Oligonucleotides containing ligands at internal positions

Abstract

The present disclosure provides oligonucleotides comprising a group of a ligand at an internal position. The disclosure also provides pharmaceutical compositions and kits comprising the oligonucleotides, methods of delivering the oligonucleotides, methods of modulating protein activity using the oligonucleotides, and methods of using the oligonucleotides or pharmaceutical compositions thereof to treat, prevent, or diagnose a disease (e.g., e.g., e.g., atherosclerosis) in a subject in need thereof. , central nervous system diseases, neurodegenerative diseases, and neurocognitive diseases).

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application USSN 63 / 520,337, filed August 17, 2023, pursuant to 35 USC § 119(e), the contents of which are incorporated herein by reference. Background Technology

[0003] When using compounds (e.g., oligonucleotides) for therapeutic, preventative, or diagnostic applications, it is often desirable to deliver the compound to a specific location (e.g., to a desired cell, organ, or tissue, or to a specific location on the subject) to enhance therapeutic or preventative effects or facilitate diagnostic purposes. This is often the case when attempting to deliver therapeutic compounds in vivo. Furthermore, the ability to effectively deliver compounds to a specific location can limit or potentially eliminate unintended consequences (such as off-target effects) that may result from the administration of the compound. One advantageous strategy for delivering compounds (such as therapeutic, preventative, or diagnostic compounds) to desired locations in vivo is to link or attach the compound to a target ligand.

[0004] One class of compounds that can be targeted using targeting ligands are oligomers, such as proteins, peptides, antibodies, and oligonucleotides. Oligomers (e.g., oligonucleotides) containing nucleotide sequences at least partially complementary to the target nucleic acid have been shown to alter the function and activity of the target in vitro and in vivo. When delivered to cells containing the target nucleic acid (such as mRNA or precursor mRNA), oligonucleotides have been shown to regulate the expression or activity of the target nucleic acid. In some cases, oligonucleotides can reduce gene expression by inhibiting the translation of the nucleic acid target and / or triggering the degradation of the target nucleic acid.

[0005] If the target nucleic acid is mRNA, one mechanism by which oligonucleotides can regulate the expression of the mRNA target is through RNA interference. RNA interference is a biological process by which RNA or RNA-like compounds (such as chemically modified RNA compounds) can silence gene expression at least partially through the RNA-induced silencing complex (RISC) pathway. Additionally, oligonucleotides can regulate the expression of target nucleic acids (such as target mRNA) through RNase recruitment mechanisms, microRNA mechanisms, occupation-based mechanisms, and editing mechanisms. Oligonucleotides can be single-stranded or double-stranded. Oligonucleotides can include DNA, RNA, and RNA-like compounds, and they can also contain modified nucleosides comprising one or more modified sugars, modified nucleobases, and modified inter-nucleoside bonds.

[0006] There is a need for new compounds for delivering agents (e.g., therapeutic agents, preventative agents, and diagnostic agents) to subjects. Summary of the Invention

[0007] In one aspect, this disclosure provides oligonucleotides comprising an oligonucleotide chain modified at an internal position with at least one ligand. In another aspect, this disclosure relates to oligonucleotides comprising a modified oligonucleotide chain of formula I:

[0008]

[0009] (I),

[0010] Or a pharmaceutically acceptable salt or prodrug, wherein:

[0011] It is a divalent group of an oligonucleotide chain;

[0012] The s1 instances of the nucleoside indirect head were independently... Substitute;

[0013] s1 can be 1, 2, 3, 4, 5, or 6;

[0014] L A and L 4 Each instance is a connector independently;

[0015] A 4 Each instance is independently a ligand or lipid group, provided that A 4 At least one instance is a group of a ligand;

[0016] Each of y5 and y6 is independently 0 or 1;

[0017] When y5 is 0, L 5 C is hydrogen, substituted or unsubstituted 1-6 Alkyl or oxygen protecting group; or when y5 is 1, L 5 For connectors;

[0018] When y6 is 0, L 6 C is hydrogen, substituted or unsubstituted 1-6 Alkyl or oxygen protecting group; or when y6 is 1, L 6 For connectors;

[0019] If it exists, then A 5 and A 6 Each of these groups is independently a ligand or a lipid group; and

[0020] Each of the ligands is different from each of the lipids.

[0021] The oligonucleotide contains one or more groups of a ligand conjugated at one or more internal sites on the oligonucleotide (e.g., sites other than the 5′ or 3′ end). In some embodiments, the ligand is not a lipid. In some embodiments, the oligonucleotide also contains one or more groups of a lipid at one or more internal sites. In some embodiments, the oligonucleotide also contains one or more groups of a ligand and / or a lipid group at the 5′ end and / or 3′ end.

[0022] Oligonucleotides can be used to deliver pharmaceutical agents to a subject (e.g., a human). In some embodiments, at least one instance of the pharmaceutical agent is an oligonucleotide chain. In some embodiments, the ligand is capable of selectively targeting a location within the subject (e.g., the subject's brain, or a region of the subject's brain). In some embodiments, the ligand is capable of selectively targeting a specific type of cell (e.g., cells of the central nervous system, such as neurons). In some embodiments, the ligand is capable of selectively binding to or otherwise selectively recognizing one or more receptors. In some embodiments, the oligonucleotide is capable of selectively targeting the oligonucleotide chain to a location within the subject (e.g., the subject's brain, or a region of the subject's brain). In some embodiments, the oligonucleotide is capable of selectively delivering the oligonucleotide chain to cells (e.g., cells of the central nervous system, such as neurons). In some embodiments, the oligonucleotide is capable of selectively binding to or otherwise selectively recognizing one or more receptors. Oligonucleotides can be used to treat, prevent, or diagnose diseases. Oligonucleotides may be superior to pharmaceuticals and certain known oligonucleotides (e.g., certain known oligonucleotides that do not contain one or more groups of a ligand conjugated at one or more internal sites) because they may exhibit higher potency, efficacy, bioavailability, safety, and / or patient compliance; a wider therapeutic window; fewer and / or milder side effects; and / or lower toxicity and / or treatment resistance. One or more of these advantages may be at least in part because the oligonucleotide contains one or more groups of a ligand conjugated at one or more internal sites.

[0023] This disclosure also provides pharmaceutical compositions and kits, each of which comprises the oligonucleotides disclosed herein. This disclosure also provides methods for using such oligonucleotides, pharmaceutical compositions, and kits.

[0024] In another respect, this disclosure provides methods for delivering any oligonucleotide or pharmaceutical composition provided herein to a subject.

[0025] On the other hand, this disclosure provides any oligonucleotide or pharmaceutical composition provided herein for use in the manufacture of a medicament for delivery of any oligonucleotide or pharmaceutical composition to a subject.

[0026] On the other hand, this disclosure provides any oligonucleotide or pharmaceutical composition provided herein for the purpose of delivering any oligonucleotide or pharmaceutical composition to a subject.

[0027] On the other hand, this disclosure provides methods for treating a subject in need of treatment with any of the oligonucleotides or pharmaceutical compositions provided herein.

[0028] On the other hand, this disclosure provides the use of any oligonucleotide or pharmaceutical composition provided herein for the manufacture of a medicament for treating a disease in a subject in need.

[0029] On the other hand, this disclosure provides any oligonucleotide or pharmaceutical composition provided herein for the treatment of a disease in a subject in need.

[0030] On the other hand, this disclosure provides methods for preventing disease in subjects in need using any of the oligonucleotides or pharmaceutical compositions provided herein.

[0031] On the other hand, this disclosure provides the use of any oligonucleotide or pharmaceutical composition provided herein for the manufacture of a medicament for the prevention of disease in subjects in need.

[0032] On the other hand, this disclosure provides any oligonucleotide or pharmaceutical composition provided herein for the prevention of disease in subjects in need.

[0033] On the other hand, this disclosure provides a method for preparing any of the oligonucleotides provided herein, which includes subjecting a compound of formula A-1 to suitable conditions:

[0034]

[0035] (A-1),

[0036] Or its salts, and compounds of formula A-2:

[0037] L 4E2 –L 4D2 –A 4

[0038] (A-2),

[0039] or its salt in contact, wherein:

[0040] M 1 and M 2 Each of these groups is independently a fragment of an oligonucleotide chain or a nucleoside;

[0041] L 4D1 and L 4D2 Each of them is independently a single key or connector;

[0042] L 4E1 The first reactive component;

[0043] L 4E2 This is the second reactive component;

[0044] L 4E1 and L 4E2 They can react with each other under suitable conditions to form L 4E3 ;and

[0045] L 4D1 –L 4E3 –L 4D2 For L 4 .

[0046] It should be understood that the implementation schemes provided in this document regarding the selection of preferred variables can be used alone or in combination with one or more implementation schemes or other preferred variable selections provided in this document, as each combination has been explicitly listed herein.

[0047] It should be recognized that the concepts described above and other concepts discussed below can be combined and arranged in any suitable way, as this disclosure is not limited in this respect. Furthermore, other advantages and novel features of this disclosure will become apparent from the following detailed description of various non-limiting embodiments.

[0048] definition

[0049] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7th edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0050] The compounds described herein (e.g., oligonucleotides) may contain one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further covers compounds as single isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0051] Unless otherwise stated, the formulas and structures described herein include compounds that do not contain isotopically enriched atoms, and also compounds that do contain isotopically enriched atoms. For example, except for replacing hydrogen with deuterium or tritium, etc. 18 F substitute 19 F or use 13 C or 14 Compounds enriched with carbon substitutes for carbon outside the carbon and having the structure of this invention are within the scope of this disclosure. Such compounds can be used as analytical tools or probes, for example, in bioassays.

[0052] When a range of values ​​is listed (“range”), it encompasses every value within that range and its subranges. Unless otherwise specified, a range includes the values ​​at both ends of the range. For example, “C” 1-6 "Alkyl" encompasses C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0053] The term "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 100 carbon atoms ("C..."). 1–100 Alkyl group). In some embodiments, the alkyl group has 1 to 20 carbon atoms (“C10”). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C12”). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and n-dodecyl (C9). 12), etc. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (e.g., halogens, such as fluorine) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C14. 1–12 Alkyl groups (such as unsubstituted C4) 1–6 Alkyl groups, such as -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), and unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is a substituted C. 1-12 Alkyl groups (such as substituted C4 groups) 1-6 Alkyl groups, such as –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3 or benzyl (Bn)).

[0054] The term "heteroalkyl" refers to an alkyl group that also includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorus located within the parent chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In some embodiments, heteroalkyl refers to a saturated group ("heteroalkyl group") having 1 to 100 carbon atoms and 1 or more heteroatoms within the parent chain. 1-100 Alkyl group (“heteroalkyl”). In some embodiments, heteroalkyl refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms within the parent chain (“heteroalkyl”). 1-20 Alkyl group (“heteroalkyl”). In some embodiments, heteroalkyl refers to a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-12 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-11 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-10 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-9 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-8 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-7Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroalkyl”). 1-6 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroalkyl”). 1-5 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroalkyl”). 1-4 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroalkyl”). 1-3 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroalkyl”). 1-2 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms within the parent chain (“heteroC1 alkyl”). 2-6 Alkyl group”. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituented by one or more substituents (e.g., oxo, substituted or unsubstituted C). 1-6 Alkyl (e.g., –CH3)) substitution (“substituted heteroalkyl”). In some embodiments, the heteroalkyl is an unsubstituted heteroalkyl group. 1-12 Alkyl group. In some embodiments, the heteroalkyl group is a substituted heteroC. 1-12 Alkyl group. In some embodiments, the unsubstituted hetero-C1 alkyl group is –OCH3 or –CH2OH. In some embodiments, the substituted hetero-C1 alkyl group is –C(=O)NH2. In some embodiments, the unsubstituted hetero-C2 alkyl group is –OCH2CH3, –CH2OCH3, or –CH2CH2OH. The term "hetero-C" is used in this context. z1-z2 "alkyl" and "C" z1-z2 "Heteroalkyl" is used interchangeably, where each of z1 and z2 is an independent integer.

[0055] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group having 1 to 100 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, the alkenyl group has 1 to 100 carbon atoms ("C..."). 1-100 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has at least 2 carbon atoms. In some embodiments, the alkenyl group has 1 to 20 carbon atoms (“C”). 1-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 12 carbon atoms (“C”). 1-12Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 11 carbon atoms (“C”). 1-11 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 10 carbon atoms (“C”). 1-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 9 carbon atoms (“C”). 1-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 8 carbon atoms (“C”). 1-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 7 carbon atoms (“C”). 1-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 5 carbon atoms (“C”). 1-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 4 carbon atoms (“C”). 1-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 3 carbon atoms (“C”). 1-3 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkenyl group (“C1 alkenyl”). In some embodiments, the alkenyl group has one carbon atom (“C1 alkenyl”). In some embodiments, the alkenyl group is C1. 2–3 alkenyl, C 2–4 alkenyl, C 2–5 alkenyl, C 2–6 alkenyl, C 2–7 alkenyl, C 2–8 alkenyl, C 2–9 alkenyl, C 2–10 alkenyl, C 2–12 alkenyl, C 2–16 alkenyl, C 2–20 alkenyl, C 2–30 alkenyl, C 2–40 alkenyl, C 2–50 alkenyl, C 2–60 alkenyl, C 2–70 alkenyl, C 2–80 alkenyl, C 2–90 alkenyl or C 2–100 Alkenyl. One or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 1-4 Examples of alkenyl groups include methylidenyl (C1), vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 1-6 Examples of alkenyl groups include the aforementioned C 2-4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 1-20 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 1-20 Alkenyl. In alkenyl groups, the stereochemical C=C double bond is not specified (e.g., −CH=CHCH3 or It can be in the (E) or (Z) configuration.

[0056] The term "heteroalkenyl" refers to an alkenyl group that also includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorus located within the parent chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In some embodiments, heteroalkenyl refers to a group having 1 to 100 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl group"). 1-100 In some embodiments, the heteroalkenyl group has at least two carbon atoms. In some embodiments, the heteroalkenyl group refers to a group having 1 to 20 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“heteroalkenyl”). 1-20 In some embodiments, a heteroalkenyl group refers to a group having 1 to 12 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“heteroalkenyl”). 1-12 In some embodiments, a heteroalkenyl group refers to a group having 1 to 11 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“heteroalkenyl”). 1-11 In some embodiments, a heteroalkenyl group refers to a group having 1 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain (“heteroalkenyl”). 1-10 In some embodiments, the heteroalkenyl group has 1 to 9 carbon atoms, at least one double bond, and one or more heteroatoms (“heteroalkenyl”) within the parent chain. 1-9 In some embodiments, the heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and one or more heteroatoms (“heteroalkenyl”) within the parent chain. 1-8 In some embodiments, the heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and one or more heteroatoms (“heteroalkenyl”) within the parent chain. 1-7 In some embodiments, the heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and one or more heteroatoms (“heteroalkenyl”) within the parent chain. 1-6("heterene"). In some embodiments, the heteroene group has 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heterene") within the parent chain. 1-5 In some embodiments, the heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroalkenyl”) within the parent chain. 1-4 In some embodiments, the heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroalkenyl”) within the parent chain. 1-3 In some embodiments, the heteroalkenyl group has 1 to 2 carbon atoms, at least one double bond, and 1 heteroatom (“heteroalkenyl”) within the parent chain. 1-2 In some embodiments, the heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroalkenyl”) within the parent chain. 1-6 (alkenyl group). In some embodiments, the heteroalkenyl group is C. 2–3 Heterene, C 2–4 Heterene, C 2–5 Heterene, C 2–6 Heterene, C 2–7 Heterene, C 2–8 Heterene, C 2–9 Heterene, C 2–10 Heterene, C 2–12 Heterene, C 2–16 Heterene, C 2–20 Heterene, C 2–30 Heterene, C 2–40 Heterene, C 2–50 Heterene, C 2–60 Heterene, C 2–70 Heterene, C 2–80 Heterene, C 2–90 Heterene or C 2–100 Heterenyl. Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (“unsubstituted heteroalkenyl”) or substituent with one or more substituents (e.g., oxo, substituted or unsubstituted C). 1-6 Alkyl (e.g., –CH3)) substitution (“substituted heteroalkenyl”). In some embodiments, the heteroalkenyl is an unsubstituted heterocrystal. 1-20 Alkenyl. In some embodiments, the heteroalkenyl group is a substituted heteroC. 1-20 Alkenyl group. In some embodiments, the unsubstituted heteroC1 alkenyl group is –CH=NH or =N–CH3. The term "heteroC" is used in this context. z1-z2 "Alkenyl" and "C" z1-z2 "Heteroalkenyl" can be used interchangeably, where each of z1 and z2 is an independent integer.

[0057] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having 1 to 100 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds). 1-100 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 1 to 20 carbon atoms (“C”). 1-20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group has at least two carbon atoms. In some embodiments, the alkynyl group has one to ten carbon atoms (“C”). 1-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 1 to 9 carbon atoms (“C”). 1-9 The alkynyl group (“Alynyl”) has 1 to 8 carbon atoms in some embodiments. 1-8 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 1 to 7 carbon atoms (“C”). 1-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 1 to 6 carbon atoms (“C”). 1-6 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 1 to 5 carbon atoms (“C”). 1-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 1 to 4 carbon atoms (“C”). 1-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 1 to 3 carbon atoms (“C”). 1-3 The alkynyl group (“C”) has one to two carbon atoms in some embodiments. 1-2 The alkynyl group (“C1 alkynyl”) is present in some embodiments. In some embodiments, the alkynyl group is C1. 2–3 alkynyl group, C 2–4 alkynyl group, C 2–5 alkynyl group, C 2–6 alkynyl group, C 2–7 alkynyl group, C 2–8 alkynyl group, C 2–9 alkynyl group, C 2–10 alkynyl group, C 2–12 alkynyl group, C 2–16 alkynyl group, C 2–20 alkynyl group, C 2–30 alkynyl group, C 2–40 alkynyl group, C 2–50 alkynyl group, C 2–60 alkynyl group, C 2–70 alkynyl group, C 2–80 alkynyl group, C 2–90 alkynyl or C 2–100 Alkynyl group. One or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 1-4Examples of alkynyl groups include, but are not limited to, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 1-6 Examples of alkynyl groups include the aforementioned C 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octyynyl (C8), etc. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 1-20 Alkynyl group. In some embodiments, the alkynyl group is a substituted C- group. 1-20 Alkyne group.

