Compounds targeting PMP22 for the treatment of Charcot-Marie-Tooth disease

Abstract

Provided herein are compounds for inhibiting peripheral myelin protein 22 (PMP22) mRNA. Also provided herein are methods of using such compounds for the treatment of Charcot-Marie-Tooth disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 280,773, filed November 18, 2021, the contents of which are incorporated herein in their entirety for all purposes.

[0002] Federally Sponsored Research Statement This invention was made with government support under Grant No. 1R43NS119090-01A1 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Reference to electronic sequence listing The contents of the electronic sequence listing (052974-509001WO_Sequence_Listing_ST26.xml; size: 1,512,837 bytes; created: November 14, 2022) are incorporated herein by reference in their entirety.

[0004] The present disclosure relates to compounds and methods for the treatment of Charcot-Marie-Tooth disease. More particularly, the present disclosure relates to inhibitors of PMP22 and their use in the treatment of Charcot-Marie-Tooth disease. [Background technology]

[0005] Charcot-Marie-Tooth (CMT) disease is a hereditary peripheral neuropathy characterized by slowly progressive muscular atrophy. CMT is one of the most common inherited neuropathies, affecting approximately 150,000 people throughout the United States and Europe. There are several subtypes of CMT disease, each with a different genetic cause. The most common form of CMT, accounting for 60% of cases, is CMT type 1A (CMT1A), which is caused by excess peripheral myelin protein 22 (PMP22) protein due to duplication of one PMP22 allele.

[0006] The PMP22 protein is a major component of myelin, making up 2-5% of myelin and insulating peripheral nerves. While the exact role of PMP22 is unknown, there is evidence that overexpression of PMP22 alters the proliferation and differentiation of Schwann cells, the cells responsible for generating the myelin sheath around nerve cells. The myelin sheath is a protective layer of lipids and proteins that acts as an insulator around nerve axons and promotes their ability to rapidly conduct nerve signals. In addition to causing defects in the ability to generate new myelin, excess PMP22 protein in the myelin sheath has been reported to directly destabilize the sheath, leading to increased rates of demyelination. Defects in the myelin sheath reduce the speed at which nerve signals can propagate along nerves, known as motor nerve conduction velocity (MNCV). This leads to progressive muscular atrophy of the peripheral limbs, resulting in muscle weakness, foot structural abnormalities, and abnormal spinal curvature.

[0007] Overexpression of PMP22 in mice induces characteristic symptoms of CMT1A disease, including muscle weakness, impaired gait, defective myelination, and reduced nerve conduction velocity. Overexpression of PMP22 under the control of a conditionally regulated promoter led to demyelination of neurons, which was reversed upon subsequent suppression of PMP22 expression. Within one week, new myelin formation was observed, and within 12 weeks, myelinated neurons were similar to those present in transgenic mice lacking PMP22 expression.

[0008] Mice with three to four copies of the human PMP22 gene develop pathology similar to that observed in subjects with CMT1A, and therefore these mice are used as an experimental model of CMT1A. In this model, treatment with antisense oligonucleotides complementary to human PMP22 reduced PMP22 mRNA levels, leading to restoration of myelination, improvement in MNCV, and reversal of other neuropathic endpoints. However, the high doses required in mouse models correspond to doses unlikely to be tolerated in human subjects, and therefore antisense oligonucleotides targeted to PMP22 have not progressed to development as a treatment for CMT1A.

[0009] While a few promising therapies have been evaluated in clinical trials, no effective treatment has yet been identified for any CMT disease, including CMT1A. Existing treatments consist of physical therapy, occupational therapy, and orthopedic devices to help patients cope with disabling symptoms, and analgesics for patients with severe pain. Therefore, there remains an unmet medical need for therapeutic agents for the treatment of CMT1A. Summary of the Invention

[0010] Provided herein, inter alia, are nucleic acid compounds targeted to peripheral myelin protein 22 (PMP22) mRNA.

[0011] In embodiments, a compound is provided comprising an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein each of the antisense strand and the sense strand is 15-25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to the nucleotide sequence of PMP22 mRNA (SEQ ID NO: 1170), and the nucleotide sequence of the sense strand has no more than two mismatches with the nucleotide sequence of the antisense strand.

[0012] In embodiments, each of the antisense strand and the sense strand is 15 to 25 nucleotides in length, and the nucleotide sequence of the antisense strand is set forth in SEQ ID NOs: 491, 492, 493, 494, 495, 497, 498, 503, 504, 506, 510, 511, 514, 515, 516, 518, 524, 526, 529, 531, 532, 533, 534, 535, 536, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605 45, 546, 547, 548, 550, 553, 554, 556, 558, 559, 560, 561, 563, 567, 569, 575, 576, 579, 580, 581, 582, 583, 585, 590, 591, 595, 597, 600, 605, 609, 610, 618, 622, 623, 628, 630, 631, 633, 635, 637, 639, 641, 642, 643, 644, 645, 1112, 1113 13, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1122, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 11 and 1144, wherein the nucleotide sequence of the sense strand has no more than two mismatches with the nucleotide sequence of the antisense strand.

[0013] In embodiments, the antisense and sense strands are not covalently linked.

[0014] In embodiments, at least one nucleotide of the antisense strand is a modified nucleotide. In embodiments, at least one nucleotide of the sense strand is a modified nucleotide. In embodiments, the 5'-terminal nucleotide of the antisense strand comprises a 5'-VP modification.

[0015] In an embodiment, the antisense strand is 21 to 23 nucleotides in length. In an embodiment, the sense strand is 21 to 23 nucleotides in length.

[0016] In embodiments, hybridization of the antisense strand to the sense strand forms at least one blunt end. In embodiments, at least one strand comprises a 3' nucleotide overhang of 1 to 5 nucleotides.

[0017] In embodiments, the compound comprises a ligand covalently attached to the antisense or sense strand.

[0018] In embodiments, the compound has the structure: [ka] It has.

[0019] A is a sense strand or an antisense strand, and t is an integer of 1 to 5.

[0020] L 3 and L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25)-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 ) —O—, —SS—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. 23 , R 24 and R 25 are independently hydrogen or unsubstituted C1-C 10 It is alkyl.

[0021] L 5 -L 5A -L 5B -L 5C -L 5D -L 5E -It is. L 6 -L 6A -L 6B -L 6C -L 6D -L 6E -It is. L 5A , L 5B , L 5C , L 5D , L 5E , L 6A , L 6B , L 6C , L 6D , and L 6Eare independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and each R 23 , R 24 and R 25 are independently hydrogen or unsubstituted C1-C 10 It is alkyl.

[0022] R 1 and R 2 are independently unsubstituted C1 to C 25 alkyl, and R 1 and R 2 At least one of the following is unsubstituted C9-C 19 R is alkyl. 3 is hydrogen, —NH, —OH, —SH, —C(O)H, —C(O)NH, —NHC(O)H, —NHC(O)OH, —NHC(O)NH, —C(O)OH, —OC(O)H, —N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0023] In embodiments, provided herein are pharmaceutical compositions comprising compounds as described herein.

[0024] In embodiments, provided herein is a method for inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA in a cell, the method comprising contacting the cell with a compound provided herein, thereby inhibiting expression of PMP22 mRNA in the cell.

[0025] In embodiments, provided herein is a method for inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA in a subject, comprising inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA by administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.

[0026] In embodiments, provided herein are methods for increasing myelination and / or slowing the decline of myelination in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein.

[0027] In embodiments, provided herein are methods for treating Charcot-Marie-Tooth disease (CMT) in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In embodiments, the Charcot-Marie-Tooth disease (CMT) is Charcot-Marie-Tooth type 1A (CMT1A). [Brief explanation of the drawings]

[0028] [Figure 1] 1 shows the mean percent of hPMP22 mRNA remaining in the sciatic and brachial plexus nerves of C3-PMP22 mice after 12 weeks of treatment with 10 mg / kg DT-000812 or 30 mg / kg. [Figure 2] Shown are mean motor nerve conduction velocities (MNCV) in wild-type mice treated with PBS, and C3-PMP22 mice treated with PBS, 10 mg / kg DT-000812, and 30 mg / kg DT-000812 at the indicated time points. [Figure 3-1]Figure 3A shows the average compound muscle action potentials in wild-type mice treated with PBS and C3-PMP22 mice (CMT1A mice) treated with PBS, 10 mg / kg DT-000812, and 30 mg / kg DT-000812 at the indicated time points. Figure 3B shows representative CMAP traces recorded from wild-type mice treated with PBS and C3-PMP22 mice (CMT1A mice) treated with PBS, 10 mg / kg DT-000812, and 30 mg / kg DT-000812 for 12 weeks. [Figure 3-2] (As mentioned above.) [Figure 4] Shown is the average percentage of unmyelinated axons in wild-type mice treated with PBS and C3-PMP22 mice treated with PBS, 10 mg / kg DT-000812, and 30 mg / kg DT-000812 for 12 weeks. [Figure 5] Representative images of nerve cross sections in mice treated with PBS, 10 mg / kg DT-000812, and 30 mg / kg DT-000812 for 12 weeks are shown. [Figure 6] Representative CMAP traces are shown for wild-type mice treated with PBS, and C3-PMP22 mice (CMT1A mice) treated with PBS, 3 mg / kg DT-001252, 10 mg / kg DT-001252, and 30 mg / kg DT-001252 for 12 weeks. The mean CMAP for each treatment group after 12 weeks of treatment is also shown. [Figure 7] Shown is the average percentage of unmyelinated axons in wild-type mice treated with PBS and C3-PMP22 mice (CMT1A mice) treated with PBS, 30 mg / kg DT-000812, 3 mg / kg DT-001252, 10 mg / kg DT-001252, and 30 mg / kg DT-001252 for 12 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0029] 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 documents referenced herein are incorporated by reference in their entirety unless otherwise indicated. Conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed unless otherwise indicated. Furthermore, the use of the terms "including" and other forms such as "include," "includes," and "included" is not intended to be limiting. As used herein, whether in a transitional phrase or in the body of a claim, the terms "comprise(s)" and "comprising" are to be construed as having an open-ended meaning. That is, the 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.

[0030] When substituents are designated in a conventional chemical formula and written from left to right, they equally encompass the chemically identical substituents that would occur if the structure were written from right to left, e.g., -CHO- is equivalent to -OCH-.

[0031] "Charcot-Marie-Tooth disease" or "CMT" refers to a hereditary peripheral neuropathy that affects both motor and sensory nerves. CMT is characterized by muscle weakness and atrophy in the legs and arms, foot deformities, and loss of sensation and / or numbness. CMT disease includes, among others, the CMT1A subtype.

[0032] "Charcot-Marie-Tooth type 1A" or CMT1A refers to a subtype of CMT resulting from a duplication of one PMP22 allele, resulting in three copies of the PMP22 gene in the subject.

[0033] "Nerve conduction velocity" refers to the rate at which an electrical impulse travels through a nerve. In embodiments, the nerve conduction velocity is motor nerve conduction velocity. In embodiments, the nerve conduction velocity is sensory nerve conduction velocity. In embodiments, nerve conduction velocity may be determined by electroneurography, i.e., nerve conduction testing.

[0034] The "compound muscle action potential" is a quantitative measure of the amplitude of the electrical impulse transmitted to a muscle and correlates with the number of muscle fibers that can be activated. In an embodiment, the compound muscle action potential is determined by electromyography (EMG).

[0035] "Ameliorate" means to reduce the severity of symptoms and / or clinical indicators of a disease.

[0036] "Slowing the progression of" means reducing the rate at which symptoms and / or clinical indicators of a disease become more severe.

[0037] "Therapeutically effective amount" means an amount of a compound sufficient to confer a therapeutic effect on a subject.

[0038] As used herein, "subject" means a human or non-human animal selected for treatment or therapy. In embodiments, the subject is a human.

[0039] "Administering" means providing a pharmaceutical agent or pharmaceutical composition to a subject, and includes administration performed by a healthcare professional and self-administration. In embodiments, administering is intravenous administration. In embodiments, administering is subcutaneous administration.

[0040] "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 slowing the progression of at least one clinical indicator and / or symptom of a disease in the subject.

[0041] "Delaying the onset of" means delaying the onset of a condition or disease in a subject at risk of developing the disease or condition. In embodiments, subjects at risk of developing a disease or condition are identified using clinical evaluations similar to those used to diagnose the disease or condition. For example, subjects at risk of developing CMT1A may be identified by genetic testing for amplification of the PMP22 gene. In embodiments, subjects at risk of developing a disease or condition receive treatment similar to that received by subjects already with the disease or condition.

[0042] "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 potency of the compound, the mode of administration, the severity of the disease in the subject, any concomitant medications the subject is receiving, and the subject's characteristics, such as the subject's medical history, age, and weight.

[0043] "Pharmaceutical salt" means a salt form of a compound that retains the biological effectiveness and properties of the compound and does not have undesired effects when administered to a subject.

[0044] "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.

[0045] "Oligonucleotide" means a polymer of linked monomeric nucleotides, one or more of which may be modified nucleotides.

[0046] "Double-stranded nucleic acid" refers to a structure in which a first nucleotide sequence 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 oligonucleotide, which is a complementary oligonucleotide, 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 is long enough and self-complementary to form a duplex structure, as in the case of shRNA.Such double-stranded nucleic acid includes a stem-loop structure.Double-stranded nucleic acid may contain one or more modifications to the naturally occurring termini, sugars, nucleobases, and / or phosphate groups.

[0047] "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 by) 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 include nucleotide overhangs.

[0048] " Antisense strand " refers to the oligonucleotide that is complementary to target RNA (for example, mRNA) and is incorporated into RNA-induced silencing complex (RISC), and induces gene silencing in a sequence-specific manner through RNA interference pathway.Antisense strand can also be referred to as " guide strand ".

[0049] "Sense strand" refers to an oligonucleotide that is complementary to the antisense strand of a double-stranded nucleic acid. The sense strand is usually degraded after the incorporation of the antisense strand into RISC. The sense strand can also be referred to as a "passenger strand."

[0050] "Nucleotide overhang" refers to one or more unpaired nucleotides extending from the double-stranded region of a double-stranded nucleic acid. For example, when 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 nucleotide overhang can be modified nucleotides. The nucleotide overhang can be present in the antisense strand, the sense strand, or both the antisense and sense strands.

[0051] "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., there are no nucleotide overhangs. A double-stranded nucleic acid can have blunt ends at one or both ends.

[0052] "siRNA" refers to a double-stranded nucleic acid formed from separate antisense and sense strands that induces gene silencing in a sequence-specific manner by promoting pre-translational mRNA degradation via the RNA interference pathway. The antisense and sense strands of siRNA are not covalently linked.

[0053] "shRNA" means a double-stranded nucleic acid containing a loop structure that is processed in cells into siRNAs that induce gene silencing in a sequence-specific manner by promoting pre-translational mRNA degradation via the RNA interference pathway.

[0054] " Single-stranded nucleic acid " refers to an antisense strand that does not hybridize with a complementary strand. Single-stranded nucleic acid is incorporated into RISC, which induces gene silencing in a sequence-specific manner by promoting pre-translational mRNA degradation through the RNA interference pathway.

[0055] "Hybridize" means that one nucleotide sequence anneals to another nucleotide sequence based at least in part on the complementarity of the nucleotide sequences. In an embodiment, the antisense strand hybridizes to the sense strand. In an embodiment, the antisense strand hybridizes to the target mRNA sequence.

[0056] "Complementary" means that the nucleobases have the capacity to non-covalently pair through hydrogen bonding.

[0057] "Fully complementary" or "100% complementary" means that each nucleic acid base of a first nucleotide sequence is complementary to each nucleic acid base of a second nucleotide sequence. In an embodiment, the antisense strand is completely complementary to its target mRNA. In an embodiment, the sense strand and the antisense strand of a double-stranded nucleic acid are completely complementary over their entire length. In an embodiment, the sense strand and the antisense strand of a 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 a single-stranded nucleotide.

[0058] "Percent complementarity" refers to the percentage of nucleobases of an oligonucleotide that are complementary to the same length of a target nucleic acid. The percent complementarity is calculated by dividing the number of nucleobases of an oligonucleotide that are complementary to the nucleobases at corresponding positions in the target nucleic acid by the total number of nucleobases in the oligonucleotide.

[0059] "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.

[0060] "Percent identity" means the number of nucleobases in a first nucleotide sequence that are identical to nucleobases at corresponding positions in a second nucleotide sequence, divided by the total number of nucleobases in the first nucleotide sequence.

[0061] "Mismatch" means a nucleobase of a first nucleotide sequence that is unable to form Watson-Crick pairing with a nucleobase at a corresponding position in a second nucleotide sequence.

[0062] "Nucleoside" means 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.

[0063] "Nucleotide" means a nucleoside covalently linked at the 5' carbon of a pentafuranosyl sugar to a phosphate group. The nucleotide can be modified at one or more of the nucleobase, sugar moiety, internucleotide linkage, and / or phosphate group.

[0064] "Nucleobase" refers to a heterocyclic base moiety capable of non-covalent pairing. Nucleobases include pyrimidines and purines. Unless otherwise specified, conventional nucleobase abbreviations are used herein. Nucleobase abbreviations include, but are not limited to, A (adenine), C (cytosine), G (guanine), T (thymine), and U (uracil).

[0065] Unless otherwise indicated, 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.

[0066] "Modified nucleoside" means a nucleoside having one or more modifications relative to a naturally occurring nucleoside. Such modifications 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.

[0067] "Modified nucleotide" means a nucleotide having one or more modifications relative to a naturally occurring nucleotide. The modifications can occur 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 a modified phosphate group.

[0068] "Modified nucleobase" means a nucleobase having one or more alterations relative to a naturally occurring nucleobase.

[0069] By "modified phosphate group" is meant any change from the naturally occurring phosphate group of a nucleotide.

[0070] "Modified internucleotide linkage" means any change from the naturally occurring phosphodiester bond between two nucleotides.

[0071] "Phosphorothioate internucleotide linkage" means a substituted phosphodiester internucleotide linkage in which one of the non-bridging atoms is a sulfur atom.

[0072] "Modified sugar moiety" means a sugar of a nucleotide having any alteration and / or substitution from a naturally occurring sugar moiety.

[0073] "Beta-D-deoxyribonucleoside" refers to the naturally occurring nucleoside monomer of DNA.

[0074] "Beta-D-ribonucleoside" refers to the naturally occurring nucleoside monomer of RNA.

[0075] "2'-O-methyl sugar" or "2'-OMe sugar" means a sugar having an O-CH3 substitution at the 2' position of a pentofuranosyl sugar.

[0076] A "2'-O-methoxyethyl sugar" or "2'-MOE sugar" means a sugar having an OCH2CH2OCH3 substitution at the 2' position of the pentofuranosyl sugar.

[0077] "2'-fluoro sugar" or "2'-F sugar" means a sugar having a fluoro substitution at the 2' position of the pentofuranosyl sugar.

[0078] "Bicyclic sugar" means a modified sugar moiety comprising a bond connecting the 2'-carbon and 4'-carbon of a pentafuranosyl sugar resulting in a bicyclic structure. Non-limiting exemplary bicyclic sugar moieties include LNA, ENA, cEt, S-cEt, and R-cEt.

