5-C8alkylene. In embodiments, L10is independently unsubstituted C5-C8alkylene.

[0206] In embodiments, –L1A-L1B- is independently,

[0207] In embodiments, –L1A-L1B- is independently. In embodiments, –L1A-L1B- is independently In embodiments, –L1A-L1B- is independently ,orIn embodiments, –L1A-L1B- is independentlyIn embodiments, –L1A-L1B- is independently , or .

[0208] In embodiments, –L1A-L1B- is independently , , , or , and is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L1A-L1B- is independently or that is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L1A-L1B- is independently , orthat is attached to a 3’ carbon of the oligonucleotide.

[0209] In embodiments, –L1A-L1B- is independently ,or ,and is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L1A-L1B- is independently attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L1A-L1B- is independently that is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety).

[0210] In embodiments, an –L1A-L1B- is independently , , , or and is attached to a 5’ carbon of the oligonucleotide. In embodiments, an –L1A-L1B- is independently or that is attached to a 5’ carbon of the oligonucleotide. In embodiments, an –L1A-L1B- is independentlyor that is attached to a 5’ carbon of the oligonucleotide.

[0211] In embodiments where the oligonucleotide includes a morpholino moiety, L1Ais independently -P(O)(N(CH3)2)-N- or -P(O)(N(CH3)2)-O-. In embodiments, L1Bis substituted or unsubstituted heterocycloalkyl. In embodiments, L1Bis substituted heterocycloalkyl. In embodiments, L1Bis unsubstituted heterocycloalkyl. In embodiments, L1Bis substituted or unsubstituted piperidinylene. In embodiments, L1Bis substituted piperidinylene. In embodiments, L1Bis unsubstituted piperidinylene. In embodiments, L1Bis substituted or unsubstituted piperazinylene. In embodiments, L1Bis substituted piperazinylene. In embodiments, L1Bis unsubstituted piperazinylene. In embodiments, an –L1A-L1B- is independently or is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, an –L1A-L1B- is independently that is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, an –L1A-L1B- is independently that is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety).

[0212] In embodiments, an –L1A-L1B- is independently is attached to a nucleobase of the oligonucleotide. In embodiments, an –L1A-L1B- is independently and is attached to a nucleobase of the oligonucleotide.

[0213] In embodiments, L1Cis independently substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L1Dis independently a bond, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and L1Eis independently a bond, substituted or unsubstituted heteroalkylene, or -NHC(O)-.

[0214] In embodiments, L1Cis independently substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted alkylene. In embodiments, L1Cis independently substituted or unsubstituted C1- C10 alkylene, or substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted C1-C10alkylene. In embodiments, L1Cis independently substituted C1-C10 alkylene. In embodiments, L1Cis independently unsubstituted C1-C10 alkylene. In embodiments, L1Cis independently substituted or unsubstituted C1-C8alkylene. In embodiments, L1Cis independently substituted C1-C8alkylene. In embodiments, L1Cis independently unsubstituted C1-C8 alkylene. In embodiments, L1Cis independently substituted or unsubstituted C3-C8alkylene. In embodiments, L1Cis independently substituted C3-C8 alkylene. In embodiments, L1Cis independently unsubstituted C3-C8alkylene. In embodiments, L1Cis independently substituted or unsubstituted C3-C7alkylene. In embodiments, L1Cis independently substituted C3-C7 alkylene. In embodiments, L1Cis independently unsubstituted C3-C7alkylene.

[0215] In embodiments, L1Cis independently R1C-substituted or unsubstituted alkylene. In embodiments, L1Cis independently R1C-substituted or unsubstituted C1-C10 alkylene. In embodiments, L1Cis independently R1C-substituted C1-C10alkylene. In embodiments, L1Cis independently unsubstituted C1-C10 alkylene. In embodiments, L1Cis independently R1C- substituted or unsubstituted C1-C8 alkylene. In embodiments, L1Cis independently R1C- substituted C1-C8 alkylene. In embodiments, L1Cis independently unsubstituted C1-C8 alkylene. In embodiments, L1Cis independently R1C-substituted or unsubstituted C3-C8 alkylene. In embodiments, L1Cis independently R1C-substituted C3-C8 alkylene. In embodiments, L1Cis independently unsubstituted C3-C8 alkylene. In embodiments, L1Cis independently R1C- substituted or unsubstituted C3-C7alkylene. In embodiments, L1Cis independently R1C- substituted C3-C7 alkylene. In embodiments, L1Cis independently unsubstituted C3-C7 alkylene.

[0216] In embodiments, L1Cis independently substituted or unsubstituted heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Cis independently substituted 2 to 10 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 10 memberedheteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Cis independently substituted 5 to 8 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 5 to 8 membered heteroalkylene.

[0217] In embodiments, L1Cis independently R1C-substituted or unsubstituted heteroalkylene. In embodiments, L1Cis independently R1C-substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Cis independently R1C-substituted 2 to 10 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Cis independently R1C-substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently R1C-substituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Cis independently R1C-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Cis independently R1C-substituted 5 to 8 membered heteroalkylene. In embodiments, L1Cis independently unsubstituted 5 to 8 membered heteroalkylene.

[0218] R1Cis independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0219] In emdobiments, L1Dis independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1Dis independently a bond.

[0220] In embodiments, L1Dis independently substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted alkylene. In embodiments, L1Dis independently substituted or unsubstituted C1- C10alkylene, or substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted C1-C10 alkylene. In embodiments, L1Dis independently substituted C1-C10alkylene. In embodiments, L1Dis independently unsubstituted C1-C10 alkylene. In embodiments, L1Dis independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1Dis independently substituted C1-C8alkylene. In embodiments,L1Dis independently unsubstituted C1-C8 alkylene. In embodiments, L1Dis independently substituted or unsubstituted C3-C8alkylene. In embodiments, L1Dis independently substituted C3-C8 alkylene. In embodiments, L1Dis independently unsubstituted C3-C8 alkylene. In embodiments, L1Dis independently substituted or unsubstituted C3-C7alkylene. In embodiments, L1Dis independently substituted C3-C7 alkylene. In embodiments, L1Dis independently unsubstituted C3-C7alkylene.

[0221] In embodiments, L1Dis independently R1D-substituted or unsubstituted alkylene. In embodiments, L1Dis independently R1D-substituted or unsubstituted C1-C10alkylene. In embodiments, L1Dis independently R1D-substituted C1-C10 alkylene. In embodiments, L1Dis independently unsubstituted C1-C10 alkylene. In embodiments, L1Dis independently R1D- substituted or unsubstituted C1-C8alkylene. In embodiments, L1Dis independently R1D- substituted C1-C8 alkylene. In embodiments, L1Dis independently unsubstituted C1-C8 alkylene. In embodiments, L1Dis independently R1D-substituted or unsubstituted C3-C8alkylene. In embodiments, L1Dis independently R1D-substituted C3-C8 alkylene. In embodiments, L1Dis independently unsubstituted C3-C8alkylene. In embodiments, L1Dis independently R1D- substituted or unsubstituted C3-C7 alkylene. In embodiments, L1Dis independently R1D- substituted C3-C7alkylene. In embodiments, L1Dis independently unsubstituted C3-C7alkylene.

[0222] In embodiments, L1Dis independently substituted or unsubstituted heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Dis independently substituted 2 to 10 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Dis independently substituted 5 to 8 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 5 to 8 membered heteroalkylene.

[0223] In embodiments, L1Dis independently R1D-substituted or unsubstituted heteroalkylene. In embodiments, L1Dis independently R1D-substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Dis independently R1D-substituted 2 to 10 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 10 memberedheteroalkylene. In embodiments, L1Dis independently R1D-substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently R1D-substituted 2 to 8 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, R1D-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Dis independently R1D-substituted 5 to 8 membered heteroalkylene. In embodiments, L1Dis independently unsubstituted 5 to 8 membered heteroalkylene.

[0224] In embodiments, L1Dis independently substituted or unsubstituted arylene. In embodiments, L1Dis independently substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L1Dis independently substituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L1Dis independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L1Dis independently substituted or unsubstituted C6-C12arylene. In embodiments, L1Dis independently substituted C6-C12 arylene. In embodiments, L1Dis independently unsubstituted C6-C12arylene. In embodiments, L1Dis independently substituted or unsubstituted C6-C10 arylene. In embodiments, L1Dis independently substituted C6-C10 arylene. In embodiments, L1Dis independently unsubstituted C6-C10arylene. In embodiments, L1Dis independently substituted or unsubstituted phenylene. In embodiments, L1Dis independently substituted phenylene. In embodiments, L1Dis independently unsubstituted phenylene. In embodiments, L1Dis independently substituted or unsubstituted biphenylene. In embodiments, L1Dis independently substituted biphenylene. In embodiments, L1Dis independently unsubstituted biphenylene. In embodiments, L1Dis independently substituted or unsubstituted naphthylene. In embodiments, L1Dis independently substituted naphthylene. In embodiments, L1Dis independently unsubstituted naphthylene.

[0225] In embodiments, L1Dis independently R1D-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L1Dis independently R1D-substituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L1Dis independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L1Dis independently R1D-substituted or unsubstituted C6-C12arylene. In embodiments, L1Dis independently R1D-substituted C6-C12arylene. In embodiments, L1Dis independently unsubstituted C6-C12 arylene. In embodiments, L1Dis independently R1D-substituted or unsubstituted C6-C10arylene. In embodiments, L1Dis independently R1D-substituted C6-C10 arylene. In embodiments, L1Dis independently unsubstituted C6-C10arylene. In embodiments, L1Dis independently R1D-substituted orunsubstituted phenylene. In embodiments, L1Dis independently R1D-substituted phenylene. In embodiments, L1Dis independently unsubstituted phenylene. In embodiments, L1Dis independently R1D-substituted or unsubstituted biphenylene. In embodiments, L1Dis independently R1D-substituted biphenylene. In embodiments, L1Dis independently unsubstituted biphenylene. In embodiments, L1Dis independently R1D-substituted or unsubstituted naphthylene. In embodiments, L1Dis independently R1D-substituted naphthylene. In embodiments, L1Dis independently unsubstituted naphthylene.

[0226] In embodiments, L1Dis independently substituted or unsubstituted heteroarylene. In embodiments, L1Dis independently substituted heteroarylene. In embodiments, L1Dis independently unsubstituted heteroarylene. In embodiments, L1Dis independently substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1Dis independently substituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1Dis independently unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, L1Dis independently substituted or unsubstituted 5 to 12 membered heteroarylene. In embodiments, L1Dis independently substituted 5 to 12 membered heteroarylene. In embodiments, L1Dis independently unsubstituted 5 to 12 membered heteroarylene. In embodiments, L1Dis independently substituted or unsubstituted 5 to 10 membered heteroarylene. In embodiments, L1Dis independently substituted 5 to 10 membered heteroarylene. In embodiments, L1Dis independently unsubstituted 5 to 10 membered heteroarylene. In embodiments, L1Dis independently substituted or unsubstituted 5 to 9 membered heteroarylene. In embodiments, L1Dis independently substituted 5 to 9 membered heteroarylene. In embodiments, L1Dis independently unsubstituted 5 to 9 membered heteroarylene. In embodiments, L1Dis independently substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L1Dis independently substituted 5 to 6 membered heteroarylene. In embodiments, L1Dis independently unsubstituted 5 to 6 membered heteroarylene.

[0227] R1Dis independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0228] In embodiments, L1Eis independently a bond, substituted or unsubstituted 2 to 10 membered heteroalkylene, or -NHC(O)-. In embodiments, L1Eis independently a bond. In embodiments, L1Eis independently -NHC(O)-.

[0229] In embodiments, L1Eis independently substituted or unsubstituted heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Eis independently substituted 2 to 10 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently substituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently substituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 5 to 8 membered heteroalkylene.

[0230] In embodiments, L1Eis independently R1E-substituted or unsubstituted heteroalkylene. In embodiments, L1Eis independently R1E-substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Eis independently R1E-substituted 2 to 10 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1Eis independently R1E-substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently R1E-substituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1Eis independently R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently R1E-substituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently unsubstituted 5 to 8 membered heteroalkylene.

[0231] R1Eis independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0232] In embodiments, L1Cis independently R1C-substituted or unsubstituted C1-C7alkylene, or R1C-substituted or unsubstituted 5 to 8 membered heteroalkylene; L1Dis independently a bond, R1D-substituted or unsubstituted C1-C7alkylene, or R1D-substituted or unsubstituted 5 to 8membered heteroalkylene; and L1Eis independently a bond, R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene, or -NHC(O)-. In embodiments, L1Cis independently R1C-substituted or unsubstituted C1-C7alkylene. In embodiments, L1Cis independently R1C-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Dis independently a bond. In embodiments, L1Dis independently R1D-substituted or unsubstituted C1-C7 alkylene. In embodiments, L1Eis independently a bond. In embodiments, L1Eis independently R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently -NHC(O)-.

[0233] In embodiments, R1Cis independently oxo, or -L8C-L2C-R8C. In embodiments, R1Cis independently oxo. In embodiments, R1Cis independently -L8C-L2C-R8C. L8Cis independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene. L8Cis independently a bond, substituted or unsubstituted C1-C6alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene. L2Cis independently a bond, or an unsubstituted alkylene. R8Cis independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0234] In embodiments, R1Dis independently oxo, or -L8D-L2D-R8D. In embodiments, R1Dis independently oxo. In embodiments, R1Dis independently -L8D-L2D-R8D. L8Dis independently a bond, substituted or unsubstituted C1-C6alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene. L8Dis independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene. L2Dis independently a bond, or an unsubstituted alkylene. R8Dis independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0235] In embodiments, R1Eis independently oxo, or -L8E-L2E-R8E. In embodiments, R1Eis independently oxo. In embodiments, R1Eis independently -L8E-L2E-R8E. L8Eis independently a bond, substituted or unsubstituted C1-C6alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene. L8Eis independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene. L2Eis independently a bond, or an unsubstituted alkylene. R8Eis independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0236] In embodiments, the half-life extension motif has the structure of:(III-a). L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L2Ais independently a bond, or an unsubstituted alkylene. L1A, L1B, L1C, L1D, L1E, L2C, L8C, and R8Care as described above.

[0237] In embodiments, the half-life extension motif has the structure of: (III-b). L1A, L1B, L1C, L1D, L1E, L2A, L2D, L8A, L8D, and R8Dare as described above.

[0238] In embodiments, the half-life extension motif has the structure of: (III-c). L1A, L1B, L1C, L1D, L1E, L2A, L2E, L8A, L8E, and R8Eare as described above.

[0239] In embodiments, the half-life extension motif has the structure of:(III-d). L1A, L1B, L1C, L1D, L1E, L2A, L2C, L2D, L8A, L8C, L8D, R8Cand R8Dare as described above.

[0240] In embodiments, the half-life extension motif has the structure of: (III-e). L1A, L1B, L1C, L1D, L1E, L2A, L2D, L2E, L8A, L8D, L8E, R8Dand R8Eare as described above.

