Nucleic acid and half-life motif-containing compounds

Abstract

Disclosed herein are compounds comprising nucleic acids (A), their preparation, and their uses.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 940,835, filed November 26, 2019, which is incorporated herein in its entirety for all purposes.

[0002] Reference to a "Sequence Listing," table, or computer program listing appendix submitted as an ASCII file The sequence listing set forth in file DTX-003-01WO_ST25.TXT (created November 23, 2020, size 1,174 bytes, machine format IBM-PC, MS Windows operating system) is incorporated herein by reference.

[0003] The present disclosure relates to the field of biologically active compounds that contain nucleic acids. More specifically, the present disclosure relates to nucleic acid-containing compounds, their preparation, and their uses. [Background technology]

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

[0005] Provided herein, inter alia, is a compound or compounds comprising a nucleic acid (A) covalently linked to a half-life extending motif (HLEM).

[0006] In one aspect, there is provided a compound having the formula (I) (HLEM)zA (I), where z is an integer of 1 to 5.

[0007] In embodiments, the half-life extending motif has the structure: [ka] k is an integer of 1 to 5.

[0008] L1 is independently a covalent linker. L2 is independently an unsubstituted alkylene.

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

[0010] In an embodiment, the compound has the formula (II) (HLEM)zA-(UM)t (II), where t is an integer of 1 to 5.

[0011] In embodiments, the uptake motifs independently have the structure [ka]

[0012] L3 and L4 are 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-, -OP(O)(S)-O-, -OP(O)(R25)-O-, -OP(S)(R25)-O-, -OP(O)(NR23R24)-N-, -OP(S)(NR23R24)-N-, -OP (O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-, -SS-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. Each R23, R24, and R25 is independently hydrogen or unsubstituted C1-C10 alkyl.

[0013] L5 is -L5A-L5B-L5C-L5D-L5E-. L6 is -L6A-L6B-L6C-L6D-L6E-. L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are 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] R1 and R2 are independently unsubstituted C1-C25 alkyl, and at least one of R1 and R2 is unsubstituted C9-C19 alkyl. R3 is 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 one aspect, a method is provided that includes contacting a cell with a compound, or a compound that includes a nucleic acid (A), as described herein.

[0016] In one aspect, a method is provided that includes administering to a subject a compound described herein or a compound that includes a nucleic acid (A).

[0017] In one aspect, there is provided a compound or compound comprising a nucleic acid (A) described herein for use in therapy.

[0018] In one aspect, a method of introducing a nucleic acid into a cell in a subject is provided, the method comprising administering to the subject a compound comprising a nucleic acid (A) described herein.

[0019] In one aspect, a cell is provided that comprises a compound comprising a nucleic acid (A) described herein.

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

[0021] Other aspects are disclosed below. [Brief explanation of the drawings]

[0022] [Figure 1A] 1 illustrates the structure of DT-000137 according to an exemplary embodiment. [Figure 1B] 1 illustrates the structure of DT-000146 according to an exemplary embodiment. [Figure 1C] 1 illustrates the structure of DT-000347 according to an exemplary embodiment. [Figure 1D] 1 illustrates the structure of a DT-000155 in accordance with an exemplary embodiment. [Figure 1E] 1 illustrates the structure of a DT-000156 in accordance with an exemplary embodiment. [Figure 1F] 1 illustrates the structure of DT-000157 according to an exemplary embodiment. [Figure 1G] 1 illustrates the structure of DT-000272 according to an exemplary embodiment. [Figure 1H] 1 illustrates the structure of DT-000273 according to an exemplary embodiment. [Figure 1I] 1 illustrates the structure of DT-000274 according to an exemplary embodiment. [Figure 1J] 1 illustrates the structure of DT-000275 according to an exemplary embodiment. [Figure 1K] 1 illustrates the structure of DT-000276 according to an exemplary embodiment. [Figure 1L] 1 illustrates the structure of DT-000277 according to an exemplary embodiment. [Figure 1M] 1 illustrates the structure of DT-000278 according to an exemplary embodiment. [Figure 1N]1 illustrates the structure of a DT-000350 in accordance with an exemplary embodiment. [Figure 1O] The structure of DT-000183 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0023] definition Unless otherwise defined, all technical and scientific terms, abbreviations, chemical structures, and chemical formulas used herein have the same meaning as commonly understood by those skilled in the art. The chemical structures and formulas described 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 otherwise specified. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are employed unless otherwise indicated. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. As used herein, the terms "comprise" and "comprising," whether in transitional phrases or in the body of a claim, should be construed as having an open-ended meaning. That is, the term should be construed 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 include additional features or components.

[0024] Where substituents are specified by their conventional chemical formula 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-.

[0025] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monovalent, or polyunsaturated, and can include monovalent, divalent, and polyvalent radicals. An alkyl can contain a specified number of carbons (e.g., C1-C10 means 1 to 10 carbons). An alkyl is a non-cyclized 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, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those having one or more double 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 higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. An alkenyl may contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. An alkynyl may contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds.

[0026] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring includes a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., a bridging group of the form (CH)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, a fused bicyclic cycloalkyl ring system comprises a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, a bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or two groups, 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, optionally substituted with one or two groups that are independently oxo or thia.In embodiments, the polycyclic cycloalkyl ring system is (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) a monocyclic cycloalkyl ring (base ring) fused to either of two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0027] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond), but are not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring includes a monocyclic cycloalkenyl ring in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge (i.e., a bridging group of the form (CH)w, where w is 1, 2, or 3) between 1 to 3 additional carbon atoms. Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, the fused bicyclic cycloalkenyl ring system comprises 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, the cycloalkenyl group is optionally substituted with one or two groups, each independently oxo or thia. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl.In embodiments, a polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0028] In embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring, where the ring is saturated or unsaturated but not aromatic, and contains at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 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. A 6- or 7-membered ring can contain zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include 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, Examples of heterocyclic heterocycles include, but are not limited to, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are 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-2yl, 2,3-dihydrobenzofuran-3yl, indolin-1yl, indolin-2yl, indolin-3yl, 2,3-dihydrobenzothien-2yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups, each 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, and is optionally substituted with one or two groups, each independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic 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.

[0029] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified by, but not limited to, -CHCHCHCH-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with 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 8 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.

[0030] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, stable linear or branched chains, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, S, Si, or P), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (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 a non-cyclizing 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)-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. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain up to eight, optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one double bond. A heteroalkenyl may optionally contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds.The term "heteroalkynyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one triple bond. In addition to one or more triple bonds, a heteroalkynyl may optionally contain more than one triple bond and / or one or more double bonds.

[0031] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). 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)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups as used herein include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, e.g., -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, e.g., -NR'R'', etc.

[0032] 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, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0033] 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, and 3-bromopropyl.

[0034] The term "acyl," unless otherwise stated, means -C(O)R, where R is 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.

[0035] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, one ring having five members and the other having six members, and at least one ring being a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 6 members, and at least one ring is a heteroaryl ring. A 6,5-fused ring heteroarylene refers to two rings fused together, one having 6 members and the other having 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a 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, benzoxazolyl, 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, and the like. aryl, 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. The heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0036] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings in a spirocyclic ring can be the same or different. The individual rings in a spirocyclic ring can be substituted or unsubstituted, and can have different substituents from the other individual rings in a set of spirocyclic rings. The possible substituents of the individual rings in a spirocyclic ring are the possible substituents of the same ring (e.g., the substituents of a cycloalkyl ring or heterocycloalkyl ring) when they are not part of a spirocyclic ring. The spirocyclic ring can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings in a spirocyclic ring group can be any of the rings in the previous list, including all rings of one type (e.g., all rings are substituted heterocycloalkylene, and each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic and each ring can be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted and each substituent can optionally be different.

[0037] symbol [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0038] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0039] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: [ka]

[0040] The alkylarylene moiety may be substituted (e.g., by a substituent) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH, -SOH, -OSOH, -SONH, -NHNH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl at the alkylene moiety or arylene linker (e.g., at carbons 2, 3, 4, or 6). In embodiments, the alkylarylene is unsubstituted.

[0041] 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.

[0042] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from 0 to (2m'+1), where m' is the total number of carbon atoms in such radical, and include, but are not limited to, -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', It can be one or more of a variety of groups selected from: -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'S02R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR''. 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 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as each R', R'', R''', and R'''' group when more than one of these groups is present. R' and R'', when attached to the same nitrogen atom, may combine 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 intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0043] Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups vary and include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′′, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′′′, —NR″C(O)R′, —NR-C(NR′R″R′′)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSOR′, —NR′ 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 the compounds described herein include more than one R group, for example, each of the R groups is independently selected for each R', R", R'", and R"" group when more than one of these groups is present.

[0044] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be shown as substituents on the ring (commonly referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (a floating substituent on a single ring) can be a substituent on either the fused or spirocyclic ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, according to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown attached to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), it will be understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen, according to the rules of chemical valence.

[0045] Two or more substituents may optionally join to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. These so-called ring-forming substituents are typically, but 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 form 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.

[0046] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of formula -T-C(O)-(CRR')U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer 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 formula -A-(CH)B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)-, -S(O)NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in 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 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.

[0047] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0048] As used herein, a "substituent" 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, -SON2NH2, -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. For example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (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, -SON2NH2, -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. For example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (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, -SON2NH2, -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. For example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one group selected from the following: 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, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, —OC H2F, -OCH2Cl, -OCH2Br, -OCHI, 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).

[0049] As used herein, a "size-limited substituent" or "size-limited substituent" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, 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-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0050] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent," 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.

[0051] 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., 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., 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).

[0052] 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, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0053] 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-limiting substituent, and when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0054] 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, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0055] In embodiments, a substituted moiety (e.g., 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) is substituted with at least one substituent, size-limiting substituent, or lower substituent; when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be different.

[0056] In embodiments of the compounds herein, each substituted or unsubstituted alkyl can be a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted 2-20 membered heteroalkyl, and each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C3-C8 cycloalkyl. wherein each substituted or unsubstituted heterocycloalkyl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 3-8 membered heterocycloalkyl, each or unsubstituted aryl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 5-10 membered heteroaryl. In embodiments herein, each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted 2-20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C3-C8 cycloalkylene, and each The substituted or unsubstituted heterocycloalkylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 3- to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 5- to 10-membered heteroarylene.

[0057] In embodiments, each substituted or unsubstituted alkyl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 3-7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 5-9 membered heteroaryl. In embodiments, each substituted or unsubstituted alkylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, each substituted or unsubstituted arylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 5-9 membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0058] Certain compounds provided herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)-, (S)-, (D)-, or (L) for amino acids, are encompassed within the scope of this disclosure. The compounds provided herein do not include compounds known in the art to be too unstable to synthesize and / or isolate. The compounds provided herein include 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 compounds described herein contain olefinic bonds or other geometrically asymmetric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0059] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0060] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0061] It will be apparent to one of ordinary skill 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.

[0062] When 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 individual isomers or selective synthesis of individual isomers can be achieved by applying various methods well known to practitioners of the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Unless otherwise specified, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the (R) and (S) configurations of each asymmetric center. Thus, single stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the compounds, that are generally recognized by those skilled in the art as stable, are within the scope of the present disclosure.

[0063] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, fluoride by F, or the replacement of a carbon by a C- or C-enriched carbon are within the scope of this disclosure.

[0064] 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 tritium (H), iodine-125 (I), or carbon-14 (C). All isotopic variations of the compounds provided herein, whether radioactive or not, are included within the present disclosure.

[0065] It should be noted that throughout this application, alternatives, e.g., each amino acid position containing more than one possible amino acid, are described in terms of a Markush group. It is specifically contemplated that each member of a Markush group should be considered separately, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0066] "Analog" or "analogue" is used according to its plain and ordinary meaning within chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0067] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with a[n]" means that the specified group can be substituted with one or more of any or all of the specified substituents. For example, if a group such as an alkyl group or heteroaryl group is "substituted with unsubstituted C1-C20 alkyl or unsubstituted 2-20 membered heteroalkyl," the group can include one or more unsubstituted C1-C20 alkyl and / or one or more unsubstituted 2-20 membered heteroalkyl.

[0068] Additionally, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group is present in a description of a chemical genus (such as Formula (I)), Roman numeral decimal notation may be used to distinguish between each occurrence of that particular R group. For example, when multiple R substituents are present, each R substituent may be distinguished as R13.1, R13.2, R13.3, R13.4, etc., where R13.1, R13.2, R13.3, R13.4, etc. are each defined within the definition of R and are optionally different. As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with a[n]" means that the specified group may be substituted with one or more of any or all of the specified substituents. For example, if a group such as an alkyl group or heteroaryl group is "substituted with unsubstituted C1-C20 alkyl or unsubstituted 2-20 membered heteroalkyl," the group can include one or more unsubstituted C1-C20 alkyls and / or one or more unsubstituted 2-20 membered heteroalkyls.

[0069] The description of compounds provided herein is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when group can be substituted with one or more of several substituents, such substitutions are selected to comply with the principles of chemical bonding and to bring about compounds that are not inherently unstable and / or are known by those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0070] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of a compound and are not undesirable for biological or other pharmaceutical uses. 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 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, etc., with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., in particular, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO87 / 05297, Johnston et al., published September 11, 1987 (the entirety of which is incorporated herein by reference).

[0071] "Contacting" is used according to its plain and ordinary meaning to refer to the process of allowing at least two different species (e.g., chemical compounds, biomolecules, or cells) to come into sufficient proximity to react, interact, or come into physical contact. For example, contacting includes the process of allowing a compound to come into sufficient proximity with a cell to bind to a cell surface receptor.

[0072] 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 in close enough proximity to induce a desired biological effect within the cell.

[0073] As defined herein, terms such as "inhibition," "inhibit," "inhibiting," and the like refer to adversely affecting (e.g., decreasing) an activity or function compared to the activity or function in the absence of the inhibitor. In embodiments, inhibition refers to adversely affecting (e.g., decreasing) the concentration or level of a biomolecule, such as a protein or mRNA, compared 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 decrease in the activity of a specific biomolecular target, e.g., a protein target or an mRNA target. Thus, inhibition includes at least partially, partially, or completely blocking a stimulus; reducing, preventing, or delaying activation; or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a biomolecule. In embodiments, inhibition refers to a decrease in the activity of a target biomolecule resulting from a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a decrease in the activity of a target biomolecule from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0074] The term "inhibitor" also refers to a compound, composition, or substance that can detectably reduce the expression or activity of a given gene or protein. For example, an inhibitor may reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control in the absence of the inhibitor. Inhibitors include, for example, biological molecules such as synthetic molecules or oligonucleotides.

[0075] As used herein, the terms "expression" and "gene expression" refer to the steps involved in translating nucleic acids into proteins, including mRNA expression and protein expression. Expression can be detected using conventional techniques for detecting nucleic acids or proteins (e.g., PCR, ELISA, Southern blot, Southern blotting, Western blotting, flow cytometry, FISH, immunofluorescence, immunohistochemistry).

[0076] An "effective amount" is an amount of a compound sufficient to achieve a specified purpose (e.g., achieve an effect in a subject to which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or alleviate one or more symptoms of a disease or condition) compared to the absence of the compound. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein compared to the absence of the antagonist.

[0077] As used herein, the term "in vivo" refers to a process that takes place within the body of a subject.

[0078] As used herein, the term "subject" means a human or non-human animal selected for treatment or therapy. In embodiments, the subject is a human.

[0079] As used herein, the term "ex vivo" refers to a process carried out in vitro on isolated tissues or cells, where the treated tissues or cells include 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 tissues or cells non-viable. In embodiments, the ex vivo process is carried out in vitro using primary cells.

[0080] The term "administration" means providing an agent or composition to a subject and includes administration by a medical professional and self-administration.

[0081] The term "therapy" refers to the application of one or more specific procedures used to improve at least one indication or disease or condition. In embodiments, the specific procedure is the administration of one or more drugs.

[0082] The term "modulate" is used herein in its ordinary sense as understood by those skilled in the art, and thus refers to the act of changing or altering one or more characteristics. For example, in terms of the effect of a modulator on a target molecule, it means modulating the properties or function of the target molecule, or a means for changing the amount of the target molecule by increasing or decreasing it. A disease modulator reduces the symptoms, causes, or characteristics of the target disease.

[0083] The term "nucleic acid" refers to a compound comprising at least two nucleotide monomers covalently linked to each other. Nucleic acids include polynucleotides and oligonucleotides, including double-stranded and single-stranded oligonucleotides, and modified versions thereof.

[0084] The term "polynucleotide" refers to nucleic acids of longer lengths, such as 200, 300, 500, 1000, 2000, 3000, 5000, 7000, or 10,000 nucleotides in length. Non-limiting examples of polynucleotides include genes, gene fragments, exons, introns, intergenic DNA (including, but not limited to, heterochromatic DNA), messenger RNA (mRNA), long non-coding RNA, transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA sequences, and isolated RNA sequences. Polynucleotides useful in the methods of the present disclosure can include naturally occurring nucleic acid sequences and their variants, artificial nucleic acid sequences, or combinations of such sequences.

[0085] The term "oligonucleotide" refers to a shorter length nucleic acid, for example, a nucleic acid less than 100 nucleotides in length. Oligonucleotides can be single-stranded or double-stranded. Oligonucleotides can include naturally occurring ribonucleotides, naturally occurring deoxyribonucleotides, and / or naturally occurring nucleotides with one or more modifications to the terminus, sugar, nucleobase, and / or internucleotide bond. Non-limiting examples of oligonucleotides include double-stranded oligonucleotides, single-stranded oligonucleotides, antisense oligonucleotides, small interfering RNAs (siRNAs), microRNA mimics, short hairpin RNAs (shRNAs), single-stranded small interfering RNAs (ssRNAi), RNase H oligonucleotides, anti-microRNA oligonucleotides, steric blocking oligonucleotides, exon skipping oligonucleotides, CRISPR guide RNAs, and aptamers.

[0086] The term "double-stranded oligonucleotide" refers to an oligonucleotide that is substantially double-stranded. A double-stranded oligonucleotide may include a structure in which a duplex region is formed between two non-covalently linked antiparallel oligonucleotides, such as siRNA or microRNA mimics. Such double-stranded oligonucleotides may have short nucleotide overhangs at one or both ends of the duplex structure. A double-stranded oligonucleotide may also include a single oligonucleotide that is long enough and self-complementary to form a double-stranded structure, such as shRNA. Such double-stranded oligonucleotides include stem-loop structures. A double-stranded nucleic acid may include one or more modifications to the naturally occurring termini, sugars, nucleobases, and / or phosphate groups. Non-limiting examples of double-stranded oligonucleotides include small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA mimics.

[0087] The term "small interfering RNA" or "siRNA" refers to a double-stranded oligonucleotide formed from separate antisense and sense strands that interferes with gene expression in a sequence-specific manner by promoting pre-translational mRNA degradation via the RNA interference pathway. The antisense and sense strands of siRNA are not covalently linked.

[0088] The term "microRNA mimic" refers to a synthetic version of a naturally occurring microRNA. A microRNA mimic includes an antisense strand complementary to one or more target mRNAs and a sense strand complementary to the antisense strand. In naturally occurring microRNAs, the antisense strand is typically only partially complementary to its target mRNA, and the sense strand is only partially complementary to the antisense strand. A microRNA mimic may include a nucleobase sequence that is 100% identical to a naturally occurring microRNA, or may include a nucleobase sequence that is less than 100% identical to a naturally occurring microRNA. For example, a microRNA mimic may include a sense strand that is 100% complementary to the antisense strand.

[0089] The term "single-stranded RNA interference" or "ssRNAi" refers to a single-stranded oligonucleotide that interferes with the expression of genes in a sequence-specific manner by promoting pre-translational mRNA degradation via the RNA interference pathway.

[0090] The term "antisense strand" refers to the siRNA or ssRNAi oligonucleotide that is complementary to target mRNA, is incorporated into RNA-induced silencing complex (RISC), and induces sequence-specific gene silencing via the RNA interference pathway.Antisense strand is sometimes also called "guide strand".

[0091] The term "sense strand" refers to an oligonucleotide that is complementary to the antisense strand of a double-stranded oligonucleotide. The sense strand is typically degraded after the antisense strand is incorporated into RISC. The sense strand is sometimes referred to as the "passenger strand."

[0092] The term "duplex region" refers to the structure formed by nucleotide base pairing of complementary oligonucleotide sequences. The duplex region can be formed from a portion of the complementary sequence or from the full-length complementary sequence.

[0093] The term "short hairpin RNA" or "shRNA" refers to a double-stranded oligonucleotide containing a loop structure that is processed intracellularly into siRNA that interferes with gene expression in a sequence-specific manner by promoting pre-translational mRNA degradation via the RNA interference pathway.

[0094] The term "nucleotide overhang" refers to adjacent single-stranded nucleotides at the ends of an oligonucleotide in a double-stranded oligonucleotide.