[0079] "Locked Nucleic Acid (LNA) sugar" means a substituted sugar moiety containing a -CH2-O- linkage between the 4' and 2' furanose ring atoms.

[0080] "ENA sugar" means a substituted sugar moiety containing a -(CH2)2-O- bond between the 4' and 2' furanose ring atoms.

[0081] "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, e.g., a modified nucleobase and / or phosphate group.

[0082] "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, e.g., a modified nucleobase and / or phosphate group.

[0083] "Bicyclic nucleotide" means a nucleotide having a bond connecting the 2'-carbon and the 4'-carbon of a pentafuranosyl sugar. Bicyclic nucleotides can have further modifications in addition to a modified sugar moiety, e.g., a modified nucleobase and / or phosphate group.

[0084] "5'-(E)-vinylphosphonate" or "5'-VP" refers to a compound having the structure: [ka] or a salt thereof, where the wavy line represents the point of attachment to the 5' carbon of the pentafuranosyl sugar of the nucleotide.

[0085] "5-methylcytosine" means a cytosine nucleobase having a 5-methyl substitution on the cytosine ring.

[0086] "Unmethylated cytosine" means a cytosine nucleobase that does not have a methyl substitution at the 5-position of the cytosine ring.

[0087] "5-methyluracil" means a uracil nucleobase having a 5-methyl substitution on the uracil ring. 5-methyluracil nucleobase may also be referred to as thymine.

[0088] "Unmethylated uracil" means a uracil nucleobase that does not have a methyl group substitution at the 5-position of the uracil ring.

[0089] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. Alkyl refers to any group having a specified number of carbons (e.g., C1 to C6). 10 means 1 to 10 carbons). An alkyl is a non-cyclized chain. 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, methyl, homologs and isomers of, for example, 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-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. The alkenyl may contain, in addition to one or more double bonds, two or more double bonds and / or one or more triple bonds. The alkynyl may contain, in addition to one or more triple bonds, two or more triple bonds and / or one or more double bonds.

[0090] The term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring contains a monocyclic cycloalkyl ring, where two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge (i.e., (CH)) of 1 to 3 additional carbon atoms. w(wherein w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, a fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, a bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, a cycloalkyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted with one or two groups, each independently oxo or thia. In embodiments, the polycyclic cycloalkyl ring system is (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) a monocyclic cycloalkyl ring (base ring) fused to either of two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, a polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.In embodiments, the polycyclic cycloalkyl ring system is (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) a monocyclic cycloalkyl ring (base ring) fused to either of two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydropentanethrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0091] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing 3 to 8 carbon atoms, and such groups are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond), but are not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or fused bicyclic rings. In embodiments, bridged monocyclic rings contain monocyclic cycloalkenyl rings, where two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge (i.e., (CH)) of 1 to 3 additional carbon atoms. w(wherein w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, the fused bicyclic cycloalkenyl ring system contains a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkenyl ring contains (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) a monocyclic cycloalkenyl ring (base ring) fused to either of two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkenyl ring system contains (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) a monocyclic cycloalkenyl ring (base ring) fused to either of two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0092] In embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, and the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3 dioxanyl, 1,3 dioxolanyl, 1,3 dithiolanyl, 1,3 dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, o- ... Examples of heterocyclic heterocycles include, but are not limited to, xazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heterocyclyl. Heterocyclyl bicyclic heterocycles are linked to the parent molecular moiety via any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2yl, 2,3-dihydrobenzofuran-3yl, indolin-1yl, indolin-2yl, indolin-3yl, 2,3-dihydrobenzothien-2yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups, each independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic cyclocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, and the bicyclic heterocyclyl is optionally substituted with one or two groups, each independently oxo or thia. A polycyclic heterocyclyl ring system is (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) a monocyclic heterocyclyl ring (base ring) fused to either of two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, the polycyclic heterocyclyl ring system is (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl; or (ii) a monocyclic heterocyclyl ring (base ring) fused to either of two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0093] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, as exemplified but not limited by -CHCHCHCH-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0094] The term "heteroalkyl," alone or in combination with another term, means, unless otherwise indicated, a stable straight or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, S, Si, or P), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. A heteroalkyl is an acyclic chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive (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 may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with another term, means, unless otherwise specified, a heteroalkyl containing at least one double bond. A heteroalkenyl may 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 specified, a heteroalkyl containing at least one triple bond. A heteroalkynyl may optionally contain, in addition to one or more triple bonds, two or more triple bonds and / or one or more double bonds.

[0095] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited to, -CHCH-S-CHCH- 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.). Additionally, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups, as used herein, include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. Where "heteroalkyl" is described followed by a specific heteroalkyl group (e.g., -NR'R", etc.), it will be 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" should not be construed herein as excluding specific heteroalkyl groups (e.g., -NR'R", etc.).

[0096] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise specified, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0097] 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 intended 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.

[0098] The term "acyl," unless otherwise indicated, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0099] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably 1 to 3 rings) that are 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. 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 an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, where one ring has five members and the other has six members, and where at least one ring is a heteroaryl ring. Similarly, a 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. A 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 through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, pridinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5 ... Examples of aryl and heteroaryl ring systems include 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-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl or heteroaryl, respectively. Heteroaryl group substituents can be -O- attached to a ring heteroatom nitrogen.

[0100] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring may be the same or different. The individual rings in a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings within the series of spirocyclic rings. The possible substituents for the individual rings within a spirocyclic ring are the possible substituents for the same ring when not part of a spirocyclic ring (e.g., the substituents for a cycloalkyl or heterocycloalkyl ring). A spirocyclic ring may be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group may be any of the groups listed immediately above, including all rings being one type (e.g., all rings are substituted heterocycloalkylene, and each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is a heterocyclic ring and each ring can be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted and each substituent can optionally be different.

[0101] symbol" [ka] " denotes the point of attachment of a chemical moiety to the rest of the molecule or chemical formula.

[0102] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.

[0103] The term "alkylarylene" refers to 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.

[0104] The alkylarylene moiety can be substituted (e.g., by a substituent) on the alkylene portion or on the arylene linker (e.g., on carbon 2, 3, 4, or 6) with halogen, oxo, -N3, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3-SO3H, -OSO3H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted.

[0105] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the specified radical. Preferred substituents for each type of radical are provided below.

[0106] Substituents for the alkyl and heteroalkyl groups (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) include, but are not limited to, -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', - It can be one or more of a variety of groups selected from NR″C(O)2R′, —NR—C(NR′R″R′′)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′, —NR′NR″R′′′, —ONR′R″, —NR′C(O)NR″NR′′R′″, —CN, —NO2, —NR′SO2R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″ (a number ranging from 0 to (2m′+1), where m′ is the total number of carbon atoms in such group). R, R', R'', R''', and R'''' preferably each independently represent 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 groups, or arylalkyl groups. When the compounds described herein include two or more R groups, for example, each of the R groups is independently selected, as are R', R'', R''', and R'''' groups, respectively, 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., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0107] Similar to the substituents described for the alkyl group, substituents for the aryl and heteroaryl groups are varied and include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)R′, —NR—C(NR′R″R′″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSOR′, —N 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 the R', R'', R''', and R'''' groups, respectively, when more than one of these groups is present.

[0108] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as a substituent on the ring rather than on a specific atom of the ring (commonly referred to as a variable substituent). In such cases, the substituent may be attached to any of the ring atoms (subject to the rules of chemical valency), and in the case of a fused or spirocyclic ring, a substituent depicted in association with one member of the fused or spirocyclic ring (a variable substituent on a single ring) may be a substituent on either the fused or spirocyclic ring (a variable substituent on multiple rings). When a substituent is attached to a ring rather than to a specific atom (a variable substituent) and the subscript for the substituent is an integer greater than 1, multiple substituents may be present on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (variable substituent), the point of attachment can be any atom of the ring and, in the case of a fused or spirocyclic ring, any atom of either the fused or spirocyclic ring, subject to the rules of chemical valency. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is depicted with another variable substituent (including, but not limited to, the point of attachment to the rest of the molecule), the variable substituent can be attached to the heteroatom. When a ring heteroatom is depicted in a structure or formula bearing a variable substituent as attached to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), it will be understood that when the heteroatom is attached to the variable substituent, the substituent replaces the hydrogen, subject to the rules of chemical valency.

[0109] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl 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.

[0110] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be 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 from 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 -B- (wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4). One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') d- (wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-). The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0111] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0112] "Substituent," as used herein, refers to the following moieties: (A) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H , -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -O CHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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 10aryl, 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) (i) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H , -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -O CHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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 alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from aryl, phenyl, or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl); (ii) (a) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H , -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -O CHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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 alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), (b) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CHF2, -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SCH3, -SO3H , -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCBr3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -O CHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, 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).

[0113] "Size-constrained substituent" or "size-constrained substituent group," as used herein, 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-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.

[0114] A "lower substituent" or "lower substituent group," as used herein, means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, 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.

[0115] 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, unsubstituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively).

[0116] 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.

[0117] 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-constrained substituent, and when a substituted moiety is substituted with multiple size-constrained substituents, each size-constrained substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-constrained substituents, each size-constrained substituent is different.

[0118] 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.

[0119] 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-constrained substituent, or lower substituent; when a substituted moiety is substituted with multiple groups selected from substituents, size-constrained substituents, and lower substituents; each substituent, size-constrained substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-constrained substituents, and lower substituents; each substituent, size-constrained substituent, and / or lower substituent is different.

[0120] In embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted (e.g., may be substituted with a substituent, a size-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained substituent, or a lower substituent) or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted 5- to 10-membered heteroarylene.

[0121] In embodiments, each substituted or unsubstituted alkyl is a substituted (e.g., may be substituted with a substituent, a size-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained 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-constrained substituent, or a lower substituent) or unsubstituted C6-C7 10arylene, and / or each substituted or unsubstituted heteroarylene is a substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted 5- to 9-membered heteroarylene. In embodiments, the compound is a species described in the Examples section below, in the Figures, or in the Tables.

[0122] Certain compounds provided herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids, as (D)- or (L)-, are encompassed within the scope of this disclosure. The compounds provided herein do not include those known in the art to be too unstable to synthesize and / or isolate. The compounds provided herein include racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers, can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include E and Z geometric isomers.

[0123] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

[0124] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0125] It will be apparent to one of ordinary skill in the art that certain compounds provided herein may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0126] 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 is achieved by the application of various methods well 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 intended to include all stereochemical forms of the structure; i.e., (R) and (S) configurations with respect to each asymmetric center. Accordingly, 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.

[0127] 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 with deuterium or tritium, or the replacement of fluorine with 18 Replacement of carbon by F or 13 C-rich carbon or 14 Compounds having this structure except for the replacement with a C-rich carbon are within the scope of this disclosure.

[0128] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds provided herein, whether radioactive or not, are included within the disclosure.

[0129] It should be noted that throughout this application, alternatives are described in Markush groups, e.g., at each amino acid position containing two or more possible amino acids. It is specifically contemplated that each member of a Markush group is considered separately, thereby including alternative embodiments, and that the Markush group is not to be read as a single unit.

[0130] "Analog" or "analogue" is used according to its plain and ordinary meaning in 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, e.g., the replacement of an atom by an atom of a different element, or the presence of a particular functional group, or the replacement of a functional group by another functional group, or 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.

[0131] The terms "a" or "an," as used herein, mean one or more. Additionally, the phrase "substituted with a[n]," as used herein, means that the specified group can be substituted with one or more of any or all of the listed substituents. For example, when a group such as an alkyl or heteroaryl group is referred to as "unsubstituted C1-C 20 When "substituted with alkyl, or unsubstituted 2- to 20-membered heteroalkyl," the group is also substituted with one or more unsubstituted C1-C 20 It may contain alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl.

[0132] When a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group occurs in a description of a chemical genus (such as formula (I)), Roman decimal symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13When substituents are present, each R 13 The substituents are R 13.1 , R 13.2 , R 13.3 , R 13.4 may be distinguished as R 13.1 , R 13.2 , R 13.3 , R 13.4 Each of these is R 13

[0023] The terms "a" or "an," as used herein, mean one or more. Additionally, the phrase "substituted with a[n]," as used herein, means that the specified group can be substituted with one or more of any or all of the listed substituents. For example, when a group such as an alkyl or heteroaryl group is "substituted with an unsubstituted C1-C 20 When "substituted with alkyl, or unsubstituted 2- to 20-membered heteroalkyl," the group is also substituted with one or more unsubstituted C1-C 20 It may contain alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl.

[0133] The description of compounds provided herein is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more substituents, such substituents are selected according to the principles of chemical bonding to obtain compounds known to those skilled in the art that are not inherently unstable and / or unlikely to be unstable under ambient conditions, such as aqueous, neutral, and some known physiological conditions.For example, heterocycloalkyl or heteroaryl are 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 inherently unstable compounds.

[0134] compound Embodiments of the present disclosure relate to compounds targeted to human peripheral myelin protein 22 (PMP22) mRNA (NCBI Reference Sequence NM_000304.4; SEQ ID NO: 1170, deposited by GenBank on November 22, 2018). The compounds include double-stranded and single-stranded nucleic acids that act via the RNA interference pathway to inhibit expression of PMP22 mRNA. In embodiments, the compounds are double-stranded nucleic acids comprising an antisense strand complementary to PMP22 mRNA and a sense strand complementary to the antisense strand. In embodiments, the antisense and sense strands of the compounds are two separate strands, not covalently linked, forming a small interfering RNA (siRNA). In embodiments, the antisense and sense strands of the compounds are covalently linked by a nucleotide linker to form a short hairpin RNA (shRNA). In embodiments, the compounds are single-stranded nucleic acids comprising an antisense strand complementary to PMP22 mRNA (ssRNAi).

[0135] Provided herein is a compound comprising an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein each of the antisense strand and the sense strand is 15-25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to human peripheral myelin protein 22 mRNA (SEQ ID NO: 1170), and the nucleotide sequence of the sense strand has no more than two mismatches with the nucleotide sequence of the antisense strand in the double-stranded region.

[0136] Provided herein is a compound comprising an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein each of the antisense strand and the sense strand is 15 to 25 nucleotides in length, and the nucleotide sequence of the antisense strand is selected from the group consisting of SEQ ID NOs: 491, 492, 493, 494, 495, 497, 498, 503, 504, 506, 510, 511, 514, 515, 516, 518, 524, 526, 529, 531, 532, 533, 534, 535, 536 , 538, 539, 540, 541, 542, 543, 545, 546, 547, 548, 550, 553, 554, 556, 558, 559, 560, 561, 563, 567, 569, 575, 576, 579, 580, 581, 582, 583, 585, 590, 591, 595, 597, 600, 605, 609, 610, 618, 622, 623, 628, 630, 631, 633, 635, 637, 639, 641, 642, 643, 644, 645 5, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1122, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, and 1144, wherein the nucleotide sequence of the sense strand has no more than two mismatches with the nucleotide sequence of the antisense strand.

[0137] The present specification provides a compound comprising a single-stranded nucleic acid comprising an antisense strand, wherein the antisense strand is 15 to 25 nucleotides in length, and the nucleotide sequence of the antisense strand is any of SEQ ID NOs: 491, 492, 493, 494, 495, 497, 498, 503, 504, 506, 510, 511, 514, 515, 516, 518, 524, 526, 529, 531, 532, 533, 534, 535, 536, 538, and 539. , 540, 541, 542, 543, 545, 546, 547, 548, 550, 553, 554, 556, 558, 559, 560, 561, 563, 567, 569, 575, 576, 579, 580, 581, 582, 583, 585, 590, 591, 595, 597, 600, 605, 609, 610, 618, 622, 623, 628, 630, 631, 633, 635, 637, 639, 641, 642 2, 643, 644, 645, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1122, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1166, 1167, 1168, 1169, 1118, 1121, 1123, 1126, and 1144.

[0138] In embodiments, the nucleotide sequence of the antisense strand is selected from the group consisting of SEQ ID NOs: 491, 492, 493, 494, 495, 497, 498, 503, 504, 506, 510, 511, 514, 515, 516, 518, 524, 526, 529, 531, 532, 533, 534, 535, 536, 538, 539, 540, 541, 542, 543, 545, 546, 547, 548, 550, 553, 554, 555 6, 558, 559, 560, 561, 563, 567, 569, 575, 576, 579, 580, 581, 582, 583, 585, 590, 591, 595, 597, 600, 605, 609, 610, 618, 622, 623, 628, 630, 631, 633, 635, 637, 639, 641, 642, 643, 644, 645, 1112, 1113, 1114, 1115, 1116, 1117, 1118 18, 1119, 1120, 1122, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 11 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1118, 1121, 1123, 1126, and 1144.

[0139] In embodiments, the nucleotide sequence of the antisense strand is selected from the group consisting of SEQ ID NOs: 491, 492, 493, 494, 495, 497, 498, 503, 504, 506, 510, 511, 514, 515, 516, 518, 524, 526, 529, 531, 532, 533, 534, 535, 536, 538, 539, 540, 541, 542, 543, 545, 546, 547, 548, 550, 553, 554, 556, 558, 559, 560, 561, 563, 567, 569, 575, 576, 579, 580, 581, 582, 583, 585, 590, 591, 595, 597, 600, 605, 609, 610, 618, 622, 623, 628, 630, 631, 633, 635, 637, 639, 641, 642, 643, 644, 645, 1112 , 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1122, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1118, 1121, 1123, 1126, and 1144.

[0140] The characteristics of the compound are provided below, such as length, nucleotide sequence and nucleotide modification.It is understood that the embodiment of antisense strand can be applied to the antisense strand of single-stranded nucleic acid or double-stranded nucleic acid.Furthermore, it is understood that the embodiment of sense strand can be applied to the sense strand of any double-stranded nucleic acid provided herein, including siRNA and shRNA.

[0141] In an embodiment, the antisense strand is 15 to 25 nucleotides in length. In an embodiment, the antisense strand is 17 to 23 nucleotides in length. In an embodiment, the antisense strand is 19 to 21 nucleotides in length. In an embodiment, the antisense strand is 21 to 23 nucleotides in length. In an embodiment, the antisense strand is 15 nucleotides in length. In an embodiment, the antisense strand is 16 nucleotides in length. In an embodiment, the antisense strand is 17 nucleotides in length. In an embodiment, the antisense strand is 18 nucleotides in length. In an embodiment, the antisense strand is 19 nucleotides in length. In an embodiment, the antisense strand is 20 nucleotides in length. In an embodiment, the antisense strand is 21 nucleotides in length. In an embodiment, the antisense strand is 22 nucleotides in length. In an embodiment, the antisense strand is 23 nucleotides in length. In an embodiment, the antisense strand is 24 nucleotides in length. In an embodiment, the antisense strand is 25 nucleotides in length.

[0142] In embodiments, the nucleotide sequence of the antisense strand is at least 95% complementary to SEQ ID NO: 1170. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to SEQ ID NO: 1170. In embodiments, the nucleotide sequence of the antisense strand is 100% complementary to nucleotides 213-233 of SEQ ID NO: 1170.

