Three-type lipid-modified staggered nucleic acid compounds

Abstract

Disclosed herein are compounds that include 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 Application No. 63 / 279,270, filed November 15, 2021, the contents of which are incorporated herein in their entirety for all purposes.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (052974-508001WO_Sequence_Listing_ST26.xml; size: 7,080 bytes; and creation date: November 10, 2022) are incorporated herein by reference in their entirety. [Background technology]

[0003] Delivery of therapeutic nucleic acids into cells remains a challenging area of ​​research, and therefore there is a need for improved nucleic acid compounds and methods for introducing such compounds into cells. Summary of the Invention

[0004] In particular, the following structure: [ka] Provided herein are compounds having the formula:

[0005] A is a nucleic acid.

[0006] L 4 and L 6are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, —OPO2-O—, —OP(S)(O)—O—, —OP(S)2-O—, —S(O)2NH-, 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.

[0007] L 5 is independently a bond, 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.

[0008] L 7 is independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0009] L 1 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 1A -L 1B -L 1C -L 1D -L 1E is.

[0010] L 2 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 2A -L 2B -L 2C -L 2D -L 2E is.

[0011] L 3 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 3A -L 3B -L 3C -L 3D -L 3E is.

[0012] L 1A , L 1B , L 1C , L 1D , L 1E , L 2A , L 2B , L 2C , L 2D , L 2E , L 3A , L 3B , L 3C , L 3D and L 3E are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O)C(O)—, —OPO—O—, —OP(S)(O)—O—, —OP(S)—O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C1 to C 25 It is alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0013] L 1A -L 1B -L 1C -L 1D -L 1E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; L 1A , L 1B , L 1C , L 1D or L 1E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0014] L 2A -L 2B -L 2C -L 2D -L 2E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; L 2A , L 2B , L2C , L 2D or L 2E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0015] L 3A -L 3B -L 3C -L 3D -L 3E is not a bond, or a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene containing a terminal carbon atom, and L 3A , L 3B , L 3C , L 3D or L 3E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0016] R 1 , R 2 and R 3 are independently unsubstituted C1 to C 25 It is alkyl.

[0017] t is an integer of 1 to 5.

[0018] L 1 and L 2 is -NH(CO)-, and L 3 and L 7 is -(CH2)4-NH(CO)-, then R 1 , R 2 and R 3 At least one of the 15 Not alkyl, L 1 and L 7 is -NH(CO)-, and L 2 and L 3 is -(CH2)4-NH(CO)-, then R 1 , R 2 and R 3 At least one of the 15 Not alkyl.

[0019] In one aspect, a method is provided that includes contacting a cell with a compound as described herein.

[0020] In one aspect, a method is provided that includes administering to a subject a compound as described herein.

[0021] In one aspect, there is provided a compound as described herein for use in the preparation of a medicament.

[0022] 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 as described herein.

[0023] In one aspect, a cell comprising a compound as described herein is provided.

[0024] In one aspect, a pharmaceutical composition is provided that includes a pharmaceutically acceptable excipient and a compound as described herein.

[0025] Other aspects of the invention are disclosed below. DETAILED DESCRIPTION OF THE INVENTION

[0026] overview In particular, compounds are provided that comprise a nucleic acid (A) covalently linked to one or more uptake motifs (UM), which comprise a medium or long chain fatty acid.

[0027] 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 one of ordinary skill in the art. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless otherwise indicated. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used 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, regardless of transitional phrases or the body of the claims, the terms "comprise(s)" and "comprising" are to be construed as having an open-ended meaning. That is, these terms are to 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 also include additional features or components.

[0028] Where substituents are specified by their conventional chemical formula written from left to right, they equally encompass the chemically identical substituents that result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0029] "Compound" means a molecule comprising linked monomeric nucleotides. The compound may have one or more modified nucleotides. In embodiments, the compound comprises a double-stranded nucleic acid. In embodiments, the compound comprises a single-stranded nucleic acid. The compound may be provided as a pharmaceutical salt. The compound may be provided as a pharmaceutical composition.

[0030] "Oligonucleotide" means a polymer of linked monomeric nucleotides, one or more of which may be modified nucleotides.

[0031] "Double-stranded nucleic acid" refers to a first nucleotide sequence that hybridizes to a second nucleotide sequence to form a duplex structure.Double-stranded nucleic acid includes structures formed by annealing a first oligonucleotide to a second complementary oligonucleotide, such as in the case of siRNA.Such double-stranded nucleic acid may have short nucleotide overhangs at one or both ends of the duplex structure.Double-stranded nucleic acid also includes structures formed from a single oligonucleotide that has sufficient length and self-complementarity to form a duplex structure, such as shRNA.Such double-stranded nucleic acid includes stem-loop structures.Double-stranded nucleic acid may contain one or more modifications to the naturally occurring termini, sugars, nucleobases, and / or phosphate groups.

[0032] "Double-stranded region" refers to a portion of a double-stranded nucleic acid in which nucleotides of a first nucleotide sequence hybridize to nucleotides of a second nucleotide sequence. A double-stranded region can be a defined portion within a double-stranded nucleic acid that is shorter than (e.g., encompassed within) the entire double-stranded nucleic acid. Alternatively, a double-stranded region can be the same length as the entire double-stranded nucleic acid. A double-stranded region can contain one or more mismatches between the first and second nucleotide sequences and retain the ability to hybridize to each other. A double-stranded region does not contain nucleotide overhangs.

[0033] " Antisense strand " refers to the oligonucleotide that is complementary to target RNA (e.g., mRNA) and is incorporated into the RNA-induced silencing complex (RISC) to direct sequence-specific gene silencing via the RNA interference pathway. Antisense strand can also be called " guide strand ".

[0034] "Sense strand" refers to the oligonucleotide that is complementary to the antisense strand of a double-stranded nucleic acid. The sense strand is typically degraded after the antisense strand is incorporated into RISC. The sense strand can also be called "passenger strand".

[0035] "Nucleotide overhang" refers to an extension of one or more unpaired nucleotides from the double-stranded region of a double-stranded nucleic acid. For example, if the 3'-end of the antisense strand extends beyond the 5'-end of the sense strand, the 3'-end of the antisense strand has a nucleotide overhang. The nucleotide overhang can be 1, 2, 3, 4 or 5 nucleotides. One or more nucleotides of the oligonucleotide can be modified nucleotides. The nucleotide overhang can be present in the antisense strand, the sense strand, or both the antisense strand and the sense strand.

[0036] "Blunt end" means a given end of a double-stranded nucleic acid that has no unpaired nucleotides extending from the double-stranded region, i.e., no nucleotide overhang. A double-stranded nucleic acid can have a blunt end at one or both ends.

[0037] "siRNA" refers to a double-stranded nucleic acid formed from separate antisense and sense strands that directs sequence-specific gene silencing by promoting pre-translational mRNA degradation via the RNA interference pathway. The antisense and sense strands of an siRNA are not covalently linked.

[0038] "shRNA" refers to a double-stranded nucleic acid containing a loop structure that is processed intracellularly into siRNA that directs gene silencing in a sequence-specific manner by promoting pre-translational mRNA degradation via the RNA interference pathway.

[0039] "Single-stranded nucleic acid" refers to an antisense strand that does not hybridize to a complementary strand. Single-stranded nucleic acids are incorporated into RISC and direct sequence-specific gene silencing by promoting pre-translational mRNA degradation via the RNA interference pathway.

[0040] "Hybridize" refers to the annealing of one nucleotide sequence to another nucleotide sequence based at least in part on nucleotide sequence complementarity. In some embodiments, the antisense strand hybridizes to the sense strand. In some embodiments, the antisense strand hybridizes to a target mRNA sequence.

[0041] "Complementary" means nucleobases capable of non-covalent pairing through hydrogen bonding.

[0042] "Fully complementary" means that each nucleic acid base of the first nucleotide sequence is complementary to each nucleic acid base of the second nucleotide sequence.In some embodiments, the antisense strand is completely complementary to its target mRNA.In some embodiments, the sense strand and the antisense strand of the double-stranded nucleic acid are completely complementary over their entire length.In some embodiments, the sense strand and the antisense strand of the double-stranded nucleic acid 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.

[0043] "Identical" in the context of nucleotide sequences means having the same nucleotide sequence, independent of sugar, linkage and / or nucleobase modifications and independent of the methylation state of any pyrimidines present.

[0044] "Percent identity" means the number of nucleobases in a first nucleotide sequence that are identical to the nucleobases at corresponding positions in a second nucleotide sequence, divided by the total number of nucleobases in the first nucleotide sequence.

[0045] "Mismatch" means a nucleobase of a first nucleotide sequence that is not capable of Watson-Crick pairing with a nucleobase at a corresponding position in a second nucleotide sequence.

[0046] "Nucleoside" refers to a monomer of a nucleobase and a pentofuranosyl sugar (e.g., either ribose or deoxyribose). A nucleoside can include a base such as A, C, G, T, or U, or modifications thereof. A nucleoside can be modified at the base and / or sugar. In embodiments, a nucleoside is a deoxyribonucleoside. In embodiments, a nucleoside is a ribonucleoside.

[0047] "Nucleotide" means a nucleoside covalently linked to a phosphate group on the 5' carbon of a pentafuranosyl sugar. The nucleotide can be modified at one or more of the nucleobase, sugar moiety, internucleotide linkage, and / or phosphate group.

[0048] "Nucleobase" means a heterocyclic base moiety capable of non-covalent pairing. Nucleobases include pyrimidines and purines.

[0049] Unless otherwise specified, numbering of nucleotide atoms follows standard numbering conventions, with pentafuranosyl sugar carbons numbered 1' to 5' and nucleobase atoms numbered 1 to 9 for purines and 1 to 6 for pyrimidines.

[0050] "Modified nucleotide" means a nucleotide having one or more modifications compared to a naturally occurring nucleotide. Such changes can occur in the nucleobase and / or sugar moiety of the nucleoside. A modified nucleoside can have a modified sugar moiety and an unmodified nucleobase. A modified nucleoside can have a modified sugar moiety and a modified nucleobase.

[0051] "Modified nucleotide" means a nucleotide having one or more changes compared to a naturally occurring nucleotide. The changes can be in the internucleoside linkage, nucleobase, and / or sugar moiety of the nucleotide. A modified nucleotide can have a modified sugar moiety and an unmodified phosphate group. A modified nucleotide can have an unmodified sugar moiety and a modified phosphate group. A modified nucleotide can have a modified sugar moiety and an unmodified nucleobase. A modified nucleotide can have a modified sugar moiety and an unmodified phosphate group.

[0052] "Modified nucleobase" means a nucleobase having one or more alterations compared to a naturally occurring nucleotide.

[0053] "Modified phosphate group" means any change from the naturally occurring phosphate group of a nucleotide.

[0054] "Modified internucleotide linkage" means any change from the naturally occurring phosphodiester bond between two nucleotides.

[0055] "Phosphorothioate internucleotide linkage" means a substituted phosphodiester internucleotide linkage in which one of the non-bridging atoms is a sulfur atom.

[0056] "Modified sugar moiety" means the sugar of a nucleotide having any alteration and / or substitution from a naturally occurring sugar moiety.

[0057] "β-D-deoxyribonucleoside" refers to the naturally occurring nucleoside monomers of DNA.

[0058] "β-D-ribonucleoside" refers to a naturally occurring nucleoside monomer of RNA.

[0059] "2'-O-methyl sugar" or "2'-OMe sugar" means a sugar having an O-CH3 substitution at the 2' position of a pentofuranosyl sugar.

[0060] A "2'-O-methoxyethyl sugar" or "2'-MOE sugar" means a sugar having an OCH2CH2OCH3 substitution at the 2' position of the pentofuranosyl sugar.

[0061] "2'-fluoro sugar" or "2'-F sugar" means a sugar having a fluoro substitution at the 2' position of the pentofuranosyl sugar.

[0062] "Bicyclic sugar" means a modified sugar moiety containing a bond connecting the 2'-carbon and 4'-carbon of a pentafuranosyl sugar to result in a bicyclic structure. Non-limiting exemplary bicyclic sugar moieties include LNA, ENA, cEt, S-cEt, and R-cEt.

[0063] "Locked Nucleic Acid (LNA) sugar" means a substituted sugar moiety containing a -CH2-O- linkage between the 4' and 2' furanose ring atoms.

[0064] "ENA sugar" means a substituted sugar moiety containing a -(CH2)2-O- bond between the 4' and 2' furanose ring atoms.

[0065] "2'-O-methyl nucleotide" means a nucleotide having an O-methyl substitution at the 2' position of the pentofuranosyl sugar. 2'-O-methyl nucleotides can have further modifications, in addition to a modified sugar moiety, such as a modified nucleobase and / or phosphate group.

[0066] "2'-fluoronucleotide" means a nucleotide having a fluoro substitution at the 2' position of the pentofuranosyl sugar. 2'-O-fluoronucleotides can have further modifications, in addition to a modified sugar moiety, such as a modified nucleobase and / or phosphate group.

[0067] "Bicyclic nucleotide" means a nucleotide having a bond connecting the 2'-carbon and the 4'-carbon of a pentafuranosyl sugar. In addition to a modified sugar moiety, a bicyclic nucleotide may have further modifications, such as modified nucleobases and / or phosphate groups.

[0068] "Pharmaceutical salt" means a salt form of a compound that retains the biological effectiveness and properties of the compound and does not have undesirable effects when administered to a subject.

[0069] "Therapeutically effective amount" means the amount of a compound sufficient to provide a therapeutic benefit to a subject.

[0070] As used herein, "subject" means a human or non-human animal selected for treatment or therapy. In embodiments, the subject is a human.

[0071] "Administering" means providing a pharmaceutical agent or composition to a subject, and includes administration by a healthcare professional and self-administration. In some embodiments, administering is intraocular administration. In some embodiments, administering is topical administration.

[0072] "Treating" or "treatment" means the administration of one or more pharmaceutical agents to a subject to achieve a desired clinical result, including, but not limited to, alleviating, ameliorating, or delaying the progression of at least one indicator or symptom of a disease in the subject.

[0073] "Preventing the onset of" means preventing the appearance of at least one indicator or symptom of a disease in a subject at risk of developing the disease.

[0074] "Effective amount" means a sufficient amount of a compound that, when administered to a subject, is sufficient to treat the disease in the subject. The effective amount may vary depending on one or more of the compound, its mode of administration, the severity of the disease in the subject, the concomitant medications the subject is receiving, and the subject's characteristics, such as the subject's medical history, age, and weight.

[0075] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbons) or combinations thereof, which may be fully saturated, monovalent, or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. Alkyl is an alkyl group having a specified number of carbons (e.g., C1 to C6). 10 means 1 to 10 carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. The alkyl is uncyclized. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of methyl, such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those containing 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 the higher homologs and isomers. Alkoxy is an alkyl attached to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. An alkenyl contains one or more double bonds. An alkynyl contains one or more triple bonds.

[0076] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from alkyl, exemplified but not limited to, -CH2CH2CH2CH2-. Typically, as used herein, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred. A "lower alkyl" or "lower alkylene" is a short-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 group derived from an alkene. The term "alkynylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from an alkyne. In embodiments, an alkylene is fully saturated. In embodiments, an alkylene is monounsaturated. In embodiments, an alkylene is polyunsaturated. An alkenylene contains one or more double bonds. An alkynylene contains one or more triple bonds.

[0077] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroatom (e.g., O, N, S, Si, or P) can 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. A 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-S-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 (e.g., -CH2-NH-OCH3 and -CH2-O-Si(CH3)3). A heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain 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 can optionally contain, in addition to one or more double bonds, two or more double bonds and / or one or more triple bonds.The term "heteroalkynyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkynyl containing at least one triple bond. A heteroalkynyl can optionally contain, in addition to one or more triple bonds, two or more triple bonds and / or one or more double bonds. In embodiments, a heteroalkyl is fully saturated. In embodiments, a heteroalkyl is monounsaturated. In embodiments, a heteroalkyl is polyunsaturated.

[0078] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified 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'- refers to 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 described followed by a specific heteroalkyl group, such as —NR′R″, it is understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described for clarity. Thus, the term “heteroalkyl,” as used herein, should not be interpreted as excluding specific heteroalkyl groups, such as —NR′R″. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from a heteroalkene. The term “heteroalkynylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from a heteroalkyne. In embodiments, a heteroalkylene is fully saturated. In embodiments, a heteroalkylene is monounsaturated. In embodiments, heteroalkylene is polyunsaturated. Heteroalkenylene contains one or more double bonds. Heteroalkynylene contains one or more triple bonds.

[0079] The terms "cycloalkyl" and "heterocycloalkyl," alone or in combination with other terms, refer to cyclic versions of "alkyl" and "heteroalkyl," respectively, unless otherwise stated. Cycloalkyl and heterocycloalkyl are not aromatic. Furthermore, 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 a heterocycloalkyl, respectively. In embodiments, a cycloalkyl is fully saturated. In embodiments, a cycloalkyl is monounsaturated. In embodiments, a cycloalkyl is polyunsaturated. In embodiments, a heterocycloalkyl is fully saturated. In embodiments, a heterocycloalkyl is monounsaturated. In embodiments, a heterocycloalkyl is polyunsaturated.

[0080] 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 from 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a cycloalkyl ring, and the rings are attached to the parent molecular moiety through any carbon atom contained within the cycloalkyl ring of the multiple rings.

[0081] In embodiments, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, or polycyclic heterocycloalkyl ring system. In embodiments, a heterocycloalkyl group is fully saturated. A bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a heterocycloalkyl ring, and the rings are attached to the parent molecular moiety through any atom contained within the heterocycloalkyl ring of the multiple rings.

[0082] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0083] The term "acyl," unless otherwise specified, means -C(O)R, in which 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.

[0084] 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. Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring and the rings are attached to the parent molecular moiety through any carbon atom contained within the aryl ring of the multiple rings. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, where 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, where at least one of the fused rings is a heteroaromatic ring and the rings are attached to the parent molecular moiety through any atom contained within the heteroaromatic ring of the multiple rings). 5,6-fused ring heteroarylene refers to two rings fused together, one ring having 5 members and the other ring having 6 members, and at least one ring is a heteroaryl ring. Similarly, 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, and at least one ring is a heteroaryl ring. Also, 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule via 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, benzoxazolylbenzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,

[0033] Examples of aryl and heteroaryl ring systems include 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.

[0085] Spirocycles are two or more rings in which adjacent rings are joined through a single atom. The individual rings within a spirocycle can be the same or different. The individual rings of a spirocycle can be substituted or unsubstituted and can have different substituents than the other individual rings within a series of spirocycles. The possible substituents for an individual ring within a spirocycle are the possible substituents for the same ring when not part of a spirocycle (e.g., substituents for a cycloalkyl or heterocycloalkyl ring). A spirocycle can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocycle group can be any of the preceding lists, including having all rings of one type (e.g., all rings can be substituted heterocycloalkylene, and each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocycle system, a heterocyclic spirocycle refers to a spirocycle in which at least one ring is a heterocyclic ring, and each ring can be a different ring. When referring to a spiro ring system, a substituted spiro ring means that at least one ring is substituted, and each substituent can optionally be different.

[0086] Sign “ [ka] " indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0087] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0088] 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] It has.

[0089] The alkylarylene moiety can be substituted (e.g., with a substituent) on the alkylene portion (e.g., at carbons 2, 3, 4, or 6) or on the arylene linker 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. In some embodiments, the alkylarylene is unsubstituted.

[0090] 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.

[0091] Substituents for the alkyl and heteroalkyl groups (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are: -OR', ═O, ═NR', ═N-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 and m' may be one or more of a variety of groups selected from, but not limited to, (NR'R''R'')=NR'''', -NR-C(NR'R'')=NR'''', -S(O)R', -S(O)R', -S(O)NR'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'', which range in number from 0 to (2m'+1), where m' is the total number of carbon atoms in such group. 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 the compounds described herein include more than one R group, for example, each of the R groups is independently selected, as are each R', R'', R''', and R'''' group when two or more of these groups are present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CHOCH3, etc.).

[0092] Similar to the substituents described for the alkyl group, substituents for the aryl and heteroaryl groups can vary and include, for example, the following: -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'NR''R''', -ONR'R'', -NR and R', R', R''', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected, as are each R', R'', R''', and R''' groups when more than one of these groups is present.

[0093] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be shown as a substituent on the ring rather than on a specific atom of the ring (commonly referred to as a floating substituent). 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 spiro ring, a substituent shown as associated with one member of the fused or spiro ring (a floating substituent on a single ring) may be a substituent on any of the fused or spiro rings (floating substituents on multiple rings). When a substituent is attached to a ring but not to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, the multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spiro 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 spiro ring, any atom of either the fused or spiro ring, subject to the rules of chemical valence. When a ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring is depicted with additional floating substituents (including, but not limited to, points of attachment to the rest of the molecule), the floating substituents may be attached to the heteroatoms. When a ring heteroatom is depicted attached to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in a structure or formula having floating substituents, it is understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen, subject to the rules of chemical valence.

[0094] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such 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 the 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 the cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0095] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are of the formula -TC(O)-(CRR') q Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -U-, where T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r Optionally, one of the single bonds of the new ring so formed may be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be substituted with a substituent of the formula -(CRR') s -X'-(C''R''R'') dwherein s and d are independently an integer 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.

[0096] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0097] As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2 NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl , -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., 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-C 10 Aryl, C10 aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2 NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl , -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., 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-C 10 Aryl, C 10 aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2 NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl , -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., 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-C 10 Aryl, C 10 aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from the following: oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCF3, —OCBr3, —OCI3; -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., 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-C 10 Aryl, C 10 aryl or phenyl) or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0098] As used herein, a "size-limited substituent" or "size-limited substituent group" means a group selected from all of the substituents described above for "substituent," and each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20each 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; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0099] 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 2-8 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 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0100] In some embodiments, each substituent described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each 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 described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limiting substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower-rank substituent.

[0101] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20 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; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C6 alkylene, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0102] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 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 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0103] 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).

[0104] 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.

[0105] 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 the substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent can optionally be different. In embodiments, when the substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0106] 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 can optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0107] 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 a substituent, a size-limiting substituent, and a lower substituent, 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 a substituent, a size-limiting substituent, and a lower substituent, each substituent, size-limiting substituent, and / or lower substituent is different.

[0108] In embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkyl is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 2-20 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-C8 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 3-8 membered heterocycloalkyl; and 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-C8 10aryl, 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-limiting substituent, or a lower substituent) or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 2-20 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-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted (e.g., substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 3-8 membered heterocycloalkylene; and 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-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted (eg, substituted with a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted 5- to 10-membered heteroarylene.

[0109] 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, and 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-C8 10 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 heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and 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-C8 10and / 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 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section, Figures, or Tables below.

[0110] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds, and for amino acids, enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or as (D)- or (L)-, are encompassed within the scope of the present disclosure. Compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers, can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other center of geometric asymmetry, unless otherwise specified, it is intended that the compound include both E- and Z-geometric isomers.

[0111] As used herein, the term "isomers" refers to compounds that have the same number and type of atoms and therefore the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

[0112] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0113] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0114] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the (R) and (S) configuration of each asymmetric center. Accordingly, single stereochemical isomers of the present compounds as well as enantiomeric and diastereomeric mixtures are within the scope of the disclosure.

[0115] When the compounds disclosed herein contain 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 known to those skilled in 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 meant 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 present compounds that are generally recognized by those skilled in the art as stable are within the scope of the present disclosure.

[0116] Additionally, 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, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0117] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0118] It should be noted that throughout this application, options are written in Markush groups, e.g., at each amino acid position containing more than one possible amino acid. In particular, it is contemplated that each member of a Markush group should be considered separately, thereby constituting a separate embodiment, and that the Markush group should not be read as a single unit.