[0241] In embodiments, the half-life extension motif has the structure of: (III-f). L1A, L1B, L1C, L1D, L1E, L2A, L2C, L2E, L8A, L8C, L8E, R8Cand R8Eare as described above.

[0242] In embodiments, the half-life extension motif has the structure of:ĨIII-g). L1A, L1B, L1C, L1D, L1E, L2A, L2C, L2D, L2E, L8A, L8C, L8D, L2E, R8C, R8Dand R8Eare as described above.

[0243] In embodiments, L8Ais independently a bond. In embodiments, L8Ais independently substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L8Ais independently substituted or unsubstituted alkylene. In embodiments, L8Ais independently substituted or unsubstituted C1-C10 alkylene, or substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L8Ais independently substituted or unsubstituted C1-C10 alkylene. In embodiments, L8Ais independently substituted C1-C10 alkylene. In embodiments, L8Ais independently unsubstituted C1-C10 alkylene. In embodiments, L8Ais independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L8Ais independently substituted C1-C8alkylene. In embodiments, L8Ais independently unsubstituted C1-C8 alkylene. In embodiments, L8Ais independently substituted or unsubstituted C3-C8 alkylene. In embodiments, L8Ais independently substituted C3-C8alkylene. In embodiments, L8Ais independently unsubstituted C3-C8 alkylene. In embodiments, L8Ais independently substituted or unsubstituted C3-C7alkylene. In embodiments, L8Ais independently substituted C3-C7 alkylene. In embodiments, L8Ais independently unsubstituted C3-C7 alkylene.

[0244] In embodiments, L8Ais independently R8A-substituted or unsubstituted alkylene. In embodiments, L8Ais independently R8A-substituted or unsubstituted C1-C10 alkylene. In embodiments, L8Ais independently R8A-substituted C1-C10 alkylene. In embodiments, L8Ais independently unsubstituted C1-C10alkylene. In embodiments, L8Ais independently R8A- substituted or unsubstituted C1-C8 alkylene. In embodiments, L8Ais independently R8A- substituted C1-C8alkylene. In embodiments, L8Ais independently unsubstituted C1-C8alkylene. In embodiments, L8Ais independently R8A-substituted or unsubstituted C3-C8 alkylene. In embodiments, L8Ais independently R8A-substituted C3-C8alkylene. In embodiments, L8Aisindependently unsubstituted C3-C8 alkylene. In embodiments, L8Ais independently R8A- substituted or unsubstituted C3-C7alkylene. In embodiments, L8Ais independently R8A- substituted C3-C7 alkylene. In embodiments, L8Ais independently unsubstituted C3-C7 alkylene.

[0245] In embodiments, L8Ais independently substituted or unsubstituted heteroalkylene. In embodiments, L8Ais independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L8Ais independently substituted 2 to 10 membered heteroalkylene. In embodiments, L8Ais independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L8Ais independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L8Ais independently substituted 2 to 8 membered heteroalkylene. In embodiments, L8Ais independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L8Ais independently substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L8Ais independently substituted 5 to 8 membered heteroalkylene. In embodiments, L8Ais independently unsubstituted 5 to 8 membered heteroalkylene.

[0246] In embodiments, L8Ais independently R8A-substituted or unsubstituted heteroalkylene. In embodiments, L8Ais independently R8A-substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L8Ais independently R8A-substituted 2 to 10 membered heteroalkylene. In embodiments, L8Ais independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L8Ais independently R8A-substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L8Ais independently R8A-substituted 2 to 8 membered heteroalkylene. In embodiments, L8Ais independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, R8A-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L8Ais independently R8A-substituted 5 to 8 membered heteroalkylene. In embodiments, L8Ais independently unsubstituted 5 to 8 membered heteroalkylene.

[0247] In embodiments, L2Ais independently an unsubstituted C2-C24 alkylene. In embodiments, L2Ais independently an unsubstituted C2-C22alkylene. In embodiments, L2Ais independently an unsubstituted C5-C22 alkylene. In embodiments, L2Ais independently an unsubstituted C10-C22alkylene. In embodiments, L2Ais independently an unsubstituted C12-C22alkylene. In embodiments, L2Ais independently an unsubstituted C10-C20 alkylene. In embodiments, L2Ais independently an unsubstituted C12-C20alkylene. In embodiments, L2Aisindependently an unsubstituted C10-C18 alkylene. In embodiments, L2Ais independently an unsubstituted C12-C18alkylene. In embodiments, L2Ais independently an unsubstituted C10-C16alkylene. In embodiments, L2Ais independently an unsubstituted C12-C16 alkylene. In embodiments, L2Ais independently an unsubstituted C14-C16alkylene. In embodiments, L2Ais independently an unsubstituted C14-C15 alkylene. In embodiments, L2Ais independently an unsubstituted C14alkylene. In embodiments, L2Ais independently an unsubstituted C15alkylene. In embodiments, L2Ais independently an unsubstituted C16 alkylene.

[0248] In embodiments, L2Ais independently an unsubstitued unbranched C2-C24 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C2-C22alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C5-C22 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C10-C22 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C12-C22alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C10-C20 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C12-C20alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C10-C18 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C12-C18alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C10-C16 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C12-C16alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C14-C16 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C14-C15alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C14 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C15 alkylene. In embodiments, L2Ais independently an unsubstitued unbranched C16 alkylene.

[0249] In embodiments, L2Ais independently an unsubstitued ununbranched saturated C2-C24 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C2-C22 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C5-C22alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C10-C22 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C12-C22alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C10-C20 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C12-C20alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C10-C18 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C12-C18alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C10-C16 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C12-C16alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C14-C16 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C14-C15alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C14 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C15alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched saturated C16 alkylene.

[0250] In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C2- C24 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C2-C22 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C5-C22alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C10-C22 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C12-C22alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C10-C20 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C12-C20alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C10-C18 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C12-C18alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C10-C16 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C12-C16alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C14- C16 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C14-C15 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C14 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C15 alkylene. In embodiments, L2Ais independently an unsubstitued ununbranched unsaturated C16 alkylene. In embodiments, L8Ais independently a bond and L2Ais independently an unsubstituted C2-C22alkylene.

[0251] In embodiments, L2Ais independently a bond and L8Ais independently an unsubstituted C2-C22 alkylene.

[0252] In embodiments, L8Ais independently an unsubstituted C2-C24 alkylene. In embodiments, L8Ais independently an unsubstituted C2-C22alkylene. In embodiments, L8Aisindependently an unsubstituted C5-C22 alkylene. In embodiments, L8Ais independently an unsubstituted C10-C22alkylene. In embodiments, L8Ais independently an unsubstituted C12-C22alkylene. In embodiments, L8Ais independently an unsubstituted C10-C20 alkylene. In embodiments, L8Ais independently an unsubstituted C12-C20alkylene. In embodiments, L8Ais independently an unsubstituted C10-C18 alkylene. In embodiments, L8Ais independently an unsubstituted C12-C18alkylene. In embodiments, L8Ais independently an unsubstituted C10-C16alkylene. In embodiments, L8Ais independently an unsubstituted C12-C16 alkylene. In embodiments, L8Ais independently an unsubstituted C14-C16alkylene. In embodiments, L8Ais independently an unsubstituted C14-C15 alkylene. In embodiments, L8Ais independently an unsubstituted C14 alkylene. In embodiments, L8Ais independently an unsubstituted C15 alkylene. In embodiments, L8Ais independently an unsubstituted C16alkylene.

[0253] In embodiments, L8Ais independently an unsubstitued unbranched C2-C24alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C2-C22 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C5-C22alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C10-C22 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C12-C22alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C10-C20 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C12-C20alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C10-C18 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C12-C18alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C10-C16 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C12-C16 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C14-C16 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C14-C15 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C14 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C15 alkylene. In embodiments, L8Ais independently an unsubstitued unbranched C16alkylene.

[0254] In embodiments, L8Ais independently an unsubstitued ununbranched saturated C2-C24alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C2-C22 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C5-C22alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C10-C22 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C12-C22alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C10-C20 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C12-C20alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C10-C18 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C12-C18alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C10-C16 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C12-C16alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C14-C16 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C14-C15alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C14 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C15 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched saturated C16alkylene.

[0255] In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C2- C24alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C2-C22 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C5-C22alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C10-C22 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C12-C22alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C10-C20 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C12-C20alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C10-C18 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C12-C18 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C10-C16 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C12-C16 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C14- C16 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C14-C15alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C14 alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C15alkylene. In embodiments, L8Ais independently an unsubstitued ununbranched unsaturated C16 alkylene.

[0256] In embodiments, R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently a bond or an unsubstituted C2-C22alkylene; and R8Cis independently hydrogen, C1-C3alkyl, or -COOH.In embodiments, R1Cis independently –NHC(O)-L2C-R8C. In embodiments, L2Cis independently a bond or an unsubstituted C2-C22alkylene. In embodiments, L2Cis independently a bond. In embodiments, L2Cis independently an unsubstituted C2-C22 alkylene. In embodiments, R8Cis independently hydrogen, C1-C3alkyl, or -COOH. In embodiments, R8Cis independently hydrogen. In embodiments, R8Cis independently C1-C3 alkyl. In embodiments, R8Cis independently -COOH.

[0257] In embodiments, R1Cis independently –NHC(O)-L2C-R8C, L2Cis independently a bond, and R8Cis independently C1-C3 alkyl. In embodiments, R1Cis independently –NHC(O)-CH3. In embodiments, R1Cis independently –NHC(O)-CH2CH3. In embodiments, R1Cis independently – NHC(O)-CH(CH3)2. In embodiments, R1Cis independently –NHC(O)-CH2CH2CH3.

[0258] In embodiments, R1Cis independently –NHC(O)-L2C-R8C, L2Cis independently an unsubstituted C10-C22 alkylene, and R8Cis independently -COOH. In embodiments, R1Cis independently –NHC(O)-L2C-COOH.

[0259] In embodiments, L2Cis independently an unsubstitued unbranched C2-C24alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C2-C22 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C5-C22alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C10-C22 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C12-C22alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C10-C20 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C12-C20alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C10-C18 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C12-C18 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C10-C16 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C12-C16 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C14-C16 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C14-C15 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C14alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C15 alkylene. In embodiments, L2Cis independently an unsubstitued unbranched C16alkylene.

[0260] In embodiments, L2Cis independently an unsubstitued ununbranched saturated C2-C24alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C2-C22alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C5-C22 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C10-C22alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C12-C22 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C10-C20alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C12-C20 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C10-C18alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C12-C18 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C10-C16alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C12-C16 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C14-C16 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C14-C15alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C14 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C15alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched saturated C16 alkylene.

[0261] In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C2- C24 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C2-C22alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C5-C22 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C10-C22alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C12-C22 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C10-C20 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C12-C20 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C10-C18 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C12-C18 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C10-C16 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C12-C16alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C14- C16alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C14-C15 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C14alkylene. In embodiments, L2Cis independently an unsubstitued ununbranchedunsaturated C15 alkylene. In embodiments, L2Cis independently an unsubstitued ununbranched unsaturated C16alkylene.

[0262] In embodiments, R1Dis independently –NHC(O)-L2D-R8D; L2Dis independently a bond or an unsubstituted C2-C22 alkylene; and R8Dis independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R1Dis independently –NHC(O)-L2D-R8D. In embodiments, L2Dis independently a bond or an unsubstituted C2-C22 alkylene. In embodiments, L2Dis independently a bond. In embodiments, L2Dis independently an unsubstituted C2-C22alkylene. In embodiments, R8Dis independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R8Dis independently hydrogen. In embodiments, R8Dis independently C1-C3alkyl. In embodiments, R8Dis independently -COOH.

[0263] In embodiments, R1Dis independently –NHC(O)-L2D-R8D, L2Dis independently a bond, and R8Dis independently C1-C3alkyl. In embodiments, R1Dis independently –NHC(O)-CH3. In embodiments, R1Dis independently –NHC(O)-CH2DH3. In embodiments, R1Dis independently – NHC(O)-CH(CH3)2. In embodiments, R1Dis independently –NHC(O)-CH2DH2DH3.

[0264] In embodiments, R1Dis independently –NHC(O)-L2D-R8D, L2Dis independently an unsubstituted C10-C22 alkylene, and R8Dis independently -COOH. In embodiments, R1Dis independently –NHC(O)-L2D-COOH.

[0265] In embodiments, L2Dis independently an unsubstitued unbranched C2-C24 alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C2-C22alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C5-C22 alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C10-C22alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C12-C22 alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C10-C20alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C12-C20 alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C10-C18alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C12-C18alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C10-C16 alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C12-C16alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C14-C16 alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C14-C15alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C14 alkylene. In embodiments,L2Dis independently an unsubstitued unbranched C15 alkylene. In embodiments, L2Dis independently an unsubstitued unbranched C16alkylene.

[0266] In embodiments, L2Dis independently an unsubstitued ununbranched saturated C2-C24alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C2-C22 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C5-C22alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C10-C22 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C12-C22alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C10-C20 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C12-C20alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C10-C18 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C12-C18 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C10-C16alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C12-C16 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C14-C16alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C14-C15 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C14alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C15 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched saturated C16alkylene.

[0267] In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C2- C24alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C2-C22 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C5-C22 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C10-C22 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C12-C22 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C10-C20alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C12-C20 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C10-C18alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C12-C18 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C10-C16alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C12-C16 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C14-C16 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C14-C15alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C14 alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C15alkylene. In embodiments, L2Dis independently an unsubstitued ununbranched unsaturated C16 alkylene.

[0268] In embodiments, R1Eis independently –NHC(O)-L2E-R8E; L2Eis independently a bond or an unsubstituted C2-C22alkylene; and R8Eis independently hydrogen, C1-C3alkyl, or -COOH. In embodiments, R1Eis independently –NHC(O)-L2E-R8E. In embodiments, L2Eis independently a bond or an unsubstituted C2-C22alkylene. In embodiments, L2Eis independently a bond. In embodiments, L2Eis independently an unsubstituted C2-C22 alkylene. In embodiments, R8Eis independently hydrogen, C1-C3alkyl, or -COOH. In embodiments, R8Eis independently hydrogen. In embodiments, R8Eis independently C1-C3 alkyl. In embodiments, R8Eis independently -COOH.

[0269] In embodiments, R1Eis independently –NHC(O)-L2E-R8E, L2Eis independently a bond, and R8Eis independently C1-C3 alkyl. In embodiments, R1Eis independently –NHC(O)-CH3. In embodiments, R1Eis independently –NHC(O)-CH2EH3. In embodiments, R1Eis independently – NHC(O)-CH(CH3)2. In embodiments, R1Eis independently –NHC(O)-CH2EH2EH3.

[0270] In embodiments, R1Eis independently –NHC(O)-L2E-R8E, L2Eis independently an unsubstituted C10-C22 alkylene, and R8Eis independently -COOH. In embodiments, R1Eis independently –NHC(O)-L2E-COOH.

[0271] In embodiments, L2Eis independently an unsubstitued unbranched C2-C24alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C2-C22 alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C5-C22alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C10-C22 alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C12-C22alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C10-C20alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C12-C20 alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C10-C18alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C12-C18 alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C10-C16alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C12-C16 alkylene. Inembodiments, L2Eis independently an unsubstitued unbranched C14-C16 alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C14-C15alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C14 alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C15alkylene. In embodiments, L2Eis independently an unsubstitued unbranched C16 alkylene.