[0143] In an embodiment, the sense strand is 15 to 25 nucleotides in length. In an embodiment, the sense strand is 17 to 23 nucleotides in length. In an embodiment, the sense strand is 19 to 21 nucleotides in length. In an embodiment, the sense strand is 21 to 23 nucleotides in length. In an embodiment, the sense strand is 15 nucleotides in length. In an embodiment, the sense strand is 16 nucleotides in length. In an embodiment, the sense strand is 17 nucleotides in length. In an embodiment, the sense strand is 18 nucleotides in length. In an embodiment, the sense strand is 19 nucleotides in length. In an embodiment, the sense strand is 20 nucleotides in length. In an embodiment, the sense strand is 21 nucleotides in length. In an embodiment, the sense strand is 22 nucleotides in length. In an embodiment, the sense strand is 23 nucleotides in length. In an embodiment, the sense strand is 24 nucleotides in length. In an embodiment, the sense strand is 25 nucleotides in length.

[0144] In embodiments, the length of the sense strand is the same as the length of the antisense strand. In embodiments, the length of the sense strand is longer than the length of the antisense strand. In embodiments, the length of the sense strand is shorter than the length of the antisense strand.

[0145] The double-stranded region of the double-stranded nucleic acid can be 15 to 25 nucleobase pairs in length, depending on the lengths of the sense and antisense strands. In an embodiment, the double-stranded region is 17 to 23 nucleobase pairs in length. In an embodiment, the double-stranded region is 19 to 21 nucleobase pairs in length. In an embodiment, the double-stranded region is 21 to 23 nucleotides in length. In an embodiment, the double-stranded region is 15 nucleobase pairs in length. In an embodiment, the double-stranded region is 16 nucleobase pairs in length. In an embodiment, the double-stranded region is 17 nucleobase pairs in length. In an embodiment, the double-stranded region is 18 nucleobase pairs in length. In an embodiment, the double-stranded region is 19 nucleobase pairs in length. In an embodiment, the double-stranded region is 20 nucleobase pairs in length. In an embodiment, the double-stranded region is 21 nucleobase pairs in length. In an embodiment, the double-stranded region is 22 nucleobase pairs in length. In an embodiment, the double-stranded region is 23 nucleobase pairs in length. In an embodiment, the double-stranded region is 24 nucleobase pairs in length. In an embodiment, the double-stranded region is 25 nucleobase pairs in length.

[0146] In embodiments, the nucleotide sequence of the sense strand has one or less mismatch with the nucleotide sequence of the antisense strand of the double-stranded nucleic acid. In embodiments, the nucleotide sequence of the sense strand has no mismatch with the nucleotide sequence of the antisense strand of the double-stranded nucleic acid. Single-stranded nucleotide overhangs and nucleotide linkers are not taken into account when determining the number of mismatches in the double-stranded region of the double-stranded nucleic acid provided herein. For example, a double-stranded nucleic acid comprising an antisense strand that is 23 nucleotides long and a sense strand that is 21 nucleotides long will have no mismatches throughout the double-stranded region if the nucleotide sequence of the sense strand is completely complementary to the nucleotide sequence of the antisense strand throughout the entire length. Alternatively, a double-stranded nucleic acid comprising a sense strand that is 20 nucleotides long, an antisense strand that is 22 nucleotides long, and a nucleotide linker that is 8 nucleotides long will have no mismatches throughout the double-stranded region if the nucleotide sequence of the sense strand is completely complementary to the nucleotide sequence of the antisense strand throughout the entire length.

[0147] In an embodiment, the double-stranded nucleic acid comprises an antisense strand 19 nucleotides in length and a sense strand 19 nucleotides in length. In an embodiment, the antisense strand is 22 nucleotides in length and the sense strand is 20 nucleotides in length. In an embodiment, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length. In an embodiment, the antisense strand is 23 nucleotides in length with two deoxythymidines at its 3' end and the sense strand is 21 nucleotides in length with two deoxythymidines at its 3' end.

[0148] In embodiments of a compound comprising a double-stranded nucleic acid in which the antisense strand and the sense strand are separate, non-covalently linked strands, the terminal nucleotides may form nucleobase pairs, in which case the end of the double-stranded nucleic acid is blunt-ended. Alternatively, one or more unpaired nucleotides of the antisense strand and / or the sense strand may extend beyond the end of the complementary strand, resulting in a nucleotide overhang of one or more terminal single-stranded nucleotides. In embodiments, at least one of the 5' and 3' ends of the double-stranded nucleic acid is blunt-ended. In embodiments, both the 5' and 3' ends of the double-stranded nucleic acid are blunt-ended. In embodiments, at least one end of the double-stranded nucleic acid comprises a nucleotide overhang. In embodiments, each end of the double-stranded nucleic acid comprises a nucleotide overhang. In embodiments, one end of the double-stranded nucleic acid is blunt-ended, and the other end of the double-stranded nucleic acid comprises a nucleotide overhang. In embodiments, the antisense strand comprises a nucleotide overhang at its 3' end. In embodiments, the sense strand comprises a nucleotide overhang at its 3' end. In embodiments, the antisense strand and the sense strand each comprise a nucleotide overhang at their 3'-end. In embodiments, at least one of the antisense strand and the sense strand comprises a nucleotide overhang at their 5'-end. In embodiments, the antisense strand and the sense strand each comprise a nucleotide overhang at their respective 5'-end.

[0149] In embodiments, the nucleotide overhang is 1 to 5 single-stranded nucleotides. In embodiments, the nucleotide overhang is 1 single-stranded nucleotide. In embodiments, the nucleotide overhang is 2 single-stranded nucleotides. In embodiments, the nucleotide overhang is 3 single-stranded nucleotides. In embodiments, the nucleotide overhang is 3 single-stranded nucleotides. In embodiments, the nucleotide overhang is 4 single-stranded nucleotides. In embodiments, the nucleotide overhang is 5 single-stranded nucleotides. In embodiments, at least one of the single-stranded nucleotides of the nucleotide overhang is a modified nucleotide. In embodiments, each of the single-stranded nucleotides of the nucleotide overhang is a modified nucleotide. In embodiments, the modified nucleotide is a 2'-O-methyl nucleotide. In embodiments, the nucleotide overhang is 2 single-stranded nucleotides, each nucleotide being a 2'-O-methoxyethyl nucleotide.

[0150] In embodiments, at least one nucleotide of the nucleotide overhang at the 3' end of the antisense strand is complementary to a corresponding nucleotide of SEQ ID NO: 1170. In embodiments, each nucleotide of the nucleotide overhang at the 3' end of the antisense strand is complementary to a corresponding nucleotide of SEQ ID NO: 1170. In some embodiments, at least one nucleotide of the nucleotide overhang at the 3' end of the antisense strand is not complementary to a corresponding nucleotide of SEQ ID NO: 1170. In embodiments, each nucleotide of the nucleotide overhang at the 3' end of the antisense strand is not complementary to a corresponding nucleotide of SEQ ID NO: 1170.

[0151] In embodiments, at least one single-stranded nucleotide of the nucleotide overhang is a deoxythymidine nucleotide. In embodiments, the nucleotide overhang is two single-stranded nucleotides, each nucleotide being a deoxythymidine nucleotide. In embodiments, the nucleotide sequence of the antisense strand comprises a nucleotide overhang of two deoxythymidine nucleotides. In embodiments, the sense strand comprises a nucleotide overhang of two deoxythymidine nucleotides. In embodiments, the antisense strand and the sense strand comprise nucleotide overhangs of two deoxythymidine nucleotides.

[0152] Non-limiting examples of double-stranded nucleic acids containing blunt ends or nucleotide overhangs are provided in Table 1 below.

[0153] In a first example, if the antisense strand is 21 nucleotides in length and the sense strand is 21 nucleotides in length, and the nucleotide sequence of the antisense strand is perfectly complementary to the nucleotide sequence of the sense strand across the double-stranded region, the length of the double-stranded region is 19 nucleic acid base pairs, and each end of the double-stranded nucleic acid has a dTdT overhang.

[0154] In a second example, if the antisense strand is 21 nucleotides in length and the sense strand is 19 nucleotides in length, and the nucleotide sequence of the antisense strand is perfectly complementary to the nucleotide sequence of the sense strand across the double-stranded region, the length of the double-stranded region is 19 nucleic acid base pairs, and the 3' end of the antisense strand includes a dTdT overhang.

[0155] In a third example, if the antisense strand is 19 nucleotides in length and the sense strand is 19 nucleotides in length, and the nucleotide sequence of the antisense strand is perfectly complementary to the nucleotide sequence of the sense strand across the double-stranded region, the length of the double-stranded region is 19 nucleic acid base pairs and each end is blunt-ended.

[0156] In a fourth example, if the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length, the length of the double-stranded region is 21 nucleic acid base pairs, and the 3' end of the antisense strand includes a two-nucleotide overhang.

[0157] [Table 1]

[0158] In embodiments of double-stranded nucleic acids comprising a nucleotide linker, the end not linked by the nucleotide linker may form a blunt end or a nucleotide overhang of one or more single-stranded nucleotides. In embodiments, the unlinked end of the double-stranded nucleic acid is a blunt end. In embodiments, the unlinked end comprises a nucleotide overhang of one or more single-stranded nucleotides. In embodiments, the unlinked end of the guide strand comprises a nucleotide overhang. In embodiments, the unlinked end of the sense strand comprises a nucleotide overhang. In embodiments, the 3' end of the guide strand comprises a nucleotide overhang. In embodiments, the 3' end of the sense strand comprises a nucleotide overhang. In embodiments, the 5' end of the sense strand comprises a nucleotide overhang. In embodiments, the 5' end of the sense strand comprises a nucleotide overhang.

[0159] In an embodiment of the double-stranded nucleic acid in which the antisense strand and the sense strand are covalently linked by a nucleotide linker, the nucleotide linker is 4 to 16 nucleotides in length. In an embodiment, the nucleotide linker is 4 nucleotides in length. In an embodiment, the nucleotide linker is 4 nucleotides in length. In an embodiment, the nucleotide linker is 5 nucleotides in length. In an embodiment, the nucleotide linker is 6 nucleotides in length. In an embodiment, the nucleotide linker is 7 nucleotides in length. In an embodiment, the nucleotide linker is 8 nucleotides in length. In an embodiment, the nucleotide linker is 9 nucleotides in length. In an embodiment, the nucleotide linker is 10 nucleotides in length. In an embodiment, the nucleotide linker is 11 nucleotides in length. In an embodiment, the nucleotide linker is 12 nucleotides in length. In an embodiment, the nucleotide linker is 13 nucleotides in length. In an embodiment, the nucleotide linker is 14 nucleotides in length. In an embodiment, the nucleotide linker is 15 nucleotides in length. In an embodiment, the nucleotide linker is 16 nucleotides in length.

[0160] Although the sequence listing accompanying this application identifies each nucleotide sequence as "RNA" or "DNA" as appropriate, in practice, those sequences may be modified by any combination of the chemical modifications specified herein. Those of skill in the art will readily understand that designations such as "RNA" or "DNA" describing modified nucleotides in the sequence listing are somewhat arbitrary. For example, a nucleic acid provided herein that includes a nucleotide containing a 2'-O-methyl sugar moiety and a thymine base may be described as a DNA residue in the sequence listing, even if the nucleotide is modified and is not a naturally occurring DNA nucleotide.

[0161] Thus, the nucleic acid sequences provided in the Sequence Listing are intended to encompass nucleic acids containing any combination of natural or modified RNA and / or DNA, including, but not limited to, such nucleic acids with modified nucleic acid bases. As a further example and without limitation, a nucleic acid having the nucleotide sequence "ATCGATCG" in the Sequence Listing encompasses any nucleic acid having such a nucleotide sequence, whether modified or unmodified, including, but not limited to, such nucleic acids containing RNA bases, for example, those having the sequence "AUCGAUCG" and those having some DNA bases and some RNA bases, such as "AUCGATCG," and oligonucleotides with other modified bases, such as "ATmeCGAUCG" (meC indicates 5-methylcytosine).

[0162] Modified nucleotides The double-stranded and single-stranded nucleic acids provided herein can contain one or more modified nucleotides, which can be selected over unmodified forms for desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for other oligonucleotide or nucleic acid targets, increased stability in the presence of nucleases, and / or reduced immune stimulation.

[0163] In embodiments, at least one nucleotide of antisense strand is modified nucleotide.In embodiments, at least one nucleotide of sense strand is modified nucleotide.In embodiments, each nucleotide of antisense strand that forms double-stranded region is modified nucleotide.In embodiments, each nucleotide of sense strand that forms double-stranded region comprises modified nucleotide.

[0164] In embodiments, the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a modified 5'-terminal phosphate group. In embodiments, the modified nucleotide comprises a modified sugar moiety. In embodiments, the modified nucleotide comprises a modified internucleotide linkage. In embodiments, the modified nucleotide comprises a modified nucleobase. In embodiments, the modified nucleotide comprises a modified 5'-terminal phosphate group. In embodiments, the modified nucleotide comprises a modification at the 5'-carbon of the pentafuranosyl sugar. In embodiments, the modified nucleotide comprises a modification at the 3'-carbon of the pentafuranosyl sugar. In embodiments, the modified nucleotide comprises a modification at the 2'-carbon of the pentafuranosyl sugar. In embodiments, the modified nucleotide is present at the 5'-terminus of the antisense strand or the sense strand. In embodiments, the modified nucleotide is present at the 3'-terminus of the antisense strand or the sense strand. In embodiments, the modified nucleotide is present at an internal nucleotide of the antisense strand or the sense strand. In embodiments, the modified nucleotide comprises a ligand attached to the 2', 3, or 5' carbon of the pentafuranosyl sugar. In embodiments, the nucleotide comprises a ligand attached to the nucleobase.

[0165] Modified nucleotides can contain modified sugar moieties, naturally occurring nucleobases, and naturally occurring internucleotide linkages.Modified nucleotides can contain modified sugar moieties, naturally occurring nucleobases, and modified internucleotide linkages.

[0166] In embodiments, the modified sugar moiety is modified at the 2' carbon of the pentafuranosyl sugar, as opposed to the naturally occurring 2'-OH of RNA or 2'-H of DNA. In embodiments, the modification at the 2' carbon of the pentafuranosyl sugar is selected from F, OCF, OCH (also referred to as "2'-OMe" or "2'-O-methyl"), OCHCHOCH (also referred to as "2'-O-methoxyethyl" or "2'-MOE"), 2'-O(CH)SCH, O-(CH)-ON(CH), -O(CH)O(CH)N(CH), and O-CH-C(=O)-N(H)CH.

[0167] In an embodiment, the modified sugar moiety is a 2'-fluoro sugar (also referred to as a 2'-F sugar). In an embodiment, the modified sugar moiety is a 2'-O-methyl sugar (also referred to as a "2'-OMe sugar" or a "2'-OCH3" sugar). In an embodiment, the modified sugar moiety is a 2'-O-methoxyethyl sugar (also referred to as a 2'-OCH2CH2OCH3 or a 2'-MOE sugar).

[0168] In embodiments, the modified nucleotide comprising a modified sugar moiety is selected from a 2'-fluoro nucleotide, a 2'-O-methyl nucleotide, a 2'-O-methoxyethyl nucleotide, and a bicyclic sugar nucleotide. In embodiments, the modified nucleotide is a 2'-fluoro nucleotide, where the 2' carbon of the pentafuranosyl sugar has a fluoro substitution. In embodiments, the modified nucleotide is a 2'-O-methyl nucleotide, where the 2' carbon of the pentafuranosyl sugar has a 2'-O-methyl substitution. In embodiments, the modified nucleotide is a 2'-O-methoxyethyl nucleotide, where the 2' carbon of the pentafuranosyl sugar has a 2'-O-methoxyethyl substitution. Other modified nucleotides may be named similarly.

[0169] In embodiments, modified nucleotides comprise a modified sugar moiety, in which the ribose has a covalent bond between the 2' and 4' carbons. Such modified sugar moieties may be referred to as "bicyclic sugars," and nucleotides comprising such sugar moieties may be referred to as "bicyclic nucleic acids." In embodiments, the covalent bond in the bicyclic sugar is a methyleneoxy bond (4'-CH2-O-2'), also known as "LNA." In embodiments, the covalent bond in the bicyclic sugar is an ethyleneoxy bond (4'-(CH2)2-O-2'), also known as "ENA." In embodiments, the covalent bond in the bicyclic moiety is a methyl (methyleneoxy) bond (4'-CH(CH3)-O-2'), also known as "constrained ethyl" or "cEt." In certain embodiments, the -CH(CH3)- bridge is constrained in the S orientation ("S-cEt"). In certain embodiments, the -CH(CH3)- bridge is constrained in the R orientation ("R-cEt"). In embodiments, the covalent bond of the bicyclic sugar is a (4'-CH(CH-OMe)-O-2' bond, also known as a "c-MOE." In embodiments, the bicyclic sugar is a D-sugar in the alpha configuration. In certain such embodiments, the bicyclic sugar is a D-sugar in the beta configuration. In certain such embodiments, the bicyclic sugar is an L-sugar in the alpha configuration. In certain such embodiments, the bicyclic sugar is an L-sugar in the beta configuration.

[0170] In an embodiment, the modified sugar moiety is a 1,5-anhydrohexitol nucleic acid, also known as a "hexitol nucleic acid" or "HNA."

[0171] In embodiments, the oxygen of the pentafuranosyl sugar is replaced with a sulfur to form a thio-sugar. In embodiments, the thio-sugar is modified at the 2' carbon.

[0172] In embodiments, the modified internucleotide linkage is a phosphorothioate internucleotide linkage. In embodiments, the modified internucleotide linkage is a methylphosphonate internucleotide linkage.

[0173] In embodiments, the first two internucleotide linkages at the 5'-end of the sense strand and the last two internucleotide linkages at the 3'-end of the sense strand are phosphorothioate internucleotide linkages. In embodiments, the first two internucleotide linkages at the 5'-end of the antisense strand and the last two internucleotide linkages at the 3'-end of the antisense strand are phosphorothioate internucleotide linkages. In embodiments, the first two internucleotide linkages at the 5'-end of the sense strand and the last two internucleotide linkages at the 3'-end of the sense strand are phosphorothioate internucleotide linkages, and the first two internucleotide linkages at the 5'-end of the antisense strand and the last two internucleotide linkages at the 3'-end of the antisense strand are phosphorothioate internucleotide linkages.

[0174] In embodiments, the modified nucleobase is selected from 5-hydroxymethylcytosine, 7-deazaguanine, and 7-deazaadenine. In embodiments, the modified nucleobase is selected from 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone. In embodiments, the modified nucleobase is selected from 5-substituted pyrimidines, 6-azapyrimidines, and N-2, N-6, and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil, and 5-propynylcytosine.

[0175] In embodiments, the modified nucleotide comprises a phosphate group modification at the 5'-carbon of the pentafuranosyl sugar. In embodiments, the modified phosphate group is 5'-(E)-vinylphosphonate (5'-VP).

[0176] In embodiments, the modified nucleotides are phosphorodiamidite-linked morpholino nucleotides.

[0177] In embodiments, the modified nucleotides include acyclic nucleoside derivatives that lack a bond between the 2' and 3' carbons of the sugar ring, also known as "unlocked nucleic acids" or "UNAs."