[0119] "Analog" or "analogue" is used according to its simple ordinary meaning within chemistry and biology to refer to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, for example, by the replacement of one atom with an atom of a different element, or the presence or absence of a particular functional group, or the replacement of one functional group with another, or by the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analogue is a compound that is similar or equivalent in function and appearance, but not similar or equivalent in structure or origin to the reference compound.

[0120] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with [n]" means that the specified group can be substituted with any one or more or all of the specified substituents. For example, when a group such as an alkyl or heteroaryl group is "unsubstituted C1-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl", the group must also contain one or more unsubstituted C1-C 20 It may contain alkyl and / or one or more unsubstituted 2-20 membered heteroalkyl.

[0121] 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 specific R group is present in a description of a chemical genus (such as formula (I)), Roman alphabet symbols may be used to distinguish between each occurrence of that specific R group. For example, multiple R 13When substituents are present, each R 13 The substituents are R 13A , R 13B , R 13C , R 13D etc., where R 13A , R 13B , R 13C , R 13D Each of these is R 13 Within the definition of , optionally defined differently.

[0122] The description of compounds provided herein is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group can be substituted with one or more of a plurality of substituents, such substitutions are selected to provide a compound that is compatible with the principles of chemical bonding and is not inherently unstable and / or is not known to those skilled in the art as being 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 a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding an inherently unstable compound.

[0123] Conjugate Compounds Embodiments of the present disclosure relate to nucleic acid compounds covalently linked to uptake motifs comprising medium and / or long chain fatty acids. The nucleic acid compounds include double-stranded and single-stranded nucleic acids that target mRNA and act via an antisense mechanism to inhibit mRNA expression.

[0124] In some embodiments, the compound comprising the uptake motif has the structure (I): [ka] It has.

[0125] A is a nucleic acid.

[0126] L 4 and L 6are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, —OPO2-O—, —OP(S)(O)—O—, —OP(S)2-O—, —S(O)2NH-, 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] L 5 is independently a bond, 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.

[0128] L 7 is independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0129] L 1 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 1A -L 1B -L 1C -L 1D -L 1E is.

[0130] L 2 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 2A -L 2B -L 2C -L 2D -L 2E is.

[0131] L 3 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 3A -L 3B -L 3C -L 3D -L 3E is.

[0132] L 1A , L 1B , L 1C , L 1D , L 1E , L 2A , L 2B , L 2C , L 2D , L 2E , L 3A , L 3B , L 3C , L 3D and L 3E are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O)C(O)—, —OPO—O—, —OP(S)(O)—O—, —OP(S)—O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C1 to C 25 It is alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0133] L 1A -L 1B -L 1C -L 1D -L 1E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; L 1A , L 1B , L 1C , L 1D or L 1E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0134] L 2A -L 2B -L 2C -L 2D -L 2E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; L 2A , L 2B , L2C , L 2D or L 2E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0135] L 3A -L 3B -L 3C -L 3D -L 3E is not a bond, or a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene containing a terminal carbon atom, and L 3A , L 3B , L 3C , L 3D or L 3E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0136] R 1 , R 2 and R 3 are independently unsubstituted C1 to C 25 It is alkyl.

[0137] t is an integer of 1 to 5.

[0138] In some embodiments, the compound comprising the uptake motif has the structure (I): [ka] It has.

[0139] A is a nucleic acid.

[0140] L 4 and L 6are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, —OPO2-O—, —OP(S)(O)—O—, —OP(S)2-O—, —S(O)2NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0141] L 5 is independently a bond, 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.

[0142] L 7 is independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0143] L 1 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 1A -L 1B -L 1C -L 1D -L 1E is.

[0144] L 2 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 2A -L 2B -L 2C -L 2D -L 2E is.

[0145] L 3 are independently a bond, a substituted or unsubstituted 2 to 50 membered heteroalkylene, or L 3A -L 3B -L 3C -L 3D -L 3E is.

[0146] L 1A , L 1B , L 1C , L 1D , L 1E , L 2A , L 2B , L 2C , L 2D , L 2E , L 3A , L 3B , L 3C , L 3D and L 3E are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O)C(O)—, —OPO—O—, —OP(S)(O)—O—, —OP(S)—O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C1 to C 25 It is alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0147] L 1A -L 1B -L 1C -L 1D -L 1E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; L 1A , L 1B , L 1C , L 1D or L 1E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0148] L 2A -L 2B -L 2C -L 2D -L 2E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; L 2A , L 2B , L2C , L 2D or L 2E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0149] L 3A -L 3B -L 3C -L 3D -L 3E is not a bond, or a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene containing a terminal carbon atom, and L 3A , L 3B , L 3C , L 3D or L 3E At least one of is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene.

[0150] R 1 , R 2 and R 3 are independently unsubstituted C8 to C 20 It is alkyl.

[0151] t is an integer of 1 to 5.

[0152] In some embodiments, L 1A -L 1B -L 1C -L 1D -L 1E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene. 1A -L 1B -L 1C -L 1D -L 1E is not a bond. 1A -L 1B -L 1C -L 1D -L 1E is not a substituted or unsubstituted alkylene containing a terminal carbon atom. 1A -L 1B -L 1C -L 1D -L1E is not a substituted alkylene containing a terminal carbon atom. 1A -L 1B -L 1C -L 1D -L 1E is not an unsubstituted alkylene containing a terminal carbon atom. 1A -L 1B -L 1C -L 1D -L 1E is not a substituted or unsubstituted heteroalkylene containing a terminal carbon atom. 1A -L 1B -L 1C -L 1D -L 1E is not a substituted heteroalkylene containing a terminal carbon atom. 1A -L 1B -L 1C -L 1D -L 1E is not an unsubstituted heteroalkylene containing a terminal carbon atom.

[0153] In some embodiments, L 1A , L 1B , L 1C , L 1D , or L 1E At least one of L is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1A is not a bond. 1A is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1A is not a substituted 2- to 25-membered heteroalkylene. 1A is not unsubstituted 2- to 25-membered heteroalkylene. 1B is not a bond. 1B is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1B is not a substituted 2- to 25-membered heteroalkylene. 1Bis not unsubstituted 2- to 25-membered heteroalkylene. 1C is not a bond. 1C is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1C is not a substituted 2- to 25-membered heteroalkylene. 1C is not unsubstituted 2- to 25-membered heteroalkylene. 1D is not a bond. 1D is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1D is not a substituted 2- to 25-membered heteroalkylene. 1D is not unsubstituted 2- to 25-membered heteroalkylene. 1E is not a bond. 1E is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1E is not a substituted 2- to 25-membered heteroalkylene. 1E is not unsubstituted 2- to 25-membered heteroalkylene.

[0154] In some embodiments, L 2A -L 2B -L 2C -L 2D -L 2E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene. 2A -L 2B -L 2C -L 2D -L 2E is not a bond. 2A -L 2B -L 2C -L 2D -L 2E is not a substituted or unsubstituted alkylene containing a terminal carbon atom. 2A -L2B -L 2C -L 2D -L 2E is not a substituted alkylene containing a terminal carbon atom. 2A -L 2B -L 2C -L 2D -L 2E is not an unsubstituted alkylene containing a terminal carbon atom. 2A -L 2B -L 2C -L 2D -L 2E is not a substituted or unsubstituted heteroalkylene containing a terminal carbon atom. 2A -L 2B -L 2C -L 2D -L 2E is not a substituted heteroalkylene containing a terminal carbon atom. 2A -L 2B -L 2C -L 2D -L 2E is not an unsubstituted heteroalkylene containing a terminal carbon atom.

[0155] In some embodiments, L 2A , L 2B , L 2C , L 2D , or L 2E At least one of L is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2A is not a bond. 2A is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2A is not a substituted 2- to 25-membered heteroalkylene. 2A is not unsubstituted 2- to 25-membered heteroalkylene. 2B is not a bond. 2B is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2Bis not a substituted 2- to 25-membered heteroalkylene. 2B is not unsubstituted 2- to 25-membered heteroalkylene. 2C is not a bond. 2C is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2C is not a substituted 2- to 25-membered heteroalkylene. 2C is not unsubstituted 2- to 25-membered heteroalkylene. 2D is not a bond. 2D is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2D is not a substituted 2- to 25-membered heteroalkylene. 2D is not unsubstituted 2- to 25-membered heteroalkylene. 2E is not a bond. 2E is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2E is not a substituted 2- to 25-membered heteroalkylene. 2E is not unsubstituted 2- to 25-membered heteroalkylene.

[0156] In some embodiments, L 3A -L 3B -L 3C -L 3D -L 3E is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene. 3A -L 3B -L 3C -L 3D -L 3E is not a bond. 3A -L 3B -L 3C -L 3D -L 3Eis not a substituted or unsubstituted alkylene containing a terminal carbon atom. 3A -L 3B -L 3C -L 3D -L 3E is not a substituted alkylene containing a terminal carbon atom. 3A -L 3B -L 3C -L 3D -L 3E is not an unsubstituted alkylene containing a terminal carbon atom. 3A -L 3B -L 3C -L 3D -L 3E is not a substituted or unsubstituted heteroalkylene containing a terminal carbon atom. 3A -L 3B -L 3C -L 3D -L 3E is not a substituted heteroalkylene containing a terminal carbon atom. 3A -L 3B -L 3C -L 3D -L 3E is not an unsubstituted heteroalkylene containing a terminal carbon atom.

[0157] In some embodiments, L 3A , L 3B , L 3C , L 3D , or L 3E At least one of L is not a bond or a substituted or unsubstituted 2- to 25-membered heteroalkylene. 3A is not a bond. 3A is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 3A is not a substituted 2- to 25-membered heteroalkylene. 3A is not unsubstituted 2- to 25-membered heteroalkylene. 3B is not a bond. 3Bis not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 3B is not a substituted 2- to 25-membered heteroalkylene. 3B is not unsubstituted 2- to 25-membered heteroalkylene. 3C is not a bond. 3C is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 3C is not a substituted 2- to 25-membered heteroalkylene. 3C is not unsubstituted 2- to 25-membered heteroalkylene. 3D is not a bond. 3D is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 3D is not a substituted 2- to 25-membered heteroalkylene. 3D is not unsubstituted 2- to 25-membered heteroalkylene. 3E is not a bond. 3E is not a substituted or unsubstituted 2- to 25-membered heteroalkylene. 3E is not a substituted 2- to 25-membered heteroalkylene. 3E is not unsubstituted 2- to 25-membered heteroalkylene.

[0158] In some embodiments, L 1 , L 2 and L 3 is independently a substituted or unsubstituted 2- to 50-membered heteroalkylene. 1 is a substituted or unsubstituted 2- to 50-membered heteroalkylene. 1 is a substituted or unsubstituted 2- to 45-membered heteroalkylene. 1 is a substituted or unsubstituted 2-40 membered heteroalkylene. 1is a substituted or unsubstituted 2- to 35-membered heteroalkylene. 1 is a substituted or unsubstituted 2-30 membered heteroalkylene. 1 is a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1 is a substituted or unsubstituted 2- to 20-membered heteroalkylene. 1 is a substituted or unsubstituted 2- to 15-membered heteroalkylene. 1 is a substituted or unsubstituted 2-10 membered heteroalkylene. 1 is a substituted or unsubstituted 2-5 membered heteroalkylene. 2 is a substituted or unsubstituted 2- to 50-membered heteroalkylene. 2 is a substituted or unsubstituted 2- to 45-membered heteroalkylene. 2 is a substituted or unsubstituted 2-40 membered heteroalkylene. 2 is a substituted or unsubstituted 2- to 35-membered heteroalkylene. 2 is a substituted or unsubstituted 2-30 membered heteroalkylene. 2 is a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2 is a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2 is a substituted or unsubstituted 2- to 15-membered heteroalkylene. 2 is a substituted or unsubstituted 2-10 membered heteroalkylene. 2 is a substituted or unsubstituted 2-5 membered heteroalkylene. 3 is a substituted or unsubstituted 2- to 50-membered heteroalkylene. 3 is a substituted or unsubstituted 2- to 45-membered heteroalkylene. 3is a substituted or unsubstituted 2-40 membered heteroalkylene. 3 is a substituted or unsubstituted 2- to 35-membered heteroalkylene. 3 is a substituted or unsubstituted 2-30 membered heteroalkylene. 3 is a substituted or unsubstituted 2- to 25-membered heteroalkylene. 3 is a substituted or unsubstituted 2- to 20-membered heteroalkylene. 3 is a substituted or unsubstituted 2- to 15-membered heteroalkylene. 3 is a substituted or unsubstituted 2-10 membered heteroalkylene. 3 is a substituted or unsubstituted 2- to 5-membered heteroalkylene.

[0159] In some embodiments, L 1 is a substituted 2- to 50-membered heteroalkylene. 1 is a substituted 2-45 membered heteroalkylene. 1 is a substituted 2-40 membered heteroalkylene. 1 is a substituted 2- to 35-membered heteroalkylene. 1 is a substituted 2-30 membered heteroalkylene. 1 is a substituted 2- to 25-membered heteroalkylene. 1 is a substituted 2- to 20-membered heteroalkylene. 1 is a substituted 2- to 15-membered heteroalkylene. 1 is a substituted 2-10 membered heteroalkylene. 1 is a substituted 2-5 membered heteroalkylene.

[0160] In some embodiments, L 2 is a substituted 2- to 50-membered heteroalkylene.2 is a substituted 2-45 membered heteroalkylene. 2 is a substituted 2-40 membered heteroalkylene. 2 is a substituted 2- to 35-membered heteroalkylene. 2 is a substituted 2-30 membered heteroalkylene. 2 is a substituted 2- to 25-membered heteroalkylene. 2 is a substituted 2- to 20-membered heteroalkylene. 2 is a substituted 2- to 15-membered heteroalkylene. 2 is a substituted 2-10 membered heteroalkylene. 2 is a substituted 2-5 membered heteroalkylene.

[0161] In some embodiments, L 3 is a substituted 2- to 50-membered heteroalkylene. 3 is a substituted 2-45 membered heteroalkylene. 3 is a substituted 2-40 membered heteroalkylene. 3 is a substituted 2- to 35-membered heteroalkylene. 3 is a substituted 2-30 membered heteroalkylene. 3 is a substituted 2- to 25-membered heteroalkylene. 3 is a substituted 2- to 20-membered heteroalkylene. 3 is a substituted 2- to 15-membered heteroalkylene. 3 is a substituted 2-10 membered heteroalkylene. 3 is a substituted 2-5 membered heteroalkylene.

[0162] In some embodiments, L 1is unsubstituted 2-50 membered heteroalkylene. 1 is unsubstituted 2-45 membered heteroalkylene. 1 is unsubstituted 2-40 membered heteroalkylene. 1 is unsubstituted 2- to 35-membered heteroalkylene. 1 is unsubstituted 2-30 membered heteroalkylene. 1 is unsubstituted 2- to 25-membered heteroalkylene. 1 is unsubstituted 2- to 20-membered heteroalkylene. 1 is unsubstituted 2-15 membered heteroalkylene. 1 is unsubstituted 2-10 membered heteroalkylene. 1 is an unsubstituted 2-5 membered heteroalkylene.

[0163] In some embodiments, L 2 is unsubstituted 2-50 membered heteroalkylene. 2 is unsubstituted 2-45 membered heteroalkylene. 2 is unsubstituted 2-40 membered heteroalkylene. 2 is unsubstituted 2- to 35-membered heteroalkylene. 2 is unsubstituted 2-30 membered heteroalkylene. 2 is unsubstituted 2- to 25-membered heteroalkylene. 2 is unsubstituted 2- to 20-membered heteroalkylene. 3 is unsubstituted 2-50 membered heteroalkylene. 2 is unsubstituted 2-15 membered heteroalkylene. 2 is unsubstituted 2-10 membered heteroalkylene. 2is unsubstituted 2-5 membered heteroalkylene. 3 is unsubstituted 2-45 membered heteroalkylene. 3 is unsubstituted 2-40 membered heteroalkylene. 3 is unsubstituted 2- to 35-membered heteroalkylene. 3 is unsubstituted 2-30 membered heteroalkylene. 3 is unsubstituted 2- to 25-membered heteroalkylene. 3 is unsubstituted 2- to 20-membered heteroalkylene. 3 is unsubstituted 2-15 membered heteroalkylene. 3 is unsubstituted 2-10 membered heteroalkylene. 3 is an unsubstituted 2-5 membered heteroalkylene.

[0164] In some embodiments, L 1 , L 2 and L 3 are independently 10 is a substituted or unsubstituted 2- to 50-membered heteroalkylene, and R 10 is independently oxo, hydroxyl, or unsubstituted C1-C4 alkyl. In embodiments, R 10 is independently oxo. In some embodiments, R 10 is independently hydroxyl. In embodiments, R 10 is independently unsubstituted C1-C4 alkyl. In embodiments, R 10 is independently methyl. In some embodiments, R 10 is independently ethyl. In embodiments, R 10 is independently propyl. In embodiments, R 10 is independently isopropyl. In embodiments, R 10 is independently butyl. In embodiments, R 10is independently isobutyl. In some embodiments, R 10 are independently t-butyl.

[0165] In some embodiments, L 1 is R 10 In some embodiments, L is a substituted 2- to 50-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 4-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 40-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 3-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 30-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 25-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 20-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 15-membered heteroalkylene. 1 is R 10 In some embodiments, L is a substituted 2- to 10-membered heteroalkylene. 1 is R 10 It is a substituted 2- to 5-membered heteroalkylene.

[0166] In some embodiments, L 2 is R 10 In some embodiments, L is a substituted 2- to 50-membered heteroalkylene. 2 is R 10 In some embodiments, L is a substituted 2- to 4-membered heteroalkylene. 2 is R 10 In some embodiments, L is a substituted 2- to 40-membered heteroalkylene. 2 is R 10 In some embodiments, L is a substituted 2- to 3-membered heteroalkylene.2 is R 10 In some embodiments, L is a substituted 2- to 30-membered heteroalkylene. 2 is R 10 In some embodiments, L is a substituted 2- to 25-membered heteroalkylene. 2 is R 10 In some embodiments, L is a substituted 2- to 20-membered heteroalkylene. 2 is R 10 In some embodiments, L is a substituted 2- to 15-membered heteroalkylene. 2 is R 10 In some embodiments, L is a substituted 2- to 10-membered heteroalkylene. 2 is R 10 It is a substituted 2- to 5-membered heteroalkylene.

[0167] In some embodiments, L 3 is R 10 In some embodiments, L is a substituted 2- to 50-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 4-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 40-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 3-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 30-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 25-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 20-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 15-membered heteroalkylene. 3 is R 10 In some embodiments, L is a substituted 2- to 10-membered heteroalkylene. 3 is R 10 It is a substituted 2- to 5-membered heteroalkylene.

[0168] 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.

[0169] In some embodiments, the nucleic acid (A) is an oligonucleotide. In some embodiments, the nucleic acid (A) is a double-stranded nucleic acid or a single-stranded nucleic acid.

[0170] In some embodiments, one L 6 is attached to the 3' carbon of the oligonucleotide. In some embodiments, the 3' carbon is the 3' carbon of the 3' terminal nucleotide.

[0171] In some embodiments, one L 6 is attached to the 5' carbon of the double-stranded or single-stranded nucleic acid. In some embodiments, the 5' carbon is the 5' carbon of the 5' terminal nucleotide.

[0172] In some embodiments, one L 6 is attached to the 2' carbon of the double-stranded or single-stranded nucleic acid. 6 is attached to the 2' carbon of the 3' terminal nucleic acid.

[0173] In some embodiments, one L 6 is attached to the 2' hydroxy oxygen of the double-stranded or single-stranded nucleic acid. 6 is bound to the 2' hydroxyl oxygen of the 3' terminal nucleic acid.

[0174] In some embodiments, one L 6 is attached to the nucleobase of the double-stranded nucleic acid or the single-stranded nucleic acid. 6 is attached to a carbon atom of a nucleobase of a double-stranded or single-stranded nucleic acid. 6is attached to the nitrogen atom of the nucleobase of the double-stranded nucleic acid or the single-stranded nucleic acid. 6 is bound to the oxygen atom of the nucleobase of a double-stranded or single-stranded nucleic acid.

[0175] In some embodiments, one L 6 is attached at its 3' end to the 3' nitrogen of the oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety). 6 is attached at its 5' end to the 6' carbon of the oligonucleotide (e.g., the 6' carbon of the morpholino moiety). In some embodiments, the double-stranded or single-stranded nucleic acid comprises a morpholino moiety. In some embodiments, when the double-stranded or single-stranded nucleic acid comprises a morpholino moiety, one L 6 is attached to the 3' nitrogen of the morpholino moiety. In some embodiments, when the double-stranded nucleic acid or single-stranded nucleic acid comprises a morpholino moiety, one L 6 is attached to the 6' carbon of the morpholino moiety.

[0176] In some embodiments, the nucleic acid (A) is a double-stranded oligonucleotide. 6 is attached to the 3' carbon of the double-stranded oligonucleotide. 6 is attached to the 3' carbon of the double-stranded oligonucleotide at either of its 3' ends. 6 is attached to the 3' carbon of the double-stranded oligonucleotide at the 3' end of the antisense strand. 6 is attached to the 3' carbon of the double-stranded oligonucleotide at the 3' end of its sense strand.

[0177] In some embodiments, one L 6 is attached to the 3' nitrogen of the double-stranded oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety) at either of its 3' ends. 6is attached to the 3' nitrogen of the double-stranded oligonucleotide (e.g., the 3' nitrogen of the morpholino moiety) at the 3' end of the antisense strand. 6 is attached to the 3' nitrogen of the double-stranded oligonucleotide (eg, the 3' nitrogen of the morpholino moiety) at the 3' end of its sense strand.

[0178] In some embodiments, one L 6 is attached to the 5' carbon of the double-stranded oligonucleotide. 6 is attached to the 5' carbon of the double-stranded oligonucleotide at either of its 5' ends. 6 is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of the antisense strand. 6 is attached to the 5' carbon of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0179] In some embodiments, one L 6 is attached to the 6' carbon of the double-stranded oligonucleotide (e.g., the 6' carbon of the morpholino moiety) at either of its 5' ends. 6 is attached to the 6' carbon of the double-stranded oligonucleotide (e.g., the 6' carbon of the morpholino moiety) at the 5' end of the antisense strand. 6 is attached at the 5' end of the sense strand to the 6' carbon of the double-stranded oligonucleotide (eg, the 6' carbon of the morpholino moiety).

[0180] In some embodiments, one L 6 is attached to the 2' carbon of the double-stranded oligonucleotide. 6 is attached to the 2' carbon of the double-stranded oligonucleotide at either of its 3' ends. 6 is attached to the 2' carbon at the 3' end of the sense strand. 6is attached to the 2' carbon at the 3' end of the antisense strand.

[0181] In some embodiments, one L 6 is attached to the 2' hydroxy oxygen of the double-stranded or single-stranded nucleic acid. 6 is bound to the 2' hydroxyl oxygen of the 3' terminal nucleic acid.

[0182] In some embodiments, one L 6 is attached to the 2' hydroxy oxygen of the double-stranded oligonucleotide. 6 is attached to the 2' hydroxy oxygen of the double-stranded oligonucleotide at either of its 3' ends. 6 is attached to the 2' hydroxy oxygen at the 3' end of the sense strand. 6 is attached to the 2' hydroxyl oxygen at the 3' end of the antisense strand.