[0095] The term " single-stranded oligonucleotide " refers to the oligonucleotide that is not hybridized with complementary strand.Non-limiting examples of single-stranded oligonucleotide include single-stranded small interfering RNA (ssRNAi), RNaseH oligonucleotide (the oligonucleotide that is chemically modified to induce the degradation of target RNA via RNaseH), anti-microRNA oligonucleotide (the oligonucleotide that is complementary to microRNA), steric blocking oligonucleotide (the oligonucleotide that interferes with the activity of target RNA without degrading target RNA), exon skipping oligonucleotide (the oligonucleotide that hybridizes with exon annealing site and changes splicing), CRISPR guide RNA and aptamer.

[0096] The term "hybridize" refers to the annealing of one nucleic acid to another nucleic acid based on the complementarity of the nucleic acid base sequences. In embodiments, the antisense strand hybridizes with the sense strand. In embodiments, the antisense strand hybridizes with the target mRNA sequence.

[0097] The term "complementary" refers to nucleobases capable of non-covalently pairing through hydrogen bonding.

[0098] The term "fully complementary" means that each nucleic acid base of the first nucleic acid is complementary to each nucleic acid base of the second nucleic acid.In an embodiment, the antisense strand is completely complementary to its target mRNA.In an embodiment, the sense strand and the antisense strand of the double-stranded oligonucleotide are completely complementary over their entire length.In an embodiment, the sense strand and the antisense strand of the double-stranded oligonucleotide are completely complementary over the entire length of the double-stranded region of the siRNA, and one or both ends of either strand contain single-stranded nucleotides.

[0099] The term "nucleoside" refers to a monomer of a nucleobase and a pentofuranosyl sugar (e.g., either ribose or deoxyribose). A nucleoside can be modified at the nucleobase and / or sugar. In embodiments, a nucleoside is a deoxyribonucleoside. In embodiments, a nucleoside is a ribonucleoside.

[0100] The term "nucleotide" refers to a nucleoside covalently linked to the phosphate group of the 5' carbon of a pentafuranosyl sugar. The nucleotide may be modified at one or more of the nucleobase, sugar, or phosphate group. The nucleotide may have a ligand attached directly or via a linker. In embodiments, the nucleotide is a deoxyribonucleotide. In embodiments, the nucleotide is a ribonucleotide.

[0101] The term "nucleobase" refers to the heterocyclic base portion of a nucleoside or nucleotide. Non-limiting examples of nucleobases include cytosine or a derivative thereof (e.g., a cytosine analog), guanine or a derivative thereof (e.g., a guanine analog), adenine or a derivative thereof (e.g., an adenine analog), thymine or a derivative thereof (e.g., a thymine analog), uracil or a derivative thereof (e.g., a uracil analog), hypoxanthine or a derivative thereof (e.g., a hypoxanthine analog), xanthine or a derivative thereof (e.g., a xanthine analog), 7-methylguanine or a derivative thereof (e.g., a 7-methylguanine analog), and 7-methylguanine or a derivative thereof (e.g., a 7-methylguanine analog). In embodiments, the nucleobase may be adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, or isoguanine, and may optionally be substituted or modified. In embodiments, the nucleobase may be adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, or isoguanine, and may optionally be substituted or modified. In embodiments, the nucleobase may be adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, or isoguanine, and may optionally be substituted or modified. In embodiments, the nucleobase may be adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, or isoguanine, and may optionally be substituted or modified. [ka] and may be optionally substituted or modified.

[0102] The term "modified nucleotide" refers to a nucleotide having one or more modifications relative to naturally occurring nucleotides. Modifications can occur in the internucleoside linkage between the nucleotides, the nucleobase, and / or the sugar moiety. Modified nucleotides can be selected over unmodified forms for desirable properties, such as enhanced cellular uptake, enhanced affinity for other oligonucleotides or nucleic acid targets, increased stability in the presence of nucleases, and / or reduced immune stimulation. Modified nucleotides can have modified sugar moieties and unmodified phosphate groups. Modified nucleotides can have unmodified sugar moieties and modified phosphate groups. Modified nucleotides can have modified sugar moieties and unmodified nucleobases. Modified nucleotides can have modified sugar moieties and modified phosphate groups. Nucleic acids, polynucleotides, and oligonucleotides can contain one or more modified nucleotides.

[0103] As used herein, the term "complement" refers to a nucleotide (e.g., RNA or DNA) or sequence of nucleotides that can base-pair with a complementary nucleotide or sequence of nucleotides. As described herein and generally known in the art, the complementary (matching) nucleotide of adenosine is thymidine, and the complementary (matching) nucleotide of guanidine is cytosine. Thus, a complement can include a sequence of nucleotides that base-pair with the corresponding complementary nucleotides of a second nucleic acid sequence. The complementary nucleotides can partially or completely match the nucleotides of the second nucleic acid sequence. When the complementary nucleotides completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. When the complementary nucleotides partially match the nucleotides of the second nucleic acid sequence, only a portion of the complementary nucleotides form base pairs with the nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding sequences and non-coding sequences, where the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of a complementary sequence is a sense sequence and an antisense sequence, where the sense sequence comprises complementary nucleotides to the antisense sequence, thus forming the complement of the antisense sequence.

[0104] As described herein, when sequence complementarity is partial, only some nucleic acids are matched according to base pairing, or when complete, all nucleic acids are matched according to base pairing.Therefore, two sequences that are complementary to each other can have a certain percentage of nucleotides involved in nucleic acid base pairing (i.e., about 60% complementarity over a certain region, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher complementarity).

[0105] "Hybridize" refers to 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 certain embodiments, the other nucleic acid is a single-stranded nucleic acid. The tendency for hybridization between nucleic acids depends on the temperature and ionic strength of their environment, the length of the nucleic acid, and the degree of complementarity. The effects of these parameters on hybridization are described, for example, in Sambrook J, Fritsch EF, Maniatis T., Molecular cloning: a laboratory manual, Cold Spring Harbor Laboratory Press, New York (1989). As used herein, the hybridization of a primer or DNA extension product is extendible by phosphodiester bond formation with an available nucleotide or nucleotide analog, respectively, that can form a phosphodiester bond.

[0106] The term "identical" or percentage "identity" refers to a specified percentage of amino acid residues or nucleotides that are the same or identical (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%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 1510%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, 159%, 16 "Identity" refers to two or more sequences or subsequences that share (or have) at least one identity (e.g., 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 two of the foregoing values). This definition also refers to or can be applied to the complement of a test sequence. The definition also includes sequences with deletions and / or additions, as well as those with substitutions. As described below, preferred algorithms can account for gaps, insertions, etc. Alignment for purposes of determining percent sequence identity can be accomplished in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared, can be determined by known methods.

[0107] compound In particular, compounds are provided that include a nucleic acid (A) covalently linked to one or more half-life extending motifs (HLEMs). For example, the compound includes a nucleic acid (A) covalently linked to one half-life extending motif (HLEM), two half-life extending motifs (HLEMs), three half-life extending motifs (HLEMs), four half-life extending motifs (HLEMs), or five half-life extending motifs (HLEMs).

[0108] In one aspect, the compound has the formula (I): (HLEM)zA (I), In the formula, z is an integer of 1 to 5.

[0109] 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.

[0110] In one embodiment, the nucleic acid is covalently linked to one or more uptake motifs (UM), for example, the nucleic acid is covalently linked to one uptake motif (UM), two uptake motifs (UM), three uptake motifs (UM), four uptake motifs (UM), or five uptake motifs (UM).

[0111] In one embodiment, the compound has the formula (II): (HLEM)zA-(UM)t (II), In the formula, t is an integer of 1 to 5.

[0112] 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.

[0113] In embodiments, the half-life extending motif has the structure: [ka] k is an integer of 1 to 5.

[0114] L1 is independently a covalent linker. L2 is independently an unsubstituted alkylene.

[0115] In an embodiment, k is 1. In an embodiment, k is 2. In an embodiment, k is 3. In an embodiment, k is 4. In an embodiment, k is 5. In an embodiment, k is an integer from 1 to 3. In an embodiment, k is an integer from 1 to 2.

[0116] In embodiments, one or more L2 may bind to one or more atoms of L1. In embodiments, one or more L2 may bind to one or more atoms of L1, and the one or more atoms may be the same or different. In embodiments, one or more L2 bind to the same atom. In embodiments, one or more L2 bind to different atoms. In embodiments, one or more L2 bind to the same or different atoms.

[0117] In embodiments, one or more L2 may independently bind to L1A, L1B, L1C, L1D, or L1E. In embodiments, L2 may independently bind to L1A. In embodiments, one L2 may independently bind to L1B. In embodiments, one L2 may independently bind to L1C. In embodiments, one L2 may independently bind to L1D. In embodiments, one L2 may independently bind to L1E.

[0118] In embodiments, L1A, L1B, L1C, L1D, and L1E are 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—, —OP(O)(S)—O—, —OP(O)(R22)-O—, —OP(S)(R22)-O—, —OP(O)(NR20R21)-N—, —OP(S)(NR20 R21)-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-, -SS-, 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, R21, and R22 is independently hydrogen or unsubstituted C1-C10 alkyl.

[0119] In embodiments, one or more L2 may independently bind to L1A, L1B, L1C, L1D, or L1E. In embodiments, one or more L2 may independently bind to L1A. In embodiments, one or more L2 may independently bind to L1B. In embodiments, one or more L2 may independently bind to L1C. In embodiments, one or more L2 may independently bind to L1D. In embodiments, one or more L2 may independently bind to L1E.

[0120] In embodiments, at least one L2 may independently bind to L1A. In embodiments, at least one L2 may independently bind to L1B. In embodiments, at least one L2 may independently bind to L1C. In embodiments, at least one L2 may independently bind to L1D. In embodiments, at least one L2 may independently bind to L1E.

[0121] In embodiments, one L2 may independently bind to L1A. In embodiments, one L2 may independently bind to L1B. In embodiments, one L2 may independently bind to L1C. In embodiments, one L2 may independently bind to L1D. In embodiments, one L2 may independently bind to L1E.

[0122] In embodiments, L1A is selected from the group consisting of 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-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(S)(R22)-O-, -OP(O)(NR20R21)-N-, -OP(S)(NR20R21)-N-, -OP( O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-, -SS-, 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.

[0123] In embodiments, L1A is a bond. In embodiments, L1A is -N(R20)-. In embodiments, L1A is -O- or -S-. In embodiments, L1A is -C(O)-. In embodiments, L1A is -N(R20)C(O)- or -C(O)N(R21)-. In embodiments, L1A is -N(R20)C(O)N(R21)-. In embodiments, L1A is -C(O)O- or -OC(O)-. In embodiments, L1A is -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1A is -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(O)(NR20R21)-N-, or -OP(O)(NR20R21)-O-. In embodiments, L1A is -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, or -P(S)(NR20R21)-O-. In embodiments, L1A is -SS-.

[0124] In embodiments, L1A is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1A is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1A is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1A is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1A is independently substituted C1-C20 alkylene. In embodiments, L1A is independently unsubstituted C1-C20 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1A is independently substituted C1-C12 alkylene. In embodiments, L1A is independently unsubstituted C1-C12 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1A is independently substituted C1-C8 alkylene. In embodiments, L1A is independently unsubstituted C1-C8 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1A is independently substituted C1-C6 alkylene. In embodiments, L1A is independently unsubstituted C1-C6 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1A is independently substituted C1-C4 alkylene. In embodiments, L1A is independently unsubstituted C1-C4 alkylene. In embodiments, L1A is independently substituted or unsubstituted ethylene. In embodiments, L1A is independently substituted ethylene. In embodiments, L1A is independently unsubstituted ethylene. In embodiments, L1A is independently substituted or unsubstituted methylene. In embodiments, L1A is independently substituted methylene. In embodiments, L1A is independently unsubstituted methylene.

[0125] In embodiments, L1A is independently substituted or unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1A is independently substituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1A is independently unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1A is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L1A is independently substituted 2-20 membered heteroalkylene. In embodiments, L1A is independently unsubstituted 2- to 20-membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1A is independently substituted 2- to 8-membered heteroalkylene. In embodiments, L1A is independently unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1A is independently substituted 2- to 6-membered heteroalkylene. In embodiments, L1A is independently unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1A is independently substituted 4- to 6-membered heteroalkylene. In embodiments, L1A is independently unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L1A is independently substituted 2-3 membered heteroalkylene. In embodiments, L1A is independently unsubstituted 2-3 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 4-5 membered heteroalkylene. In embodiments, L1A is independently substituted 4-5 membered heteroalkylene. In embodiments, L1A is independently unsubstituted 4-5 membered heteroalkylene.

[0126] In embodiments, L1B is selected from the group consisting of 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-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(S)(R22)-O-, -OP(O)(NR20R21)-N-, -OP(S)(NR20R21)-N-, -OP( O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-, -SS-, 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.

[0127] In embodiments, L1B is a bond. In embodiments, L1B is -N(R20)-. In embodiments, L1B is -O- or -S-. In embodiments, L1B is -C(O)-. In embodiments, L1B is -N(R20)C(O)- or -C(O)N(R21)-. In embodiments, L1B is -N(R20)C(O)N(R21)-. In embodiments, L1B is -C(O)O- or -OC(O)-. In embodiments, L1B is -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1B is -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(O)(NR20R21)-N-, or -OP(O)(NR20R21)-O-. In embodiments, L1B is -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, or -P(S)(NR20R21)-O-. In embodiments, L1B is -SS-.

[0128] In embodiments, L1B is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1B is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1B is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1B is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1B is independently substituted C1-C20 alkylene. In embodiments, L1B is independently unsubstituted C1-C20 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1B is independently substituted C1-C12 alkylene. In embodiments, L1B is independently unsubstituted C1-C12 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1B is independently substituted C1-C8 alkylene. In embodiments, L1B is independently unsubstituted C1-C8 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1B is independently substituted C1-C6 alkylene. In embodiments, L1B is independently unsubstituted C1-C6 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1B is independently substituted C1-C4 alkylene. In embodiments, L1B is independently unsubstituted C1-C4 alkylene. In embodiments, L1B is independently substituted or unsubstituted ethylene. In embodiments, L1B is independently substituted ethylene. In embodiments, L1B is independently unsubstituted ethylene. In embodiments, L1B is independently substituted or unsubstituted methylene. In embodiments, L1B is independently substituted methylene. In embodiments, L1B is independently unsubstituted methylene.

[0129] In embodiments, L1B is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). In embodiments, L1B is independently substituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). In embodiments, L1B is independently unsubstituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). In embodiments, L1B is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L1B is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L1B is independently an unsubstituted 2- to 20-membered heteroalkylene. In embodiments, L1B is independently a substituted or unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1B is independently a substituted 2- to 8-membered heteroalkylene. In embodiments, L1B is independently an unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1B is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1B is independently a substituted 2- to 6-membered heteroalkylene. In embodiments, L1B is independently an unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1B is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1B is independently a substituted 4- to 6-membered heteroalkylene. In embodiments, L1B is independently an unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L1B is independently substituted 2-3 membered heteroalkylene. In embodiments, L1B is independently unsubstituted 2-3 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 4-5 membered heteroalkylene. In embodiments, L1B is independently substituted 4-5 membered heteroalkylene. In embodiments, L1B is independently unsubstituted 4-5 membered heteroalkylene.

[0130] In embodiments, L1C is selected from the group consisting of 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-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(S)(R22)-O-, -OP(O)(NR20R21)-N-, -OP(S)(NR20R21)-N-, -OP( O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-, -SS-, 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.

[0131] In embodiments, L1C is a bond. In embodiments, L1C is -N(R20)-. In embodiments, L1C is -O- or -S-. In embodiments, L1C is -C(O)-. In embodiments, L1C is -N(R20)C(O)- or -C(O)N(R21)-. In embodiments, L1C is -N(R20)C(O)N(R21)-. In embodiments, L1C is -C(O)O- or -OC(O)-. In embodiments, L1C is -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1C is -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(O)(NR20R21)-N-, or -OP(O)(NR20R21)-O-. In embodiments, L1C is -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, or -P(S)(NR20R21)-O-. In embodiments, L1C is -SS-.

[0132] In embodiments, L1C is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1C is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1C is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1C is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1C is independently substituted C1-C20 alkylene. In embodiments, L1C is independently unsubstituted C1-C20 alkylene. In embodiments, L1C is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1C is independently substituted C1-C12 alkylene. In embodiments, L1C is independently unsubstituted C1-C12 alkylene. In embodiments, L1C is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1C is independently substituted C1-C8 alkylene. In embodiments, L1C is independently unsubstituted C1-C8 alkylene. In embodiments, L1C is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1C is independently substituted C1-C6 alkylene. In embodiments, L1C is independently unsubstituted C1-C6 alkylene. In embodiments, L1C is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1C is independently substituted C1-C4 alkylene. In embodiments, L1C is independently unsubstituted C1-C4 alkylene. In embodiments, L1C is independently substituted or unsubstituted ethylene. In embodiments, L1C is independently substituted ethylene. In embodiments, L1C is independently unsubstituted ethylene. In embodiments, L1C is independently substituted or unsubstituted methylene. In embodiments, L1C is independently substituted methylene. In embodiments, L1C is independently unsubstituted methylene.

[0133] In embodiments, L1C is independently substituted or unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1C is independently substituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1C is independently unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1C is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L1C is independently substituted 2-20 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2- to 20-membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1C is independently substituted 2- to 8-membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1C is independently substituted 2- to 6-membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1C is independently substituted 4- to 6-membered heteroalkylene. In embodiments, L1C is independently unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L1C is independently substituted 2-3 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2-3 membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 4-5 membered heteroalkylene. In embodiments, L1C is independently substituted 4-5 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 4-5 membered heteroalkylene.

[0134] In embodiments, L1D is selected from the group consisting of 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-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(S)(R22)-O-, -OP(O)(NR20R21)-N-, -OP(S)(NR20R21)-N-, -OP( O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-, -SS-, 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.

[0135] In embodiments, L1D is a bond. In embodiments, L1D is -N(R20)-. In embodiments, L1D is -O- or -S-. In embodiments, L1D is -C(O)-. In embodiments, L1D is -N(R20)C(O)- or -C(O)N(R21)-. In embodiments, L1D is -N(R20)C(O)N(R21)-. In embodiments, L1D is -C(O)O- or -OC(O)-. In embodiments, L1D is -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L1D is -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(O)(NR20R21)-N-, or -OP(O)(NR20R21)-O-. In embodiments, L1D is -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, or -P(S)(NR20R21)-O-. In embodiments, L1D is -SS-.

[0136] In embodiments, L1D is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1D is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1D is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L1D is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1D is independently substituted C1-C20 alkylene. In embodiments, L1D is independently unsubstituted C1-C20 alkylene. In embodiments, L1D is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1D is independently substituted C1-C12 alkylene. In embodiments, L1D is independently unsubstituted C1-C12 alkylene. In embodiments, L1D is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1D is independently substituted C1-C8 alkylene. In embodiments, L1D is independently unsubstituted C1-C8 alkylene. In embodiments, L1D is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1D is independently substituted C1-C6 alkylene. In embodiments, L1D is independently unsubstituted C1-C6 alkylene. In embodiments, L1D is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1D is independently substituted C1-C4 alkylene. In embodiments, L1D is independently unsubstituted C1-C4 alkylene. In embodiments, L1D is independently substituted or unsubstituted ethylene. In embodiments, L1D is independently substituted ethylene. In embodiments, L1D is independently unsubstituted ethylene. In embodiments, L1D is independently substituted or unsubstituted methylene. In embodiments, L1D is independently substituted methylene. In embodiments, L1D is independently unsubstituted methylene.

[0137] In embodiments, L1D is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). In embodiments, L1D is independently substituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). In embodiments, L1D is independently unsubstituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). In embodiments, L1D is independently substituted or unsubstituted 2 to 20-membered heteroalkylene. In embodiments, L1D is independently substituted 2 to 20-membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2- to 20-membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1D is independently substituted 2- to 8-membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1D is independently substituted 2- to 6-membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1D is independently substituted 4- to 6-membered heteroalkylene. In embodiments, L1D is independently unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L1D is independently substituted 2-3 membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2-3 membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 4-5 membered heteroalkylene. In embodiments, L1D is independently substituted 4-5 membered heteroalkylene. In embodiments, L1D is independently unsubstituted 4-5 membered heteroalkylene.

[0138] In embodiments, L1E is selected from the group consisting of 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-, -OP(O)(S)-O-, -OP(O)(R22)-O-, -OP(S)(R22)-O-, -OP(O)(NR20R21)-N-, -OP(S)(NR20R21)-N-, -OP( O)(NR20R21)-O-, -O-P(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O)(NR20R21)-O-, -P(S)(NR20R21)-O-, -SS-, 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.

[0139] In embodiments, L1E is a bond. In embodiments, L1E is -N(R20)-. In embodiments, L1E is -O- or -S-. In embodiments, L1E is -C(O)-. In embodiments, L1E is -N(R20)C(O)- or -C(O)N(R21)-. In embodiments, L1E is -N(R20)C(O)N(R21)-. In embodiments, L1E is -C(O)O- or -OC(O)-. In embodiments, L1E is -N(R20)C(O)O- or -OC(O)N(R21)-. In embodiments, L is -OPO-O-, -OP(O)(S)-O-, -OP(O)(R)-O-, -OP(O)(NR)-N-, or -OP(O)(NR)-O-. In embodiments, L is -P(O)(NR)-N-, -P(S)(NR)-N-, -P(O)(NR)-O-, or -P(S)(NR)-O-. In embodiments, L is -SS-.