[0058] The term "heteroyne group" refers to an ynyl group that also includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorus located within the parent chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In some embodiments, a heteroyne group refers to a group having 1 to 100 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroyne group"). 1-100 The alkynyl group (“heteroyne”) is mentioned. In some embodiments, the alkynyl group has at least two carbon atoms. In some embodiments, the alkynyl group refers to a group having 1 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain (“heteroyne”). 1-20 In some embodiments, a heteroynyl group refers to a group having 1 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain (“heteroylated group”). 1-10 The heteroynyl group ("heterynyl group") has 1 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms ("heterynyl group") within the parent chain in some embodiments. 1-9 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms ("heteroylated C") within the parent chain. 1-8 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms ("heteroylated C") within the parent chain. 1-7 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms ("heteroylated C") within the parent chain. 1-6 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroylated C") within the parent chain. 1-5 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroylated C") within the parent chain.1-4 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroylated C") within the parent chain. 1-3 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 2 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroylated C") within the parent chain. 1-2 ("Hydynyl group"). In some embodiments, the heteroynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroylated C") within the parent chain. 1-6 (Alynyl group). In some embodiments, the heteroyyn group is C. 2–3 Neyne group, C 2–4 Neyne group, C 2–5 Neyne group, C 2–6 Neyne group, C 2–7 Neyne group, C 2–8 Neyne group, C 2–9 Neyne group, C 2–10 Neyne group, C 2–12 Neyne group, C 2–16 Neyne group, C 2–20 Neyne group, C 2–30 Neyne group, C 2–40 Neyne group, C 2–50 Neyne group, C 2–60 Neyne group, C 2–70 Neyne group, C 2–80 Neyne group, C 2–90 pyrynyl or C 2–100 Zeyne group. Unless otherwise specified, each instance of a zeyne group is independently unsubstituted (“unsubstituted zeyne group”) or substituented by one or more substituents (e.g., oxo group, substituted or unsubstituted C). 1-6 Alkyl (e.g., –CH3)) substitution (“substituted heteroynyl”). In some embodiments, the heteroynyl group is an unsubstituted hetero-C 1-20 Alkynyl group. In some embodiments, the heteroyne group is a substituted hetero-C group. 1-20 Alkynyl group. In some embodiments, the unsubstituted hetero-C1 alkynyl group is –C≡N. The term "hetero-C" is used in this context. z1-z2 "Alkyne" and "C" z1-z2 "Zeyne group" can be used interchangeably, where each of z1 and z2 is an independent integer.

[0059] The term "carbocyclic" or "carbocyclic" refers to a non-aromatic ring system having 3 to 14 ring carbon atoms ("C"). 3-14 A group consisting of a carbocyclic group (“C”) and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 14 cyclic carbon atoms (“C”). 3-14 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 13 cyclic carbon atoms (“C”). 3-13(Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 12 cyclic carbon atoms (“C”). 3-12 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 11 cyclic carbon atoms (“C”). 3-11 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 10 cyclic carbon atoms (“C”). 3-10 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 7 cyclic carbon atoms (“C”). 3-7 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 4 to 6 cyclic carbon atoms (“C”). 4-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 5 to 6 cyclic carbon atoms (“C”). 5-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group). Example C 3-6 Carbocyclic groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl (C 10 ), etc. Example C 3-8 Carbocyclic groups include the aforementioned C 3-10 Carbocyclic and cycloundecyl (C 11 ), spiro[5.5]undecyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or polycyclic (e.g., containing fused ring systems, bridging ring systems, or spirocyclic systems, such as bicyclic systems (“bicyclic carbocyclic”) or tricyclic systems (“tricyclic carbocyclic”)) and may be saturated, or may contain one or more carbon-carbon double or triple bonds. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the carbocyclic ring, and in such cases, the number of carbons continues to represent the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclic group is independently unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3-14 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-14 Carbon cyclic group.

[0060] In some implementations, "carbocyclic group" is a monocyclic, saturated carbocyclic group ("C") having 3 to 14 ring carbon atoms. 3-14 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (“C”). 4-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-14 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-14 Cycloalkyl. In some embodiments, where the valence allows, the carbocyclic group includes 0, 1, or 2 C=C double bonds in the carbocyclic system.

[0061] The term "heterocyclic group" or "heterocyclic" refers to a group having a 3- to 14-membered non-aromatic ring system with a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or polycyclic (e.g., fused ring systems, bridging ring systems, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group") or tricyclic systems ("tricyclic heterocyclic group")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclic polycyclic systems can include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes ring systems in which a heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or ring systems in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the heterocyclic ring. In such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of a heterocyclic group is independently unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3-14 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-14 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclic group, wherein, where valence permits, one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur.

[0062] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1 cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0063] Exemplary 3-membered heterocyclic groups containing one heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include aziridinyl, oxiranyl, and thiiranyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrroliyl, dihydropyrroliyl, and pyrroliyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include dioxolanyl, oxathiolanyl, and dithiopentanyl. Exemplary 5-membered heterocyclic groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include triazineyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include azirheptanyl, oxetaneheptyl, and thioheptanyl. Exemplary bicyclic heterocyclic groups include indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphridyl, decahydro-1,8-naphridyl, octahydropyrrolo[3,2-b]pyrrole, indololinyl, phthalimide, naphthalimide, chromenyl, 1H-benzo[e][1,4]diazazolyl, 1,4,5,7-tetrahydropyranolo[3,4-b]pyrrole, 5,6- Dihydro-4H-furano[3,2-b]pyrrolithyl, 6,7-dihydro-5H-furano[3,2-b]pyrrolithyl, 5,7-dihydro-4H-thieno[2,3-c]pyrrolithyl, 2,3-dihydro-1H-pyrroli[2,3-b]pyridyl, 2,3-dihydrofurano[2,3-b]pyridyl, 4,5,6,7-tetrahydro-1H-pyrroli[2,3-b]pyridyl, 4,5,6,7-tetrahydrofurano[3,2-c]pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridyl, 1,2,3,4-tetrahydro-1,6-naphthidyl, etc.

[0064] The term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring arrangement) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6-14Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C14”). 14 "Aryl"; for example, anthracene. "Aryl" also includes a ring system in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or attachment site is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0065] The term "heteroaryl" refers to a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons in a cyclic arrangement) having a cyclic carbon atom provided in the aromatic ring system and 1–4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, where the valence allows. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or two rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the attachment point is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the attachment point is on the aryl or heteroaryl ring, and in such cases, the number of ring members represents the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl, in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the attachment point can be on either ring, for example, a ring carrying a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In some embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0066] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0067] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrole, furanyl, and phenylthio. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include aziryl, oxazinyl, and thioazinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazole, benzotriazolyl, benzobenzylthio, isobenzobenzylthio, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinel, dibenzofuranyl, carbazoleyl, acridinel, phenothiazinyl, phenotoxazinyl, and phenothiazinyl.

[0068] The term “halogen” or “halogen” refers to fluorine (fluorinated group, -F), chlorine (chloroinated group, -Cl), bromine (brominated group, -Br) or iodine (iodolated group, -I).

[0069] The term "alkoxy" refers to an -O-alkyl substituent.

[0070] Adding the prefix "-ene" to a group indicates that the resulting group is a polyvalent (e.g., divalent, trivalent, or tetravalent) moiety. For example, alkylene is the polyvalent moiety of an alkyl group, alkenylene is the polyvalent moiety of an alkenyl group, ynynylene is the polyvalent moiety of an alkyne group, heteroalkylene is the polyvalent moiety of a heteroalkyl group, heteroalkenylene is the polyvalent moiety of a heteroalkenyl group, heteroynylene is the polyvalent moiety of a heteroynyl group, carbocyclic is the polyvalent moiety of a carbocyclic group, heterocyclic is the polyvalent moiety of a heterocyclic group, arylene is the polyvalent moiety of an aryl group, and heteroarylene is the polyvalent moiety of a heteroaryl group. In some embodiments, the unsubstituted C1 heteroalkylene is –OCH2– or –CH2O–. In some embodiments, the substituted C1 heteroalkylene is –NHC(=O)– or –C(=O)NH–. In some embodiments, the unsubstituted C2 heteroalkylene is –OCH2CH2– or –CH2CH2O–. In some embodiments, the unsubstituted C4 heteroalkyl group is –(OCH2CH2)2– or –(CH2CH2O)2–. In some embodiments, the unsubstituted C6 heteroalkyl group is –(OCH2CH2)3– or –(CH2CH2O)3–. In some embodiments, the unsubstituted C8 heteroalkyl group is –(OCH2CH2)4– or –(CH2CH2O)4–. In some embodiments, the unsubstituted C… 10 The heteroalkyl group is –(OCH2CH2)5– or –(CH2CH2O)5–. In some embodiments, the unsubstituted C… 12 The heteroalkyl group is –(OCH2CH2)6– or –(CH2CH2O)6–.

[0071] Unless otherwise expressly provided, the groups are optionally substituted. The term "optionally substituted" means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are optionally substituted. "Optionally substituted" means substituted or unsubstituted groups (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" ynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted" means that at least one hydrogen atom present on a group is replaced by a permitted substituent, such as a substituent that, upon substitution, produces a stable compound (e.g., a compound that does not spontaneously undergo transformation (such as by rearrangement, cyclization, elimination, or other reactions)). Unless otherwise specified, a "substituted" group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permitted substituents of an organic compound, and includes any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all such combinations to obtain a stable compound. For the purposes of this disclosure, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or satisfy the valence of the heteroatom and result in the formation of a stable moiety by any suitable substituent as described herein. This disclosure is not in any way limited to the exemplary substituents described herein.

[0072] Exemplary carbon substituents include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OR aa 、−ON(R bb )2、−N(R bb )2、−N(R bb )3 + X − 、−N(OR cc )R bb -SH, -SR aa -SSR cc 、−C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、−CO2R aa 、−OC(=O)R aa 、−OCO2R aa 、−C(=O)N(R bb )2、−OC(=O)N(Rbb )2、−NR bb C(=O)R aa 、−NR bb CO2R aa 、−NR bb C(=O)N(R bb )2、−C(=NR bb )R aa 、−C(=NR bb )OR aa 、−OC(=NR bb )R aa 、−OC(=NR bb )OR aa 、−C(=NR bb )N(R bb )2、−OC(=NR bb )N(R bb )2、−NR bb C(=NR bb )N(R bb )2、−C(=O)NR bb SO2R aa 、−NR bb SO2R aa 、−SO2N(R bb )2、−SO2R aa 、−SO2OR aa 、−OSO2R aa 、−S(=O)R aa 、−OS(=O)R aa 、−Si(R aa )3、−OSi(R aa )3 −C(=S)N(R bb )2、−C(=O)SR aa 、−C(=S)SR aa 、−SC(=S)SR aa 、−SC(=O)SR aa 、−OC(=O)SR aa 、−SC(=O)OR aa 、−SC(=O)R aa 、−P(=O)(R aa )2、−P(=O)(OR cc )2、−OP(=O)(R aa )2、−OP(=O)(OR cc )2、−P(=O)(N(R bb )2)2、−OP(=O)(N(R bb )2)2、−NR bbP(=O)(R aa )2、−NR bb P(=O)(OR cc )2、−NR bb P(=O)(N(R bb )2)2、−P(R cc )2、−P(OR cc )2、−P(R cc )3 + X − 、−P(OR cc )3 + X − 、−P(R cc 4. −P(OR) cc 4. −OP(R) cc )2、−OP(R cc )3 + X − -OP(OR) cc 2. −OP(OR) cc )3 + X − 、−OP(R cc 4. −OP(OR) cc )4、−B(R aa )2、−B(OR cc )2、−BR aa (OR cc C 1–20 Alkyl, C 1–20 All-halogenated alkyl, C 1–20 alkenyl, C 1–20 alkynyl, hetero-C 1–20 Alkyl, hetero C 1–20 alkenyl, hetero-C 1–20 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; wherein X − To counteract ions;

[0073] Or two hydrogen atom on a carbon atom are surrounded by =O, =S, =NN(R) groups. bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NRbb or = NOR cc Substitute;

[0074] R aa Each instance is independently selected from C 1–20 Alkyl, C 1–20 All-halogenated alkyl, C 1–20 alkenyl, C 1–20 alkynyl, hetero-C 1–20 Alkyl, hetero C 1–20 alkenyl, hetero-C 1–20 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R aa The groups are linked to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0075] R bb Each instance is independently selected from hydrogen, −OH, −OR aa 、−N(R cc )2、−CN、−C(=O)R aa 、−C(=O)N(R cc )2、−CO2R aa -SO2R aa 、−C(=NR cc OR aa 、−C(=NR cc )N(R cc )2、−SO2N(R cc )2、−SO2R cc -SO2OR cc -SOR aa 、−C(=S)N(R cc )2、−C(=O)SR cc 、−C(=S)SR cc 、−P(=O)(R aa )2、−P(=O)(OR cc )2、−P(=O)(N(R cc )2)2、C 1–20 Alkyl, C 1–20 All-halogenated alkyl, C 1–20 alkenyl, C 1–20 alkynyl, hetero-C 1–20 Alkyl, hetero C 1–20 alkenyl, hetero-C 1–20 alkynyl group, C 3-10Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb The groups are linked to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0076] R cc Each instance is independently selected from hydrogen, C 1–20 Alkyl, C 1–20 All-halogenated alkyl, C 1–20 alkenyl, C 1–20 alkynyl, hetero-C 1–20 Alkyl, hetero C 1–20 alkenyl, hetero-C 1–20 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R cc The groups are linked to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0077] R dd Each instance is independently selected from halogens, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OR. ee 、−ON(R ff )2、−N(R ff )2、−N(R ff )3 + X − 、−N(OR ee )R ff -SH, -SR ee -SSR ee 、−C(=O)R ee -CO2H, -CO2R ee 、−OC(=O)R ee 、−OCO2R ee 、−C(=O)N(R ff )2、−OC(=O)N(R ff )2、−NR ff C(=O)R ee ,−NR ff CO2R ee ,−NR ff C(=O)N(Rff )2、−C(=NR ff OR ee 、−OC(=NR ff )R ee 、−OC(=NR ff OR ee 、−C(=NR ff )N(R ff )2、−OC(=NR ff )N(R ff )2、−NR ff C(=NR ff )N(R ff )2、−NR ff SO2R ee 、−SO2N(R ff )2、−SO2R ee -SO2OR ee -OSO2R ee 、−S(=O)R ee 、−Si(R ee )3、−OSi(R ee 3、−C(=S)N(R) ff )2、−C(=O)SR ee 、−C(=S)SR ee 、−SC(=S)SR ee 、−P(=O)(OR ee )2、−P(=O)(R ee )2、−OP(=O)(R ee )2、−OP(=O)(OR ee 2. C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 1–10 alkenyl, C 1–10 alkynyl, hetero-C 1–10 Alkyl, hetero C 1–10 alkenyl, hetero-C 1–10 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal R groups dd Substituent linkages form =O or =S; where X − To counteract ions;

[0078] R ee Each instance is independently selected from C 1-10Alkyl, C 1-10 All-halogenated alkyl, C 1-10 alkenyl, C 1-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 1-10 alkenyl, hetero-C 1-10 alkynyl group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0079] R ff Each instance is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 1-10 alkenyl, C 1-10 alkynyl, hetero-C 1-10 Alkyl, hetero C 1-10 alkenyl, hetero-C 1-10 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff The groups are linked to form a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aryl, or heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0080] R gg Each instance is independently a halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC 1–6 Alkyl, −ON(C) 1–6 Alkyl)2、−N(C 1–6 Alkyl)2、−N(C 1–6 Alkyl)3 + X − 、−NH(C 1–6 Alkyl)2 + X − 、−NH2(C 1–6 alkyl) + X − 、−NH3 + X − 、−N(OC 1–6 Alkyl)(C 1–6 Alkyl), −N(OH)(C 1–6 Alkyl), −NH(OH), −SH, −SC 1–6Alkyl, −SS(C 1–6 Alkyl), −C(=O)(C 1–6 Alkyl), −CO2H, −CO2(C 1–6 Alkyl), −OC(=O)(C 1–6 alkyl), −OCO2(C 1–6 Alkyl groups), −C(=O)NH2, −C(=O)N(C 1–6 Alkyl)2、−OC(=O)NH(C 1–6 Alkyl), −NHC(=O)(C 1–6 alkyl), −N(C) 1–6 Alkyl)C(=O)(C 1–6 Alkyl), −NHCO2(C 1–6 Alkyl), −NHC(=O)N(C 1–6 Alkyl)2、−NHC(=O)NH(C 1–6 Alkyl groups), −NHC(=O)NH2, −C(=NH)O(C 1–6 Alkyl), −OC(=NH)(C 1–6 Alkyl), −OC(=NH)OC 1–6 Alkyl group, −C(=NH)N(C 1–6 Alkyl)2、−C(=NH)NH(C 1–6 Alkyl groups), −C(=NH)NH2, −OC(=NH)N(C 1–6 Alkyl)2、−OC(NH)NH(C 1–6 Alkyl groups), −OC(NH)NH2, −NHC(NH)N(C 1–6 Alkyl)2, −NHC(=NH)NH2, −NHSO2(C 1–6 Alkyl), −SO2N(C 1–6 alkyl)2、−SO2NH(C 1–6 Alkyl groups, -SO2NH2, -SO2C 1–6 Alkyl, −SO2OC 1–6 Alkyl, −OSO2C 1–6 Alkyl, −SOC 1–6 Alkyl, −Si(C) 1–6 Alkyl)3、−OSi(C 1–6 alkyl)3−C(=S)N(C 1–6 Alkyl)2、C(=S)NH(C 1–6 Alkyl), C(=S)NH2, −C(=O)S(C 1–6 Alkyl), −C(=S)SC 1–6 Alkyl, −SC(=S)SC 1–6 Alkyl, −P(=O)(OC) 1–6Alkyl)2、−P(=O)(C 1–6 Alkyl)2、−OP(=O)(C 1–6 Alkyl)2、−OP(=O)(OC 1–6 Alkyl)2, C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 1–10 alkenyl, C 1–10 alkynyl, hetero-C 1–10 Alkyl, hetero C 1–10 alkenyl, hetero-C 1–10 alkynyl group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 heterocyclic or 5-10 heteroaryl; or two geminal Rs gg Substituents can link to form =O or =S; and

[0081] Each X - To counteract ions.