[0178] In one embodiment, the antisense strand is 21 nucleotides long, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-fluoro nucleotides, nucleotides 20 and 21 are beta-D-deoxy nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern can be represented by the following pattern I: 5'-N M S N F S N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M S N S N-3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0179] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-O-methyl nucleotides, nucleotides 20 and 21 are beta-D-deoxy nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern can be represented by the following pattern II: 5'-N F S N M S N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N S N-3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0180] In one embodiment, the antisense strand is 19 nucleotides long, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern can be represented by the following pattern III: 5'-N M S N F S N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M S N F S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0181] In an embodiment, the sense strand is 19 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-O-methyl nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide is a phosphodiester internucleotide bond. Such a modification pattern can be represented by the following pattern IV: 5'-N F S N M S N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N M S N F -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0182] In one embodiment, the antisense strand is 23 nucleotides long, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern can be represented by the following pattern V: 5'-N M S N F S N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0183] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern can be represented by Pattern VI: 5'-N F S N M S N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N M S N F -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0184] In one embodiment, the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern VII: 5'-N M S N F S N M N F N M N F N M N F N M N F N M N M N M N F N M N F N M N F N M N F N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0185] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern VIII: 5'-N F S N M S N F N M N F N M N F N M N F N F N F N M N F N M N F N M N F N M N F S N M S N F -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0186] In one embodiment, the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern IX: 5'-N M S N F S N M N F N M N F N M N F N M N M N M N F N M N F N M N F N M N F N M N F N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0187] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by pattern X: 5'-N F S N M S N F N M N F N M N F N M N F N M N F N F N F N M N F N M N F N M N F S N M S N F -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0188] In an embodiment, the sense strand is 23 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxy nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern XI: 5'-N F S N M S N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N F S N S N-3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0189] In an embodiment, the sense strand is 23 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by pattern XII: 5'-N F S N M S N F N M N F N M N F N M N F N F N F N M N F N M N F N M N F N M N F N M N F S N S N-3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0190] In an embodiment, the sense strand is 23 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by Pattern XIII: 5'-N F S N M S N F N M N F N M N F N M N F N M N F N F N F N M N F N M N F N M N F N M N F S N S N-3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0191] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-methyl nucleotides, nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern XIV: 5'-N M S N M S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0192] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by pattern XV: 5'-N M S N M S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0193] In one embodiment, the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 8, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern XVI: 5'-N M S N F S N M N F N M N F N M N F N M N M N M N F N M N F N M N F N M N F N M N F N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0194] In one embodiment, the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19, 20, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 6, 14, and 16 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern XVII: 5'-N M S N F S N M N F N M N F N M N F N M N M N M N F N M N F N M N F N M N F N M N F N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, "N" is a beta-D-deoxynucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0195] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 7, 9, 10, and 11 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern XVIII: 5'-N M S N M S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0196] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 7, 9, 10, and 11 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by pattern XIX: 5'-N M S N M S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0197] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1 and 2 are 2'-O-methoxyethyl nucleotides, nucleotides 3, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by pattern XX: 5'-N E S N E S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N E " is a 2'-O-methoxyethyl nucleotide, and "N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0198] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 2 and 3 are 2'-O-methoxyethyl nucleotides, nucleotides 1, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by Pattern XXI: 5'-N E S N E S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N E " is a 2'-O-methoxyethyl nucleotide, and "N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0199] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 2, 3, 19, and 20 are 2'-O-methoxyethyl nucleotides, nucleotides 1, 4, 6, 8, 12, 14, 16, 18, and 21 are 2'-O-methyl nucleotides, nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. Such a modification pattern may be represented by Pattern XXII: 5'-N E S N E S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N E " is a 2'-O-methoxyethyl nucleotide, and "N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0200] In an embodiment, the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, and 4 are 2'-O-methoxyethyl nucleotides, nucleotides 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond. Such a modification pattern may be represented by Pattern XXIII: 5'-N E S N E S N M N M N F N M N F N M N F N M N F N M N F N M N F N M N F N M N M S N M S N M -3'("N E " is a 2'-O-methoxyethyl nucleotide, and "N M " is a 2'-O-methyl nucleotide, and "N F " is a 2'-fluoronucleotide, the superscript "S" is a phosphorothioate internucleotide linkage, and each other internucleotide linkage is a phosphodiester internucleotide linkage).

[0201] In embodiments, the antisense strand has a modification pattern of pattern I and a 5'-VP at the 5'-terminal nucleotide. In embodiments, the antisense strand has a modification pattern of pattern III and a 5'-VP at the 5'-terminal nucleotide. In embodiments, the antisense strand has a modification pattern of pattern V and a 5'-VP at the 5'-terminal nucleotide. In embodiments, the antisense strand has a modification pattern of pattern VII and a 5'-VP at the 5'-terminal nucleotide. In embodiments, the antisense strand has a modification pattern of pattern IX and a 5'-VP at the 5'-terminal nucleotide. In embodiments, the antisense strand has a modification pattern of pattern XVI and a 5'-VP at the 5'-terminal nucleotide. In embodiments, the antisense strand has a modification pattern of pattern XVII and a 5'-VP at the 5'-terminal nucleotide.

[0202] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded region, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 21 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxynucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate nucleotides. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-O-methyl nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern represented by Pattern I, and the sense strand has a modification pattern represented by Pattern II.

[0203] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 19 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19, which are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18, which are 2'-fluoro nucleotides; the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages; and each other. The internucleotide bond is modified to be a phosphodiester internucleotide bond; and the sense strand is 21 nucleotides long, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified such that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-O-methyl nucleotides, nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. In such an embodiment, the antisense strand has a modification pattern represented by pattern III, and the sense strand has a modification pattern represented by pattern II.

[0204] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 21 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxynucleotides; and the first two internucleotide bonds at the 5' end and the last two nucleotides at the 3' end are 2'-O-methyl nucleotides; and the sense strand is 19 nucleotides long, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19, which are 2'-fluoro nucleotides, and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18, which are 2'-O-methyl nucleotides, and the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern represented by pattern I, and the sense strand has a modification pattern represented by pattern IV.

[0205] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 19 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19, are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate nucleotides. and the sense strand is 19 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-fluoro nucleotides, and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-O-methyl nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern represented by Pattern III, and the sense strand has a modification pattern represented by Pattern IV.

[0206] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23, are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides; the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds; and each other internucleotide bond is a phosphodiester internucleotide bond. In such an embodiment, the antisense strand has a modification pattern represented by pattern V, and the sense strand has a modification represented by pattern VI.

[0207] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23, are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are: nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides; nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides; the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds; and each other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern represented by pattern VII, and the sense strand has a modification pattern represented by pattern VIII.

[0208] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23, are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides; nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-O-methyl nucleotides; the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds; and each other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern IX, and the sense strand has a modification pattern of pattern X.

[0209] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, respectively. and the sense strand is 23 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, and nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. In such an embodiment, the antisense strand has a modification pattern represented by pattern V, and the sense strand has a modification represented by pattern XI.

[0210] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, respectively. and the sense strand is 23 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, nucleotides 22 and 23 are beta-D-deoxynucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern represented by pattern VII, and the sense strand has a modification pattern represented by pattern XII.

[0211] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand form an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, respectively. and the sense strand is 23 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides; nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-O-methyl nucleotides; nucleotides 22 and 23 are beta-D-deoxynucleotides; the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds; and each other internucleotide bond is modified to be a phosphodiester internucleotide bond. In such an embodiment, the antisense strand has a modification pattern of pattern IX, and the sense strand has a modification pattern of pattern XIII.

[0212] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate nucleotides. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern V, and the sense strand has a modification pattern of pattern XIV.

[0213] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 8, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate nucleotides. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern XVI, and the sense strand has a modification pattern of pattern XV.

[0214] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 8, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate nucleotides. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 7, 9, 10, and 11 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern XVII, and the sense strand has a modification pattern of pattern XVIII.

[0215] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 8, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are: and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are nucleotides 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21, are 2'-O-methyl nucleotides, and nucleotides 7, 9, 10, and 11 are 2'-fluoro nucleotides, and the first two internucleotide bonds at the 5' end are modified to be phosphorothioate internucleotide linkages and every other internucleotide linkage is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern XVII, and the sense strand has a modification pattern of pattern XIX.

[0216] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, respectively. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1 and 2 are 2'-O-methoxyethyl nucleotides, nucleotides 3, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern V, and the sense strand has a modification pattern of pattern XX.

[0217] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, respectively. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 2 and 3 are 2'-O-methoxyethyl nucleotides, nucleotides 1, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern V, and the sense strand has a modification pattern of pattern XXI.

[0218] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, respectively. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 2, 3, 19, and 20 are 2'-O-methoxyethyl nucleotides, nucleotides 1, 4, 6, 8, 12, 14, 16, 18, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern V, and the sense strand has a modification pattern of pattern XXII.

[0219] In embodiments, the compound comprises an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein the antisense strand and the sense strand are not covalently linked (i.e., the antisense strand and the sense strand are derived from an siRNA), the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides; and the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, respectively. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, and 4 are 2'-O-methoxyethyl nucleotides, nucleotides 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide linkage. In such an embodiment, the antisense strand has a modification pattern of pattern V, and the sense strand has a modification pattern of pattern XXIV.

[0220] Conjugated Compounds In embodiments, the compounds provided herein comprise a covalently bound ligand. In embodiments, the compounds provided herein comprise a ligand covalently bound to the antisense strand. In embodiments, the compounds provided herein comprise a ligand covalently bound to the sense strand. In embodiments, the ligand comprises an uptake motif with one or more long-chain fatty acids (LFCA).

[0221] In embodiments, the compound containing the uptake motif has the structure (I): [ka] (wherein A is a double-stranded nucleic acid, and t is an integer of 1 to 5). In an embodiment, A is a sense strand. In an embodiment, A is an antisense strand.

[0222] L 3 and L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 )-O-, -SS-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. Each R 23 , R 24 and R 25 are independently hydrogen or unsubstituted C1-C 10 It is alkyl.

[0223] L 5 -L 5A -L 5B -L 5C -L 5D -L 5E - and L 6 -L 6A -L 6B -L 6C -L 6D -L 6E -It is. L 5A , L 5B , L 5C , L 5D , L 5E , L 6A , L 6B , L 6C , L 6D , and L 6E are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0224] R 1 and R 2 are independently unsubstituted C1 to C 25 alkyl, and R 1 and R 2 At least one of the following is unsubstituted C9-C 19 In embodiments, R 1 and R 2 are independently unsubstituted C1 to C 20 alkyl, and R 1 and R 2 At least one of the following is unsubstituted C9-C 19 It is alkyl.

[0225] R 3 is hydrogen, -hydrogen, -NH, -OH, -SH, -C(O)H, -C(O)NH, -NHC(O)H, -NHC(O)OH, -NHC(O)NH, -C(O)OH, -OC(O)H, -N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0226] In an embodiment, t is 1. In an embodiment, t is 2. In an embodiment, t is 3. In an embodiment, t is 4. In an embodiment, t is 5.

[0227] In one embodiment, one L 3 is attached to the 3' carbon of the nucleotide. 3 is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand. 3 is attached to the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0228] In one embodiment, one L 3 is attached to the 5' carbon of the nucleotide. 3 is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand. 3 is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0229] In one embodiment, one L 3 is attached to the 2' carbon of the nucleotide. 3 is attached to the 2' carbon of a nucleotide of the sense strand. 3 is attached to the 2' carbon of a nucleotide in the antisense strand.

[0230] In one embodiment, one L 3is attached to the nucleobase. In an embodiment, one L 3 is attached to a nucleobase of the sense strand. 3 is attached to a nucleobase of the antisense strand.

[0231] In one embodiment, one L 3 is attached to the phosphate group of the 3' carbon of the nucleotide. 3 is attached to the phosphate group of the 3' carbon of the 3' terminal nucleotide of the sense strand. 3 is attached to the phosphate bond of the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0232] In one embodiment, one L 3 is attached to the phosphate group of the 5' carbon of the nucleotide. 3 is attached to the phosphate group of the 5' carbon of the 5' terminal nucleotide of the sense strand. 3 is attached to the phosphate bond of the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0233] In one embodiment, one L 3 is attached to the phosphate group of the 2' carbon of the nucleotide. 3 is attached to the phosphate group of the 2' carbon of a nucleotide of the sense strand. 3 is attached to the phosphate group of the 2' carbon of a nucleotide in the antisense strand.

[0234] In an embodiment, L 3 is a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24)-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 )-O-, -SS-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0235] In an embodiment, L 3 is a bond. In embodiments, L 3 is -N(R 23 In an embodiment, L 3 is —O— or —S—. In an embodiment, L 3 is —C(O)—. In an embodiment, L 3 is -N(R 23 )C(O)- or -C(O)N(R 24 )-. In an embodiment, L 3 is -N(R 23 )C(O)N(R 24 In an embodiment, L 3 is -C(O)O- or In an embodiment, L 3 is -N(R 23 )C(O)O- or -OC(O)N(R24 In an embodiment, L 3 -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, or -OP(O)(NR 23 R 24 )-O-. In an embodiment, L 3 is -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O- or -P(S)(NR 23 R 24 )-O-. In an embodiment, L 3 is -SS-.

[0236] In an embodiment, L 3 are independently substituted or unsubstituted alkylene (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 3 are independently substituted alkylene (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 3 are independently unsubstituted alkylene (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 3 are independently substituted or unsubstituted C1-C 23 In an embodiment, L is an alkylene. 3 are independently substituted C1 to C 23 In an embodiment, L is an alkylene. 3 are independently unsubstituted C1 to C 23 In an embodiment, L is an alkylene. 3are independently substituted or unsubstituted C1-C 12 In an embodiment, L is an alkylene. 3 are independently substituted C1 to C 12 In an embodiment, L is an alkylene. 3 are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 3 is independently a substituted or unsubstituted C1-C8 alkylene. 3 is independently a substituted C1-C8 alkylene. 3 is independently an unsubstituted C1-C8 alkylene. 3 is independently a substituted or unsubstituted C1-C6 alkylene. 3 is independently a substituted C1-C6 alkylene. 3 is independently an unsubstituted C1-C6 alkylene. 3 is independently a substituted or unsubstituted C1-C4 alkylene. 3 is independently a substituted C1-C4 alkylene. 3 is independently an unsubstituted C1-C4 alkylene. 3 is independently substituted or unsubstituted ethylene. 3 is independently a substituted ethylene. 3 is independently unsubstituted ethylene. 3 is independently substituted or unsubstituted methylene. 3 is independently a substituted methylene. 3 is independently unsubstituted methylene.

[0237] In an embodiment, L 3 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 3is independently a substituted heteroalkylene (e.g., 2 to 23-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 3 is independently an unsubstituted heteroalkylene (e.g., 2 to 23-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 3 is independently a substituted or unsubstituted 2- to 23-membered heteroalkylene. 3 is independently a substituted 2- to 23-membered heteroalkylene. 3 is independently an unsubstituted 2- to 23-membered heteroalkylene. 3 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 3 is independently a substituted 2-8 membered heteroalkylene. 3 is independently an unsubstituted 2-8 membered heteroalkylene. 3 is independently a substituted or unsubstituted 2- to 6-membered heteroalkylene. 3 is independently a substituted 2- to 6-membered heteroalkylene. 3 is independently an unsubstituted 2- to 6-membered heteroalkylene. 3 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 3 is independently a substituted 4- to 6-membered heteroalkylene. 3 is independently an unsubstituted 4- to 6-membered heteroalkylene. 3 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 3 is independently a substituted 2-3 membered heteroalkylene. 3 is independently an unsubstituted 2-3 membered heteroalkylene. 3 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 3is independently a substituted 4- to 5-membered heteroalkylene. 3 is independently an unsubstituted 4- to 5-membered heteroalkylene.

[0238] In an embodiment, L 4 is a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 )-O-, -SS-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0239] In an embodiment, L 4 is a bond. In embodiments, L 4 is -N(R 23 In an embodiment, L 4is —O— or —S—. In an embodiment, L 4 is —C(O)—. In an embodiment, L 4 is -N(R 23 )C(O)- or -C(O)N(R 24 )-. In an embodiment, L 4 is -N(R 23 )C(O)N(R 24 In an embodiment, L 4 is —C(O)O— or —OC(O)—. In an embodiment, L 4 is -N(R 23 )C(O)O- or -OC(O)N(R 24 In an embodiment, L 4 -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, or -OP(O)(NR 23 R 24 )-O-. In an embodiment, L 4 is -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O- or -P(S)(NR 23 R 24 )-O-. In an embodiment, L 4 is -SS-.

[0240] In an embodiment, L 4 are independently substituted or unsubstituted alkylene (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 4 are independently substituted alkylene (e.g., C1-C 23 , 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 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 4 are independently substituted or unsubstituted C1-C 23 In an embodiment, L is an alkylene. 4 are independently substituted C1 to C 23 In an embodiment, L is an alkylene. 4 are independently unsubstituted C1 to C 23 In an embodiment, L is an alkylene. 4 are independently substituted or unsubstituted C1-C 12 In an embodiment, L is an alkylene. 4 are independently substituted C1 to C 12 In an embodiment, L is an alkylene. 4 are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 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. 4is independently a substituted ethylene. 4 is independently unsubstituted ethylene. 4 is independently substituted or unsubstituted methylene. 4 is independently a substituted methylene. 4 is independently unsubstituted methylene.

[0241] In an embodiment, L 4 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 23-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 4 is independently a substituted heteroalkylene (e.g., 2 to 23-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 4 is independently an unsubstituted heteroalkylene (e.g., 2 to 23-membered, 2 to 12-membered, 2 to 8-membered, 2 to 6-membered, 4 to 6-membered, 2 to 3-membered, or 4 to 5-membered). 4 is independently a substituted or unsubstituted 2- to 23-membered heteroalkylene. 4 is independently a substituted 2- to 23-membered heteroalkylene. 4 is independently an unsubstituted 2- to 23-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 an 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 an unsubstituted 2- to 6-membered heteroalkylene. 4is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 4 is independently a substituted 4- to 6-membered heteroalkylene. 4 is independently an 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 an 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.

[0242] R 23 are independently hydrogen or unsubstituted alkyl (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 23 is independently hydrogen. 23 are independently unsubstituted C1 to C 23 In embodiments, R 23 are independently hydrogen or unsubstituted C1-C 12 In embodiments, R 23 are independently hydrogen or unsubstituted C1-C 10 In embodiments, R 23 is independently hydrogen or unsubstituted C1-C8 alkyl. 23 is independently hydrogen or unsubstituted C1-C6 alkyl. 23 is independently hydrogen or unsubstituted C1-C4 alkyl. 23 are independently hydrogen or unsubstituted C1-C2 alkyl.

[0243] R 24 are independently hydrogen or unsubstituted alkyl (e.g., C1-C 24 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 24 is independently hydrogen. 24 are independently unsubstituted C1 to C 24 In embodiments, R 24 are independently hydrogen or unsubstituted C1-C 12 In embodiments, R 24 are independently hydrogen or unsubstituted C1-C 10 In embodiments, R 24 is independently hydrogen or unsubstituted C1-C8 alkyl. 24 is independently hydrogen or unsubstituted C1-C6 alkyl. 24 is independently hydrogen or unsubstituted C1-C4 alkyl. 24 are independently hydrogen or unsubstituted C1-C2 alkyl.