[0183] In some embodiments, one L 6 is attached to the nucleobase of the double-stranded oligonucleotide. 6 is attached to a nucleobase of the sense strand of the double-stranded oligonucleotide. 6 is attached to a nucleobase of the antisense strand of the double-stranded oligonucleotide. 6 is attached to a nucleobase of the double-stranded oligonucleotide at either of its 3' ends. 6 is attached to the nucleobase of the double-stranded oligonucleotide at the 3' end of the antisense strand. 6 is attached to a nucleobase of the double-stranded oligonucleotide at the 3' end of the sense strand. 6 is attached to a nucleobase of the double-stranded oligonucleotide at either of its 5' ends.6 is attached to the nucleobase of the double-stranded oligonucleotide at the 5' end of the antisense strand. 6 is attached to the nucleobase of the double-stranded oligonucleotide at the 5' end of its sense strand.

[0184] In some embodiments, the nucleic acid (A) is a single-stranded oligonucleotide. 6 is attached at the 3' end to the 3' carbon of the single-stranded oligonucleotide.

[0185] In some embodiments, one L 6 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.

[0186] In some embodiments, one L 6 is attached at the 5' end to the 5' carbon of the single-stranded oligonucleotide.

[0187] In some embodiments, one L 6 is attached at the 5' end to the 6' carbon of the single-stranded oligonucleotide (eg, the 6' carbon of the morpholino moiety).

[0188] In some embodiments, one L 6 is attached to the 2' carbon of the single-stranded oligonucleotide. 6 is attached at its 5' end to the 2' carbon of the single-stranded oligonucleotide. 6 is attached at its 3' end to the 2' carbon of a single-stranded oligonucleotide.

[0189] In some embodiments, one L 6 is attached to the 2' hydroxy oxygen of the double-stranded or single-stranded nucleic acid. 6is attached at its 3' end to the 2' hydroxy oxygen of the double-stranded nucleic acid. 6 is attached at its 3' end to the 2' hydroxy oxygen of a single-stranded nucleic acid.

[0190] In some embodiments, one L 6 is attached to the nucleobase of the single-stranded oligonucleotide. 6 is attached to the nucleobase of the single-stranded oligonucleotide at the 3' end. 6 is attached to the nucleobase of a single-stranded oligonucleotide at its 5' end.

[0191] In some embodiments, L 4 and L 6 are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, —OPO2-O—, —OP(S)(O)—O—, —OP(S)2-O—, —S(O)2NH-, substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), or 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). 4 and L 6 are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, —OPO2-O—, —OP(S)(O)—O—, —OP(S)2-O—, —S(O)2NH-, substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2- to 8-membered heteroalkylene.

[0192] In some embodiments, L 4 is independently a bond. 4is independently —NH—. In some embodiments, L 4 is independently —O—. In some embodiments, L 4 is independently -S-. In some embodiments, L 4 is independently —C(O)—. In some embodiments, L 4 is independently —NHC(O)—. In some embodiments, L 4 is independently —NHC(O)NH—. In some embodiments, L 4 is independently —C(O)O—. In embodiments, L 4 is independently —OC(O)—. In some embodiments, L 4 is independently —C(O)NH—. In embodiments, L 4 is independently -OPO2-O-. In some embodiments, L 4 is independently -OP(S)(O)-O-. In embodiments, L 4 is independently -OP(S)-O-. In some embodiments, L 4 are independently —S(O)2NH—.

[0193] In some embodiments, L 4 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 4 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 4 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 4 are independently substituted C1 to C 20 In some embodiments, L 4 are independently unsubstituted C1 to C 20In some embodiments, L 4 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 4 are independently substituted C1 to C 12 In some embodiments, L 4 are independently unsubstituted C1 to C 12 In some embodiments, L 4 is independently a substituted or unsubstituted C1-C8 alkylene. 4 is independently a substituted C1-C8 alkylene. 4 is independently an unsubstituted C1-C8 alkylene. 4 is independently a substituted or unsubstituted C1-C6 alkylene. 4 is independently a substituted C1-C6 alkylene. 4 is independently an unsubstituted C1-C6 alkylene. 4 is independently a substituted or unsubstituted C1-C4 alkylene. 4 is independently a substituted C1-C4 alkylene. 4 is independently an unsubstituted C1-C4 alkylene. 4 is independently substituted or unsubstituted ethylene. 4 is independently a substituted ethylene. 4 is independently unsubstituted ethylene. In embodiments, L 4 is independently substituted or unsubstituted methylene. 4 is independently substituted methylene. 4 is independently unsubstituted methylene.

[0194] In some embodiments, L 4is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 4 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 4 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 4 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 4 is independently a substituted 2- to 20-membered heteroalkylene. 4 is independently unsubstituted 2- to 20-membered heteroalkylene. 4 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 4 is independently a substituted 2- to 12-membered heteroalkylene. 4 is independently unsubstituted 2- to 12-membered heteroalkylene. 4 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 4 is independently a substituted 2-8 membered heteroalkylene. 4 is independently unsubstituted 2-8 membered heteroalkylene. 4 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 4 is independently a substituted 2- to 6-membered heteroalkylene. 4 is independently unsubstituted 2- to 6-membered heteroalkylene. 4 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 4is independently a substituted 4- to 6-membered heteroalkylene. 4 is independently unsubstituted 4- to 6-membered heteroalkylene. 4 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 4 is independently a substituted 2-3 membered heteroalkylene. 4 is independently unsubstituted 2-3 membered heteroalkylene. 4 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 4 is independently a substituted 4- to 5-membered heteroalkylene. 4 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0195] In some embodiments, L 6 is independently a bond. 6 is independently —NH—. In some embodiments, L 6 is independently —O—. In some embodiments, L 6 is independently -S-. In some embodiments, L 6 is independently —C(O)—. In some embodiments, L 6 is independently —NHC(O)—. In some embodiments, L 6 is independently —NHC(O)NH—. In some embodiments, L 6 is independently —C(O)O—. In embodiments, L 6 is independently —OC(O)—. In some embodiments, L 6 is independently —C(O)NH—. In embodiments, L 6 is independently -OPO2-O-. In some embodiments, L 6 is independently -OP(S)(O)-O-. In embodiments, L 6is independently -OP(S)-O-. In some embodiments, L 6 are independently —S(O)2NH—.

[0196] In some embodiments, L 6 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 6 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 6 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 6 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 6 are independently substituted C1 to C 20 In some embodiments, L 6 are independently unsubstituted C1 to C 20 In some embodiments, L 6 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 6 are independently substituted C1 to C 12 In some embodiments, L 6 are independently unsubstituted C1 to C 12 In some embodiments, L 6 is independently a substituted or unsubstituted C1-C8 alkylene. 6 is independently a substituted C1-C8 alkylene. 6 is independently an unsubstituted C1-C8 alkylene. 6is independently a substituted or unsubstituted C1-C6 alkylene. 6 is independently a substituted C1-C6 alkylene. 6 is independently an unsubstituted C1-C6 alkylene. 6 is independently a substituted or unsubstituted C1-C4 alkylene. 6 is independently a substituted C1-C4 alkylene. 6 is independently an unsubstituted C1-C4 alkylene. 6 is independently substituted or unsubstituted ethylene. 6 is independently a substituted ethylene. 6 is independently unsubstituted ethylene. In embodiments, L 6 is independently substituted or unsubstituted methylene. 6 is independently substituted methylene. 6 is independently unsubstituted methylene.

[0197] In some embodiments, L 6 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 6 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 6 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 6 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 6 is independently a substituted 2- to 20-membered heteroalkylene. 6is independently unsubstituted 2- to 20-membered heteroalkylene. 6 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 6 is independently a substituted 2- to 12-membered heteroalkylene. 6 is independently unsubstituted 2- to 12-membered heteroalkylene. 6 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 6 is independently a substituted 2-8 membered heteroalkylene. 6 is independently unsubstituted 2-8 membered heteroalkylene. 6 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 6 is independently a substituted 2- to 6-membered heteroalkylene. 6 is independently unsubstituted 2- to 6-membered heteroalkylene. 6 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 6 is independently a substituted 4- to 6-membered heteroalkylene. 6 is independently unsubstituted 4- to 6-membered heteroalkylene. 6 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 6 is independently a substituted 2-3 membered heteroalkylene. 6 is independently unsubstituted 2-3 membered heteroalkylene. 6 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 6 is independently a substituted 4- to 5-membered heteroalkylene. 6 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0198] In some embodiments, L 4 and L 6 are independently -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, -OPO2-O-, -OP(S)(O)-O-, -OP(S)2-O-, -S(O)2NH-, R 20 Substituted or unsubstituted C1-C8 alkylene, or R 20 is a substituted or unsubstituted 2- to 8-membered heteroalkylene, and R 20 is independently oxo, hydroxyl, or substituted or unsubstituted C1-C4 alkyl. 4 and L 6 are independently 20 In some embodiments, L is a substituted or unsubstituted C1-C8 alkylene. 4 and L 6 are independently 20 In some embodiments, L is a substituted C1-C8 alkylene. 4 and L 6 is independently an unsubstituted C1-C8 alkylene. 4 and L 6 are independently 20 In some embodiments, L is a substituted or unsubstituted 2- to 8-membered heteroalkylene. 4 and L 6 are independently 20 In some embodiments, L is a substituted 2- to 8-membered heteroalkylene. 4 and L 6 is independently an unsubstituted 2- to 8-membered heteroalkylene.

[0199] In embodiments, R 20 is independently oxo, hydroxyl, or unsubstituted C1-C4 alkyl. In embodiments, R 20 is independently oxo. In some embodiments, R 20 is independently hydroxyl. In embodiments, R 20is independently unsubstituted C1-C4 alkyl. In embodiments, R 20 is independently methyl. In some embodiments, R 20 is independently ethyl. In embodiments, R 20 is independently propyl. In embodiments, R 20 is independently isopropyl. In embodiments, R 20 is independently butyl. In embodiments, R 20 is independently isobutyl. In some embodiments, R 20 are independently t-butyl.

[0200] In some embodiments, L 4 are independently 20 Substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 4 are independently 20 Substitution C1~C 20 In some embodiments, L 4 are independently 20 Substitution C1~C 12 In some embodiments, L 4 are independently 20 In some embodiments, L is a substituted C1-C8 alkylene. 4 are independently 20 In some embodiments, L is a substituted C1-C6 alkylene. 4 are independently 20 In some embodiments, L is a substituted C1-C4 alkylene. 4 are independently 20 In some embodiments, L is a substituted ethylene. 4 are independently 20 It is a substituted methylene.

[0201] In some embodiments, L 4 are independently20 and substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 4 are independently 20 In some embodiments, L is a substituted 2- to 20-membered heteroalkylene. 4 are independently 20 In some embodiments, L is a substituted 2- to 8-membered heteroalkylene. 4 are independently 20 In some embodiments, L is a substituted 2- to 6-membered heteroalkylene. 4 are independently 20 In some embodiments, L is a substituted 4- to 6-membered heteroalkylene. 4 are independently 20 In some embodiments, L is a substituted 2- to 3-membered heteroalkylene. 4 are independently 20 It is a substituted 4- to 5-membered heteroalkylene.

[0202] In some embodiments, L 6 are independently 20 Substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 6 are independently 20 Substitution C1~C 20 In some embodiments, L 6 are independently 20 Substitution C1~C 12 In some embodiments, L 6 are independently 20 In some embodiments, L is a substituted C1-C8 alkylene. 6 are independently 20 In some embodiments, L is a substituted C1-C6 alkylene. 6 are independently 20 In some embodiments, L is a substituted C1-C4 alkylene. 6 are independently20 In some embodiments, L is a substituted ethylene. 6 are independently 20 It is a substituted methylene.

[0203] In some embodiments, L 6 are independently 20 and substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 6 are independently 20 In some embodiments, L is a substituted 2- to 20-membered heteroalkylene. 6 are independently 20 In some embodiments, L is a substituted 2- to 8-membered heteroalkylene. 6 are independently 20 In some embodiments, L is a substituted 2- to 6-membered heteroalkylene. 6 are independently 20 In some embodiments, L is a substituted 4- to 6-membered heteroalkylene. 6 are independently 20 In some embodiments, L is a substituted 2- to 3-membered heteroalkylene. 6 are independently 20 It is a substituted 4- to 5-membered heteroalkylene.

[0204] In some embodiments, L 6 is, independently, [ka] In some embodiments, L 6 is, independently, [ka] is.

[0205] In some embodiments, L 4 independently, -L 14 -NH-C(O)- or -L 14-C(O)-NH-, and L 14 are independently substituted or unsubstituted C1-C 20 It is alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene.

[0206] In some embodiments, L 14 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 14 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 14 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 14 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 14 are independently substituted C1 to C 20 In some embodiments, L 14 are independently unsubstituted C1 to C 20 In some embodiments, L 14 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 14 are independently substituted C1 to C 12 In some embodiments, L 14 are independently unsubstituted C1 to C 12 In some embodiments, L 14 is independently a substituted or unsubstituted C1-C8 alkylene. 14 is independently a substituted C1-C8 alkylene. 14is independently an unsubstituted C1-C8 alkylene. 14 is independently a substituted or unsubstituted C1-C6 alkylene. 14 is independently a substituted C1-C6 alkylene. 14 is independently an unsubstituted C1-C6 alkylene. 14 is independently a substituted or unsubstituted C1-C4 alkylene. 14 is independently a substituted C1-C4 alkylene. 14 is independently an unsubstituted C1-C4 alkylene. 14 is independently substituted or unsubstituted ethylene. 14 is independently a substituted ethylene. 14 is independently unsubstituted ethylene. In embodiments, L 14 is independently substituted or unsubstituted methylene. 14 is independently substituted methylene. 14 is independently unsubstituted methylene.

[0207] In some embodiments, L 14 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 14 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 14 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 14 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 14is independently a substituted 2- to 20-membered heteroalkylene. 14 is independently unsubstituted 2- to 20-membered heteroalkylene. 14 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 14 is independently a substituted 2- to 12-membered heteroalkylene. 14 is independently unsubstituted 2- to 12-membered heteroalkylene. 14 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 14 is independently a substituted 2-8 membered heteroalkylene. 14 is independently unsubstituted 2-8 membered heteroalkylene. 14 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 14 is independently a substituted 2- to 6-membered heteroalkylene. 14 is independently unsubstituted 2- to 6-membered heteroalkylene. 14 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 14 is independently a substituted 4- to 6-membered heteroalkylene. 14 is independently unsubstituted 4- to 6-membered heteroalkylene. 14 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 14 is independently a substituted 2-3 membered heteroalkylene. 14 is independently unsubstituted 2-3 membered heteroalkylene. 14 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 14 is independently a substituted 4- to 5-membered heteroalkylene.14 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0208] In some embodiments, L 14 is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 14 is independently substituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 14 is independently unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 14 is independently substituted or unsubstituted 2- to 20-membered heteroalkenylene. 14 is independently a substituted 2- to 20-membered heteroalkenylene. 14 is independently unsubstituted 2- to 20-membered heteroalkenylene. 14 is independently substituted or unsubstituted 2- to 12-membered heteroalkenylene. 14 is independently a substituted 2- to 12-membered heteroalkenylene. 14 is independently unsubstituted 2- to 12-membered heteroalkenylene. 14 is independently substituted or unsubstituted 2-8 membered heteroalkenylene. 14 is independently a substituted 2-8 membered heteroalkenylene. 14 is independently unsubstituted 2-8 membered heteroalkenylene. 14 is independently substituted or unsubstituted 2- to 6-membered heteroalkenylene. 14 is independently a substituted 2- to 6-membered heteroalkenylene. 14is independently unsubstituted 2- to 6-membered heteroalkenylene. 14 is independently substituted or unsubstituted 4- to 6-membered heteroalkenylene. 14 is independently a substituted 4- to 6-membered heteroalkenylene. 14 is independently unsubstituted 4- to 6-membered heteroalkenylene. 14 is independently substituted or unsubstituted 2-3 membered heteroalkenylene. 14 is independently a substituted 2-3 membered heteroalkenylene. 14 is independently unsubstituted 2-3 membered heteroalkenylene. 14 is independently substituted or unsubstituted 4- to 5-membered heteroalkenylene. 14 is independently a substituted 4- to 5-membered heteroalkenylene. 14 are independently unsubstituted 4- to 5-membered heteroalkenylene.

[0209] In some embodiments, L 4 independently, -L 14 -NH-C(O)- or -L 14 In some embodiments, L 14 is a substituted or unsubstituted C1-C8 alkylene. 14 is a substituted C1-C8 alkylene. 14 is unsubstituted C1-C8 alkylene.

[0210] In some embodiments, L 4 is, independently, [ka] In some embodiments, L 4 is, independently, [ka] In some embodiments, L 4 is, independently, [ka] In some embodiments, L 4 is, independently, [ka] In some embodiments, L 4 is, independently, [ka] is.

[0211] In some embodiments, L 5 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 5 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 5 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 5 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 5 are independently substituted C1 to C 20 In some embodiments, L 5 are independently unsubstituted C1 to C 20 In some embodiments, L 5are independently substituted or unsubstituted C1-C 12 In some embodiments, L 5 are independently substituted C1 to C 12 In some embodiments, L 5 are independently unsubstituted C1 to C 12 In some embodiments, L 5 is independently a substituted or unsubstituted C1-C8 alkylene. 5 is independently a substituted C1-C8 alkylene. 5 is independently an unsubstituted C1-C8 alkylene. 5 is independently a substituted or unsubstituted C1-C6 alkylene. 5 is independently a substituted C1-C6 alkylene. 5 is independently an unsubstituted C1-C6 alkylene. 5 is independently a substituted or unsubstituted C1-C4 alkylene. 5 is independently a substituted C1-C4 alkylene. 5 is independently an unsubstituted C1-C4 alkylene. 5 is independently substituted or unsubstituted ethylene. 5 is independently a substituted ethylene. 5 is independently unsubstituted ethylene. In embodiments, L 5 is independently substituted or unsubstituted methylene. 5 is independently substituted methylene. 5 is independently unsubstituted methylene.

[0212] In some embodiments, L 5is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 5 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 5 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 5 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 5 is independently a substituted 2- to 20-membered heteroalkylene. 5 is independently unsubstituted 2- to 20-membered heteroalkylene. 5 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 5 is independently a substituted 2- to 12-membered heteroalkylene. 5 is independently unsubstituted 2- to 12-membered heteroalkylene. 5 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 5 is independently a substituted 2-8 membered heteroalkylene. 5 is independently unsubstituted 2-8 membered heteroalkylene. 5 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 5 is independently a substituted 2- to 6-membered heteroalkylene. 5 is independently unsubstituted 2- to 6-membered heteroalkylene. 5 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 5is independently a substituted 4- to 6-membered heteroalkylene. 5 is independently unsubstituted 4- to 6-membered heteroalkylene. 5 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 5 is independently a substituted 2-3 membered heteroalkylene. 5 is independently unsubstituted 2-3 membered heteroalkylene. 5 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 5 is independently a substituted 4- to 5-membered heteroalkylene. 5 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0213] In some embodiments, L 5 are independently substituted or unsubstituted cycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 5 are independently substituted cycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 5 are independently unsubstituted cycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 5 are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 5 are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 5 are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 5 is independently a substituted or unsubstituted C3-C8 cycloalkylene.5 is independently a substituted C3-C8 cycloalkylene. 5 is independently an unsubstituted C3-C8 cycloalkylene. 5 is independently a substituted or unsubstituted C3-C6 cycloalkylene. 5 is independently a substituted C3-C6 cycloalkylene. 5 is independently an unsubstituted C3-C6 cycloalkylene. 5 is independently a substituted or unsubstituted C4-C6 cycloalkylene. 5 is independently a substituted C4-C6 cycloalkylene. 5 is independently an unsubstituted C4-C6 cycloalkylene. 5 is independently a substituted or unsubstituted C5-C6 cycloalkylene. 5 is independently a substituted C5-C6 cycloalkylene. 5 is independently an unsubstituted C5-C6 cycloalkylene. 5 is independently substituted or unsubstituted hexylene. 5 is independently a substituted hexylene. 5 is independently unsubstituted hexylene.

[0214] In some embodiments, L 5 is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 5 is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 5is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 5 is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 5 is independently a substituted 3- to 10-membered heterocycloalkylene. 5 is independently unsubstituted 3- to 10-membered heterocycloalkylene. 5 is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 5 is independently a substituted 3- to 8-membered heterocycloalkylene. 5 is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 5 is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 5 is independently a substituted 3- to 6-membered heterocycloalkylene. 5 is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 5 is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 5 is independently a substituted 4- to 6-membered heterocycloalkylene. 5 is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 5 is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 5 is independently a substituted 4- to 5-membered heterocycloalkylene. 5 is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 5 is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 5is independently a substituted 5- to 6-membered heterocycloalkylene. 5 is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0215] In some embodiments, L 5 are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 5 are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 5 are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 5 are independently substituted or unsubstituted C-C 12 In some embodiments, L 5 are independently substituted C6 to C 12 In some embodiments, L 5 are independently unsubstituted C6-C 12 In some embodiments, L 5 are independently substituted or unsubstituted C-C 10 In some embodiments, L 5 are independently substituted C6 to C 10 In some embodiments, L 5 are independently unsubstituted C6-C 10 In some embodiments, L 5 is independently substituted or unsubstituted phenylene. 5 is independently substituted phenylene. In embodiments, L 5 is independently unsubstituted phenylene. In embodiments, L 5 is independently substituted or unsubstituted biphenylene. 5is independently substituted biphenylene. In embodiments, L 5 is independently unsubstituted biphenylene. In some embodiments, L 5 is independently substituted or unsubstituted naphthylene. 5 is independently a substituted naphthylene. 5 is independently unsubstituted naphthylene.

[0216] In some embodiments, L 5 is independently substituted or unsubstituted heteroarylene. In some embodiments, L 5 is independently substituted heteroarylene. In some embodiments, L 5 is independently unsubstituted heteroarylene. In some embodiments, L 5 is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, 4 to 6-membered, or 5 to 6-membered). 5 is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, 4 to 6-membered, or 5 to 6-membered). 5 is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, 4 to 6-membered, or 5 to 6-membered). 5 is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 5 is independently a substituted 5- to 12-membered heteroarylene. 5 is independently unsubstituted 5- to 12-membered heteroarylene. 5 is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 5 is independently a substituted 5- to 10-membered heteroarylene. 5 is independently unsubstituted 5- to 10-membered heteroarylene. 5is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 5 is independently a substituted 5- to 9-membered heteroarylene. 5 is independently an unsubstituted 5- to 9-membered heteroarylene. 5 is independently a substituted or unsubstituted 4- to 6-membered heteroarylene. 5 is independently a substituted 4- to 6-membered heteroarylene. 5 is independently an unsubstituted 4- to 6-membered heteroarylene. 5 is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 5 is independently a substituted 5- to 6-membered heteroarylene. 5 are independently unsubstituted 5- to 6-membered heteroarylene.

[0217] In some embodiments, L 5 are independently bonds.

[0218] In some embodiments, L 7 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 7 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 7 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 7 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 7are independently substituted C1 to C 20 In some embodiments, L 7 are independently unsubstituted C1 to C 20 In some embodiments, L 7 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 7 are independently substituted C1 to C 12 In some embodiments, L 7 are independently unsubstituted C1 to C 12 In some embodiments, L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 7 is independently a substituted C1-C8 alkylene. 7 is independently an unsubstituted C1-C8 alkylene. 7 is independently a substituted or unsubstituted C1-C6 alkylene. 7 is independently a substituted C1-C6 alkylene. 7 is independently an unsubstituted C1-C6 alkylene. 7 is independently a substituted or unsubstituted C1-C4 alkylene. 7 is independently a substituted C1-C4 alkylene. 7 is independently an unsubstituted C1-C4 alkylene. 7 is independently substituted or unsubstituted ethylene. 7 is independently a substituted ethylene. 7 is independently unsubstituted ethylene. In embodiments, L 7 is independently substituted or unsubstituted methylene. 7 is independently substituted methylene. 7is independently unsubstituted methylene.