[0082] In some embodiments, each carbon atom substituent is independently a halogenated, substituted (e.g., substituted by one or more halogens), or unsubstituted C atom. 1-6 Alkyl, −OR aa 、−SR aa 、−N(R bb )2, –CN, –SCN, –NO2, –C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2、−OC(=O)R aa 、−OCO2R aa 、−OC(=O)N(R bb )2、−NR bb C(=O)R aa ,−NR bb CO2R aa or −NR bb C(=O)N(R bb 2. In some embodiments, each carbon atom substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C atom. 1-10 Alkyl, −OR aa 、−SR aa 、−N(R bb )2, -CN, -SCN, –NO2, −C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2、−OC(=O)R aa 、−OCO2R aa 、−OC(=O)N(Rbb )2、−NR bb C(=O)R aa ,−NR bb CO2R aa or −NR bb C(=O)N(R bb )2, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-10 Alkyl groups, oxygen-protecting groups when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, neopentyl, or benzoyl) or sulfur-protecting groups when attached to a sulfur atom (e.g., acetamylmethyl, t-Bu, 3-nitro-2-pyridinesulfonyl, 2-pyridinesulfonyl, or triphenylmethyl); and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1–10 Alkyl groups, or nitrogen-protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In some embodiments, each carbon atom substituent is independently halogenated, substituted (e.g., substituted with one or more halogens), or unsubstituted. 1-6 Alkyl, −OR aa 、−SR aa 、−N(R bb 2. –CN, –SCN, or –NO2. In some embodiments, each carbon atom substituent is independently a halogen, substituted (e.g., substituted by one or more halogen moieties), or unsubstituted C. 1-10 Alkyl, −OR aa 、−SR aa 、−N(R bb )2, -CN, -SCN or –NO2, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1–10 Alkyl groups, oxygen-protecting groups when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, neopentyl, or benzoyl) or sulfur-protecting groups when attached to a sulfur atom (e.g., acetamylmethyl, t-Bu, 3-nitro-2-pyridinesulfonyl, 2-pyridinesulfonyl, or triphenylmethyl); and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1–10Alkyl groups, or nitrogen-protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0083] In some embodiments, each nitrogen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, −C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2 or nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-10 Alkyl, −C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2 or nitrogen protecting group, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-10 Alkyl groups, or oxygen-protecting groups when attached to oxygen atoms; and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-10 Alkyl or nitrogen protecting group. In some embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or nitrogen protecting group.

[0084] In some embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen protecting groups include −OH, −OR, etc. aa 、−N(R cc )2、−C(=O)R aa 、−C(=O)N(R cc )2、−CO2R aa -SO2R aa 、−C(=NR cc )R aa 、−C(=NR cc OR aa 、−C(=NR cc )N(R cc )2、−SO2N(R cc )2、−SO2R cc -SO2OR cc -SOR aa 、−C(=S)N(R cc )2、−C(=O)SR cc 、−C(=S)SR cc C1–10 Alkyl (e.g., aralkyl, heteroaralkyl), C 1–20 alkenyl, C 1–20 alkynyl, hetero-C 1–20 Alkyl, hetero C 1–20 alkenyl, hetero-C 1–20 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl groups, and 5-14 heteroaryl groups, wherein each alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd As defined herein, nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TWGreene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999.

[0085] For example, in some embodiments, at least one nitrogen protecting group is an amide group (e.g., including nitrogen protecting groups (e.g., -C(=O)R)). aa (The part of the nitrogen atom directly attached). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, 2-picolinamide, 3-pyridinecarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0086] In some embodiments, at least one nitrogen protecting group is a carbamate group (e.g., including nitrogen protecting groups (e.g., −C(=O)OR)). aa(The portion of the nitrogen atom directly attached to the nitrogen protecting group). In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfonyl)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiopheneyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylcarbamate... Silyl ethyl ester (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Py 2-(N,N-dicyclohexylformamido)ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate , p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinyl benzyl carbamate (Msz), 9-anthraylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithiaalkyl)]methyl carbamate (Dmoc), 4-methylbenzenethio carbamate (Mtpc), 2,4-dimethylbenzenethio carbamate (Bmpc), 2-phosphonoethyl carbamate (Peoc), 2-triphenylphosphonoisopropyl carbamate (Ppoc), 1,1-Dimethyl-2-cyanoethyl ester, m-chloro-p-acyloxybenzyl ester of carbamate, p-(dihydroxyboryl)benzyl ester of carbamate, 5-benzisoxazolyl methyl ester of carbamate, 2-(trifluoromethyl)-6-chromone methyl ester of carbamate (Tcroc), m-nitrophenyl ester of carbamate, 3,5-dimethoxybenzyl ester of carbamate, o-nitrobenzyl ester of carbamate, 3,4-dimethoxy-6-nitrobenzyl ester of carbamate, phenyl (o-nitro)benzyl ester of carbamate (Phenyl) methyl ester, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyyl vinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido) carbamate Propylene ester, 1,1-dimethylpropynyl ester of carbamate, di(2-pyridyl)methyl ester of carbamate, 2-furanylmethyl ester of carbamate, 2-iodoethyl ester of carbamate, isobornyl ester of carbamate, isobutyl ester of carbamate, isonicotinyl ester of carbamate, p-(p'-methoxyphenylazo)benzyl ester of carbamate, 1-methylcyclobutyl ester of carbamate, 1-methylcyclohexyl ester of carbamate, 1-methyl-1-cyclopropylmethyl ester of carbamate, 1 1-Methyl-1-(3,5-dimethoxyphenyl)ethyl ester, 1-methyl-1-(p-phenylazophenyl)ethyl ester of carbamate, 1-methyl-1-phenylethyl ester of carbamate, 1-methyl-1-(4-pyridyl)ethyl ester of carbamate, phenyl ester of carbamate, p-(phenylazo)benzyl ester of carbamate, 2,4,6-tri-tert-butylphenyl ester of carbamate, 4-(trimethylammonium)benzyl ester of carbamate, and 2,4,6-trimethylbenzyl ester of carbamate.

[0087] In some embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., including nitrogen protecting groups (e.g., −S(=O)2R)). aaThe portion of the nitrogen atom directly attached to the nitrogen protecting group. In some such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of: p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide ( Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethylsulfonamide.

[0088] In some embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of: phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethylsilylazopentanyl adduct (STABASE), 5 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridinone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptanamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr) N-9-Phenylenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)trimethylmethyl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclo) Hexenylamine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphamides (Dpp), dimethylthiophosphamides (Mpt), diphenylthiophosphamides (Ppt), dialkylaminophosphates, dibenzylaminophosphates, diphenylaminophosphates, benzylsulfonamides, o-nitrobenzenesulfonamides (Nps), 2,4-dinitrobenzenesulfonamides, pentachlorobenzenesulfonamides, 2-nitro-4-methoxybenzenesulfonamides, triphenylmethylsulfonamides, and 3-nitropyridinesulfonamides (Npys). In some embodiments, two examples of the nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, are N,N'-isopropylidene diamines.

[0089] In some embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0090] In some embodiments, each oxygen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-10 Alkyl, −C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2 or oxygen protecting group. In some embodiments, each oxygen atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl, −C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2 or oxygen protecting group, where R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-10 Alkyl groups, or oxygen-protecting groups when attached to oxygen atoms; and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-10 Alkyl or nitrogen protecting group. In some embodiments, each oxygen atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or oxygen protecting group.

[0091] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include −R aa 、−N(R bb )2、−C(=O)SR aa 、−C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2、−C(=NR bb )R aa 、−C(=NR bb OR aa 、−C(=NR bb )N(R bb )2、−S(=O)R aa -SO2R aa 、−Si(R aa )3、−P(R cc )2、−P(R cc )3 + X − 、−P(OR cc)2、−P(OR cc )3 + X − 、−P(=O)(R aa )2、−P(=O)(OR cc )2 and −P(=O)(N(R bb )2)2, where X − R aa R bb and R cc As defined herein, oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999.

[0092] In some embodiments, each oxygen protecting group, together with the oxygen atom to which it is attached, is selected from the group consisting of: methyl, methoxymethyl (MOM), methyl thiomethyl (MTM), tert-butyl thiomethyl, (phenyl dimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEM) OR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylbridged benzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1 -Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N-oxo anion group (oxido), diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptanyl, triphenylmethyl, 4,4′-dimethoxytriphenylmethyl (4,4′-dimethoxy) Triphenylmethyl or DMT), α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoylmethyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthaliminophenyl)methyl, 4,4',4''-tris(acetylpropionyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 4,4'-dimethoxy-3"'-[N-(imidazolylmethyl)]triphenylmethyl ether (IDTr-OR), 4,4'-dimethoxy-3"'-[N-(imidazolylethyl)carbamoyl]triphenylmethyl ether (IETr-OR), 1,1-Bis(4-methoxyphenyl)-1'-pyrenemethyl, 9-anthrayl, 9-(9-phenyl)xanthyl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiopentane-2-yl, benzisothiazolyl S,S-dioxane, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl tert-hexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilane alkyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxovalerate (acetylpropionate), 4,4-(ethylidene dithio)valerate (acetylpropionyl dithioacetal), neovalerate, adamantinate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate) Methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonyl)ethyl carbonate (Peoc), isobutyl carbonate, ethylene carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azide Butyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, dichlorophenylacetic acid, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthyl ester, nitrate, N,N,N',N'-Tetramethyldiaminophosphate alkyl ester, N-phenylcarbamate alkyl ester, borate ester, dimethylphosphinothioyl, 2,4-dinitrophenylsulfenic acid alkyl ester, sulfate ester, methanesulfonate (methanesulfonate), benzylsulfonate and toluenesulfonate (Ts).

[0093] In some embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, neopentanoyl, or benzoyl.

[0094] In some embodiments, each sulfur atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-10 Alkyl, −C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2 or sulfur protecting group. In some embodiments, each sulfur atom substituent is independently either substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-10 Alkyl, −C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2 or sulfur protecting group, wherein R aa C is hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-10 Alkyl groups, or oxygen-protecting groups when attached to oxygen atoms; and each R bb C is independently hydrogen, substituted (e.g., substituted by one or more halogens), or unsubstituted. 1-10 Alkyl or nitrogen protecting group. In some embodiments, each sulfur atom substituent is independently substituted (e.g., substituted by one or more halogens) or unsubstituted C. 1-6 Alkyl or sulfur protecting group.

[0095] In some embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also known as "thiol protecting groups"). In some embodiments, each sulfur protecting group is selected from the group consisting of: −R aa 、−N(R bb )2、−C(=O)SR aa 、−C(=O)R aa -CO2R aa 、−C(=O)N(R bb )2、−C(=NR bb )R aa 、−C(=NR bb OR aa 、−C(=NRbb )N(R bb )2、−S(=O)R aa -SO2R aa 、−Si(R aa )3、−P(R cc )2、−P(R cc )3 + X − 、−P(OR cc )2、−P(OR cc )3 + X − 、−P(=O)(R aa )2、−P(=O)(OR cc )2 and −P(=O)(N(R bb )2)2, where R aa R bb and R cc As defined herein, sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999.

[0096] In some embodiments, the molecular weight of the substituent is less than 250, less than 200, less than 150, less than 100, or less than 50 g / mol. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In some embodiments, the substituent is composed of carbon, hydrogen, fluorine, and / or chlorine atoms. In some embodiments, the substituent contains 0, 1, 2, or 3 hydrogen bond donors. In some embodiments, the substituent contains 0, 1, 2, or 3 hydrogen bond acceptors.

[0097] "Click chemistry" is a chemical approach first proposed by K. Barry Sharpless in 2001 and is carefully designed to rapidly and reliably generate substances by linking small units together via coupling reactions. See, for example, Kolb, Finn and Sharpless, Angewandte Chemie International Edition (2001) 40: 2004–2021; Evans, Australian Journal of Chemistry (2007) 60: 384–395. Exemplary coupling reactions include, but are not limited to, the formation of esters, thioesters, and amides (e.g., peptide coupling) from activated acids or acyl halides; nucleophilic substitution reactions (e.g., nucleophilic substitution of halides or ring-opening of strained ring systems); azide-alkyne Huisgen cycloaddition; thiol-alkyne addition; imine formation; Michael addition (e.g., maleimide addition); and Diels-Alder reactions (e.g., tetrazine [4+2] cycloaddition).

[0098] As used herein, the term "salt" means any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds obtained by the neutralization reaction of acids and bases. Salts consist of one or more cations (positively charged ions) and one or more anions (negative ions), and are therefore electrically neutral (without a net charge). Salts of the compounds disclosed herein include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods known in the art (such as ion exchange). Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. +(C 1–4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0099] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1–4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations that counteract the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0100] The term "prodrug" refers to a compound that can be converted into the oligonucleotide described herein under physiological conditions or by solvent degradation. A prodrug may be a precursor to an oligonucleotide and may be pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but at least one conversion product (e.g., an oligonucleotide) may be active. Compared to oligonucleotides, prodrugs may have advantages such as higher solubility, higher permeability, higher absorption, improved distribution, improved metabolism, improved excretion, higher exposure, higher tissue compatibility, slower delivery, more sustained delivery, lower toxicity, and / or a wider therapeutic window (see, for example, Bundgard, H., DESIGN OF PRODRUGS (1985), pp. 7–9, 21–24 (Elsevier, Amsterdam). Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press). A discussion of prodrugs was provided in 1987. A prodrug can be a compound in which the hydrogen atom of the oligonucleotide –OH, –NH2, –SH, –C(=O)OH, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O– is replaced by a protecting group (“PG”, e.g., the carbon-bonded moiety, such as a substituted or unsubstituted alkyl or substituted or unsubstituted phenyl). Prodrugs include –OPG, –NPG2, –SPG, –C(=O)OPG, –OP(=O)(OPG)O–, –SP(=O)( Prodrugs such as –OP(=O)(OPG)S– or –OP(=O)(SPG)O– can be converted under physiological conditions or through solvent decomposition to form –OH, –NH2, –SH, –C(=O)OH, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S– or –OP(=O)(SH)O–. Examples of prodrugs include, but are not limited to, glutathione, acyloxy, thioacyloxy, 2-alkoxycarbonylethyl, disulfide, thiaminal, and enol ester derivatives of phosphorus-modified nucleic acids.Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., “Prodrugsor phosphonates and phosphates: crossing the membrane” Top. Curr. Chem., 2015, 360:115-160. In some embodiments, the prodrug is any of the types described herein.

[0101] The term "subject" to which the treatment is intended refers to a human (e.g., male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged, or elderly person)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog) or a bird (e.g., a commercially relevant bird, such as a chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal can be male or female at any developmental stage. The non-human animal can be a transgenic animal or a genetically engineered animal. The term "patient" refers to a human subject who requires treatment for a disease.

[0102] The term “administer (administering or administration)” means the implantation, absorption, ingestion, injection, inhalation or other introduction of the compound or pharmaceutical composition described herein into or onto a subject.

[0103] The terms "treatment (treatment, treat, and treating)" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen). Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0104] The term "preventing" refers to preventive treatment for subjects who have never had or are not currently suffering from a disease but are at risk of developing it, or who have previously had a disease but are at risk of recurrence. In some implementations, subjects are at higher risk of developing or recurring the disease compared to generally healthy members of the subject population.

[0105] The terms “symptoms,” “disease,” and “symptoms” are used interchangeably.

[0106] The term "effective amount" of a compound described herein refers to an amount sufficient to elicit the desired biological response. The effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint; the severity of side effects, disease, or condition; the identity, pharmacokinetics, and pharmacodynamics of the specific compound; the condition being treated; the manner, route, and desired or required frequency of administration; and the species, age, and health or general condition of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactic treatment. In some embodiments, the effective amount is a single dose of the compound described herein. In some embodiments, the effective amount is a combination of multiple doses of the compound described herein. In some embodiments, the desired dose is delivered three times a day, twice a day, once a day, every other day, every three days, weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the desired dose is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0107] A "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a symptom, or to delay or minimize one or more signs and / or symptoms associated with the symptom. In some embodiments, a therapeutically effective amount is an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the symptom, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0108] The "preventive effective amount" of a compound is an amount sufficient to prevent the symptoms or one or more signs and / or symptoms associated with the symptoms, or to prevent their recurrence. In some embodiments, the preventive effective amount refers to an amount that improves overall prevention and / or enhances the preventive efficacy of another preventive agent.

[0109] The term "composition" refers to a mixture of substances. The term "pharmaceutical composition" refers to a composition suitable for administration to a subject.

[0110] symbol" "" indicates the attachment point between the chemical part and the rest of the compound or chemical formula.

[0111] The term "small molecule" refers to a naturally occurring or artificially produced (e.g., chemically synthesized) molecule having a relatively low molecular weight. Typically, small molecules are organic compounds (i.e., containing carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl groups, carbonyl groups, and heterocycles). In some embodiments, the molecular weight of the small molecule does not exceed 2,000 g / mol. In some embodiments, the molecular weight of the small molecule does not exceed 1,500 g / mol. In some embodiments, the molecular weight of the small molecule does not exceed 1,000 g / mol, 900 g / mol, 800 g / mol, 700 g / mol, 600 g / mol, 500 g / mol, 400 g / mol, 300 g / mol, 200 g / mol, or 100 g / mol. In some embodiments, the small molecule has a molecular weight of at least 100 g / mol, at least 200 g / mol, at least 300 g / mol, at least 400 g / mol, at least 500 g / mol, at least 600 g / mol, at least 700 g / mol, at least 800 g / mol, or at least 900 g / mol, or at least 1,000 g / mol. Combinations of the above ranges (e.g., at least 200 g / mol and not exceeding 500 g / mol) are also possible. In some embodiments, the small molecule is a therapeutically active agent, such as a drug (e.g., a molecule approved by the US Food and Drug Administration, as provided in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule is also referred to as a “small organometallic molecule”. Preferred small molecules are biologically active because they produce biological effects in animals (preferably mammals, more preferably humans). Small molecules include radionuclides and imaging agents. In some embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug is one that has been deemed safe and effective for use in humans or animals by the appropriate government or regulatory agency. For example, the FDA lists drugs approved for human use under 21 CFR §§ 330.5, 331 to 361, and 440 to 460; and lists drugs approved for veterinary use under 21 CFR §§ 500 to 589. According to this disclosure, all listed drugs are considered acceptable for use.