[0272] In embodiments, L2Eis independently an unsubstitued ununbranched saturated C2-C24 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C2-C22alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C5-C22 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C10-C22alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C12-C22 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C10-C20 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C12-C20alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C10-C18 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C12-C18alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C10-C16 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C12-C16alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C14-C16 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C14-C15alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C14 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C15alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched saturated C16 alkylene.

[0273] In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C2- C24 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C2-C22 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C5-C22alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C10-C22 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C12-C22alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C10-C20 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C12-C20alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C10-C18 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C12-C18alkylene. Inembodiments, L2Eis independently an unsubstitued ununbranched unsaturated C10-C16 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C12-C16alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C14- C16alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C14-C15 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C14alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C15 alkylene. In embodiments, L2Eis independently an unsubstitued ununbranched unsaturated C16alkylene.

[0274] In embodiments, L1Cis independently R1C-substituted or unsubstituted 5 to 8 membered heteroalkylene, L1Dis independently a bond, or R1D-substituted or unsubstituted 5 to 8 membered heteroalkylene, and L1Eis independently R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene or -NHC(O)-. In embodiments, each R1C, R1D, or R1Eis independently oxo, or – COOH.

[0275] In embodiments, L1Cis independently unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Dis independently oxo-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene wherein R1Eis independently oxo, or –COOH. In embodiments, L1Cis independently unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Dis independently a bond. In embodiments, L1Eis independently -NHC(O)-. In embodiments, -L1C-

[0276] In embodiments, L1Cis independently R1C-substituted C2-C5 alkyl; L1Dis independently an unsubstituted phenylene, or an unsubstituted biphenylene; L1Eis independently R1E- substituted or unsubstituted 5 to 8 membered heteroalkylene or -NHC(O)-; R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently a bond, or an unsubstituted C10-C22alkylene; R8Cis independently an unsubstituted C1-C3 alkyl, or –COOH; and R1Eis oxo.

[0277] In embodiments, L1Cis independently R1C-substituted ethylene. In embodiments, L1Dis independently an unsubstituted biphenylene. In embodiments, L1Eisindependently -NHC(O)-. In embodiments, R1Cis independently –NHC(O)-L2C-R8C, and L2Cis independently a bond or R8Cis independently an unsubstituted C1-C3alkyl. In embodiments, R1Cis independently –NHC(O)-CH3. In embodiments, R1Cis independently –NHC(O)-CH2CH3. In embodiments, R1Cis independently –NHC(O)-CH(CH3)2. In embodiments, R1Cis independently –NHC(O)-CH2CH2CH3. In embodiments, R1Cis independently –NHC(O)- L2C- COOH. In embodiments, -L1C-L1D-L1E- may formIn embodiments, -L1C-L1D-L1E- may formIn embodiments, - L1C-L1D-L1E- may form. In embodiments, -L1C-L1D-L1E- may form.

[0278] In embodiments, L1Cis independently R1C-substituted ethylene. In embodiments, L1Dis independently an unsubstituted phenylene. In embodiments, L1Eis independently R1E- substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently oxo-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, R1Cis independently –NHC(O)-L2C-R8C, and L2Cis independently a bond or R8Cis independently an unsubstituted C1-C3 alkyl. In embodiments, R1Cis independently –NHC(O)- CH3. In embodiments, R1Cis independently –NHC(O)-CH2CH3. In embodiments, R1Cis independently –NHC(O)-CH(CH3)2. In embodiments, R1Cis independently –NHC(O)-CH2CH2CH3. In embodiments, R1Cis independently –NHC(O)- L2C-COOH. In embodiments, - L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form .

[0279] In embodiments, L1Cis independently R1C-substituted or unsubstituted ethylene or n- pentylene, L1Dis independently a bond, L1Eis independently -NHC(O)-, R1Cis independently – NHC(O)-L2C-R8C, L2Cis independently a bond or an unsubstituted C10-C22 alkylene, and R8Cis independently an unsubstituted C1-C3alkyl, or –COOH.

[0280] In embodiments, L1Cis independently R1C-substituted n-pentylene. In embodiments, L1Cis independently unsubstituted n-pentylene. In embodiments, L1Dis independently a bond. In embodiments, L1Eis independently -NHC(O)-. In embodiments, R1Cis independently – NHC(O)-L2C-R8C, and L2Cis independently a bond and R8Cis independently an unsubstituted C1- C3alkyl. In embodiments, R1Cis independently –NHC(O)-CH3. In embodiments, R1Cis independently –NHC(O)-CH2CH3. In embodiments, R1Cis independently –NHC(O)-CH(CH3)2. In embodiments, R1Cis independently –NHC(O)-CH2CH2CH3. In embodiments, R1Cis independently –NHC(O)-L2C-COOH. In embodiments, -L1C-L1D-L1E- may form. In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form .

[0281] In embodiments, L1Cis independently R1C-substituted ethylene. In embodiments, L1Dis independently a bond. In embodiments, L1Eis independently -NHC(O)-. In embodiments, R1Cis independently –NHC(O)-L2C-R8C, and L2Cis independently a bond and R8Cis independently an unsubstituted C1-C3 alkyl. In embodiments, R1Cis independently –NHC(O)- CH3. In embodiments, R1Cis independently –NHC(O)-CH2CH3. In embodiments, R1Cis independently –NHC(O)-CH(CH3)2. In embodiments, R1Cis independently –NHC(O)- CH2CH2CH3. In embodiments, R1Cis independently –NHC(O)-L2C-R8C, L2Cis independently an unsubstituted C10-C22 alkylene, and R8Cis independently -COOH. In embodiments, R1Cis independently –NHC(O)- L2C-COOH. In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form .

[0282] In embodiments, L1Cis independently R1C-substituted or unsubstituted n-pentylene, L1Dis independently oxo-substituted or unsubstituted 5 to 8 membered heteroalkylene, L1Eis independently -NHC(O)-, R1Cis independently –NHC(O)-L2C-R8C, L2Cis independently a bond or an unsubstituted C10-C22 alkylene, and R8Cis independently an unsubstituted C1-C3 alkyl, or - COOH.

[0283] In embodiments, L1Cis independently R1C-substituted n-pentylene. In embodiments, L1Dis independently oxo-substituted or unsubstituted 5 to 8 membered heteroalkylene. In embodiments, L1Eis independently -NHC(O)-. In embodiments, R1Cis independently – NHC(O)-L2C-R8C, L2Cis independently a bond, and R8Cis independently an unsubstituted C1-C3 alkyl. In embodiments, R1Cis independently –NHC(O)-CH3. In embodiments, R1Cis independently –NHC(O)-CH2CH3. In embodiments, R1Cis independently –NHC(O)-CH(CH3)2.In embodiments, R1Cis independently –NHC(O)-CH2CH2CH3. In embodiments, R1Cis independently –NHC(O)-L2C-R8C, L2Cis independently an unsubstituted C10-C22alkylene, and R8Cis independently an unsubstituted C1-C3 alkyl. In embodiments, R1Cis independently – NHC(O)-L2C-R8C, L2Cis independently an unsubstituted C10-C22alkylene, and R8Cis independently an unsubstituted methyl. In embodiments, R1Cis independently –NHC(O)-L2C- R8C, L2Cis independently an unsubstituted C10-C22alkylene, and R8Cis independently an unsubstituted ethyl. In embodiments, R1Cis independently –NHC(O)-L2C-R8C, L2Cis independently an unsubstituted C10-C22alkylene, and R8Cis independently -COOH. In embodiments, R1Cis independently –NHC(O)-L2C-COOH. In embodiments, R1Cis independently –NHC(O)-L2C-R8C, L2Cis independently an unsubstituted C10-C22 alkylene, and R8Cis independently -COOH. In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D-L1E- may form .

[0284] In embodiments, L1Cis independently R1C-substituted methylene, L1Dis independently a bond, L1Eis independently -NHC(O)-, R1Cis independently –L8C-L2C-R8C, L8Cis independently an unsubstituted C1-C6 alkylene or oxo-substituted 2 to 12 membered heteroalkylene, L2Cis independently a bond, and R8Cis independently an unsubstituted C1-C6alkyl or oxo-substituted 2 to 12 membered heteroalkyl.

[0285] In embodiments, L1Cis independently R1C-substituted methylene. In embodiments, L1Dis independently a bond. In embodiments, L1Eis independently -NHC(O)-. In embodiments, R1Cis independently –L8C-L2C-R8C. In embodiments, L8Cis independently an unsubstituted C1- C6alkylene or oxo-substituted 2 to 12 membered heteroalkylene. In embodiments, L8Cis independently an unsubstituted C1-C6 alkylene. In embodiments, L8Cis independently oxo- substituted 2 to 12 membered heteroalkylene. In embodiments, R8Cis independently an unsubstituted C1-C6 alkyl. In embodiments, R8Cis independently oxo-substituted 2 to 12 membered heteroalkyl. In embodiments, L8Cis independently unsubstituted C1-C6 alkylene, L2Cis a bond, and R8Cis independently oxo-substituted 2 to 12 membered heteroalkyl. In embodiments, L8Cis independently unsubstituted C4 alkylene, L2Cis a bond, and R8Cis independently oxo-substituted 2-5 membered heteroalkyl. In embodiments, L8Cis independently unsubstituted C4 alkylene, L2Cis a bond, and R8Cis independently oxo-substituted and C1-C20 alkyl substituted 2 to 12 membered heteroalkyl. In embodiments, L8Cis independently unsubstituted C1-C6 alkylene, L2Cis a bond, and R8Cis independently oxo- and C1-C15 alkyl- substituted 2 to 12 membered heteroalkyl. In embodiments, L8Cis independently unsubstituted C4 alkylene, L2Cis a bond, and R8Cis independently oxo- and C14-C15 alkyl-substituted 2 to 12 membered heteroalkyl. In embodiments, L8Cis independently oxo-substituted 2 to 12 membered heteroalkylene, L2Cis a bond, R8Cis independently oxo-substituted 2 to 12 membered heteroalkyl. In embodiments, L8Cis independently oxo-substituted 2 to 12 membered heteroalkylene, L2Cis a bond, R8Cis independently oxo- and C1-C15 alkyl-substituted 2 to 12 membered heteroalkyl. In embodiments, L8Cis independently oxo-substituted 2 to 12 membered heteroalkylene, L2Cis a bond, R8Cis independently oxo- and C14-C15alkyl-substituted 2 to 12 membered heteroalkyl. In embodiments, -L1C-L1D-L1E- may form. Inembodiments, -L1C-L1D-L1E- may form . In embodiments, -L1C-L1D- L1E- may form . In embodiments, -L1C-L1D-L1E- may form .

[0286] In embodiments, L1is , , , , ,, ,,.

[0287] In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently .In embodiments, L1is independently. In embodiments, L1is independently. In embodiments, L1is independently. In embodiments, L1is independently. In embodiments, L1is independently. In embodiments, L1is independentlyembodiments, L1isindependently . In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently . In embodiments, L1is independently . O H N N H O HN O O In embodiments, L1is independently . In embodiments, L1is independently O O O H O N N O O N H H HN O O . In embodiments,L1is independently . .

[0288] In embodiments, L1is , , , , , or . In embodiments, L1is. In embodiments, L1is . In embodiments, L1is . In embodiments, L1is . In embodiments, L1is . In embodiments, L1is .

[0289] In embodiments, the HLEM is ,, , , or . In embodiments, the HLEM is . In embodiments, the HLEM is . In embodiments, the HLEM is. In embodiments, the HLEM is . In embodiments, the HLEM is .

[0290] In embodiments, the compound includes from one to five optionally different half-life extension motifs. In embodiments, the compound includes from one to four optionally different half-life extension motifs. In embodiments, the compound includes from one to three optionally different half-life extension motifs. In embodiments, the compound includes from one to two optionally different half-life extension motifs. In embodiments, the compound includes from two to five different half-life extension motifs. In embodiments, the compound includes from two to four different half-life extension motifs. In embodiments, the compound includes from two to three different half-life extension motifs. In embodiments, the compound includes two different half-life extension motifs. In embodiments, compound includes only one half-life extension motif.

[0291] In embodiments, the uptake motif independently has the structure: (IV).

[0292] L3and L4are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, - C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O- P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, - P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. Each R23, R24and R25is independently hydrogen or unsubstituted C1-C10 alkyl.

[0293] L5is -L5A-L5B-L5C-L5D-L5E- and L6is -L6A-L6B-L6C-L6D-L6E-. L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6Eare independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.

[0294] R1and R2are independently unsubstituted C1-C25alkyl, wherein at least one of R1and R2is unsubstituted C9-C19 alkyl. In embodiments, R1and R2are independently unsubstituted C1- C20alkyl, wherein at least one of R1and R2is unsubstituted C9-C19alkyl.

[0295] R3is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O) OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0296] t is an integer from 1 to 5.

[0297] In embodiments, t is 1. In embodiments, t is 2. In embodiment, t is 3. In embodiments, t is 4. In embodiment t is 5.

[0298] In embodiments, one L3is attached to a 3’ carbon of the oligonucleotide. In embodiments, one L3is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, one L3is attached to a 5’ carbon of the oligonucleotide. In embodiments, one L3is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, one L3is attached to a 2’ carbon of the oligonucleotide In embodiments, one L3is attached to a nucleobase of the oligonucleotide.

[0299] In embodiments, one L3is attached to a 3’ carbon of the oligonucleotide at a 3’ end. In embodiments, one L3is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at a 3’ end. In embodiments, one L3is attached to a 5’ carbon of the oligonucleotide at a 5’ end. In embodiments, one L3is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at a 5’ end.

[0300] In embodiments, one L3is attached to a 3’ carbon of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, one L3is attached to a 3’ carbon of the double-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, one L3is attached to a 3’ carbon of the double-stranded oligonucleotide at the 3’end of its sense strand.

[0301] In embodiments, one L3is attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at either of its 3’ ends. In embodiments, one L3is attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at the 3’end of its antisense strand. In embodiments, one L3is attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at the 3’end of its sense strand.

[0302] In embodiments, one L3is attached to a 5’ carbon of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, one L3is attached to a 5’ carbon of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, one L3is attached to a 5’ carbon of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0303] In embodiments, one L3is attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at either of its 5’ ends. In embodiments, one L3is attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at the 5’ end of its antisense strand. In embodiments, one L3is attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at the 5’ end of its sense strand.

[0304] In embodiments, one L3is attached to a 2’ carbon of the double-stranded oligonucleotide. In embodiments, one L3is attached to a 2’ carbon of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, one L3is attached to a 2’ carbon of the double-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, one L3is attached to a 2’ carbon of the double-stranded oligonucleotide at the 3’end of its sense strand. In embodiments, one L3is attached to a 2’ carbon of the double-stranded oligonucleotide at eitherof its 5’ ends. In embodiments, one L3is attached to a 2’ carbon of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, one L3is attached to a 2’ carbon of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0305] In embodiments, one L3is attached to a nucleobase of the double-stranded oligonucleotide. In embodiments, one L3is attached to a a nucleobase of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, one L3is attached to a nucleobase of the double-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, one L3is attached to a nucleobase of the double-stranded oligonucleotide at the 3’end of its sense strand. In embodiments, one L3is attached to a nucleobase of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, one L3is attached to a nucleobase of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, one L3is attached to a nucleobase of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0306] In embodiments, one L3is attached to a 3’ carbon of the single-stranded oligonucleotide at the 3’ end. In embodiments, one L3is attached to a 3’ nitrogen of the single- stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at the 3’ end of the single-stranded oligonucleotide.