[0219] In some embodiments, L 7 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 7 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 7 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 7 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 7 is independently a substituted 2- to 20-membered heteroalkylene. 7 is independently unsubstituted 2- to 20-membered heteroalkylene. 7 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 7 is independently a substituted 2- to 12-membered heteroalkylene. 7 is independently unsubstituted 2- to 12-membered heteroalkylene. 7 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 7 is independently a substituted 2-8 membered heteroalkylene. 7 is independently unsubstituted 2-8 membered heteroalkylene. 7 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 7 is independently a substituted 2- to 6-membered heteroalkylene. 7 is independently unsubstituted 2- to 6-membered heteroalkylene.7 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 7 is independently a substituted 4- to 6-membered heteroalkylene. 7 is independently unsubstituted 4- to 6-membered heteroalkylene. 7 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 7 is independently a substituted 2-3 membered heteroalkylene. 7 is independently unsubstituted 2-3 membered heteroalkylene. 7 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 7 is independently a substituted 4- to 5-membered heteroalkylene. 7 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0220] In some embodiments, L 7 are independently bonds.

[0221] In some embodiments, L 7 independently, -L 17 -NH-C(O)- or -L 17 -C(O)-NH-, and L 17 are independently substituted or unsubstituted C1-C 20 It is alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene.

[0222] In some embodiments, L 17 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 17 are independently substituted alkylene (e.g., C1-C 20 , C1~C12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 17 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 17 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 17 are independently substituted C1 to C 20 In some embodiments, L 17 are independently unsubstituted C1 to C 20 In some embodiments, L 17 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 17 are independently substituted C1 to C 12 In some embodiments, L 17 are independently unsubstituted C1 to C 12 In some embodiments, L 17 is independently a substituted or unsubstituted C1-C8 alkylene. 17 is independently a substituted C1-C8 alkylene. 17 is independently an unsubstituted C1-C8 alkylene. 17 is independently a substituted or unsubstituted C1-C6 alkylene. 17 is independently a substituted C1-C6 alkylene. 17 is independently an unsubstituted C1-C6 alkylene. 17 is independently a substituted or unsubstituted C1-C4 alkylene. 17 is independently a substituted C1-C4 alkylene. 17is independently an unsubstituted C1-C4 alkylene. 17 is independently substituted or unsubstituted ethylene. 17 is independently a substituted ethylene. 17 is independently unsubstituted ethylene. In embodiments, L 17 is independently substituted or unsubstituted methylene. 17 is independently substituted methylene. 17 is independently unsubstituted methylene.

[0223] In some embodiments, L 17 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 17 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 17 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 17 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 17 is independently a substituted 2- to 20-membered heteroalkylene. 17 is independently unsubstituted 2- to 20-membered heteroalkylene. 17 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 17 is independently a substituted 2- to 12-membered heteroalkylene. 17 is independently unsubstituted 2- to 12-membered heteroalkylene. 17is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 17 is independently a substituted 2-8 membered heteroalkylene. 17 is independently unsubstituted 2-8 membered heteroalkylene. 17 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 17 is independently a substituted 2- to 6-membered heteroalkylene. 17 is independently unsubstituted 2- to 6-membered heteroalkylene. 17 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 17 is independently a substituted 4- to 6-membered heteroalkylene. 17 is independently unsubstituted 4- to 6-membered heteroalkylene. 17 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 17 is independently a substituted 2-3 membered heteroalkylene. 17 is independently unsubstituted 2-3 membered heteroalkylene. 17 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 17 is independently a substituted 4- to 5-membered heteroalkylene. 17 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0224] In some embodiments, L 17 is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 17is independently substituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 17 is independently unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 17 is independently substituted or unsubstituted 2- to 20-membered heteroalkenylene. 17 is independently a substituted 2- to 20-membered heteroalkenylene. 17 is independently unsubstituted 2- to 20-membered heteroalkenylene. 17 is independently substituted or unsubstituted 2- to 12-membered heteroalkenylene. 17 is independently a substituted 2- to 12-membered heteroalkenylene. 17 is independently unsubstituted 2- to 12-membered heteroalkenylene. 17 is independently substituted or unsubstituted 2-8 membered heteroalkenylene. 17 is independently a substituted 2-8 membered heteroalkenylene. 17 is independently unsubstituted 2-8 membered heteroalkenylene. 17 is independently substituted or unsubstituted 2- to 6-membered heteroalkenylene. 17 is independently a substituted 2- to 6-membered heteroalkenylene. 17 is independently unsubstituted 2- to 6-membered heteroalkenylene. 17 is independently substituted or unsubstituted 4- to 6-membered heteroalkenylene. 17 is independently a substituted 4- to 6-membered heteroalkenylene. 17 is independently unsubstituted 4- to 6-membered heteroalkenylene. 17is independently substituted or unsubstituted 2-3 membered heteroalkenylene. 17 is independently a substituted 2-3 membered heteroalkenylene. 17 is independently unsubstituted 2-3 membered heteroalkenylene. 17 is independently substituted or unsubstituted 4- to 5-membered heteroalkenylene. 17 is independently a substituted 4- to 5-membered heteroalkenylene. 17 are independently unsubstituted 4- to 5-membered heteroalkenylene.

[0225] In some embodiments, L 7 independently -L 17 In some embodiments, L 7 independently -L 17 In some embodiments, L 17 is a substituted or unsubstituted C1-C8 alkylene. 17 is a substituted C1-C8 alkylene. 17 is unsubstituted C1-C8 alkylene.

[0226] In some embodiments, L 7 are independently -NHC(O)-.

[0227] In some embodiments, L 7 is, independently, [ka] In some embodiments, L 7 is, independently, [ka] In some embodiments, L 7 is, independently, [ka] In some embodiments, L 7 is, independently, [ka] In some embodiments, L 7 is, independently, [ka] is.

[0228] In some embodiments, -L 6 -L 5 -L 4 - is independently a bond or a substituted or unsubstituted 2 to 50 membered heteroalkylene. 6 -L 5 -L 4 - is independently a bond.

[0229] In some embodiments, -L 6 -L 5 -L 4 - is substituted or unsubstituted 2 to 50 membered heteroalkylene. 6 -L 5 -L 4 - is substituted or unsubstituted 2 to 45 membered heteroalkylene. 6 -L 5 -L 4 - is substituted or unsubstituted 2 to 40 membered heteroalkylene. 6 -L 5 -L 4 - is substituted or unsubstituted 2 to 35 membered heteroalkylene. 6 -L 5 -L 4 - is substituted or unsubstituted 2-30 membered heteroalkylene. 6 -L5 -L 4 - is substituted or unsubstituted 2 to 25 membered heteroalkylene. 6 -L 5 -L 4 - is substituted or unsubstituted 2- to 20-membered heteroalkylene. 6 -L 5 -L 4 - is substituted or unsubstituted 2-15 membered heteroalkylene. 6 -L 5 -L 4 - is substituted or unsubstituted 2-10 membered heteroalkylene. 6 -L 5 -L 4 - is a substituted or unsubstituted 2- to 5-membered heteroalkylene.

[0230] In some embodiments, -L 6 -L 5 -L 4 - is a substituted 2- to 50-membered heteroalkylene. 6 -L 5 -L 4 - is a substituted 2- to 45-membered heteroalkylene. 6 -L 5 -L 4 - is a substituted 2-40 membered heteroalkylene. 6 -L 5 -L 4 - is a substituted 2- to 35-membered heteroalkylene. 6 -L 5 -L 4 - is a substituted 2-30 membered heteroalkylene. 6 -L 5 -L 4 - is a substituted 2- to 25-membered heteroalkylene. 6 -L 5 -L 4 - is a substituted 2- to 20-membered heteroalkylene.3 is a substituted 2- to 50-membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-15 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-10 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-5 membered heteroalkylene.

[0231] In some embodiments, -L 6 -L 5 -L 4 - is unsubstituted 2-50 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-45 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-40 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2- to 35-membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-30 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2- to 25-membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2- to 20-membered heteroalkylene. 3 is unsubstituted 2-50 membered heteroalkylene. 6 -L 5 -L 4- is unsubstituted 2-15 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-10 membered heteroalkylene. 6 -L 5 -L 4 - is unsubstituted 2-5 membered heteroalkylene.

[0232] In some embodiments, -L 6 -L 5 -L 4 - is independently R 11 In some embodiments, R is a substituted or unsubstituted 2- to 50-membered heteroalkylene. 11 is oxo, hydroxyl, or unsubstituted C1-C4 alkyl. 11 is oxo. In some embodiments, R 11 is hydroxyl. In embodiments, R 11 is unsubstituted C1-C4 alkyl. In embodiments, R 11 is methyl. In embodiments, R 11 is ethyl. In embodiments, R 11 is propyl. In embodiments, R 11 is isopropyl. In embodiments, R 11 is butyl. In embodiments, R 11 is isobutyl. In embodiments, R 11 is t-butyl.

[0233] In some embodiments, -L 6 -L 5 -L 4 - is independently R 11 In some embodiments, -L is a substituted 2- to 50-membered heteroalkylene. 6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 4-membered heteroalkylene.6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 40-membered heteroalkylene. 6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 3-membered heteroalkylene. 6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 30-membered heteroalkylene. 6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 25-membered heteroalkylene. 6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 20-membered heteroalkylene. 6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 15-membered heteroalkylene. 6 -L 5 -L 4 -R 11 In some embodiments, -L is a substituted 2- to 11-membered heteroalkylene. 6 -L 5 -L 4 -R 11 It is a substituted 2- to 5-membered heteroalkylene.

[0234] In some embodiments, -L 6 -L 5 -L 4 - is independently, -L 10 -NH-C(O) or -L 10 -C(O)-NH-, and L 10 are independently substituted or unsubstituted C1-C 20 It is alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene.

[0235] In some embodiments, L 10 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 10 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 10 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 10 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 10 are independently substituted C1 to C 20 In some embodiments, L 10 are independently unsubstituted C1 to C 20 In some embodiments, L 10 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 10 are independently substituted C1 to C 12 In some embodiments, L 10 are independently unsubstituted C1 to C 12 In some embodiments, L 10 is independently a substituted or unsubstituted C1-C8 alkylene. 10 is independently a substituted C1-C8 alkylene. 10 is independently an unsubstituted C1-C8 alkylene. 10 is independently a substituted or unsubstituted C1-C6 alkylene. 10is independently a substituted C1-C6 alkylene. 10 is independently an unsubstituted C1-C6 alkylene. 10 is independently a substituted or unsubstituted C1-C4 alkylene. 10 is independently a substituted C1-C4 alkylene. 10 is independently an unsubstituted C1-C4 alkylene. 10 is independently substituted or unsubstituted ethylene. 10 is independently a substituted ethylene. 10 is independently unsubstituted ethylene. In embodiments, L 10 is independently substituted or unsubstituted methylene. 10 is independently substituted methylene. 10 is independently unsubstituted methylene.

[0236] In some embodiments, L 10 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 10 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 10 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 10 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 10 is independently a substituted 2- to 20-membered heteroalkylene. 10 is independently unsubstituted 2- to 20-membered heteroalkylene. 10is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 10 is independently a substituted 2- to 12-membered heteroalkylene. 10 is independently unsubstituted 2- to 12-membered heteroalkylene. 10 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 10 is independently a substituted 2-8 membered heteroalkylene. 10 is independently unsubstituted 2-8 membered heteroalkylene. 10 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 10 is independently a substituted 2- to 6-membered heteroalkylene. 10 is independently unsubstituted 2- to 6-membered heteroalkylene. 10 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 10 is independently a substituted 4- to 6-membered heteroalkylene. 10 is independently unsubstituted 4- to 6-membered heteroalkylene. 10 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 10 is independently a substituted 2-3 membered heteroalkylene. 10 is independently unsubstituted 2-3 membered heteroalkylene. 10 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 10 is independently a substituted 4- to 5-membered heteroalkylene. 10 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0237] In some embodiments, L 10is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 10 is independently substituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 10 is independently unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 10 is independently substituted or unsubstituted 2- to 20-membered heteroalkenylene. 10 is independently a substituted 2- to 20-membered heteroalkenylene. 10 is independently unsubstituted 2- to 20-membered heteroalkenylene. 10 is independently substituted or unsubstituted 2- to 12-membered heteroalkenylene. 10 is independently a substituted 2- to 12-membered heteroalkenylene. 10 is independently unsubstituted 2- to 12-membered heteroalkenylene. 10 is independently substituted or unsubstituted 2-8 membered heteroalkenylene. 10 is independently a substituted 2-8 membered heteroalkenylene. 10 is independently unsubstituted 2-8 membered heteroalkenylene. 10 is independently substituted or unsubstituted 2- to 6-membered heteroalkenylene. 10 is independently a substituted 2- to 6-membered heteroalkenylene. 10 is independently unsubstituted 2- to 6-membered heteroalkenylene. 10 is independently substituted or unsubstituted 4- to 6-membered heteroalkenylene. 10is independently a substituted 4- to 6-membered heteroalkenylene. 10 is independently unsubstituted 4- to 6-membered heteroalkenylene. 10 is independently substituted or unsubstituted 2-3 membered heteroalkenylene. 10 is independently a substituted 2-3 membered heteroalkenylene. 10 is independently unsubstituted 2-3 membered heteroalkenylene. 10 is independently substituted or unsubstituted 4- to 5-membered heteroalkenylene. 10 is independently a substituted 4- to 5-membered heteroalkenylene. 10 are independently unsubstituted 4- to 5-membered heteroalkenylene.

[0238] In some embodiments, -L 6 -L 5 -L 4 - is independently -L 10 In some embodiments, -L 6 -L 5 -L 4 - is independently -L 10 In some embodiments, L 10 is a substituted or unsubstituted C1-C8 alkylene. 10 is a substituted C1-C8 alkylene. 10 is unsubstituted C1-C8 alkylene.

[0239] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] is.

[0240] In some embodiments, -L 6 -L 5 -L 4 - is independently, -OL 10 -NH-C(O)- or -OL 10 -C(O)-NH-, and L 10 are independently substituted or unsubstituted C1-C 20 It is alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene.

[0241] In some embodiments, -L 6 -L 5 -L 4 - is independently -OL 10 In some embodiments, -L 6 -L 5 -L4 -, -OL 10 In some embodiments, L 10 is a substituted or unsubstituted C1-C8 alkylene. 10 is a substituted C1-C8 alkylene. 10 is hydroxyalkyl-substituted C1-C8 alkylene. 10 is a hydroxymethyl-substituted C1-C8 alkylene. 10 is unsubstituted C1-C8 alkylene.

[0242] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] is.

[0243] In some embodiments, -L 6 -L 5 -L 4 - is independently -OPO2-OL 10 -NH-C(O)- or -OPO2-OL 10 -C(O)-NH-, and L 10 are independently substituted or unsubstituted C1-C 20 It is alkylene, or substituted or unsubstituted 2- to 20-membered heteroalkylene.

[0244] In some embodiments, -L 6 -L 5 -L 4 - is independently -OPO2-OL 10 In some embodiments, -L 6 -L 5 -L 4 - is independently -OPO2-OL 10 In some embodiments, L 10 is a substituted or unsubstituted C1-C8 alkylene. 10 is a substituted C1-C8 alkylene. 10 is hydroxyalkyl-substituted C1-C8 alkylene. 10 is a hydroxymethyl-substituted C1-C8 alkylene. 10 is unsubstituted C1-C8 alkylene.

[0245] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] is.

[0246] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] and is attached to the 3' carbon of a double-stranded or single-stranded nucleic acid. In some embodiments, the 3' carbon is the 3' carbon of the 3' terminal nucleotide.

[0247] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] and is attached to the 5' carbon of a double-stranded or single-stranded nucleic acid. In some embodiments, the 5' carbon is the 5' carbon of the 5' terminal nucleotide. In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] and is attached to the 5' carbon of the double-stranded or single-stranded nucleic acid. 6 -L 5 -L 4 - is independently [ka] and is attached to the 5' carbon of the double-stranded or single-stranded nucleic acid. 6 -L 5 -L 4 - is independently [ka] and is attached to the 5' carbon of the double-stranded or single-stranded nucleic acid. 6 -L 5 -L 4 - is independently [ka] and is attached to the 5' carbon of a double-stranded or single-stranded nucleic acid.

[0248] In some embodiments, -L 6 -L 5 -L 4 - is independently [ka] and is bound to the nucleotide bases of double-stranded or single-stranded nucleic acids.

[0249] In some embodiments, L 1 is independently -NHC(O)-, -C(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 1 is independently —NHC(O)—. In some embodiments, L 1 is independently —C(O)NH—. In embodiments, L 1 is substituted or unsubstituted alkylene. In some embodiments, L 1 is a substituted or unsubstituted heteroalkylene.

[0250] In some embodiments, L 1 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1 are independently substituted or unsubstituted C1-C 20In some embodiments, L 1 are independently substituted C1 to C 20 In some embodiments, L 1 are independently unsubstituted C1 to C 20 In some embodiments, L 1 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 1 are independently substituted C1 to C 12 In some embodiments, L 1 are independently unsubstituted C1 to C 12 In some embodiments, L 1 is independently a substituted or unsubstituted C1-C8 alkylene. 1 is independently a substituted C1-C8 alkylene. 1 is independently an unsubstituted C1-C8 alkylene. 1 is independently a substituted or unsubstituted C1-C6 alkylene. 1 is independently a substituted C1-C6 alkylene. 1 is independently an unsubstituted C1-C6 alkylene. 1 is independently a substituted or unsubstituted C1-C4 alkylene. 1 is independently a substituted C1-C4 alkylene. 1 is independently an unsubstituted C1-C4 alkylene. 1 is independently substituted or unsubstituted ethylene. 1 is independently a substituted ethylene. 1 is independently unsubstituted ethylene. In embodiments, L 1 is independently substituted or unsubstituted methylene. 1is independently substituted methylene. 1 is independently unsubstituted methylene.

[0251] In some embodiments, L 1 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1 is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1 is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1 is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1 is independently a substituted 2- to 25-membered heteroalkylene. 1 is independently unsubstituted 2- to 25-membered heteroalkylene. 1 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 1 is independently a substituted 2- to 20-membered heteroalkylene. 1 is independently unsubstituted 2- to 20-membered heteroalkylene. 1 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 1 is independently a substituted 2- to 12-membered heteroalkylene. 1 is independently unsubstituted 2- to 12-membered heteroalkylene. 1 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 1is independently a substituted 2-8 membered heteroalkylene. 1 is independently unsubstituted 2-8 membered heteroalkylene. 1 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 1 is independently a substituted 2- to 6-membered heteroalkylene. 1 is independently unsubstituted 2- to 6-membered heteroalkylene. 1 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 1 is independently a substituted 4- to 6-membered heteroalkylene. 1 is independently unsubstituted 4- to 6-membered heteroalkylene. 1 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 1 is independently a substituted 2-3 membered heteroalkylene. 1 is independently unsubstituted 2-3 membered heteroalkylene. 1 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 1 is independently a substituted 4- to 5-membered heteroalkylene. 1 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0252] In some embodiments, L 1 L 1A -L 1B -L 1C -L 1D -L 1E In some embodiments, L 1A are independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L 1Bare independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene; L 1C are independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene; L 1D are independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene; L 1E is independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0253] In some embodiments, L 1A is independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 1B is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene. 1C is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene. 1D is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene. 1E is independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0254] In some embodiments, L 1A are independently a bond, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2- to 8-membered heteroalkylene; L 1Bare independently a bond, -O-, -NHC(O)-, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2- to 8-membered heteroalkylene, or substituted or unsubstituted phenylene; L 1C are independently a bond, -O-, -NHC(O)-, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C2-C8 alkynylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene; L 1D are independently a bond, -O-, -NHC(O)-, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2- to 8-membered heteroalkylene, or substituted or unsubstituted phenylene; L 1E is independently a bond, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2-8 membered heteroalkylene. 1A is independently a bond, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2-8 membered heteroalkylene. 1B is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene. 1C is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C2-C8 alkynylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene. 1D is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene. 1E are independently a bond, -NHC(O)-, substituted or unsubstituted C1 to C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.

[0255] In some embodiments, L 1Aare independently unsubstituted C1-C8 alkylene or unsubstituted 2-8 membered heteroalkylene; L 1B are independently a bond, -O-, -NHC(O)-, unsubstituted C1-C8 alkylene, unsubstituted C2-C8 alkynylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene; L 1C are independently a bond, -O-, -NHC(O)-, unsubstituted C1-C8 alkylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene; L 1D are independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, or unsubstituted 2-8 membered heteroalkylene; L 1E are independently -NHC(O)-.

[0256] In some embodiments, L 1A is independently an unsubstituted C1-C8 alkylene or an unsubstituted 2-8 membered heteroalkylene. 1B is independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, unsubstituted C2-C8 alkynylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene. 1C is independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene. 1D is independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, or unsubstituted 2-8 membered heteroalkylene. 1E are independently -NHC(O)-.

[0257] In some embodiments, L 1A is independently a bond. 1A is independently —NH—. In some embodiments, L 1A is independently —O—. In some embodiments, L 1A is independently -S-. In some embodiments, L 1Ais independently —C(O)—. In some embodiments, L 1A is independently —NHC(O)—. In some embodiments, L 1A is independently —S(O)C(O)—. In embodiments, L 1A is independently -OPO2-O-. In some embodiments, L 1A is independently -OP(S)(O)-O-. In embodiments, L 1A is independently -OP(S)-O-. In some embodiments, L 1A is independently —S(O)NH—. In some embodiments, L 1A is independently —NHC(O)NH—. In some embodiments, L 1A is independently —C(O)O—. In embodiments, L 1A is independently —OC(O)—. In some embodiments, L 1A is independently —C(O)NH—. In embodiments, L 1A is not a bond.

[0258] In some embodiments, L 1A are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1A are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1A are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1A are independently substituted or unsubstituted C1-C 25In some embodiments, L 1A are independently substituted C1 to C 25 In some embodiments, L 1A are independently unsubstituted C1 to C 25 In some embodiments, L 1A are independently substituted or unsubstituted C1-C 20 In some embodiments, L 1A are independently substituted C1 to C 20 In some embodiments, L 1A are independently unsubstituted C1 to C 20 In some embodiments, L 1A are independently substituted or unsubstituted C1-C 12 In some embodiments, L 1A are independently substituted C1 to C 12 In some embodiments, L 1A are independently unsubstituted C1 to C 12 In some embodiments, L 1A is independently a substituted or unsubstituted C1-C8 alkylene. 1A is independently a substituted C1-C8 alkylene. 1A is independently an unsubstituted C1-C8 alkylene. 1A is independently a substituted or unsubstituted C1-C6 alkylene. 1A is independently a substituted C1-C6 alkylene. 1A is independently an unsubstituted C1-C6 alkylene. 1A is independently a substituted or unsubstituted C1-C4 alkylene. 1A is independently a substituted C1-C4 alkylene. 1A is independently an unsubstituted C1-C4 alkylene. 1Ais independently substituted or unsubstituted ethylene. 1A is independently a substituted ethylene. 1A is independently unsubstituted ethylene. In embodiments, L 1A is independently substituted or unsubstituted methylene. 1A is independently substituted methylene. 1A is independently unsubstituted methylene.