[0112] The terms "peptide," "polypeptide," or "protein" refer to oligomers or polymers of amino acid residues covalently linked together by peptide bonds. Peptides, polypeptides, or proteins can have any size, structure, and function, and can be a single peptide, polypeptide, or protein, or a collection (e.g., a complex) of peptides, polypeptides, and proteins, optionally small molecules and / or metal ions. In some embodiments, a peptide comprises between 2 and 10, between 11 and 20, between 21 and 30, between 31 and 40, or between 41 and 50 (inclusive) amino acid residues. In some embodiments, the peptide or protein comprises between 51 and 100, between 101 and 200, between 201 and 300, between 301 and 500, between 501 and 1,000, between 1,001 and 3,000, between 3,001 and 10,000, or between 10,001 and 30,000 (inclusive). The peptide, polypeptide, or protein may contain only natural amino acids and no non-natural amino acids; contain only non-natural amino acids and no natural amino acids; or contain both natural and non-natural amino acids. The peptide, polypeptide, or protein may contain only amino acid analogs, or contain amino acid analogs in addition to natural and / or non-natural amino acids. In some embodiments, the amino acid residues of the peptide, polypeptide, or protein are residues of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and / or valine, in D and / or L form (e.g., in L form). One or more amino acid residues in the peptide, polypeptide, or protein may be α-amino acid residues or their homologs (e.g., β-amino acid residues). One or more amino acid residues in the peptide, polypeptide, or protein may be protected or unprotected. One or more (e.g., two) ends of the peptide, polypeptide, or protein may be protected (e.g., to form an ester or amide) or unprotected (e.g., as –NH2, –NH3). + –C(=O)OH or –C(=O)O – One or more amino acid residues in a peptide, polypeptide, or protein may be modified or unmodified. Modifications to the amino acid residues in a peptide, polypeptide, or protein may include the addition of carbohydrate groups, hydroxyl groups, phosphate groups, farnesyl groups, isofarnesyl groups, fatty acid groups, or linkers for conjugation or functionalization. Peptides, polypeptides, or proteins may be naturally occurring, recombinant, synthetic, or combinations thereof. Peptides, polypeptides, or proteins may be fragments of naturally occurring peptides, polypeptides, or proteins.

[0113] The term "nucleic acid" refers to a compound composed of linked monomeric nucleotides or nucleosides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0114] The term "oligomeric compound" or "oligomer" refers to a compound consisting of a small number of linked (e.g., covalently linked) subunits. In the context of proteins, peptides, polypeptides, or antibodies, a "subunit" refers to an amino acid (e.g., protected or unprotected) or a peptide bond. In the context of oligonucleotides, a "subunit" refers to a nucleotide, nucleoside, nucleotide base, nucleoside connector, or sugar, or a modified nucleotide, nucleoside, nucleotide base, nucleoside connector, or sugar, or a combination thereof (e.g., a combination of nucleotide bases, nucleoside connectors, or sugars, each of which may be modified or unmodified). A small number can be between 6 and 100 (inclusive). In some implementation schemes, the number of individuals is between 6 and 9, between 10 and 13, between 14 and 18, between 19 and 23, between 24 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100 (inclusive).

[0115] The term "oligonucleotide" refers to an oligomer of linked (e.g., covalently linked) nucleotides and / or nucleosides (e.g., oligomers of nucleic acids and nucleotides), each of which may be independently modified or unmodified. Oligonucleotides may be composed of, but are not limited to, ribonucleic acid (e.g., composed of ribonucleosides), deoxyribonucleic acid (e.g., composed of deoxyribonucleosides), modified nucleic acids (e.g., composed of modified nucleobases, sugars, and / or phosphate groups), or combinations thereof. Oligonucleotides may contain one or more loops in their structure (e.g., stem loops, hairpin loops, or internal loops in RNA structures). Oligonucleotides may be single-stranded or double-stranded and may be RNA, DNA, or hybrids thereof. Oligonucleotides may include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), proviruses, lysogens, repetitive DNA, satellite DNA, viral DNA, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), messenger RNA (mRNA), pre-mRNA, transfer RNA (tRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozymes, flexible enzymes, and small nucleolar RNA. (snoRNA), spliced ​​leader RNA, viral RNA, antisense oligonucleotides (e.g., antisense DNA and antisense RNA), interfering RNA compounds (RNAi compounds), circular RNA (circRNA) compounds, microRNAs (miRNAs) that target oligonucleotides, miRNA mimics, occupation-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and editing compounds (e.g., ADAR recruitment compounds, ADAR targeting compounds, single-stranded guide nucleic acids, or combinations thereof). RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics).RNAi compounds function at least in part through the RNA-induced silencing complex (RISC) pathway, thereby causing sequence-specific degradation and / or sequestration of the target nucleic acid through a process known as RNA interference (RNAi). The term "RNAi compound" is intended to be equivalent to other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, short interfering RNA, short interfering oligonucleotide, short interfering nucleic acid, modified short interfering oligonucleotide, chemically modified siRNA, etc. Additionally, the term "RNAi" is intended to be equivalent to other terms used to describe sequence-specific RNA interference. In some embodiments, the oligonucleotide comprises 6-100 nucleotides and a nucleoside. In some embodiments, the oligonucleotide comprises 10-50 nucleotides and a nucleoside. In some embodiments, the oligonucleotide comprises 14-30 nucleotides and a nucleoside. In some embodiments, the oligonucleotide comprises 20-23 nucleotides and a nucleoside. In some implementations, the oligonucleotide comprises 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides and nucleosides.

[0116] Double-stranded oligonucleotides may contain "blunt ends" or "hanging ends." In blunt-ended oligonucleotides, the two strands of the oligonucleotide are of equal length and terminate at the same base position, resulting in no unpaired bases at either end. In contrast, oligonucleotides with hanging ends (or "sticky ends") contain unpaired nucleotides at each end. In some embodiments, both ends of the oligonucleotide are blunt. In some embodiments, each end of the oligonucleotide is hanging. In some embodiments, one end of the oligonucleotide is blunt and the other end is hanging. In some embodiments, the oligonucleotide contains between 6 and 8, between 9 and 11, between 12 and 14, between 15 and 17, between 18 and 20, between 21 and 24, between 25 and 28, between 29 and 32, between 33 and 36, or between 37 and 40 (inclusive) paired base pairs.

[0117] The term "nucleobase" refers to the nitrogenous portion at the 1′ position of a nucleoside. Nucleobases can include purine and pyrimidine bases. The five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are referred to as major or classical nucleobases. Nucleobases can include unmodified and modified nucleobases. When a nucleobase is listed in a formula definition, it refers to the portion covalently bonded to the listed formula.

[0118] The term "nucleobase sequence" refers to the sequence of adjacent nucleobases in a nucleic acid or oligonucleotide that is independent of any sugar or nucleoside bond.

[0119] The term "nucleoside" refers to a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently either unmodified or modified. A nucleoside can be either unmodified or modified. "Modified nucleoside" refers to a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abase-free nucleosides that lack a nucleobase and optionally contain a non-nucleobase moiety at the corresponding position (e.g., the 1' position).

[0120] The terms “internucleoside linkage”, “internucleoside linker”, “internucleosidic linkage”, and “internucleosidic linker” are used interchangeably.

[0121] The terms “target nucleic acid,” “target RNA,” and “nucleic acid target” all refer to nucleic acids that can be targeted by oligonucleotides (e.g., groups of ligands contained in oligonucleotides) as described herein.

[0122] "Target region" refers to the portion of a target nucleic acid that is targeted by one or more oligonucleotides (e.g., groups of ligands contained in the oligonucleotide).

[0123] "Terminal group" refers to a chemical group or atomic group covalently attached to the end of an oligonucleotide.

[0124] The terms "sense oligonucleotide," "sense oligonucleotide chain," or "sense chain" refer to a chain of double-stranded oligonucleotides containing regions substantially complementary to the antisense region of the double-stranded oligonucleotide. The sense chain can carry a translatable codon in the 5′ to 3′ direction.

[0125] The terms "antisense oligonucleotide," "antisense oligonucleotide chain," or "antisense chain" refer to an oligonucleotide containing a region complementary to or at least partially complementary to the target nucleic acid or the sense strand of the nucleic acid. In some embodiments, the antisense chain does not carry a translatable codon in the 5′ to 3′ direction. In some embodiments, the antisense chain and the sense strand or target nucleic acid are at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% complementary to each other. In some embodiments, the antisense chain and the sense strand or target nucleic acid are completely complementary to each other (100% complementary).

[0126] As used interchangeably herein, the terms “microRNA” and “miRNA” refer to short (e.g., about 20 to about 24 nucleotides in length) non-coding ribonucleic acid (RNA) that participate in the post-transcriptional regulation of gene expression in multicellular organisms by influencing mRNA stability and translation. miRNA is transcribed by RNA polymerase II into part of a capped and polyadenylated primary transcript (pri-miRNA), which may be protein-coding or non-coding. The primary transcript is cleaved by Drosha ribonuclease III to produce a stem-loop precursor miRNA (pre-miRNA) of about 70 nucleotides in length, which is further processed in the RNAi pathway. As part of this pathway, the precursor miRNA is cleaved by cytoplasmic Dicer ribonuclease to generate mature miRNA and antisense miRNA asterisk (miRNA). The product. Mature miRNAs are incorporated into the RNA-induced silencing complex (RISC), which recognizes target mRNAs through incomplete base pairing (i.e., partial complementarity) with the miRNA and most commonly leads to translational repression or destabilization of the target mRNA. This mechanism is most commonly achieved through the binding of the miRNA to the 3′ untranslated region (UTR) of the target mRNA, which can reduce gene expression by inhibiting translation (e.g., by blocking ribosome entry for translation) or directly leading to transcript degradation. The term (i.e., miRNA) may be used herein to refer to any form of subject miRNA (e.g., precursor, primary, and / or mature miRNA).

[0127] As used interchangeably herein, the terms “small interfering RNA,” “short interfering RNA,” and “siRNA” refer to RNA compounds that exist as non-coding single-stranded or double-stranded RNA (dsRNA) compounds having a length of about 20 to about 24 nucleotides and that can be used for RNA interference (RNAi). siRNAs are often found to have a phosphorylated 5′ end and a hydroxylated 3′ end, the 3′ end typically having a two-nucleotide overhang extending beyond the 5′ end of the antiparallel strand (e.g., the complementary strand of the dsRNA compound). siRNAs can interfere with the expression of specific genes by binding to a target sequence (e.g., a target nucleic acid sequence) complementary to them and promoting (e.g., facilitating, triggering, initiating) the degradation of mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. RNAi acts at least in part through the RNA-induced silencing complex (RISC) pathway or Ago2, without RNase H, to regulate the target nucleic acid and / or the protein encoded by the target nucleic acid. After integration and dissociation into the RISC complex, the siRNA pairs with its target mRNA (e.g., complete complementarity) and cleaves it, thus preventing it from being used as a translation template. As discussed above, also as part of the RNAi pathway, the RISC complex loaded with miRNA scans cytoplasmic mRNA for potential complementarity (e.g., partial complementarity).

[0128] The term "circRNA" refers to RNA that is covalently closed (i.e., the 5′ and 3′ ends are linked together) to form a continuous loop. CircRNAs are resistant to exonuclease degradation and are generally much more stable than their linear counterparts of the same sequence. Therefore, circRNAs typically have a longer half-life than linear RNAs. They have many different biological functions and are known, for example, as transcription regulators, microRNA sponges, and protein templates. CircRNAs are also known to interact with proteins, for example, by mediating or altering protein-protein interactions, isolating proteins, recruiting proteins to chromatin, and facilitating protein translocation.

[0129] "Short hairpin RNA" ("shRNA") refers to RNA compounds with tight hairpin turns that can be used, for example, to silence the expression of target genes via RNAi. Due to the presence of the hairpin structure, shRNA typically has a lower degradation rate and turnover rate compared to other RNAi agents.

[0130] The term "mRNA" or "mRNA molecule" refers to messenger RNA or RNA that serves as a template for protein synthesis in a cell. The sequence of the mRNA strand is based on the sequence of the complementary strand of DNA containing the sequence encoding the protein to be synthesized.

[0131] As may be used herein, the term "ADAR recruiting compound" refers to a nucleic acid configured to increase the concentration of adenosine deaminase (ADAR) enzymes that act on ribonucleic acid at sites surrounding the nucleic acid. In some embodiments, the concentration increase is relative to the concentration at which the ADAR recruiting compound is not present at a given site. In some embodiments, the ADAR recruiting compound comprises a double-stranded RNA duplex.

[0132] As may be used herein, the term "ADAR-targeting compound" refers to a nucleic acid configured to direct an ADAR compound to a desired location (e.g., a guide nucleic acid). As used herein, the term "direction" means increasing the concentration of ADAR at the desired location compared to the concentration in the absence of the ADAR-targeting compound. In some embodiments, the ADAR-targeting compound may be configured to control the desired location by altering the sequence and / or properties of the nucleic acid (e.g., by modifying nucleotide bases, sugars, nucleoside linkages, or other components). In some embodiments, the ADAR-targeting compound comprises an ADAR recruitment compound and a single-stranded guide nucleic acid. In some embodiments, the ADAR-targeting compound comprises a double-stranded RNA duplex and a single-stranded guide nucleic acid.

[0133] As may be used herein, the term "single-stranded guide nucleic acid" or "guide RNA" refers to a single-stranded nucleic acid containing a specific sequence that is at least partially complementary to a target sequence. In some embodiments, the target sequence is located, adjacent to, or near the site where ADAR concentration is to be modulated. In some embodiments, the level of complementarity is sufficient to facilitate binding of the single-stranded guide nucleic acid to the target sequence (e.g., annealing).

[0134] "Modified oligonucleotides" refers to oligonucleotides in which at least one sugar, nucleobase, or nucleoside link is modified.

[0135] "Nucleobase sequence" refers to the sequence of adjacent nucleobases in a nucleic acid or oligonucleotide that is independent of any sugar or nucleoside bond.

[0136] The term "oligomeric duplex" refers to a duplex formed by two oligomers with complementary nucleobase sequences. Each oligomer in an oligomeric duplex may be referred to as a "duplexed oligomer." The oligonucleotides of each oligomer in an oligomeric duplex may include non-complementary dangling nucleosides. "Phosphorothioate," "phosphorothioate link," or "phosphorothioate linker" refers to a modified phosphate link in which one non-bridging oxygen atom is replaced by a sulfur atom.

[0137] "Phosphorothiolate", "sulfurothiolate linking", or "sulfurothiolate linker" refers to a modified phosphate linker in which one or each of the bridging oxygen atoms is replaced by a sulfur atom.

[0138] "Connector" refers to a multivalent (e.g., divalent, trivalent, or tetravalent) chemical part (e.g., a combination of atoms having appropriate valences according to known chemical principles) that covalently connects two or more (e.g., three or four) components of a compound (e.g., an oligonucleotide) provided herein.

[0139] The term "ligand" refers to a substance that binds to or otherwise interacts with proteins, nucleic acids, or other biomolecules. In some embodiments, the ligand is selected from the group consisting of: small molecules; saccharin; oligosaccharides; polysaccharides; biomacromolecules, such as peptides, proteins, and peptide analogs and derivatives; peptide mimics; antibodies and their antigen-binding fragments; nucleic acids; nucleic acid analogs and derivatives; extracts prepared from biological materials (such as bacteria, plants, fungi, or animal cells); animal tissues; and naturally occurring or synthetic compositions. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand binds to a protein (e.g., a receptor). In some embodiments, the ligand binds to tropomyosin receptor kinase B (TrkB), cannabinoid receptor type 1 (CB1), α4β... 1 / 7 The ligand binds to an integrin receptor or an N-methyl-D-aspartate (NMDA) receptor. In some embodiments, the ligand is capable of selectively targeting the oligonucleotide (e.g., its oligonucleotide chain) to body regions or cells. In some embodiments, the ligand is capable of targeting the oligonucleotide (e.g., its oligonucleotide chain) to the subject's brain (e.g., the subject's striatum, cerebellum, brainstem, hippocampus, frontal cortex, or spinal cord). In some embodiments, the ligand is capable of targeting the oligonucleotide (e.g., its oligonucleotide chain) to central nervous system (CNS) cells (e.g., neurons). In some embodiments, the ligand is not a lipid.

[0140] The term "internal position" in an oligonucleotide chain refers to a position within the oligonucleotide chain other than a 5′ or 3′ nucleotide. In some embodiments, the internal position is located at an internucleotide link (e.g., an internucleotide link between a 5′ nucleotide and the second nucleotide counting from the 5′ end; an internucleotide link between a 3′ nucleotide and the second nucleotide counting from the 3′ end; an internucleotide link between the nth and (n+1)th nucleotides counting from the 5′ end, where n is an integer between 2 and 20, where the number of nucleotides in the oligonucleotide chain allows). In some embodiments, the internal position is located on an "internal nucleotide" (a nucleotide that is not a 5′ or 3′ nucleotide). Oligonucleotides containing modifications (e.g., ligand conjugations) at their internal positions may be referred to as "internal modified oligonucleotides."