[0140] In embodiments, LIE is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, LIE is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, LIE is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, LIE is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, LIE is independently substituted C1-C20 alkylene. In embodiments, LIE is independently unsubstituted C1-C20 alkylene. In embodiments, LIE is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, LIE is independently substituted C1-C12 alkylene. In embodiments, LIE is independently unsubstituted C1-C12 alkylene. In embodiments, LIE is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, LIE is independently substituted C1-C8 alkylene. In embodiments, LIE is independently unsubstituted C1-C8 alkylene. In embodiments, LIE is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, LIE is independently substituted C1-C6 alkylene. In embodiments, LIE is independently unsubstituted C1-C6 alkylene. In embodiments, LIE is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, LIE is independently substituted C1-C4 alkylene. In embodiments, LIE is independently unsubstituted C1-C4 alkylene. In embodiments, LIE is independently substituted or unsubstituted ethylene. In embodiments, LIE is independently substituted ethylene. In embodiments, LIE is independently unsubstituted ethylene. In embodiments, LIE is independently substituted or unsubstituted methylene. In embodiments, LIE is independently substituted methylene. In embodiments, LIE is independently unsubstituted methylene.

[0141] In embodiments, L1E is independently substituted or unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1E is independently substituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1E is independently unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L1E is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L1E is independently substituted 2-20 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2- to 20-membered heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1E is independently substituted 2- to 8-membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2- to 8-membered heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1E is independently substituted 2- to 6-membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2- to 6-membered heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1E is independently substituted 4- to 6-membered heteroalkylene. In embodiments, L1E is independently unsubstituted 4- to 6-membered heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L1E is independently substituted 2-3 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2-3 membered heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 4-5 membered heteroalkylene. In embodiments, L1E is independently substituted 4-5 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 4-5 membered heteroalkylene.

[0142] In embodiments, each R20, R21, and R22 is independently hydrogen or unsubstituted C1-C10 alkyl.

[0143] In embodiments, R20 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R20 is independently hydrogen. In embodiments, R20 is unsubstituted C1-C10 alkyl. In embodiments, R20 is unsubstituted C1-C8 alkyl. In embodiments, R20 is unsubstituted C1-C6 alkyl. In embodiments, R20 is unsubstituted C1-C5 alkyl. In embodiments, R20 is unsubstituted C1-C4 alkyl. In embodiments, R20 is unsubstituted C1-C3 alkyl. In embodiments, R20 is unsubstituted methyl. In embodiments, R20 is unsubstituted ethyl. In embodiments, R20 is unsubstituted propyl. In embodiments, R20 is unsubstituted isopropyl. In embodiments, R20 is unsubstituted n-butyl. In embodiments, R20 is unsubstituted t-butyl. In embodiments, R20 is unsubstituted 2-butyl. In an embodiment, R20 is unsubstituted isobutyl.

[0144] In embodiments, R21 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R21 is independently hydrogen. In embodiments, R21 is unsubstituted C1-C10 alkyl. In embodiments, R21 is unsubstituted C1-C8 alkyl. In embodiments, R21 is unsubstituted C1-C6 alkyl. In embodiments, R21 is unsubstituted C1-C5 alkyl. In embodiments, R21 is unsubstituted C1-C4 alkyl. In embodiments, R21 is unsubstituted C1-C3 alkyl. In embodiments, R21 is unsubstituted methyl. In embodiments, R21 is unsubstituted ethyl. In embodiments, R21 is unsubstituted propyl. In embodiments, R21 is unsubstituted isopropyl. In embodiments, R21 is unsubstituted n-butyl. In embodiments, R21 is unsubstituted t-butyl. In embodiments, R21 is unsubstituted 2-butyl. In an embodiment, R21 is unsubstituted isobutyl.

[0145] In embodiments, R22 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R22 is independently hydrogen. In embodiments, R22 is unsubstituted C1-C10 alkyl. In embodiments, R22 is unsubstituted C1-C8 alkyl. In embodiments, R22 is unsubstituted C1-C6 alkyl. In embodiments, R22 is unsubstituted C1-C5 alkyl. In embodiments, R22 is unsubstituted C1-C4 alkyl. In embodiments, R22 is unsubstituted C1-C3 alkyl. In embodiments, R22 is unsubstituted methyl. In embodiments, R22 is unsubstituted ethyl. In embodiments, R22 is unsubstituted propyl. In embodiments, R22 is unsubstituted isopropyl. In embodiments, R22 is unsubstituted n-butyl. In embodiments, R22 is unsubstituted t-butyl. In embodiments, R22 is unsubstituted 2-butyl. In an embodiment, R22 is unsubstituted isobutyl.

[0146] In embodiments, each of R20, R21, and R22 is independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R20 is hydrogen and each R21 and R22 is independently unsubstituted C1-C3 alkyl. In embodiments, R21 is hydrogen and each R20 and R22 is independently unsubstituted C1-C3 alkyl. In embodiments, R22 is hydrogen and each R20 and R21 is independently unsubstituted C1-C3 alkyl. In embodiments, R20, R21, and R22 are hydrogen. In embodiments, R20 is unsubstituted C1-C3 alkyl and R21 and R22 are hydrogen. In embodiments, R21 is unsubstituted C1-C3 alkyl and R20 and R22 are hydrogen. In embodiments, R22 is unsubstituted C1-C3 alkyl and R20 and R21 are hydrogen. In an embodiment, each of R20, R21, and R22 is independently unsubstituted C1-C3 alkyl.

[0147] In embodiments, L2 is independently unsubstituted C2-C24 alkylene. In embodiments, L2 is independently unsubstituted C2-C22 alkylene. In embodiments, L2 is independently unsubstituted C5-C22 alkylene. In embodiments, L2 is independently unsubstituted C10-C22 alkylene. In embodiments, L2 is independently unsubstituted C12-C22 alkylene. In embodiments, L2 is independently unsubstituted C10-C20 alkylene. In embodiments, L2 is independently unsubstituted C12-C20 alkylene. In embodiments, L2 is independently unsubstituted C10-C18 alkylene. In embodiments, L2 is independently unsubstituted C12-C18 alkylene. In embodiments, L2 is independently unsubstituted C10-C16 alkylene. In embodiments, L2 is independently an unsubstituted C12-C16 alkylene. In embodiments, L2 is independently an unsubstituted C14-C16 alkylene. In embodiments, L2 is independently an unsubstituted C14-C15 alkylene. In embodiments, L2 is independently an unsubstituted C14 alkylene. In embodiments, L2 is independently an unsubstituted C15 alkylene. In embodiments, L2 is independently an unsubstituted C16 alkylene.

[0148] In embodiments, L2 is independently unsubstituted unbranched C2-C24 alkylene. In embodiments, L2 is independently unsubstituted unbranched C2-C22 alkylene. In embodiments, L2 is independently unsubstituted unbranched C5-C22 alkylene. In embodiments, L2 is independently unsubstituted unbranched C10-C22 alkylene. In embodiments, L2 is independently unsubstituted unbranched C12-C22 alkylene. In embodiments, L2 is independently unsubstituted unbranched C10-C20 alkylene. In embodiments, L2 is independently unsubstituted unbranched C12-C20 alkylene. In embodiments, L2 is independently unsubstituted unbranched C10-C18 alkylene. In embodiments, L2 is independently unsubstituted unbranched C12-C18 alkylene. In embodiments, L2 is independently unsubstituted unbranched C10-C16 alkylene. In embodiments, L2 is independently unsubstituted unbranched C12-C16 alkylene. In embodiments, L2 is independently unsubstituted unbranched C14-C16 alkylene. In embodiments, L2 is independently unsubstituted unbranched C14-C15 alkylene. In embodiments, L2 is independently unsubstituted unbranched C14 alkylene. In embodiments, L2 is independently unsubstituted unbranched C15 alkylene. In embodiments, L2 is independently unsubstituted unbranched C16 alkylene.

[0149] In embodiments, L2 is independently an unsubstituted, unbranched, saturated C2-C24 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C2-C22 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C5-C22 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C10-C22 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C12-C22 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C10-C20 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C10-C18 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C12-C18 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C10-C16 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C12-C16 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C14-C16 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C14-C15 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C14 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C15 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C16 alkylene.

[0150] In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C2-C24 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C2-C22 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C5-C22 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C10-C22 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C12-C22 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C10-C20 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C10-C18 alkylene. In embodiments, L2 is independently unsubstituted, unbranched, unsaturated C12-C18 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, unsaturated C10-C16 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, saturated C12-C16 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, unsaturated C14-C16 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, unsaturated C14-C15 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, unsaturated C14 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, unsaturated C15 alkylene. In embodiments, L2 is independently an unsubstituted, unbranched, unsaturated C16 alkylene.

[0151] In embodiments, the largest dimension of L1 is less than 200 angstroms. In embodiments, the largest dimension of L1 is less than 190 angstroms. In embodiments, the largest dimension of L1 is less than 180 angstroms. In embodiments, the largest dimension of L1 is less than 170 angstroms. In embodiments, the largest dimension of L1 is less than 160 angstroms. In embodiments, the largest dimension of L1 is less than 150 angstroms. In embodiments, the largest dimension of L1 is less than 140 angstroms. In embodiments, the largest dimension of L1 is less than 130 angstroms. In embodiments, the largest dimension of L1 is less than 120 angstroms. In embodiments, the largest dimension of L1 is less than 110 angstroms. In embodiments, the largest dimension of L1 is less than 100 angstroms. In embodiments, the largest dimension of L1 is less than 90 angstroms. In embodiments, the largest dimension of L1 is less than 80 angstroms. In embodiments, the maximum dimension of L1 is less than 70 Angstroms. In embodiments, the maximum dimension of L1 is less than 60 Angstroms. In embodiments, the maximum dimension of L1 is less than 50 Angstroms. In embodiments, the maximum dimension of L1 is less than 40 Angstroms. In embodiments, the maximum dimension of L1 is less than 30 Angstroms. In embodiments, the maximum dimension of L1 is less than 20 Angstroms. In embodiments, the maximum dimension of L1 is less than 10 Angstroms.

[0152] In embodiments, the maximum dimension of each of L1A, L1B, L1C, L1D, and L1E is independently less than 50 angstroms. In embodiments, the maximum dimension of each of L1A, L1B, L1C, L1D, and L1E is independently less than 40 angstroms. In embodiments, the maximum dimension of each of L1A, L1B, L1C, L1D, and L1E is independently less than 30 angstroms. In embodiments, the maximum dimension of each of L1A, L1B, L1C, L1D, and L1E is independently less than 20 angstroms. In embodiments, the maximum dimension of each of L1A, L1B, L1C, L1D, and L1E is independently less than 10 angstroms.

[0153] In embodiments, the largest dimension of L1A is independently less than 50 angstroms. In embodiments, the largest dimension of L1A is independently less than 40 angstroms. In embodiments, the largest dimension of L1A is independently less than 30 angstroms. In embodiments, the largest dimension of L1A is independently less than 20 angstroms. In embodiments, the largest dimension of L1A is independently less than 10 angstroms.

[0154] In embodiments, the largest dimension of L1B is independently less than 50 Angstroms. In embodiments, the largest dimension of L1B is independently less than 40 Angstroms. In embodiments, the largest dimension of L1B is independently less than 30 Angstroms. In embodiments, the largest dimension of L1B is independently less than 20 Angstroms. In embodiments, the largest dimension of L1B is independently less than 10 Angstroms.

[0155] In embodiments, the largest dimension of L1C is independently less than 50 Angstroms. In embodiments, the largest dimension of L1C is independently less than 40 Angstroms. In embodiments, the largest dimension of L1C is independently less than 30 Angstroms. In embodiments, the largest dimension of L1C is independently less than 20 Angstroms. In embodiments, the largest dimension of L1C is independently less than 10 Angstroms.

[0156] In embodiments, the maximum dimension of L1D is independently less than 50 angstroms. In embodiments, the maximum dimension of L1D is independently less than 40 angstroms. In embodiments, the maximum dimension of L1D is independently less than 30 angstroms. In embodiments, the maximum dimension of L1D is independently less than 20 angstroms. In embodiments, the maximum dimension of L1D is independently less than 10 angstroms.

[0157] In embodiments, the maximum dimension of L1E is independently less than 50 Angstroms. In embodiments, the maximum dimension of L1E is independently less than 40 Angstroms. In embodiments, the maximum dimension of L1E is independently less than 30 Angstroms. In embodiments, the maximum dimension of L1E is independently less than 20 Angstroms. In embodiments, the maximum dimension of L1E is independently less than 10 Angstroms.

[0158] In embodiments, the nucleic acid (A) is an oligonucleotide. In embodiments, one L1A is attached to the 3' carbon of the oligonucleotide. In embodiments, one L1A is attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, one L1A is attached to the 5' carbon of the oligonucleotide. In embodiments, one L1A is attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety). In embodiments, one L1A is attached to the 2' carbon of the oligonucleotide. In embodiments, one L1A is attached to a nucleobase of the oligonucleotide.

[0159] In embodiments, at least one L1A is attached to the 3' carbon of the oligonucleotide at its 3' end. In embodiments, at least one L1A is attached to the 3' nitrogen of the oligonucleotide at its 3' end (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, at least one L1A is attached to the 5' carbon of the oligonucleotide at its 5' end. In embodiments, at least one L1A is attached to the 6' carbon of the oligonucleotide at its 5' end (e.g., the 6' carbon of the morpholino moiety).

[0160] In an embodiment, the nucleic acid (A) is a double-stranded oligonucleotide. In an embodiment, one L1A is bound to the 3' carbon of the double-stranded oligonucleotide. In an embodiment, one L1A is bound to the 3' carbon of the double-stranded oligonucleotide at either of its 3' ends. In an embodiment, one L1A is bound to the 3' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand. In an embodiment, one L1A is bound to the 3' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand.

[0161] In an embodiment, one L1A is attached to the 3' nitrogen of the double-stranded oligonucleotide at either of its 3' ends (e.g., the 3' nitrogen of the morpholino moiety). In an embodiment, one L1A is attached to the 3' nitrogen of the double-stranded oligonucleotide at the 3' end of its antisense strand (e.g., the 3' nitrogen of the morpholino moiety). In an embodiment, one L1A is attached to the 3' nitrogen of the double-stranded oligonucleotide at the 3' end of its sense strand (e.g., the 3' nitrogen of the morpholino moiety).

[0162] In some embodiments, one L1A is attached to the 5' carbon of the double-stranded oligonucleotide at either of its 5' ends.In some embodiments, one L1A is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand.In some embodiments, one L1A is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0163] In embodiments, one L1A is attached to the 6' carbon of the double-stranded oligonucleotide at either of its 5' ends (e.g., the 6' carbon of the morpholino moiety). In embodiments, one L1A is attached to the 6' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand (e.g., the 6' carbon of the morpholino moiety). In embodiments, one L1A is attached to the 6' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand (e.g., the 6' carbon of the morpholino moiety).

[0164] In embodiments, one L1A is attached to the 2' carbon of the double-stranded oligonucleotide. In embodiments, one L1A is attached to the 5' carbon of the double-stranded oligonucleotide at either of its 2' ends. In embodiments, one L1A is attached to the 2' carbon at the 5' end of the sense strand. In embodiments, one L1A is attached to the 2' carbon at the 5' end of the antisense strand. In embodiments, one L1A is attached to the 2' carbon at either of its 3' ends. In embodiments, one L1A is attached to the 2' carbon at the 3' end of the sense strand. In embodiments, one L1A is attached to the 2' carbon at the 3' end of the antisense strand.

[0165] In embodiments, one L1A is bound to a nucleobase of the double-stranded oligonucleotide. In embodiments, one L1A is bound to a nucleobase of the sense strand of the double-stranded oligonucleotide. In embodiments, one L1A is bound to a nucleobase of the antisense strand of the double-stranded oligonucleotide. In embodiments, one L1A is bound to a nucleobase of the double-stranded oligonucleotide at either of its 3' ends. In embodiments, one L1A is bound to a nucleobase of the double-stranded oligonucleotide at the 3' end of its antisense strand. In embodiments, one L1A is bound to a nucleobase of the double-stranded oligonucleotide at the 3' end of its sense strand. In embodiments, one L1A is bound to a nucleobase of the double-stranded oligonucleotide at either of its 5' ends. In embodiments, one L1A is bound to a nucleobase of the double-stranded oligonucleotide at the 5' end of its antisense strand. In embodiments, one L1A is bound to a nucleobase of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0166] In an embodiment, the nucleic acid (A) is a single-stranded oligonucleotide. In an embodiment, one L1A is attached to the 3' carbon of the single-stranded oligonucleotide at the 3' end.

[0167] In embodiments, one L1A is attached to the 3' nitrogen of the single-stranded oligonucleotide (eg, the 3' nitrogen of the morpholino moiety) at the 3' end of the single-stranded oligonucleotide.

[0168] In an embodiment, one L1A is attached to the 5' carbon of the single-stranded oligonucleotide at the 5' end.

[0169] In embodiments, one L1A is attached to the 6' carbon of the single-stranded oligonucleotide at the 5' end (eg, the 6' carbon of the morpholino moiety).

[0170] In an embodiment, one L1A is attached to the 2' carbon of the single-stranded oligonucleotide. In an embodiment, an L1A is attached to the 2' carbon of the single-stranded oligonucleotide at its 5' end. In an embodiment, one L1A is attached to the 2' carbon of the single-stranded oligonucleotide at its 3' end.

[0171] In one embodiment, one L1A is bound to the nucleic acid base of the single-stranded oligonucleotide.In one embodiment, one L1A is bound to the nucleic acid base of the single-stranded oligonucleotide at the 3' end.In one embodiment, one L1A is bound to the nucleic acid base of the single-stranded oligonucleotide at the 5' end.

[0172] In embodiments, L1A is independently -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(CH3)-O-, -OP(O)(N(CH3)2)-N-, -OP(O)(N(CH3)2)-O-, -OP(S)(N(CH3)2)-N-, -OP(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, L1A is independently -O-, -C(O)-, -C(O)O-, or -OC(O)-. In embodiments, L1A is independently -OPO2-O-, -OP(O)(S)-O-, -OP(O)(CH3)-O-, or -OP(S)(CH3)-O-. In embodiments, L1A is independently -OP(O)(N(CH3)2)-N-, -OP(O)(N(CH3)2)-O-, -OP(S)(N(CH3)2)-N-, or -OP(S)(N(CH3)2)-O-. In embodiments, L1A is 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-.

[0173] In embodiments, L1A is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1A is independently substituted or unsubstituted C1-C2 alkylene.

[0174] In embodiments, L1A is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-16 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-12 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-6 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-4 membered heteroalkylene. In embodiments, L1A is independently substituted or unsubstituted 2-3 membered heteroalkylene.

[0175] In embodiments, L1A is independently [ka] In embodiments, L1A is independently -OPO2-O-. In embodiments, L1A is independently -OP(O)(S)-O-. In embodiments, L1A is independently -O-. In embodiments, L1A is independently -S-.

[0176] ). In embodiments, L1A is attached to the 3' nitrogen of the morpholino moiety. In embodiments, L1A is independently -C(O)-. In embodiments, L1A is attached to the 6' carbon of the morpholino moiety. In embodiments, L1A is independently -OP(O)(N(CH3)2)-N-. In embodiments, L1A is independently -OP(O)(N(CH3)2)-O-. In embodiments, L1A is independently -P(O)(N(CH3)2)-N-. In embodiments, L1A is independently -P(O)(N(CH3)2)-O-.

[0177] In embodiments, L1B is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L1B is independently substituted or unsubstituted C1-C2 alkylene.

[0178] In embodiments, L1B is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-16 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-12 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-6 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-4 membered heteroalkylene. In embodiments, L1B is independently substituted or unsubstituted 2-3 membered heteroalkylene.

[0179] In embodiments, L1B is independently -L10-NH-C(O)- or -L10-C(O)-NH-. L10 is substituted or unsubstituted alkylene.

[0180] In embodiments, L10 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L10 is independently substituted C1-C20 alkylene. In embodiments, L10 is independently a hydroxy (OH) substituted C1-C20 alkylene. In embodiments, L10 is independently a hydroxymethyl substituted C1-C20 alkylene. In embodiments, L10 is independently an unsubstituted C1-C20 alkylene. In embodiments, L10 is independently a substituted or unsubstituted C1-C12 alkylene. In embodiments, L10 is independently a substituted C1-C12 alkylene. In embodiments, L10 is independently a hydroxy (OH) substituted C1-C12 alkylene. In embodiments, L10 is independently a hydroxymethyl substituted C1-C12 alkylene. In embodiments, L10 is independently an unsubstituted C1-C12 alkylene. In embodiments, L10 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, L10 is independently a substituted C1-C8 alkylene. In embodiments, L10 is independently a hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L10 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L10 is independently an unsubstituted C1-C8 alkylene. In embodiments, L10 is independently a substituted or unsubstituted C1-C6 alkylene. In embodiments, L10 is independently a substituted C1-C6 alkylene. In embodiments, L10 is independently a hydroxy(OH)-substituted C1-C6 alkylene. In embodiments, L10 is independently a hydroxymethyl-substituted C1-C6 alkylene. In embodiments, L10 is independently an unsubstituted C1-C6 alkylene.In embodiments, L10 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L10 is independently substituted C1-C4 alkylene. In embodiments, L10 is independently hydroxy(OH)-substituted C1-C4 alkylene. In embodiments, L10 is independently hydroxymethyl-substituted C1-C4 alkylene. In embodiments, L10 is independently unsubstituted C1-C4 alkylene. In embodiments, L10 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L10 is independently substituted C1-C2 alkylene. In embodiments, L10 is independently hydroxy(OH)-substituted C1-C2 alkylene. In embodiments, L10 is independently hydroxymethyl-substituted C1-C2 alkylene. In embodiments, L10 is independently unsubstituted C1-C2 alkylene.