[0244] R 25 are independently hydrogen or unsubstituted alkyl (e.g., C1-C 25 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 25 is independently hydrogen. 25 are independently unsubstituted C1 to C 25 In embodiments, R 25 are independently hydrogen or unsubstituted C1-C 12 In embodiments, R 25 are independently hydrogen or unsubstituted C1-C 10 In embodiments, R 25 is independently hydrogen or unsubstituted C1-C8 alkyl. 25is independently hydrogen or unsubstituted C1-C6 alkyl. 25 is independently hydrogen or unsubstituted C1-C4 alkyl. 25 are independently hydrogen or unsubstituted C1-C2 alkyl.

[0245] In an embodiment, L 3 and L 4 are independently a bond, —NH—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —OPO—O—, —OP(O)(S)—O—, —OP(O)(CH)—O—, —OP(S)(CH)—O—, —OP(O)(N(CH))—N—, —OP(O)(N(CH))—O—, —OP(S)(N(CH))—N—, —OP(S)(N(CH))—O—, —P(O)(N(CH))—N—, —P(O)(N(CH))—O—, —P(S)(N(CH))—N—, —P(S)(N(CH))—O—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In an embodiment, L 3 are independently a bond, —NH—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —OPO—O—, —OP(O)(S)—O—, —OP(O)(CH)—O—, —OP(S)(CH)—O—, —OP(O)(N(CH))—N—, —OP(O)(N(CH))—O—, —OP(S)(N(CH))—N—, —OP(S)(N(CH))—O—, —P(O)(N(CH))—N—, —P(O)(N(CH))—O—, —P(S)(N(CH))—N—, —P(S)(N(CH))—O—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In an embodiment, L 4are independently a bond, —NH—, —O—, —C(O)—, —C(O)O—, —OC(O)—, —OPO—O—, —OP(O)(S)—O—, —OP(O)(CH)—O—, —OP(S)(CH)—O—, —OP(O)(N(CH))—N—, —OP(O)(N(CH))—O—, —OP(S)(N(CH))—N—, —OP(S)(N(CH))—O—, —P(O)(N(CH))—N—, —P(O)(N(CH))—O—, —P(S)(N(CH))—N—, —P(S)(N(CH))—O—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0246] In an embodiment, L 3 is, independently, [ka] In an embodiment, L 3 is independently -OPO2-O-. In an embodiment, L 3 is independently -OP(O)(S)-O-. In an embodiment, L 3 is independently —O—. In an embodiment, L 3 are independently -S-.

[0247] In an embodiment, L 4 is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 In an embodiment, 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).

[0248] In an embodiment, L 4 is independently a substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 4 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 4 is independently an oxo-substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 4 is independently unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered).

[0249] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; 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). 4 independently, -L 7 -NH-C(O)-; 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). 4 independently, -L 7 -C(O)-NH-; L 7are 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).

[0250] In an embodiment, 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 an embodiment, L is an alkylene. 7 are independently substituted C1 to C 20 In an embodiment, L is an alkylene. 7 are independently hydroxy (OH)-substituted C1-C 20 In an embodiment, L is an alkylene. 7 are independently hydroxymethyl-substituted C1-C 20 In an embodiment, L is an alkylene. 7 are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 7 are independently substituted or unsubstituted C1-C 12 In an embodiment, L is an alkylene. 7 are independently substituted C1 to C 12 In an embodiment, L is an alkylene. 7 are independently hydroxy (OH)-substituted C1-C 12 In an embodiment, L is an alkylene. 7are independently hydroxymethyl-substituted C1-C 12 In an embodiment, L is an alkylene. 7 are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 7 is independently a substituted or unsubstituted C1-C8 alkylene. 7 is independently a substituted C1-C8 alkylene. 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 7 is independently a hydroxymethyl-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 a hydroxy (OH)-substituted C1-C6 alkylene. 7 is independently a hydroxymethyl-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 a hydroxy (OH)-substituted C1-C4 alkylene. 7 is independently a hydroxymethyl-substituted C1-C4 alkylene. 7 is independently an unsubstituted C1-C4 alkylene. 7 is independently a substituted or unsubstituted C1-C2 alkylene. 7 is independently a substituted C1-C2 alkylene. 7is independently a hydroxy (OH)-substituted C1-C2 alkylene. 7 is independently a hydroxymethyl-substituted C1-C2 alkylene. 7 is independently an unsubstituted C1-C2 alkylene.

[0251] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; 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). 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted C1-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently an unsubstituted C1-C8 alkylene.

[0252] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted C3-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently an unsubstituted C3-C8 alkylene.

[0253] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted C5-C8 alkylene. 4 independently, -L 7-NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently an unsubstituted C5-C8 alkylene.

[0254] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently substituted or unsubstituted octylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted octylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted octylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently unsubstituted octylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently a hydroxy (OH)-substituted octylene. 4 independently, -L 7-NH-C(O)-, and L 7 is independently a hydroxymethyl-substituted octylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently unsubstituted octylene.

[0255] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently substituted or unsubstituted heptylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted heptylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted heptylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently unsubstituted heptylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently a hydroxy (OH)-substituted heptylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently a hydroxymethyl-substituted heptylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently unsubstituted heptylene.

[0256] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently substituted or unsubstituted hexylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a substituted hexylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted hexylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently unsubstituted hexylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently a hydroxy (OH)-substituted hexylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently a hydroxymethyl-substituted hexylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently unsubstituted hexylene.

[0257] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently substituted or unsubstituted pentylene. 4 independently, -L 7 -NH-C(O)- or -L 7-C(O)-NH-; L 7 is independently a substituted pentylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted pentylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-; L 7 is independently unsubstituted pentylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently a hydroxy (OH)-substituted pentylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently a hydroxymethyl-substituted pentylene. 4 independently, -L 7 -NH-C(O)-, and L 7 is independently unsubstituted pentylene.

[0258] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] is.

[0259] In an embodiment, -L 3 -L 4 - is independently, -L 7 -NH-C(O)- or -L 7 In an embodiment, L 7 is independently a substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 7 is independently a substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 7 is independently an oxo-substituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 7 is independently an unsubstituted heteroalkylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 7 is independently substituted or unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 7 is independently a substituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 7 is independently oxo-substituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered). 7 is independently unsubstituted heteroalkenylene (e.g., 2 to 20-membered, 2 to 12-membered, 2 to 10-membered, 2 to 8-membered, 2 to 6-membered, or 2 to 4-membered).

[0260] In an embodiment, L 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 an oxo-substituted 2- to 20-membered heteroalkylene. 7 is independently an 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 an oxo-substituted 2- to 12-membered heteroalkylene. 7 is independently an unsubstituted 2- to 12-membered heteroalkylene. 7 is independently a substituted or unsubstituted 2- to 10-membered heteroalkylene. 7 is independently a substituted 2- to 10-membered heteroalkylene. 7 is independently an oxo-substituted 2- to 10-membered heteroalkylene. 7 is independently an unsubstituted 2- to 10-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 an oxo-substituted 2-8 membered heteroalkylene. 7 is independently an 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 an oxo-substituted 2- to 6-membered heteroalkylene. 7 is independently an unsubstituted 2- to 6-membered heteroalkylene. 7 is independently a substituted or unsubstituted 2-4 membered heteroalkylene. 7is independently a substituted 2-4 membered heteroalkylene. 7 is independently an oxo-substituted 2-4 membered heteroalkylene. 7 is independently an unsubstituted 2- to 4-membered heteroalkylene.

[0261] In an embodiment, L 7 is independently a substituted or unsubstituted 2- to 20-membered heteroalkenylene. 7 is independently a substituted 2- to 20-membered heteroalkenylene. 7 is independently an oxo-substituted 2- to 20-membered heteroalkenylene. 7 is independently unsubstituted 2- to 20-membered heteroalkenylene. 7 is independently a substituted or unsubstituted 2- to 12-membered heteroalkenylene. 7 is independently a substituted 2- to 12-membered heteroalkenylene. 7 is independently an oxo-substituted 2- to 12-membered heteroalkenylene. 7 is independently unsubstituted 2- to 12-membered heteroalkenylene. 7 is independently a substituted or unsubstituted 2- to 10-membered heteroalkenylene. 7 is independently a substituted 2- to 10-membered heteroalkenylene. 7 is independently an oxo-substituted 2- to 10-membered heteroalkenylene. 7 is independently unsubstituted 2-10 membered heteroalkenylene. 7 is independently a substituted or unsubstituted 2-8 membered heteroalkenylene. 7 is independently a substituted 2-8 membered heteroalkenylene. 7 is independently an oxo-substituted 2-8 membered heteroalkenylene. 7is independently an unsubstituted 2-8 membered heteroalkenylene. 7 is independently a substituted or unsubstituted 2- to 6-membered heteroalkenylene. 7 is independently a substituted 2- to 6-membered heteroalkenylene. 7 is independently an oxo-substituted 2- to 6-membered heteroalkenylene. 7 is independently unsubstituted 2- to 6-membered heteroalkenylene. 7 is independently a substituted or unsubstituted 2-4 membered heteroalkenylene. 7 is independently a substituted 2-4 membered heteroalkenylene. 7 is independently an oxo-substituted 2-4 membered heteroalkenylene. 7 is independently unsubstituted 2-4 membered heteroalkenylene.

[0262] In an embodiment, -L 3 -L 4 - is independently, -L 7 -NH-C(O)- or -OL 7 In an embodiment, 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). 3 -L 4 - is independently, -OL 7 -NH-C(O)- or -OL 7 -C(O)-NH-; 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). 3 -L 4 - is independently, -OL 7 -NH-C(O)-; L 7are 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). 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; 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).

[0263] In an embodiment, L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C1-C8 alkylene.

[0264] In an embodiment, -L 3 -L 4 - is, independently, -OL7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L 4 - independently, OL 7 -C(O)-NH-; L 7 is independently a substituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C3-C8 alkylene.

[0265] In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7-C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C5-C8 alkylene.

[0266] In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently an unsubstituted C1-C8 alkylene.

[0267] In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a substituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently an unsubstituted C3-C8 alkylene.

[0268] In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 3 -L4 - is independently, -OL 7 -NH-C(O)-; L 7 is independently an unsubstituted C5-C8 alkylene.

[0269] In an embodiment, -L 3 -L 4 - is independently [ka] , [ka] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] is.

[0270] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-, -OP(O)(S)-OL 7 -NH-C(O)-, -OPO2-OL 7 -C(O)-NH- or -OP(O)(S)-OL 7 In an embodiment, L 7are 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). 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)- or -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently substituted or unsubstituted alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently substituted or unsubstituted alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently substituted or unsubstituted alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH- or -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently substituted or unsubstituted alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently substituted or unsubstituted alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently substituted or unsubstituted alkylene.

[0271] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7-NH-C(O)- or -OPO2-OL 7 -C(O)-NH-; 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). In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; 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). 3 -L 4 - is independently -OPO2-O-L7-C(O)-NH-; 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).

[0272] In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)- or -OP(O)(S)-OL 7 -C(O)-NH-; 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). In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-L 7 -NH-C(O)-; 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).3 -L 4 - is independently -OP(O)(S)-L 7 -C(O)-NH-; 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).

[0273] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C1-C8 alkylene.

[0274] In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C1-C8 alkylene.

[0275] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a substituted C3-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. 3 -L 4- is independently -OPO2-OL 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C3-C8 alkylene.

[0276] In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a substituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C3-C8 alkylene.

[0277] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7-C(O)-NH-; L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C5-C8 alkylene.

[0278] In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. 3 -L4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -C(O)-NH-; L 7 is independently an unsubstituted C5-C8 alkylene.

[0279] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 3 -L 4 - is independently -OPO2-L 7 -NH-C(O)-; L 7 is independently an unsubstituted C1-C8 alkylene.

[0280] In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-OL 7-NH-C(O)-; L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)2-OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently an unsubstituted C1-C8 alkylene.

[0281] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a substituted C3-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. 3-L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. 3 -L 4 - is independently -OPO2-L 7 -NH-C(O)-; L 7 is independently an unsubstituted C3-C8 alkylene.

[0282] In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a substituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently an unsubstituted C3-C8 alkylene.

[0283] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 3 -L 4 - is independently -OPO2-L 7 -NH-C(O)-; L 7 is independently an unsubstituted C5-C8 alkylene.

[0284] In an embodiment, -L 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a hydroxy (OH)-substituted C5-C8 alkylene.3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 3 -L 4 - is independently -OP(O)(S)-OL 7 -NH-C(O)-; L 7 is independently an unsubstituted C5-C8 alkylene.

[0285] In an embodiment, -L 3 -L 4 - is attached to the 3' carbon of a nucleotide of the sense strand. 3 -L 4 - is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand. 3 -L 4 - is attached to the 3' carbon of the antisense sense strand. 3 -L 4 - is attached to the 3' carbon of the 3' terminal nucleotide of the antisense sense strand.

[0286] In an embodiment, -L 3 -L 4 - is attached to the 5' carbon of a nucleotide of the sense strand. 3 -L 4 - is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand. 3 -L 4 - is attached to the 5' carbon of a nucleotide of the antisense strand. 3 -L 4 - is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0287] In an embodiment, -L 3 -L 4 - is attached to the 2' carbon of a nucleotide of the sense strand. 3 -L4 - is attached to the 2' carbon of a nucleotide in the antisense strand.

[0288] In an embodiment, -L 3 -L 4 - is attached to a nucleobase of the sense strand. 3 -L 4 - is attached to the nucleobase of the antisense strand.

[0289] In an embodiment, -L 3 -L 4 - is independently [ka] is.

[0290] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] is.

[0291] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand.

[0292] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0293] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand.

[0294] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0295] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand.

[0296] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0297] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand.

[0298] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0299] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand.

[0300] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0301] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand.

[0302] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0303] In an embodiment, -L 3 -L 4 - is independently attached to a nucleobase of the sense strand. 3 -L 4 - is independently [ka] and is attached to the nucleobase of the sense strand. In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the nucleobase of the antisense strand.

[0304] In an embodiment, -L 3 -L 4 - is independently [ka] is.

[0305] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand.

[0306] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0307] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand.

[0308] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0309] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand.

[0310] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0311] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand.

[0312] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0313] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand.

[0314] In an embodiment, -L 3 -L 4 - is independently [ka] which is attached to the 3' carbon of the 3' terminal nucleotide of the antisense strand.

[0315] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the 5' terminal nucleotide of the sense strand.

[0316] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the 5' terminal nucleotide of the antisense strand.

[0317] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 2' carbon of a nucleotide in the sense strand.

[0318] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 2' carbon of a nucleotide in the antisense strand.

[0319] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 2' carbon of a nucleotide in the sense strand.

[0320] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 2' carbon of a nucleotide in the antisense strand.

[0321] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the nucleobase of the sense strand.

[0322] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the nucleobase of the antisense strand.

[0323] In embodiments, R 3 are independently hydrogen, —NH, —OH, —SH, —C(O)H, —C(O)NH, —NHC(O)H, —NHC(O)OH, —NHC(O)NH, —C(O)OH, —OC(O)H, —N, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In an embodiment, R 3 is independently hydrogen. 3is independently —NH. In an embodiment, R 3 is independently —OH. In an embodiment, R 3 is independently -SH. In an embodiment, R 3 is independently —C(O)H. In an embodiment, R 3 is independently —C(O)NH. In an embodiment, R 3 is independently —NHC(O)H. In an embodiment, R 3 is independently —NHC(O)OH. In an embodiment, R 3 is independently —NHC(O)NH. In an embodiment, R 3 is independently —C(O)OH. In an embodiment, R 3 is independently —OC(O)H. In an embodiment, R 3 are independently -N3.

[0324] In embodiments, R 3 are independently substituted or unsubstituted alkyl (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 3 are independently substituted or unsubstituted C1-C 20 In embodiments, R 3 are independently substituted C1 to C 20 In embodiments, R 3 are independently unsubstituted C1 to C 20 In embodiments, R 3 are independently substituted or unsubstituted C1-C 12 In embodiments, R 3 are independently substituted C1 to C 12 In embodiments, R 3 are independently unsubstituted C1 to C 12 In embodiments, R 3 is independently a substituted or unsubstituted C1-C8 alkyl. 3is independently a substituted C1-C8 alkyl. 3 is independently an unsubstituted C1-C8 alkyl. 3 is independently a substituted or unsubstituted C1-C6 alkyl. 3 is independently a substituted C1-C6 alkyl. 3 is independently an unsubstituted C1-C6 alkyl. 3 is independently a substituted or unsubstituted C1-C4 alkyl. 3 is independently a substituted C1-C4 alkyl. 3 is independently an unsubstituted C1-C4 alkyl. 3 is independently substituted or unsubstituted ethyl. In an embodiment, R 3 is independently substituted ethyl. In an embodiment, R 3 is independently unsubstituted ethyl. In an embodiment, R 3 is independently substituted or unsubstituted methyl. In an embodiment, R 3 is independently a substituted methyl. 3 is independently unsubstituted methyl.

[0325] In an embodiment, L 6 is independently —NHC(O)—. In an embodiment, L 6 is independently —C(O)NH—. In an embodiment, L 6 is independently substituted or unsubstituted alkylene. 6 is independently substituted or unsubstituted heteroalkylene.

[0326] In an embodiment, 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). 6are 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 an embodiment, L is an alkylene. 6 are independently substituted C1 to C 20 In an embodiment, L is an alkylene. 6 are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 6 are independently substituted or unsubstituted C1-C 12 In an embodiment, L is an alkylene. 6 are independently substituted C1 to C 12 In an embodiment, L is an alkylene. 6 are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 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. 6 is 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. 6 is independently substituted or unsubstituted methylene. 6 is independently a substituted methylene. 6 is independently unsubstituted methylene.

[0327] In an embodiment, L 6 is independently a 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. 6 is independently an unsubstituted 2- to 20-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 an 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. 6is independently an 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 an 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 an 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.

[0328] In an embodiment, L 6A are independently a bond or unsubstituted alkylene; L 6B are independently a bond, —NHC(O)—, or unsubstituted arylene; L 6C are independently a bond, unsubstituted alkylene, or unsubstituted arylene; L 6D are independently a bond or unsubstituted alkylene; L 6E is independently a bond or —NHC(O)—. 6A is independently a bond or unsubstituted alkylene. 6B is independently a bond, —NHC(O)—, or unsubstituted arylene. 6C is independently a bond, unsubstituted alkylene, or unsubstituted arylene. 6D is independently a bond or unsubstituted alkylene. 6E is independently a bond or —NHC(O)—.

[0329] In an embodiment, L 6A are independently a bond or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 6A are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 6A are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 6A is independently an unsubstituted C1-C8 alkylene. 6A is independently an unsubstituted C1-C6 alkylene. 6A is independently an unsubstituted C1-C4 alkylene. 6A is independently unsubstituted ethylene. 6A is independently unsubstituted methylene. 6A are independently bonds.