[0141] The term "lipid" or "lipophilic moiety" refers to organic compounds that are substantially insoluble in water under ambient temperature and pressure. Lipids can be LIPID MAPS.®Lipids listed in the LMSD structural database. Lipids can be fatty acyls, glycerides, glycerophospholipids, sphingolipids, glycolipids, polyketides, sterol lipids, or isopentenol lipids. Fatty acyls can be fatty acids or conjugates, octadecanoic acid-like substances, eicosanoic acid-like substances, docosanoid-like substances, fatty alcohols, fatty aldehydes, fatty esters, fatty amides, fatty nitriles, fatty ethers, hydrocarbons, oxygenated hydrocarbons, or fatty acyl glycosides. Glycerides can be monosubstituted glycerol, disubstituted glycerol, trisubstituted glycerol, glycosyl monosubstituted glycerol, glycosyl disubstituted glycerol, betaine monosubstituted glycerol, or betaine disubstituted glycerol. Glycerophospholipids can be glycerophosphate choline, glycerophosphate ethanolamine, glycerophosphate serine, glycerophosphate glycerol, glycerophosphate glycerophosphate esters, glycerophosphate inositol, glycerophosphate inositol monophosphate, glycerophosphate inositol diphosphate, glycerophosphate inositol triphosphate, glycerophosphate esters, glycerophosphate pyrophosphate, glycerophosphate glycerophosphate glycerol, CDP-glycerol, glycosyl glycerophospholipids, glycerophosphate inositol polysaccharides, glycerophosphate choline, glycerophosphate ethanolamine, diglycerophosphate tetraether phospholipids, glycerophosphate nonitol tetraether phospholipids, oxidized glycerophospholipids, glycerophosphate ethanolamine polysaccharides, dihydroxyacetone phosphate esters, glycerophosphate ethanol, glycerophosphate threonine, or cyclic glycerophosphatidic acids. Sphingolipids can be sphingosine bases, ceramides, phosphospholipids, phosphonate sphingolipids, neutral glycosphingolipids, acidic glycosphingolipids, basic glycosphingolipids, amphoteric glycosphingolipids, or arsenosphingolipids. Glycolipids can be acylaminosaccharides, acylaminoglycoglycans, acyltrehalose, or acyltrehalose glycans. Polyketides can be linear polyketides, halogenated lactones, anomeric lactones, macrolides, lactone polyketides, ansamycin, polyenes, linear tetracyclines, angucyclines, polyether antibiotics, aflatoxins, cytochalasin, flavonoids, aromatic polyketides, nonribosomal peptide / polyketide hybrids, or phenolic lipids. Sterol lipids can be sterols, steroids, open-ring steroids, bile acids or their derivatives, or steroid conjugates. Isopentenol lipids can be isoprene, quinones, hydroquinones, polyisoprenols, or hopanes. The term lipid includes, for example, cholesterol, retinoic acid, cholic acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O-hexadecylglycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecanyl, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytriphenylmethyl, or phenoxazine. Lipids can be hydrocarbons (e.g., substituted or unsubstituted, saturated or unsaturated, branched or straight-chain hydrocarbons). Hydrocarbons can be alkanes, alkenes, or alkynes.Unsubstituted hydrocarbons can be C7-C in size. 36 (That is, the unsubstituted hydrocarbon contains a total of 7-36 carbon atoms in the main chain and branches (if present). The substituted hydrocarbon can be a hydrocarbon that is substituted with at least one or more halogen (e.g., F) atoms, provided the valence allows. In some embodiments, each substituent of the substituted hydrocarbon is not another hydrocarbon. The size of the substituted hydrocarbon can be C7-C. 36 (That is, the substituted hydrocarbon contains a total of 7-36 carbon atoms in the main chain and branches (if present), excluding atoms in the substituents).

[0142] The term "unsaturated" or "partially unsaturated" refers to a portion that includes at least one double or triple bond.

[0143] The term "saturated" refers to a portion that does not contain double or triple bonds; that is, the portion contains only single bonds. Detailed Implementation

[0144] In one aspect, this disclosure provides oligonucleotides having a ligand group internally contained therein. This disclosure also provides pharmaceutical compositions and kits comprising any oligonucleotide disclosed herein. This disclosure further provides methods for delivering any oligonucleotide disclosed herein to a subject, methods for treating a disease in a subject in need using any oligonucleotide disclosed herein, methods for preventing a disease in a subject in need using any oligonucleotide disclosed herein, and methods for modulating protein activity in a subject, cell, tissue, or biological sample. In some embodiments, the disease is a CNS disease, a neurodegenerative disease, or a neurocognitive impairment.

[0145] Oligonucleotides

[0146] In one aspect, this disclosure provides oligonucleotides comprising a modified oligonucleotide chain of formula I:

[0147]

[0148] (I),

[0149] Or a pharmaceutically acceptable salt or prodrug, wherein:

[0150] It is a divalent group of an oligonucleotide chain;

[0151] The s1 instances of the nucleoside indirect head were independently... Substitute;

[0152] s1 can be 1, 2, 3, 4, 5, or 6;

[0153] L A and L 4Each instance is a connector independently;

[0154] A 4 Each instance is independently a ligand or lipid group, provided that A 4 At least one instance is a group of a ligand;

[0155] Each of y5 and y6 is independently 0 or 1;

[0156] When y5 is 0, L 5 C is hydrogen, substituted or unsubstituted 1-6 Alkyl or oxygen protecting group; or when y5 is 1, L 5 For connectors;

[0157] When y6 is 0, L 6 C is hydrogen, substituted or unsubstituted 1-6 Alkyl or oxygen protecting group; or when y6 is 1, L 6 For connectors;

[0158] If it exists, then A 5 and A 6 Each of these groups is independently a ligand or a lipid group; and

[0159] Each of the ligands is different from each of the lipids.

[0160] In some implementations, s1 is 1. In some implementations, s1 is 2, 3, 4, 5, or 6.

[0161] In some implementations, y5 is 0. In some implementations, y5 is 1. In some implementations, y6 is 0. In some implementations, y6 is 1.

[0162] In some embodiments, the oligonucleotide chain has a nucleotide sequence that is at least partially complementary to a target nucleic acid sequence (e.g., a target nucleic acid expressed intracellularly). In some embodiments, the oligonucleotide is capable of altering the expression of an underlying gene when delivered to a cell expressing the target nucleic acid. In some embodiments, the oligonucleotide is capable of inhibiting the expression of an underlying gene when delivered to a cell expressing the target nucleic acid. Gene expression can be altered or inhibited in vitro or in vivo. In some embodiments, the oligonucleotide comprises one or more ribonucleic acids (e.g., one or more ribonucleosides), deoxyribonucleic acid (e.g., one or more deoxyribonucleosides), modified nucleic acids (e.g., one or more modified nucleotides, sugars, and / or nucleoside linkages), or combinations thereof. In some embodiments, the oligonucleotide comprises ribonucleic acid (RNA). In some embodiments, the oligonucleotide comprises deoxyribonucleic acid (DNA). In some embodiments, the oligonucleotide comprises modifications (e.g., modified nucleotides, modified sugars, or modified nucleoside linkages).

[0163] In some embodiments, the oligonucleotide is double-stranded (e.g., composed of two single-stranded nucleic acids). In some embodiments, the double-stranded oligonucleotide comprises a first oligonucleotide chain having a region complementary to the target nucleic acid and a second oligonucleotide chain having a region complementary to the first oligonucleotide chain. The first and second oligonucleotide chains can be modified independently. In some embodiments, the first oligonucleotide chain is coupled with a ligand (e.g., TrkB, CB1, α4β). 1 / 7 One or more groups of an integrin or NMDA receptor ligand are linked. In some embodiments, the second oligonucleotide chain is linked to a ligand (e.g., TrkB, CB1, α4β). 1 / 7 One or more groups of an integrin or NMDA receptor ligand are linked. In some embodiments, the oligonucleotide contains one or more groups of the ligand at one or more internal positions. In some embodiments, the oligonucleotide contains one or more groups of the ligand at one or more internal positions and optionally also contains a group of the ligand at the 5′ end and / or a group of the ligand at the 3′ end.

[0164] In some implementations, the length of the oligonucleotide chain is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 nucleotides.

[0165] In some embodiments, the oligonucleotide chain is 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100 nucleotides (inclusive) in length. In some embodiments, the oligonucleotide chain is from about 6 nucleotides to about 100 nucleotides (inclusive) in length. In some embodiments, the oligonucleotide chain is from about 20 nucleotides to about 90 nucleotides (inclusive) in length. In some embodiments, the oligonucleotide chain is from about 30 nucleotides to about 80 nucleotides (inclusive) in length. In some embodiments, the oligonucleotide chain is from about 40 nucleotides to about 70 nucleotides (inclusive) in length. In some implementations, the oligonucleotide chain is about 50 nucleotides to about 60 nucleotides in length.

[0166] In some implementations, the oligonucleotide chain is about 14 nucleotides to about 23 nucleotides in length.

[0167] In some embodiments, the oligonucleotide is a therapeutic oligonucleotide. Therapeutic oligonucleotides may include, for example, but not limited to, RNA (e.g., small interfering RNA (siRNA), microRNA (miRNA) antagonists, miRNA mimics, ADAR recruitment compounds, ADAR targeting compounds, guide RNA, antisense oligonucleotides, short hairpin RNA (shRNA), circular RNA (circRNA)) or combinations thereof.

[0168] In some implementations, the miRNA is a precursor, primary, and / or mature miRNA.

[0169] In some embodiments, the oligonucleotide comprises an antisense oligonucleotide chain. In some embodiments, the antisense oligonucleotide chain is complementary to the sense oligonucleotide chain (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary). In some embodiments, the antisense oligonucleotide chain is complementary to the precursor mRNA. In some embodiments, the antisense oligonucleotide chain blocks translation and promotes the degradation of the mRNA transcript. In some embodiments, the antisense oligonucleotide (alone or together with a complementary sense oligonucleotide) is capable of silencing gene expression via the RNA-induced silencing complex (RISC) pathway. In some embodiments, the antisense oligonucleotide chain recruits RNase H and promotes the degradation of the mRNA transcript. In some embodiments, the antisense oligonucleotide chain targets miRNA, thereby inhibiting miRNA-regulated mRNA expression and promoting miRNA degradation. In some embodiments, the oligonucleotide comprises or recruits an editing complex to edit RNA.

[0170] Some oligonucleotides of this disclosure may exist in both non-solvable and solvable forms, including hydrated forms. Some oligonucleotides of this disclosure may exist in crystalline or amorphous forms.

[0171] In some embodiments, the oligonucleotide comprises an oligonucleotide chain containing a gene (e.g., a human gene) or a portion thereof (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides) associated with a disease (e.g., a CNS disease) having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity. In some embodiments, the oligonucleotide comprises an antisense oligonucleotide. In some embodiments, the oligonucleotide comprises a sense oligonucleotide. In some embodiments, the oligonucleotide is a single-stranded oligonucleotide. In some embodiments, the oligonucleotide is a double-stranded oligonucleotide. In some implementations, the disease is associated with the overexpression of a gene. In some implementations, "associated with" means "at least partially caused by".

[0172] In some embodiments, the oligonucleotide comprises an oligonucleotide chain having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to the microtubule-associated protein tau (MAPT) gene (e.g., the human MAPT gene) or a portion thereof (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides thereof). In some embodiments, the oligonucleotide comprises an antisense oligonucleotide. In some embodiments, the oligonucleotide comprises a sense oligonucleotide. In some embodiments, the oligonucleotide is a single-stranded oligonucleotide. In some embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human MAPT gene can be found, for example, in GenBank accessions NM_001377265.1 (incorporated herein as SEQ ID NO: 1) and NT_010783.14, nucleotides 2624000 to 2761000 (incorporated herein as SEQ ID NO: 2). Further examples of MAPT sequences are readily available from publicly available databases such as GenBank, UniProt, and OMIM. Further information about MAPT can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=MAPT. As used herein, MAPT also refers to variations of the MAPT gene, including variants available in SNP databases. Many sequence variations within the MAPT gene have been identified and can be found, for example, at NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov / snp / ?term=MAPT). In some embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample. In some embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample to a degree of 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to expression, translation, or activity in a negative control (e.g., as measured by immunoassay, hybridization-based assay, or sequencing-based assay (e.g., RNA-Seq)).

[0173] In some embodiments, the oligonucleotide comprises an oligonucleotide chain having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to the superoxide dismutase type 1 (SOD1) gene (e.g., the human SOD1 gene) or a portion thereof (e.g., 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides thereof). In some embodiments, the oligonucleotide comprises an antisense oligonucleotide. In some embodiments, the oligonucleotide comprises a sense oligonucleotide. In some embodiments, the oligonucleotide is a single-stranded oligonucleotide. In some embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human SOD1 gene can be found, for example, nucleotides 5092 to 138872 of NG_007398.2 (incorporated herein as SEQ ID NO: 3), and GenBank accession number NM_016835.5 (incorporated herein as SEQ ID NO: 4). Further examples of SOD1 sequences are readily available from publicly accessible databases such as GenBank, UniProt, and OMIM. Further information about SOD1 can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=SOD1. As used herein, SOD1 also refers to variations of the SOD1 gene, including variants available in SNP databases. Many sequence variations within the SOD1 gene have been identified and can be found, for example, at NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov / snp / ?term=SOD1). In some embodiments, the oligonucleotide inhibits the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample. In some embodiments, the oligonucleotide inhibits the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample to a degree of 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to expression, translation, or activity in a negative control (e.g., as measured by immunoassay, hybridization-based assay, or sequencing-based assay (e.g., RNA-Seq)).

[0174] In some embodiments, the oligonucleotide comprises an oligonucleotide chain having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to the leucine-rich repeat kinase 2 (LRRK2) gene (e.g., the human LRRK2 gene) or a portion thereof (e.g., 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides thereof). In some embodiments, the oligonucleotide comprises an antisense oligonucleotide. In some embodiments, the oligonucleotide comprises a sense oligonucleotide. In some embodiments, the oligonucleotide is a single-stranded oligonucleotide. In some embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human LRRK2 gene can be found, for example, in GenBank accessions NM_198578.4 (incorporated herein as SEQ ID NO: 5) and NG_011709.2, nucleotides 5002 to 149290 (incorporated herein as SEQ ID NO: 6). Further examples of LRRK2 sequences are readily available from publicly accessible databases such as GenBank, UniProt, and OMIM. Further information about LRRK2 can be found, for example, at www.ncbi.nlm.nih.gov / gene / ?term=LRRK2. As used herein, LRRK2 also refers to variations of the LRRK2 gene, including variants available in SNP databases. Many sequence variations within the LRRK2 gene have been identified and can be found, for example, at NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov / snp / ?term=LRRK2). In some embodiments, the oligonucleotide inhibits the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample. In some embodiments, the oligonucleotide inhibits the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample to a degree of 3-10%, 10-20%, 20-40%, 40-60%, 60-90%, or 90-99% relative to expression, translation, or activity in a negative control (e.g., as measured by immunoassay, hybridization-based assay, or sequencing-based assay (e.g., RNA-Seq)).

[0175] In some implementations, The oligonucleotide chain is a sense oligonucleotide chain, and the oligonucleotide chain also contains an antisense oligonucleotide chain. In some embodiments, It is an antisense oligonucleotide chain, and the oligonucleotide also contains a sense oligonucleotide chain.

[0176] connector

[0177] In some embodiments, the oligonucleotides provided herein contain one or more adapters (e.g., L... A L 4 L 5 and L 6 ).

[0178] In some embodiments, the linker comprises a chain structure, such as a hydrocarbon chain, or an oligomer of repeating units, or a combination of such repeating units. In some embodiments, the linker comprises 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, or 46-50 (inclusive) repeating units. In some embodiments, the repeating unit is -CH2-. In some embodiments, the repeating unit is –CH2CH2O- or –OCH2CH2-. In some implementations, the connector is 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100 atoms long between any two attachment points.

[0179] In some embodiments, the joint contains carbon atoms in its main chain (e.g., 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100 (inclusive) carbon atoms). In some embodiments, the joint contains heteroatoms (e.g., nitrogen, oxygen, sulfur, phosphorus) in its main chain (e.g., 1-3, 4-6, 7-9, 10-12, 13-15, 16-18, 19-21, 22-24, 25-27, 28-30, 31-33, 34-36, or 37-40 (inclusive) heteroatoms). In some embodiments, the connector comprises an amide, ester, disulfide, or combination thereof in its main chain. In some embodiments, the connector comprises a hydrazone, oxime, imine, guanidine, urea, carbamate, alkyl, sulfonamide, heterocycle, or combination thereof in its main chain. In some embodiments, the connector comprises one or more groups independently selected from the group consisting of alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxyamino. In some embodiments, the connector comprises at least one phosphorus atom in its main chain. In some embodiments, the connector comprises at least one nonpolar linking group. In some embodiments, the connector comprises at least one polar linking group. In some embodiments, the connector comprises at least one linking group formed by a click chemistry reaction of the first and second click chemistry reactive portions. In some embodiments, the connector is substituted. In some embodiments, the linker is substituted with alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, carbonyl, halogen, aryl, heterocyclic, aromatic heterocyclic, cyano, amide, carbamoyl, carboxylic acid, ester, thioether, alkyl thioether, thiol, urea, or combinations thereof. Those skilled in the art will recognize that each of these groups may further be substituted. In some embodiments, the linker is substituted with one, two, three, four, five, six, seven, eight, nine, ten, or more than ten substituents.

[0180] In some implementations, the connector is a key (e.g., a single key).

[0181] In some embodiments, the linker is an optionally substituted alkylene group. In some embodiments, the terminal main chain carbon atom of the alkylene group serves as the attachment point. In some embodiments, the internal main chain carbon atom of the alkylene group serves as the attachment point. In some embodiments, the linker is an optionally substituted alkenyl group. In some embodiments, the linker is an optionally substituted ynylene group. In some embodiments, the linker is a substituted or unsubstituted C-axis. 1-100 Alkylene, substituted or unsubstituted C 2-100 alkenyl, or substituted or unsubstituted C2-100 Ethyne group. In some embodiments, where the valence allows, C 1-100 Alkylene, C 2-100 imide or C 2-100 One or more (e.g., two, three, or four) backbone atoms of the ynynyl group are independently substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl groups. In some embodiments, the linker is a substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 alkenyl, or substituted or unsubstituted C 7-70 Ethyne group. In some embodiments, where the valence allows, C 7-70 Alkylene, C 7-70 imide or C 7-70 One or more (e.g., two, three, or four) backbone atoms of the ynynyl group are independently substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic. In some embodiments, where valence permits, C 7-70 Alkylene, C 7-70 imide or C 7-70 One or both main-chain atoms of the ynynyl group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, an aryl group, or a heterocyclic group. In some embodiments, the linker is a substituted or unsubstituted C- group. 1-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 Alkylene, substituted or unsubstituted C 2-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 alkenyl, or substituted or unsubstituted C 2-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C53-60 Or C 61-70 Ethyne group. In some embodiments, where the valence allows, C 1-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 Alkylene, C 2-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 alkenyl, or C 2-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 One or more (e.g., two, three, or four) main chain atoms of the ynynyl group are independently substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group.

[0182] In some embodiments, the linker is an optionally substituted alkenyl group comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten double bonds. In some embodiments, the linker is an optionally substituted ynylene group comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten triple bonds. In some embodiments, the linker is an optionally substituted alkylene, alkenylene, or ynylene group and comprises one or more (e.g., two, three, four, or five) branch points. In some embodiments, the linker comprises two, three, four, or five branch points.