[0181] In an embodiment, L1B independently comprises: [ka] In an embodiment, L1B is independently [ka] is.

[0182] In an embodiment, L1B independently comprises: [ka] 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.

[0183] In an embodiment, L1B independently comprises: [ka] where w1, w2, w3, and w4 are as described above.

[0184] In an embodiment, w1 is 0. In an embodiment, w1 is 1. In an embodiment, w1 is 2. In an embodiment, w1 is 3. In an embodiment, w1 is 4. In an embodiment, w1 is 5. In an embodiment, w1 is 6. In an embodiment, w1 is 7. In an embodiment, w1 is 8. In an embodiment, w1 is 9. In an embodiment, w1 is 10. In an embodiment, w2 is 0. In an embodiment, w2 is 1. In an embodiment, w2 is 2. In an embodiment, w2 is 3. In an embodiment, w2 is 4. In an embodiment, w2 is 5. In an embodiment, w3 is 0. In an embodiment, w3 is 1. In an embodiment, w3 is 2. In an embodiment, w3 is 3. In an embodiment, w3 is 4. In an embodiment, w3 is 5. In an embodiment, 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.

[0185] In an embodiment, L1B independently comprises: [ka] is.

[0186] In an embodiment, L1B independently comprises: [ka] In an embodiment, L1B is independently [ka] In an embodiment, w4 is 0. In an embodiment, w1 is 1. In an embodiment, w1 is 2. In an embodiment, w2 is 3. In an embodiment, w4 is 0 and w1 is 2. In an embodiment, w4 is 0 and w1 is 3. In an embodiment, w4 is 0 and w1 is 4.

[0187] In an embodiment, L1B independently comprises: [ka] In an embodiment, L1B is independently [ka] is.

[0188] In embodiments, -L1A-L1B- is independently -O-L10-NH-C(O)- or -O-L10-C(O)-NH-. L10 is 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-.

[0189] In embodiments, L10 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L10 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L10 is independently substituted C1-C20 alkylene. In embodiments, L10 is independently a hydroxy (OH) substituted C1-C20 alkylene. In embodiments, L10 is independently a hydroxymethyl substituted C1-C20 alkylene. In embodiments, L10 is independently an unsubstituted C1-C20 alkylene. In embodiments, L10 is independently a substituted or unsubstituted C1-C12 alkylene. In embodiments, L10 is independently a substituted C1-C12 alkylene. In embodiments, L10 is independently a hydroxy (OH) substituted C1-C12 alkylene. In embodiments, L10 is independently a hydroxymethyl substituted C1-C12 alkylene. In embodiments, L10 is independently an unsubstituted C1-C12 alkylene. In embodiments, L10 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, L10 is independently a substituted C1-C8 alkylene. In embodiments, L10 is independently a hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L10 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L10 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, L10 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, L10 is independently a substituted C5-C8 alkylene. In embodiments, L10 is independently a hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, L10 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, L10 is independently an unsubstituted C5-C8 alkylene.In embodiments, L10 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L10 is independently substituted C1-C6 alkylene. In embodiments, L10 is independently hydroxy(OH)-substituted C1-C6 alkylene. In embodiments, L10 is independently hydroxymethyl-substituted C1-C6 alkylene. In embodiments, L10 is independently unsubstituted C1-C6 alkylene. In embodiments, L10 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L10 is independently substituted C1-C4 alkylene. In embodiments, L10 is independently hydroxy(OH)-substituted C1-C4 alkylene. In embodiments, L10 is independently hydroxymethyl-substituted C1-C4 alkylene. In embodiments, L10 is independently unsubstituted C1-C4 alkylene. In embodiments, L10 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L10 is independently substituted C1-C2 alkylene. In embodiments, L10 is independently hydroxy (OH)-substituted C1-C2 alkylene. In embodiments, L10 is independently hydroxymethyl-substituted C1-C2 alkylene. In embodiments, L10 is independently unsubstituted C1-C2 alkylene.

[0190] In an embodiment, -L1A-L1B- is independently [ka] In an embodiment, -L1A-L1B- is independently: [ka] In an embodiment, -L1A-L1B- is independently: [ka] In an embodiment, -L1A-L1B- is independently: [ka] is.

[0191] 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, L10 is 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, L10 is independently substituted or unsubstituted alkylene. In embodiments, L10 is independently substituted or unsubstituted C5-C8 alkylene. In embodiments, L10 is independently substituted C5-C8 alkylene. In embodiments, L10 is independently hydroxy (OH)-substituted C5-C8 alkylene. In embodiments, L10 is independently hydroxymethyl-substituted C5-C8 alkylene. In embodiments, L10 is independently unsubstituted C5-C8 alkylene.

[0192] In an embodiment, -L1A-L1B- is independently [ka] is.

[0193] In an embodiment, -L1A-L1B- is independently [ka] In an embodiment, -L1A-L1B- is independently: [ka] In an embodiment, -L1A-L1B- is independently: [ka] In an embodiment, -L1A-L1B- is independently: [ka] In an embodiment, -L1A-L1B- is independently: [ka] is.

[0194] In an embodiment, -L1A-L1B- is independently [ka] and is attached to the 3' carbon of the oligonucleotide. In embodiments, -L1A-L1B- are independently attached to the 3' carbon of the oligonucleotide. [ka] In embodiments, -L1A-L1B- is independently attached to the 3' carbon of the oligonucleotide: [ka] is.

[0195] In an embodiment, -L1A-L1B- is independently [ka] and binds to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, -L1A-L1B- are independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] In embodiments, -L1A-L1B- is independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] is.

[0196] In an embodiment, -L1A-L1B- is independently [ka] and is attached to the 5' carbon of the oligonucleotide. In embodiments, -L1A-L1B- are independently attached to the 5' carbon of the oligonucleotide: [ka] In embodiments, -L1A-L1B- is independently attached to the 5' carbon of the oligonucleotide: [ka] is.

[0197] In embodiments where the oligonucleotide comprises a morpholino moiety, L1A is independently -P(O)(N(CH3)2)-N- or -P(O)(N(CH3)2)-O-. In embodiments, L1B is a substituted or unsubstituted heterocycloalkyl. In embodiments, L1B is a substituted heterocycloalkyl. In embodiments, L1B is an unsubstituted heterocycloalkyl. In embodiments, L1B is a substituted or unsubstituted piperidinylene. In embodiments, L1B is a substituted piperidinylene. In embodiments, L1B is an unsubstituted piperidinylene. In embodiments, L1B is a substituted or unsubstituted piperazinylene. In embodiments, L1B is a substituted piperazinylene. In embodiments, L1B is an unsubstituted piperazinylene. In embodiments, -L1A-L1B- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety), [ka] In embodiments, -L1A-L1B- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety), [ka] In embodiments, -L1A-L1B- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety), [ka] is.

[0198] In embodiments, -L1A-L1B- are independently linked to a nucleobase of an oligonucleotide. In embodiments, -L1A-L1B- are independently [ka] and binds to the nucleobase of the oligonucleotide.

[0199] In embodiments, L is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; L is independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and L is independently a bond, substituted or unsubstituted heteroalkylene, or -NHC(O)-.

[0200] In embodiments, L1C is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted alkylene. In embodiments, L1C is independently substituted or unsubstituted C1-C10 alkylene or substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted C1-C10 alkylene. In embodiments, L1C is independently substituted C1-C10 alkylene. In embodiments, L1C is independently unsubstituted C1-C10 alkylene. In embodiments, L1C is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1C is independently substituted C1-C8 alkylene. In embodiments, L1C is independently unsubstituted C1-C8 alkylene. In embodiments, L1C is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, L1C is independently substituted C3-C8 alkylene. In embodiments, L1C is independently unsubstituted C3-C8 alkylene. In embodiments, L1C is independently substituted or unsubstituted C3-C7 alkylene. In embodiments, L1C is independently substituted C3-C7 alkylene. In embodiments, L1C is independently unsubstituted C3-C7 alkylene.

[0201] In embodiments, L1C is independently R1C-substituted or unsubstituted alkylene. In embodiments, L1C is independently R1C-substituted or unsubstituted C1-C10 alkylene. In embodiments, L1C is independently R1C-substituted C1-C10 alkylene. In embodiments, L1C is independently unsubstituted C1-C10 alkylene. In embodiments, L1C is independently R1C-substituted or unsubstituted C1-C8 alkylene. In embodiments, L1C is independently R1C-substituted C1-C8 alkylene. In embodiments, L1C is independently unsubstituted C1-C8 alkylene. In embodiments, L1C is independently R1C-substituted or unsubstituted C3-C8 alkylene. In embodiments, L1C is independently R1C-substituted C3-C8 alkylene. In embodiments, L1C is independently unsubstituted C3-C8 alkylene. In embodiments, L1C is independently R1C-substituted or unsubstituted C3-C7 alkylene. In embodiments, L1C is independently R1C-substituted C3-C7 alkylene. In embodiments, L1C is independently unsubstituted C3-C7 alkylene.

[0202] In embodiments, L1C is independently substituted or unsubstituted heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1C is independently substituted 2-10 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L1C is independently substituted 2-8 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L1C is independently substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1C is independently substituted 5-8 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 5-8 membered heteroalkylene.

[0203] In embodiments, L1C is independently R1C-substituted or unsubstituted heteroalkylene. In embodiments, L1C is independently R1C-substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1C is independently R1C-substituted 2-10 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L1C is independently R1C-substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L1C is independently R1C-substituted 2-8 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L1C is independently R1C-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1C is independently R1C-substituted 5-8 membered heteroalkylene. In embodiments, L1C is independently unsubstituted 5-8 membered heteroalkylene.

[0204] R 1C is 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.

[0205] In embodiments, L1D is independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1D is independently a bond.

[0206] In embodiments, L1D is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted alkylene. In embodiments, L1D is independently substituted or unsubstituted C1-C10 alkylene or substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted C1-C10 alkylene. In embodiments, L1D is independently substituted C1-C10 alkylene. In embodiments, L1D is independently unsubstituted C1-C10 alkylene. In embodiments, L1D is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L1D is independently substituted C1-C8 alkylene. In embodiments, L1D is independently unsubstituted C1-C8 alkylene. In embodiments, L1D is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, L1D is independently substituted C3-C8 alkylene. In embodiments, L1D is independently unsubstituted C3-C8 alkylene. In embodiments, L1D is independently substituted or unsubstituted C3-C7 alkylene. In embodiments, L1D is independently substituted C3-C7 alkylene. In embodiments, L1D is independently unsubstituted C3-C7 alkylene.

[0207] In embodiments, L1D is independently R1D-substituted or unsubstituted alkylene. In embodiments, L1D is independently R1D-substituted or unsubstituted C1-C10 alkylene. In embodiments, L1D is independently R1D-substituted C1-C10 alkylene. In embodiments, L1D is independently unsubstituted C1-C10 alkylene. In embodiments, L1D is independently R1D-substituted or unsubstituted C1-C8 alkylene. In embodiments, L1D is independently R1D-substituted C1-C8 alkylene. In embodiments, L1D is independently unsubstituted C1-C8 alkylene. In embodiments, L1D is independently R1D-substituted or unsubstituted C3-C8 alkylene. In embodiments, L1D is independently R1D-substituted C3-C8 alkylene. In embodiments, L is independently an unsubstituted C-C alkylene. In embodiments, L is independently an R-substituted or unsubstituted C-C alkylene. In embodiments, L is independently an R-substituted C-C alkylene. In embodiments, L is independently an unsubstituted C-C alkylene.

[0208] In embodiments, L1D is independently substituted or unsubstituted heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1D is independently substituted 2-10 membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L1D is independently substituted 2-8 membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L1D is independently substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1D is independently substituted 5-8 membered heteroalkylene. In embodiments, L1D is independently unsubstituted 5-8 membered heteroalkylene.

[0209] In embodiments, L1D is independently R1D-substituted or unsubstituted heteroalkylene. In embodiments, L1D is independently R1D-substituted or unsubstituted 2-10-membered heteroalkylene. In embodiments, L1D is independently R1D-substituted 2-10-membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2-10-membered heteroalkylene. In embodiments, L1D is independently R1D-substituted or unsubstituted 2-8-membered heteroalkylene. In embodiments, L1D is independently R1D-substituted 2-8-membered heteroalkylene. In embodiments, L1D is independently unsubstituted 2-8-membered heteroalkylene. In embodiments, L1D is independently R1D-substituted or unsubstituted 5-8-membered heteroalkylene. In embodiments, L1D is independently R1D-substituted 5-8-membered heteroalkylene. In embodiments, L1D is independently unsubstituted 5-8-membered heteroalkylene.

[0210] In embodiments, L is independently substituted or unsubstituted arylene. In embodiments, L is independently substituted or unsubstituted arylene (e.g., C-C, C-C, or phenyl). In embodiments, L is independently substituted arylene (e.g., C-C, C-C, or phenyl). In embodiments, L is independently unsubstituted arylene (e.g., C-C, C-C, or phenyl). In embodiments, L is independently substituted or unsubstituted C-C arylene. In embodiments, L is independently substituted C-C arylene. In embodiments, L is independently unsubstituted C-C arylene. In embodiments, L is independently substituted or unsubstituted C-C arylene. In embodiments, L1D is independently a substituted C6-C10 arylene. In embodiments, L1D is independently an unsubstituted C6-C10 arylene. In embodiments, L1D is independently a substituted or unsubstituted phenylene. In embodiments, L1D is independently a substituted phenylene. In embodiments, L1D is independently an unsubstituted phenylene. In embodiments, L1D is independently a substituted or unsubstituted biphenylene. In embodiments, L1D is independently a substituted biphenylene. In embodiments, L1D is independently an unsubstituted biphenylene. In embodiments, L1D is independently a substituted or unsubstituted naphthylene. In embodiments, L1D is independently a substituted naphthylene. In embodiments, L1D is independently an unsubstituted naphthylene.

[0211] In embodiments, L is independently R-substituted or unsubstituted arylene (e.g., C-C, C-C, or phenyl). In embodiments, L is independently R-substituted arylene (e.g., C-C, C-C, or phenyl). In embodiments, L is independently unsubstituted arylene (e.g., C-C, C-C, or phenyl). In embodiments, L is independently R-substituted or unsubstituted C-C arylene. In embodiments, L is independently R-substituted C-C arylene. In embodiments, L is independently unsubstituted C-C arylene. In embodiments, L is independently R-substituted or unsubstituted C-C arylene. In embodiments, L is independently an R-substituted C6-C10 arylene. In embodiments, L is independently an unsubstituted C6-C10 arylene. In embodiments, L is independently an R-substituted or unsubstituted phenylene. In embodiments, L is independently an R-substituted phenylene. In embodiments, L is independently an unsubstituted phenylene. In embodiments, L is independently an R-substituted or unsubstituted biphenylene. In embodiments, L is independently an R-substituted biphenylene. In embodiments, L is independently an unsubstituted biphenylene. In embodiments, L is independently an R-substituted or unsubstituted naphthylene. In embodiments, L is independently an R-substituted naphthylene. In embodiments, L is independently an unsubstituted naphthylene.

[0212] In embodiments, L1D is independently substituted or unsubstituted heteroarylene. In embodiments, L1D is independently substituted heteroarylene. In embodiments, L1D is independently unsubstituted heteroarylene. In embodiments, L1D is independently substituted or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). In embodiments, L1D is independently substituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). In embodiments, L1D is independently unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). In embodiments, L1D is independently substituted or unsubstituted 5-12 membered heteroarylene. In embodiments, L1D is independently substituted 5-12 membered heteroarylene. In embodiments, L1D is independently unsubstituted 5-12 membered heteroarylene. In embodiments, L1D is independently substituted or unsubstituted 5-10 membered heteroarylene. In embodiments, L1D is independently substituted 5-10 membered heteroarylene. In embodiments, L1D is independently unsubstituted 5-10 membered heteroarylene. In embodiments, L1D is independently substituted or unsubstituted 5-9 membered heteroarylene. In embodiments, L1D is independently substituted 5-9 membered heteroarylene. In embodiments, L1D is independently unsubstituted 5-9 membered heteroarylene. In embodiments, L1D is independently substituted or unsubstituted 5-6 membered heteroarylene. In embodiments, L1D is independently substituted 5-6 membered heteroarylene. In embodiments, L1D is independently unsubstituted 5-6 membered heteroarylene.

[0213] R1D is 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.

[0214] In embodiments, L1E is independently a bond, a substituted or unsubstituted 2-10 membered heteroalkylene, or -NHC(O)-. In embodiments, L1E is independently a bond. In embodiments, L1E is independently -NHC(O)-.

[0215] In embodiments, L1E is independently substituted or unsubstituted heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1E is independently substituted 2-10 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L1E is independently substituted 2-8 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L1E is independently substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1E is independently substituted 5-8 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 5-8 membered heteroalkylene.

[0216] In embodiments, L1E is independently R1E-substituted or unsubstituted heteroalkylene. In embodiments, L1E is independently R1E-substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L1E is independently R1E-substituted 2-10 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L1E is independently R1E-substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L1E is independently R1E-substituted 2-8 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L1E is independently R1E-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1E is independently R1E-substituted 5-8 membered heteroalkylene. In embodiments, L1E is independently unsubstituted 5-8 membered heteroalkylene.

[0217] R1E is 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.

[0218] In embodiments, L1C is independently R1C-substituted or unsubstituted C1-C7 alkylene or R1C-substituted or unsubstituted 5-8 membered heteroalkylene; L1D is independently a bond, R1D-substituted or unsubstituted C1-C7 alkylene, or R1D-substituted or unsubstituted 5-8 membered heteroalkylene; and L1E is independently a bond, R1E-substituted or unsubstituted 5-8 membered heteroalkylene, or -NHC(O)-. In embodiments, L1C is independently an R1C-substituted or unsubstituted C1-C7 alkylene. In embodiments, L1C is independently an R1C-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1D is independently a bond. In embodiments, L1D is independently an R1D-substituted or unsubstituted C1-C7 alkylene. In embodiments, L1E is independently a bond. In embodiments, L1E is independently an R1E-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1E is independently -NHC(O)-.

[0219] In embodiments, R1C is independently oxo, or -L8C-L2C-R8C. In embodiments, R1C is independently oxo. In embodiments, R1C is independently -L8C-L2C-R8C. L8C is independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. L8C is independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. L2C is independently a bond or unsubstituted alkylene. R8C is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0220] In embodiments, R1D is independently oxo, or -L8D-L2D-R8D. In embodiments, R1D is independently oxo. In embodiments, R1D is independently -L8D-L2D-R8D. L8D is independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. L8D is independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. L2D is independently a bond or unsubstituted alkylene. R8D is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0221] In embodiments, R1E is independently oxo, or -L8E-L2E-R8E. In embodiments, R1E is independently oxo. In embodiments, R1E is independently -L8E-L2E-R8E. L8E is independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. L8E is independently a bond, substituted or unsubstituted C1-C6 alkylene, or substituted or unsubstituted 2-6 membered heteroalkylene. L2E is independently a bond or unsubstituted alkylene. R8E is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0222] In embodiments, the half-life extending motif has the structure: [ka] L8A is independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L2A is independently a bond or unsubstituted alkylene. L1A, L1B, L1C, L1D, L1E, L2C, L8C, and R8C are as defined above.

[0223] In embodiments, the half-life extending motif has the structure: [ka] L1A, L1B, L1C, L1D, L1E, L2A, L2D, L8A, L8D, and R8D are as described above.

[0224] In embodiments, the half-life extending motif has the structure: [ka] L1A, L1B, L1C, L1D, L1E, L2A, L2E, L8A, L8E, and R8E are as described above.

[0225] In embodiments, the half-life extending motif has the structure: [ka] L1A, L1B, L1C, L1D, L1E, L2A, L2C, L2D, L8A, L8C, L8D, R8C, and R8D are as described above.

[0226] In embodiments, the half-life extending motif has the structure: [ka] L1A, L1B, L1C, L1D, L1E, L2A, L2D, L2E, L8A, L8D, L8E, R8D, and R8E are as described above.

[0227] In embodiments, the half-life extending motif has the structure: [ka] L1A, L1B, L1C, L1D, L1E, L2A, L2C, L2E, L8A, L8C, L8E, R8C, and R8E are as described above.