[0307] In embodiments, one L3is attached to a 5’ carbon of the single-stranded oligonucleotide at the 5’ end.

[0308] In embodiments, one L3is attached to a 6’ carbon of the single-stranded oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at the 5’ end.

[0309] In embodiments, one L3is attached to a 2’ carbon of the single-stranded oligonucleotide. In embodiments, one L3is attached to a 2’ carbon of the single-stranded oligonucleotide at the 5’ end. In embodiments, one L3is attached to a 2’ carbon of the single- stranded oligonucleotide at the 3’ end.

[0310] In embodiments, one L3is attached to a nucleobase of the single-stranded oligonucleotide. In embodiments, one L3is attached to a nucleobase of the single-stranded oligonucleotide at the of 3’ end. In embodiments, one L3is attached to a nucleobase of the single-stranded oligonucleotide at the 5’ end.

[0311] In embodiments, L3is a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)- , -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, - O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, - P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0312] In embodiments, L3is a bond. In embodiments, L3is -N(R23)-. In embodiments, L3is -O- or -S-. In embodiments, L3is -C(O)-. In embodiments, L3is -N(R23)C(O)- or - C(O)N(R24)-. In embodiments, L3is -N(R23)C(O)N(R24)-. In embodiments, L3is -C(O)O- or -OC(O)-. In embodiments, L3is -N(R23)C(O)O- or -OC(O)N(R24)-. In embodiments, L3is -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(O)(NR23R24)-N-, or O- P(O)(NR23R24)-O-. In embodiments, L3is -P(O)(NR23R24)-N-,-P(S)(NR23R24)-N-, - P(O)(NR23R24)-O- or -P(S)(NR23R24)-O-. In embodiments, L3is -S-S-.

[0313] In embodiments, L3is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3is independently substituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3is independently substituted or unsubstituted C1-C23 alkylene. In embodiments, L3is independently substituted C1-C23alkylene. In embodiments, L3is independently unsubstituted C1-C23 alkylene. In embodiments, L3is independently substituted or unsubstituted C1-C12alkylene. In embodiments, L3is independently substituted C1-C12alkylene. In embodiments, L3is independently unsubstituted C1-C12 alkylene. In embodiments, L3is independently substituted or unsubstituted C1-C8alkylene. In embodiments, L3is independently substituted C1-C8alkylene. In embodiments, L3is independently unsubstituted C1-C8alkylene. In embodiments, L3is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L3is independently substituted C1-C6alkylene. In embodiments, L3is independently unsubstituted C1-C6 alkylene. In embodiments, L3is independently substituted or unsubstituted C1-C4alkylene. In embodiments, L3is independently substituted C1-C4alkylene. In embodiments, L3is independently unsubstituted C1-C4 alkylene. In embodiments, L3is independently substituted or unsubstituted ethylene. In embodiments, L3is independentlysubstituted ethylene. In embodiments, L3is independently unsubstituted ethylene. In embodiments, L3is independently substituted or unsubstituted methylene. In embodiments, L3is independently substituted methylene. In embodiments, L3is independently unsubstituted methylene.

[0314] In embodiments, L3is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L3is independently substituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L3is independently unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L3is independently substituted or unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L3is independently substituted 2 to 23 membered heteroalkylene. In embodiments, L3is independently unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L3is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L3is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L3is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L3is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L3is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L3is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L3is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L3is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L3is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L3is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L3is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L3is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L3is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L3is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L3is independently unsubstituted 4 to 5 membered heteroalkylene.

[0315] In embodiments, L4is a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, -C(O)N(R24)- , -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O-P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, - P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0316] In embodiments, L4is a bond. In embodiments, L4is -N(R23)-. In embodiments, L4is -O- or -S-. In embodiments, L4is -C(O)-. In embodiments, L4is -N(R23)C(O)- or - C(O)N(R24)-. In embodiments, L4is -N(R23)C(O)N(R24)-. In embodiments, L4is -C(O)O- or -OC(O)-. In embodiments, L4is -N(R23)C(O)O- or -OC(O)N(R24)-. In embodiments, L4is -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(O)(NR23R24)-N-, or O- P(O)(NR23R24)-O-. In embodiments, L4is -P(O)(NR23R24)-N-,-P(S)(NR23R24)-N-, - P(O)(NR23R24)-O- or -P(S)(NR23R24)-O-. In embodiments, L4is -S-S-.

[0317] In embodiments, L4is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4is independently substituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4is independently substituted or unsubstituted C1-C23alkylene. In embodiments, L4is independently substituted C1-C23 alkylene. In embodiments, L4is independently unsubstituted C1-C23alkylene. In embodiments, L4is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L4is independently substituted C1-C12 alkylene. In embodiments, L4is independently unsubstituted C1-C12alkylene. In embodiments, L4is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L4is independently substituted C1-C8alkylene. In embodiments, L4is independently unsubstituted C1-C8alkylene. In embodiments, L4is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L4is independently substituted C1-C6alkylene. In embodiments, L4is independently unsubstituted C1-C6alkylene. In embodiments, L4is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L4is independently substituted C1-C4 alkylene. In embodiments, L4is independently unsubstituted C1-C4alkylene. In embodiments, L4is independently substituted or unsubstituted ethylene. In embodiments, L4is independently substituted ethylene. In embodiments, L4is independently unsubstituted ethylene. In embodiments, L4is independently substituted or unsubstituted methylene. In embodiments, L4isindependently substituted methylene. In embodiments, L4is independently unsubstituted methylene.

[0318] In embodiments, L4is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L4is independently substituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L4is independently unsubstituted heteroalkylene (e.g., 2 to 23 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L4is independently substituted or unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L4is independently substituted 2 to 23 membered heteroalkylene. In embodiments, L4is independently unsubstituted 2 to 23 membered heteroalkylene. In embodiments, L4is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L4is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L4is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L4is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L4is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L4is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L4is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L4is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L4is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L4is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L4is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L4is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L4is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L4is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L4is independently unsubstituted 4 to 5 membered heteroalkylene.

[0319] R23is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R23is independently hydrogen. In embodiments, R23is independently unsubstituted C1-C23alkyl. In embodiments, R23is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R23is independently hydrogen or unsubstituted C1- C10alkyl. In embodiments, R23is independently hydrogen or unsubstituted C1-C8alkyl. Inembodiments, R23is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R23is independently hydrogen or unsubstituted C1-C4alkyl. In embodiments, R23is independently hydrogen or unsubstituted C1-C2 alkyl.

[0320] R24is independently hydrogen or unsubstituted alkyl (e.g., C1-C24, C1-C12, C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R24is independently hydrogen. In embodiments, R24is independently unsubstituted C1-C24 alkyl. In embodiments, R24is independently hydrogen or unsubstituted C1-C12alkyl. In embodiments, R24is independently hydrogen or unsubstituted C1- C10 alkyl. In embodiments, R24is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R24is independently hydrogen or unsubstituted C1-C6alkyl. In embodiments, R24is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R24is independently hydrogen or unsubstituted C1-C2 alkyl.

[0321] R25is independently hydrogen or unsubstituted alkyl (e.g., C1-C25, C1-C12, C1-C8, C1- C6, C1-C4, or C1-C2). In embodiments, R25is independently hydrogen. In embodiments, R25is independently unsubstituted C1-C25 alkyl. In embodiments, R25is independently hydrogen or unsubstituted C1-C12alkyl. In embodiments, R25is independently hydrogen or unsubstituted C1- C10 alkyl. In embodiments, R25is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R25is independently hydrogen or unsubstituted C1-C6alkyl. In embodiments, R25is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R25is independently hydrogen or unsubstituted C1-C2alkyl.

[0322] In embodiments, L3and L4are independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O- P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O- P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, - P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L3is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O- P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O- P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, - P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L4is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O- P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, - P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

[0323] In embodiments, L3is independently . In embodiments, L3is independently -OPO2-O-. In embodiments, L3is independently -O-P(O)(S)-O-. In embodiments, L3is independently -O-. In embodiments, L3is independently –S-.

[0324] In embodiments, L3is attached to the 3’nitrogen of a morpholino moiety. In embodiments, L3is independently –C(O)-. In embodiments, L3is attached to the 6’ carbon of a morpholino moiety. In embodiments, L3is independently -O-P(O)(N(CH3)2)-N-. In embodiments, L3is independently -O-P(O)(N(CH3)2)-O-. In embodiments, L3is independently - P(O)(N(CH3)2)-N-. In embodiments, L3is independently -P(O)(N(CH3)2)-O-.

[0325] In embodiments, L4is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-. In embodiments, L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0326] In embodiments, L4is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L4is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L4is independently oxo-substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L4is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).

[0327] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, orC1-C2). In embodiments, L4is independently –L7-NH-C(O)-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4is independently –L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0328] In embodiments, L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7is independently substituted or unsubstituted C1-C20alkylene. In embodiments, L7is independently substituted C1-C20 alkylene. In embodiments, L7is independently hydroxy(OH)-substituted C1-C20alkylene. In embodiments, L7is independently hydroxymethyl- substituted C1-C20 alkylene. In embodiments, L7is independently unsubstituted C1-C20 alkylene. In embodiments, L7is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L7is independently substituted C1-C12 alkylene. In embodiments, L7is independently hydroxy(OH)-substituted C1-C12 alkylene. In embodiments, L7is independently hydroxymethyl-substituted C1-C12 alkylene. In embodiments, L7is independently unsubstituted C1-C12 alkylene. In embodiments, L7is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L7is independently substituted C1-C8alkylene. In embodiments, L7is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L7is independently hydroxymethyl-substituted C1-C8alkylene. In embodiments, L7is independently unsubstituted C1-C8 alkylene. In embodiments, L7is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L7is independently substituted C1-C6alkylene. In embodiments, L7is independently hydroxy(OH)-substituted C1-C6 alkylene. In embodiments, L7is independently hydroxymethyl-substituted C1-C6 alkylene. In embodiments, L7is independently unsubstituted C1-C6 alkylene. In embodiments, L7is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L7is independently substituted C1-C4 alkylene. In embodiments, L7is independently hydroxy(OH)-substituted C1-C4alkylene. In embodiments, L7is independently hydroxymethyl-substituted C1-C4 alkylene. In embodiments, L7is independently unsubstituted C1-C4alkylene. In embodiments, L7is independently substituted or unsubstituted C1-C2alkylene. In embodiments, L7is independently substituted C1-C2 alkylene. In embodiments, L7is independently hydroxy(OH)-substituted C1-C2alkylene. In embodiments, L7is independentlyhydroxymethyl-substituted C1-C2 alkylene. In embodiments, L7is independently unsubstituted C1-C2alkylene.

[0329] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted C1-C8alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C1-C8alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently unsubstituted C1-C8 alkylene.

[0330] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted C3-C8alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted C3-C8 alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C3-C8alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C3-C8 alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently unsubstituted C3-C8 alkylene.

[0331] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted C5-C8alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted C5-C8 alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C5-C8alkylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently unsubstituted C5-C8alkylene.

[0332] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted octylene. In embodiments, L4is independently –L7- NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted octylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxy(OH)- substituted octylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently unsubstituted octylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently hydroxy(OH)-substituted octylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently hydroxymethyl-substituted octylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently unsubstituted octylene.

[0333] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted heptylene. In embodiments, L4is independently –L7- NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted heptylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxy(OH)- substituted heptylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently unsubstituted heptylene. In embodiments, L4is independently –L7-NH- C(O)- and L7is independently hydroxy(OH)-substituted heptylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently hydroxymethyl-substituted heptylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently unsubstituted heptylene.

[0334] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted hexylene. In embodiments, L4is independently –L7- NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted hexylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxy(OH)- substituted hexylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently unsubstituted hexylene. In embodiments, L4is independently –L7-NH- C(O)- and L7is independently hydroxy(OH)-substituted hexylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently hydroxymethyl-substituted hexylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently unsubstituted hexylene.

[0335] In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted or unsubstituted pentylene. In embodiments, L4is independently –L7- NH-C(O)- or –L7-C(O)-NH-; and L7is independently substituted pentylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently hydroxy(OH)- substituted pentylene. In embodiments, L4is independently –L7-NH-C(O)- or –L7-C(O)-NH-; and L7is independently unsubstituted pentylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently hydroxy(OH)-substituted pentylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently hydroxymethyl-substituted pentylene. In embodiments, L4is independently –L7-NH-C(O)- and L7is independently unsubstituted pentylene.

[0336] In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently .

[0337] In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently . In embodiments, L4is independently .

[0338] In embodiments, –L3-L4- is independently –L7-NH-C(O)- or –L7-C(O)-NH-. In embodiments, L7is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7is independently oxo-substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7is independently substituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7is independently oxo- substituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered). In embodiments, L7is independently unsubstituted heteroalkenylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 10 membered, 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered).

[0339] In embodiments, L7is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L7is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L7is independently oxo-substituted 2 to 20 membered heteroalkylene. In embodiments, L7is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L7is independently substituted or unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L7is independently substituted 2 to 12 membered heteroalkylene. In embodiments, L7is independently oxo-substituted 2 to 12 membered heteroalkylene. In embodiments, L7is independently unsubstituted 2 to 12 membered heteroalkylene. In embodiments, L7is independently substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L7is independently substituted 2 to 10 membered heteroalkylene. In embodiments, L7is independently oxo-substituted 2 to 10 membered heteroalkylene. In embodiments, L7is independently unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L7is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L7is independently substituted 2 to 8 memberedheteroalkylene. In embodiments, L7is independently oxo-substituted 2 to 8 membered heteroalkylene. In embodiments, L7is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L7is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L7is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L7is independently oxo-substituted 2 to 6 membered heteroalkylene. In embodiments, L7is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L7is independently substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L7is independently substituted 2 to 4 membered heteroalkylene. In embodiments, L7is independently oxo-substituted 2 to 4 membered heteroalkylene. In embodiments, L7is independently unsubstituted 2 to 4 membered heteroalkylene.