[0259] In some embodiments, L 1A is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1A is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1A is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1A is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1A is independently a substituted 2- to 25-membered heteroalkylene. 1A is independently unsubstituted 2- to 25-membered heteroalkylene. 1A is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 1A is independently a substituted 2- to 20-membered heteroalkylene. 1A is independently unsubstituted 2- to 20-membered heteroalkylene. 1A is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 1Ais independently a substituted 2- to 12-membered heteroalkylene. 1A is independently unsubstituted 2- to 12-membered heteroalkylene. 1A is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 1A is independently a substituted 2-8 membered heteroalkylene. 1A is independently unsubstituted 2-8 membered heteroalkylene. 1A is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 1A is independently a substituted 2- to 6-membered heteroalkylene. 1A is independently unsubstituted 2- to 6-membered heteroalkylene. 1A is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 1A is independently a substituted 4- to 6-membered heteroalkylene. 1A is independently unsubstituted 4- to 6-membered heteroalkylene. 1A is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 1A is independently a substituted 2-3 membered heteroalkylene. 1A is independently unsubstituted 2-3 membered heteroalkylene. 1A is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 1A is independently a substituted 4- to 5-membered heteroalkylene. 1A is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0260] In some embodiments, L 1A are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1A are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1A are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1A are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 1A are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 1A are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 1A is independently a substituted or unsubstituted C3-C8 cycloalkylene. 1A is independently a substituted C3-C8 cycloalkylene. 1A is independently an unsubstituted C3-C8 cycloalkylene. 1A is independently a substituted or unsubstituted C3-C6 cycloalkylene. 1A is independently a substituted C3-C6 cycloalkylene. 1A is independently an unsubstituted C3-C6 cycloalkylene. 1A is independently a substituted or unsubstituted C4-C6 cycloalkylene. 1A is independently a substituted C4-C6 cycloalkylene. 1A is independently an unsubstituted C4-C6 cycloalkylene. 1A is independently a substituted or unsubstituted C5-C6 cycloalkylene. 1Ais independently a substituted C5-C6 cycloalkylene. 1A is independently an unsubstituted C5-C6 cycloalkylene. 1A is independently substituted or unsubstituted hexylene. 1A is independently a substituted hexylene. 1A is independently unsubstituted hexylene.

[0261] In some embodiments, L 1A is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1A is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1A is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1A is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 1A is independently a substituted 3- to 10-membered heterocycloalkylene. 1A is independently unsubstituted 3- to 10-membered heterocycloalkylene. 1A is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 1A is independently a substituted 3- to 8-membered heterocycloalkylene. 1A is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 1A is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 1A is independently a substituted 3- to 6-membered heterocycloalkylene.1A is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 1A is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 1A is independently a substituted 4- to 6-membered heterocycloalkylene. 1A is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 1A is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 1A is independently a substituted 4- to 5-membered heterocycloalkylene. 1A is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 1A is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 1A is independently a substituted 5- to 6-membered heterocycloalkylene. 1A is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0262] In some embodiments, L 1A is independently substituted or unsubstituted arylene. In some embodiments, L 1A are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1A are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1A are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1A are independently substituted or unsubstituted C-C 12 In some embodiments, L1A are independently substituted C6 to C 12 In some embodiments, L 1A are independently unsubstituted C6-C 12 In some embodiments, L 1A are independently substituted or unsubstituted C-C 10 In some embodiments, L 1A are independently substituted C6 to C 10 In some embodiments, L 1A are independently unsubstituted C6-C 10 In some embodiments, L 1A is independently substituted or unsubstituted phenylene. 1A is independently substituted phenylene. In embodiments, L 1A is independently unsubstituted phenylene. In embodiments, L 1A is independently substituted or unsubstituted biphenylene. 1A is independently substituted biphenylene. In embodiments, L 1A is independently unsubstituted biphenylene. In some embodiments, L 1A is independently substituted or unsubstituted naphthylene. 1A is independently a substituted naphthylene. 1A is independently unsubstituted naphthylene.

[0263] In some embodiments, L 1A is independently substituted or unsubstituted heteroarylene. In some embodiments, L 1A is independently substituted heteroarylene. In some embodiments, L 1A is independently unsubstituted heteroarylene. In some embodiments, L 1A is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).1A is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1A is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1A is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 1A is independently a substituted 5- to 12-membered heteroarylene. 1A is independently unsubstituted 5- to 12-membered heteroarylene. 1A is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 1A is independently a substituted 5- to 10-membered heteroarylene. 1A is independently unsubstituted 5- to 10-membered heteroarylene. 1A is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 1A is independently a substituted 5- to 9-membered heteroarylene. 1A is independently an unsubstituted 5- to 9-membered heteroarylene. 1A is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 1A is independently a substituted 5- to 6-membered heteroarylene. 1A are independently unsubstituted 5- to 6-membered heteroarylene.

[0264] In some embodiments, L 1B is independently a bond. 1B is independently —NH—. In some embodiments, L 1B is independently —O—. In some embodiments, L 1B is independently -S-. In some embodiments, L 1Bis independently —C(O)—. In some embodiments, L 1B is independently —NHC(O)—. In some embodiments, L 1B is independently —S(O)C(O)—. In embodiments, L 1B is independently -OPO2-O-. In some embodiments, L 1B is independently -OP(S)(O)-O-. In embodiments, L 1B is independently -OP(S)-O-. In some embodiments, L 1B is independently —S(O)NH—. In some embodiments, L 1B is independently —NHC(O)NH—. In some embodiments, L 1B is independently —C(O)O—. In embodiments, L 1B is independently —OC(O)—. In some embodiments, L 1B is independently —C(O)NH—. In embodiments, L 1B is not a bond.

[0265] In some embodiments, L 1B are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1B are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1B are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1B are independently substituted or unsubstituted C1-C 25In some embodiments, L 1B are independently substituted C1 to C 25 In some embodiments, L 1B are independently unsubstituted C1 to C 25 In some embodiments, L 1B are independently substituted or unsubstituted C1-C 20 In some embodiments, L 1B are independently substituted C1 to C 20 In some embodiments, L 1B are independently unsubstituted C1 to C 20 In some embodiments, L 1B are independently substituted or unsubstituted C1-C 12 In some embodiments, L 1B are independently substituted C1 to C 12 In some embodiments, L 1B are independently unsubstituted C1 to C 12 In some embodiments, L 1B is independently a substituted or unsubstituted C1-C8 alkylene. 1B is independently a substituted C1-C8 alkylene. 1B is independently an unsubstituted C1-C8 alkylene. 1B is independently a substituted or unsubstituted C1-C6 alkylene. 1B is independently a substituted C1-C6 alkylene. 1B is independently an unsubstituted C1-C6 alkylene. 1B is independently a substituted or unsubstituted C1-C4 alkylene. 1B is independently a substituted C1-C4 alkylene. 1B is independently an unsubstituted C1-C4 alkylene. 1Bis independently substituted or unsubstituted ethylene. 1B is independently a substituted ethylene. 1B is independently unsubstituted ethylene. In embodiments, L 1B is independently substituted or unsubstituted methylene. 1B is independently substituted methylene. 1B is independently unsubstituted methylene.

[0266] In some embodiments, L 1B is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1B is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1B is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1B is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1B is independently a substituted 2- to 25-membered heteroalkylene. 1B is independently unsubstituted 2- to 25-membered heteroalkylene. 1B is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 1B is independently a substituted 2- to 20-membered heteroalkylene. 1B is independently unsubstituted 2- to 20-membered heteroalkylene. 1B is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 1Bis independently a substituted 2- to 12-membered heteroalkylene. 1B is independently unsubstituted 2- to 12-membered heteroalkylene. 1B is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 1B is independently a substituted 2-8 membered heteroalkylene. 1B is independently unsubstituted 2-8 membered heteroalkylene. 1B is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 1B is independently a substituted 2- to 6-membered heteroalkylene. 1B is independently unsubstituted 2- to 6-membered heteroalkylene. 1B is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 1B is independently a substituted 4- to 6-membered heteroalkylene. 1B is independently unsubstituted 4- to 6-membered heteroalkylene. 1B is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 1B is independently a substituted 2-3 membered heteroalkylene. 1B is independently unsubstituted 2-3 membered heteroalkylene. 1B is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 1B is independently a substituted 4- to 5-membered heteroalkylene. 1B is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0267] In some embodiments, L 1B are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1B are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1B are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1B are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 1B are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 1B are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 1B is independently a substituted or unsubstituted C3-C8 cycloalkylene. 1B is independently a substituted C3-C8 cycloalkylene. 1B is independently an unsubstituted C3-C8 cycloalkylene. 1B is independently a substituted or unsubstituted C3-C6 cycloalkylene. 1B is independently a substituted C3-C6 cycloalkylene. 1B is independently an unsubstituted C3-C6 cycloalkylene. 1B is independently a substituted or unsubstituted C4-C6 cycloalkylene. 1B is independently a substituted C4-C6 cycloalkylene. 1B is independently an unsubstituted C4-C6 cycloalkylene. 1B is independently a substituted or unsubstituted C5-C6 cycloalkylene. 1Bis independently a substituted C5-C6 cycloalkylene. 1B is independently an unsubstituted C5-C6 cycloalkylene. 1B is independently substituted or unsubstituted hexylene. 1B is independently a substituted hexylene. 1B is independently unsubstituted hexylene.

[0268] In some embodiments, L 1B is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1B is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1B is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1B is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 1B is independently a substituted 3- to 10-membered heterocycloalkylene. 1B is independently unsubstituted 3- to 10-membered heterocycloalkylene. 1B is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 1B is independently a substituted 3- to 8-membered heterocycloalkylene. 1B is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 1B is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 1B is independently a substituted 3- to 6-membered heterocycloalkylene.1B is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 1B is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 1B is independently a substituted 4- to 6-membered heterocycloalkylene. 1B is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 1B is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 1B is independently a substituted 4- to 5-membered heterocycloalkylene. 1B is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 1B is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 1B is independently a substituted 5- to 6-membered heterocycloalkylene. 1B is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0269] In some embodiments, L 1B is independently substituted or unsubstituted arylene. In some embodiments, L 1B are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1B are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1B are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1B are independently substituted or unsubstituted C-C 12 In some embodiments, L1B are independently substituted C6 to C 12 In some embodiments, L 1B are independently unsubstituted C6-C 12 In some embodiments, L 1B are independently substituted or unsubstituted C-C 10 In some embodiments, L 1B are independently substituted C6 to C 10 In some embodiments, L 1B are independently unsubstituted C6-C 10 In some embodiments, L 1B is independently substituted or unsubstituted phenylene. 1B is independently substituted phenylene. In embodiments, L 1B is independently unsubstituted phenylene. In embodiments, L 1B is independently substituted or unsubstituted biphenylene. 1B is independently substituted biphenylene. In embodiments, L 1B is independently unsubstituted biphenylene. In some embodiments, L 1B is independently substituted or unsubstituted naphthylene. 1B is independently a substituted naphthylene. 1B is independently unsubstituted naphthylene.

[0270] In some embodiments, L 1B is independently substituted or unsubstituted heteroarylene. In some embodiments, L 1B is independently substituted heteroarylene. In some embodiments, L 1B is independently unsubstituted heteroarylene. In some embodiments, L 1B is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).1B is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1B is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1B is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 1B is independently a substituted 5- to 12-membered heteroarylene. 1B is independently unsubstituted 5- to 12-membered heteroarylene. 1B is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 1B is independently a substituted 5- to 10-membered heteroarylene. 1B is independently unsubstituted 5- to 10-membered heteroarylene. 1B is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 1B is independently a substituted 5- to 9-membered heteroarylene. 1B is independently an unsubstituted 5- to 9-membered heteroarylene. 1B is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 1B is independently a substituted 5- to 6-membered heteroarylene. 1B are independently unsubstituted 5- to 6-membered heteroarylene.

[0271] In some embodiments, L 1C is independently a bond. 1C is independently —NH—. In some embodiments, L 1C is independently —O—. In some embodiments, L 1C is independently -S-. In some embodiments, L 1Cis independently —C(O)—. In some embodiments, L 1C is independently —NHC(O)—. In some embodiments, L 1C is independently —S(O)C(O)—. In embodiments, L 1C is independently -OPO2-O-. In some embodiments, L 1C is independently -OP(S)(O)-O-. In embodiments, L 1C is independently -OP(S)-O-. In some embodiments, L 1C is independently —S(O)NH—. In some embodiments, L 1C is independently —NHC(O)NH—. In some embodiments, L 1C is independently —C(O)O—. In embodiments, L 1C is independently —OC(O)—. In some embodiments, L 1C is independently —C(O)NH—. In embodiments, L 1C is not a bond.

[0272] In some embodiments, L 1C are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1C are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1C are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1C are independently substituted or unsubstituted C1-C 25In some embodiments, L 1C are independently substituted C1 to C 25 In some embodiments, L 1C are independently unsubstituted C1 to C 25 In some embodiments, L 1C are independently substituted or unsubstituted C1-C 20 In some embodiments, L 1C are independently substituted C1 to C 20 In some embodiments, L 1C are independently unsubstituted C1 to C 20 In some embodiments, L 1C are independently substituted or unsubstituted C1-C 12 In some embodiments, L 1C are independently substituted C1 to C 12 In some embodiments, L 1C are independently unsubstituted C1 to C 12 In some embodiments, L 1C is independently a substituted or unsubstituted C1-C8 alkylene. 1C is independently a substituted C1-C8 alkylene. 1C is independently an unsubstituted C1-C8 alkylene. 1C is independently a substituted or unsubstituted C1-C6 alkylene. 1C is independently a substituted C1-C6 alkylene. 1C is independently an unsubstituted C1-C6 alkylene. 1C is independently a substituted or unsubstituted C1-C4 alkylene. 1C is independently a substituted C1-C4 alkylene. 1C is independently an unsubstituted C1-C4 alkylene. 1Cis independently substituted or unsubstituted ethylene. 1C is independently a substituted ethylene. 1C is independently unsubstituted ethylene. In embodiments, L 1C is independently substituted or unsubstituted methylene. 1C is independently substituted methylene. 1C is independently unsubstituted methylene.

[0273] In some embodiments, L 1C is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1C is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1C is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1C is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1C is independently a substituted 2- to 25-membered heteroalkylene. 1C is independently unsubstituted 2- to 25-membered heteroalkylene. 1C is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 1C is independently a substituted 2- to 20-membered heteroalkylene. 1C is independently unsubstituted 2- to 20-membered heteroalkylene. 1C is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 1Cis independently a substituted 2- to 12-membered heteroalkylene. 1C is independently unsubstituted 2- to 12-membered heteroalkylene. 1C is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 1C is independently a substituted 2-8 membered heteroalkylene. 1C is independently unsubstituted 2-8 membered heteroalkylene. 1C is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 1C is independently a substituted 2- to 6-membered heteroalkylene. 1C is independently unsubstituted 2- to 6-membered heteroalkylene. 1C is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 1C is independently a substituted 4- to 6-membered heteroalkylene. 1C is independently unsubstituted 4- to 6-membered heteroalkylene. 1C is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 1C is independently a substituted 2-3 membered heteroalkylene. 1C is independently unsubstituted 2-3 membered heteroalkylene. 1C is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 1C is independently a substituted 4- to 5-membered heteroalkylene. 1C is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0274] In some embodiments, L 1C are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1C are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1C are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1C are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 1C are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 1C are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 1C is independently a substituted or unsubstituted C3-C8 cycloalkylene. 1C is independently a substituted C3-C8 cycloalkylene. 1C is independently an unsubstituted C3-C8 cycloalkylene. 1C is independently a substituted or unsubstituted C3-C6 cycloalkylene. 1C is independently a substituted C3-C6 cycloalkylene. 1C is independently an unsubstituted C3-C6 cycloalkylene. 1C is independently a substituted or unsubstituted C4-C6 cycloalkylene. 1C is independently a substituted C4-C6 cycloalkylene. 1C is independently an unsubstituted C4-C6 cycloalkylene. 1C is independently a substituted or unsubstituted C5-C6 cycloalkylene. 1Cis independently a substituted C5-C6 cycloalkylene. 1C is independently an unsubstituted C5-C6 cycloalkylene. 1C is independently substituted or unsubstituted hexylene. 1C is independently a substituted hexylene. 1C is independently unsubstituted hexylene.

[0275] In some embodiments, L 1C is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1C is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1C is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1C is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 1C is independently a substituted 3- to 10-membered heterocycloalkylene. 1C is independently unsubstituted 3- to 10-membered heterocycloalkylene. 1C is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 1C is independently a substituted 3- to 8-membered heterocycloalkylene. 1C is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 1C is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 1C is independently a substituted 3- to 6-membered heterocycloalkylene.1C is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 1C is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 1C is independently a substituted 4- to 6-membered heterocycloalkylene. 1C is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 1C is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 1C is independently a substituted 4- to 5-membered heterocycloalkylene. 1C is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 1C is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 1C is independently a substituted 5- to 6-membered heterocycloalkylene. 1C is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0276] In some embodiments, L 1C is independently substituted or unsubstituted arylene. In some embodiments, L 1C are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1C are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1C are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1C are independently substituted or unsubstituted C-C 12 In some embodiments, L1C are independently substituted C6 to C 12 In some embodiments, L 1C are independently unsubstituted C6-C 12 In some embodiments, L 1C are independently substituted or unsubstituted C-C 10 In some embodiments, L 1C are independently substituted C6 to C 10 In some embodiments, L 1C are independently unsubstituted C6-C 10 In some embodiments, L 1C is independently substituted or unsubstituted phenylene. 1C is independently substituted phenylene. In embodiments, L 1C is independently unsubstituted phenylene. In embodiments, L 1C is independently substituted or unsubstituted biphenylene. 1C is independently substituted biphenylene. In embodiments, L 1C is independently unsubstituted biphenylene. In some embodiments, L 1C is independently substituted or unsubstituted naphthylene. 1C is independently a substituted naphthylene. 1C is independently unsubstituted naphthylene.

[0277] In some embodiments, L 1C is independently substituted or unsubstituted heteroarylene. In some embodiments, L 1C is independently substituted heteroarylene. In some embodiments, L 1C is independently unsubstituted heteroarylene. In some embodiments, L 1C is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).1C is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1C is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1C is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 1C is independently a substituted 5- to 12-membered heteroarylene. 1C is independently unsubstituted 5- to 12-membered heteroarylene. 1C is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 1C is independently a substituted 5- to 10-membered heteroarylene. 1C is independently unsubstituted 5- to 10-membered heteroarylene. 1C is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 1C is independently a substituted 5- to 9-membered heteroarylene. 1C is independently an unsubstituted 5- to 9-membered heteroarylene. 1C is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 1C is independently a substituted 5- to 6-membered heteroarylene. 1C are independently unsubstituted 5- to 6-membered heteroarylene.

[0278] In some embodiments, L 1D is independently a bond. 1D is independently —NH—. In some embodiments, L 1D is independently —O—. In some embodiments, L 1D is independently -S-. In some embodiments, L 1Dis independently —C(O)—. In some embodiments, L 1D is independently —NHC(O)—. In some embodiments, L 1D is independently —S(O)C(O)—. In embodiments, L 1D is independently -OPO2-O-. In some embodiments, L 1D is independently -OP(S)(O)-O-. In embodiments, L 1D is independently -OP(S)-O-. In some embodiments, L 1D is independently —S(O)NH—. In some embodiments, L 1D is independently —NHC(O)NH—. In some embodiments, L 1D is independently —C(O)O—. In embodiments, L 1D is independently —OC(O)—. In some embodiments, L 1D is independently —C(O)NH—. In embodiments, L 1D is not a bond.

[0279] In some embodiments, L 1D are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1D are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1D are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1D are independently substituted or unsubstituted C1-C 25In some embodiments, L 1D are independently substituted C1 to C 25 In some embodiments, L 1D are independently unsubstituted C1 to C 25 In some embodiments, L 1D are independently substituted or unsubstituted C1-C 20 In some embodiments, L 1D are independently substituted C1 to C 20 In some embodiments, L 1D are independently unsubstituted C1 to C 20 In some embodiments, L 1D are independently substituted or unsubstituted C1-C 12 In some embodiments, L 1D are independently substituted C1 to C 12 In some embodiments, L 1D are independently unsubstituted C1 to C 12 In some embodiments, L 1D is independently a substituted or unsubstituted C1-C8 alkylene. 1D is independently a substituted C1-C8 alkylene. 1D is independently an unsubstituted C1-C8 alkylene. 1D is independently a substituted or unsubstituted C1-C6 alkylene. 1D is independently a substituted C1-C6 alkylene. 1D is independently an unsubstituted C1-C6 alkylene. 1D is independently a substituted or unsubstituted C1-C4 alkylene. 1D is independently a substituted C1-C4 alkylene. 1D is independently an unsubstituted C1-C4 alkylene. 1Dis independently substituted or unsubstituted ethylene. 1D is independently a substituted ethylene. 1D is independently unsubstituted ethylene. In embodiments, L 1D is independently substituted or unsubstituted methylene. 1D is independently substituted methylene. 1D is independently unsubstituted methylene.

[0280] In some embodiments, L 1D is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1D is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1D is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1D is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1D is independently a substituted 2- to 25-membered heteroalkylene. 1D is independently unsubstituted 2- to 25-membered heteroalkylene. 1D is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 1D is independently a substituted 2- to 20-membered heteroalkylene. 1D is independently unsubstituted 2- to 20-membered heteroalkylene. 1D is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 1Dis independently a substituted 2- to 12-membered heteroalkylene. 1D is independently unsubstituted 2- to 12-membered heteroalkylene. 1D is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 1D is independently a substituted 2-8 membered heteroalkylene. 1D is independently unsubstituted 2-8 membered heteroalkylene. 1D is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 1D is independently a substituted 2- to 6-membered heteroalkylene. 1D is independently unsubstituted 2- to 6-membered heteroalkylene. 1D is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 1D is independently a substituted 4- to 6-membered heteroalkylene. 1D is independently unsubstituted 4- to 6-membered heteroalkylene. 1D is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 1D is independently a substituted 2-3 membered heteroalkylene. 1D is independently unsubstituted 2-3 membered heteroalkylene. 1D is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 1D is independently a substituted 4- to 5-membered heteroalkylene. 1D is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0281] In some embodiments, L 1D are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1D are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1D are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1D are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 1D are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 1D are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 1D is independently a substituted or unsubstituted C3-C8 cycloalkylene. 1D is independently a substituted C3-C8 cycloalkylene. 1D is independently an unsubstituted C3-C8 cycloalkylene. 1D is independently a substituted or unsubstituted C3-C6 cycloalkylene. 1D is independently a substituted C3-C6 cycloalkylene. 1D is independently an unsubstituted C3-C6 cycloalkylene. 1D is independently a substituted or unsubstituted C4-C6 cycloalkylene. 1D is independently a substituted C4-C6 cycloalkylene. 1D is independently an unsubstituted C4-C6 cycloalkylene. 1D is independently a substituted or unsubstituted C5-C6 cycloalkylene. 1Dis independently a substituted C5-C6 cycloalkylene. 1D is independently an unsubstituted C5-C6 cycloalkylene. 1D is independently substituted or unsubstituted hexylene. 1D is independently a substituted hexylene. 1D is independently unsubstituted hexylene.

[0282] In some embodiments, L 1D is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1D is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1D is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1D is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 1D is independently a substituted 3- to 10-membered heterocycloalkylene. 1D is independently unsubstituted 3- to 10-membered heterocycloalkylene. 1D is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 1D is independently a substituted 3- to 8-membered heterocycloalkylene. 1D is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 1D is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 1D is independently a substituted 3- to 6-membered heterocycloalkylene.1D is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 1D is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 1D is independently a substituted 4- to 6-membered heterocycloalkylene. 1D is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 1D is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 1D is independently a substituted 4- to 5-membered heterocycloalkylene. 1D is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 1D is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 1D is independently a substituted 5- to 6-membered heterocycloalkylene. 1D is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0283] In some embodiments, L 1D is independently substituted or unsubstituted arylene. In some embodiments, L 1D are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1D are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1D are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1D are independently substituted or unsubstituted C-C 12 In some embodiments, L1D are independently substituted C6 to C 12 In some embodiments, L 1D are independently unsubstituted C6-C 12 In some embodiments, L 1D are independently substituted or unsubstituted C-C 10 In some embodiments, L 1D are independently substituted C6 to C 10 In some embodiments, L 1D are independently unsubstituted C6-C 10 In some embodiments, L 1D is independently substituted or unsubstituted phenylene. 1D is independently substituted phenylene. In embodiments, L 1D is independently unsubstituted phenylene. In embodiments, L 1D is independently substituted or unsubstituted biphenylene. 1D is independently substituted biphenylene. In embodiments, L 1D is independently unsubstituted biphenylene. In some embodiments, L 1D is independently substituted or unsubstituted naphthylene. 1D is independently a substituted naphthylene. 1D is independently unsubstituted naphthylene.