[0228] In embodiments, the half-life extending motif has the structure: [ka] L1A, L1B, L1C, L1D, L1E, L2A, L2C, L2D, L2E, L8A, L8C, L8D, L2E, R8C, R8D, and R8E are as described above.

[0229] In embodiments, L8A is independently a bond. In embodiments, L8A is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. In embodiments, L8A is independently substituted or unsubstituted alkylene. In embodiments, L8A is independently substituted or unsubstituted C1-C10 alkylene or substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L8A is independently substituted or unsubstituted C1-C10 alkylene. In embodiments, L8A is independently substituted C1-C10 alkylene. In embodiments, L8A is independently unsubstituted C1-C10 alkylene. In embodiments, L8A is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L8A is independently substituted C1-C8 alkylene. In embodiments, L8A is independently unsubstituted C1-C8 alkylene. In embodiments, L8A is independently substituted or unsubstituted C3-C8 alkylene. In embodiments, L8A is independently substituted C3-C8 alkylene. In embodiments, L8A is independently unsubstituted C3-C8 alkylene. In embodiments, L8A is independently substituted or unsubstituted C3-C7 alkylene. In embodiments, L8A is independently substituted C3-C7 alkylene. In embodiments, L8A is independently unsubstituted C3-C7 alkylene.

[0230] In embodiments, L is independently an RA-substituted or unsubstituted alkylene. In embodiments, L is independently an RA-substituted or unsubstituted C1-C10 alkylene. In embodiments, L is independently an RA-substituted C1-C10 alkylene. In embodiments, L is independently unsubstituted C1-C10 alkylene. In embodiments, L is independently an RA-substituted C1-C8 alkylene. In embodiments, L is independently an RA-substituted C1-C8 alkylene. In embodiments, L is independently unsubstituted C1-C8 alkylene. In embodiments, L is independently an RA-substituted or unsubstituted C3-C8 alkylene. In embodiments, L is independently an RA-substituted C3-C8 alkylene. In embodiments, L is independently an unsubstituted C-C alkylene. In embodiments, L is independently an R-substituted or unsubstituted C-C alkylene. In embodiments, L is independently an R-substituted C-C alkylene. In embodiments, L is independently an unsubstituted C-C alkylene.

[0231] In embodiments, L8A is independently substituted or unsubstituted heteroalkylene. In embodiments, L8A is independently substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L8A is independently substituted 2-10 membered heteroalkylene. In embodiments, L8A is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L8A is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L8A is independently substituted 2-8 membered heteroalkylene. In embodiments, L8A is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L8A is independently substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L8A is independently substituted 5-8 membered heteroalkylene. In embodiments, L8A is independently unsubstituted 5-8 membered heteroalkylene.

[0232] In embodiments, L8A is independently RA-substituted or unsubstituted heteroalkylene. In embodiments, L8A is independently RA-substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L8A is independently RA-substituted 2-10 membered heteroalkylene. In embodiments, L8A is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L8A is independently RA-substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L8A is independently RA-substituted 2-8 membered heteroalkylene. In embodiments, L8A is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L8A is independently RA-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L8A is independently RA-substituted 5-8 membered heteroalkylene. In embodiments, L8A is independently unsubstituted 5-8 membered heteroalkylene.

[0233] In embodiments, L2A is independently unsubstituted C2-C24 alkylene. In embodiments, L2A is independently unsubstituted C2-C22 alkylene. In embodiments, L2A is independently unsubstituted C5-C22 alkylene. In embodiments, L2A is independently unsubstituted C10-C22 alkylene. In embodiments, L2A is independently unsubstituted C12-C22 alkylene. In embodiments, L2A is independently unsubstituted C10-C20 alkylene. In embodiments, L2A is independently unsubstituted C12-C20 alkylene. In embodiments, L2A is independently unsubstituted C10-C18 alkylene. In embodiments, L2A is independently unsubstituted C12-C18 alkylene. In embodiments, L2A is independently unsubstituted C10-C16 alkylene. In embodiments, L2A is independently an unsubstituted C12-C16 alkylene. In embodiments, L2A is independently an unsubstituted C14-C16 alkylene. In embodiments, L2A is independently an unsubstituted C14-C15 alkylene. In embodiments, L2A is independently an unsubstituted C14 alkylene. In embodiments, L2A is independently an unsubstituted C15 alkylene. In embodiments, L2A is independently an unsubstituted C16 alkylene.

[0234] In embodiments, L2A is independently unsubstituted unbranched C2-C24 alkylene. In embodiments, L2A is independently unsubstituted unbranched C2-C22 alkylene. In embodiments, L2A is independently unsubstituted unbranched C5-C22 alkylene. In embodiments, L2A is independently unsubstituted unbranched C10-C22 alkylene. In embodiments, L2A is independently unsubstituted unbranched C12-C22 alkylene. In embodiments, L2A is independently unsubstituted unbranched C10-C20 alkylene. In embodiments, L2A is independently unsubstituted unbranched C12-C20 alkylene. In embodiments, L2A is independently unsubstituted unbranched C10-C18 alkylene. In embodiments, L2A is independently unsubstituted unbranched C12-C18 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched C10-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched C12-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched C14-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched C14-C15 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched C14 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched C15 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched C16 alkylene.

[0235] In embodiments, L2A is independently an unsubstituted, unbranched, saturated C2-C24 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C2-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C5-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C10-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C12-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C10-C20 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C10-C18 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C12-C18 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C10-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C12-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C14-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C14-C15 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C14 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C15 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C16 alkylene.

[0236] In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C2-C24 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C2-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C5-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C10-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C12-C22 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C10-C20 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C10-C18 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C12-C18 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C10-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C12-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C14-C16 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C14-C15 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C14 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C15 alkylene. In embodiments, L2A is independently an unsubstituted, unbranched, unsaturated C16 alkylene. In embodiments, L8A is independently a bond and L2A is independently an unsubstituted C2-C22 alkylene.

[0237] In embodiments, L2A is independently a bond and L8A is independently an unsubstituted C2-C22 alkylene.

[0238] In embodiments, L8A is independently unsubstituted C2-C24 alkylene. In embodiments, L8A is independently unsubstituted C2-C22 alkylene. In embodiments, L8A is independently unsubstituted C5-C22 alkylene. In embodiments, L8A is independently unsubstituted C10-C22 alkylene. In embodiments, L8A is independently unsubstituted C12-C22 alkylene. In embodiments, L8A is independently unsubstituted C10-C20 alkylene. In embodiments, L8A is independently unsubstituted C12-C20 alkylene. In embodiments, L8A is independently unsubstituted C10-C18 alkylene. In embodiments, L8A is independently unsubstituted C12-C18 alkylene. In embodiments, L8A is independently unsubstituted C10-C16 alkylene. In embodiments, L8A is independently an unsubstituted C12-C16 alkylene. In embodiments, L8A is independently an unsubstituted C14-C16 alkylene. In embodiments, L8A is independently an unsubstituted C14-C15 alkylene. In embodiments, L8A is independently an unsubstituted C14 alkylene. In embodiments, L8A is independently an unsubstituted C15 alkylene. In embodiments, L8A is independently an unsubstituted C16 alkylene.

[0239] In embodiments, L8A is independently unsubstituted unbranched C2-C24 alkylene. In embodiments, L8A is independently unsubstituted unbranched C2-C22 alkylene. In embodiments, L8A is independently unsubstituted unbranched C5-C22 alkylene. In embodiments, L8A is independently unsubstituted unbranched C10-C22 alkylene. In embodiments, L8A is independently unsubstituted unbranched C12-C22 alkylene. In embodiments, L8A is independently unsubstituted unbranched C10-C20 alkylene. In embodiments, L8A is independently unsubstituted unbranched C12-C20 alkylene. In embodiments, L8A is independently unsubstituted unbranched C10-C18 alkylene. In embodiments, L8A is independently unsubstituted unbranched C12-C18 alkylene. In embodiments, L8A is independently unsubstituted unbranched C10-C16 alkylene. In embodiments, L8A is independently unsubstituted unbranched C12-C16 alkylene. In embodiments, L8A is independently unsubstituted unbranched C14-C16 alkylene. In embodiments, L8A is independently unsubstituted unbranched C14-C15 alkylene. In embodiments, L8A is independently unsubstituted unbranched C14 alkylene. In embodiments, L8A is independently unsubstituted unbranched C15 alkylene. In embodiments, L8A is independently unsubstituted unbranched C16 alkylene.

[0240] In embodiments, L8A is independently an unsubstituted, unbranched, saturated C2-C24 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C2-C22 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C5-C22 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C10-C22 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C12-C22 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C10-C20 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C10-C18 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C12-C18 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C10-C16 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C12-C16 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C14-C16 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C14-C15 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C14 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C15 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, saturated C16 alkylene.

[0241] In embodiments, L8A is independently unsubstituted, unbranched, unsaturated C2-C24 alkylene. In embodiments, L8A is independently unsubstituted, unbranched, unsaturated C2-C22 alkylene. In embodiments, L8A is independently unsubstituted, unbranched, unsaturated C5-C22 alkylene. In embodiments, L8A is independently unsubstituted, unbranched, unsaturated C10-C22 alkylene. In embodiments, L8A is independently unsubstituted, unbranched, unsaturated C12-C22 alkylene. In embodiments, L8A is independently unsubstituted, unbranched, unsaturated C10-C20 alkylene. In embodiments, L8A is independently unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L8A is independently unsubstituted, unbranched, unsaturated C10-C18 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C12-C18 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C10-C16 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C12-C16 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C14-C16 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C14-C15 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C14 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C15 alkylene. In embodiments, L8A is independently an unsubstituted, unbranched, unsaturated C16 alkylene.

[0242] In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently a bond or unsubstituted C2-C22 alkylene, and R8C is independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R1C is independently -NHC(O)-L2C-R8C. In embodiments, L2C is independently a bond or unsubstituted C2-C22 alkylene. In embodiments, L2C is independently a bond. In embodiments, L2C is independently unsubstituted C2-C22 alkylene. In embodiments, R8C is independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R8C is independently hydrogen. In embodiments, R8C is independently C1-C3 alkyl. In embodiments, R8C is independently -COOH.

[0243] In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently a bond and R8C is independently C1-C3 alkyl. In embodiments, R1C is independently -NHC(O)-CH3. In embodiments, R1C is independently -NHC(O)-CH2CH3. In embodiments, R1C is independently -NHC(O)-CH(CH3)2. In embodiments, R1C is independently -NHC(O)-CH2CH2CH3.

[0244] In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently unsubstituted C10-C22 alkylene, and R8C is independently -COOH. In embodiments, R1C is independently -NHC(O)-L2C-COOH.

[0245] In embodiments, L2C is independently unsubstituted unbranched C2-C24 alkylene. In embodiments, L2C is independently unsubstituted unbranched C2-C22 alkylene. In embodiments, L2C is independently unsubstituted unbranched C5-C22 alkylene. In embodiments, L2C is independently unsubstituted unbranched C10-C22 alkylene. In embodiments, L2C is independently unsubstituted unbranched C12-C22 alkylene. In embodiments, L2C is independently unsubstituted unbranched C10-C20 alkylene. In embodiments, L2C is independently unsubstituted unbranched C12-C20 alkylene. In embodiments, L2C is independently unsubstituted unbranched C10-C18 alkylene. In embodiments, L2C is independently unsubstituted unbranched C12-C18 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched C10-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched C12-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched C14-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched C14-C15 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched C14 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched C15 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched C16 alkylene.

[0246] In embodiments, L2C is independently an unsubstituted, unbranched, saturated C2-C24 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C2-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C5-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C10-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C12-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C10-C20 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C10-C18 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C12-C18 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C10-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C12-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C14-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C14-C15 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C14 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C15 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C16 alkylene.

[0247] In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C2-C24 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C2-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C5-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C10-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C12-C22 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C10-C20 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C10-C18 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C12-C18 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C10-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C12-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C14-C16 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C14-C15 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C14 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C15 alkylene. In embodiments, L2C is independently an unsubstituted, unbranched, unsaturated C16 alkylene.

[0248] In embodiments, R1D is independently -NHC(O)-L2D-R8D, where L2D is independently a bond or unsubstituted C2-C22 alkylene, and R8D is independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R1D is independently -NHC(O)-L2D-R8D. In embodiments, L2D is independently a bond or unsubstituted C2-C22 alkylene. In embodiments, L2D is independently a bond. In embodiments, L2D is independently unsubstituted C2-C22 alkylene. In embodiments, L2D is independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R8D is independently hydrogen. In embodiments, L2D is independently C1-C3 alkyl. In embodiments, R8D is independently -COOH.

[0249] In embodiments, R1D is independently -NHC(O)-L2D-R8D, where L2D is independently a bond and R8D is independently C1-C3 alkyl. In embodiments, R1D is independently -NHC(O)-CH3. In embodiments, R1D is independently -NHC(O)-CH2DH3. In embodiments, R1D is independently -NHC(O)-CH(CH3)2. In embodiments, R1D is independently -NHC(O)-CH2DH2DH3.

[0250] In embodiments, R is independently -NHC(O)-L-R, where L is independently unsubstituted C-C alkylene, and R is independently -COOH. In embodiments, R is independently -NHC(O)-L-COOH.

[0251] In embodiments, L2D is independently unsubstituted unbranched C2-C24 alkylene. In embodiments, L2D is independently unsubstituted unbranched C2-C22 alkylene. In embodiments, L2D is independently unsubstituted unbranched C5-C22 alkylene. In embodiments, L2D is independently unsubstituted unbranched C10-C22 alkylene. In embodiments, L2D is independently unsubstituted unbranched C12-C22 alkylene. In embodiments, L2D is independently unsubstituted unbranched C10-C20 alkylene. In embodiments, L2D is independently unsubstituted unbranched C12-C20 alkylene. In embodiments, L2D is independently unsubstituted unbranched C10-C18 alkylene. In embodiments, L2D is independently unsubstituted unbranched C12-C18 alkylene. In embodiments, L2D is independently unsubstituted unbranched C10-C16 alkylene. In embodiments, L2D is independently unsubstituted unbranched C12-C16 alkylene. In embodiments, L2D is independently unsubstituted unbranched C14-C16 alkylene. In embodiments, L2D is independently unsubstituted unbranched C14-C15 alkylene. In embodiments, L2D is independently unsubstituted unbranched C14 alkylene. In embodiments, L2D is independently unsubstituted unbranched C15 alkylene. In embodiments, L2D is independently unsubstituted unbranched C16 alkylene.

[0252] In embodiments, L2D is independently an unsubstituted, unbranched, saturated C2-C24 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C2-C22 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C5-C22 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C10-C22 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C12-C22 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C10-C20 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C10-C18 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C12-C18 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C10-C16 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C12-C16 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C14-C16 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C14-C15 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C14 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C15 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, saturated C16 alkylene.

[0253] In embodiments, L2D is independently unsubstituted, unbranched, unsaturated C2-C24 alkylene. In embodiments, L2D is independently unsubstituted, unbranched, unsaturated C2-C22 alkylene. In embodiments, L2D is independently unsubstituted, unbranched, unsaturated C5-C22 alkylene. In embodiments, L2D is independently unsubstituted, unbranched, unsaturated C10-C22 alkylene. In embodiments, L2D is independently unsubstituted, unbranched, unsaturated C12-C22 alkylene. In embodiments, L2D is independently unsubstituted, unbranched, unsaturated C10-C20 alkylene. In embodiments, L2D is independently unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2D is independently unsubstituted, unbranched, unsaturated C10-C18 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C12-C18 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C10-C16 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C12-C16 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C14-C16 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C14-C15 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C14 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C15 alkylene. In embodiments, L2D is independently an unsubstituted, unbranched, unsaturated C16 alkylene.

[0254] In embodiments, R1E is independently -NHC(O)-L2E-R8E, where L2E is independently a bond or unsubstituted C2-C22 alkylene, and R8E is independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R1E is independently -NHC(O)-L2E-R8E. In embodiments, L2E is independently a bond or unsubstituted C2-C22 alkylene. In embodiments, L2E is independently a bond. In embodiments, L2E is independently unsubstituted C2-C22 alkylene. In embodiments, R8E is independently hydrogen, C1-C3 alkyl, or -COOH. In embodiments, R8E is independently hydrogen. In embodiments, R8E is independently C1-C3 alkyl. In embodiments, R8E is independently -COOH.

[0255] In embodiments, R1E is independently -NHC(O)-L2E-R8E, where L2E is independently a bond and R8E is independently C1-C3 alkyl. In embodiments, R1E is independently -NHC(O)-CH3. In embodiments, R1E is independently -NHC(O)-CH2EH3. In embodiments, R1E is independently -NHC(O)-CH(CH3)2. In embodiments, R1E is independently -NHC(O)-CH2EH2EH3.

[0256] In embodiments, R is independently -NHC(O)-L-R, where L is independently unsubstituted C-C alkylene and R is independently -COOH. In embodiments, R is independently -NHC(O)-L-COOH.

[0257] In embodiments, L2E is independently unsubstituted unbranched C2-C24 alkylene. In embodiments, L2E is independently unsubstituted unbranched C2-C22 alkylene. In embodiments, L2E is independently unsubstituted unbranched C5-C22 alkylene. In embodiments, L2E is independently unsubstituted unbranched C10-C22 alkylene. In embodiments, L2E is independently unsubstituted unbranched C12-C22 alkylene. In embodiments, L2E is independently unsubstituted unbranched C10-C20 alkylene. In embodiments, L2E is independently unsubstituted unbranched C12-C20 alkylene. In embodiments, L2E is independently unsubstituted unbranched C10-C18 alkylene. In embodiments, L2E is independently unsubstituted unbranched C12-C18 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched C10-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched C12-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched C14-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched C14-C15 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched C14 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched C15 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched C16 alkylene.

[0258] In embodiments, L2E is independently an unsubstituted, unbranched, saturated C2-C24 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C2-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C5-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C10-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C12-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C10-C20 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C10-C18 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C12-C18 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C10-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C12-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C14-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C14-C15 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C14 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C15 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C16 alkylene.

[0259] In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C2-C24 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C2-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C5-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C10-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C12-C22 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C10-C20 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, saturated C12-C20 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C10-C18 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C12-C18 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C10-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C12-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C14-C16 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C14-C15 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C14 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C15 alkylene. In embodiments, L2E is independently an unsubstituted, unbranched, unsaturated C16 alkylene.

[0260] In embodiments, L1C is independently R1C-substituted or unsubstituted 5-8 membered heteroalkylene, L1D is independently a bond or R1D-substituted or unsubstituted 5-8 membered heteroalkylene, and L1E is independently R1E-substituted or unsubstituted 5-8 membered heteroalkylene or -NHC(O)-. In embodiments, each R1C, R1D, or R1E is independently oxo, or -COOH.

[0261] In embodiments, L1C is independently unsubstituted 5-8 membered heteroalkylene. In embodiments, L1D is independently oxo-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1E is independently R1E-substituted or unsubstituted 5-8 membered heteroalkylene, where R1E is independently oxo or -COOH. In embodiments, L1C is independently unsubstituted 5-8 membered heteroalkylene. In embodiments, L1D is independently a bond. In embodiments, L1E is independently -NHC(O)-. In embodiments, -L1C-L1D-L1E- is [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] can be formed.

[0262] In embodiments, L1C is independently R1C-substituted C2-C5 alkyl, L1D is independently unsubstituted phenylene or unsubstituted biphenylene, L1E is independently R1E-substituted or unsubstituted 5-8 membered heteroalkylene or -NHC(O)-, R1C is independently -NHC(O)-L2C-R8C, L2C is independently a bond or unsubstituted C10-C22 alkylene, R8C is independently unsubstituted C1-C3 alkyl or -COOH, and R1E is oxo.

[0263] In embodiments, L1C is independently an R1C-substituted ethylene. In embodiments, L1D is independently unsubstituted biphenylene. In embodiments, L1E is independently -NHC(O)-. In embodiments, R1C is independently -NHC(O)-L2C-R8, where L2C is independently a bond, or R8C is independently unsubstituted C1-C3 alkyl. In embodiments, R1C is independently -NHC(O)-CH3. In embodiments, R1C is independently -NHC(O)-CH2CH3. In embodiments, R1C is independently -NHC(O)-CH(CH3)2. In embodiments, R1C is independently -NHC(O)-CH2CH2CH3. In embodiments, R1C is independently -NHC(O)-L2C-COOH. In embodiments, -L1C-L1D-L1E- is [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] can be formed.

[0264] In embodiments, L1C is independently an R1C-substituted ethylene. In embodiments, L1D is independently unsubstituted phenylene. In embodiments, L1E is independently an R1E-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1E is independently an oxo-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, R1C is independently -NHC(O)-L2C-R8, where L2C is independently a bond, or R8C is independently unsubstituted C1-C3 alkyl. In embodiments, R1C is independently -NHC(O)-CH3. In embodiments, R1C is independently -NHC(O)-CH2CH3. In embodiments, R1C is independently -NHC(O)-CH(CH3)2. In embodiments, R1C is independently -NHC(O)-CH2CH2CH3. In embodiments, R1C is independently -NHC(O)-L2C-COOH. In embodiments, -L1C-L1D-L1E- is [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] can be formed.