[0340] In embodiments, L7is independently substituted or unsubstituted 2 to 20 membered heteroalkenylene. In embodiments, L7is independently substituted 2 to 20 membered heteroalkenylene. In embodiments, L7is independently oxo-substituted 2 to 20 membered heteroalkenylene. In embodiments, L7is independently unsubstituted 2 to 20 membered heteroalkenylene. In embodiments, L7is independently substituted or unsubstituted 2 to 12 membered heteroalkenylene. In embodiments, L7is independently substituted 2 to 12 membered heteroalkenylene. In embodiments, L7is independently oxo-substituted 2 to 12 membered heteroalkenylene. In embodiments, L7is independently unsubstituted 2 to 12 membered heteroalkenylene. In embodiments, L7is independently substituted or unsubstituted 2 to 10 membered heteroalkenylene. In embodiments, L7is independently substituted 2 to 10 membered heteroalkenylene. In embodiments, L7is independently oxo-substituted 2 to 10 membered heteroalkenylene. In embodiments, L7is independently unsubstituted 2 to 10 membered heteroalkenylene. In embodiments, L7is independently substituted or unsubstituted 2 to 8 membered heteroalkenylene. In embodiments, L7is independently substituted 2 to 8 membered heteroalkenylene. In embodiments, L7is independently oxo-substituted 2 to 8 membered heteroalkenylene. In embodiments, L7is independently unsubstituted 2 to 8 membered heteroalkenylene. In embodiments, L7is independently substituted or unsubstituted 2 to 6 membered heteroalkenylene. In embodiments, L7is independently substituted 2 to 6 membered heteroalkenylene. In embodiments, L7is independently oxo-substituted 2 to 6 membered heteroalkenylene. In embodiments, L7is independently unsubstituted 2 to 6 membered heteroalkenylene. In embodiments, L7is independently substituted or unsubstituted 2 to 4membered heteroalkenylene. In embodiments, L7is independently substituted 2 to 4 membered heteroalkenylene. In embodiments, L7is independently oxo-substituted 2 to 4 membered heteroalkenylene. In embodiments, L7is independently unsubstituted 2 to 4 membered heteroalkenylene.

[0341] In embodiments, –L3-L4- is independently –O-L7-NH-C(O)- or –O-L7-C(O)-NH-. In embodiments, L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1- C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- is independently –O-L7-NH-C(O)- or –O- L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- is independently –O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- is independently–O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0342] In embodiments, –L3-L4- is independently–O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, –L3-L4- is independently–O-L7- C(O)-NH-; and L7is independently substituted C1-C8alkylene. In embodiments, –L3-L4- is independently–O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently–O-L7-C(O)- NH-and L7is independently hydroxymethyl-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently–O-L7- C(O)-NH-; and L7is independently unsubstituted C1-C8 alkylene.

[0343] In embodiments, –L3-L4- is independently–O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C3-C8alkylene. In embodiments, –L3-L4- is independently–O-L7- C(O)-NH-; and L7is independently substituted C3-C8 alkylene. In embodiments, –L3-L4- is independently–O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently–O-L7-C(O)-NH- and L7is independently hydroxymethyl-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently–O-L7- C(O)-NH-; and L7is independently unsubstituted C3-C8 alkylene.

[0344] In embodiments, –L3-L4- is independently–O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C5-C8alkylene. In embodiments, –L3-L4- is independently–O-L7- C(O)-NH-; and L7is independently substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently–O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C5-C8alkylene. In embodiments, –L3-L4- is independently–O-L7-C(O)-NH- and L7is independently hydroxymethyl-substituted C5-C8alkylene. In embodiments, –L3-L4- is independently–O-L7- C(O)-NH-; and L7is independently unsubstituted C5-C8 alkylene.

[0345] In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C1-C8alkylene. In embodiments, –L3-L4- is independently -O-L7- NH-C(O)-; and L7is independently substituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -O-L7- NH-C(O)-; and L7is independently unsubstituted C1-C8 alkylene.

[0346] In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C3-C8alkylene. In embodiments, –L3-L4- is independently -O-L7- NH-C(O)-; and L7is independently substituted C3-C8 alkylene. In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -O-L7- NH-C(O)-; and L7is independently unsubstituted C3-C8alkylene.

[0347] In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -O-L7- NH-C(O)-; and L7is independently substituted C5-C8alkylene. In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -O-L7- NH-C(O)-; and L7is independently unsubstituted C5-C8alkylene. ime3nts, –L -L4- is independently . In embodiments, –L3-L4- is independently . In embodiments, –L3-L4- is independently .

[0349] In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-, -OP(O)(S)-O-L7- NH-C(O)-, -OPO2-O-L7-C(O)-NH-or –OP(O)(S)-O-L7-C(O)-NH-. In embodiments, L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)- or -OP(O)(S)-O-L7- NH-C(O)-; and L7is independently substituted or unsubstituted alkylene. In embodiments, –L3- L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted alkylene. In embodiments, –L3-L4- is independently –OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH- or –OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7- C(O)-NH-; and L7is independently substituted or unsubstituted alkylene. In embodiments, –L3- L4- is independently –OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene.

[0350] In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)- or -OPO2-O-L7- C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- is independently -OPO2-O-L7-NH- C(O)-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1- C4, or C1-C2).

[0351] In embodiments, –L3-L4- is independently –OP(O)(S)-O-L7-NH-C(O)- or -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- isindependently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0352] In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C1- C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently unsubstituted C1-C8alkylene.

[0353] In embodiments, –L3-L4- is independently –OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently unsubstituted C1-C8 alkylene.

[0354] In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently substituted C3-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C3- C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently unsubstituted C3-C8 alkylene.

[0355] In embodiments, –L3-L4- is independently –OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted C3-C8 alkylene.In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently unsubstituted C3-C8 alkylene.

[0356] In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C5-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C5- C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-C(O)-NH-; and L7is independently unsubstituted C5-C8 alkylene.

[0357] In embodiments, –L3-L4- is independently –OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently substituted C5-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-; and L7is independently unsubstituted C5-C8alkylene.

[0358] In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C1-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C1- C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently unsubstituted C1-C8 alkylene.

[0359] In embodiments, –L3-L4- is independently –OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C1-C8alkylene. In embodiments, –L3-L4- isindependently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)2-O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently unsubstituted C1-C8alkylene.

[0360] In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C3- C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently unsubstituted C3-C8 alkylene.

[0361] In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C3-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently unsubstituted C3-C8 alkylene.

[0362] In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C5-C8alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C5- C8 alkylene. In embodiments, –L3-L4- is independently -OPO2-O-L7-NH-C(O)-; and L7is independently unsubstituted C5-C8 alkylene.

[0363] In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted or unsubstituted C5-C8alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, –L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-; and L7is independently unsubstituted C5-C8alkylene.

[0364] In embodiments, -L3-L4- is attached to a 3’ carbon of the oligonucleotide. In embodiments, -L3-L4- is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, -L3-L4- is attached to a 5’ carbon of the oligonucleotide. In embodiments, -L3-L4- is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, -L3-L4- is attached to a 2’ carbon of the oligonucleotide. In embodiments, -L3-L4- is attached to a nucleobase of the oligonucleotide.

[0365] In embodiments, at least -L3-L4- is attached to a 3’ carbon of the oligonucleotide at a 3’ end. In embodiments, at least -L3-L4- is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at a 3’ end. In embodiments, at least -L3-L4- is attached to a 5’ carbon of the oligonucleotide at a 5’ end. In embodiments, at least -L3-L4- is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety) at a 5’ end.

[0366] In embodiments, –L3-L4- is independently , , , , , , ,, , , , or .

[0367] In embodiments, –L3-L4- is independently , , or , . In embodiments, –L3-L4- is independently , or . In embodiments, –L3-L4- is independently ,or . In embodiments, –L3-L4- is independently or . In embodiments, –L3-L4- is independently , or .

[0368] In embodiments, –L3-L4- is independently , , , or , and is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independently or that is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independently , orthat is attached to a 3’ carbon of the oligonucleotide.

[0369] In embodiments, –L3-L4- is independently ,or ,and is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L3-L4- is independently attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L3-L4- is independently that is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety).

[0370] In embodiments, an –L3-L4- is independently , , , or and is attached to a 5’ carbon of the oligonucleotide. In embodiments, an –L3-L4- is independently or that is attached to a 5’ carbon of the oligonucleotide. Inembodiments, an –L3-L4- is independently or that is attached to a 5’ carbon of the oligonucleotide.

[0371] In embodiments where the oligonucleotide includes a morpholino moiety, L3is independently -P(O)(N(CH3)2)-N- or -P(O)(N(CH3)2)-O-. In embodiments, L4is substituted or unsubstituted heterocycloalkyl. In embodiments, L4is substituted heterocycloalkyl. In embodiments, L4is unsubstituted heterocycloalkyl. In embodiments, L4is substituted or unsubstituted piperidinylene. In embodiments, L4is substituted piperidinylene. In embodiments, L4is unsubstituted piperidinylene. In embodiments, L4is substituted or unsubstituted piperazinylene. In embodiments, L4is substituted piperazinylene. In embodiments, L4is unsubstituted piperazinylene. In embodiments, an –L3-L4- is independently or is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, an –L3-L4- is independently that is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, an –L3-L4- is independently that is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety).

[0372] In embodiments, an –L3-L4- is independently is attached to a nucleobase of the oligonucleotide. In embodiments, an –L3-L4- is independently and is attached to a nucleobase of the oligonucleotide.

[0373] In embodiments, -L3-L4- is attached to a 3’ carbon of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, -L3-L4- is attached to a 3’ carbon of thedouble-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, -L3-L4- is attached to a 3’ carbon of the double-stranded oligonucleotide at the 3’end of its sense strand

[0374] In embodiments, -L3-L4- is attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at either of its 3’ ends. In embodiments, -L3-L4- is attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety) at the 3’end of its antisense strand. In embodiments, - L3-L4- is attached to a 3’ nitrogen of the double-stranded oligonucleotide (e.g., PMO) at the 3’end of its sense strand.

[0375] In embodiments, -L3-L4- is attached to a 5’ carbon of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, -L3-L4- is attached to a 5’ carbon of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, -L3-L4- is attached to a 5’ carbon of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0376] In embodiments, -L3-L4- is attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of the morpholino moiety) at either of its 5’ ends. In embodiments, -L3-L4- is attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of the morpholino moiety) at the 5’ end of its antisense strand. In embodiments, -L3- L4- is attached to a 6’ carbon of the double-stranded oligonucleotide (e.g., the 6’ carbon of the morpholino moiety) at the 5’ end of its sense strand.

[0377] In embodiments, -L3-L4- is attached to a 2’ carbon of the double-stranded oligonucleotide. In embodiments, -L3-L4- is attached to a 2’ carbon of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, -L3-L4- is attached to a 2’ carbon of the double-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, -L3-L4- is attached to a 2’ carbon of the double-stranded oligonucleotide at the 3’end of its sense strand. In embodiments, -L3-L4- is attached to a 2’ carbon of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, -L3-L4- is attached to a 2’ carbon of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, -L3-L4- is attached to a 2’ carbon of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0378] In embodiments, -L3-L4- is attached to a nucleobase of the double-stranded oligonucleotide. In embodiments, -L3-L4- is attached to a nucleobase of the double-stranded oligonucleotide at either of its 3’ ends. In embodiments, -L3-L4- is attached to a nucleobase of the double-stranded oligonucleotide at the 3’end of its antisense strand. In embodiments, -L3-L4-is attached to a nucleobase of the double-stranded oligonucleotide at the 3’end of its sense strand. In embodiments, -L3-L4- is attached to a nucleobase of the double-stranded oligonucleotide at either of its 5’ ends. In embodiments, -L3-L4- is attached to a nucleobase of the double-stranded oligonucleotide at the 5’ end of its antisense strand. In embodiments, -L3- L4- is attached to a nucleobase of the double-stranded oligonucleotide at the 5’ end of its sense strand.

[0379] In embodiments, -L3-L4- is attached to a 3’ carbon of the single-stranded oligonucleotide at the 3’ end.

[0380] In embodiments, -L3-L4- is attached to a 3’ nitrogen of the single-stranded oligonucleotide at the 3’ end(e.g., the 3’ nitrogen of a morpholino moiety).

[0381] In embodiments, -L3-L4- is attached to a 5’ carbon of the single-stranded oligonucleotide at the 5’ end of the single-stranded oligonucleotide.

[0382] In embodiments, -L3-L4- is attached to a 6’ carbon of the single-stranded oligonucleotide at its 5’ end (e.g., the 6’ carbon of a morpholino moiety). In embodiments, –L3- L4- is independently.

[0383] In embodiments, -L3-L4- is attached to a 2’ carbon of the single-stranded oligonucleotide. In embodiments, -L3-L4- is attached to a 2’ carbon of the single-stranded oligonucleotide at the 3’ end. In embodiments, -L3-L4- is attached to a 2’ carbon of the single- stranded oligonucleotide at the 5’ end.

[0384] In embodiments, -L3-L4- is attached to a nucleobase of the single-stranded oligonucleotide. In embodiments, -L3-L4- is attached to a nucleobase of the single-stranded oligonucleotide at its of 3’ end. In embodiments, -L3-L4- is attached to a nucleobase of the single-stranded oligonucleotide at its 5’ end.

[0385] In embodiments, –L3-L4- is independently, , , or .

[0386] In embodiments, –L3-L4- is independently or that is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independently or that is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L3-L4- is independently or that is attached to a 5’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independently or that is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, – L3-L4- is independently or that is attached to a 2’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlythat is attached to a nucleobase of the oligonucleotide.

[0387] In embodiments, –L3-L4- is independentlythat is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlythat is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L3-L4- is independentlythat is attached to a 5’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlythat is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety MO). In embodiments, –L3-L4- is independentlythat is attached to a 2’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlythat is attached to a nucleobase of the oligonucleotide.

[0388] In embodiments, –L3-L4- is independentlythat is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlythat is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L3-L4- is independentlyand is attached to a 5’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlythat is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, – L3-L4- is independentlyand is attached to a 2’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlyand is attached to a nucleobase of the oligonucleotide.

[0389] In embodiments, –L3-L4- is independentlythat is attached to a 3’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlythat is attached to a 3’ nitrogen of the oligonucleotide (e.g., the 3’ nitrogen of a morpholino moiety). In embodiments, –L3-L4- is independentlythat is attached to a 5’ carbon of the oligonucleotide.In embodiments, –L3-L4- is independentlythat is attached to a 6’ carbon of the oligonucleotide (e.g., the 6’ carbon of a morpholino moiety). In embodiments, –L3-L4- is independentlythat is attached to a 2’ carbon of the oligonucleotide. In embodiments, –L3-L4- is independentlyand is attached to a nucleobase of the oligonucleotide.

[0390] In embodiments, R3is independently hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O) OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3is independently hydrogen. In embodiments, R3is independently -NH2. In embodiments, R3is independently –OH. In embodiments, R3is independently –SH. In embodiments, R3is independently -C(O)H. In embodiments, R3is independently -C(O)NH2. In embodiments, R3is independently -NHC(O)H. In embodiments, R3is independently -NHC(O)OH. In embodiments, R3is independently -NHC(O)NH2. In embodiments, R3is independently -C(O)OH. In embodiments, R3is independently -OC(O)H. In embodiments, R3is independently –N3.