[0330] In an embodiment, L 6B is independently a bond. 6B is independently —NHC(O)—. In an embodiment, L 6B are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl). In an embodiment, L 6B are independently unsubstituted C6-C 12 In embodiments, L 6B are independently unsubstituted C6-C 10 In embodiments, L 6B is independently unsubstituted phenylene. 6B is independently unsubstituted naphthylene. 6B is independently unsubstituted biphenylene.

[0331] In an embodiment, L 6C are independently a bond or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 6C are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 6C are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 6C is independently an unsubstituted C1-C8 alkylene. 6C is independently unsubstituted C2-C8 alkynylene. 6C is independently an unsubstituted C1-C6 alkylene. 6C is independently an unsubstituted C1-C4 alkylene. 6C is independently unsubstituted ethylene. 6C is independently unsubstituted methylene. 6C are independently a bond or unsubstituted alkynylene (e.g., C-C 20 , C2~C 12 , C2 to C8, C2 to C6, C2 to C4, or C2 to C2). 6C are independently unsubstituted C2 to C 20 In embodiments, L is alkynylene. 6C are independently unsubstituted C2 to C 12 In embodiments, L is alkynylene. 6C is independently unsubstituted C2-C8 alkynylene. 6C is independently unsubstituted C2-C6 alkynylene. 6C is independently an unsubstituted C2-C4 alkynylene. 6C is independently unsubstituted ethynylene. 6C are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10, or phenyl). In an embodiment, L 6C are independently unsubstituted C6-C 12 In embodiments, L 6C are independently unsubstituted C6-C 10 In embodiments, L 6C is independently unsubstituted phenylene. 6C is independently unsubstituted naphthylene. 6C are independently bonds.

[0332] In an embodiment, L 6D are independently a bond or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 6D are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 6D are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 6A is independently an unsubstituted C1-C8 alkylene. 6D is independently an unsubstituted C1-C6 alkylene. 6D is independently an unsubstituted C1-C4 alkylene. 6D is independently unsubstituted ethylene. 6D is independently unsubstituted methylene. 6D are independently bonds.

[0333] In an embodiment, L 6E is independently a bond. 6E are independently —NHC(O)—.

[0334] In an embodiment, L 6A is independently a bond or unsubstituted C1-C8 alkylene.6B is independently a bond, —NHC(O)—, or unsubstituted phenylene. 6C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene. 6D is independently a bond or unsubstituted C1-C8 alkylene. 6E is independently a bond or —NHC(O)—.

[0335] In an embodiment, L 6 are independent, combined, [ka] In an embodiment, L 6 is independently a bond. 6 is, independently, [ka] In an embodiment, L 6 is, independently, [ka] In an embodiment, L 6 is, independently, [ka] In an embodiment, L 6 is, independently, [ka] In an embodiment, L 6 is, independently, [ka] is.

[0336] In an embodiment, L 5 is independently —NHC(O)—. In an embodiment, L 5 is independently —C(O)NH—. In an embodiment, L 5 is independently substituted or unsubstituted alkylene. 5 is independently substituted or unsubstituted heteroalkylene.

[0337] In an embodiment, 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 an embodiment, L is an alkylene. 5 are independently substituted C1 to C 20 In an embodiment, L is an alkylene. 5 are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 5 are independently substituted or unsubstituted C1-C 12 In an embodiment, L is an alkylene. 5 are independently substituted C1 to C 12 In an embodiment, L is an alkylene. 5 are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 5 is independently a substituted or unsubstituted C1-C8 alkylene. 5is 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. 5 is independently substituted or unsubstituted methylene. 5 is independently a substituted methylene. 5 is independently unsubstituted methylene.

[0338] In an embodiment, L 5 is independently a 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. 5is independently a substituted 2- to 20-membered heteroalkylene. 5 is independently an unsubstituted 2- to 20-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 an 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 an unsubstituted 2- to 6-membered heteroalkylene. 5 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 5 is independently a substituted 4- to 6-membered heteroalkylene. 5 is independently an 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 an 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.

[0339] In an embodiment, L 5A are independently a bond or unsubstituted alkylene; L 5B are independently a bond, —NHC(O)—, or unsubstituted arylene; L 5Care independently a bond, unsubstituted alkylene, or unsubstituted arylene; L 5D are independently a bond or unsubstituted alkylene; L 5E is independently a bond or —NHC(O)—. 5A is independently a bond or unsubstituted alkylene. 5B is independently a bond, —NHC(O)—, or unsubstituted arylene. 5C is independently a bond, unsubstituted alkylene, or unsubstituted arylene. 5D is independently a bond or unsubstituted alkylene. 5E is independently a bond or —NHC(O)—.

[0340] In an embodiment, L 5A are independently a bond or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 5A are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 5A are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 5A is independently an unsubstituted C1-C8 alkylene. 5A is independently an unsubstituted C1-C6 alkylene. 5A is independently an unsubstituted C1-C4 alkylene. 5A is independently unsubstituted ethylene. 5A is independently unsubstituted methylene. 5A are independently bonds.

[0341] In an embodiment, L 5B is independently a bond. 5Bis independently —NHC(O)—. In an embodiment, L 5B are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl). In an embodiment, L 5B are independently unsubstituted C6-C 12 In embodiments, L 5B are independently unsubstituted C6-C 10 In embodiments, L 5B is independently unsubstituted phenylene. 5B is independently unsubstituted naphthylene.

[0342] In an embodiment, L 5C are independently a bond or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 5C are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 5C are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 5C is independently an unsubstituted C1-C8 alkylene. 5C is independently unsubstituted C2-C8 alkynylene. 5C is independently an unsubstituted C1-C6 alkylene. 5C is independently an unsubstituted C1-C4 alkylene. 5C is independently unsubstituted ethylene. 5C is independently unsubstituted methylene. 5C are independently a bond or unsubstituted alkynylene (e.g., C-C 20 , C2~C 12 , C2 to C8, C2 to C6, C2 to C4, or C2 to C2). 5C are independently unsubstituted C2 to C20 In embodiments, L is alkynylene. 5C are independently unsubstituted C2 to C 12 In embodiments, L is alkynylene. 5C is independently unsubstituted C2-C8 alkynylene. 5C is independently unsubstituted C2-C6 alkynylene. 5C is independently an unsubstituted C2-C4 alkynylene. 5C is independently unsubstituted ethynylene. 5C are independently unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl). In an embodiment, L 5C are independently unsubstituted C6-C 12 In embodiments, L 5C are independently unsubstituted C6-C 10 In embodiments, L 5C is independently unsubstituted phenylene. 5C is independently unsubstituted naphthylene. 5C are independently bonds.

[0343] In an embodiment, L 5D are independently a bond or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 5D are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 5D are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 5A is independently an unsubstituted C1-C8 alkylene. 5D is independently an unsubstituted C1-C6 alkylene. 5Dis independently an unsubstituted C1-C4 alkylene. 5D is independently unsubstituted ethylene. 5D is independently unsubstituted methylene. 5D are independently bonds.

[0344] In an embodiment, L 5E is independently a bond. 5E are independently —NHC(O)—.

[0345] In an embodiment, L 5A is independently a bond or unsubstituted C1-C8 alkylene. 5B is independently a bond, —NHC(O)—, or unsubstituted phenylene. 5C is independently a bond, unsubstituted C2-C8 alkynylene, or unsubstituted phenylene. 5D is independently a bond or unsubstituted C1-C8 alkylene. 5E is independently a bond or —NHC(O)—.

[0346] In an embodiment, L 5 are independent, combined, [ka] In an embodiment, L 5 is independently a bond. 5 is, independently, [ka] In an embodiment, L 5 is, independently, [ka] In an embodiment, L5 is, independently, [ka] In an embodiment, L 5 is, independently, [ka] In an embodiment, L 5 is, independently, [ka] is.

[0347] In embodiments, R 1 is an unsubstituted alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1 is an unsubstituted unbranched alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1 is an unsubstituted unbranched saturated alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 1 is an unsubstituted unbranched unsaturated alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2).

[0348] In embodiments, R1 is unsubstituted C1 to C 17 In embodiments, R 1 is the unsubstituted C 11 ~C 17 In embodiments, R 1 is the unsubstituted C 13 ~C 17 In embodiments, R 1 is the unsubstituted C 14 ~C 15 In embodiments, R 1 is the unsubstituted C 15 In embodiments, R 1 is the unsubstituted C 14 It is alkyl.

[0349] In embodiments, R 1 is unsubstituted unbranched C1 to C 17 In embodiments, R 1 is an unsubstituted unbranched C 11 ~C 17 In embodiments, R 1 is an unsubstituted unbranched C 13 ~C 17 In embodiments, R 1 is an unsubstituted unbranched C 14 ~C 15 In embodiments, R 1 is an unsubstituted unbranched C 14 In embodiments, R 1 is an unsubstituted unbranched C 15 It is alkyl.

[0350] In embodiments, R 1 is unsubstituted unbranched saturated C1~C 17 In embodiments, R 1 is an unsubstituted unbranched saturated C 11 ~C 17 In embodiments, R 1 is an unsubstituted unbranched saturated C 13 ~C 17 In embodiments, R 1is an unsubstituted unbranched saturated C 14 ~C 15 In embodiments, R 1 is an unsubstituted unbranched saturated C 14 In embodiments, R 1 is an unsubstituted unbranched saturated C 15 It is alkyl.

[0351] In embodiments, R 1 is an unsubstituted unbranched unsaturated C1-C 17 In embodiments, R 1 is an unsubstituted unbranched unsaturated C 11 ~C 17 In embodiments, R 1 is an unsubstituted unbranched unsaturated C 13 ~C 17 In embodiments, R 1 is an unsubstituted unbranched unsaturated C 14 ~C 15 In embodiments, R 1 is an unsubstituted unbranched unsaturated C 14 In embodiments, R 1 is an unsubstituted unbranched unsaturated C 15 It is alkyl.

[0352] In embodiments, R 2 is an unsubstituted alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2 is an unsubstituted unbranched alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 2 is an unsubstituted unbranched saturated alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2).

[0353] In embodiments, R 2 is an unsubstituted unbranched unsaturated alkyl (e.g., C1-C 25 , C1~C 20 , C1~C 17 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2).

[0354] In embodiments, R 2 is unsubstituted C1 to C 17 In embodiments, R 2 is the unsubstituted C 11 ~C 17 In embodiments, R 2 is the unsubstituted C 13 ~C 17 In embodiments, R 2 is the unsubstituted C 14 ~C 15 In embodiments, R 2 is the unsubstituted C 14 In embodiments, R 2 is the unsubstituted C 15 It is alkyl.

[0355] In embodiments, R 2 is unsubstituted unbranched C1 to C 17 In embodiments, R 2 is an unsubstituted unbranched C 11 ~C 17 In embodiments, R 2 is an unsubstituted unbranched C 13 ~C 17 In embodiments, R 2 is an unsubstituted unbranched C 14 ~C 15 In embodiments, R 2 is an unsubstituted unbranched C 14 In embodiments, R 2 is an unsubstituted unbranched C15 It is alkyl.

[0356] In embodiments, R 2 is unsubstituted unbranched saturated C1~C 17 In embodiments, R 2 is an unsubstituted unbranched saturated C 11 ~C 17 In embodiments, R 2 is an unsubstituted unbranched saturated C 13 ~C 17 In embodiments, R 2 is an unsubstituted unbranched saturated C 14 ~C 15 In embodiments, R 2 is an unsubstituted unbranched saturated C 14 In embodiments, R 2 is an unsubstituted unbranched saturated C 15 It is alkyl.

[0357] In embodiments, R 2 is an unsubstituted unbranched unsaturated C1-C 17 In embodiments, R 2 is an unsubstituted unbranched unsaturated C 11 ~C 17 In embodiments, R 2 is an unsubstituted unbranched unsaturated C 13 ~C 17 In embodiments, R 2 is an unsubstituted unbranched unsaturated C 14 ~C 15 In embodiments, R 2 is an unsubstituted unbranched unsaturated C 14 In embodiments, R 2 is an unsubstituted unbranched unsaturated C 15 It is alkyl.

[0358] In embodiments, R 1 and R 2 At least one of the following is unsubstituted C1 to C 19 In embodiments, R 1 and R2 At least one of the following is unsubstituted C9-C 19 In embodiments, R 1 and R 2 At least one of the groups is unsubstituted C 11 ~C 19 In embodiments, R 1 and R 2 At least one of the groups is unsubstituted C 13 ~C 19 It is alkyl.

[0359] In embodiments, R 1 is unsubstituted C1 to C 19 In embodiments, R 1 is unsubstituted C9-C 19 In embodiments, R 1 is the unsubstituted C 11 ~C 19 In embodiments, R 1 is the unsubstituted C 13 ~C 19 In embodiments, R 1 is unsubstituted unbranched C1 to C 19 In embodiments, R 1 is unsubstituted unbranched C9-C 19 In embodiments, R 1 is an unsubstituted unbranched C 11 ~C 19 In embodiments, R 1 is an unsubstituted unbranched C 13 ~C 19 In embodiments, R 1 is unsubstituted unbranched saturated C1~C 19 In embodiments, R 1 is unsubstituted unbranched saturated C9-C 19 In embodiments, R 1 is an unsubstituted unbranched saturated C 11 ~C 19 In embodiments, R 1 is an unsubstituted unbranched saturated C 13 ~C 19In embodiments, R 1 is an unsubstituted unbranched unsaturated C1-C 19 In embodiments, R 1 is an unsubstituted unbranched unsaturated C9-C 19 In embodiments, R 1 is an unsubstituted unbranched unsaturated C 11 ~C 19 In embodiments, R 1 is an unsubstituted unbranched unsaturated C 13 ~C 19 It is alkyl.

[0360] In embodiments, R 2 is unsubstituted C1 to C 19 In embodiments, R 2 is unsubstituted C9-C 19 In embodiments, R 2 is the unsubstituted C 11 ~C 19 In embodiments, R 2 is the unsubstituted C 13 ~C 19 In embodiments, R 2 is unsubstituted unbranched C1 to C 19 In embodiments, R 2 is unsubstituted unbranched C9-C 19 In embodiments, R 2 is an unsubstituted unbranched C 11 ~C 19 In embodiments, R 2 is an unsubstituted unbranched C 13 ~C 19 In embodiments, R 2 is unsubstituted unbranched saturated C1~C 19 In embodiments, R 2 is unsubstituted unbranched saturated C9-C 19 In embodiments, R 2 is an unsubstituted unbranched saturated C 11 ~C 19 In embodiments, R 2is an unsubstituted unbranched saturated C 13 ~C 19 In embodiments, R 2 is an unsubstituted unbranched unsaturated C1-C 19 In embodiments, R 2 is an unsubstituted unbranched unsaturated C9-C 19 In embodiments, R 2 is an unsubstituted unbranched unsaturated C 11 ~C 19 In embodiments, R 2 is an unsubstituted unbranched unsaturated C 13 ~C 19 It is alkyl.

[0361] L 1A are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). In an embodiment, L 1A are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered).

[0362] In an embodiment, L 1A are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20)C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, 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), unsubstituted cycloalkylene (e.g., C3 to C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1A When is substituted, L 1A is substituted with a substituent. 1A When is substituted, L 1A is substituted with size-constrained substituents. 1A When is substituted, L 1A is substituted with a lower substituent.

[0363] L1B are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1B are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered).

[0364] In an embodiment, L 1B are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1B When is substituted, L 1B is substituted with a substituent. 1B When is substituted, L 1B is substituted with size-constrained substituents. 1B When is substituted, L 1B is substituted with a lower substituent.

[0365] L 1C are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1Care independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered).

[0366] In an embodiment, L 1C are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, unsubstituted alkylene (e.g., C1-C 20 , C1~C12 , C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1C When is substituted, L 1C is substituted with a substituent. 1C When is substituted, L 1C is substituted with size-constrained substituents. 1C When is substituted, L 1C is substituted with a lower substituent.

[0367] R 1C are independently substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1C are independently substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkyl (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1C are independently unsubstituted alkyl (e.g., C1-C 20 , C1~C 12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1C When is substituted, R 1C is substituted with a substituent. In an embodiment, R 1C When is substituted, R 1C is substituted with size-constrained substituents. In embodiments, R 1C When is substituted, R 1C is substituted with a lower substituent. 1C is substituted with oxo (=O).

[0368] L 1D are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1D are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21)-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered).

[0369] In an embodiment, L 1D are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10, or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1D When is substituted, L 1D is substituted with a substituent. 1D When is substituted, L 1D is substituted with size-constrained substituents. 1D When is substituted, L 1D is substituted with a lower substituent.

[0370] R 1D are independently substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1D are independently substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkyl (e.g., C1-C 20 , C1~C12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1D are independently unsubstituted alkyl (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1D When is substituted, R 1D is substituted with a substituent. In an embodiment, R 1D When is substituted, R 1D is substituted with size-constrained substituents. In embodiments, R 1DWhen is substituted, R 1D is substituted with a lower substituent.

[0371] L 1E are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1E are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R 21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered).

[0372] In an embodiment, L 1E are independently a bond, -N(R 20 )-, -O-, -S-, -C(O)-, -N(R 20 )C(O)-, -C(O)N(R 21 )-, -N(R 20 )C(O)N(R 21 )-, -C(O)O-, -OC(O)-, -N(R 20 )C(O)O-, -OC(O)N(R 21 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 22 )-O-, -OP(S)(R 22 )-O-, -OP(O)(NR 20 R 21 )-N-, -OP(S)(NR 20 R 21 )-N-, -OP(O)(NR 20 R 21 )-O-, -OP(S)(NR 20 R21 )-O-, -P(O)(NR 20 R 21 )-N-, -P(S)(NR 20 R 21 )-N-, -P(O)(NR 20 R 21 )-O-, -P(S)(NR 20 R 21 ) -O-, -SS-, 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), unsubstituted cycloalkylene (e.g., C3 to C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 1E When is substituted, L 1E is substituted with a substituent. 1E When is substituted, L 1E is substituted with size-constrained substituents. 1E When is substituted, L 1E is substituted with a lower substituent.

[0373] R 1E are independently substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1E are independently substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkyl (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1E are independently unsubstituted alkyl (e.g., C1-C 20 , C1~C 12, C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 1E When is substituted, R 1E is substituted with a substituent. In an embodiment, R 1E When is substituted, R 1E is substituted with size-constrained substituents. In embodiments, R 1E When is substituted, R 1E is substituted with a lower substituent.

[0374] L 3 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 3 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 Cycloalkylene (e.g., C3-C substituted with a substituent, a size-constrained substituent, or a lower substituent) 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 3 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 ) -O-, -SS-, unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 3 When is substituted, L 3 is substituted with a substituent. 3 When is substituted, L 3 is substituted with size-constrained substituents. 3 When is substituted, L 3 is substituted with a lower substituent.