[0284] In some embodiments, L 1D is independently substituted or unsubstituted heteroarylene. In some embodiments, L 1D is independently substituted heteroarylene. In some embodiments, L 1D is independently unsubstituted heteroarylene. In some embodiments, L 1D is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).1D is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1D is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1D is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 1D is independently a substituted 5- to 12-membered heteroarylene. 1D is independently unsubstituted 5- to 12-membered heteroarylene. 1D is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 1D is independently a substituted 5- to 10-membered heteroarylene. 1D is independently unsubstituted 5- to 10-membered heteroarylene. 1D is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 1D is independently a substituted 5- to 9-membered heteroarylene. 1D is independently an unsubstituted 5- to 9-membered heteroarylene. 1D is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 1D is independently a substituted 5- to 6-membered heteroarylene. 1D are independently unsubstituted 5- to 6-membered heteroarylene.

[0285] In some embodiments, L 1E is independently a bond. 1E is independently —NH—. In some embodiments, L 1E is independently —O—. In some embodiments, L 1E is independently -S-. In some embodiments, L 1Eis independently —C(O)—. In some embodiments, L 1E is independently —NHC(O)—. In some embodiments, L 1E is independently —S(O)C(O)—. In embodiments, L 1E is independently -OPO2-O-. In some embodiments, L 1E is independently -OP(S)(O)-O-. In embodiments, L 1E is independently -OP(S)-O-. In some embodiments, L 1E is independently —S(O)NH—. In some embodiments, L 1E is independently —NHC(O)NH—. In some embodiments, L 1E is independently —C(O)O—. In embodiments, L 1E is independently —OC(O)—. In some embodiments, L 1E is independently —C(O)NH—. In embodiments, L 1E is not a bond.

[0286] In some embodiments, L 1E are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1E are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1E are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1E are independently substituted or unsubstituted C1-C 25In some embodiments, L 1E are independently substituted C1 to C 25 In some embodiments, L 1E are independently unsubstituted C1 to C 25 In some embodiments, L 1E are independently substituted or unsubstituted C1-C 20 In some embodiments, L 1E are independently substituted C1 to C 20 In some embodiments, L 1E are independently unsubstituted C1 to C 20 In some embodiments, L 1E are independently substituted or unsubstituted C1-C 12 In some embodiments, L 1E are independently substituted C1 to C 12 In some embodiments, L 1E are independently unsubstituted C1 to C 12 In some embodiments, L 1E is independently a substituted or unsubstituted C1-C8 alkylene. 1E is independently a substituted C1-C8 alkylene. 1E is independently an unsubstituted C1-C8 alkylene. 1E is independently a substituted or unsubstituted C1-C6 alkylene. 1E is independently a substituted C1-C6 alkylene. 1E is independently an unsubstituted C1-C6 alkylene. 1E is independently a substituted or unsubstituted C1-C4 alkylene. 1E is independently a substituted C1-C4 alkylene. 1E is independently an unsubstituted C1-C4 alkylene. 1Eis independently substituted or unsubstituted ethylene. 1E is independently a substituted ethylene. 1E is independently unsubstituted ethylene. In embodiments, L 1E is independently substituted or unsubstituted methylene. 1E is independently substituted methylene. 1E is independently unsubstituted methylene.

[0287] In some embodiments, L 1E is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1E is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1E is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 1E is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 1E is independently a substituted 2- to 25-membered heteroalkylene. 1E is independently unsubstituted 2- to 25-membered heteroalkylene. 1E is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 1E is independently a substituted 2- to 20-membered heteroalkylene. 1E is independently unsubstituted 2- to 20-membered heteroalkylene. 1E is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 1Eis independently a substituted 2- to 12-membered heteroalkylene. 1E is independently unsubstituted 2- to 12-membered heteroalkylene. 1E is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 1E is independently a substituted 2-8 membered heteroalkylene. 1E is independently unsubstituted 2-8 membered heteroalkylene. 1E is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 1E is independently a substituted 2- to 6-membered heteroalkylene. 1E is independently unsubstituted 2- to 6-membered heteroalkylene. 1E is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 1E is independently a substituted 4- to 6-membered heteroalkylene. 1E is independently unsubstituted 4- to 6-membered heteroalkylene. 1E is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 1E is independently a substituted 2-3 membered heteroalkylene. 1E is independently unsubstituted 2-3 membered heteroalkylene. 1E is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 1E is independently a substituted 4- to 5-membered heteroalkylene. 1E is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0288] In some embodiments, L 1E are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1E are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1E are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 1E are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 1E are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 1E are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 1E is independently a substituted or unsubstituted C3-C8 cycloalkylene. 1E is independently a substituted C3-C8 cycloalkylene. 1E is independently an unsubstituted C3-C8 cycloalkylene. 1E is independently a substituted or unsubstituted C3-C6 cycloalkylene. 1E is independently a substituted C3-C6 cycloalkylene. 1E is independently an unsubstituted C3-C6 cycloalkylene. 1E is independently a substituted or unsubstituted C4-C6 cycloalkylene. 1E is independently a substituted C4-C6 cycloalkylene. 1E is independently an unsubstituted C4-C6 cycloalkylene. 1E is independently a substituted or unsubstituted C5-C6 cycloalkylene. 1Eis independently a substituted C5-C6 cycloalkylene. 1E is independently an unsubstituted C5-C6 cycloalkylene. 1E is independently substituted or unsubstituted hexylene. 1E is independently a substituted hexylene. 1E is independently unsubstituted hexylene.

[0289] In some embodiments, L 1E is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1E is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1E is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 1E is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 1E is independently a substituted 3- to 10-membered heterocycloalkylene. 1E is independently unsubstituted 3- to 10-membered heterocycloalkylene. 1E is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 1E is independently a substituted 3- to 8-membered heterocycloalkylene. 1E is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 1E is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 1E is independently a substituted 3- to 6-membered heterocycloalkylene.1E is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 1E is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 1E is independently a substituted 4- to 6-membered heterocycloalkylene. 1E is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 1E is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 1E is independently a substituted 4- to 5-membered heterocycloalkylene. 1E is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 1E is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 1E is independently a substituted 5- to 6-membered heterocycloalkylene. 1E is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0290] In some embodiments, L 1E is independently substituted or unsubstituted arylene. In some embodiments, L 1E are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1E are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1E are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 1E are independently substituted or unsubstituted C-C 12 In some embodiments, L1E are independently substituted C6 to C 12 In some embodiments, L 1E are independently unsubstituted C6-C 12 In some embodiments, L 1E are independently substituted or unsubstituted C-C 10 In some embodiments, L 1E are independently substituted C6 to C 10 In some embodiments, L 1E are independently unsubstituted C6-C 10 In some embodiments, L 1E is independently substituted or unsubstituted phenylene. 1E is independently substituted phenylene. In embodiments, L 1E is independently unsubstituted phenylene. In embodiments, L 1E is independently substituted or unsubstituted biphenylene. 1E is independently substituted biphenylene. In embodiments, L 1E is independently unsubstituted biphenylene. In some embodiments, L 1E is independently substituted or unsubstituted naphthylene. 1E is independently a substituted naphthylene. 1E is independently unsubstituted naphthylene.

[0291] In some embodiments, L 1E is independently substituted or unsubstituted heteroarylene. In some embodiments, L 1E is independently substituted heteroarylene. In some embodiments, L 1E is independently unsubstituted heteroarylene. In some embodiments, L 1E is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).1E is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1E is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1E is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 1E is independently a substituted 5- to 12-membered heteroarylene. 1E is independently unsubstituted 5- to 12-membered heteroarylene. 1E is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 1E is independently a substituted 5- to 10-membered heteroarylene. 1E is independently unsubstituted 5- to 10-membered heteroarylene. 1E is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 1E is independently a substituted 5- to 9-membered heteroarylene. 1E is independently an unsubstituted 5- to 9-membered heteroarylene. 1E is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 1E is independently a substituted 5- to 6-membered heteroarylene. 1E are independently unsubstituted 5- to 6-membered heteroarylene.

[0292] In some embodiments, L 1 independently, -L 11 -NH-C(O)- or -L 11 -C(O)-NH-, and L 11 are independently substituted or unsubstituted C1-C 20It is alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene.

[0293] In some embodiments, L 11 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 11 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 11 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 11 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 11 are independently substituted C1 to C 20 In some embodiments, L 11 are independently unsubstituted C1 to C 20 In some embodiments, L 11 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 11 are independently substituted C1 to C 12 In some embodiments, L 11 are independently unsubstituted C1 to C 12 In some embodiments, L 11 is independently a substituted or unsubstituted C1-C8 alkylene. 11 is independently a substituted C1-C8 alkylene. 11 is independently an unsubstituted C1-C8 alkylene. 11is independently a substituted or unsubstituted C1-C6 alkylene. 11 is independently a substituted C1-C6 alkylene. 11 is independently an unsubstituted C1-C6 alkylene. 11 is independently a substituted or unsubstituted C1-C4 alkylene. 11 is independently a substituted C1-C4 alkylene. 11 is independently an unsubstituted C1-C4 alkylene. 11 is independently substituted or unsubstituted ethylene. 11 is independently a substituted ethylene. 11 is independently unsubstituted ethylene. In embodiments, L 11 is independently substituted or unsubstituted methylene. 11 is independently substituted methylene. 11 is independently unsubstituted methylene.

[0294] In some embodiments, L 11 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 11 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 11 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 11 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 11 is independently a substituted 2- to 20-membered heteroalkylene. 11is independently unsubstituted 2- to 20-membered heteroalkylene. 11 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 11 is independently a substituted 2- to 12-membered heteroalkylene. 11 is independently unsubstituted 2- to 12-membered heteroalkylene. 11 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 11 is independently a substituted 2-8 membered heteroalkylene. 11 is independently unsubstituted 2-8 membered heteroalkylene. 11 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 11 is independently a substituted 2- to 6-membered heteroalkylene. 11 is independently unsubstituted 2- to 6-membered heteroalkylene. 11 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 11 is independently a substituted 4- to 6-membered heteroalkylene. 11 is independently unsubstituted 4- to 6-membered heteroalkylene. 11 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 11 is independently a substituted 2-3 membered heteroalkylene. 11 is independently unsubstituted 2-3 membered heteroalkylene. 11 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 11 is independently a substituted 4- to 5-membered heteroalkylene. 11 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0295] In some embodiments, L 11 is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 11 is independently substituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 11 is independently unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 11 is independently substituted or unsubstituted 2- to 20-membered heteroalkenylene. 11 is independently a substituted 2- to 20-membered heteroalkenylene. 11 is independently unsubstituted 2- to 20-membered heteroalkenylene. 11 is independently substituted or unsubstituted 2- to 12-membered heteroalkenylene. 11 is independently a substituted 2- to 12-membered heteroalkenylene. 11 is independently unsubstituted 2- to 12-membered heteroalkenylene. 11 is independently substituted or unsubstituted 2-8 membered heteroalkenylene. 11 is independently a substituted 2-8 membered heteroalkenylene. 11 is independently unsubstituted 2-8 membered heteroalkenylene. 11 is independently substituted or unsubstituted 2- to 6-membered heteroalkenylene. 11 is independently a substituted 2- to 6-membered heteroalkenylene. 11 is independently unsubstituted 2- to 6-membered heteroalkenylene. 11is independently substituted or unsubstituted 4- to 6-membered heteroalkenylene. 11 is independently a substituted 4- to 6-membered heteroalkenylene. 11 is independently unsubstituted 4- to 6-membered heteroalkenylene. 11 is independently substituted or unsubstituted 2-3 membered heteroalkenylene. 11 is independently a substituted 2-3 membered heteroalkenylene. 11 is independently unsubstituted 2-3 membered heteroalkenylene. 11 is independently substituted or unsubstituted 4- to 5-membered heteroalkenylene. 11 is independently a substituted 4- to 5-membered heteroalkenylene. 11 are independently unsubstituted 4- to 5-membered heteroalkenylene.

[0296] In some embodiments, L 1 independently -L 11 In some embodiments, L 1 independently -L 11 In some embodiments, L 11 is a substituted or unsubstituted C1-C8 alkylene. 11 is a substituted C1-C8 alkylene. 11 is unsubstituted C1-C8 alkylene.

[0297] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] is.

[0298] In some embodiments, L 1 are independent, combined, [ka] In some embodiments, L 1 is independently a bond. 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] In some embodiments, L 1 is, independently, [ka] is.

[0299] In some embodiments, L 2 is independently -NHC(O)-, -C(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 2 is independently —NHC(O)—. In some embodiments, L 2 is independently —C(O)NH—. In embodiments, L 2 is substituted or unsubstituted alkylene. In some embodiments, L 2 is a substituted or unsubstituted heteroalkylene.

[0300] In some embodiments, L 2 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2are independently substituted or unsubstituted C1-C 20 In some embodiments, L 2 are independently substituted C1 to C 20 In some embodiments, L 2 are independently unsubstituted C1 to C 20 In some embodiments, L 2 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 2 are independently substituted C1 to C 12 In some embodiments, L 2 are independently unsubstituted C1 to C 12 In some embodiments, L 2 is independently a substituted or unsubstituted C1-C8 alkylene. 2 is independently a substituted C1-C8 alkylene. 2 is independently an unsubstituted C1-C8 alkylene. 2 is independently a substituted or unsubstituted C1-C6 alkylene. 2 is independently a substituted C1-C6 alkylene. 2 is independently an unsubstituted C1-C6 alkylene. 2 is independently a substituted or unsubstituted C1-C4 alkylene. 2 is independently a substituted C1-C4 alkylene. 2 is independently an unsubstituted C1-C4 alkylene. 2 is independently substituted or unsubstituted ethylene. 2 is independently a substituted ethylene. 2 is independently unsubstituted ethylene. In embodiments, L 2is independently substituted or unsubstituted methylene. 2 is independently substituted methylene. 2 is independently unsubstituted methylene.

[0301] In some embodiments, L 2 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2 is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2 is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2 is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2 is independently a substituted 2- to 25-membered heteroalkylene. 2 is independently unsubstituted 2- to 25-membered heteroalkylene. 2 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2 is independently a substituted 2- to 20-membered heteroalkylene. 2 is independently unsubstituted 2- to 20-membered heteroalkylene. 2 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 2 is independently a substituted 2- to 12-membered heteroalkylene. 2 is independently unsubstituted 2- to 12-membered heteroalkylene. 2 is independently a substituted or unsubstituted 2-8 membered heteroalkylene.2 is independently a substituted 2-8 membered heteroalkylene. 2 is independently unsubstituted 2-8 membered heteroalkylene. 2 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 2 is independently a substituted 2- to 6-membered heteroalkylene. 2 is independently unsubstituted 2- to 6-membered heteroalkylene. 2 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 2 is independently a substituted 4- to 6-membered heteroalkylene. 2 is independently unsubstituted 4- to 6-membered heteroalkylene. 2 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 2 is independently a substituted 2-3 membered heteroalkylene. 2 is independently unsubstituted 2-3 membered heteroalkylene. 2 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 2 is independently a substituted 4- to 5-membered heteroalkylene. 2 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0302] In some embodiments, L 2 L 2A -L 2B -L 2C -L 2D -L 2E In some embodiments, L 2A are independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L 2Bare independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene; L 2C are independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene; L 2D are independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene; L 2E is independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0303] In some embodiments, L 2A is independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 2B is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene. 2C is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene. 2D is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene. 2E is independently a bond, —NHC(O)—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0304] In some embodiments, L 2A are independently a bond, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2- to 8-membered heteroalkylene; L 2Bare independently a bond, -O-, -NHC(O)-, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2- to 8-membered heteroalkylene, or substituted or unsubstituted phenylene; L 2C are independently a bond, -O-, -NHC(O)-, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C2-C8 alkynylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene; L 2D are independently a bond, -O-, -NHC(O)-, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2- to 8-membered heteroalkylene, or substituted or unsubstituted phenylene; L 2E is independently a bond, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2-8 membered heteroalkylene. 2A is independently a bond, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, or substituted or unsubstituted 2-8 membered heteroalkylene. 2B is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene. 2C is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C2-C8 alkynylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene. 2D is independently a bond, —O—, —NHC(O)—, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2-8 membered heteroalkylene, or substituted or unsubstituted phenylene. 2E are independently a bond, -NHC(O)-, substituted or unsubstituted C1 to C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.

[0305] In some embodiments, L 2Aare independently unsubstituted C1-C8 alkylene or unsubstituted 2-8 membered heteroalkylene; L 2B are independently a bond, -O-, -NHC(O)-, unsubstituted C1-C8 alkylene, unsubstituted C2-C8 alkynylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene; L 2C are independently a bond, -O-, -NHC(O)-, unsubstituted C1-C8 alkylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene; L 2D are independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, or unsubstituted 2-8 membered heteroalkylene; L 2E are independently -NHC(O)-.

[0306] In some embodiments, L 2A is independently an unsubstituted C1-C8 alkylene or an unsubstituted 2-8 membered heteroalkylene. 2B is independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, unsubstituted C2-C8 alkynylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene. 2C is independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, unsubstituted 2-8 membered heteroalkylene, or unsubstituted phenylene. 2D is independently a bond, —O—, —NHC(O)—, unsubstituted C1-C8 alkylene, or unsubstituted 2-8 membered heteroalkylene. 2E are independently -NHC(O)-.

[0307] In some embodiments, L 2A is independently a bond. 2A is independently —NH—. In some embodiments, L 2A is independently —O—. In some embodiments, L 2A is independently -S-. In some embodiments, L 2Ais independently —C(O)—. In some embodiments, L 2A is independently —NHC(O)—. In some embodiments, L 2A is independently —S(O)C(O)—. In embodiments, L 2A is independently -OPO2-O-. In some embodiments, L 2A is independently -OP(S)(O)-O-. In embodiments, L 2A is independently -OP(S)-O-. In some embodiments, L 2A is independently —S(O)NH—. In some embodiments, L 2A is independently —NHC(O)NH—. In some embodiments, L 2A is independently —C(O)O—. In embodiments, L 2A is independently —OC(O)—. In some embodiments, L 2A is independently —C(O)NH—. In embodiments, L 2A is not a bond.

[0308] In some embodiments, L 2A are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2A are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2A are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2A are independently substituted or unsubstituted C1-C 25In some embodiments, L 2A are independently substituted C1 to C 25 In some embodiments, L 2A are independently unsubstituted C1 to C 25 In some embodiments, L 2A are independently substituted or unsubstituted C1-C 20 In some embodiments, L 2A are independently substituted C1 to C 20 In some embodiments, L 2A are independently unsubstituted C1 to C 20 In some embodiments, L 2A are independently substituted or unsubstituted C1-C 12 In some embodiments, L 2A are independently substituted C1 to C 12 In some embodiments, L 2A are independently unsubstituted C1 to C 12 In some embodiments, L 2A is independently a substituted or unsubstituted C1-C8 alkylene. 2A is independently a substituted C1-C8 alkylene. 2A is independently an unsubstituted C1-C8 alkylene. 2A is independently a substituted or unsubstituted C1-C6 alkylene. 2A is independently a substituted C1-C6 alkylene. 2A is independently an unsubstituted C1-C6 alkylene. 2A is independently a substituted or unsubstituted C1-C4 alkylene. 2A is independently a substituted C1-C4 alkylene. 2A is independently an unsubstituted C1-C4 alkylene. 2Ais independently substituted or unsubstituted ethylene. 2A is independently a substituted ethylene. 2A is independently unsubstituted ethylene. In embodiments, L 2A is independently substituted or unsubstituted methylene. 2A is independently substituted methylene. 2A is independently unsubstituted methylene.

[0309] In some embodiments, L 2A is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2A is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2A is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2A is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2A is independently a substituted 2- to 25-membered heteroalkylene. 2A is independently unsubstituted 2- to 25-membered heteroalkylene. 2A is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2A is independently a substituted 2- to 20-membered heteroalkylene. 2A is independently unsubstituted 2- to 20-membered heteroalkylene. 2A is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 2Ais independently a substituted 2- to 12-membered heteroalkylene. 2A is independently unsubstituted 2- to 12-membered heteroalkylene. 2A is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 2A is independently a substituted 2-8 membered heteroalkylene. 2A is independently unsubstituted 2-8 membered heteroalkylene. 2A is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 2A is independently a substituted 2- to 6-membered heteroalkylene. 2A is independently unsubstituted 2- to 6-membered heteroalkylene. 2A is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 2A is independently a substituted 4- to 6-membered heteroalkylene. 2A is independently unsubstituted 4- to 6-membered heteroalkylene. 2A is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 2A is independently a substituted 2-3 membered heteroalkylene. 2A is independently unsubstituted 2-3 membered heteroalkylene. 2A is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 2A is independently a substituted 4- to 5-membered heteroalkylene. 2A is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0310] In some embodiments, L 2A are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2A are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2A are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2A are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 2A are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 2A are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 2A is independently a substituted or unsubstituted C3-C8 cycloalkylene. 2A is independently a substituted C3-C8 cycloalkylene. 2A is independently an unsubstituted C3-C8 cycloalkylene. 2A is independently a substituted or unsubstituted C3-C6 cycloalkylene. 2A is independently a substituted C3-C6 cycloalkylene. 2A is independently an unsubstituted C3-C6 cycloalkylene. 2A is independently a substituted or unsubstituted C4-C6 cycloalkylene. 2A is independently a substituted C4-C6 cycloalkylene. 2A is independently an unsubstituted C4-C6 cycloalkylene. 2A is independently a substituted or unsubstituted C5-C6 cycloalkylene. 2Ais independently a substituted C5-C6 cycloalkylene. 2A is independently an unsubstituted C5-C6 cycloalkylene. 2A is independently substituted or unsubstituted hexylene. 2A is independently a substituted hexylene. 2A is independently unsubstituted hexylene.

[0311] In some embodiments, L 2A is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2A is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2A is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2A is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 2A is independently a substituted 3- to 10-membered heterocycloalkylene. 2A is independently unsubstituted 3- to 10-membered heterocycloalkylene. 2A is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 2A is independently a substituted 3- to 8-membered heterocycloalkylene. 2A is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 2A is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 2A is independently a substituted 3- to 6-membered heterocycloalkylene.2A is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 2A is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 2A is independently a substituted 4- to 6-membered heterocycloalkylene. 2A is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 2A is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 2A is independently a substituted 4- to 5-membered heterocycloalkylene. 2A is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 2A is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 2A is independently a substituted 5- to 6-membered heterocycloalkylene. 2A is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0312] In some embodiments, L 2A is independently substituted or unsubstituted arylene. In some embodiments, L 2A are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2A are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2A are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2A are independently substituted or unsubstituted C-C 12 In some embodiments, L2A are independently substituted C6 to C 12 In some embodiments, L 2A are independently unsubstituted C6-C 12 In some embodiments, L 2A are independently substituted or unsubstituted C-C 10 In some embodiments, L 2A are independently substituted C6 to C 10 In some embodiments, L 2A are independently unsubstituted C6-C 10 In some embodiments, L 2A is independently substituted or unsubstituted phenylene. 2A is independently substituted phenylene. In embodiments, L 2A is independently unsubstituted phenylene. In embodiments, L 2A is independently substituted or unsubstituted biphenylene. 2A is independently substituted biphenylene. In embodiments, L 2A is independently unsubstituted biphenylene. In some embodiments, L 2A is independently substituted or unsubstituted naphthylene. 2A is independently a substituted naphthylene. 2A is independently unsubstituted naphthylene.