[0391] In embodiments, R3is independently substituted or unsubstituted alkyl (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R3is independently substituted or unsubstituted C1-C20 alkyl. In embodiments, R3is independently substituted C1-C20 alkyl. In embodiments, R3is independently unsubstituted C1-C20alkyl. In embodiments, R3is independently substituted or unsubstituted C1-C12 alkyl. In embodiments, R3is independently substituted C1-C12alkyl. In embodiments, R3is independently unsubstituted C1-C12alkyl. In embodiments, R3is independently substituted or unsubstituted C1-C8 alkyl. In embodiments, R3is independently substituted C1-C8alkyl. In embodiments, R3is independently unsubstituted C1- C8 alkyl. In embodiments, R3is independently substituted or unsubstituted C1-C6 alkyl. Inembodiments, R3is independently substituted C1-C6 alkyl. In embodiments, R3is independently unsubstituted C1-C6alkyl. In embodiments, R3is independently substituted or unsubstituted C1- C4 alkyl. In embodiments, R3is independently substituted C1-C4 alkyl. In embodiments, R3is independently unsubstituted C1-C4alkyl. In embodiments, R3is independently substituted or unsubstituted ethyl. In embodiments, R3is independently substituted ethyl. In embodiments, R3is independently unsubstituted ethyl. In embodiments, R3is independently substituted or unsubstituted methyl. In embodiments, R3is independently substituted methyl. In embodiments, R3is independently unsubstituted methyl.

[0392] In embodiments, L6is independently -NHC(O)-. In embodiments, L6is independently –C(O)NH-. In embodiments, L6is independently substituted or unsubstituted alkylene. In embodiments, L6is independently substituted or unsubstituted heteroalkylene.

[0393] In embodiments, L6is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6is independently substituted or unsubstituted C1-C20alkylene. In embodiments, L6is independently substituted C1-C20alkylene. In embodiments, L6is independently unsubstituted C1-C20 alkylene. In embodiments, L6is independently substituted or unsubstituted C1-C12alkylene. In embodiments, L6is independently substituted C1-C12alkylene. In embodiments, L6is independently unsubstituted C1-C12 alkylene. In embodiments, L6is independently substituted or unsubstituted C1-C8alkylene. In embodiments, L6is independently substituted C1-C8 alkylene. In embodiments, L6is independently unsubstituted C1-C8 alkylene. In embodiments, L6is independently substituted or unsubstituted C1-C6alkylene. In embodiments, L6is independently substituted C1-C6 alkylene. In embodiments, L6is independently unsubstituted C1-C6alkylene. In embodiments, L6is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L6is independently substituted C1-C4 alkylene. In embodiments, L6is independently unsubstituted C1-C4 alkylene. In embodiments, L6is independently substituted or unsubstituted ethylene. In embodiments, L6is independently substituted ethylene. In embodiments, L6is independently unsubstituted ethylene. In embodiments, L6is independently substituted or unsubstituted methylene. In embodiments, L6is independently substituted methylene. In embodiments, L6is independently unsubstituted methylene.

[0394] In embodiments, L6is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L6is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L6is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L6is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L6is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L6is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L6is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L6is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L6is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L6is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L6is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L6is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L6is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L6is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L6is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L6is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L6is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L6is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L6is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L6is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L6is independently unsubstituted 4 to 5 membered heteroalkylene.

[0395] In embodiments, L6Ais independently a bond or unsubstituted alkylene; L6Bis independently a bond, -NHC(O)-, or unsubstituted arylene; L6Cis independently a bond, unsubstituted alkylene, or unsubstituted arylene; L6Dis independently a bond or unsubstituted alkylene; and L6Eis independently a bond or -NHC(O)-. In embodiments, L6Ais independently a bond or unsubstituted alkylene. In embodiments, L6Bis independently a bond, -NHC(O)-, or unsubstituted arylene. In embodiments, L6Cis independently a bond, unsubstituted alkylene, orunsubstituted arylene. In embodiments, L6Dis independently a bond or unsubstituted alkylene. In embodiments, L6Eis independently a bond or -NHC(O)-.

[0396] In embodiments, L6Ais independently a bond or unsubstituted alkylene (e.g., C1-C20, C1- C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6Ais independently unsubstituted C1-C20 alkylene. In embodiments, L6Ais independently unsubstituted C1-C12alkylene. In embodiments, L6Ais independently unsubstituted C1-C8 alkylene. In embodiments, L6Ais independently unsubstituted C1-C6alkylene. In embodiments, L6Ais independently unsubstituted C1-C4alkylene. In embodiments, L6Ais independently unsubstituted ethylene. In embodiments, L6Ais independently unsubstituted methylene. In embodiments, L6Ais independently a bond.

[0397] In embodiments, L6Bis independently a bond. In embodiments, L6Bis independently -NHC(O)-. In embodiments, L6Bis independently unsubstituted arylene (e.g., C6- C12, C6-C10, or phenyl). In embodiments, L6Bis independently unsubstituted C6-C12arylene. In embodiments, L6Bis independently unsubstituted C6-C10 arylene. In embodiments, L6Bis independently unsubstituted phenylene. In embodiments, L6Bis independently unsubstituted naphthylene. In embodiments, L6Bis independently unsubstituted biphenylene.

[0398] In embodiments, L6Cis independently a bond or unsubstituted alkylene (e.g., C1-C20, C1- C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6Cis independently unsubstituted C1-C20alkylene. In embodiments, L6Cis independently unsubstituted C1-C12 alkylene. In embodiments, L6Cis independently unsubstituted C1-C8 alkylene. L6Cis independently unsubstituted C2-C8 alkynylene. In embodiments, L6Cis independently unsubstituted C1-C6alkylene. In embodiments, L6Cis independently unsubstituted C1-C4 alkylene. In embodiments, L6Cis independently unsubstituted ethylene. In embodiments, L6Cis independently unsubstituted methylene. In embodiments, L6Cis independently a bond or unsubstituted alkynylene (e.g., C2- C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L6Cis independently unsubstituted C2-C20 alkynylene. In embodiments, L6Cis independently unsubstituted C2-C12 alkynylene. In embodiments, L6Cis independently unsubstituted C2-C8alkynylene. In embodiments, L6Cis independently unsubstituted C2-C6 alkynylene. In embodiments, L6Cis independently unsubstituted C2-C4alkynylene. In embodiments, L6Cis independently unsubstituted ethynylene. In embodiments, L6Cis independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L6Cis independently unsubstituted C6-C12 arylene. In embodiments, L6Cis independently unsubstituted C6-C10 arylene. In embodiments, L6Cis independently unsubstitutedphenylene. In embodiments, L6Cis independently unsubstituted naphthylene. In embodiments, L6Cis independently a bond.

[0399] In embodiments, L6Dis independently a bond or unsubstituted alkylene (e.g., C1-C20, C1- C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6Dis independently unsubstituted C1-C20 alkylene. In embodiments, L6Dis independently unsubstituted C1-C12alkylene. In embodiments, L6Ais independently unsubstituted C1-C8 alkylene. In embodiments, L6Dis independently unsubstituted C1-C6alkylene. In embodiments, L6Dis independently unsubstituted C1-C4alkylene. In embodiments, L6Dis independently unsubstituted ethylene. In embodiments, L6Dis independently unsubstituted methylene. In embodiments, L6Dis independently a bond.

[0400] In embodiments, L6Eis independently a bond. In embodiments, L6Eis independently -NHC(O)-.

[0401] In embodiments, L6Ais independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L6Bis independently a bond, -NHC(O)-, or unsubstituted phenylene. In embodiments, L6Cis independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene. In embodiments, L6Dis independently a bond or unsubstituted C1-C8alkylene. In embodiments, L6Eis independently a bond or -NHC(O)-.

[0402] In embodiments, L6is independently a bond,,. In embodiments, L6is independently . In embodiments, L6is independently . In embodiments, L6is independently .

[0403] In embodiments, L5is independently -NHC(O)-. In embodiments, L5is independently –C(O)NH-. In embodiments, L5is independently substituted or unsubstituted alkylene. In embodiments, L5is independently substituted or unsubstituted heteroalkylene.

[0404] In embodiments, L5is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5is independently substituted or unsubstituted C1-C20alkylene. In embodiments, L5is independently substituted C1-C20 alkylene. In embodiments, L5is independently unsubstituted C1-C20alkylene. In embodiments, L5is independently substituted or unsubstituted C1-C12alkylene. In embodiments, L5is independently substituted C1-C12alkylene. In embodiments, L5is independently unsubstituted C1-C12 alkylene. In embodiments, L5is independently substituted or unsubstituted C1-C8alkylene. In embodiments, L5is independently substituted C1-C8 alkylene. In embodiments, L5is independently unsubstituted C1-C8 alkylene. In embodiments, L5is independently substituted or unsubstituted C1-C6alkylene. In embodiments, L5is independently substituted C1-C6 alkylene. In embodiments, L5is independently unsubstituted C1-C6alkylene. In embodiments, L5is independently substituted orunsubstituted C1-C4 alkylene. In embodiments, L5is independently substituted C1-C4 alkylene. In embodiments, L5is independently unsubstituted C1-C4alkylene. In embodiments, L5is independently substituted or unsubstituted ethylene. In embodiments, L5is independently substituted ethylene. In embodiments, L5is independently unsubstituted ethylene. In embodiments, L5is independently substituted or unsubstituted methylene. In embodiments, L5is independently substituted methylene. In embodiments, L5is independently unsubstituted methylene.

[0405] In embodiments, L5is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L5is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L5is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L5is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L5is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L5is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L5is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L5is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L5is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L5is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L5is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L5is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L5is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L5is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L5is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L5is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L5is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L5is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L5is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L5is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L5is independently unsubstituted 4 to 5 membered heteroalkylene.

[0406] In embodiments, L5Ais independently a bond or unsubstituted alkylene; L5Bis independently a bond, -NHC(O)-, or unsubstituted arylene; L5Cis independently a bond, unsubstituted alkylene, or unsubstituted arylene; L5Dis independently a bond or unsubstituted alkylene; and L5Eis independently a bond or -NHC(O)-. In embodiments, L5Ais independently a bond or unsubstituted alkylene. In embodiments, L5Bis independently a bond, -NHC(O)-, or unsubstituted arylene. In embodiments, L5Cis independently a bond, unsubstituted alkylene, or unsubstituted arylene. In embodiments, L5Dis independently a bond or unsubstituted alkylene. In embodiments, L5Eis independently a bond or -NHC(O)-.

[0407] In embodiments, L5Ais independently a bond or unsubstituted alkylene (e.g., C1-C20, C1- C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5Ais independently unsubstituted C1-C20 alkylene. In embodiments, L5Ais independently unsubstituted C1-C12alkylene. In embodiments, L5Ais independently unsubstituted C1-C8 alkylene. In embodiments, L5Ais independently unsubstituted C1-C6 alkylene. In embodiments, L5Ais independently unsubstituted C1-C4 alkylene. In embodiments, L5Ais independently unsubstituted ethylene. In embodiments, L5Ais independently unsubstituted methylene. In embodiments, L5Ais independently a bond.

[0408] In embodiments, L5Bis independently a bond. In embodiments, L5Bis independently -NHC(O)-. In embodiments, L5Bis independently unsubstituted arylene (e.g., C6- C12, C6-C10, or phenyl). In embodiments, L5Bis independently unsubstituted C6-C12 arylene. In embodiments, L5Bis independently unsubstituted C6-C10arylene. In embodiments, L5Bis independently unsubstituted phenylene. In embodiments, L5Bis independently unsubstituted naphthylene.

[0409] In embodiments, L5Cis independently a bond or unsubstituted alkylene (e.g., C1-C20, C1- C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5Cis independently unsubstituted C1-C20 alkylene. In embodiments, L5Cis independently unsubstituted C1-C12alkylene. In embodiments, L5Cis independently unsubstituted C1-C8 alkylene. L5Cis independently unsubstituted C2-C8 alkynylene. In embodiments, L5Cis independently unsubstituted C1-C6alkylene. In embodiments, L5Cis independently unsubstituted C1-C4 alkylene. In embodiments, L5Cis independently unsubstituted ethylene. In embodiments, L5Cis independently unsubstituted methylene. In embodiments, L5Cis independently a bond or unsubstituted alkynylene (e.g., C2- C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L5Cis independently unsubstituted C2-C20 alkynylene. In embodiments, L5Cis independently unsubstituted C2-C12 alkynylene. In embodiments, L5Cis independently unsubstituted C2-C8 alkynylene. In embodiments, L5Cisindependently unsubstituted C2-C6 alkynylene. In embodiments, L5Cis independently unsubstituted C2-C4alkynylene. In embodiments, L5Cis independently unsubstituted ethynylene. In embodiments, L5Cis independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L5Cis independently unsubstituted C6-C12arylene. In embodiments, L5Cis independently unsubstituted C6-C10 arylene. In embodiments, L5Cis independently unsubstituted phenylene. In embodiments, L5Cis independently unsubstituted naphthylene. In embodiments, L5Cis independently a bond.

[0410] In embodiments, L5Dis independently a bond or unsubstituted alkylene (e.g., C1-C20, C1- C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5Dis independently unsubstituted C1-C20alkylene. In embodiments, L5Dis independently unsubstituted C1-C12 alkylene. In embodiments, L5Ais independently unsubstituted C1-C8alkylene. In embodiments, L5Dis independently unsubstituted C1-C6 alkylene. In embodiments, L5Dis independently unsubstituted C1-C4 alkylene. In embodiments, L5Dis independently unsubstituted ethylene. In embodiments, L5Dis independently unsubstituted methylene. In embodiments, L5Dis independently a bond.

[0411] In embodiments, L5Eis independently a bond. In embodiments, L5Eis independently -NHC(O)-.

[0412] In embodiments, L5Ais independently a bond or unsubstituted C1-C8alkylene. In embodiments, L5Bis independently a bond, -NHC(O)-, or unsubstituted phenylene. In embodiments, L5Cis independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene. In embodiments, L5Dis independently a bond or unsubstituted C1-C8alkylene. In embodiments, L5Eis independently a bond or -NHC(O)-.

[0413] In embodiments, L5is independently a bond, , , , , or . In embodiments, L5is independently a bond. In embodiments,L5is independently . In embodiments, L5is independently . In embodiments, L5is independently . In embodiments, L5is independently . In embodiments, L5is independently .

[0414] In embodiments, R1is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1is unsubstituted unbranched alkyl (e.g., C1-C25, C1- C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1is unsubstituted unbranched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0415] In embodiments, R1is unsubstituted C1-C17alkyl. In embodiments, R1is unsubstituted C11-C17 alkyl. In embodiments, R1is unsubstituted C13-C17 alkyl. In embodiments, R1is unsubstituted C14-C15alkyl. In embodiments, R1is unsubstituted C15alkyl. In embodiments, R1is unsubstituted C14 alkyl.

[0416] In embodiments, R1is unsubstituted unbranched C1-C17 alkyl. In embodiments, R1is unsubstituted unbranched C11-C17 alkyl. In embodiments, R1is unsubstituted unbranched C13- C17 alkyl. In embodiments, R1is unsubstituted unbranched C14-C15 alkyl. In embodiments, R1is unsubstituted unbranched C14 alkyl. In embodiments, R1is unsubstituted unbranched C15 alkyl.

[0417] In embodiments, R1is unsubstituted unbranched saturated C1-C17 alkyl. In embodiments, R1is unsubstituted unbranched saturated C11-C17alkyl. In embodiments, R1is unsubstituted unbranched saturated C13-C17 alkyl. In embodiments, R1is unsubstituted unbranched saturated C14-C15alkyl. In embodiments, R1is unsubstituted unbranched saturated C14 alkyl. In embodiments, R1is unsubstituted unbranched saturated C15 alkyl.