[0265] In embodiments, L1C is independently R1C-substituted or unsubstituted ethylene or n-pentylene, L1D is independently a bond, L1E is independently -NHC(O)-, R1C is independently -NHC(O)-L2C-R8C, L2C is independently a bond or unsubstituted C10-C22 alkylene, and R8C is independently unsubstituted C1-C3 alkyl, or -COOH.

[0266] In embodiments, L1C is independently R1C-substituted n-pentylene. In embodiments, L1C is independently unsubstituted n-pentylene. In embodiments, L1D is independently a bond. In embodiments, L1E is independently -NHC(O)-. In embodiments, R1C is independently -NHC(O)-L2C-R8, L2C is independently a bond, and R8C is independently unsubstituted C1-C3 alkyl. In embodiments, R1C is independently -NHC(O)-CH3. In embodiments, R1C is independently -NHC(O)-CH2CH3. In embodiments, R1C is independently -NHC(O)-CH(CH3)2. In embodiments, R1C is independently -NHC(O)-CH2CH2CH3. In embodiments, R1C is independently -NHC(O)-L2C-COOH. In an embodiment, -L1C-L1D-L1E- is [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] can be formed.

[0267] In embodiments, L1C is independently an R1C-substituted ethylene. In embodiments, L1D is independently a bond. In embodiments, L1E is independently -NHC(O)-. In embodiments, R1C is independently -NHC(O)-L2C-R8, L2C is independently a bond, and R8C is independently unsubstituted C1-C3 alkyl. In embodiments, R1C is independently -NHC(O)-CH3. In embodiments, R1C is independently -NHC(O)-CH2CH3. In embodiments, R1C is independently -NHC(O)-CH(CH3)2. In embodiments, R1C is independently -NHC(O)-CH2CH2CH3. In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently unsubstituted C10-C22 alkylene and R8C is independently -COOH. In embodiments, R1C is independently -NHC(O)-L2C-COOH. In embodiments, -L1C-L1D-L1E- is [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] can be formed.

[0268] In embodiments, L1C is independently R1C-substituted or unsubstituted n-pentylene, L1D is independently oxo-substituted or unsubstituted 5-8 membered heteroalkylene, L1E is independently -NHC(O)-, R1C is independently -NHC(O)-L2C-R8C, L2C is independently a bond or unsubstituted C10-C22 alkylene, and R8C is independently unsubstituted C1-C3 alkyl, or -COOH.

[0269] In embodiments, L1C is independently R1C-substituted n-pentylene. In embodiments, L1D is independently oxo-substituted or unsubstituted 5-8 membered heteroalkylene. In embodiments, L1E is independently -NHC(O)-. In embodiments, R1C is independently -NHC(O)-L2C-R8, where L2C is independently a bond and R8C is independently unsubstituted C1-C3 alkyl. In embodiments, R1C is independently -NHC(O)-CH3. In embodiments, R1C is independently -NHC(O)-CH2CH3. In embodiments, R1C is independently -NHC(O)-CH(CH3)2. In embodiments, R1C is independently -NHC(O)-CH2CH2CH3. In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently unsubstituted C10-C22 alkylene and R8C is independently unsubstituted C1-C3 alkyl. In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently unsubstituted C10-C22 alkylene and R8C is independently unsubstituted methyl. In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently unsubstituted C10-C22 alkylene and R8C is independently unsubstituted ethyl. In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently unsubstituted C10-C22 alkylene and R8C is independently -COOH. In embodiments, R1C is independently -NHC(O)-L2C-COOH. In embodiments, R1C is independently -NHC(O)-L2C-R8C, where L2C is independently unsubstituted C10-C22 alkylene and R8C is independently -COOH. In embodiments, -L1C-L1D-L1E- is [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] can be formed.

[0270] In embodiments, L1C is independently R1C-substituted methylene, L1D is independently a bond, L1E is independently -NHC(O)-, R1C is independently -L8C-L2C-R8C, where L8C is independently unsubstituted C1-C6 alkylene or oxo-substituted 2-12 membered heteroalkylene, L2C is independently a bond, and R8C is independently unsubstituted C1-C6 alkyl or oxo-substituted 2-12 membered heteroalkyl.

[0271] In embodiments, L1C is independently R1C-substituted methylene. In embodiments, L1D is independently a bond. In embodiments, L1E is independently -NHC(O)-. In embodiments, R1C is independently -L8C-L2C-R8C. In embodiments, L8C is independently unsubstituted C1-C6 alkylene or oxo-substituted 2-12 membered heteroalkylene. In embodiments, L8C is independently unsubstituted C1-C6 alkylene. In embodiments, L8C is independently oxo-substituted 2-12 membered heteroalkylene. In embodiments, R8C is independently unsubstituted C1-C6 alkyl. In embodiments, R8C is independently oxo-substituted 2-12 membered heteroalkyl. In embodiments, L8C is independently unsubstituted C1-C6 alkylene, L2C is a bond, and R8C is independently oxo-substituted 2-12 membered heteroalkyl. In embodiments, L8C is independently unsubstituted C4 alkylene, L2C is a bond, and R8C is independently oxo-substituted 2-5 membered heteroalkyl. In embodiments, L8C is independently unsubstituted C4 alkylene, L2C is a bond, and R8C is independently oxo-substituted and C1-C20 alkyl-substituted 2-12 membered heteroalkyl. In embodiments, L8C is independently unsubstituted C1-C6 alkylene, L2C is a bond, and R8C is independently oxo- and C1-C15 alkyl-substituted 2-12 membered heteroalkyl. In embodiments, L8C is independently unsubstituted C4 alkylene, L2C is a bond, and R8C is independently oxo- and C14-C15 alkyl-substituted 2-12 membered heteroalkyl. In embodiments, L8C is independently oxo-substituted 2-12 membered heteroalkylene, L2C is a bond, and R8C is independently oxo-substituted 2-12 membered heteroalkyl. In embodiments, L8C is independently oxo-substituted 2-12 membered heteroalkylene, L2C is a bond, and R8C is independently oxo- and C1-C15 alkyl-substituted 2-12 membered heteroalkyl. In embodiments, L8C is independently oxo-substituted 2-12 membered heteroalkylene, L2C is a bond, and R8C is independently oxo- and C14-C15 alkyl-substituted 2-12 membered heteroalkyl.In an embodiment, -L1C-L1D-L1E- is: [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] In an embodiment, -L1C-L1D-L1E- may form [ka] can be formed.

[0272] In an embodiment, L1 is [ka] [ka] [ka] is.

[0273] In an embodiment, L1 is independently [ka] In an embodiment, L1 is independently [ka] In an embodiment, L1 is independently [ka] In an embodiment, L1 is independently [ka] In an embodiment, L1 is independently [ka] In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] is. In an embodiment, L1 is independently [ka] In an embodiment, L1 is independently [ka] is.

[0274] In an embodiment, L1 is [ka] In an embodiment, L1 is [ka] In an embodiment, L1 is [ka] In an embodiment, L1 is [ka] In an embodiment, L1 is [ka] In an embodiment, L1 is [ka] In an embodiment, L1 is [ka] is.

[0275] In embodiments, the HLEM is [ka] In an embodiment, the HLEM is [ka] In an embodiment, the HLEM is [ka] In an embodiment, the HLEM is [ka] In an embodiment, the HLEM is [ka] In an embodiment, the HLEM is [ka] is.

[0276] In embodiments, the compound comprises one to five optionally different half-life extending motifs. In embodiments, the compound comprises one to four optionally different half-life extending motifs. In embodiments, the compound comprises one to three optionally different half-life extending motifs. In embodiments, the compound comprises one to two optionally different half-life extending motifs. In embodiments, the compound comprises two to five different half-life extending motifs. In embodiments, the compound comprises two to four different half-life extending motifs. In embodiments, the compound comprises two to three different half-life extending motifs. In embodiments, the compound comprises two different half-life extending motifs. In embodiments, the compound comprises only one half-life extending motif.

[0277] In embodiments, the uptake motifs independently have the structure [ka]

[0278] L3 and L4 are 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-, -OP(O)(S)-O-, -OP(O)(R25)-O-, -OP(S)(R25)-O-, -OP(O)(NR23R24)-N-, -OP(S)(NR23R24)-N-, -OP (O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-, -SS-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. Each R23, R24, and R25 is independently hydrogen or unsubstituted C1-C10 alkyl.

[0279] L5 is -L5A-L5B-L5C-L5D-L5E- and L6 is -L6A-L6B-L6C-L6D-L6E-. L5A, L5B, L5C, L5D, L5E, L6A, L6B, L6C, L6D, and L6E are 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.

[0280] R1 and R2 are independently unsubstituted C1-C25 alkyl, and at least one of R1 and R2 is unsubstituted C9-C19 alkyl. In embodiments, R1 and R2 are independently unsubstituted C1-C20 alkyl, and at least one of R1 and R2 is unsubstituted C9-C19 alkyl.

[0281] R3 is 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.

[0282] t is an integer of 1 to 5.

[0283] 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.

[0284] In embodiments, one L3 is attached to the 3' carbon of the oligonucleotide. In embodiments, one L3 is attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, one L3 is attached to the 5' carbon of the oligonucleotide. In embodiments, one L3 is attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety). In embodiments, one L3 is attached to the 2' carbon of the oligonucleotide, and in embodiments, one L3 is attached to the nucleobase of the oligonucleotide.

[0285] In embodiments, one L3 is attached to the 3' carbon of the oligonucleotide at the 3' end. In embodiments, one L3 is attached to the 3' nitrogen of the oligonucleotide at the 3' end (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, one L3 is attached to the 5' carbon of the oligonucleotide at the 5' end. In embodiments, one L3 is attached to the 6' carbon of the oligonucleotide at the 5' end (e.g., the 6' carbon of the morpholino moiety).

[0286] In some embodiments, one L3 is attached to the 3' carbon of the double-stranded oligonucleotide at either of its 3' ends.In some embodiments, one L3 is attached to the 3' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand.In some embodiments, one L3 is attached to the 3' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand.

[0287] In an embodiment, one L3 is bound to the 3' nitrogen of the double-stranded oligonucleotide at either of its 3' ends (e.g., the 3' nitrogen of the morpholino moiety). In an embodiment, one L3 is bound to the 3' nitrogen of the double-stranded oligonucleotide at the 3' end of its antisense strand (e.g., the 3' nitrogen of the morpholino moiety). In an embodiment, one L3 is bound to the 3' nitrogen of the double-stranded oligonucleotide at the 3' end of its sense strand (e.g., the 3' nitrogen of the morpholino moiety).

[0288] In some embodiments, one L3 is attached to the 5' carbon of the double-stranded oligonucleotide at either of its 5' ends.In some embodiments, one L3 is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand.In some embodiments, one L3 is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0289] In embodiments, one L3 is attached to the 6' carbon of the double-stranded oligonucleotide at either of its 5' ends (e.g., the 6' carbon of the morpholino moiety). In embodiments, one L3 is attached to the 6' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand (e.g., the 6' carbon of the morpholino moiety). In embodiments, one L3 is attached to the 6' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand (e.g., the 6' carbon of the morpholino moiety).

[0290] In embodiments, one L3 is attached to the 2' carbon of the double-stranded oligonucleotide. In embodiments, one L3 is attached to the 2' carbon of the double-stranded oligonucleotide at either of its 3' ends. In embodiments, one L3 is attached to the 2' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand. In embodiments, one L3 is attached to the 2' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand. In embodiments, one L3 is attached to the 2' carbon of the double-stranded oligonucleotide at either of its 5' ends. In embodiments, one L3 is attached to the 2' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand. In embodiments, one L3 is attached to the 2' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0291] In an embodiment, one L3 binds to the nucleobase of the double-stranded oligonucleotide. In an embodiment, one L3 binds to the nucleobase of the double-stranded oligonucleotide at either of its 3'-ends. In an embodiment, one L3 binds to the nucleobase of the double-stranded oligonucleotide at the 3'-end of its antisense strand. In an embodiment, one L3 binds to the nucleobase of the double-stranded oligonucleotide at the 3'-end of its sense strand. In an embodiment, one L3 binds to the nucleobase of the double-stranded oligonucleotide at either of its 5'-ends. In an embodiment, one L3 binds to the nucleobase of the double-stranded oligonucleotide at the 5'-end of its antisense strand. In an embodiment, one L3 binds to the nucleobase of the double-stranded oligonucleotide at the 5'-end of its sense strand.

[0292] In embodiments, one L3 is attached to the 3' carbon of the single-stranded oligonucleotide at the 3' end. In embodiments, one L3 is attached to the 3' nitrogen of the single-stranded oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety) at the 3' end of the single-stranded oligonucleotide.

[0293] In an embodiment, one L3 is attached to the 5' carbon of the single-stranded oligonucleotide at the 5' end.

[0294] In embodiments, one L3 is attached to the 6' carbon of the single-stranded oligonucleotide at the 5' end (eg, the 6' carbon of the morpholino moiety).

[0295] In some embodiments, one L3 is attached to the 2' carbon of the single-stranded oligonucleotide. In some embodiments, one L3 is attached to the 2' carbon of the single-stranded oligonucleotide at the 5' end. In some embodiments, one L3 is attached to the 2' carbon of the single-stranded oligonucleotide at the 3' end.

[0296] In embodiments, one L3 binds to the nucleic acid base of single-stranded oligonucleotide.In embodiments, one L3 binds to the nucleic acid base of single-stranded oligonucleotide at 3 '-end.In embodiments, one L3 binds to the nucleic acid base of single-stranded oligonucleotide at 5 '-end.

[0297] In an embodiment, L3 is selected from the group consisting of 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-, -OP(O)(S)-O-, -OP(O)(R25)-O-, -OP(S)(R25)-O-, -OP(O)(NR23R24)-N-, -OP(S)(NR23R24)-N-, -OP( O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-, -SS-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0298] In embodiments, L3 is a bond. In embodiments, L3 is -N(R23)-. In embodiments, L3 is -O- or -S-. In embodiments, L3 is -C(O)-. In embodiments, L3 is -N(R23)C(O)- or -C(O)N(R24)-. In embodiments, L3 is -N(R23)C(O)N(R24)-. In embodiments, L3 is -C(O)O- or -OC(O)-. In embodiments, L3 is -N(R23)C(O)O- or -OC(O)N(R24)-. In embodiments, L3 is -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R25)-O-, -OP(O)(NR23R24)-N-, or OP(O)(NR23R24)-O-. In embodiments, L3 is -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, or -P(S)(NR23R24)-O-. In embodiments, L3 is -SS-.

[0299] In embodiments, L3 is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3 is independently substituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3 is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L3 is independently substituted or unsubstituted C1-C23 alkylene. In embodiments, L3 is independently substituted C1-C23 alkylene. In embodiments, L3 is independently unsubstituted C1-C23 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L3 is independently substituted C1-C12 alkylene. In embodiments, L3 is independently unsubstituted C1-C12 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L3 is independently substituted C1-C8 alkylene. In embodiments, L3 is independently unsubstituted C1-C8 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L3 is independently substituted C1-C6 alkylene. In embodiments, L3 is independently unsubstituted C1-C6 alkylene. In embodiments, L3 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L3 is independently substituted C1-C4 alkylene. In embodiments, L3 is independently unsubstituted C1-C4 alkylene. In embodiments, L3 is independently substituted or unsubstituted ethylene. In embodiments, L3 is independently substituted ethylene. In embodiments, L3 is independently unsubstituted ethylene. In embodiments, L3 is independently substituted or unsubstituted methylene. In embodiments, L3 is independently substituted methylene. In embodiments, L3 is independently unsubstituted methylene.

[0300] In embodiments, L3 is 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, L3 is 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, L3 is 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, L3 is independently substituted or unsubstituted 2 to 23-membered heteroalkylene. In embodiments, L3 is independently substituted 2 to 23-membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2 to 23-membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L3 is independently substituted 2-8 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 2-6 membered heteroalkylene. In embodiments, L3 is independently substituted 2-6 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2-6 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 4-6 membered heteroalkylene. In embodiments, L3 is independently substituted 4-6 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 4-6 membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L3 is independently substituted 2-3 membered heteroalkylene. In embodiments, L3 is independently unsubstituted 2- to 3-membered heteroalkylene. In embodiments, L3 is independently substituted or unsubstituted 4- to 5-membered heteroalkylene. In embodiments, L3 is independently substituted 4- to 5-membered heteroalkylene. In embodiments, L3 is independently unsubstituted 4- to 5-membered heteroalkylene.

[0301] In an embodiment, L4 is selected from the group consisting of 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-, -OP(O)(S)-O-, -OP(O)(R25)-O-, -OP(S)(R25)-O-, -OP(O)(NR23R24)-N-, -OP(S)(NR23R24)-N-, -OP( O)(NR23R24)-O-, -O-P(S)(NR23R24)-O-, -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, -P(S)(NR23R24)-O-, -SS-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0302] In embodiments, L4 is a bond. In embodiments, L4 is -N(R23)-. In embodiments, L4 is -O- or -S-. In embodiments, L4 is -C(O)-. In embodiments, L4 is -N(R23)C(O)- or -C(O)N(R24)-. In embodiments, L4 is -N(R23)C(O)N(R24)-. In embodiments, L4 is -C(O)O- or -OC(O)-. In embodiments, L4 is -N(R23)C(O)O- or -OC(O)N(R24)-. In embodiments, L4 is -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R25)-O-, -OP(O)(NR23R24)-N-, or OP(O)(NR23R24)-O-. In embodiments, L4 is -P(O)(NR23R24)-N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, or -P(S)(NR23R24)-O-. In embodiments, L4 is -SS-.

[0303] In embodiments, L4 is independently substituted or unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently substituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently unsubstituted alkylene (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently substituted or unsubstituted C1-C23 alkylene. In embodiments, L4 is independently substituted C1-C23 alkylene. In embodiments, L4 is independently unsubstituted C1-C23 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L4 is independently substituted C1-C12 alkylene. In embodiments, L4 is independently unsubstituted C1-C12 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L4 is independently substituted C1-C8 alkylene. In embodiments, L4 is independently unsubstituted C1-C8 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L4 is independently substituted C1-C6 alkylene. In embodiments, L4 is independently unsubstituted C1-C6 alkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L4 is independently substituted C1-C4 alkylene. In embodiments, L4 is independently unsubstituted C1-C4 alkylene. In embodiments, L4 is independently substituted or unsubstituted ethylene. In embodiments, L4 is independently substituted ethylene. In embodiments, L4 is independently unsubstituted ethylene. In embodiments, L4 is independently substituted or unsubstituted methylene. In embodiments, L4 is independently substituted methylene. In embodiments, L4 is independently unsubstituted methylene.

[0304] In embodiments, L4 is 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, L4 is 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, L4 is 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, L4 is independently substituted or unsubstituted 2 to 23-membered heteroalkylene. In embodiments, L4 is independently substituted 2 to 23-membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2 to 23-membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L4 is independently substituted 2-8 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 2-6 membered heteroalkylene. In embodiments, L4 is independently substituted 2-6 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2-6 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 4-6 membered heteroalkylene. In embodiments, L4 is independently substituted 4-6 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 4-6 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L4 is independently substituted 2-3 membered heteroalkylene. In embodiments, L4 is independently unsubstituted 2- to 3-membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted 4- to 5-membered heteroalkylene. In embodiments, L4 is independently substituted 4- to 5-membered heteroalkylene. In embodiments, L4 is independently unsubstituted 4- to 5-membered heteroalkylene.

[0305] R23 is independently hydrogen or unsubstituted alkyl (e.g., C1-C23, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R23 is independently hydrogen. In embodiments, R23 is independently unsubstituted C1-C23 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R23 is independently hydrogen or unsubstituted C1-C2 alkyl.

[0306] R24 is independently hydrogen or unsubstituted alkyl (e.g., C1-C24, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R24 is independently hydrogen. In embodiments, R24 is independently unsubstituted C1-C24 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R24 is independently hydrogen or unsubstituted C1-C2 alkyl.

[0307] R25 is independently hydrogen or unsubstituted alkyl (e.g., C1-C25, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R25 is independently hydrogen. In embodiments, R25 is independently unsubstituted C1-C25 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C12 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C10 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C8 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R25 is independently hydrogen or unsubstituted C1-C2 alkyl.

[0308] In embodiments, L3 and L4 are independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(CH3)-O-, -OP(S)(CH3)-O-, -OP(O)(N(CH3)2)-N-, -OP(O)(N(CH3)2)-O-, -OP(S)(N(CH3)2)-N-, -OP(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, L3 is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(CH3)-O-, -OP(S)(CH3)-O-, -OP(O)(N(CH3)2)-N-, -OP(O)(N(CH3)2)-O-, -OP(S)(N(CH3)2)-N-, -OP(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, L4 is independently a bond, -NH-, -O-, -C(O)-, -C(O)O-, -OC(O)-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(CH3)-O-, -OP(S)(CH3)-O-, -OP(O)(N(CH3)2)-N-, -OP(O)(N(CH3)2)-O-, -OP(S)(N(CH3)2)-N-, -OP(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.