[0183] In some embodiments, the linker is an optionally substituted heteroalkyl group. In some embodiments, the terminal main chain atom of the heteroalkyl group serves as the attachment point. In some embodiments, the internal main chain atom of the heteroalkyl group serves as the attachment point. In some embodiments, the linker is an optionally substituted alkenyl group. In some embodiments, the linker is an optionally substituted ynyne group. In some embodiments, the linker is a substituted or unsubstituted C- group. 1-100Heteroalkyl, substituted or unsubstituted C 2-100 Hesperidyl group, or substituted or unsubstituted C 2-100 Hypo-acetylenic group. In some embodiments, where the valence allows, C 1-100 Heteroalkyl, C 2-100 Hesperyl or C 2-100 One or more (e.g., two, three, or four) backbone atoms of the heterocyclic group are independently substituted or unsubstituted carbocyclic, heterocyclic, aryl, or heterocyclic groups. In some embodiments, the linker is a substituted or unsubstituted C- group. 7-70 Heteroalkyl, substituted or unsubstituted C 7-70 Hesperidyl group, or substituted or unsubstituted C 7-70 Hypo-acetylenic group. In some embodiments, where the valence allows, C 7-70 Heteroalkyl, C 7-70 Hesperyl or C 7-70 One or more (e.g., two, three, or four) backbone atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, an aryl group, or a heterocyclic group. In some embodiments, where the valence allows, C 7-70 Heteroalkyl, C 7-70 Hesperyl or C 7-70 One or both main-chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, an aryl group, or a heterocyclic group. In some embodiments, the linker is a substituted or unsubstituted C- group. 1-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 Heteroalkyl, substituted or unsubstituted C 1-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 Hesperidyl group, or substituted or unsubstituted C 2-6 C 7-12 C 13-18 C 19-24 C25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 Hypo-acetylenic group. In some embodiments, where the valence allows, C 1-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 Heteroalkyl, C 1-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 imidene alkenyl, or C 2-6 C 7-12 C 13-18 C 19-24 C 25-30 C 31-36 C 37-44 C 45-52 C 53-60 Or C 61-70 One or more (e.g., two, three, or four) main chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, a substituted or unsubstituted aryl group, or a heterocyclic group.

[0184] In some embodiments, the substituted or unsubstituted heteroaryl group replacing one of the main chain atoms is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group. In some embodiments, the substituted or unsubstituted heteroaryl group replacing one of the main chain atoms is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group fused with a substituted or unsubstituted 7- to 9-membered monocyclic heterocyclic group. In some embodiments, the substituted or unsubstituted heteroaryl group replacing one of the main chain atoms is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl group fused with a substituted or unsubstituted 7- to 9-membered monocyclic heterocyclic group, wherein the monocyclic heterocyclic group is fused with one or two substituted or unsubstituted phenyl groups. In some embodiments, the substituted or unsubstituted heteroaryl group or substituted or unsubstituted heterocyclic group replacing one of the main chain atoms is a substituted or unsubstituted 5- or 6-membered monocyclic heterocyclic group. In some embodiments, the substituted or unsubstituted heteroaryl group or substituted or unsubstituted heterocyclic group replacing one of the main chain atoms is a portion formed by a click chemistry reaction of the first and second click chemistry reactive portions.

[0185] In some embodiments, the substituted or unsubstituted heteroaryl group or substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms has the following formula:

[0186] , , , , , , , , or ;

[0187] k21 is 0, 1, 2, 3 or 4;

[0188] If it exists, then R d Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl);

[0189] k22 is 0, 1, 2, 3 or 4;

[0190] If it exists, then R e Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl);

[0191] k23 is an integer between 0 and 11 (inclusive);

[0192] If it exists, then R f Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 Alkyl); and

[0193] R g For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl).

[0194] In some embodiments, the substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms has the following formula:

[0195] , , ,

[0196] , , , , , or .

[0197] A substituted or unsubstituted heteroaryl group or a substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms can be attached in either orientation.

[0198] In some embodiments, the linker is an optionally substituted hemienyl group comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten double bonds. In some embodiments, the linker is an optionally substituted hemiynyl group comprising one, two, three, four, five, six, seven, eight, nine, ten, or more than ten triple bonds. In some embodiments, the linker is an optionally substituted hemialkyl, hemienyl, or hemiynyl group and comprises one or more (e.g., two, three, four, or five) branch points. In some embodiments, the linker comprises two, three, four, or five branch points.

[0199] In some embodiments, the optionally substituted heteroalkyl group is an optionally substituted polyethylene glycol (optionally substituted PEG). In some embodiments, the terminal main chain atoms of the PEG serve as attachment sites. In some embodiments, the internal main chain atoms of the PEG serve as attachment sites. In some embodiments, the linker comprises one or more PEG repeating units (–OCH2CH2– or –CH2CH2O–). In some embodiments, the linker comprises 2–3, 4–5, 6–7, 8–9, 10–11, 12–13, or 14–15 PEG repeating units. In some embodiments, the linker comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 PEG repeating units. In some embodiments, the linker comprises one or more (e.g., two, three, or four) PEGs.

[0200] In some embodiments, the linker comprises a moiety formed via a Michael addition reaction of a Michael donor and a Michael acceptor. In some embodiments, the Michael donor is an enol. In some embodiments, the Michael acceptor is a moiety comprising an α,β-unsaturated carbonyl group. In some embodiments, the Michael donor is -SH. In some embodiments, the Michael acceptor is... .

[0201] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, and The combination of these conditions is conditional upon:

[0202] The number of main chain atoms in the connector is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, and between 81 and 100 (inclusive); and

[0203] The connector does not include O–O, O–N, N–O, or N–N.

[0204] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, and The combination of these conditions is conditional upon:

[0205] The number of main chain atoms in the connector is between 7 and 70 (inclusive); and

[0206] The connector does not include O–O, O–N, N–O, or N–N.

[0207] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, and The combination of these conditions is conditional upon:

[0208] The number of main chain atoms of the connector is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100 (inclusive).

[0209] The connector does not contain O–O, O–N, N–O, or N–N; and

[0210] The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0211] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, and The combination of these conditions is conditional upon:

[0212] The number of main chain atoms in the connector is between 7 and 70 (inclusive);

[0213] The connector does not contain O–O, O–N, N–O, or N–N; and

[0214] The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0215] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that:

[0216] The number of main chain atoms in the connector is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, and between 81 and 100 (inclusive); and

[0217] The connector does not include O–O, O–N, N–O, or N–N.

[0218] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that:

[0219] The number of main chain atoms in the connector is between 7 and 70 (inclusive); and

[0220] The connector does not include O–O, O–N, N–O, or N–N.

[0221] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that:

[0222] The number of main chain atoms of the connector is between 2 and 6, between 7 and 12, between 13 and 20, between 21 and 30, between 31 and 40, between 41 and 50, between 51 and 60, between 61 and 80, or between 81 and 100 (inclusive).

[0223] The connector does not contain O–O, O–N, N–O, or N–N; and

[0224] The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0225] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that:

[0226] The number of main chain atoms in the connector is between 7 and 70 (inclusive);

[0227] The connector does not contain O–O, O–N, N–O, or N–N; and

[0228] The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0229] In some embodiments, the linker includes –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, or –N(CH3)C(=O)–. In some embodiments, the linker is any two or more (e.g., three, four, five, six, seven, eight, nine, or ten) combinations of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, and –N(CH3)C(=O)–, provided that the number of main chain atoms in the instance of the linker is between 7 and 70 (inclusive); and instances of the linker do not include O–O, O–N, N–O, or N–N.

[0230] In some embodiments, the connector includes cleavable bonds or portions. In some embodiments, the connector does not include cleavable bonds or portions. In some embodiments, the connector includes covalent attachment to a solid support. In some embodiments, the connector includes multiple sites for attaching ligand groups.

[0231] In some embodiments, the linker contains a peptide in the backbone of the linker. In some embodiments, the peptide contains 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, or 36-40 amino acids.

[0232] In some embodiments, the connector includes pyrrolidine, 8-amino-3,6-dioxanoic acid (ADO), 4-(N-maleimidemethyl)cyclohexane-1-carboxylic acid succinimide ester (SMCC), 6-aminohexanoic acid (AHEX or AHA), or combinations thereof.

[0233] In some implementations, L A At least one instance is Nucleoside junctions between the first and second nucleosides, counting from the 5' end. In some embodiments, L A yes Nucleoside junctions between the nth nucleotide and the (n+1)th nucleotide, starting from the 5′ end; and... Where the number of nucleotides allows, n is an integer between 2 and 20 (inclusive). In some embodiments, L A At least one instance is Nucleoside junctions between the first and second nucleosides, counting from the 3' end. In some embodiments, L A yes Nucleoside junctions between the nth nucleotide and the (n+1th)th nucleotide, starting from the 3' end; and If the number of nucleotides is allowed, n is an integer between 2 and 20 (inclusive).

[0234] In some implementations, L A It has the following formula: ;

[0235] Z A1 and Z A2 Each instance is independently a single-bonded, substituted, or unsubstituted C 1-6 Alkylene, or substituted or unsubstituted C 2-6 alkenyl;

[0236] W A Each instance is independently, where the valence allows, a group consisting of: substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -O-, -OP(=O)(OR c )O-、-N(R c )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR c -、-NR c C(=O)-、-C(=O)R c -、-NR c C(=O)O-、-NRc C(=O)NR c -, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R c )-、-S(=O)2NR c -、-NR c S(=O)2- or combinations thereof;

[0237] R c Each instance is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen-protecting group when attached to a nitrogen atom, or oxygen-protecting group when attached to an oxygen atom, or R C Two instances are linked to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; and

[0238] Key C 4A Attach to L 4 .

[0239] In some implementation schemes, Z A1 At least one instance is substituted or unsubstituted C 1-6 Alkylene. In some embodiments, Z A1 At least one instance is substituted or unsubstituted C 1-3 Alkylene. In some embodiments, Z A1 At least one instance is unsubstituted C 1-3 Alkylene. In some embodiments, Z A2 At least one instance is substituted or unsubstituted C 1-6 Alkylene. In some embodiments, Z A2 At least one instance is substituted or unsubstituted C 1-3 Alkylene. In some embodiments, Z A2 At least one instance is unsubstituted C 1-3 Alkylene.

[0240] In some implementation schemes, W A -N(R) c )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR c -or-NR c C(=O)-. In some implementations, W A -N(R) c )-、-C(=O)NR c-or-NR c C(=O)-.

[0241] In some implementation schemes, R c Each instance is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0242] In some implementations, L A Having a style or In some implementations, L A Having a style .

[0243] In some implementations, L A Having a style , , , , or .

[0244] In some implementations, L4 is

[0245] ;

[0246] –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L 4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR aS(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –、–C(=O–、–C(=NR) a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a )O–;

[0247] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R group attached to a nitrogen atom. a Two instances of this form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage;

[0248] L 4B1 L 4B2 and L 4B6 Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-100 Alkylene, or substituted or unsubstituted C 1-100 Heteroalkyl;

[0249] L 4C1 and L 4C2Each of these is a single bond, a substituted or unsubstituted heterocyclic group replacing one of the main chain atoms, or a substituted or unsubstituted heteroaryl group replacing one of the main chain atoms; and

[0250] Key C 4B Attach to A 4 .

[0251] In some implementations, –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L 4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 Each of the – symbols is independently a single bond, –O–, –NR. a –、–C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L 4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L 4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L 4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 At least one of the following is independently –C(=O)O–, –OC(=O–, –OP(=O)(OR) a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a In some implementations, –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L 4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 At least one of the following is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S– or –OP(=O)(SH)O–.

[0252] In some implementation schemes, R a At least one instance is independently hydrogen or substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R a Each instance is independently hydrogen or substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R a Each instance is independently either hydrogen or unsubstituted C. 1-6 alkyl.

[0253] In some implementations, L 4B1 L 4B2 and L 4B6 Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-20 Alkylene or substituted or unsubstituted C 1-20 Heteroalkyl groups. In some embodiments, L 4B1 L 4B2 and L 4B6 Each of the C values ​​is independently substituted or unsubstituted. 1-10 Alkylene or substituted or unsubstituted C 1-10 Heteroalkyl groups. In some embodiments, L 4B1 L 4B2 and L 4B6 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 4B1 L 4B2 and L 4B6 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0254] In some implementations, L 4C1 and L 4C2 Each of them is an independent single bond. In some implementations, L 4C1 and L 4C2 Each of them is independently a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms. In some embodiments, L 4C1 and L 4C2 Each of them independently (It can be attached in either direction).

[0255] In some implementations, L4 is

[0256] ;

[0257] Each of p1 and p2 is an independent integer from 1 to 10 (inclusive);

[0258] Each of p3 and p5 is an independent integer from 0 to 10 (inclusive);

[0259] –L 4A21 –L 4A22 Each instance of – is independently a single key, –O–, –S–, –S–S–, –NR a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NRa )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –、–C(=O–、–C(=NR) a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a )O–;

[0260] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted phenyl, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R-group attached to a nitrogen atom. aTwo instances are linked by nitrogen atoms to form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups; and

[0261] Key C 4B Attach to A 4 .

[0262] In some implementations, –L 4A21 –L 4A22 At least one instance of – is –NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 4A21 –L 4A22 At least one instance of – is –NH–C(=O)– or –C(=O)–NH–. In some embodiments, –L 4A21 –L 4A22 At least one instance of – is –O–C(=O)– or –C(=O)–O–. In some implementations, –L 4A21 –L 4A22 At least one instance of – is –O–. In some implementations, –L 4A21 –L 4A22 At least one instance of – is –NH–. In some implementations, –L 4A21 –L 4A22 At least one instance of – is –C(=O)–.

[0263] In some implementations, L 4 The linker can be a combination of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, and –N(CH3)C(=O)–, provided that the number of main chain atoms in the linker instance is between 7 and 70 (inclusive); and the linker instance does not contain O–O, O–N, N–O, or N–N. In some embodiments, L 4 Combinations of –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, and –NHC(=O)–, provided that L 4 The number of main chain atoms in the examples is between 7 and 70 (inclusive); the examples of linkers do not contain O–O, O–N, N–O, or N–N; and the total number of –C(=O)NH– and –NHC(=O)– in the examples of linkers is between 0 and 4 (inclusive). In some embodiments, L 4The linker is –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, or –N(CH3)C(=O)–, or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that the number of main chain atoms in the linker instance is between 7 and 70 (inclusive); and the linker instance does not contain O–O, O–N, N–O, or N–N. In some embodiments, L 4 –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH– or –NHC(=O)–, or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that L 4 The number of main chain atoms in the instances is between 7 and 70 (inclusive); the instances of the linker do not contain O–O, O–N, N–O or N–N; and the total number of –C(=O)NH– and –NHC(=O)– in the instances of the linker is between 0 and 4 (inclusive).

[0264] In some implementations, for:

[0265] .

[0266] In some implementations, L 5 for

[0267] ;

[0268] –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NRa )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –、–C(=O–、–C(=NR) a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a )O–;

[0269] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R group attached to a nitrogen atom. a Two instances of this form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage;

[0270] L 5B1 L 5B2 and L 5B6Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-100 Alkylene, or substituted or unsubstituted C 1-100 Heteroalkyl;

[0271] L 5C1 and L 5C2 Each of these is a single bond, a substituted or unsubstituted heterocyclic group replacing one of the main chain atoms, or a substituted or unsubstituted heteroaryl group replacing one of the main chain atoms; and

[0272] Key C 5B Attach to A 5 .

[0273] In some implementations, –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 Each of the – symbols is independently a single bond, –O–, –NR. a –、–C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 Each of the following is an independent single bond, –C(=O)NRa –or–NR a C(=O) –. In some implementations, –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 At least one of the following is independently –C(=O)O–, –OC(=O–, –OP(=O)(OR) a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a In some implementations, –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 At least one of the following is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S– or –OP(=O)(SH)O–.

[0274] In some implementation schemes, R a At least one instance is independently hydrogen or substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R aEach instance is independently hydrogen or substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R a Each instance is independently either hydrogen or unsubstituted C. 1-6 alkyl.

[0275] In some implementations, L 5B1 L 5B2 and L 5B6 Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-20 Alkylene or substituted or unsubstituted C 1-20 Heteroalkyl groups. In some embodiments, L 5B1 L 5B2 and L 5B6 Each of the C values ​​is independently substituted or unsubstituted. 1-10 Alkylene or substituted or unsubstituted C 1-10 Heteroalkyl groups. In some embodiments, L 5B1 L 5B2 and L 5B6 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 5B1 L 5B2 and L 5B6 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0276] In some implementations, L 5C1 and L 5C2 Each of them is an independent single bond. In some implementations, L 5C1 and L 5C2 Each of these is independently a substituted or unsubstituted subheterocyclic group that replaces one of the main chain atoms. In some embodiments, L 5C1 and L 5C2 Each of them independently (It can be attached in either direction).

[0277] In some implementations, L 5 for

[0278] or ;

[0279] k21 is 0, 1, 2, 3 or 4;

[0280] If it exists, then R d Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C)1-6 alkyl);

[0281] k22 is 0, 1, 2, 3 or 4;

[0282] If it exists, then R e Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl);

[0283] Each of q1, q2, q4, q5, q8, and q9 is an independent integer from 0 to 10 (inclusive);

[0284] Each of q3, q6, and q7 is an independent integer from 1 to 10 (inclusive);

[0285] –L 5A21 –L 5A22 –、–L 5A23 –L 5A24 – and – L 5A25 –L 5A26 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a–、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –、–C(=O–、–C(=NR) a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a )O–;

[0286] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted phenyl, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R-group attached to a nitrogen atom. a Two instances are linked by nitrogen atoms to form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups; and

[0287] Key C 5A Attach to A 5 .

[0288] In some implementations, k21 is 0. In some implementations, k21 is 1. In some implementations, k21 is 2. In some implementations, k22 is 0. In some implementations, k22 is 1. In some implementations, k22 is 2.

[0289] In some implementations, if present, then R d Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, if present, R d Each instance is independently an unreplaced C 1-6 Alkyl group. In some embodiments, if present, R... e Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, if present, R e Each instance is independently an unreplaced C 1-6alkyl.