[0418] In embodiments, R1is unsubstituted unbranched unsaturated C1-C17 alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C11-C17alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C13-C17 alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C14-C15alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C14 alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C15 alkyl.

[0419] In embodiments, R2is unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2is unsubstituted unbranched alkyl (e.g., C1-C25, C1- C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2is unsubstituted unbranched saturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R2is unsubstituted unbranched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0420] In embodiments, R2is unsubstituted C1-C17alkyl. In embodiments, R2is unsubstituted C11-C17 alkyl. In embodiments, R2is unsubstituted C13-C17 alkyl. In embodiments, R2is unsubstituted C14-C15alkyl. In embodiments, R2is unsubstituted C14alkyl. In embodiments, R2is unsubstituted C15 alkyl.

[0421] In embodiments, R2is unsubstituted unbranched C1-C17alkyl. In embodiments, R2is unsubstituted unbranched C11-C17 alkyl. In embodiments, R2is unsubstituted unbranched C13- C17 alkyl. In embodiments, R2is unsubstituted unbranched C14-C15 alkyl. In embodiments, R2is unsubstituted unbranched C14 alkyl. In embodiments, R2is unsubstituted unbranched C15 alkyl.

[0422] In embodiments, R2is unsubstituted unbranched saturated C1-C17 alkyl. In embodiments, R2is unsubstituted unbranched saturated C11-C17 alkyl. In embodiments, R2is unsubstituted unbranched saturated C13-C17alkyl. In embodiments, R2is unsubstituted unbranched saturated C14-C15 alkyl. In embodiments, R2is unsubstituted unbranched saturated C14alkyl. In embodiments, R2is unsubstituted unbranched saturated C15alkyl.

[0423] In embodiments, R2is unsubstituted unbranched unsaturated C1-C17alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C11-C17 alkyl. In embodiments, R2isunsubstituted unbranched unsaturated C13-C17 alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C14-C15alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C14 alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C15 alkyl.

[0424] In embodiments, at least one of R1and R2is unsubstituted C1-C19 alkyl. In embodiments, at least one of R1and R2is unsubstituted C9-C19alkyl. In embodiments, at least one of R1and R2is unsubstituted C11-C19 alkyl. In embodiments, at least one of R1and R2is unsubstituted C13-C19alkyl.

[0425] In embodiments, R1is unsubstituted C1-C19 alkyl. In embodiments, R1is unsubstituted C9-C19alkyl. In embodiments, R1is unsubstituted C11-C19alkyl. In embodiments, R1is unsubstituted C13-C19 alkyl. In embodiments, R1is unsubstituted unbranched C1-C19 alkyl. In embodiments, R1is unsubstituted unbranched C9-C19 alkyl. In embodiments, R1is unsubstituted unbranched C11-C19alkyl. In embodiments, R1is unsubstituted unbranched C13-C19alkyl. In embodiments, R1is unsubstituted unbranched saturated C1-C19 alkyl. In embodiments, R1is unsubstituted unbranched saturated C9-C19alkyl. In embodiments, R1is unsubstituted unbranched saturated C11-C19 alkyl. In embodiments, R1is unsubstituted unbranched saturated C13-C19alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C1-C19alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C9-C19 alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C11-C19alkyl. In embodiments, R1is unsubstituted unbranched unsaturated C13-C19 alkyl.

[0426] In embodiments, R2is unsubstituted C1-C19alkyl. In embodiments, R2is unsubstituted C9-C19 alkyl. In embodiments, R2is unsubstituted C11-C19 alkyl. In embodiments, R2is unsubstituted C13-C19 alkyl. In embodiments, R2is unsubstituted unbranched C1-C19 alkyl. In embodiments, R2is unsubstituted unbranched C9-C19 alkyl. In embodiments, R2is unsubstituted unbranched C11-C19 alkyl. In embodiments, R2is unsubstituted unbranched C13-C19 alkyl. In embodiments, R2is unsubstituted unbranched saturated C1-C19 alkyl. In embodiments, R2is unsubstituted unbranched saturated C9-C19 alkyl. In embodiments, R2is unsubstituted unbranched saturated C11-C19alkyl. In embodiments, R2is unsubstituted unbranched saturated C13-C19 alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C1-C19 alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C9-C19alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C11-C19 alkyl. In embodiments, R2is unsubstituted unbranched unsaturated C13-C19alkyl.

[0427] L1Ais independently a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, - O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, - P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group...

Claims

WHAT IS CLAIMED IS:

1. A compound comprising a nucleic acid (A) covalently bonded to a half-life extension motif (HLEM).

2. The compound of claim 1, wherein the compound has a formula (I) (HLEM)z-A (I), wherein z is an integer from 1 to 5.

3. The compound of claim 1, wherein the nucleic acid is covalently bonded to an uptake motif (UM).

4. The compound of claim 3, wherein the compound has a formula (II): (HLEM)z-A-(UM)t (II), wherein t is an integer from 1 to 5.

5. The compound of claim 1, wherein the half-life extension motif has the structure:wherein: L1is independently a covalent linker; L2is independently an unsubstituted alkylene; and k is an integer from 1 to 5.

6. The compound of claim 5, wherein L1is L1A-L1B-L1C-L1D-L1E; L2is an unsubstituted C2-C22alkylene; L1A, L1B, L1C, L1D, and L1Eare independently a bond, -N(R20)-, -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21)- , -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N(R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -O- P(O)(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -O-P(O)(NR20R21)-N-, -O-P(S)(NR20R21)-N-, - O-P(O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and each R20, R21and R22is independently hydrogen or unsubstituted C1-C10 alkyl.

7. The compound of claim 5, wherein the largest dimension of L1is less than 200 angstroms.

8. The compound of claim 5, wherein the longest linear atomic path L1is 1 to 60 atoms in length.

9. The compound of claim 6, wherein the largest dimension of each of L1A, L1B, L1C, L1D, and L1Eis independently less than 40 angstroms.

10. The compound of claim 6, wherein each of L1A, L1B, L1C, L1D, and L1Eis independently 1 to 20 atoms in length.

11. The compound of claim 1, wherein each of R20, R21and R22is independently hydrogen or unsubstituted C1-C3 alkyl.

12. The compound of claim 1, wherein the nucleic acid is an oligonucleotide.

13. The compound of claim 12, wherein one L1Ais attached to a 3’ carbon of the oligonucleotide.

14. The compound of claim 12, wherein one L1Ais attached to a 3’ nitrogen of the oligonucleotide.

15. The compound of claim 12, wherein one L1Ais attached to a 5’ carbon of the oligonucleotide.

16. The compound of claim 12, wherein one L1Ais attached to a 6’ carbon of the oligonucleotide.

17. The compound of claim 12, wherein one L1Ais attached to a 2’ carbon of the oligonucleotide.

18. The compound of claim 12, wherein one L1Ais attached to a nucleobase of the oligonucleotide.

19. The compound of claim 6, wherein L1Ais independently -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O- P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O- P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, - P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

20. The compound of claim 6, wherein L1Ais independently.

21. The compound of claim 6, wherein L1Ais independently -OPO2-O- or – OP(O)(S)-O-.

22. The compound of claim 6, wherein L1Ais independently -O-.

23. The compound of claim 6, wherein L1Ais independently -C(O)-.

24. The compound of claim 6, wherein L1Ais independently -O-P(O)(N(CH3)2)-N-.

25. The compound of claim 6, wherein L1Bis independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

26. The compound of claim 6, wherein L1Bis independently –L10-NH-C(O)- or –L10- C(O)-NH-, wherein L10is substituted or unsubstituted alkylene.

27. The compound of claim 6, wherein L1Bis independently.

28. The compound of claim 6, wherein L1Bis independently.

29. The compound of claim 6, wherein L1Bis independentlyw1 is an integer from 0 to 10; w2 is an integer from 0 to 5; w3 is an integer from 0 to 5; and w4 is an integer from 0 to 5.

30. The compound of claim 6, wherein L1Bis independently ,w1 is an integer from 0 to 10; and w2 is an integer from 0 to 5.

31. The compound of claim 6, wherein L1Bis independently.

32. The compound of claim 6, wherein L1Bis independently.

33. The compound of claim 6, wherein –L1A-L1B- is independently –O-L10-NH-C(O)- or –O-L10-C(O)-NH-, wherein L10is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene.

34. The compound of claim 6, wherein –L1A-L1B- is independently –O-L10-NH-C(O)-, wherein L10is independently substituted or unsubstituted C5-C8 alkylene.

35. The compound of claim 6, wherein –L1A-L1B- is independently36. The compound of claim 6, wherein –L1A-L1B- is independently -OPO2-O-L10-NH- C(O)-, -OP(O)(S)-O-L10-NH-C(O)-, -OPO2-O-L10-C(O)-NH-or -OP(O)(S)-O-L10-C(O)-NH-, wherein L10is independently substituted or unsubstituted alkylene.

37. The compound of claim 6, wherein –L1A-L1B- is independently -OPO2-O-L10-NH- C(O)- or –OP(O)(S)-O-L10-NH-C(O)-, wherein L10is independently substituted or unsubstituted C5-C8 alkylene.

38. The compound of claim 6, wherein –L1A-L1B- is independentlyHO39. The compound of claim 12, wherein an –L1A-L1B- is independently, or , and is attached to a 3’ carbon of the oligonucleotide.

40. The compound of claim 12, wherein an –L1A-L1B- is independently ,or , and is attached to a 3’ nitrogen of the oligonucleotide.

41. The compound of claim 12, wherein an –L1A-L1B- is independently , , , or and is attached to a 5’ carbon of the oligonucleotide.

42. The compound of claim 12, wherein an –L1A-L1B- is independently O N N P O NMe2and is attached to a 6’ carbon of the oligonucleotide.

43. The compound of claim 12, wherein an –L1A-L1B- is independently attached to a nucleobase of the oligonucleotide.

44. The compound of claim 6, wherein: L1Cis independently substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L1Dis independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and L1Eis independently a bond, substituted or unsubstituted heteroalkylene, or -NHC(O)-.

45. The compound of claim 6, wherein L1Cis independently substituted or unsubstituted C1-C10alkylene, or substituted or unsubstituted 2 to 10 membered heteroalkylene; L1Dis independently a bond, substituted or unsubstituted C1-C10 alkylene, or substituted or unsubstituted 2 to 10 membered heteroalkylene; and L1Eis independently a bond, substituted or unsubstituted 2 to 10 membered heteroalkylene, or -NHC(O)-.

46. The compound of claim 6, wherein: L1Cis independently substituted or unsubstituted C1-C7 alkylene, or substituted or unsubstituted 5 to 8 membered heteroalkylene; L1Dis independently a bond, substituted or unsubstituted C1-C7alkylene, or substituted or unsubstituted 5 to 8 membered heteroalkylene; and L1Eis independently a bond, substituted or unsubstituted 5 to 8 membered heteroalkylene, or -NHC(O)-.

47. The compound of claim 6, wherein: L1Cis independently R1C-substituted or unsubstituted C1-C7alkylene, or R1C-substituted or unsubstituted 5 to 8 membered heteroalkylene;L1Dis independently a bond, R1D-substituted or unsubstituted C1-C7 alkylene, or R1D- substituted or unsubstituted 5 to 8 membered heteroalkylene; and L1Eis independently a bond, R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene, or -NHC(O)-; R1Cis independently oxo, or -L8C-L2C-R8C; R1Dis independently oxo, or -L8D-L2D-R8D; R1Eis independently oxo, or -L8E-L2E-R8E; each L8C, L8D, and L8Eis independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2 to 6 membered heteroalkylene, each L2C, L2D, and L2Eis independently a bond, or an unsubstituted alkylene; and each R8C, R8D, and R8Eis independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

48. The compound of claim 47, wherein the half-life extension motif has the structure:wherein L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and L2Ais independently a bond, or an unsubstituted alkylene.

49. The compound of claim 47, wherein the half-life extension motif has the structure:(III-b), wherein L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and L2Ais independently a bond, or an unsubstituted alkylene.

50. The compound of claim 47, wherein the half-life extension motif has the structure:(III-c), wherein L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and L2Ais independently a bond, or an unsubstituted alkylene.

51. The compound of claim 47, wherein the half-life extension motif has the structure:wherein L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and L2Ais independently a bond, or an unsubstituted alkylene.

52. The compound of claim 47, wherein the half-life extension motif has the structure:wherein L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and L2Ais independently a bond, or an unsubstituted alkylene.

53. The compound of claim 47, wherein the half-life extension motif has the structure:(III-f), wherein L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and L2Ais independently a bond, or an unsubstituted alkylene. .

54. The compound of claim 47, wherein the half-life extension motif has the structure:wherein L8Ais independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and L2Ais independently a bond, or an unsubstituted alkylene.

55. The compound of claim 47, wherein: R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently a bond or an unsubstituted C2-C22alkylene; and R8Cis independently hydrogen, unsubstituted C1-C3alkyl, or -COOH.

56. The compound of claim 47, wherein: R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently a bond; and R8Cis independently unsubstituted C1-C3 alkyl.

57. The compound of claim 47, wherein: R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently an unsubstituted C10-C22 alkylene; and R8Cis independently an unsubstituted C1-C3 alkyl, or –COOH.

58. The compound of claim 47, wherein: R1Dis independently –NHC(O)-L2D-R8D; L2Dis independently a bond or an unsubstituted C2-C22alkylene; R8Dis independently hydrogen, unsubstituted C1-C3 alkyl, or -COOH.

59. The compound of claim 47, wherein: R1Eis independently –NHC(O)-L2E-R8E; L2Eis independently a bond or an unsubstituted C2-C22 alkylene; R8Eis independently hydrogen, unsubstituted C1-C3 alkyl, or COOH .

60. The compound of claim 47, wherein: L1Cis independently R1C-substituted or unsubstituted C3-C7 alkylene; L1Dis independently a bond, or an unsubstituted arylene; L1Eis independently R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene or -NHC(O)-.

61. The compound of claim 47, wherein L1Cis independently R1C-substituted or unsubstituted 5 to 8 membered heteroalkylene; L1Dis independently a bond, or R1D-substituted or unsubstituted 5 to 8 membered heteroalkylene;L1Eis independently R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene or -NHC(O)-; each R1C, R1D, or R1Eis independently oxo, or -COOH.

62. The compound of claim 47, wherein: L1Cis independently R1C-substituted C2-C5alkyl; L1Dis independently an unsubstituted phenylene, or an unsubstituted biphenylene; and L1Eis independently R1E-substituted or unsubstituted 5 to 8 membered heteroalkylene or -NHC(O)-; and R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently a bond, or an unsubstituted C10-C22 alkylene; R8Cis independently an unsubstituted C1-C3 alkyl, or –COOH; and R1Eis oxo.

63. The compound of claim 47, wherein: L1Cis independently R1C-substituted or unsubstituted ethylene or n-pentylene; L1Dis independently a bond; L1Eis independently -NHC(O)-; R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently a bond or an unsubstituted C10-C22alkylene; and R8Cis independently an unsubstituted C1-C3 alkyl, or -COOH.