[0309] In embodiments, L3 is independently [ka] In embodiments, L3 is independently -OPO2-O-. In embodiments, L3 is independently -OP(O)(S)-O-. In embodiments, L3 is independently -O-. In embodiments, L3 is independently -S-.

[0310] In embodiments, L3 is attached to the 3' nitrogen of the morpholino moiety. In embodiments, L3 is independently -C(O)-. In embodiments, L3 is attached to the 6' carbon of the morpholino moiety. In embodiments, L3 is independently -OP(O)(N(CH3)2)-N-. In embodiments, L3 is independently -OP(O)(N(CH3)2)-O-. In embodiments, L3 is independently -P(O)(N(CH3)2)-N-. In embodiments, L3 is independently -P(O)(N(CH3)2)-O-.

[0311] In embodiments, L4 is independently substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-. In embodiments, L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0312] In embodiments, L4 is independently substituted or unsubstituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L4 is independently substituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L4 is independently oxo-substituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L4 is independently unsubstituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring).

[0313] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently -L7-NH-C(O)-, where L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently -L7-C(O)-NH-, and L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0314] In embodiments, L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L7 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L7 is independently substituted C1-C20 alkylene. In embodiments, L7 is independently hydroxy (OH)-substituted C1-C20 alkylene. In embodiments, L7 is independently a hydroxymethyl-substituted C1-C20 alkylene. In embodiments, L7 is independently an unsubstituted C1-C20 alkylene. In embodiments, L7 is independently a substituted or unsubstituted C1-C12 alkylene. In embodiments, L7 is independently a substituted C1-C12 alkylene. In embodiments, L7 is independently a hydroxy(OH)-substituted C1-C12 alkylene. In embodiments, L7 is independently a hydroxymethyl-substituted C1-C12 alkylene. In embodiments, L7 is independently an unsubstituted C1-C12 alkylene. In embodiments, L7 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, L7 is independently a substituted C1-C8 alkylene. In embodiments, L7 is independently a hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, L7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L7 is independently an unsubstituted C1-C8 alkylene. In embodiments, L7 is independently a substituted or unsubstituted C1-C6 alkylene. In embodiments, L7 is independently a substituted C1-C6 alkylene. In embodiments, L7 is independently a hydroxy (OH)-substituted C1-C6 alkylene. In embodiments, L7 is independently a hydroxymethyl-substituted C1-C6 alkylene. In embodiments, L7 is independently an unsubstituted C1-C6 alkylene. In embodiments, L7 is independently a substituted or unsubstituted C1-C4 alkylene.In embodiments, L7 is independently substituted C1-C4 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C4 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C4 alkylene. In embodiments, L7 is independently unsubstituted C1-C4 alkylene. In embodiments, L7 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L7 is independently substituted C1-C2 alkylene. In embodiments, L7 is independently hydroxy(OH)-substituted C1-C2 alkylene. In embodiments, L7 is independently hydroxymethyl-substituted C1-C2 alkylene. In embodiments, L7 is independently unsubstituted C1-C2 alkylene.

[0315] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently substituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently an unsubstituted C1-C8 alkylene.

[0316] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a substituted or unsubstituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a substituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently unsubstituted C3-C8 alkylene.

[0317] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a substituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently unsubstituted C5-C8 alkylene.

[0318] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently substituted or unsubstituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently hydroxy(OH)-substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently unsubstituted octylene. In embodiments, L4 is independently -L7-NH-C(O)-, and L7 is independently hydroxy(OH)-substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted octylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted octylene.

[0319] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently substituted or unsubstituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently hydroxy(OH)-substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently unsubstituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)-, and L7 is independently hydroxy(OH)-substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted heptylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted heptylene.

[0320] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently substituted or unsubstituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently hydroxy(OH)-substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, and L7 is independently unsubstituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)-, and L7 is independently hydroxy(OH)-substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted hexylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted hexylene.

[0321] In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently substituted or unsubstituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently hydroxy(OH)-substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- or -L7-C(O)-NH-, where L7 is independently unsubstituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)-, where L7 is independently hydroxy(OH)-substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently hydroxymethyl-substituted pentylene. In embodiments, L4 is independently -L7-NH-C(O)- and L7 is independently unsubstituted pentylene.

[0322] In embodiments, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] is.

[0323] In embodiments, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] In an embodiment, L4 is independently [ka] is.

[0324] In embodiments, -L3-L4- is independently -L7-NH-C(O)- or -L7-C(O)-NH-. In embodiments, L7 is independently substituted or unsubstituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L7 is independently substituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L7 is independently oxo-substituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L7 is independently unsubstituted heteroalkylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L7 is independently substituted or unsubstituted heteroalkenylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L7 is independently substituted heteroalkenylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L7 is independently oxo-substituted heteroalkenylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring). In embodiments, L7 is independently substituted heteroalkenylene (e.g., a 2- to 20-membered ring, a 2- to 12-membered ring, a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring).

[0325] In embodiments, L7 is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L7 is independently substituted 2-20 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2-20 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2-20 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2-12 membered heteroalkylene. In embodiments, L7 is independently substituted 2-12 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2-12 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2-12 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2-10 membered heteroalkylene. In embodiments, L7 is independently substituted 2-10 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2-10 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2-10 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L7 is independently substituted 2-8 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2-8 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2-6 membered heteroalkylene. In embodiments, L7 is independently substituted 2-6 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2-6 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2-6 membered heteroalkylene. In embodiments, L7 is independently substituted or unsubstituted 2-4 membered heteroalkylene. In embodiments, L7 is independently substituted 2-4 membered heteroalkylene. In embodiments, L7 is independently oxo-substituted 2-4 membered heteroalkylene. In embodiments, L7 is independently unsubstituted 2-4 membered heteroalkylene.

[0326] In embodiments, L7 is independently substituted or unsubstituted 2-20 membered heteroalkenylene. In embodiments, L7 is independently substituted 2-20 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2-20 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2-20 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2-12 membered heteroalkenylene. In embodiments, L7 is independently substituted 2-12 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2-12 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2-12 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2-10 membered heteroalkenylene. In embodiments, L7 is independently substituted 2-10 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2-10 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2-10 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2-8 membered heteroalkenylene. In embodiments, L7 is independently substituted 2-8 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2-8 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2-8 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2-6 membered heteroalkenylene. In embodiments, L7 is independently substituted 2-6 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2-6 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2-6 membered heteroalkenylene. In embodiments, L7 is independently substituted or unsubstituted 2-4 membered heteroalkenylene. In embodiments, L7 is independently substituted 2-4 membered heteroalkenylene. In embodiments, L7 is independently oxo-substituted 2-4 membered heteroalkenylene. In embodiments, L7 is independently unsubstituted 2-4 membered heteroalkenylene.

[0327] In embodiments, -L3-L4- is independently -O-L7-NH-C(O)- or -O-L7-C(O)-NH-. In embodiments, L7 is 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-, where L7 is 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)-, where L7 is 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-, where L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0328] In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently an unsubstituted C1-C8 alkylene.

[0329] In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently an unsubstituted C3-C8 alkylene.

[0330] In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-C(O)-NH-, and L7 is independently an unsubstituted C5-C8 alkylene.

[0331] In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently an unsubstituted C1-C8 alkylene.

[0332] In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently an unsubstituted C3-C8 alkylene.

[0333] In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-L7-NH-C(O)-, and L7 is independently an unsubstituted C5-C8 alkylene.

[0334] In an embodiment, -L3-L4- is independently [ka] In an embodiment, -L3-L4- is independently [ka] In an embodiment, -L3-L4- is independently [ka] In an embodiment, -L3-L4- is independently [ka] is.

[0335] 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, L7 is 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)-, where L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-NH-C(O)-, and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH- or -O-P(O)(S)-O-L7-C(O)-NH-, and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently substituted or unsubstituted alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, and L7 is independently substituted or unsubstituted alkylene.

[0336] In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)- or -OPO2-O-L7-C(O)-NH-, where L7 is 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)-, where L7 is 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 L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0337] In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)- or -OP(O)(S)-O-L7-C(O)-NH-, where L7 is 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-NH-C(O)-, where L7 is 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 L7 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0338] In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently unsubstituted C1-C8 alkylene.

[0339] In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, where L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, where L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, where L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, where L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, where L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, and L7 is independently unsubstituted C1-C8 alkylene.

[0340] In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently unsubstituted C3-C8 alkylene.

[0341] In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, and L7 is independently unsubstituted C3-C8 alkylene.

[0342] In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-C(O)-NH-, and L7 is independently unsubstituted C5-C8 alkylene.

[0343] In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -O-P(O)(S)-O-L7-C(O)-NH-, where L7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-C(O)-NH-, and L7 is independently unsubstituted C5-C8 alkylene.

[0344] In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently unsubstituted C1-C8 alkylene.

[0345] In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)2-O-L7-NH-C(O)-, where L7 is independently hydroxy(OH)-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, and L7 is independently unsubstituted C1-C8 alkylene.

[0346] In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently unsubstituted C3-C8 alkylene.

[0347] In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a substituted or unsubstituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a hydroxy(OH)-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, and L7 is independently unsubstituted C3-C8 alkylene.

[0348] In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OPO2-O-L7-NH-C(O)-, and L7 is independently unsubstituted C5-C8 alkylene.

[0349] In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a substituted or unsubstituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a hydroxy(OH)-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, where L7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L3-L4- is independently -OP(O)(S)-O-L7-NH-C(O)-, and L7 is independently unsubstituted C5-C8 alkylene.

[0350] In embodiments, -L3-L4- is attached to the 3' carbon of the oligonucleotide. In embodiments, -L3-L4- is attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, -L3-L4- is attached to the 5' carbon of the oligonucleotide. In embodiments, -L3-L4- is attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety). In embodiments, -L3-L4- is attached to the 2' carbon of the oligonucleotide. In embodiments, -L3-L4- is attached to a nucleobase of the oligonucleotide.

[0351] In embodiments, at least -L3-L4- is attached to the 3' carbon of the oligonucleotide at the 3' end. In embodiments, at least -L3-L4- is attached to the 3' nitrogen of the oligonucleotide at the 3' end (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, at least -L3-L4- is attached to the 5' carbon of the oligonucleotide at the 5' end. In embodiments, at least -L3-L4- is attached to the 6' carbon of the oligonucleotide at the 5' end (e.g., the 6' carbon of the morpholino moiety).

[0352] In an embodiment, -L3-L4- is independently [ka] is.

[0353] In an embodiment, -L3-L4- is independently [ka] In an embodiment, -L3-L4- is independently [ka] In an embodiment, -L3-L4- is independently [ka] In an embodiment, -L3-L4- is independently [ka] In an embodiment, -L3-L4- is independently [ka] is.

[0354] In an embodiment, -L3-L4- is independently [ka] and is attached to the 3' carbon of the oligonucleotide. In embodiments, -L3-L4- is independently attached to the 3' carbon of the oligonucleotide. [ka] In embodiments, -L3-L4- is independently attached to the 3' carbon of the oligonucleotide: [ka] is.

[0355] In an embodiment, -L3-L4- is independently [ka] and binds to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety). In embodiments, -L3-L4- is independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] In embodiments, -L3-L4- is independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] is.

[0356] In an embodiment, -L3-L4- is independently [ka] and is attached to the 5' carbon of the oligonucleotide. In embodiments, -L3-L4- are independently attached to the 5' carbon of the oligonucleotide: [ka] In embodiments, -L3-L4- is independently attached to the 5' carbon of the oligonucleotide: [ka] is.

[0357] In embodiments where the oligonucleotide comprises a morpholino moiety, L3 is independently -P(O)(N(CH3)2)-N- or -P(O)(N(CH3)2)-O-. In embodiments, L4 is substituted or unsubstituted heterocycloalkyl. In embodiments, L4 is substituted heterocycloalkyl. In embodiments, L4 is unsubstituted heterocycloalkyl. In embodiments, L4 is substituted or unsubstituted piperidinylene. In embodiments, L4 is substituted piperidinylene. In embodiments, L4 is unsubstituted piperidinylene. In embodiments, L4 is substituted or unsubstituted piperazinylene. In embodiments, L4 is substituted piperazinylene. In embodiments, L4 is unsubstituted piperazinylene. In embodiments, -L3-L4- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety), [ka] In embodiments, -L3-L4- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety), [ka] In embodiments, -L3-L4- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety), [ka] is.

[0358] In embodiments, -L3-L4- are independently linked to a nucleobase of an oligonucleotide. [ka] and binds to the nucleobase of the oligonucleotide.

[0359] In some embodiments, -L3-L4- is attached to the 3' carbon of the double-stranded oligonucleotide at either of its 3' ends. In some embodiments, -L3-L4- is attached to the 3' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand. In some embodiments, -L3-L4- is attached to the 3' carbon of the double-stranded oligonucleotide at the 3' end of its sense strand.

[0360] In embodiments, -L3-L4- is attached to the 3' nitrogen of a 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 the 3' nitrogen of a 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 the 3' nitrogen of a double-stranded oligonucleotide (e.g., a PMO) at the 3' end of its sense strand.

[0361] In some embodiments, -L3-L4- is attached to the 5' carbon of the double-stranded oligonucleotide at either of its 5' ends. In some embodiments, -L3-L4- is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand. In some embodiments, -L3-L4- is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0362] In embodiments, -L3-L4- is attached to the 6' carbon of the double-stranded oligonucleotide at either of its 5' ends (e.g., the 6' carbon of the morpholino moiety). In embodiments, -L3-L4- is attached to the 6' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand (e.g., the 6' carbon of the morpholino moiety). In embodiments, -L3-L4- is attached to the 6' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand (e.g., the 6' carbon of the morpholino moiety).

[0363] In embodiments, -L3-L4- is attached to the 2' carbon of the double-stranded oligonucleotide. In embodiments, -L3-L4- is attached to the 2' carbon of the double-stranded oligonucleotide at either of its 3' ends. In embodiments, -L3-L4- is attached to the 2' carbon of the double-stranded oligonucleotide at the 3' end of its antisense strand. In embodiments, -L3-L4- is attached to the 2' carbon of the double-stranded oligonucleotide at the 3' end of its sense strand. In embodiments, -L3-L4- is attached to the 2' carbon of the double-stranded oligonucleotide at either of its 5' ends. In embodiments, -L3-L4- is attached to the 2' carbon of the double-stranded oligonucleotide at the 5' end of its antisense strand. In embodiments, -L3-L4- is attached to the 2' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0364] In embodiments, -L3-L4- is bound to a nucleobase of a double-stranded oligonucleotide. In embodiments, -L3-L4- is bound to a nucleobase of a double-stranded oligonucleotide at either of its 3' ends. In embodiments, -L3-L4- is bound to a nucleobase of a double-stranded oligonucleotide at the 3' end of its antisense strand. In embodiments, -L3-L4- is bound to a nucleobase of a double-stranded oligonucleotide at the 3' end of its sense strand. In embodiments, -L3-L4- is bound to a nucleobase of a double-stranded oligonucleotide at either of its 5' ends. In embodiments, -L3-L4- is bound to a nucleobase of a double-stranded oligonucleotide at the 5' end of its antisense strand. In embodiments, -L3-L4- is bound to a nucleobase of a double-stranded oligonucleotide at the 5' end of its sense strand.

[0365] In embodiments, -L3-L4- is attached to the 3' carbon of the single-stranded oligonucleotide at the 3' end.

[0366] In embodiments, -L3-L4- is attached to the 3' nitrogen of the single-stranded oligonucleotide at the 3' end (eg, the 3' nitrogen of the morpholino moiety).

[0367] In embodiments, -L3-L4- is attached to the 5' carbon of the single stranded oligonucleotide at the 5' end of the single stranded oligonucleotide.

[0368] In embodiments, -L3-L4- is attached at its 5' end to the 6' carbon of the single-stranded oligonucleotide (e.g., the 6' carbon of the morpholino moiety). [ka] is.

[0369] In embodiments, -L3-L4- is attached to the 2' carbon of the single-stranded oligonucleotide. In embodiments, -L3-L4- is attached to the 2' carbon of the single-stranded oligonucleotide at the 3' end. In embodiments, -L3-L4- is attached to the 2' carbon of the single-stranded oligonucleotide at the 5' end.

[0370] In embodiments, -L3-L4- is linked to the nucleobase of the single-stranded oligonucleotide. In embodiments, -L3-L4- is linked to the nucleobase of the single-stranded oligonucleotide at its 3' end. In embodiments, -L3-L4- is linked to the nucleobase of the single-stranded oligonucleotide at its 5' end.

[0371] In an embodiment, -L3-L4- is independently [ka] is.

[0372] In embodiments, -L3-L4- is independently attached to the 3' carbon of the oligonucleotide. [ka] is. In embodiments, -L3-L4- is independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] In embodiments, -L3-L4- is independently attached to the 5' carbon of the oligonucleotide: [ka] In embodiments, -L3-L4- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety), [ka] In embodiments, -L3-L4- is independently attached to the 2' carbon of the oligonucleotide: [ka] In embodiments, -L3-L4- is independently linked to a nucleobase of an oligonucleotide. [ka] is.

[0373] In embodiments, -L3-L4- is independently attached to the 3' carbon of the oligonucleotide. [ka] In embodiments, -L3-L4- is independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] In embodiments, -L3-L4- is independently attached to the 5' carbon of the oligonucleotide: [ka] In embodiments, -L3-L4- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety MO). [ka] In embodiments, -L3-L4- is independently attached to the 2' carbon of the oligonucleotide: [ka] In embodiments, -L3-L4- is independently linked to a nucleobase of an oligonucleotide. [ka] is.

[0374] In embodiments, -L3-L4- is independently attached to the 3' carbon of the oligonucleotide. [ka] In embodiments, -L3-L4- is independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] In an embodiment, -L3-L4- is independently [ka] and is attached to the 5' carbon of the oligonucleotide. In embodiments, -L3-L4- is independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety). [ka] In an embodiment, -L3-L4- is independently [ka] and is attached to the 2' carbon of the oligonucleotide. In embodiments, -L3-L4- is independently [ka] and binds to the nucleobases of the oligonucleotide.

[0375] In embodiments, -L3-L4- is independently attached to the 3' carbon of the oligonucleotide. [ka] is. In embodiments, -L3-L4- is independently attached to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety), [ka] is. In embodiments, -L3-L4- are independently attached to the 5' carbon of the oligonucleotide. [ka] is. In embodiments, -L3-L4- are independently attached to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety). [ka] is. In embodiments, -L3-L4- are independently attached to the 2' carbon of the oligonucleotide. [ka] In an embodiment, -L3-L4- is independently [ka] and binds to the nucleobases of the oligonucleotide.

[0376] In embodiments, R3 is 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, R3 is independently hydrogen. In embodiments, R3 is independently -NH2. In embodiments, R3 is independently -OH. In embodiments, R3 is independently -SH. In embodiments, R3 is independently -C(O)H. In embodiments, R3 is independently -C(O)NH2. In embodiments, R3 is independently -NHC(O)H. In embodiments, R3 is independently -NHC(O)OH. In embodiments, R3 is independently -NHC(O)NH2. In embodiments, R3 is independently -C(O)OH. In embodiments, R3 is independently -OC(O)H. In embodiments, R3 is independently -N3.

[0377] In embodiments, R3 is independently substituted or unsubstituted alkyl (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R3 is independently substituted or unsubstituted C1-C20 alkyl. In embodiments, R3 is independently substituted C1-C20 alkyl. In embodiments, R3 is independently unsubstituted C1-C20 alkyl. In embodiments, R3 is independently substituted C1-C12 alkyl. In embodiments, R3 is independently unsubstituted C1-C12 alkyl. In embodiments, R3 is independently substituted or unsubstituted C1-C8 alkyl. In embodiments, R3 is independently substituted C1-C8 alkyl. In embodiments, R3 is independently unsubstituted C1-C8 alkyl. In embodiments, R3 is independently substituted or unsubstituted C1-C6 alkyl. In embodiments, R3 is independently substituted C1-C6 alkyl. In embodiments, R3 is independently unsubstituted C1-C6 alkyl. In embodiments, R3 is independently substituted or unsubstituted C1-C4 alkyl. In embodiments, R3 is independently substituted C1-C4 alkyl. In embodiments, R3 is independently unsubstituted C1-C4 alkyl. In embodiments, R3 is independently substituted or unsubstituted ethyl. In embodiments, R3 is independently substituted ethyl. In embodiments, R3 is independently unsubstituted ethyl. In embodiments, R3 is independently substituted or unsubstituted methyl. In embodiments, R3 is independently substituted methyl. In embodiments, R3 is independently unsubstituted methyl.

[0378] In embodiments, L6 is independently -NHC(O)-. In embodiments, L6 is independently -C(O)NH-. In embodiments, L6 is independently substituted or unsubstituted alkylene. In embodiments, L6 is independently substituted or unsubstituted heteroalkylene.