[0290] In some implementations, each of q1, q2, q4, q5, q8, and q9 is independently 0. In some implementations, each of q1, q2, q4, q5, q8, and q9 is independently 1. In some implementations, each of q1, q2, q4, q5, q8, and q9 is independently 2. In some implementations, each of q1, q2, q4, q5, q8, and q9 is independently 3. In some implementations, each of q3, q6, and q7 is independently 0. In some implementations, each of q3, q6, and q7 is independently 1. In some implementations, each of q3, q6, and q7 is independently 2. In some implementations, each of q3, q6, and q7 is independently 3.

[0291] In some implementations, –L 5A23 –L 5A24 – and – L 5A25 –L 5A26 Each of the – symbols is independently a single bond, –O–, –NR. a –、–NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 5A23 –L 5A24 – and – L 5A25 –L 5A26 Each of – is independently –NR a –C(=O)– or –C(=O)–NR a –

[0292] In some implementations, –L 5A21 –L 5A22 –for–OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a In some implementations, –L 5A21 –L 5A22 –for–OP(=O)(SR a In some implementations, –L 5A21 –L 5A22 – is –OP(=O)(SH)O–.

[0293] In some implementations, L 5 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, and The combination is provided that the number of main chain atoms of the linker is between 7 and 70 (inclusive); and the linker does not contain O–O, O–N, N–O, or N–N. In some embodiments, L 5 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, and The combination is provided that the number of main chain atoms of the linker is between 7 and 70 (inclusive); the linker does not contain O–O, O–N, N–O, or N–N; and the linker's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0294] In some implementations, L 5 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, or Or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that the number of main chain atoms of the connector is between 7 and 70 (inclusive); and the connector does not contain O–O, O–N, N–O, or N–N. In some embodiments, L 5 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, or Or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that the number of main chain atoms of the linker is between 7 and 70 (inclusive); the linker does not contain O–O, O–N, N–O or N–N; and the linker’s –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0295] In some implementations, for

[0296] .

[0297] In some implementations, L 6 for

[0298] ;

[0299] –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L 6A20 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NRa –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –、–C(=O–、–C(=NR) a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a )O–;

[0300] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R group attached to a nitrogen atom. a Two instances of this form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage;

[0301] L 6B1 L 6B2 and L 6B6 Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-100 Alkylene or substituted or unsubstituted C 1-100 Heteroalkyl;

[0302] L 6C1 and L 6C2 Each of these is a single bond, a substituted or unsubstituted heterocyclic group replacing one of the main chain atoms, or a substituted or unsubstituted heteroaryl group replacing one of the main chain atoms; and

[0303] Key C 6B Attach to A 6 .

[0304] In some implementations, –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L 6A20At least one of the following is an independent single bond, –O–, or –NR. a –、–C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L 6A20 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L 6A20 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L 6A20 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L6A20 At least one of the following is independently –C(=O)O–, –OC(=O–, –OP(=O)(OR) a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a In some implementations, –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L 6A20 At least one of the following is independently –C(=O)O–, –OC(=O)–, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S– or –OP(=O)(SH)O–.

[0305] In some implementation schemes, R a At least one instance is independently hydrogen or substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R a Each instance is independently hydrogen or substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R a Each instance is independently either hydrogen or unsubstituted C. 1-6 alkyl.

[0306] In some implementations, L 6B1 L 6B2 and L 6B6 Each of the C bonds is a single bond, independently substituted or unsubstituted. 1-20 Alkylene or substituted or unsubstituted C 1-20 Heteroalkyl groups. In some embodiments, L 6B1 L 6B2 and L 6B6 Each of the C values ​​is independently substituted or unsubstituted. 1-10 Alkylene or substituted or unsubstituted C 1-10 Heteroalkyl groups. In some embodiments, L 6B1 L 6B2 and L 6B6 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 6B1 L6B2 and L 6B6 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0307] In some implementations, L 6C1 and L 6C2 Each of them is an independent single bond. In some implementations, L 6C1 and L 6C2 Each of these is independently a substituted or unsubstituted subheterocyclic group that replaces one of the main chain atoms. In some embodiments, L 6C1 and L 6C2 Each of them independently (It can be attached in either direction).

[0308] In some implementations, L 6 for

[0309] or ;

[0310] Each of r1, r2, r4, r5, r8, and r9 is an independent integer from 0 to 10 (inclusive);

[0311] Each of r3, r6, and r7 is an independent integer from 1 to 10 (inclusive);

[0312] –L 6A21 –L 6A22 –、–L 6A23 –L 6A24 – and – L 6A25 –L 6A26 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR aS(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –、–C(=O–、–C(=NR) a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a )O–;

[0313] R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted phenyl, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R-group attached to a nitrogen atom. a Two instances are linked by nitrogen atoms to form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups; and

[0314] Key C 6A Attach to A 6 .

[0315] In some implementations, k21 is 0. In some implementations, k21 is 1. In some implementations, k21 is 2. In some implementations, k22 is 0. In some implementations, k22 is 1. In some implementations, k22 is 2.

[0316] In some implementations, if present, then R d Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, if present, R d Each instance is independently an unreplaced C 1-6 Alkyl group. In some embodiments, if present, R... e Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, if present, R e Each instance is independently an unreplaced C 1-6 alkyl.

[0317] In some embodiments, each of r1, r2, r4, r5, r8, and r9 is independently 0. In some embodiments, each of r1, r2, r4, r5, r8, and r9 is independently 1. In some embodiments, each of r1, r2, r4, r5, r8, and r9 is independently 2. In some embodiments, each of r1, r2, r4, r5, r8, and r9 is independently 3. In some embodiments, each of r3, r6, and r7 is independently 0. In some embodiments, each of r3, r6, and r7 is independently 1. In some embodiments, each of r3, r6, and r7 is independently 2. In some embodiments, each of r3, r6, and r7 is independently 3.

[0318] In some implementations, –L 6A23 –L 6A24 – and – L 6A25 –L 6A26 Each of the – symbols is independently a single bond, –O–, –NR. a –、–NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 6A23 –L 6A24 – and – L 6A25 –L 6A26 Each of – is independently –NR a –C(=O)– or –C(=O)–NR a –

[0319] In some implementations, –L 6A21 –L 6A22 – for –O–, –OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SRa In some implementations, –L 6A21 –L 6A22 –for –O–.

[0320] In some implementations, L 6 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, and The combination is provided that the number of main chain atoms of the linker is between 7 and 70 (inclusive); and the linker does not contain O–O, O–N, N–O, or N–N. In some embodiments, the linker is –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, and The combination is provided that the number of main chain atoms of the linker is between 7 and 70 (inclusive); the linker does not contain O–O, O–N, N–O, or N–N; and the linker's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0321] In some implementations, L 6 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, or Or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that the number of main chain atoms of the connector is between 7 and 70 (inclusive); and the connector does not contain O–O, O–N, N–O, or N–N. In some embodiments, the connector is –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, and The combination is provided that the number of main chain atoms of the linker is between 7 and 70 (inclusive); the linker does not contain O–O, O–N, N–O, or N–N; and the linker's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0322] In some embodiments, the connector is the connector described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006 / 0148740; US 2011 / 0123520; WO2013 / 033230; WO 2012 / 037254; Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011, 19. 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carbohydr. Res. 1978, 67, 509-514; Connolly et al., J. Biol. Chem. 1982, 257, 939-945; Pavia et al., Int. J. Pep. Protein Res. 1983, 22, 539-548; Lee et al., Biochem. 1984, 23, 4255-4261; Lee et al., Glycoconjugate J. 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett. 1990, 31, 2673-2676; Biessen et al., J. Med. Chem. 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett. 1997, 38, 3487-3490; Lee et al., Bioconjug. Chem. 1997, 8, 762-765; Kato et al., Glycobiol. 2001, 11, 821-829; Rensen et al., J. Biol.Chem. 2001, 276, 37577-37584; Lee et al., Methods Enzymol. 2003, 362, 38-43; Westerlind et al., Glycoconj. J. 2004, 21, 227-241; Lee et al., Bioorg. Med. Chem. Lett. 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg. Med. Chem. 2007, 15, 7661-7676; Khorev et al., Bioorg. Med. Chem. 2008, 16, 5216-5231; Lee et al., Bioorg. Med. Chem. 2011, 19, 2494-2500; Kornilova et al., Analyt. Biochem. 2012, 425, 43-46; Pujol et al., Angew. Chemie Int. Ed. Engl. 2012, 51, 7445-7448; Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Rensen et al., Arterioscler. Thromh. Vase. Biol. 2006, 26, 169-175; van Rossenberg et al., Gene Ther. 2004, 11, 457-464; Sato et al., J. Am. Chem. Soc. 2004, 126, 14013-14022; Lee et al., J. Org. Chem. 2012, 77, 7564-7571; Biessen et al., FASEB J. 2000, 14, 1784-1792; Rajur et al., Bioconjug. Chem. 1997, 8, 935-940; Duff et al., Methods Enzymol. 2000, 313, 297-321; Maier et al., Bioconjug. Chem. 2003, 14, 18-29; Jayaprakash et al., Org. Lett.2010, 12, 5410 - 5413; Manoharan, Antisense Nucleic Acid Drug Dev. 2002, 12, 103 - 128; Merwin et al., Bioconjug. Chem. 1994, 5, 612 - 620; Tomiya et al., Bioorg. Med. Chem., 2013, 21, 5275 - 5281; International Application WO 1998 / 013381; WO 2011 / 038356; WO 1997 / 046098; WO 2008 / 098788; WO 2004 / 101619; WO 2012 / 037254; WO 2011 / 120053; WO 2011 / 100131; WO 2011 / 163121; WO 2012 / 177947; WO 2013 / 033230; WO 2013 / 075035; WO 2012 / 083185; WO 2012 / 083046; WO 2009 / 082607; WO 2009 / 134487; WO 2010 / 144740; WO 2010 / 148013; WO 1997 / 020563; WO 2010 / 088537; WO 2002 / 043771; WO 2010 / 129709; WO 2012 / 068187; WO 2009 / 126933; WO 2004 / 024757; WO 2010 / 054406; WO 2012 / 089352; WO 2012 / 089602; WO 2013 / 166121; WO 2013 / 165816; U.S. Patent Nos. 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; U.S. Patent Application Publication Nos. U.S. 2011 / 0097264; U.S. 2011 / 0097265; U.S. 2013 / 0004427; U.S. 2003 / 0119724; U.S.2011 / 0207799; US 2012 / 0035115; US 2012 / 0230938; US 2005 / 0164235; US 2006 / 0183886; US 2012 / 0136042; US 2012 / 0095075; US 2013 / 0109817; US 2006 / 0148740; US 2008 / 0206869; US 2012 / 0165393; US 2012 / 0101148; US 2013 / 0121954; US 2011 / 0123520; US 2003 / 0077829; US 2008 / 0108801; and US 2009 / 0203132...

[0323] In some embodiments, the connector comprises a structure selected from the following:

[0324] , , , , , , , , , , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and p is 1, 2, 3, 4, 5 or 6.

[0325] In some embodiments, the connector comprises a structure selected from the following:

[0326] , ,

[0327] , , , , , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0328] In some embodiments, the connector comprises a structure selected from the following:

[0329] , , , , , , , , , , , , , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0330] In some embodiments, the connector comprises a structure selected from the following:

[0331] , , , , , , , , , , , , , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0332] In some embodiments, the connector comprises a structure selected from the following:

[0333] , , , , , , , , , , , , , , , , , , and Each L is independently a triphosphate, alkylphosphonate, aminophosphate, thiophosphate, dithiophosphate, or thiophosphate; and each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0334] In some embodiments, the connector comprises a structure selected from the following:

[0335] , ,

[0336] , ,

[0337] , , , , , , , , , , , , , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0338] In some embodiments, the connector comprises a structure selected from the following:

[0339] , , , , , , , , , , , , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0340] In some embodiments, the connector comprises a structure selected from the following:

[0341] , , , , , , , , , , , , , , , , , , , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0342] In some embodiments, the connector comprises a structure selected from the following:

[0343] and , where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0344] In some embodiments, the connector comprises a structure selected from the following:

[0345] , and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0346] In some embodiments, the connector comprises a structure selected from the following:

[0347] and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0348] In some embodiments, the connector comprises a structure selected from the following:

[0349] and , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0350] In some implementations, the connector includes the following structure:

[0351] , where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0352] In some implementations, the connector includes the following structure:

[0353] , where each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0354] ligands

[0355] In the oligonucleotides disclosed herein, A 4 At least one instance is a group of a ligand; and if present, then A 5 and A 6 Each of the groups is independently a ligand or a lipid group. In some embodiments, at least one ligand is a central nervous system receptor ligand. In some embodiments, at least one ligand is a TrkB receptor ligand. In some embodiments, at least one ligand is a selective TrkB modulator. In some embodiments, at least one ligand is a non-selective TrkB modulator (i.e., a pan-TrkABC modulator). In some embodiments, at least one ligand is a CB1 receptor ligand. In some embodiments, at least one ligand is an α4β receptor ligand. 1 / 7 Integrin receptor ligand. In some embodiments, at least one ligand is an NMDA receptor ligand. In some embodiments, the ligand directs the oligonucleotide to a location within the subject. In some embodiments, the ligand targets tissue. In some embodiments, the tissue is brain tissue. In some embodiments, the ligand targets an organ. In some embodiments, the organ is the brain. In some embodiments, the ligand targets cells.

[0356] In some embodiments, the ligand targets a cellular receptor. In some embodiments, the cellular receptor is a TrkB receptor, a CB1 receptor, or an α4β receptor. 1 / 7Integrin receptors or NMDA receptors. In some embodiments, the receptors are located in the brain. In some embodiments, the receptors are located in the frontal cortex. In some embodiments, the receptors are located in the striatum. In some embodiments, the receptors are located in the cerebellum. In some embodiments, the receptors are located in the brainstem. In some embodiments, the receptors are located in the hippocampus. In some embodiments, the receptors are located in the spinal cord. In some embodiments, ligands are used to target oligonucleotides to cell types. In some embodiments, the cells are central nervous system cells. In some embodiments, the cells are neurons. In some embodiments, the cells are glial cells. In some embodiments, the cells are astrocytes. In some embodiments, the cells are oligodendrocytes. In some embodiments, the cells are ependymal cells. In some embodiments, the cells are microglia.

[0357] In some implementations, the ligand is an agonist of the receptor (e.g., TrkB, CB1, α4β). 1 / 7 (Integrin or NMDA receptor agonists). In some embodiments, the ligand is a receptor antagonist (e.g., TrkB, CB1, α4β). 1 / 7 (Integrins or NMDA receptor antagonists).

[0358] In some embodiments, the oligonucleotides provided herein comprise at least one TrkB ligand, said ligand being a group of a compound of the following formula:

[0359] , , , , ,

[0360] , or

[0361]

[0362] R 2 For hydrogen, -OR 7 -SR 8 or -NR 9 R 10 ;

[0363] R 3 For hydrogen, -OR 31 -SR 32 or -NR 33 R 34 ;

[0364] R 4 For hydrogen, -OR 35 -SR 36 or -NR37 R 38 ;

[0365] R 5 For hydrogen, -OR 39 -SR 40 or -NR 41 R 42 ;

[0366] R 6 It can be hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH or =O;

[0367] R 7 R 8 R 9 R 10 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 and R 42 Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0368] Y is CH2, NH, S, or O;

[0369] Z is an aryl group with optional substitution or a heteroaryl group with optional substitution;

[0370] R 11 and R 13 Each is independently an alkyl group that is absent, hydrogen-rich, or optionally substituted;

[0371] R 12 R 14 and R 15 Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0372] R 16 Hydrogen, halogen, –CN, –N3, –SO n16 R 1A –SO v16 NR 16B R 16C –NHNR 16B R16C –ONR 16B R 16C –NHC(O)NHNR 16B R 16C –NHC(O)NR 16B R 16C –N(O) m16 –NR 16B R 16C –C(O)R 16D –C(O)OR 16D –C(O)NR 16B R 16C –OR 16A -NR 16B SO2R 16A -NR 16B C(O)R 16D -NR 16B C(O)OR 16D –NR 16B OR 16D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0373] and Each can be a single bond or a double bond independently, where if If it is a single bond, then It is a double bond and R 13 It does not exist; and further, if If it is a single bond, then It is a double bond and R 11 It does not exist;

[0374] R 16A R 16B R 16C R 16D Each is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; R bonded to the same nitrogen atom 16B and R 16C The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups;

[0375] R 17 R 18 and R 19Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0376] R 20 Hydrogen, halogen, –CN, –N3, –SO n20 R 1A –SO v20 NR 20B R 20C –NHNR 20B R 20C –ONR 20B R 20C –NHC(O)NHNR 20B R 20C –NHC(O)NR 20B R 20C –N(O) m20 –NR 20B R 20C –C(O)R 20D –C(O)OR 20D –C(O)NR 20B R 20C –OR 20A -NR 20B SO2R 20A -NR 20B C(O)R 20D -NR 20B C(O)OR 20D –NR 20B OR 20D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0377] R 21 Hydrogen, halogen, –CN, –N3, –SO n21 R 1A –SO v21 NR 21B R 21C –NHNR 21B R 21C –ONR 21B R 21C –NHC(O)NHNR 21B R 21C –NHC(O)NR 21B R 21C –N(O) m21 –NR 21B R 21C –C(O)R21D –C(O)OR 21D –C(O)NR 21B R 21C –OR 21A -NR 21B SO2R 21A -NR 21B C(O)R 21D -NR 21B C(O)OR 21D –NR 21B OR 21D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0378] R 22 and R 23 Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0379] R 24 Hydrogen, halogen, –CN, –N3, –SO n24 R 1A –SO v24 NR 24B R 24C –NHNR 24B R 24C –ONR 24B R 24C –NHC(O)NHNR 24B R 24C –NHC(O)NR 24B R 24C –N(O) m24 –NR 24B R 24C –C(O)R 24D –C(O)OR 24D –C(O)NR 24B R 24C –OR 24A -NR 24B SO2R 24A -NR 24B C(O)R 24D –NR 24B C(O)OR 24D –NR 24B OR 24D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0380] R 20A R 20B R 20C R 20D R 21A R 21B R 21C R 21D R 24A R 24B R 24C and R 24D Each is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; R bonded to the same nitrogen atom 20B R 20C R 21B R 21C R 24B R 24C R 24B and R 24C The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups;

[0381] n16, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4;

[0382] v16, v20, v21, m16, m20, m21 and m24 are each independently 1 or 2;

[0383] z3 is 0, 1, 2, 3, 4 or 5;

[0384] z4 and z7 are each independently 0, 1 or 2;

[0385] z5 is 0, 1, 2, or 3; and

[0386] z6 and z8 are each independently 0, 1, 2, 3 or 4.