64. The compound of claim 47, wherein: L1Cis independently R1C-substituted or unsubstituted n-pentylene; L1Dis independently oxo-substituted or unsubstituted 5 to 8 membered heteroalkylene; L1Eis independently -NHC(O)-; and R1Cis independently –NHC(O)-L2C-R8C; L2Cis independently a bond or an unsubstituted C10-C22 alkylene; and R8Cis independently an unsubstituted C1-C3alkyl, or -COOH.

65. The compound of claim 47 wherein:L1Cis independently R1C-substituted methylene; L1Dis independently a bond; and L1Eis independently -NHC(O)-; and R1Cis independently –L8C-L2C-R8C; L8Cis independently an unsubstituted C1-C6 alkylene or oxo-substituted 2 to 12 membered heteroalkylene; L2Cis independently a bond; and R8Cis independently an unsubstituted C1-C6 alkyl or oxo-substituted 2 to 12 membered heteroalkyl.

66. The compound of claim 65, wherein R8Cis independently an unsubstituted C1-C6alkyl or oxo- and C1-C15 alkyl-substituted 2 to 12 membered heteroalkyl.

67. The compound of claim 5, wherein L1is: ,, , ,,,.

68. The compound of any one of claims 48 to 57, wherein each L2, L2A, L2C, L2D, or L2Eis independently an unsubstituted C2-C22 alkylene.

69. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis independently an unsubstituted C5-C22 alkylene.

70. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis independently an unsubstituted C10-C22 alkylene.

71. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted C12-C22 alkylene.

72. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted C12-C18alkylene.

73. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted C12-C16alkylene.

74. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted C14-C15alkylene.

75. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched C10-C22 alkylene.

76. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched C12-C22 alkylene.

77. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched C12-C18 alkylene.

78. The compound of a claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched C12-C16 alkylene.

79. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched C14-C15 alkylene.

80. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched saturated C10-C22alkylene.

81. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched saturated C12-C22alkylene.

82. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched saturated C12-C18alkylene.

83. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched saturated C12-C16alkylene.

84. The compound of claim 68, wherein each L2, L2A, L2C, L2D, or L2Eis an unsubstituted unbranched saturated C14-C15alkylene.

85. The compound of claim 5, comprising from one to five optionally different half- life extension motifs.

86. The compound of claim 5, comprising only one half-life extension motif.

87. The compound of claim 3, wherein the uptake motif independently has the structure:wherein: L3and L4are independently a bond, -N(R23)-, -O-, -S-, -C(O)-, -N(R23)C(O)-, - C(O)N(R24)-, -N(R23)C(O)N(R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC(O)N(R24)- , -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(R25)-O-, -O-P(S)(R25)-O-, -O-P(O)(NR23R24)-N-, -O- P(S)(NR23R24)-N-, -O-P(O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, - P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; L5is -L5A-L5B-L5C-L5D-L5E-; L6is -L6A-L6B-L6C-L6D-L6E-; R1and R2are independently unsubstituted C1-C25alkyl, wherein at least one of R1and R2is unsubstituted C9-C19alkyl; R3is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, –N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6Eare independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, –C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene; and each R23, R24and R25is independently hydrogen or unsubstituted C1-C10alkyl.

88. The compound of claim 4, wherein t is 1.

89. The compound of claim 4, wherein t is 2.

90. The compound of claim 4, wherein t is 3.

91. The compound of claim 4, wherein each of R23, R24and R25is independently hydrogen or unsubstituted C1-C3 alkyl.

92. The compound of claim 87, wherein one L3is attached to a 3’ carbon of the oligonucleotide.

93. The compound of claim 87, wherein one L3is attached to a 3’ nitrogen of the oligonucleotide.

94. The compound of claim 87, wherein one L3is attached to a 5’ carbon of the oligonucleotide.

95. The compound of claim 87, wherein one L3is attached to a 6’ carbon of the oligonucleotide.

96. The compound of claim 87, wherein one L3is attached to a nucleobase of the oligonucleotide.

97. The compound of claim 87, wherein L3and L4are independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O- P(S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)(N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O- P(S)(N(CH3)2)-O-, - P(O)(N(CH3)2)-N-, -P(O)(N(CH3)2)-O-, -P(S)(N(CH3)2)-N-, - P(S)(N(CH3)2)-O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

98. The compound of claim 87, wherein L3is independently.

99. The compound of claim 87, wherein L3is independently -OPO2-O- or – OP(O)(S)-O-.

100. The compound of claim 87, wherein L3is independently –O-.

101. The compound of claim 87, wherein L3is independently -C(O)-.

102. The compound of claim 87, wherein L3is independently -O-P(O)(N(CH3)2)-N-.

103. The compound of claim 87, wherein L4is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

104. The compound of claim 87, wherein L4is independently –L7-NH-C(O)- or –L7- C(O)-NH-, wherein L7is substituted or unsubstituted alkylene.

105. The compound of claim 87, wherein L4is independently.

106. The compound of claim 87, wherein L4is independently.

107. The compound of claim 87, wherein –L3-L4- is independently –O-L7-NH-C(O)- or –O-L7-C(O)-NH-, wherein L7is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene.

108. The compound of claim 107, wherein –L3-L4- is independently –O-L7-NH-C(O)-, wherein L7is independently substituted or unsubstituted C5-C8alkylene.

109. The compound of claim 108, wherein –L3-L4- is independently110. The compound of claim 87, wherein –L3-L4- is independently -OPO2-O-L7-NH- C(O)-, -OP(O)(S)-O-L7-NH-C(O)-, -OPO2-O-L7-C(O)-NH-or –OP(O)(S)-O-L7-C(O)-NH-, wherein L7is independently substituted or unsubstituted alkylene.

111. The compound of claim 110, wherein –L3-L4- is independently -OPO2-O-L7-NH- C(O)- or –OP(O)(S)-O-L7-NH-C(O)-, wherein L7is independently substituted or unsubstituted C5-C8 alkylene.

112. The compound of claim 111, wherein –L3-L4- is independentlyHO113. The compound of claim 112, wherein an –L3-L4- is independently HOof oligonucleotide.

114. The compound of claim 112, wherein an –L3-L4- is independentlyand is attached to a 3’ nitrogen of the oligonucleotide.

115. The compound of claim 112, wherein an –L3-L4- is independently, ,attached to a 5’ carbon of the oligonucleotide.

116. The compound of claim 112, wherein an –L3-L4- is independently O N N P O NMe2and is attached to a 6’ carbon of the oligonucleotide.

117. The compound of claim 112, wherein an –L3-L4- is independentlyand is attached to a nucleobase of the oligonucleotide.

118. The compound of one of claims 87 to 117, wherein R3is independently hydrogen.

119. The compound of one of claims 87 to 118, wherein L6is independently -NHC(O)-, –C(O)NH-,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

120. The compound of claim 119, wherein L6is independently -NHC(O)-.

121. The compound of claim 119, wherein L6Ais independently a bond or unsubstituted alkylene; L6Bis independently a bond, -NHC(O)-, or unsubstituted arylene; L6Cis independently a bond, unsubstituted alkylene, or unsubstituted arylene; L6Dis independently a bond or unsubstituted alkylene; and L6Eis independently a bond or -NHC(O)-.

122. The compound of claim 119 whereinL6Ais independently a bond or unsubstituted C1-C8 alkylene; L6Bis independently a bond, -NHC(O)-, or unsubstituted phenylene; L6Cis independently a bond, unsubstituted C2-C8alkynylene, or unsubstituted phenylene; L6Dis independently a bond or unsubstituted C1-C8 alkylene; and L6Eis independently a bond or -NHC(O)-.

123. The compound of claim 87, wherein L6is independently a bond,124. The compound of claim 87, wherein L5is independently -NHC(O)-, –C(O)NH- ,substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

125. The compound of claim 87, wherein L5is independently -NHC(O)-.

126. The compound of claim 87, wherein L5Ais independently a bond or unsubstituted alkylene; L5Bis independently a bond, -NHC(O)-, or unsubstituted arylene; L5Cis independently a bond, unsubstituted alkylene, or unsubstituted arylene; L5Dis independently a bond or unsubstituted alkylene; and L5Eis independently a bond or -NHC(O)-.

127. The compound of claim 87, wherein L5Ais independently a bond or unsubstituted C1-C8alkylene; L5Bis independently a bond, -NHC(O)-, or unsubstituted phenylene;L5Cis independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene; L5Dis independently a bond or unsubstituted C1-C8 alkylene; and L5Eis independently a bond or -NHC(O)-.

128. The compound of claim 87, wherein L5is independently a bond,129. The compound of claim 87, wherein R1is unsubstituted C1-C17 alkyl.

130. The compound of claim 87, wherein R1is unsubstituted C11-C17alkyl.

131. The compound of claim 87, wherein R1is unsubstituted C13-C17 alkyl.

132. The compound of claim 87, wherein R1is unsubstituted C14-C15alkyl.

133. The compound of claim 87, wherein R1is unsubstituted unbranched C1-C17 alkyl.

134. The compound of claim 87, wherein R1is unsubstituted unbranched C11-C17 alkyl.

135. The compound of claim 87, wherein R1is unsubstituted unbranched C13-C17alkyl.

136. The compound of claim 87, wherein R1is unsubstituted unbranched C14-C15 alkyl.

137. The compound of claim 87, wherein R1is unsubstituted unbranched saturated C1- C17 alkyl.

138. The compound of claim 87, wherein R1is unsubstituted unbranched saturated C11- C17 alkyl.

139. The compound of claim 87, wherein R1is unsubstituted unbranched saturated C13- C17 alkyl.

140. The compound of claim 87, wherein R1is unsubstituted unbranched saturated C14- C15 alkyl.

141. The compound of claim 87, wherein R2is unsubstituted C1-C17alkyl.

142. The compound of claim 87, wherein R2is unsubstituted C11-C17 alkyl.

143. The compound of claim 87, wherein R2is unsubstituted C13-C17alkyl.

144. The compound of claim 87, wherein R2is unsubstituted C14-C15 alkyl.

145. The compound of claim 87, wherein R2is unsubstituted unbranched C1-C17alkyl.

146. The compound of claim 87, wherein R2is unsubstituted unbranched C11-C17 alkyl.

147. The compound of claim 87, wherein R2is unsubstituted unbranched C13-C17 alkyl.

148. The compound of claim 87, wherein R2is unsubstituted unbranched C14-C15alkyl.

149. The compound of claim 87, wherein R2is unsubstituted unbranched saturated C1- C17alkyl.

150. The compound of claim 87, wherein R2is unsubstituted unbranched saturated C11- C17 alkyl.

151. The compound of claim 87, wherein R2is unsubstituted unbranched saturated C13- C17 alkyl.

152. The compound of claim 87, wherein R2is unsubstituted unbranched saturated C14- C15 alkyl.

153. The compound of claim 12, wherein the oligonucleotide is a single-stranded oligonucleotide or a double-stranded oligonucleotide.

154. The compound of claim 153, wherein the double-stranded oligonucleotide is a small interfering RNA, a short hairpin RNA or a microRNA mimic.

155. The compound of claim 153, wherein the single-stranded oligonucleotide is a single-strand small interfering RNA, an RNaseH oligonucleotide, an anti-microRNA oligonucleotide, a steric blocking oligonucleotide, exon-skipping oligonucleotide, a CRISPR guide RNA, or an aptamer.

156. The compound of claim 1, wherein the nucleic acid comprises one or more modified nucleotides.

157. The compound of claim 1, wherein the nucleic acid comprises one or more modified sugar moieties.

158. The compound of claim 157, wherein the modified sugar moiety comprises a 2’ modification or an unlocked sugar modification.

159. The compound of claim 158, wherein the 2’-modification is selected from 2’- fluoro modification, 2’-O-methyl modification, a 2’-O-methoxyethyl, and a bicyclic sugar modification.

160. The compound of claim 159, wherein the bicyclic sugar modification is selected from a 4’-CH(CH3)-O-2’ linkage, a 4'-(CH2)2-O-2' linkage, a 4'-CH(CH2-OMe)-O-2' linkage, 4’- CH2-N(CH3)-O-2’ linkage, and 4’-CH2-N(H)-O-2’ linkage161. The compound of claim 157, wherein the modified sugar moiety is a morpholino moiety.

162. The compound of claim 1, wherein the nucleic acid comprises one or more modified internucleotide linkages.

163. The compound of claim 162, wherein the modified internucleotide linkage selected from a phosphorothioate linkage and a phosphorodiamidite linkage.

164. The compound of claim 156, wherein the nucleic acid is a small interfering RNA (siRNA) or a single-stranded small interfering RNA (ssRNAi) and the 5’ carbon at the 5’- terminus of the antisense strand comprises a hydroxyl group, a phosphate group, or modified phosphate group.

165. The nucleic acid compound of claim 164, wherein the modified phosphate group is a 5’-(E)-vinylphosphonate.

166. The compound of claim 154, wherein the oligonucleotide is a double-stranded oligonucleotide comprising an antisense strand hybridized to a sense strand and each of the antisense strand and sense strand is independently 15 to 30 nucleotides in length.

167. The compound of claim 166, wherein each of the antisense strand and sense strand is 17 to 25 nucleotides in length.

168. The compound of claim 166, wherein each of the antisense strand and sense strand is 19 to 23 nucleotides in length.

169. The compound of claim 154, wherein the oligonucleotide is single-stranded and the oligonucleotide is 8 to 30 nucleotides in length.

170. The compound of claim 169, wherein the oligonucleotide is 12 to 25 nucleotides in length.

171. The compound of claim 169, wherein the oligonucleotide is 15 to 25 nucleotides in length.

172. The compound of claim 169, wherein the oligonucleotide is 17 to 23 nucleotides in length.

173. The compound of claim 1, wherein the compound is capable of binding a serum protein.

174. The compound of claim 1, wherein the compound is capable of binding serum albumin.

175. The compound of claim 1, wherein the compound has increased serum albumin binding compared to an identical compound lacking the one or more optionally different half-life extension motifs.

176. The compound of claim 1, wherein the compound has an increased serum half-life compared to an identical compound lacking the one or more optionally different half-life extension motifs.

177. The compound of claim 1, wherein the compound further comprises a ligand.

178. The compound of claim 177, wherein the ligand comprises a peptide, an antibody, a carbohydrate, or an additional nucleic acid.

179. The compound of claim 3, wherein the uptake motif comprises a peptide, an antibody, a carbohydrate, or an additional nucleic acid.

180. A method comprising contacting a cell with a compound of claim 1.

181. The method of claim 180, wherein the contacting occurs in vitro.

182. The method of claim 180, wherein the contacting occurs ex vivo.

183. The method of claim 180, wherein the contacting occurs in vivo.

184. A method comprising administering to a subject a compound of claim 1.

185. The method of claim 184, wherein the subject has a disease or disorder of the eye, liver, kidney, heart, adipose tissue, lung, muscle or spleen.

186. A compound of claim 1, for use in therapy.

187. A compound of claim 1, for use in the preparation of a medicament.

188. A method of introducing a nucleic acid into a cell within a subject, the method comprising administering to said subject the compound of claim 1.

189. A cell comprising the compound of claim 1.

190. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1.

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