[0375] L 4 are independently a bond, -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25)-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 4 is a bond, -N(R 23)-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 ) -O-, -SS-, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 4 are independently -N(R 23 )-, -O-, -S-, -C(O)-, -N(R 23 )C(O)-, -C(O)N(R 24 )-, -N(R 23 )C(O)N(R 24 )-, -C(O)O-, -OC(O)-, -N(R 23 )C(O)O-, -OC(O)N(R 24 )-, -OPO2-O-, -OP(O)(S)-O-, -OP(O)(R 25 )-O-, -OP(S)(R 25 )-O-, -OP(O)(NR 23 R 24 )-N-, -OP(S)(NR 23 R 24 )-N-, -OP(O)(NR 23 R 24 )-O-, -OP(S)(NR 23 R 24 )-O-, -P(O)(NR 23 R 24 )-N-, -P(S)(NR 23 R 24 )-N-, -P(O)(NR 23 R 24 )-O-, -P(S)(NR 23 R 24 ) -O-, -SS-, unsubstituted alkylene (e.g., C1-C 20 , C1~C 12, C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 4 When is substituted, L 4 is substituted with a substituent. 4 When is substituted, L 4 is substituted with size-constrained substituents. 4 When is substituted, L 4 is substituted with a lower substituent.

[0376] R 23 are independently hydrogen or unsubstituted alkyl (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 23 is independently hydrogen. 23 are independently unsubstituted C1 to C 23 In embodiments, R 23 are independently hydrogen or unsubstituted C1-C 12 In embodiments, R 23 are independently hydrogen or unsubstituted C1-C 10 In embodiments, R 23 is independently hydrogen or unsubstituted C1-C8 alkyl. 23 is independently hydrogen or unsubstituted C1-C6 alkyl. 23is independently hydrogen or unsubstituted C1-C4 alkyl. 23 are independently hydrogen or unsubstituted C1-C2 alkyl.

[0377] R 24 are independently hydrogen or unsubstituted alkyl (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 24 is independently hydrogen. 24 are independently unsubstituted C1 to C 23 In embodiments, R 24 are independently hydrogen or unsubstituted C1-C 12 In embodiments, R 24 are independently hydrogen or unsubstituted C1-C 10 In embodiments, R 24 is independently hydrogen or unsubstituted C1-C8 alkyl. 24 is independently hydrogen or unsubstituted C1-C6 alkyl. 24 is independently hydrogen or unsubstituted C1-C4 alkyl. 24 are independently hydrogen or unsubstituted C1-C2 alkyl.

[0378] R 25 are independently hydrogen or unsubstituted alkyl (e.g., C1-C 23 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4, or C1 to C2). 25 is independently hydrogen. 25 are independently unsubstituted C1 to C 23 In embodiments, R 25 are independently hydrogen or unsubstituted C1-C 12 In embodiments, R 25 are independently hydrogen or unsubstituted C1-C 10In embodiments, R 25 is independently hydrogen or unsubstituted C1-C8 alkyl. 25 is independently hydrogen or unsubstituted C1-C6 alkyl. 25 is independently hydrogen or unsubstituted C1-C4 alkyl. 25 are independently hydrogen or unsubstituted C1-C2 alkyl.

[0379] L 5 are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 5are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 5 are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 5 When is substituted, L 5 is substituted with a substituent. 5 When is substituted, L 5 is substituted with size-constrained substituents. 5 When is substituted, L 5 is substituted with a lower substituent.

[0380] L 5A are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10, or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 5A are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 5A are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, unsubstituted alkylene (e.g., C1-C 20 , C1~C 12, C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 5A When is substituted, L 5A is substituted with a substituent. 5A When is substituted, L 5A is substituted with size-constrained substituents. 5A When is substituted, L 5A is substituted with a lower substituent.

[0381] L 5B are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 5B are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). 5Bare independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), 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), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). 5B When is substituted, L 5B is substituted with a substituent. 5B When is substituted, L 5B is substituted with size-constrained substituents. 5B When is substituted, L 5B is substituted with a lower substituent.

[0382] L 5C are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12, C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) 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), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted heterocycloalkylene (e.g., 3-10 membered, 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted (e.g., substituted with a substituent, a size-constrained substituent, or a lower substituent) or unsubstituted arylene (e.g., C6-C 12 , C6~C 10 , or phenyl), or substituted (e.g., substituted with a sub...

Claims

1. 1. A compound comprising an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid, wherein each of the antisense strand and the sense strand is 15-25 nucleotides in length, the nucleotide sequence of the antisense strand is at least 90% complementary to human peripheral myelin protein 22 mRNA (SEQ ID NO: 1170), and the nucleotide sequence of the sense strand has no more than two mismatches with the nucleotide sequence of the antisense strand in the double-stranded region.

2. each of the antisense strand and the sense strand is 15 to 25 nucleotides in length, and the nucleotide sequence of the antisense strand is selected from the group consisting of SEQ ID NOs: 1118, 1121, 1123, 1126, 1144, 491, 492, 493, 494, 495, 497, 498, 503, 504, 506, 510, 511, 514, 515, 516, 518, 524, 526, 529, 531, 532, 533, 534, 535, 536, 538, 539 , 540, 541, 542, 543, 545, 546, 547, 548, 550, 553, 554, 556, 558, 559, 560, 561, 563, 567, 569, 575, 576, 579, 580, 581, 582, 583, 585, 590, 591, 595, 597, 600, 605, 609, 610, 618, 622, 623, 628, 630, 631, 633, 635, 637, 639, 641, 642, 643, 644, 645, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1122, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 2. The compound of claim 1, comprising at least 15 consecutive nucleotides of any one of 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, and 1169, wherein the nucleotide sequence of the sense strand has no more than two mismatches with the nucleotide sequence of the antisense strand.

3. The compound of claim 1 , wherein the antisense strand is 23 nucleotides in length.

4. The compound of claim 1 , wherein the nucleotide sequence of the antisense strand is at least 95%, such as at least 100%, complementary to SEQ ID NO:

1.

5. 2. The compound of claim 1, wherein the sense strand is 21 nucleotides in length.

6. 2. The compound of claim 1, wherein the double-stranded region is 15 to 25 nucleotide pairs in length, for example, 17 to 23 nucleotide pairs in length or 19 to 21 nucleotide pairs in length.

7. 2. The compound of claim 1, wherein the nucleotide sequence of the sense strand has no more than one mismatch or no mismatch with the nucleotide sequence of the antisense strand in the double-stranded region.

8. The antisense strand is (a) 21 nucleotides in length, and the nucleotide sequence of the antisense strand is SEQ ID NO:491, 492, 493, 494, 495, 497, 498, 503, 504, 506, 510, 511, 514, 515, 516, 518, 524, 526, 529, 531, 532, 533, 534, 535, 536, 538, 539, 540, 541, 542, 543, 545, 546, 547, 548, 550, 553, 554 , 556, 558, 559, 560, 561, 563, 567, 569, 575, 576, 579, 580, 581, 582, 583, 585, 590, 591, 595, 597, 600, 605, 609, 610, 618, 622, 623, 628, 630, 631, 633, 635, 637, 639, 641, 642, 643, 644, and 645, or (b) 23 nucleotides in length, and the nucleotide sequence of the antisense strand is SEQ ID NO: 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1122, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 11 3, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1118, 1126, and 1144.

9. the double-stranded nucleic acid is selected from the group consisting of SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 993 and 1164; SEQ ID NOs: 1108 and 1156; SEQ ID NOs: 1051 and 1158; SEQ ID NOs: 1069 and 1168; SEQ ID NOs: 993 and 1164; SEQ ID NOs: 1108 and 1156; SEQ ID NOs: 1047 and 1160; SEQ ID NOs: 1111 and 1161; SEQ ID NOs: 1066 and 1136; SEQ ID NOs: 1110 and 1122; SEQ ID NOs: 986 and 1142; SEQ ID NOs: 1047 and 1160; SEQ ID NOs: 1111 and 1161; SEQ ID NOs: 1066 and 1136 ; SEQ ID NOs: 1110 and 1122; SEQ ID NOs: 986 and 1142; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1018 and 1144; SEQ ID NOs: 1015 and 1144; SEQ ID NOs: 1015 and 1144; SEQ ID NOs: 1015 and 1144; SEQ ID NOs: 1091 and 1151; SEQ ID NOs: 1045 and 1152; SEQ ID NOs: 1103 and 1155; SEQ ID NOs: 1065 and 1140; SEQ ID NOs: 1067 and and 1141; SEQ ID NOs: 1021 and 1147; SEQ ID NOs: 1019 and 1143; SEQ ID NOs: 1000 and 1127; SEQ ID NOs: 1060 and 1138; SEQ ID NOs: 1034 and 1153; SEQ ID NOs: 1088 and 1157; SEQ ID NOs: 1037 and 1154; SEQ ID NOs: 1091 and 1151; SEQ ID NOs: 1045 and 1152; SEQ ID NOs: 1103 and 1155; SEQ ID NOs: 1054 and 1126; SEQ ID NOs: 1028 and 1131; SEQ ID NOs: 1097 and 1128; SEQ ID NOs: 1065 and 1140; SEQ ID NOs: 1001 and 1129; SEQ ID NOs: 994 and 1112; SEQ ID NOs: 1086 and 1145; SEQ ID NOs:977 and 1125; SEQ ID NOs:1067 and 1141; SEQ ID NOs:1021 and 1147; SEQ ID NOs:1077 and 1134; SEQ ID NOs:1022 and 1117; SEQ ID NOs:1010 and 1165; SEQ ID NOs:1071 and 1133; SEQ ID NOs:1009 and 1150; SEQ ID NOs:1081 and 1119; SEQ ID NOs:997 and 1124; SEQ ID NOs:1063 and 1130; SEQ ID NOs:1029 and 1148; SEQ ID NOs:1056 and 1163; SEQ ID NOs:1039 and 1113; SEQ ID NOs:1033 and 1149; SEQ ID NOs:1031 and 1132;SEQ ID NOs: 1008 and 1139; SEQ ID NOs: 1026 and 1118; SEQ ID NOs: 999 and 1166; SEQ ID NOs: 979 and 1169; SEQ ID NOs: 1098 and 1137; SEQ ID NOs: 1027 and 1135; SEQ ID NOs: 1073 and 1114; SEQ ID NOs: 1078 and 1116; SEQ ID NOs: 981 and 1115; SEQ ID NOs: 1030 and 1159; SEQ ID NOs: 992 and 1146; SEQ ID NOs: 1024 and 1167; SEQ ID NOs: 1007 and 1162; SEQ ID NOs: 978 and 1120; SEQ ID NOs: 10 28 and 1131; SEQ ID NOs: 1097 and 1128; SEQ ID NOs: 994 and 1112; SEQ ID NOs: 1086 and 1145; SEQ ID NOs: 977 and 1125; SEQ ID NOs: 1022 and 1117; SEQ ID NOs: 1010 and 1165; SEQ ID NOs: 1071 and 1133; SEQ ID NOs: 1009 and 1150; SEQ ID NOs: 1081 and 1119; SEQ ID NOs: 1029 and 1148; and SEQ ID NOs: 1039 and 1113.

10. 2. The compound of claim 1, wherein at least one nucleotide of the antisense strand is a modified nucleotide and / or at least one nucleotide of the sense strand is a modified nucleotide.

11. the modified nucleotide comprises one or more of a modified sugar moiety, a modified internucleotide linkage, and a modified 5'-terminal phosphate group, and optionally (a) the modified nucleotide comprising a modified sugar moiety is selected from 2'-fluoro nucleotides, 2'-O-methyl nucleotides, 2'-O-methoxyethyl nucleotides, and bicyclic sugar nucleotides; and / or (b) the modified internucleotide linkage is a phosphorothioate internucleotide linkage, and / or (c) the first two internucleotide linkages at the 5'-end of the sense strand and the last two internucleotide linkages at the 3'-end of the sense strand are phosphorothioate internucleotide linkages, and optionally, the first two internucleotide linkages at the 5'-end of the antisense strand and the last two internucleotide linkages at the 3'-end of the antisense strand are phosphorothioate internucleotide linkages.

12. The covalent bond of the bicyclic sugar 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 The compound of claim 11, wherein the bond is selected from the group consisting of -N(H)-O-2' bonds.

13. The compound of claim 11, wherein the modified phosphate group at the 5'-terminus is a 5'-(E)-vinylphosphonate.

14. (i) The antisense strand is 21 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-fluoro nucleotides, and nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-O-methyl nucleotides, nucleotides 20 and 21 are beta-D-deoxynucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (ii) the antisense strand is 21 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are such that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-O-methyl nucleotides; nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-fluoro nucleotides; nucleotides 20 and 21 are beta-D-deoxynucleotides; the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds; and each other internucleotide bond is phosphodiester and the sense strand is 19 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, and 19 are 2'-fluoro nucleotides, and nucleotides 2, 4, 6, 8, 10, 12, 14, 16, and 18 are 2'-O-methyl nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and every other internucleotide bond is a phosphodiester internucleotide bond; or (iii) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are such that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (iv) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are such that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (v) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are such that nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (vi) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are such that nucleotides 1, 3, 5, 7, 9, 10, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 12, 13, 15, 17, 19, and 21 are 2'-fluoro nucleotides, nucleotides 2, 4, 6, 8, 10, 14, 16, 18, and 20 are 2'-O-methyl nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (vii) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are such that nucleotides 1, 3, 5, 7, 8, 9, 11, 12, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 10, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 7, 9, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (viii) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are nucleotides 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19, 20, 21, 22, and 23, which are 2'-O-methyl nucleotides, and nucleotides 2, 4, 6, 14, and 16, which are 2'-fluoro nucleotides; the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds; and each other internucleotide bond is a phosphodiester internucleotide bond. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, nucleotides 7, 9, 10, and 11 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (ix) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are: nucleotides 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19, 20, 21, 22, and 23 are 2'-O-methyl nucleotides; nucleotides 2, 6, 14, and 16 are 2'-fluoro nucleotides; the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds; and each other internucleotide bond is a phosphodiester nucleotide. and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 7, 9, 10, and 11 are 2'-fluoro nucleotides, and the first two internucleotide linkages at the 5' end are phosphorothioate internucleotide linkages and every other internucleotide linkage is a phosphodiester internucleotide linkage; or (x) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and the sense strand is , 21 nucleotides in length, wherein the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 1 and 2 are 2'-O-methoxyethyl nucleotides, nucleotides 3, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; or (xi) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and the sense strand is , 21 nucleotides in length, wherein the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 2 and 3 are 2'-O-methoxyethyl nucleotides, nucleotides 1, 4, 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond; or (xii) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; and the sense strand is 21 nucleotides in length, and the nucleotides of the sense strand, counting from the 5' end of the sense strand, are modified so that nucleotides 2, 3, 19, and 20 are 2'-O-methoxyethyl nucleotides, nucleotides 1, 4, 6, 8, 12, 14, 16, 18, and 21 are 2'-O-methyl nucleotides, and nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides, the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages, and each other internucleotide linkage is a phosphodiester internucleotide linkage; or (xiii) the antisense strand is 23 nucleotides in length, and the nucleotides of the antisense strand, counting from the 5' end of the antisense strand, are modified so that nucleotides 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 22, and 23 are 2'-O-methyl nucleotides, nucleotides 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 are 2'-fluoro nucleotides, the first two internucleotide bonds at the 5' end and the last two internucleotide bonds at the 3' end are phosphorothioate internucleotide bonds, and each other internucleotide bond is a phosphodiester internucleotide bond; and the sense strand is 21 nucleotides 1, 2, 3, and 4 of the sense strand are 2'-O-methoxyethyl nucleotides; nucleotides 6, 8, 12, 14, 16, 18, 19, 20, and 21 are 2'-O-methyl nucleotides; nucleotides 5, 7, 9, 10, 11, 13, 15, and 17 are 2'-fluoro nucleotides; the first two internucleotide linkages at the 5' end and the last two internucleotide linkages at the 3' end are phosphorothioate internucleotide linkages; and each other internucleotide linkage is modified to be a phosphodiester internucleotide linkage.

15. The compound according to claim 14, wherein the phosphate group at the 5'-end of the antisense strand is a 5'-(E)-vinylphosphonate group.

16. The compound of claim 1 , wherein the compound comprises a ligand covalently attached to one or more of the antisense strand and the sense strand of the double-stranded nucleic acid.

17. The compound has the structure: 【Chemical 1】 (Wherein A is the antisense strand and / or the sense strand of the double-stranded nucleic acid; t is an integer from 1 to 5; L ３ and L ４ are independently a bond, —N(R ２３ )-, -O-, -S-, -C(O)-, -N(R ２３ )C(O)-, -C(O)N(R ２４ ) -, -N(R ２３ )C(O)N(R ２４ )-, -C(O)O-, -OC(O)-, -N(R ２３ )C(O)O-, -OC(O)N(R ２４ ) -, -OPO ２ -O-, -O-P(O)(S)-O-, -O-P(O)(R ２５ )-O-, -O-P(S)(R ２５ )-O-, -O-P(O)(NR ２３ R ２４ )-N-, -O-P(S)(NR ２３ R ２４ )-N-, -O-P(O)(NR ２３ R ２４ )-O-, -O-P(S)(NR ２３ R ２４ )-O-, -P(O)(NR ２３ R ２４ ) -N-, -P(S)(NR ２３ R ２４ ) -N-, -P(O)(NR ２３ R ２４ )-O-,-P(S)(NR ２３ R ２４ ) —O—, —S—S—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L ５ Is, -L ５Ａ -L ５Ｂ -L ５Ｃ -L ５Ｄ -L ５Ｅ - and; L ６ Is, -L ６Ａ -L ６Ｂ -L ６Ｃ -L ６Ｄ -L ６Ｅ - and; R １ and R ２ are independently unsubstituted C １ ~C ２５ alkyl, and R １ and R ２ At least one of ９ ~C １９ is alkyl; R ３ is hydrogen, -NH ２ , -OH, -SH, -C(O)H, -C(O)NH ２ , -NHC(O)H, -NHC(O)OH, -NHC(O)NH ２ , -C(O)OH, -OC(O)H, -N ３ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L ５Ａ , L ５Ｂ , L ５Ｃ , L ５Ｄ , L ５Ｅ , L ６Ａ , L ６Ｂ , L ６Ｃ , L ６Ｄ , and L ６Ｅ are independently a bond, —NH—, —O—, —S—, —C(O)—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —C(O)NH—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and Each R ２３ , R ２４ and R ２５ are independently hydrogen or unsubstituted C １ ~C １０ 17. The compound of claim 16, wherein:

18. 18. The compound of claim 17, wherein t is 1, 2, or 3.

19. 18. The compound of claim 17, wherein A is the sense strand.

20. R ２３ , R ２４ and R ２５ each independently represents hydrogen or unsubstituted C １ ~C ３ 18. The compound of claim 17, wherein the compound is alkyl.

21. One L ３ but, (i) attached to the 3' carbon of a nucleotide, optionally the 3' carbon being the 3' carbon of the 3' terminal nucleotide; or (ii) attached to the 5' carbon of a nucleotide, optionally the 5' carbon being the 5' carbon of the 5' terminal nucleotide; or (iii) The compound of claim 17, which is attached to the 2' carbon of a nucleotide.

22. L ３ and L ４ are independently a bond, —NH—, —O—, —C(O)—, —C(O)O—, —OC(O)—, or —OPO ２ -O-, -O-P(O)(S)-O-, -O-P(O)(CH ３ )-O-, -O-P(S)(CH ３ )-O-, -O-P(O)(N(CH ３ ) ２ )-N-, -O-P(O)(N(CH ３ ) ２ )-O-, -O-P(S)(N(CH ３ ) ２ )-N-, -O-P(S)(N(CH ３ ) ２ )-O-, -P(O)(N(CH ３ ) ２ )-N-, -P(O)(N(CH ３ ) ２ )-O-,-P(S)(N(CH ３ ) ２ ) -N-, -P(S)(N(CH ３ ) ２ 20. The compound of claim 17, wherein the aryl group is substituted or unsubstituted alkylene or heteroalkylene.