[0379] In embodiments, L6 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L6 is independently substituted C1-C20 alkylene. In embodiments, L6 is independently unsubstituted C1-C20 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L6 is independently substituted C1-C12 alkylene. In embodiments, L6 is independently unsubstituted C1-C12 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L6 is independently substituted C1-C8 alkylene. In embodiments, L6 is independently unsubstituted C1-C8 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L6 is independently substituted C1-C6 alkylene. In embodiments, L6 is independently unsubstituted C1-C6 alkylene. In embodiments, L6 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L6 is independently substituted C1-C4 alkylene. In embodiments, L6 is independently unsubstituted C1-C4 alkylene. In embodiments, L6 is independently substituted or unsubstituted ethylene. In embodiments, L6 is independently substituted ethylene. In embodiments, L6 is independently unsubstituted ethylene. In embodiments, L6 is independently substituted or unsubstituted methylene. In embodiments, L6 is independently substituted methylene. In embodiments, L6 is independently unsubstituted methylene.

[0380] In embodiments, L6 is independently substituted or unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L6 is independently substituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L6 is independently unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L6 is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L6 is independently substituted 2-20 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2-20 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L6 is independently substituted 2-8 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 2-6 membered heteroalkylene. In embodiments, L6 is independently substituted 2-6 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2-6 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 4-6 membered heteroalkylene. In embodiments, L6 is independently substituted 4-6 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 4-6 membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L6 is independently substituted 2-3 membered heteroalkylene. In embodiments, L6 is independently unsubstituted 2- to 3-membered heteroalkylene. In embodiments, L6 is independently substituted or unsubstituted 4- to 5-membered heteroalkylene. In embodiments, L6 is independently substituted 4- to 5-membered heteroalkylene. In embodiments, L6 is independently unsubstituted 4- to 5-membered heteroalkylene.

[0381] In embodiments, L6A is independently a bond or unsubstituted alkylene, L6B is independently a bond, -NHC(O)-, or unsubstituted arylene, L6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene, L6D is independently a bond or unsubstituted alkylene, and L6E is independently a bond or -NHC(O)-. In embodiments, L6A is independently a bond or unsubstituted alkylene. In embodiments, L6B is independently a bond, -NHC(O)-, or unsubstituted arylene. In embodiments, L6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene, and in embodiments, L6D is independently a bond or unsubstituted alkylene. In embodiments, L6E is independently a bond or -NHC(O)-.

[0382] In embodiments, L6A is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6A is independently unsubstituted C1-C20 alkylene. In embodiments, L6A is independently unsubstituted C1-C12 alkylene. In embodiments, L6A is independently unsubstituted C1-C8 alkylene. In embodiments, L6A is independently unsubstituted C1-C6 alkylene. In embodiments, L6A is independently unsubstituted C1-C4 alkylene. In embodiments, L6A is independently unsubstituted ethylene. In embodiments, L6A is independently unsubstituted methylene. In embodiments, L6A is independently a bond.

[0383] In embodiments, L6B is independently a bond. In embodiments, L6B is independently -NHC(O)-. In embodiments, L6B is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L6B is independently unsubstituted C6-C12 arylene. In embodiments, L6B is independently unsubstituted C6-C10 arylene. In embodiments, L6B is independently unsubstituted phenylene. In embodiments, L6B is independently unsubstituted naphthylene. In embodiments, L6B is independently unsubstituted biphenylene.

[0384] In embodiments, L6C is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6C is independently unsubstituted C1-C20 alkylene. In embodiments, L6C is independently unsubstituted C1-C12 alkylene. In embodiments, L6C is independently unsubstituted C1-C8 alkylene. L6C is independently unsubstituted C2-C8 alkynylene. In embodiments, L6C is independently unsubstituted C1-C6 alkylene. In embodiments, L6C is independently unsubstituted C1-C4 alkylene. In embodiments, L6C is independently unsubstituted ethylene. In embodiments, L6C is independently unsubstituted methylene. In embodiments, L6C is independently a bond or unsubstituted alkynylene (e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L6C is independently unsubstituted C2-C20 alkynylene. In embodiments, L6C is independently unsubstituted C2-C12 alkynylene. In embodiments, L6C is independently unsubstituted C2-C8 alkynylene. In embodiments, L6C is independently unsubstituted C2-C6 alkynylene. In embodiments, L6C is independently unsubstituted C2-C4 alkynylene. In embodiments, L6C is independently unsubstituted ethynylene. In embodiments, L6C is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L6C is independently an unsubstituted C6-C12 arylene. In embodiments, L6C is independently an unsubstituted C6-C10 arylene. In embodiments, L6C is independently an unsubstituted phenylene. In embodiments, L6C is independently an unsubstituted naphthylene. In embodiments, L6C is independently a bond.

[0385] In embodiments, L6D is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L6D is independently unsubstituted C1-C20 alkylene. In embodiments, L6D is independently unsubstituted C1-C12 alkylene. In embodiments, L6A is independently unsubstituted C1-C8 alkylene. In embodiments, L6D is independently unsubstituted C1-C6 alkylene. In embodiments, L6D is independently unsubstituted C1-C4 alkylene. In embodiments, L6D is independently unsubstituted ethylene. In embodiments, L6D is independently unsubstituted methylene. In embodiments, L6D is independently a bond.

[0386] In embodiments, L6E is independently a bond. In embodiments, L6E is independently -NHC(O)-.

[0387] In embodiments, L6A is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L6B is independently a bond, -NHC(O)-, or unsubstituted phenylene. In embodiments, L6C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene, and in embodiments, L6D is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L6E is independently a bond or -NHC(O)-.

[0388] In embodiments, L6 is independently a bond, [ka] In embodiments, L6 is independently a bond. In embodiments, L6 is independently [ka] In an embodiment, L6 is independently [ka] In an embodiment, L6 is independently [ka] In an embodiment, L6 is independently [ka] In an embodiment, L6 is independently [ka] is.

[0389] In embodiments, L5 is independently -NHC(O)-. In embodiments, L5 is independently -C(O)NH-. In embodiments, L5 is independently substituted or unsubstituted alkylene. In embodiments, L5 is independently substituted or unsubstituted heteroalkylene.

[0390] In embodiments, L5 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L5 is independently substituted C1-C20 alkylene. In embodiments, L5 is independently unsubstituted C1-C20 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L5 is independently substituted C1-C12 alkylene. In embodiments, L5 is independently unsubstituted C1-C12 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L5 is independently substituted C1-C8 alkylene. In embodiments, L5 is independently unsubstituted C1-C8 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L5 is independently substituted C1-C6 alkylene. In embodiments, L5 is independently unsubstituted C1-C6 alkylene. In embodiments, L5 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L5 is independently substituted C1-C4 alkylene. In embodiments, L5 is independently unsubstituted C1-C4 alkylene. In embodiments, L5 is independently substituted or unsubstituted ethylene. In embodiments, L5 is independently substituted ethylene. In embodiments, L5 is independently unsubstituted ethylene. In embodiments, L5 is independently substituted or unsubstituted methylene. In embodiments, L5 is independently substituted methylene. In embodiments, L5 is independently unsubstituted methylene.

[0391] In embodiments, L5 is independently substituted or unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L5 is independently substituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L5 is independently unsubstituted heteroalkylene (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered). In embodiments, L5 is independently substituted or unsubstituted 2-20 membered heteroalkylene. In embodiments, L5 is independently substituted 2-20 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2-20 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 2-8 membered heteroalkylene. In embodiments, L5 is independently substituted 2-8 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2-8 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 2-6 membered heteroalkylene. In embodiments, L5 is independently substituted 2-6 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2-6 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 4-6 membered heteroalkylene. In embodiments, L5 is independently substituted 4-6 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 4-6 membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 2-3 membered heteroalkylene. In embodiments, L5 is independently substituted 2-3 membered heteroalkylene. In embodiments, L5 is independently unsubstituted 2- to 3-membered heteroalkylene. In embodiments, L5 is independently substituted or unsubstituted 4- to 5-membered heteroalkylene. In embodiments, L5 is independently substituted 4- to 5-membered heteroalkylene. In embodiments, L5 is independently unsubstituted 4- to 5-membered heteroalkylene.

[0392] In embodiments, L5A is independently a bond or unsubstituted alkylene, L5B is independently a bond, -NHC(O)-, or unsubstituted arylene, L5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene, L5D is independently a bond or unsubstituted alkylene, and L5E is independently a bond or -NHC(O)-. In embodiments, L5A is independently a bond or unsubstituted alkylene. In embodiments, L5B is independently a bond, -NHC(O)-, or unsubstituted arylene. In embodiments, L5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene, and in embodiments, L5D is independently a bond or unsubstituted alkylene. In embodiments, L5E is independently a bond or -NHC(O)-.

[0393] In embodiments, L5A is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5A is independently unsubstituted C1-C20 alkylene. In embodiments, L5A is independently unsubstituted C1-C12 alkylene. In embodiments, L5A is independently unsubstituted C1-C8 alkylene. In embodiments, L5A is independently unsubstituted C1-C6 alkylene. In embodiments, L5A is independently unsubstituted C1-C4 alkylene. In embodiments, L5A is independently unsubstituted ethylene. In embodiments, L5A is independently unsubstituted methylene. In embodiments, L5A is independently a bond.

[0394] In embodiments, L5B is independently a bond. In embodiments, L5B is independently -NHC(O)-. In embodiments, L5B is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L5B is independently unsubstituted C6-C12 arylene. In embodiments, L5B is independently unsubstituted C6-C10 arylene. In embodiments, L5B is independently unsubstituted phenylene. In embodiments, L5B is independently unsubstituted naphthylene.

[0395] In embodiments, L5C is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5C is independently unsubstituted C1-C20 alkylene. In embodiments, L5C is independently unsubstituted C1-C12 alkylene. In embodiments, L5C is independently unsubstituted C1-C8 alkylene. L5C is independently unsubstituted C2-C8 alkynylene. In embodiments, L5C is independently unsubstituted C1-C6 alkylene. In embodiments, L5C is independently unsubstituted C1-C4 alkylene. In embodiments, L5C is independently unsubstituted ethylene. In embodiments, L5C is independently unsubstituted methylene. In embodiments, L5C is independently a bond or unsubstituted alkynylene (e.g., C2-C20, C2-C12, C2-C8, C2-C6, C2-C4, or C2-C2). In embodiments, L5C is independently unsubstituted C2-C20 alkynylene. In embodiments, L5C is independently unsubstituted C2-C12 alkynylene. In embodiments, L5C is independently unsubstituted C2-C8 alkynylene. In embodiments, L5C is independently unsubstituted C2-C6 alkynylene. In embodiments, L5C is independently unsubstituted C2-C4 alkynylene. In embodiments, L5C is independently unsubstituted ethynylene. In embodiments, L5C is independently unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl). In embodiments, L5C is independently an unsubstituted C6-C12 arylene. In embodiments, L5C is independently an unsubstituted C6-C10 arylene. In embodiments, L5C is independently an unsubstituted phenylene. In embodiments, L5C is independently an unsubstituted naphthylene. In embodiments, L5C is independently a bond.

[0396] In embodiments, L5D is independently a bond or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L5D is independently unsubstituted C1-C20 alkylene. In embodiments, L5D is independently unsubstituted C1-C12 alkylene. In embodiments, L5A is independently unsubstituted C1-C8 alkylene. In embodiments, L5D is independently unsubstituted C1-C6 alkylene. In embodiments, L5D is independently unsubstituted C1-C4 alkylene. In embodiments, L5D is independently unsubstituted ethylene. In embodiments, L5D is independently unsubstituted methylene. In embodiments, L5D is independently a bond.

[0397] In embodiments, L5E is independently a bond. In embodiments, L5E is independently -NHC(O)-.

[0398] In embodiments, L5A is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L5B is independently a bond, -NHC(O)-, or unsubstituted phenylene. In embodiments, L5C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene, and in embodiments, L5D is independently a bond or unsubstituted C1-C8 alkylene. In embodiments, L5E is independently a bond or -NHC(O)-.

[0399] In embodiments, L5 is independently a bond, [ka] In embodiments, L5 is independently a bond. In embodiments, L5 is independently [ka] In an embodiment, L5 is independently [ka] In an embodiment, L5 is independently [ka] In an embodiment, L5 is independently [ka] In an embodiment, L5 is independently [ka] is.

[0400] In embodiments, R1 is independently unsubstituted alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is independently unsubstituted unbranched alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R1 is independently 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, R1 is independently unsubstituted unbranched unsaturated alkyl (e.g., C1-C25, C1-C20, C1-C17, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2).

[0401] In embodiments, R1 is unsubstituted C1-C17 alkyl. In embodiments, R1 is unsubstituted C11-C17 alkyl. In embodiments, R1 is unsubstituted C13-C17 alkyl. In embodiments, R1 is unsubstituted C14-C15 alkyl. In embodiments, R1 is unsubstituted C15 alkyl. In...

Claims

1. A compound of formula (II), or a pharmaceutically acceptable salt thereof: (HLEM) z -A-(UM) t (II) (A) is a nucleic acid covalently linked to a half-life extending motif (HLEM) and an uptake motif (UM); t is 1, z is 1, The half-life extending motif has the structure of formula (III): 【Chemistry 1】 L １ But, L １Ａ -L １Ｂ -L １Ｃ -L １Ｄ -L １Ｅ and L １Ａ is —C(O)— or —OPO ２ -O-, L 1A is attached to (A), L １Ｂ are independent, -L １０ -NH-C(O)- or -L １０ —C(O)—NH—, and L １０ is a substituted or unsubstituted saturated alkylene, or a substituted or unsubstituted heteroalkylene, or L １Ｂ is independently substituted or unsubstituted heteroalkylene; L １Ｃ becomes independent and R １Ｃ a substituted saturated alkylene or an unsubstituted saturated alkylene; L １Ｄ are independently a bond, substituted or unsubstituted saturated alkylene, or oxo-substituted or unsubstituted 5- to 8-membered heteroalkylene; L １Ｅ is independently —NHC(O)—, or oxo-substituted or unsubstituted 5-8 membered heteroalkylene; R １Ｃ are independently -NHC(O)-L ２Ｃ -R ８Ｃ and L ２Ｃ are independently a bond or unsubstituted saturated alkylene; R ８Ｃ are independently hydrogen, unsubstituted saturated alkylene, or —COOH; or L １ but, 【Chemistry 2】 【change】 and L ２ are independently unsubstituted saturated alkylene; k is an integer from 1 to 5; The uptake motifs independently have the structure of formula (IV): 【Transformation 3】 During the ceremony, L 3 independently represents a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO 2 -O-, -O-P(O)(S)-O-, -O-P(O)(R 25 )-O-, -O-P(S)(R 25 )-O-, -O-P(O)(NR 23 R 24 ) -O-, -O-P(S) (NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 )-O-, -S-S-, substituted or unsubstituted saturated alkylene, or substituted or unsubstituted heteroalkylene; L 4 is independently -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, where L 7 is a substituted or unsubstituted saturated alkylene; L 5 is -L 5A -L 5B -L 5C -L 5D -L 5E -; L 5A is independently a bond or unsubstituted saturated alkylene; L 5B is independently a bond, —NHC(O)—, —NH—, —O—, —S—, —C(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, or unsubstituted phenylene; L 5C is independently a bond, unsubstituted saturated alkylene, or unsubstituted phenylene; L 5D is independently a bond or unsubstituted saturated alkylene; L 5E is independently a bond, —NHC(O)—, —NH—, —O—, —S—, —C(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, or —C(O)NH—; L 6 is -L 6A -L 6B -L 6C -L 6D -L 6E -; L 6A is independently a bond or unsubstituted saturated alkylene; L 6B is independently a bond, —NHC(O)—, —NH—, —O—, —S—, —C(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, or unsubstituted phenylene; L 6C is independently a bond, unsubstituted saturated alkylene, or unsubstituted phenylene; L 6D is independently a bond or unsubstituted saturated alkylene; L 6E is independently a bond, —NHC(O)—, —NH—, —O—, —S—, —C(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, or —C(O)NH—; R 1 is unsubstituted C 9 -C 19 saturated alkyl; R 2 is unsubstituted C 9 -C 19 saturated alkyl; R 3 is hydrogen; each R 23 , R 24 , and R 25 is independently hydrogen or unsubstituted C 1 -C 10 saturated alkyl; The compound of formula (II) has an increased serum half-life compared to the same compound lacking said half-life extending motif. A compound or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid is an oligonucleotide.

3. One L １Ａ is attached to the 3' carbon of the oligonucleotide, One L １Ａ is attached to the 3' nitrogen of the oligonucleotide, One L １Ａ is attached to the 5' carbon of the oligonucleotide, One L １Ａ is attached to the 6' carbon of the oligonucleotide, One L １Ａ is attached to the 6' carbon of the oligonucleotide, One L １Ａ is attached to the 2' carbon of said oligonucleotide, or One L １Ａ is bound to the nucleobase of the oligonucleotide; 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

4. L １Ｂ are independent, -L １０ -NH-C(O)- or -L １０ —C(O)—NH—, and L １０ is a substituted or unsubstituted C １ ~C ８ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is saturated alkylene.

5. L １Ｂ became independent, 【Chemistry 4】 and w1 is an integer from 1 to 10, w2 is an integer from 1 to 5, w4 is an integer from 1 to 5; The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

6. -L １Ａ -L １Ｂ - is independent, -OPO ２ -O-L １０ —NH—C(O)—, and L １０ are independently substituted or unsubstituted C １ ~C ８ 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is saturated alkylene.

7. -L １Ａ -L １Ｂ - is independent, 【Transformation 5】 7. The compound according to any one of claims 1 to 6, wherein:

8. L １ but, 【Transformation 6】 【change】 【change】 8. The compound according to any one of claims 1 to 7, wherein:

9. L ３ are independently a bond, —NH—, —O—, —C(O)—, —C(O)O—, —OC(O)—, or —OPO ２ -O-, -O-P(O)(S)-O-, -O-P(O)(CH ３ )-O-, -O-P(S)(CH ３ )-O-, -O-P(O)(N(CH ３ ) ２ )-O-, -O-P(S)(N(CH ３ ) ２ )-O-, -P(O)(N(CH ３ ) ２ )-O-, -P(S)(N(CH ３ ) ２ 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is -O-, substituted or unsubstituted saturated alkylene, or substituted or unsubstituted heteroalkylene.

10. L ３ are independently —O—, —C(O)—, or —OPO ２ The compound according to any one of claims 1 to 9, which is -O-, or -OP(O)(S)-O-, or a pharmaceutically acceptable salt thereof.

11. L ４ But independently -L ７ -NH-C(O)-, or -L ７ —C(O)—NH—, and L ７ is a substituted or unsubstituted C １ ~C ８ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is saturated alkylene.

12. L ４ became independent, 【Transformation 7】 12. The compound according to any one of claims 1 to 11, wherein:

13. -L ３ -L ４ - is independent, -OL ７ -NH-C(O)-, or -O-L ７ —C(O)—NH—, and L ７ is independently substituted or unsubstituted saturated alkylene, or substituted or unsubstituted heteroalkylene; or: -L ３ -L ４ - is independent, -OPO ２ -O-L ７ -NH-C(O)-, -OP(O)(S)-OL ７ -NH-C(O)-, -OPO ２ -O-L ７ -C(O)-NH-, or -OP(O)(S)-O-L ７ —C(O)—NH—, and L ７ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein are independently substituted or unsubstituted saturated alkylene.

14. -L ３ -L ４ - is independent, 【Transformation 8】 13. The compound according to any one of claims 1 to 12, wherein:

15. L ６Ａ are independently a bond or unsubstituted saturated alkylene; L ６Ｂ are independently a bond, —NHC(O)—, or unsubstituted phenylene; L ６Ｃ are independently a bond, unsubstituted saturated alkylene, or unsubstituted phenylene; L ６Ｄ are independently a bond or unsubstituted saturated alkylene; L ６Ｅ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein: are independently a bond or -NHC(O)-.

16. L ５Ａ are independently a bond or unsubstituted saturated alkylene; L ５Ｂ are independently a bond, —NHC(O)—, or unsubstituted phenylene; L ５Ｃ are independently a bond, unsubstituted saturated alkylene, or unsubstituted phenylene; L ５Ｄ are independently a bond or unsubstituted saturated alkylene; L ５Ｅ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein: are independently a bond or -NHC(O)-.

17. L ６ is —NHC(O)—, and L 5 is 【Chemistry 9】 15. The compound according to any one of claims 1 to 14, wherein:

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid is a single-stranded oligonucleotide or a double-stranded oligonucleotide.

19. 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid comprises one or more modified nucleotides.

20. 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid comprises one or more modified sugar moieties.

21. 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid comprises one or more modified internucleotide bonds.

22. 22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid is a small interfering RNA (siRNA).

23. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, 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' end of the antisense strand comprises a hydroxyl group, a phosphate group, or a modified phosphate group.

24. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein the compound further comprises a ligand, the ligand comprising a peptide, an antibody, a carbohydrate, or an additional nucleic acid.

25. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the uptake motif comprises a peptide, an antibody, a carbohydrate, or an additional nucleic acid.

26. 26. Use of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, in the preparation of a therapeutic medicament.

27. A pharmaceutical composition for introducing a nucleic acid into a cell in a subject, comprising the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

29. 29. The pharmaceutical composition of claim 28 for use in therapy.

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