[0313] In some embodiments, L 2A is independently substituted or unsubstituted heteroarylene. In some embodiments, L 2A is independently substituted heteroarylene. In some embodiments, L 2A is independently unsubstituted heteroarylene. In some embodiments, L 2A is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).2A is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2A is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2A is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 2A is independently a substituted 5- to 12-membered heteroarylene. 2A is independently unsubstituted 5- to 12-membered heteroarylene. 2A is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 2A is independently a substituted 5- to 10-membered heteroarylene. 2A is independently unsubstituted 5- to 10-membered heteroarylene. 2A is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 2A is independently a substituted 5- to 9-membered heteroarylene. 2A is independently an unsubstituted 5- to 9-membered heteroarylene. 2A is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 2A is independently a substituted 5- to 6-membered heteroarylene. 2A are independently unsubstituted 5- to 6-membered heteroarylene.

[0314] In some embodiments, L 2B is independently a bond. 2B is independently —NH—. In some embodiments, L 2B is independently —O—. In some embodiments, L 2B is independently -S-. In some embodiments, L 2Bis independently —C(O)—. In some embodiments, L 2B is independently —NHC(O)—. In some embodiments, L 2B is independently —S(O)C(O)—. In embodiments, L 2B is independently -OPO2-O-. In some embodiments, L 2B is independently -OP(S)(O)-O-. In embodiments, L 2B is independently -OP(S)-O-. In some embodiments, L 2B is independently —S(O)NH—. In some embodiments, L 2B is independently —NHC(O)NH—. In some embodiments, L 2B is independently —C(O)O—. In embodiments, L 2B is independently —OC(O)—. In some embodiments, L 2B is independently —C(O)NH—. In embodiments, L 2B is not a bond.

[0315] In some embodiments, L 2B are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2B are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2B are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2B are independently substituted or unsubstituted C1-C 25In some embodiments, L 2B are independently substituted C1 to C 25 In some embodiments, L 2B are independently unsubstituted C1 to C 25 In some embodiments, L 2B are independently substituted or unsubstituted C1-C 20 In some embodiments, L 2B are independently substituted C1 to C 20 In some embodiments, L 2B are independently unsubstituted C1 to C 20 In some embodiments, L 2B are independently substituted or unsubstituted C1-C 12 In some embodiments, L 2B are independently substituted C1 to C 12 In some embodiments, L 2B are independently unsubstituted C1 to C 12 In some embodiments, L 2B is independently a substituted or unsubstituted C1-C8 alkylene. 2B is independently a substituted C1-C8 alkylene. 2B is independently an unsubstituted C1-C8 alkylene. 2B is independently a substituted or unsubstituted C1-C6 alkylene. 2B is independently a substituted C1-C6 alkylene. 2B is independently an unsubstituted C1-C6 alkylene. 2B is independently a substituted or unsubstituted C1-C4 alkylene. 2B is independently a substituted C1-C4 alkylene. 2B is independently an unsubstituted C1-C4 alkylene. 2Bis independently substituted or unsubstituted ethylene. 2B is independently a substituted ethylene. 2B is independently unsubstituted ethylene. In embodiments, L 2B is independently substituted or unsubstituted methylene. 2B is independently substituted methylene. 2B is independently unsubstituted methylene.

[0316] In some embodiments, L 2B is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2B is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2B is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2B is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2B is independently a substituted 2- to 25-membered heteroalkylene. 2B is independently unsubstituted 2- to 25-membered heteroalkylene. 2B is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2B is independently a substituted 2- to 20-membered heteroalkylene. 2B is independently unsubstituted 2- to 20-membered heteroalkylene. 2B is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 2Bis independently a substituted 2- to 12-membered heteroalkylene. 2B is independently unsubstituted 2- to 12-membered heteroalkylene. 2B is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 2B is independently a substituted 2-8 membered heteroalkylene. 2B is independently unsubstituted 2-8 membered heteroalkylene. 2B is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 2B is independently a substituted 2- to 6-membered heteroalkylene. 2B is independently unsubstituted 2- to 6-membered heteroalkylene. 2B is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 2B is independently a substituted 4- to 6-membered heteroalkylene. 2B is independently unsubstituted 4- to 6-membered heteroalkylene. 2B is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 2B is independently a substituted 2-3 membered heteroalkylene. 2B is independently unsubstituted 2-3 membered heteroalkylene. 2B is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 2B is independently a substituted 4- to 5-membered heteroalkylene. 2B is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0317] In some embodiments, L 2B are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2B are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2B are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2B are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 2B are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 2B are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 2B is independently a substituted or unsubstituted C3-C8 cycloalkylene. 2B is independently a substituted C3-C8 cycloalkylene. 2B is independently an unsubstituted C3-C8 cycloalkylene. 2B is independently a substituted or unsubstituted C3-C6 cycloalkylene. 2B is independently a substituted C3-C6 cycloalkylene. 2B is independently an unsubstituted C3-C6 cycloalkylene. 2B is independently a substituted or unsubstituted C4-C6 cycloalkylene. 2B is independently a substituted C4-C6 cycloalkylene. 2B is independently an unsubstituted C4-C6 cycloalkylene. 2B is independently a substituted or unsubstituted C5-C6 cycloalkylene. 2Bis independently a substituted C5-C6 cycloalkylene. 2B is independently an unsubstituted C5-C6 cycloalkylene. 2B is independently substituted or unsubstituted hexylene. 2B is independently a substituted hexylene. 2B is independently unsubstituted hexylene.

[0318] In some embodiments, L 2B is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2B is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2B is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2B is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 2B is independently a substituted 3- to 10-membered heterocycloalkylene. 2B is independently unsubstituted 3- to 10-membered heterocycloalkylene. 2B is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 2B is independently a substituted 3- to 8-membered heterocycloalkylene. 2B is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 2B is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 2B is independently a substituted 3- to 6-membered heterocycloalkylene.2B is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 2B is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 2B is independently a substituted 4- to 6-membered heterocycloalkylene. 2B is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 2B is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 2B is independently a substituted 4- to 5-membered heterocycloalkylene. 2B is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 2B is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 2B is independently a substituted 5- to 6-membered heterocycloalkylene. 2B is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0319] In some embodiments, L 2B is independently substituted or unsubstituted arylene. In some embodiments, L 2B are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2B are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2B are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2B are independently substituted or unsubstituted C-C 12 In some embodiments, L2B are independently substituted C6 to C 12 In some embodiments, L 2B are independently unsubstituted C6-C 12 In some embodiments, L 2B are independently substituted or unsubstituted C-C 10 In some embodiments, L 2B are independently substituted C6 to C 10 In some embodiments, L 2B are independently unsubstituted C6-C 10 In some embodiments, L 2B is independently substituted or unsubstituted phenylene. 2B is independently substituted phenylene. In embodiments, L 2B is independently unsubstituted phenylene. In embodiments, L 2B is independently substituted or unsubstituted biphenylene. 2B is independently substituted biphenylene. In embodiments, L 2B is independently unsubstituted biphenylene. In some embodiments, L 2B is independently substituted or unsubstituted naphthylene. 2B is independently a substituted naphthylene. 2B is independently unsubstituted naphthylene.

[0320] In some embodiments, L 2B is independently substituted or unsubstituted heteroarylene. In some embodiments, L 2B is independently substituted heteroarylene. In some embodiments, L 2B is independently unsubstituted heteroarylene. In some embodiments, L 2B is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).2B is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2B is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2B is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 2B is independently a substituted 5- to 12-membered heteroarylene. 2B is independently unsubstituted 5- to 12-membered heteroarylene. 2B is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 2B is independently a substituted 5- to 10-membered heteroarylene. 2B is independently unsubstituted 5- to 10-membered heteroarylene. 2B is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 2B is independently a substituted 5- to 9-membered heteroarylene. 2B is independently an unsubstituted 5- to 9-membered heteroarylene. 2B is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 2B is independently a substituted 5- to 6-membered heteroarylene. 2B are independently unsubstituted 5- to 6-membered heteroarylene.

[0321] In some embodiments, L 2C is independently a bond. 2C is independently —NH—. In some embodiments, L 2C is independently —O—. In some embodiments, L 2C is independently -S-. In some embodiments, L 2Cis independently —C(O)—. In some embodiments, L 2C is independently —NHC(O)—. In some embodiments, L 2C is independently —S(O)C(O)—. In embodiments, L 2C is independently -OPO2-O-. In some embodiments, L 2C is independently -OP(S)(O)-O-. In embodiments, L 2C is independently -OP(S)-O-. In some embodiments, L 2C is independently —S(O)NH—. In some embodiments, L 2C is independently —NHC(O)NH—. In some embodiments, L 2C is independently —C(O)O—. In embodiments, L 2C is independently —OC(O)—. In some embodiments, L 2C is independently —C(O)NH—. In embodiments, L 2C is not a bond.

[0322] In some embodiments, L 2C are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2C are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2C are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2C are independently substituted or unsubstituted C1-C 25In some embodiments, L 2C are independently substituted C1 to C 25 In some embodiments, L 2C are independently unsubstituted C1 to C 25 In some embodiments, L 2C are independently substituted or unsubstituted C1-C 20 In some embodiments, L 2C are independently substituted C1 to C 20 In some embodiments, L 2C are independently unsubstituted C1 to C 20 In some embodiments, L 2C are independently substituted or unsubstituted C1-C 12 In some embodiments, L 2C are independently substituted C1 to C 12 In some embodiments, L 2C are independently unsubstituted C1 to C 12 In some embodiments, L 2C is independently a substituted or unsubstituted C1-C8 alkylene. 2C is independently a substituted C1-C8 alkylene. 2C is independently an unsubstituted C1-C8 alkylene. 2C is independently a substituted or unsubstituted C1-C6 alkylene. 2C is independently a substituted C1-C6 alkylene. 2C is independently an unsubstituted C1-C6 alkylene. 2C is independently a substituted or unsubstituted C1-C4 alkylene. 2C is independently a substituted C1-C4 alkylene. 2C is independently an unsubstituted C1-C4 alkylene. 2Cis independently substituted or unsubstituted ethylene. 2C is independently a substituted ethylene. 2C is independently unsubstituted ethylene. In embodiments, L 2C is independently substituted or unsubstituted methylene. 2C is independently substituted methylene. 2C is independently unsubstituted methylene.

[0323] In some embodiments, L 2C is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2C is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2C is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2C is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2C is independently a substituted 2- to 25-membered heteroalkylene. 2C is independently unsubstituted 2- to 25-membered heteroalkylene. 2C is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2C is independently a substituted 2- to 20-membered heteroalkylene. 2C is independently unsubstituted 2- to 20-membered heteroalkylene. 2C is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 2Cis independently a substituted 2- to 12-membered heteroalkylene. 2C is independently unsubstituted 2- to 12-membered heteroalkylene. 2C is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 2C is independently a substituted 2-8 membered heteroalkylene. 2C is independently unsubstituted 2-8 membered heteroalkylene. 2C is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 2C is independently a substituted 2- to 6-membered heteroalkylene. 2C is independently unsubstituted 2- to 6-membered heteroalkylene. 2C is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 2C is independently a substituted 4- to 6-membered heteroalkylene. 2C is independently unsubstituted 4- to 6-membered heteroalkylene. 2C is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 2C is independently a substituted 2-3 membered heteroalkylene. 2C is independently unsubstituted 2-3 membered heteroalkylene. 2C is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 2C is independently a substituted 4- to 5-membered heteroalkylene. 2C is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0324] In some embodiments, L 2C are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2C are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2C are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2C are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 2C are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 2C are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 2C is independently a substituted or unsubstituted C3-C8 cycloalkylene. 2C is independently a substituted C3-C8 cycloalkylene. 2C is independently an unsubstituted C3-C8 cycloalkylene. 2C is independently a substituted or unsubstituted C3-C6 cycloalkylene. 2C is independently a substituted C3-C6 cycloalkylene. 2C is independently an unsubstituted C3-C6 cycloalkylene. 2C is independently a substituted or unsubstituted C4-C6 cycloalkylene. 2C is independently a substituted C4-C6 cycloalkylene. 2C is independently an unsubstituted C4-C6 cycloalkylene. 2C is independently a substituted or unsubstituted C5-C6 cycloalkylene. 2Cis independently a substituted C5-C6 cycloalkylene. 2C is independently an unsubstituted C5-C6 cycloalkylene. 2C is independently substituted or unsubstituted hexylene. 2C is independently a substituted hexylene. 2C is independently unsubstituted hexylene.

[0325] In some embodiments, L 2C is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2C is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2C is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2C is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 2C is independently a substituted 3- to 10-membered heterocycloalkylene. 2C is independently unsubstituted 3- to 10-membered heterocycloalkylene. 2C is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 2C is independently a substituted 3- to 8-membered heterocycloalkylene. 2C is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 2C is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 2C is independently a substituted 3- to 6-membered heterocycloalkylene.2C is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 2C is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 2C is independently a substituted 4- to 6-membered heterocycloalkylene. 2C is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 2C is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 2C is independently a substituted 4- to 5-membered heterocycloalkylene. 2C is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 2C is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 2C is independently a substituted 5- to 6-membered heterocycloalkylene. 2C is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0326] In some embodiments, L 2C is independently substituted or unsubstituted arylene. In some embodiments, L 2C are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2C are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2C are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2C are independently substituted or unsubstituted C-C 12 In some embodiments, L2C are independently substituted C6 to C 12 In some embodiments, L 2C are independently unsubstituted C6-C 12 In some embodiments, L 2C are independently substituted or unsubstituted C-C 10 In some embodiments, L 2C are independently substituted C6 to C 10 In some embodiments, L 2C are independently unsubstituted C6-C 10 In some embodiments, L 2C is independently substituted or unsubstituted phenylene. 2C is independently substituted phenylene. In embodiments, L 2C is independently unsubstituted phenylene. In embodiments, L 2C is independently substituted or unsubstituted biphenylene. 2C is independently substituted biphenylene. In embodiments, L 2C is independently unsubstituted biphenylene. In some embodiments, L 2C is independently substituted or unsubstituted naphthylene. 2C is independently a substituted naphthylene. 2C is independently unsubstituted naphthylene.

[0327] In some embodiments, L 2C is independently substituted or unsubstituted heteroarylene. In some embodiments, L 2C is independently substituted heteroarylene. In some embodiments, L 2C is independently unsubstituted heteroarylene. In some embodiments, L 2C is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).2C is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2C is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2C is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 2C is independently a substituted 5- to 12-membered heteroarylene. 2C is independently unsubstituted 5- to 12-membered heteroarylene. 2C is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 2C is independently a substituted 5- to 10-membered heteroarylene. 2C is independently unsubstituted 5- to 10-membered heteroarylene. 2C is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 2C is independently a substituted 5- to 9-membered heteroarylene. 2C is independently an unsubstituted 5- to 9-membered heteroarylene. 2C is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 2C is independently a substituted 5- to 6-membered heteroarylene. 2C are independently unsubstituted 5- to 6-membered heteroarylene.

[0328] In some embodiments, L 2D is independently a bond. 2D is independently —NH—. In some embodiments, L 2D is independently —O—. In some embodiments, L 2D is independently -S-. In some embodiments, L 2Dis independently —C(O)—. In some embodiments, L 2D is independently —NHC(O)—. In some embodiments, L 2D is independently —S(O)C(O)—. In embodiments, L 2D is independently -OPO2-O-. In some embodiments, L 2D is independently -OP(S)(O)-O-. In embodiments, L 2D is independently -OP(S)-O-. In some embodiments, L 2D is independently —S(O)NH—. In some embodiments, L 2D is independently —NHC(O)NH—. In some embodiments, L 2D is independently —C(O)O—. In embodiments, L 2D is independently —OC(O)—. In some embodiments, L 2D is independently —C(O)NH—. In embodiments, L 2D is not a bond.

[0329] In some embodiments, L 2D are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2D are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2D are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2D are independently substituted or unsubstituted C1-C 25In some embodiments, L 2D are independently substituted C1 to C 25 In some embodiments, L 2D are independently unsubstituted C1 to C 25 In some embodiments, L 2D are independently substituted or unsubstituted C1-C 20 In some embodiments, L 2D are independently substituted C1 to C 20 In some embodiments, L 2D are independently unsubstituted C1 to C 20 In some embodiments, L 2D are independently substituted or unsubstituted C1-C 12 In some embodiments, L 2D are independently substituted C1 to C 12 In some embodiments, L 2D are independently unsubstituted C1 to C 12 In some embodiments, L 2D is independently a substituted or unsubstituted C1-C8 alkylene. 2D is independently a substituted C1-C8 alkylene. 2D is independently an unsubstituted C1-C8 alkylene. 2D is independently a substituted or unsubstituted C1-C6 alkylene. 2D is independently a substituted C1-C6 alkylene. 2D is independently an unsubstituted C1-C6 alkylene. 2D is independently a substituted or unsubstituted C1-C4 alkylene. 2D is independently a substituted C1-C4 alkylene. 2D is independently an unsubstituted C1-C4 alkylene. 2Dis independently substituted or unsubstituted ethylene. 2D is independently a substituted ethylene. 2D is independently unsubstituted ethylene. In embodiments, L 2D is independently substituted or unsubstituted methylene. 2D is independently substituted methylene. 2D is independently unsubstituted methylene.

[0330] In some embodiments, L 2D is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2D is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2D is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2D is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2D is independently a substituted 2- to 25-membered heteroalkylene. 2D is independently unsubstituted 2- to 25-membered heteroalkylene. 2D is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2D is independently a substituted 2- to 20-membered heteroalkylene. 2D is independently unsubstituted 2- to 20-membered heteroalkylene. 2D is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 2Dis independently a substituted 2- to 12-membered heteroalkylene. 2D is independently unsubstituted 2- to 12-membered heteroalkylene. 2D is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 2D is independently a substituted 2-8 membered heteroalkylene. 2D is independently unsubstituted 2-8 membered heteroalkylene. 2D is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 2D is independently a substituted 2- to 6-membered heteroalkylene. 2D is independently unsubstituted 2- to 6-membered heteroalkylene. 2D is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 2D is independently a substituted 4- to 6-membered heteroalkylene. 2D is independently unsubstituted 4- to 6-membered heteroalkylene. 2D is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 2D is independently a substituted 2-3 membered heteroalkylene. 2D is independently unsubstituted 2-3 membered heteroalkylene. 2D is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 2D is independently a substituted 4- to 5-membered heteroalkylene. 2D is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0331] In some embodiments, L 2D are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2D are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2D are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2D are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 2D are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 2D are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 2D is independently a substituted or unsubstituted C3-C8 cycloalkylene. 2D is independently a substituted C3-C8 cycloalkylene. 2D is independently an unsubstituted C3-C8 cycloalkylene. 2D is independently a substituted or unsubstituted C3-C6 cycloalkylene. 2D is independently a substituted C3-C6 cycloalkylene. 2D is independently an unsubstituted C3-C6 cycloalkylene. 2D is independently a substituted or unsubstituted C4-C6 cycloalkylene. 2D is independently a substituted C4-C6 cycloalkylene. 2D is independently an unsubstituted C4-C6 cycloalkylene. 2D is independently a substituted or unsubstituted C5-C6 cycloalkylene. 2Dis independently a substituted C5-C6 cycloalkylene. 2D is independently an unsubstituted C5-C6 cycloalkylene. 2D is independently substituted or unsubstituted hexylene. 2D is independently a substituted hexylene. 2D is independently unsubstituted hexylene.

[0332] In some embodiments, L 2D is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2D is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2D is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2D is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 2D is independently a substituted 3- to 10-membered heterocycloalkylene. 2D is independently unsubstituted 3- to 10-membered heterocycloalkylene. 2D is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 2D is independently a substituted 3- to 8-membered heterocycloalkylene. 2D is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 2D is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 2D is independently a substituted 3- to 6-membered heterocycloalkylene.2D is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 2D is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 2D is independently a substituted 4- to 6-membered heterocycloalkylene. 2D is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 2D is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 2D is independently a substituted 4- to 5-membered heterocycloalkylene. 2D is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 2D is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 2D is independently a substituted 5- to 6-membered heterocycloalkylene. 2D is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0333] In some embodiments, L 2D is independently substituted or unsubstituted arylene. In some embodiments, L 2D are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2D are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2D are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2D are independently substituted or unsubstituted C-C 12 In some embodiments, L2D are independently substituted C6 to C 12 In some embodiments, L 2D are independently unsubstituted C6-C 12 In some embodiments, L 2D are independently substituted or unsubstituted C-C 10 In some embodiments, L 2D are independently substituted C6 to C 10 In some embodiments, L 2D are independently unsubstituted C6-C 10 In some embodiments, L 2D is independently substituted or unsubstituted phenylene. 2D is independently substituted phenylene. In embodiments, L 2D is independently unsubstituted phenylene. In embodiments, L 2D is independently substituted or unsubstituted biphenylene. 2D is independently substituted biphenylene. In embodiments, L 2D is independently unsubstituted biphenylene. In some embodiments, L 2D is independently substituted or unsubstituted naphthylene. 2D is independently a substituted naphthylene. 2D is independently unsubstituted naphthylene.

[0334] In some embodiments, L 2D is independently substituted or unsubstituted heteroarylene. In some embodiments, L 2D is independently substituted heteroarylene. In some embodiments, L 2D is independently unsubstituted heteroarylene. In some embodiments, L 2D is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).2D is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2D is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2D is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 2D is independently a substituted 5- to 12-membered heteroarylene. 2D is independently unsubstituted 5- to 12-membered heteroarylene. 2D is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 2D is independently a substituted 5- to 10-membered heteroarylene. 2D is independently unsubstituted 5- to 10-membered heteroarylene. 2D is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 2D is independently a substituted 5- to 9-membered heteroarylene. 2D is independently an unsubstituted 5- to 9-membered heteroarylene. 2D is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 2D is independently a substituted 5- to 6-membered heteroarylene. 2D are independently unsubstituted 5- to 6-membered heteroarylene.

[0335] In some embodiments, L 2E is independently a bond. 2E is independently —NH—. In some embodiments, L 2E is independently —O—. In some embodiments, L 2E is independently -S-. In some embodiments, L 2Eis independently —C(O)—. In some embodiments, L 2E is independently —NHC(O)—. In some embodiments, L 2E is independently —S(O)C(O)—. In embodiments, L 2E is independently -OPO2-O-. In some embodiments, L 2E is independently -OP(S)(O)-O-. In embodiments, L 2E is independently -OP(S)-O-. In some embodiments, L 2E is independently —S(O)NH—. In some embodiments, L 2E is independently —NHC(O)NH—. In some embodiments, L 2E is independently —C(O)O—. In embodiments, L 2E is independently —OC(O)—. In some embodiments, L 2E is independently —C(O)NH—. In embodiments, L 2E is not a bond.