23. L ３ but, (i) independently: 【Chemistry 2】 or (ii) independently, -OPO ２ -O- or -OP(O)(S)-O-, or (iii) independently —O—, or (iv) independently —C(O)—; or (v) independently -O-P(O)(N(CH ３ ) ２ 20. The compound of claim 17, wherein:

24. L ４ but, (i) independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; and / or (ii) independently, -L ７ -NH-C(O)- or -L ７ —C(O)—NH—, and L ７ is substituted or unsubstituted alkylene, and / or (iii) independently, 【Chemistry 3】 and / or (iv) independently: 【Chemistry 4】 18. The compound of claim 17, wherein:

25. -L ３ -L ４ - is independent, -OL ７ -NH-C(O)- or -O-L ７ —C(O))—NH—, and L ７ is independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene; Optionally, -L ３ -L ４ - is independent, -OL ７ —NH—C(O)—, and L ７ are independently substituted or unsubstituted C ５ ~C ８ is alkylene, Optionally, -L ３ -L ４ - but independently, 【Chemistry 5】 18. The compound of claim 17, wherein:

26. -L ３ -L ４ - but independently, -OPO ２ -O-L ７ -NH-C(O)-, -OP(O)(S)-OL ７ -NH-C(O)-, -OPO ２ -O-L ７ -C(O)-NH- or -OP(O)(S)-O-L ７ —C(O)—NH—, and L ７ is independently substituted or unsubstituted alkylene; Optionally, -L ３ -L ４ - but independently, -OPO ２ -O-L ７ -NH-C(O)- or -OP(O)(S)-O-L ７ —NH—C(O)—, and L ７ are independently substituted or unsubstituted C ５ ~C ８ 18. The compound of claim 17 which is an alkylene.

27. -L ３ -L ４ - but independently, 【Chemistry 6】 27. The compound of claim 26, wherein:

28. -L ３ -L ４ -but, (i) independently: 【Chemistry 7】 and is attached to the 3' carbon of the 3' terminal nucleotide, or (ii) independently: 【Chemistry 8】 and is attached to the 5' carbon of the 5' terminal nucleotide, or (iii) independently, 【Chemistry 9】 and attached to the 2' carbon.

29. R ３ 18. The compound of claim 17, wherein is independently hydrogen.

30. L ６ is independently -NHC(O)-, -C(O)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

31. (i) L ６ is independently —NHC(O)—, or (ii) L ６Ａ is independently a bond or unsubstituted alkylene; L ６Ｂ are independently a bond, —NHC(O)—, or unsubstituted arylene; L ６Ｃ is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L ６Ｄ is independently a bond or unsubstituted alkylene; and L ６Ｅ is independently a bond or —NHC(O)—; or (iii) L ６Ａ are independently a bond or an unsubstituted C １ ~C ８ alkylene; L ６Ｂ are independently a bond, —NHC(O)—, or unsubstituted phenylene; L ６Ｃ are independently a bond, an unsubstituted C ２ ~C ８ alkynylene, or unsubstituted phenylene; L ６Ｄ are independently a bond or an unsubstituted C １ ~C ８ alkylene; and L ６Ｅ is independently a bond or -NHC(O)-.

32. L ６ But independently, combined, 【Chemistry 10】 18. The compound of claim 17, wherein:

33. (i) L ５ are independently —NHC(O)—, —C(O)NH—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; or (ii) L ５ is independently —NHC(O)—, or (iii) L ５Ａ is independently a bond or unsubstituted alkylene; L ５Ｂ are independently a bond, —NHC(O)—, or unsubstituted arylene; L ５Ｃ is independently a bond, unsubstituted alkylene, or unsubstituted arylene; L ５Ｄ is independently a bond or unsubstituted alkylene; and L ５Ｅ is independently a bond or —NHC(O)—, or (iv) L ５Ａ are independently a bond or an unsubstituted C １ ~C ８ alkylene; L ５Ｂ are independently a bond, —NHC(O)—, or unsubstituted phenylene; L ５Ｃ are independently a bond, an unsubstituted C ２ ~C ８ alkynylene, or unsubstituted phenylene; L ５Ｄ are independently a bond or an unsubstituted C １ ~C ８ alkylene; and L ５Ｅ is independently a bond or —NHC(O)—, or (v) L ５ But independently, combined, 【Chemistry 11】 or (vi) R １ is unsubstituted C １ ~C １７ alkyl, or (vii) R １ is unsubstituted C １１ ~C １７ alkyl, or (viii) R １ is unsubstituted C １３ ~C １７ alkyl, or (ix) R １ is unsubstituted C １４ ~C １５ alkyl, or (x)R １ is unsubstituted unbranched C １ ~C １７ alkyl, or (xi) R １ is unsubstituted unbranched C １１ ~C １７ alkyl, or (xii) R １ is unsubstituted unbranched C １３ ~C １７ alkyl, or (xiii) R １ is unsubstituted unbranched C １４ ~C １５ alkyl, or (xiv) R １ is unsubstituted unbranched saturated C １ ~C １７ alkyl, or (xv) R １ is unsubstituted unbranched saturated C １１ ~C １７ alkyl, or (xvi) R １ is unsubstituted unbranched saturated C １３ ~C １７ alkyl, or (xvii) R １ is unsubstituted unbranched saturated C １４ ~C １５ 18. The compound of claim 17, wherein the compound is alkyl.

34. R ２ is unsubstituted C １ ~C １７ Alkyl, unsubstituted C １１ ~C １７ Alkyl, unsubstituted C １３ ~C １７ Alkyl, unsubstituted C １４ ~C １５ Alkyl, unsubstituted unbranched C １ ~C １７ Alkyl, unsubstituted unbranched C １１ ~C １７ Alkyl, unsubstituted unbranched C １３ ~C １７ Alkyl, unsubstituted unbranched C １４ ~C １５ Alkyl, unsubstituted unbranched saturated C １ ~C １７ Alkyl, unsubstituted unbranched saturated C １１ ~C １７ Alkyl, unsubstituted unbranched saturated C １３ ~C １７ Alkyl or unsubstituted unbranched saturated C １４ ~C １５ 18. The compound of claim 17, wherein the compound is alkyl.

35. 18. The compound of claim 17, wherein a ligand is covalently attached to the antisense strand or a ligand is covalently attached to the sense strand.

36. (i) -L ３ -L ４ -but, 【Chemistry 12】 and -L ３ -L ４ - is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand; L ６ but, 【Chemistry 13】 and L ５ is —NHC(O)—, R ３ is hydrogen, R １ is unsubstituted unbranched C １５ is alkyl, and R ２ is unsubstituted unbranched C １５ alkyl, or (ii) -L ３ -L ４ -but, 【Chemistry 12】 , -L relative to the 3' carbon of the 3' terminal nucleotide of the sense strand ３ -L ４ -phosphate group, L ６ but, 【Chemistry 13】 and L ５ is —NHC(O)—, R ３ is hydrogen, R １ is unsubstituted unbranched C １３ is alkyl, and R ２ is unsubstituted unbranched C １３ 18. The compound of claim 17, wherein the compound is alkyl.

37. The compound is DT-000544, DT-000545, DT-000546, DT-000620, DT-000621, DT-000622, DT-000623, DT-000624, DT-000625, DT-000626, DT-000627, DT-000628, DT-000811, DT-000812, DT-000945, DT-000959, DT-000960, DT-000961, DT-000962, DT-000963, DT-000964, DT-000965, DT-000966, DT-000967, DT-001037, DT-001038, DT-001039, DT-001044, DT-001045, DT-001046, DT-001047, DT-001048, DT-001049, DT-001050, DT-001051, DT-001052, DT-001053, DT-001054, DT-001055, DT-001056, DT-001057, DT-001058, DT-001059, DT-001060, DT-001061, DT-001109, DT-001110, DT-001111, DT-001112, DT-001113, DT-001114, DT-001115, DT-001116, DT-001117, DT-001118, DT-001119, DT-001120, DT-001121, DT-001122, DT-001123, DT-001124, DT-001125, DT-001126, DT-001127, DT-001128, DT-001129, DT-001130, DT-001131, DT-001132, DT-001145, DT-001146, DT-001147, DT-001148, DT-001149, DT-001150, DT-001151, DT-001152, DT-001153, DT-001154, DT-001155, DT-001156, DT-001157, DT-001158, DT-001159, DT-001160, DT-001161, DT-001162, DT-001163, DT-001164, DT-001176, DT-001177, DT-001178, DT-001179, DT-001180, DT-001181, DT-001182, DT-001183, DT-001184, DT-001185,DT-001186、DT-001187、DT-001188、DT-001189、DT-001190、DT-001191、DT-001192、DT-001193、DT-001194、DT-001195、DT-001196、DT-001197、DT-001198、DT-001199、DT-001200、DT-001201、DT-001202、DT-001203、DT-001204、DT-001205、DT-001206、DT-001207、DT-001208、DT-001217、DT-001218、DT-001219、DT-001220、DT-001221、DT-001222、DT-001223、DT-001224、DT-001230、DT-001231、DT-001232、DT-001233、DT-001234、DT-001235、DT-001236、DT-001237、DT-001238、DT-001239、DT-001240、DT-001241、DT-001242、DT-001243、DT-001246、DT-001247、DT-001248、DT-001249、DT-001250、DT-001251、DT-001252、DT-001253、DT-001254、DT-001255、DT-001256、DT-001257、DT-001261、DT-001262、DT-001263、DT-001264、DT-001265、DT-001266、DT-001267、DT-001276、DT-001277、DT-001278、DT-001279、DT-001280、DT-001281、DT-001282、DT-001283、DT-001296、DT-001297、DT-001298、DT-001299、DT-001300、DT-001301、DT-001302、DT-001303、DT-001304、DT-001305、DT-001306、DT-001307、DT-001322、DT-001323、DT-001324、DT-001325、DT-001326、DT-001327、DT-001328、DT-001329、DT-001330、DT-001331、DT-001332、DT-001333、DT-001334、DT-001335、DT-001344、DT-001345、The compound of claim 17, selected from any one of DT-001346, DT-001347, DT-001348, DT-001349, DT-001350, DT-001351, DT-001355, DT-001356, DT-001357, DT-001358, DT-001359, DT-001360, DT-001361, DT-001362, DT-001363, DT-001364, DT-001365, DT-001366, DT-001367, DT-001368, and DT-001369.

38. 38. The compound of claim 37, wherein the compound is DT-000623, DT-000812, DT-001246, DT-001247, DT-001250, DT-001251, DT-001252, DT-001253, DT-001254, DT-001255, DT-001256, or DT-001257.

39. A compound of formula (I), or a pharmaceutical salt thereof: 【Chemical 1】 wherein A is a double-stranded nucleic acid consisting of an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid; The nucleotide sequence of the sense strand is 5'-OH-CMSCMSUMMCMCFUMMGFUMUGFMUGFGMMCFUMMGFAM-3' (SEQ ID NO:772); The nucleotide sequence of the antisense strand is 5'-VP-A M S U F S G M A F U M A F C M U F C M A F G M C F A M A F C M A F G M G F A M G F G M S A M S G M -OH-3' (SEQ ID NO: 879); a nucleotide followed by a subscript "F" is a 2'-fluoro nucleotide, a nucleotide followed by a subscript "M" is a 2'-O-methyl nucleotide, a superscript "S" is a phosphorothioate internucleotide linkage, all other internucleotide linkages are phosphodiester internucleotide linkages, "5'-VP" is a 5'-VP modification of the 5'-terminal nucleotide of the antisense strand, "5'-OH" and "OH-3'" are 5'- and 3'-terminal hydroxyl moieties, -L 3 -L 4 - is 【Chemistry 12】 wherein the phosphate group of -L 3 -L 4 - is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand; L 5 is —NHC(O)—; L 6 is 【Chemistry 13】 and R 1 is unsubstituted unbranched C 15 alkyl; R 2 is unsubstituted unbranched C 15 alkyl; R 3 is hydrogen; 39. The compound of claim 38.

40. A compound of formula (I), or a pharmaceutical salt thereof, 【Chemical 1】 wherein A is a double-stranded nucleic acid consisting of an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid; The nucleotide sequence of the sense strand is 5'-OH-C M S C M S U M C M C M U M G F U M U F G M C F U M G F A M G F U M A F U M C M S A M S U M -3' (SEQ ID NO:773); the nucleotide sequence of the antisense strand is 5'-VP-A M S U F S G M A F U M A F C M U M C M A F G M C M A M A F C M A F G M G F A M G F G M S A M S G M -OH-3' (SEQ ID NO: 901); a nucleotide followed by a subscript "F" is a 2'-fluoro nucleotide, a nucleotide followed by a subscript "M" is a 2'-O-methyl nucleotide, a superscript "S" is a phosphorothioate internucleotide linkage, all other internucleotide linkages are phosphodiester internucleotide linkages, "5'-VP" is a 5'-VP modification of the 5'-terminal nucleotide of the antisense strand, "5'-OH" and "OH-3'" are 5'- and 3'-terminal hydroxyl moieties, -L 3 -L 4 - is 【Chemistry 12】 wherein the phosphate group of -L 3 -L 4 - is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand; L 5 is —NHC(O)—; L 6 is 【Chemistry 13】 and R 1 is unsubstituted unbranched C 15 alkyl; R 2 is unsubstituted unbranched C 15 alkyl; R 3 is hydrogen; 39. The compound of claim 38.

41. A compound of formula (I), or a pharmaceutical salt thereof: 【Chemical 1】 wherein A is a double-stranded nucleic acid consisting of an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid; The nucleotide sequence of the sense strand is 5'-OH-C M S C M S U M C M C M U M G F U M U F G F C F U M G M A M G M U M A M U M C M S A M S U M -3' (SEQ ID NO:774); The nucleotide sequence of the antisense strand is 5'-VP-A M S U F S G M A M U M A F C M U M C M A M G M C M A M A F C M A F G M G M A M G M G M S A M S G M -OH-3' (SEQ ID NO: 902); a nucleotide followed by a subscript "F" is a 2'-fluoro nucleotide, a nucleotide followed by a subscript "M" is a 2'-O-methyl nucleotide, a superscript "S" is a phosphorothioate internucleotide linkage, all other internucleotide linkages are phosphodiester internucleotide linkages, "5'-VP" is a 5'-VP modification of the 5'-terminal nucleotide of the antisense strand, "5'-OH" and "OH-3'" are 5'- and 3'-terminal hydroxyl moieties, -L 3 -L 4 - is 【Chemistry 12】 wherein the phosphate group of -L 3 -L 4 - is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand; L 5 is —NHC(O)—; L 6 is 【Chemistry 13】 and R 1 is unsubstituted unbranched C 15 alkyl; R 2 is unsubstituted unbranched C 15 alkyl; R 3 is hydrogen; 39. The compound of claim 38.

42. A compound of formula (I), or a pharmaceutical salt thereof: 【Chemical 1】 wherein A is a double-stranded nucleic acid consisting of an antisense strand and a sense strand that hybridize to form a double-stranded nucleic acid; The nucleotide sequence of the sense strand is 5'-OH-CMSCMSUMMCMCMUMGFUMUFGFCFUMGMAMGMUMAMUMAMUMCMAMUMUM-3' (SEQ ID NO:775); The nucleotide sequence of the antisense strand is 5'-VP-A M S U F S G M A M U M A F C M U M C M A M G M C M A M A F C M A F G M G M A M G M G M S A M S G M -OH-3' (SEQ ID NO: 902); a nucleotide followed by a subscript "F" is a 2'-fluoro nucleotide, a nucleotide followed by a subscript "M" is a 2'-O-methyl nucleotide, a superscript "S" is a phosphorothioate internucleotide linkage, all other internucleotide linkages are phosphodiester internucleotide linkages, "5'-VP" is a 5'-VP modification of the 5'-terminal nucleotide of the antisense strand, "5'-OH" and "OH-3'" are 5'- and 3'-terminal hydroxyl moieties, -L 3 -L 4 - is 【Chemistry 12】 wherein the phosphate group of -L 3 -L 4 - is attached to the 3' carbon of the 3' terminal nucleotide of the sense strand; L 5 is —NHC(O)—; L 6 is 【Chemistry 13】 and R 1 is unsubstituted unbranched C 15 alkyl; R 2 is unsubstituted unbranched C 15 alkyl; R 3 is hydrogen; 39. The compound of claim 38.

43. 43. The compound of any one of claims 1 to 42, wherein the compound is present as a pharmaceutical salt.

44. 44. The compound of claim 43, wherein the salt is a sodium salt.

45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42.

46. 43. A compound according to any one of claims 1 to 42 for use in a method of inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA in a cell, comprising contacting said cell with a compound according to any one of claims 1 to 42, thereby inhibiting expression of PMP22 mRNA in said cell; Optionally, the cell is a peripheral nerve cell; Optionally, the cell is in vitro or in vivo.

47. 43. A compound according to any one of claims 1 to 42 for use in a method of inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 42, thereby inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA; Optionally, expression of PMP22 mRNA is inhibited in peripheral nerves of said subject; Optionally, the peripheral nerve is one or more of the sciatic nerve, brachial plexus nerve, tibial nerve, peroneal nerve, femoral nerve, lateral femoral cutaneous nerve, and spinal nerve.

48. 43. A compound according to any one of claims 1 to 42 for use in a method for increasing myelination and / or slowing the decline of myelination in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 42.

49. The compound of claim 47, wherein the subject has a peripheral demyelinating disease, specifically, the peripheral demyelinating disease is Charcot-Marie-Tooth disease (CMT), and more specifically, the CMT is Charcot-Marie-Tooth disease type 1A (CMT1A).

50. A compound according to claim 48, wherein the subject has a peripheral demyelinating disease, specifically, the peripheral demyelinating disease is Charcot-Marie-Tooth disease (CMT), and more specifically, the CMT is Charcot-Marie-Tooth disease type 1A (CMT1A).

51. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42 for use in a method of inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition, thereby inhibiting expression of peripheral myelin protein 22 (PMP22) mRNA; Optionally, expression of PMP22 mRNA is inhibited in peripheral nerves of said subject; Optionally, the peripheral nerve is one or more of the sciatic nerve, brachial plexus nerve, tibial nerve, peroneal nerve, femoral nerve, lateral femoral cutaneous nerve, and spinal nerve.

52. A pharmaceutical composition comprising a compound described in any one of claims 1 to 42 for use in a method for increasing myelination and / or slowing the decline of myelination in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition.

53. The pharmaceutical composition of claim 51, wherein the subject has a peripheral demyelinating disease, specifically, the peripheral demyelinating disease is Charcot-Marie-Tooth disease (CMT), and more specifically, the CMT is Charcot-Marie-Tooth disease type 1A (CMT1A).

54. The pharmaceutical composition of claim 52, wherein the subject has a peripheral demyelinating disease, specifically, the peripheral demyelinating disease is Charcot-Marie-Tooth disease (CMT), and more specifically, the CMT is Charcot-Marie-Tooth disease type 1A (CMT1A).

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