[0336] In some embodiments, L 2E are independently substituted or unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2E are independently substituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2E are independently unsubstituted alkylene (e.g., C1-C 25 , C1~C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2E are independently substituted or unsubstituted C1-C 25In some embodiments, L 2E are independently substituted C1 to C 25 In some embodiments, L 2E are independently unsubstituted C1 to C 25 In some embodiments, L 2E are independently substituted or unsubstituted C1-C 20 In some embodiments, L 2E are independently substituted C1 to C 20 In some embodiments, L 2E are independently unsubstituted C1 to C 20 In some embodiments, L 2E are independently substituted or unsubstituted C1-C 12 In some embodiments, L 2E are independently substituted C1 to C 12 In some embodiments, L 2E are independently unsubstituted C1 to C 12 In some embodiments, L 2E is independently a substituted or unsubstituted C1-C8 alkylene. 2E is independently a substituted C1-C8 alkylene. 2E is independently an unsubstituted C1-C8 alkylene. 2E is independently a substituted or unsubstituted C1-C6 alkylene. 2E is independently a substituted C1-C6 alkylene. 2E is independently an unsubstituted C1-C6 alkylene. 2E is independently a substituted or unsubstituted C1-C4 alkylene. 2E is independently a substituted C1-C4 alkylene. 2E is independently an unsubstituted C1-C4 alkylene. 2Eis independently substituted or unsubstituted ethylene. 2E is independently a substituted ethylene. 2E is independently unsubstituted ethylene. In embodiments, L 2E is independently substituted or unsubstituted methylene. 2E is independently substituted methylene. 2E is independently unsubstituted methylene.

[0337] In some embodiments, L 2E is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2E is independently a substituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2E is independently unsubstituted heteroalkylene (e.g., 2 to 25-membered, 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 2E is independently a substituted or unsubstituted 2- to 25-membered heteroalkylene. 2E is independently a substituted 2- to 25-membered heteroalkylene. 2E is independently unsubstituted 2- to 25-membered heteroalkylene. 2E is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2E is independently a substituted 2- to 20-membered heteroalkylene. 2E is independently unsubstituted 2- to 20-membered heteroalkylene. 2E is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 2Eis independently a substituted 2- to 12-membered heteroalkylene. 2E is independently unsubstituted 2- to 12-membered heteroalkylene. 2E is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 2E is independently a substituted 2-8 membered heteroalkylene. 2E is independently unsubstituted 2-8 membered heteroalkylene. 2E is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 2E is independently a substituted 2- to 6-membered heteroalkylene. 2E is independently unsubstituted 2- to 6-membered heteroalkylene. 2E is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 2E is independently a substituted 4- to 6-membered heteroalkylene. 2E is independently unsubstituted 4- to 6-membered heteroalkylene. 2E is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 2E is independently a substituted 2-3 membered heteroalkylene. 2E is independently unsubstituted 2-3 membered heteroalkylene. 2E is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 2E is independently a substituted 4- to 5-membered heteroalkylene. 2E is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0338] In some embodiments, L 2E are independently substituted or unsubstituted cyclocycloalkylene (e.g., C to C 10, C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2E are independently substituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2E are independently unsubstituted cyclocycloalkylene (e.g., C to C 10 , C3 to C8, C3 to C6, C4 to C6, or C5 to C6). 2E are independently substituted or unsubstituted C3-C 10 In some embodiments, L is cycloalkylene. 2E are independently substituted C3 to C 10 In some embodiments, L is cycloalkylene. 2E are independently unsubstituted C3 to C 10 In some embodiments, L is cycloalkylene. 2E is independently a substituted or unsubstituted C3-C8 cycloalkylene. 2E is independently a substituted C3-C8 cycloalkylene. 2E is independently an unsubstituted C3-C8 cycloalkylene. 2E is independently a substituted or unsubstituted C3-C6 cycloalkylene. 2E is independently a substituted C3-C6 cycloalkylene. 2E is independently an unsubstituted C3-C6 cycloalkylene. 2E is independently a substituted or unsubstituted C4-C6 cycloalkylene. 2E is independently a substituted C4-C6 cycloalkylene. 2E is independently an unsubstituted C4-C6 cycloalkylene. 2E is independently a substituted or unsubstituted C5-C6 cycloalkylene. 2Eis independently a substituted C5-C6 cycloalkylene. 2E is independently an unsubstituted C5-C6 cycloalkylene. 2E is independently substituted or unsubstituted hexylene. 2E is independently a substituted hexylene. 2E is independently unsubstituted hexylene.

[0339] In some embodiments, L 2E is independently substituted or unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2E is independently a substituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2E is independently unsubstituted heterocycloalkylene (e.g., 3 to 10-membered, 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered). 2E is independently a substituted or unsubstituted 3- to 10-membered heterocycloalkylene. 2E is independently a substituted 3- to 10-membered heterocycloalkylene. 2E is independently unsubstituted 3- to 10-membered heterocycloalkylene. 2E is independently a substituted or unsubstituted 3- to 8-membered heterocycloalkylene. 2E is independently a substituted 3- to 8-membered heterocycloalkylene. 2E is independently an unsubstituted 3- to 8-membered heterocycloalkylene. 2E is independently a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. 2E is independently a substituted 3- to 6-membered heterocycloalkylene.2E is independently an unsubstituted 3- to 6-membered heterocycloalkylene. 2E is independently a substituted or unsubstituted 4- to 6-membered heterocycloalkylene. 2E is independently a substituted 4- to 6-membered heterocycloalkylene. 2E is independently an unsubstituted 4- to 6-membered heterocycloalkylene. 2E is independently a substituted or unsubstituted 4- to 5-membered heterocycloalkylene. 2E is independently a substituted 4- to 5-membered heterocycloalkylene. 2E is independently an unsubstituted 4- to 5-membered heterocycloalkylene. 2E is independently a substituted or unsubstituted 5- to 6-membered heterocycloalkylene. 2E is independently a substituted 5- to 6-membered heterocycloalkylene. 2E is independently an unsubstituted 5- to 6-membered heterocycloalkylene.

[0340] In some embodiments, L 2E is independently substituted or unsubstituted arylene. In some embodiments, L 2E are independently substituted or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2E are independently substituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2E are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 In some embodiments, L 2E are independently substituted or unsubstituted C-C 12 In some embodiments, L2E are independently substituted C6 to C 12 In some embodiments, L 2E are independently unsubstituted C6-C 12 In some embodiments, L 2E are independently substituted or unsubstituted C-C 10 In some embodiments, L 2E are independently substituted C6 to C 10 In some embodiments, L 2E are independently unsubstituted C6-C 10 In some embodiments, L 2E is independently substituted or unsubstituted phenylene. 2E is independently substituted phenylene. In embodiments, L 2E is independently unsubstituted phenylene. In embodiments, L 2E is independently substituted or unsubstituted biphenylene. 2E is independently substituted biphenylene. In embodiments, L 2E is independently unsubstituted biphenylene. In some embodiments, L 2E is independently substituted or unsubstituted naphthylene. 2E is independently a substituted naphthylene. 2E is independently unsubstituted naphthylene.

[0341] In some embodiments, L 2E is independently substituted or unsubstituted heteroarylene. In some embodiments, L 2E is independently substituted heteroarylene. In some embodiments, L 2E is independently unsubstituted heteroarylene. In some embodiments, L 2E is independently substituted or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).2E is independently substituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2E is independently unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 2E is independently a substituted or unsubstituted 5- to 12-membered heteroarylene. 2E is independently a substituted 5- to 12-membered heteroarylene. 2E is independently unsubstituted 5- to 12-membered heteroarylene. 2E is independently a substituted or unsubstituted 5- to 10-membered heteroarylene. 2E is independently a substituted 5- to 10-membered heteroarylene. 2E is independently unsubstituted 5- to 10-membered heteroarylene. 2E is independently a substituted or unsubstituted 5- to 9-membered heteroarylene. 2E is independently a substituted 5- to 9-membered heteroarylene. 2E is independently an unsubstituted 5- to 9-membered heteroarylene. 2E is independently a substituted or unsubstituted 5- to 6-membered heteroarylene. 2E is independently a substituted 5- to 6-membered heteroarylene. 2E are independently unsubstituted 5- to 6-membered heteroarylene.

[0342] In some embodiments, L 2 independently, -L 12 -NH-C(O)- or -L 12 -C(O)-NH-, and L 12 are independently substituted or unsubstituted C1-C 20It is alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene.

[0343] In some embodiments, L 12 are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 12 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 12 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 12 are independently substituted or unsubstituted C1-C 20 In some embodiments, L 12 are independently substituted C1 to C 20 In some embodiments, L 12 are independently unsubstituted C1 to C 20 In some embodiments, L 12 are independently substituted or unsubstituted C1-C 12 In some embodiments, L 12 are independently substituted C1 to C 12 In some embodiments, L 12 are independently unsubstituted C1 to C 12 In some embodiments, L 12 is independently a substituted or unsubstituted C1-C8 alkylene. 12 is independently a substituted C1-C8 alkylene. 12 is independently an unsubstituted C1-C8 alkylene. 12is independently a substituted or unsubstituted C1-C6 alkylene. 12 is independently a substituted C1-C6 alkylene. 12 is independently an unsubstituted C1-C6 alkylene. 12 is independently a substituted or unsubstituted C1-C4 alkylene. 12 is independently a substituted C1-C4 alkylene. 12 is independently an unsubstituted C1-C4 alkylene. 12 is independently substituted or unsubstituted ethylene. 12 is independently a substituted ethylene. 12 is independently unsubstituted ethylene. In embodiments, L 12 is independently substituted or unsubstituted methylene. 12 is independently substituted methylene. 12 is independently unsubstituted methylene.

[0344] In some embodiments, L 12 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 12 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 12 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 12 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 12 is independently a substituted 2- to 20-membered heteroalkylene. 12is independently unsubstituted 2- to 20-membered heteroalkylene. 12 is independently a substituted or unsubstituted 2- to 12-membered heteroalkylene. 12 is independently a substituted 2- to 12-membered heteroalkylene. 12 is independently unsubstituted 2- to 12-membered heteroalkylene. 12 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 12 is independently a substituted 2-8 membered heteroalkylene. 12 is independently unsubstituted 2-8 membered heteroalkylene. 12 is independently a substituted...

Claims

1. The following structure: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, A is a nucleic acid; L 4 independently represents a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, or —OPO; ２ -O-, -OP(S)(O)-O-, -OP(S) ２ -O-, -S(O) ２ 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; L 6 is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O) 2 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; L ５ are independently a bond, 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; L ７ is independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; L １ is independently -L 11 -NH-C(O)- or -L 11 -C(O)-NH-, and L 11 is independently substituted or unsubstituted C 1 -C 20 alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene; L 1 is independently L 1A -L 1B -L 1C -L 1D -L 1E ; L 1A is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 1B is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 1C is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 1D is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 1E is independently —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L ２ is independently -L 12 -NH-C(O)- or -L 12 -C(O)-NH-, and L 12 is independently substituted or unsubstituted C 1 -C 20 alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene; L 2 is independently L 2A -L 2B -L 2C -L 2D -L 2E ; L 2A is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2B is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2C is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2D is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2E is independently —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L ３ is independently -L 13 -NH-C(O)- or -L 13 -C(O)-NH-, and L 13 is independently substituted or unsubstituted C 1 -C 20 alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene; L 3 is independently L 3A -L 3B -L 3C -L 3D -L 3E ; L 3A is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 3B is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 3C is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 3D is independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 3E is independently —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —S(O) 2 C(O)—, —OPO 2 —O—, —OP(S)(O)—O—, —OP(S) 2 —O—, —S(O)NH—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted C 1 -C 25 alkylene, substituted or unsubstituted 2- to 25-membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L １Ａ -L １Ｂ -L １Ｃ -L １Ｄ -L １Ｅ is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; １Ａ , L １Ｂ , L １Ｃ , L １Ｄ or L １Ｅ at least one of is not a bond or substituted or unsubstituted 2- to 25-membered heteroalkylene; L ２Ａ -L ２Ｂ -L ２Ｃ -L ２Ｄ -L ２Ｅ is not a bond, a substituted or unsubstituted alkylene containing a terminal carbon atom, or a substituted or unsubstituted heteroalkylene; ２Ａ , L ２Ｂ , L ２Ｃ , L ２Ｄ or L ２Ｅ at least one of is not a bond or substituted or unsubstituted 2- to 25-membered heteroalkylene; L ３Ａ -L ３Ｂ -L ３Ｃ -L ３Ｄ -L ３Ｅ is not a bond, or a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene containing a terminal carbon atom, and L ３Ａ , L ３Ｂ , L ３Ｃ , L ３Ｄ or L ３Ｅ at least one of is not a bond or substituted or unsubstituted 2- to 25-membered heteroalkylene; R １ , R ２ and R ３ is independently unsubstituted C 7 -C 20 alkyl; t is an integer from 1 to 5, L １ and L ２ is —NH(CO)—, and L ３ and L ７ Ga-(CH ２ ) ４ If -NH(CO)-, then R １ , R ２ and R ３ At least one of １５ Not alkyl; L １ and L ７ is —NH(CO)—, and L ２ and L ３ Ga-(CH ２ ) ４ When —NH(CO)—, R １ , R ２ and R ３ At least one of １５ Non-alkyl compounds.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein t is 1, 2, or 3.

3. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a double-stranded nucleic acid or a single-stranded nucleic acid.

4. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the double-stranded nucleic acid is a small interfering RNA, a small hairpin RNA, or a microRNA mimetic.

5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid of A comprises one or more modified nucleotides.

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid comprises one or more modified sugar moieties, wherein the modified sugar moieties comprise a 2' modification or an unlocked sugar modification.

7. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the 2' modification is selected from a 2'-fluoro modification, a 2'-O-methyl modification, a 2'-O-methoxyethyl, and a bicyclic sugar modification.

8. The bicyclic sugar modification is 4'-CH(CH ３ )-O-2' bond, 4'-(CH ２ ) ２ -O-2' bond, 4'-CH(CH ２ -OMe)-O-2' bond, 4'-CH ２ -N(CH ３ )-O-2' bond, and 4'-CH ２ 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein the bond is selected from the group consisting of --N(H)--O-2'.

9. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid comprises one or more modified internucleotide bonds.

10. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the modified internucleotide linkage is selected from a phosphorothioate linkage and a phosphorodiamidite linkage.

11. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid comprises a hydroxyl group, a phosphate group, or a modified phosphate group.

12. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the modified phosphate group is 5'-(E)-vinylphosphonate.

13. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the nucleic acid is a double-stranded nucleic acid comprising an antisense strand hybridized to a sense strand, and the antisense strand and the sense strand are each independently 15 to 30 nucleotides in length.

14. One L ６ is attached to the 3' carbon of the double-stranded nucleic acid or the single-stranded nucleic acid, and the 3' carbon is the 3' carbon of the 3'-terminal nucleotide, or a pharmaceutically acceptable salt thereof.

15. One L ６ is attached to the 5' carbon of the double-stranded nucleic acid or the single-stranded nucleic acid, and the 5' carbon is the 5' carbon of the 5'-terminal nucleotide, or a pharmaceutically acceptable salt thereof.

16. One L ６ is attached to the 2' carbon of the double-stranded nucleic acid or the single-stranded nucleic acid, or a pharmaceutically acceptable salt thereof.

17. One L ６ is attached to the 2' hydroxy oxygen of the double-stranded nucleic acid or the single-stranded nucleic acid, or a pharmaceutically acceptable salt thereof.

18. One L ６ is bound to a nucleobase of the double-stranded nucleic acid or the single-stranded nucleic acid, or a pharmaceutically acceptable salt thereof.

19. L ４ and L ６ are independently —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, —OPO ２ -O-, -OP(S)(O)-O-, -OP(S) ２ -O-, -S(O) ２ NH-, R ２０ Substituted or unsubstituted C １ ~C ８ alkylene, or R ２０ is a substituted or unsubstituted 2- to 8-membered heteroalkylene; R ２０ are independently oxo, hydroxyl, or substituted or unsubstituted C １ ~C ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

20. L ６ are independently -OPO ２ 2. The compound of claim 1, wherein R is —O—, or a pharmaceutically acceptable salt thereof.

21. L ４ are independently -L １４ -NH-C(O)- or -L １４ —C(O)—NH—, and L １４ are independently substituted or unsubstituted C １ ~C ２０ 2. The compound according to claim 1, which is alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene, or a pharmaceutically acceptable salt thereof.

22. L ５ is a substituted or unsubstituted C １ ~C ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is alkylene, substituted or unsubstituted 2-8 membered heteroalkylene, substituted or unsubstituted C3-C6 cycloalkylene, substituted or unsubstituted 4-6 membered heterocycloalkylene, substituted or unsubstituted phenylene, substituted or unsubstituted 4-6 heteroarylene, or a bond.

23. L ７ are independently substituted or unsubstituted C １ ~C ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 17 is alkylene, substituted or unsubstituted 2- to 8-membered heteroalkylene, a bond, -L 17 -NH-C(O)-, or -L 17 -C(O)-NH-, and L 17 is independently substituted or unsubstituted C 1 -C 20 alkylene, substituted or unsubstituted 2- to 20-membered heteroalkylene, or substituted or unsubstituted 2- to 20-membered heteroalkenylene.

24. L ７ are independently —NHC(O)—, 【Chemistry 2】 2. The compound of claim 1, wherein:

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein -L 6 -L 5 -L 4 - are independently -OPO 2 -O-L 10 -NH-C(O)- or -OPO 2 -O-L 10 -C(O)-NH-, and L 10 is independently substituted or unsubstituted C 1 to C 20 alkylene, or substituted or unsubstituted 2 to 20-membered heteroalkylene.

26. -L ６ -L ５ -L ４ - is independently, 【Transformation 3】 2. The compound of claim 1, wherein:

27. -L ６ -L ５ -L ４ - is independently, 【Chemistry 4】 and attached to the 3' carbon of the double-stranded nucleic acid or the single-stranded nucleic acid, or a pharmaceutically acceptable salt thereof.

28. -L ６ -L ５ -L ４ - is independently, 【Transformation 5】 and attached to the 5' carbon of the double-stranded nucleic acid or the single-stranded nucleic acid, or a pharmaceutically acceptable salt thereof.

29. L １ are independently -NHC(O)-, or a pharmaceutically acceptable salt thereof.

30. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is L 1A -L 1B -L 1C -L 1D -L 1E ; L １Ａ are independently a bond, substituted or unsubstituted C 1 -C 25 alkylene, or substituted or unsubstituted 2- to 25-membered heteroalkylene; L １Ｂ are independently a bond, —NHC(O)—, —C(O)NH—, or substituted or unsubstituted arylene; L １Ｃ are independently a bond, substituted or unsubstituted C 1 -C 25 alkylene, or substituted or unsubstituted arylene; L １Ｄ are independently a bond or substituted or unsubstituted C 1 -C 25 alkylene; L １Ｅ are independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

31. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is L 1A -L 1B -L 1C -L 1D -L 1E ; L １Ａ are independently a bond, substituted or unsubstituted C １ ~C ８ alkylene, or substituted or unsubstituted 2- to 8-membered heteroalkylene; L １Ｂ are independently a bond, —NHC(O)—, —C(O)NH—, or substituted or unsubstituted phenylene; L １Ｃ are independently a bond, substituted or unsubstituted C １ ~C ８ alkylene, or substituted or unsubstituted phenylene; L １Ｄ are independently a bond or a substituted or unsubstituted C １ ~C ８ alkylene; L １Ｅ are independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

32. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 1 is L 1A -L 1B -L 1C -L 1D -L 1E ; L １Ａ are independently a bond; L １Ｂ are independently a bond; L １Ｃ are independently a bond; L １Ｄ are independently a bond; L １Ｅ are independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

33. L １ are independently -L １１ -NH-C(O)- or -L １１ —C(O)—NH—, and L １１ are independently substituted or unsubstituted C １ ~C ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is alkylene.

34. L １ is, independently, 【Transformation 6】 2. The compound of claim 1, wherein:

35. L ２ are independently -NHC(O)-, or a pharmaceutically acceptable salt thereof.

36. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ２ Is, L ２Ａ -L ２Ｂ -L ２Ｃ -L ２Ｄ -L ２Ｅ and L ２Ａ are independently a bond, substituted or unsubstituted C 1 -C 25 alkylene, or substituted or unsubstituted 2- to 25-membered heteroalkylene; L ２Ｂ are independently a bond, —NHC(O)—, —C(O)NH—, or substituted or unsubstituted arylene; L ２Ｃ are independently a bond, substituted or unsubstituted C 1 -C 25 alkylene, or substituted or unsubstituted arylene; L ２Ｄ are independently a bond or substituted or unsubstituted C 1 -C 25 alkylene; L ２Ｅ are independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

37. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ２ Is, L ２Ａ -L ２Ｂ -L ２Ｃ -L ２Ｄ -L ２Ｅ and L ２Ａ are independently a bond, substituted or unsubstituted C １ ~C ８ alkylene, or substituted or unsubstituted 2- to 8-membered heteroalkylene; L ２Ｂ are independently a bond, —NHC(O)—, —C(O)NH—, or substituted or unsubstituted phenylene; L ２Ｃ are independently a bond, substituted or unsubstituted C １ ~C ８ alkylene, or substituted or unsubstituted phenylene; L ２Ｄ are independently a bond, substituted or unsubstituted C １ ~C ８ alkylene; L ２Ｅ are independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

38. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ２ Is, L ２Ａ -L ２Ｂ -L ２Ｃ -L ２Ｄ -L ２Ｅ and L ２Ａ are independently a bond; L ２Ｂ are independently a bond; L ２Ｃ are independently a bond; L ２Ｄ are independently a bond; L ２Ｅ are independently —NHC(O)—.

39. L ２ are independently -L １２ -NH-C(O)- or -L １２ —C(O)—NH—, and L １２ are independently substituted or unsubstituted C １ ~C ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is alkylene.

40. L ２ is, independently, 【Transformation 7】 2. The compound of claim 1, wherein:

41. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 3 is L 3A -L 3B -L 3C -L 3D -L 3E ; L 3A is independently a bond, substituted or unsubstituted C 1 -C 25 alkylene, or substituted or unsubstituted 2- to 25-membered heteroalkylene; L 3B is independently a bond, —NHC(O)—, —C(O)NH—, or substituted or unsubstituted arylene; L 3C is independently a bond, substituted or unsubstituted C 1 -C 25 alkylene, or substituted or unsubstituted arylene; L 3D is independently a bond or substituted or unsubstituted C 1 -C 25 alkylene; A compound in which L 3E is independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

42. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L ３ Is, L ３Ａ -L ３Ｂ -L ３Ｃ -L ３Ｄ -L ３Ｅ and L ３Ａ are independently unsubstituted C １ ~C ８ alkylene, or unsubstituted 2-8 membered heteroalkylene; L ３Ｂ are independently a bond, —NHC(O)—, —C(O)NH—, or unsubstituted phenylene; L ３Ｃ are independently a bond, an unsubstituted C １ ~C ８ alkylene, or unsubstituted phenylene; L ３Ｄ are independently a bond or an unsubstituted C １ ~C ８ alkylene; L ３Ｅ are independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

43. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 3 is L 3A -L 3B -L 3C -L 3D -L 3E ; L 3A is independently unsubstituted C 1 -C 8 alkylene; L 3B is independently a bond; L 3C is independently a bond; L 3D is independently a bond; A compound in which L 3E is independently —NHC(O)—, or a pharmaceutically acceptable salt thereof.

44. L ３ are independently -L １３ -NH-C(O)- or -L １３ —C(O)—NH—, and L １３ are independently substituted or unsubstituted C １ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C 1 -C 8 alkylene.

45. L ３ is, independently, 【Transformation 8】 2. The compound of claim 1, wherein:

46. R １ are independently unsubstituted C １１ ~C １７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, unsubstituted unbranched C 11 -C 17 alkyl, or unsubstituted unbranched saturated C 11 -C 17 alkyl.

47. R ２ are independently unsubstituted C １１ ~C １７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, unsubstituted unbranched C 11 -C 17 alkyl, or unsubstituted unbranched saturated C 11 -C 17 alkyl.

48. R ３ are independently unsubstituted C １１ ~C １７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl, unsubstituted unbranched C 11 -C 17 alkyl, or unsubstituted unbranched saturated C 11 -C 17 alkyl.

49. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 【Chemistry 9】 wherein the wavy line represents -L ６ -L ５ -L ４ or a pharmaceutically acceptable salt thereof.

50. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof.

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