[0387] In some implementation schemes, R 2 For hydrogen or -OR 7 In some implementations, R 2 It is hydrogen. In some implementations, R 2 For -OR 7 In some implementations, R 2 For -OH. In some embodiments, R 2 For -OCH3. In some implementations, R 3 For hydrogen or -OR31 In some implementations, R 3 It is hydrogen. In some implementations, R 3 For -OR 31 In some implementations, R 3 For -OH. In some embodiments, R 3 For -OCH3. In some implementations, R 4 For hydrogen or -OR 35 In some implementations, R 4 It is hydrogen. In some implementations, R 4 For -OR 35 In some implementations, R 4 For -OH. In some embodiments, R 4 For -OCH3. In some implementations, R 5 For hydrogen or -OR 39 In some implementations, R 5 It is hydrogen. In some implementations, R 5 For -OR 39 In some implementations, R 5 For -OH. In some embodiments, R 5 For -OCH3. In some implementations, R 6 It is hydrogen, -OH, or optionally substituted -O-alkyl. In some embodiments, R 6 It is hydrogen.

[0388] In some implementation schemes, R 7 R 8 R 9 R 10 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 and R 42 Each is independently hydrogen or optionally substituted alkyl. In some embodiments, R 7 R 8 R 9 R 10 R 31 R 32 R 33 R 34 R 35 R 36 R 37R 38 R 39 R 40 R 41 and R 42 Each is independently hydrogen. In some implementations, R 7 R 8 R 9 R 10 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 and R 42 Each is independently an optionally substituted alkyl group. In some embodiments, R 7 R 8 R 9 R 10 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 and R 42 Each is independently an unsubstituted alkyl group. In some embodiments, R 7 R 8 R 9 R 10 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 and R 42 Each is independently -CH3.

[0389] In some implementations, Y is NH or O. In some implementations, Y is O.

[0390] In some embodiments, Z is an optionally substituted aryl group. In some embodiments, Z is an optionally substituted phenyl group. In some embodiments, Z is an unsubstituted phenyl group.

[0391] In some embodiments, at least one group of the TrkB ligand has the formula , or In some embodiments, at least one group of the TrkB ligand has the formula... , , , or .

[0392] In some implementation schemes, R 11 and R 13 Each is independently either absent or hydrogen. In some implementations, R 11 and R 13 Each is independently considered non-existent. In some implementations, R 12 R 14 and R 15 Each is independently hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 12 R 14 and R 15 Each is independently hydrogen. In some implementations, R 12 R 14 and R 15 Each is independently an optionally substituted alkyl group. In some embodiments, R 12 R 14 and R 15 Each is independently an unsubstituted alkyl group. In some embodiments, R 16 It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 16 It is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0393] In some implementation schemes, R 17 R 18 and R 19 Each is independently hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 17 R 18 and R 19 Each is independently hydrogen, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group.

[0394] In some implementation schemes, R 20 It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R20 It is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R 20 It is hydrogen. In some implementations, R 21 It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 21 It is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R 21 It is hydrogen. In some implementations, R 22 and R 23 Each is independently hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 22 and R 23 Each is independently hydrogen, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group. In some embodiments, R 22 and R 23 Each is independently hydrogen. In some implementations, R 24 It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 24 It is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments, R 24 It is hydrogen.

[0395] In some implementations, n16, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, and 2. In some implementations, n16, n20, n21, n23, n24, z6, and z8 are each independently 0. In some implementations, v16, v20, v21, m16, m20, m21, and m24 are each independently 1. In some implementations, v16, v20, v21, m16, m20, m21, and m24 are each independently 2. In some implementations, z3 is 0, 1, 2, or 3. In some implementations, z3 is 0. In some implementations, z4 and z7 are each independently 0 or 1. In some implementations, z4 and z7 are each independently 0. In some implementations, z5 is 0, 1, or 2. In some implementations, z5 is 0. In some implementations, z6 and z8 are each independently 0, 1, or 2. In some implementations, z6 and z8 are each independently 0.

[0396] In some embodiments, at least one group of the TrkB ligand has the formula , , , , ,

[0397] , , ,

[0398] or .

[0399] In some embodiments, at least one TrkB ligand is a flavonoid, tropoflavin, or a derivative thereof. In some embodiments, at least one TrkB ligand is 3,7-dihydroxyflavone, 3,7,8,2′-tetrahydroxyflavone, 7,3′-dihydroxyflavone, 7,8,2′-trihydroxyflavone, 7,8,3′-trihydroxyflavone, 7,8,4′-trihydroxyflavone, geraniol (5,7,3′-trihydroxy-4′-methoxyflavone), 7-hydroxy-4′-methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavin (4′-dimethylamino-7,8-dihydroxyflavone), norbaicalin (5,7,8-trihydroxyflavone), R7, R13, Proflavin (7,8-dihydroxyflavone), 7,8-dimethoxyflavone, quercetin (3,3′,4′,5,7-pentahydroxyflavone), apigenin (4′,5,7-trihydroxyflavone), isocoumarin, gossypol (3,5,7,8,3′,4′-hexahydroxyflavone), 2-methyl-8-phenylchromene[7,8-d]imidazol-6(3H)-one, 8-phenylchromene[7,8-d]imidazol-6(3H)-one, 4-oxo-2-phenyl-4H-chromene-7,8-dimethyldiacetate, or ANA-12.

[0400] In some implementations, at least one α4β 1 / 7 Integrin ligands are compounds of the following formula:

[0401] , , ,

[0402] , , ,

[0403] , , ,

[0404] , , ,

[0405] , , ,

[0406] , 、

[0407] 、 、

[0408] 、 、

[0409] 、 、 、

[0410] 、 、

[0411] 、 、

[0412] 、 、

[0413] 、 、

[0414] 、

[0415] 、

[0416] 、 、

[0417] 、 、

[0418] 、 、

[0419] 、 、 、

[0420] 、 、

[0421] 、 、 、

[0422] 、 、

[0423] 、 、

[0424] 、 、

[0425] , ,

[0426] , or Each instance of R is .

[0427] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0428] or ,

[0429] R 2Z It is hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heteroaryl; and

[0430] R 3Z and R 4Z Each of them is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl.

[0431] In some implementation schemes, R 2Z It is hydrogen or a substituted or unsubstituted heteroalkyl group. In some embodiments, R 2Z It is hydrogen. In some implementations, R 3Z and R 4Z Each of these is either hydrogen or halogen. In some implementations, R 3Z and R 4Z Each of them is a halogen.

[0432] In some implementations, at least one α4β 1 / 7 Integrin ligands have the following formula: .

[0433] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0434] or ;

[0435] R 4Z It can be hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted –O-alkyl or optionally substituted cycloalkyl;

[0436] R 5Z It is an optionally substituted heteroalkyl or optionally substituted heterocyclic group; and

[0437] n1Z can be 1, 2, or 3.

[0438] In some implementation schemes, R 4Z It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 4Z It is hydrogen. In some implementations, R 5Z The substituted heteroalkyl group is optional. In some embodiments, n1Z is 1 or 2. In some embodiments, n1Z is 1.

[0439] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0440] ,

[0441] or

[0442] ;

[0443] R 6Z For hydrogen, –OH, –NH2, –NHR 7Z –OR 7Z Or it may not exist; and

[0444] R 7Z It can be hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl.

[0445] In some implementation schemes, R 6Z It can be hydrogen, –OH, –NH2, or absent. In some embodiments, R 6Z It is hydrogen. In some implementations, R 6Z It does not exist. In some implementations, R 7Z It is hydrogen or optionally substituted alkyl. In some embodiments, R 7Z It is hydrogen or an unsubstituted alkyl group.

[0446] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0447] ,

[0448] ,

[0449] ,

[0450] or

[0451] ;

[0452] n2Z can be 0, 1, 2, or 3.

[0453] In some implementations, n²Z is 0 or 1. In some implementations, n²Z is 0.

[0454] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0455] ,

[0456] ,

[0457] or

[0458] ;and

[0459] n3Z can be 0, 1, 2, or 3.

[0460] In some implementations, n3Z is 0 or 1. In some implementations, n3Z is 0.

[0461] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0462] , ,

[0463] , or ;

[0464] R 8Z R 9Z R 10Z and R 11Z Each of them is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted –O-alkyl, or substituted or unsubstituted cycloalkyl;

[0465] R 12Z and R 13Z Each of these is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, , , , , or ;and

[0466] R 14ZIt is an optionally substituted C1-C5 alkyl, an optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl, or an optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy.

[0467] In some implementation schemes, R 8Z R 9Z R 10Z and R 11Z Each of these is independently hydrogen, halogen, or optionally substituted alkyl. In some embodiments, R 8Z R 9Z R 10Z and R 11Z Each of them is independently an optionally substituted alkyl group. In some embodiments, R 8Z R 9Z R 10Z and R 11Z Each of them is independently an unsubstituted alkyl group. In some embodiments, R 12Z and R 13Z Each of them is a hydrogen, or In some implementations, R 12Z and R 13Z Each of them is independently H or In some implementations, R 14Z It is an optionally substituted C1-C5 alkyl group. In some embodiments, R 14Z It is an optional substituted C4 alkyl group.

[0468] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0469] or .

[0470] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0471] ,

[0472] or

[0473] ;

[0474] R 15Z H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0475] R 16Z and R17Z Each of these is independently H, a halogen, an optionally substituted alkyl group, or an optionally substituted –O–alkyl group; and

[0476] Y Z It is –CH2– or –(CH2)2–.

[0477] In some implementation schemes, R 15Z It is H, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 15Z For H. In some implementations, R 16Z and R 17Z Each of them is independently H or an optionally substituted alkyl group. In some embodiments, R 16Z and R 17Z Each of them is independently H. In some implementations, Y Z For –CH2–. In some implementations, Y Z It is –(CH2)2–.

[0478] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0479] or

[0480] ;

[0481] R 18Z For H, –OH, –NH2, –NHR 19Z –OR 19Z Or –CONHR 19Z ;

[0482] R 19Z Each instance is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0483] n4Z is 1 or 2.

[0484] In some implementation schemes, R 18Z It can be H, –OH, or –NH2. In some embodiments, R 18Z For H. In some implementations, R 19Z Each instance is independently H or an optionally substituted alkyl group. In some embodiments, R 19Z Each instance is independently H or an unsubstituted alkyl group. In some embodiments, n4Z is 1. In some embodiments, n4Z is 2.

[0485] In some implementations, α4β 1 / 7At least one group of the integrin ligand has the following formula:

[0486] or ;

[0487] R 19Z H, –CH2OR 20Z –(CH2)2OR 20Z –CH2NHCOR 20Z or –OR 20Z ;and

[0488] R 20Z It can be H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0489] In some implementation schemes, R 19Z For H or –CH2NHCOR 20Z In some implementations, R 19Z –CH2NHCOR 20Z In some implementations, R 20Z It is H or an optionally substituted alkyl group. In some embodiments, R 20Z It is H or an unsubstituted alkyl group.

[0490] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0491] or ;

[0492] R 21Z For H, –CONHR 22Z –CH2OR 22Z –(CH2)2OR 22Z –CH2NHCOR 22Z or –OR 22Z ;

[0493] R 22Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0494] X 1Z It is H or halogen.

[0495] In some implementation schemes, R 21Z For H or –CH2NHCOR 22Z In some implementations, R 21Z –CH2NHCOR 22ZIn some implementations, R 22Z It is H or an optionally substituted alkyl group. In some embodiments, R 22Z It is H or an unsubstituted alkyl group. In some embodiments, X 1Z For H. In some implementations, X 1Z It is a halogen.

[0496] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0497] or

[0498] ;

[0499] R 23Z For H, -CONHR 24Z -CH2OR 24Z -(CH2)2OR 24Z -CH2NHCOR 24Z or -OR 24Z ;

[0500] R 24Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0501] n5Z can be 0, 1, 2, or 3.

[0502] In some implementation schemes, R 23Z For H or -CONHR 24Z In some implementations, R 23Z For -CONHR 24Z In some implementations, R 24Z It is H or an optionally substituted alkyl group. In some embodiments, R 24Z It is H or an unsubstituted alkyl group. In some embodiments, n5z is 0, 1, or 2. In some embodiments, n5Z is 1.

[0503] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0504]

[0505] R 25Z For H, –CONHR 27Z –CH2OR 27Z –(CH2)2OR 27Z –CH2NHCOR 27Z or –OR27Z ;

[0506] R 26Z H, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group;

[0507] R 27Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0508] X 2Z CH2 or NH can be substituted with optional substitution.

[0509] In some implementation schemes, R 25Z For H or –CH2NHCOR 27Z In some implementations, R 25Z –CH2NHCOR 27Z In some implementations, R 26Z It is H or an optionally substituted alkyl group. In some embodiments, R 26Z It is H or an unsubstituted alkyl group. In some embodiments, R 26Z It is H or -CH3. In some implementations, R 27Z It is H, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 27Z It is H, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group. In some embodiments, X 2Z NH is optionally substituted. In some embodiments, X 2Z It is NH.

[0510] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0511] or ;

[0512] R 28Z H, –CH2OR 30Z –(CH2)2OR 30Z –CH2NHCOR 30Z or –OR 30Z ;

[0513] R 29Z For H, –OH, –NH2, –NHR 31Z or –OR 31Z ;

[0514] R 30Z H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0515] R 31Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0516] n3Z can be 1, 2, or 3.

[0517] In some implementation schemes, R 28Z H, –CH2NHCOR 30Z or –OR 30Z In some implementations, R 28Z –CH2NHCOR 30Z In some implementations, R 29Z For H, –OH, –NH2. In some implementations, R 30Z It is H, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 30Z It is H, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group. In some embodiments, R... 31Z It is H, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 31Z It is H, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group. In some embodiments, n3Z is 1. In some embodiments, n3Z is 2.

[0518] In some embodiments, at least one CB1 ligand is a compound of the following formula:

[0519] ;

[0520] X 1Y For NR 10Y or CR 11Y R 12Y ;

[0521] R 10Y R 11Y and R 12Y Each of these is independently hydrogen, an optionally substituted alkyl group, an optionally substituted heteroalkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;

[0522] R 19Y For hydrogen, -SO n19Y R 19YA –SO v19Y NR 19YB R 19YC –NHNR 19YB R 19YC –ONR 19YB R 19YC –NHC(O)NHNR19YB R 19YC –NHC(O)NR 19YB R 19YC –NR 19YB R 19YC –C(O)R 19YD –C(O)OR 19YD –C(O)NR 19YB R 19YC –OR 19YA -NR 19YB SO2R 19YA -NR 19YB C(O)R 19YD –NR 19YB C(O)OR 19YD –NR 19YB OR 19YD Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0523] R 19YA R 19YB R 19YC and R 19YD Each of these elements is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; or R bonded to the same nitrogen atom. 19YB and R 19YC Linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups;

[0524] n19Y is 0, 1, 2, 3, or 4; and

[0525] v19Y is 1 or 2.

[0526] In some implementation schemes, X 1Y For NR 10Y In some implementations, X 1Y For NH. In some implementations, R 10Y It is hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 10Y It is hydrogen, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group. In some embodiments, R 10Y It is hydrogen. In some implementations, R 19Y It is hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 19YIt is hydrogen, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group.

[0527] In some embodiments, at least one group of the CB1 ligand has the following formula: In some embodiments, at least one group of the CB1 ligand has the following formula:

[0528] or .

[0529] In some embodiments, at least one group of the CB1 ligand is a group of a compound of the following formula:

[0530] ,

[0531] in:

[0532] R 17Y For hydrogen, -SO n17Y R 17YA –SO v17Y NR 17YB R 17YC –NHNR 17YB R 17YC –ONR 17YB R 17YC –NHC(O)NHNR 17YB R 17YC –NHC(O)NR 17YB R 17YC –NR 17YB R 17YC –C(O)R 17YD –C(O)OR 17YD –C(O)NR 17YB R 17YC –OR 17YA –NR 17YB SO2R 17YA –NR 17YB C(O)R 17YD –NR 17YB C(O)OR 17YD –NR 17YB OR 17YD Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0533] R 17YA R 17YB R 17YC and R 17YDEach of these is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; wherein R is bonded to the same nitrogen atom. 17YB and R 17YC The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups;

[0534] n17Y is 0, 1, 2, 3, or 4; and

[0535] v17Y is 1 or 2.

[0536] In some implementation schemes, R 17Y It is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or –NR. 17YB R 17YC In some implementations, R 17Y For –NR 17YB R 17YC In some implementations, R 17Y For –NH2. In some implementations, R 17YB and R 17YC Each of these is independently hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 17YB and R 17YC Each of them is hydrogen.

[0537] In some embodiments, at least one group of the CB1 ligand has the following formula:

[0538] .

[0539] In some embodiments, at least one group of the CB1 ligand is a group of a compound of the following formula:

[0540] In some embodiments, at least one group of the CB1 ligand has the following formula:

[0541] .

[0542] In some embodiments, at least one group of the CB1 ligand is a group of a compound of the following formula:

[0543] ,

[0544] R 3Y R 4Y R 5Y R6Y and R 8Y Each of them is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0545] R 9Y It is hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group; or R 6Y and R 9Y Substituents may link together to form optionally substituted heterocyclic alkyl groups or optionally substituted heteroaryl groups;

[0546] R 7Y For hydrogen, -SO n7Y R 7YA –SO v7Y NR 7YB R 7YC –NHNR 7YB R 7YC –ONR 7YB R 7YC –NHC(O)NHNR 7YB R 7YC –NHC(O)NR 7YB R 7YC –NR 7YB R 7YC –C(O)R 7YD –C(O)OR 7YD –C(O)NR 7YB R 7YC –OR 7YA –NR 7YB SO2R 7YA –NR 7YB C(O)R 7YD –NR 7YB C(O)OR 7YD –NR 7YB OR 7YD Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

[0547] R 7YA R 7YB R 7YC R 7YD Each is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; wherein R bonded to the same nitrogen atom7YB and R 7YC The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups;

[0548] n7Y is 0, 1, 2, 3, or 4; and

[0549] v7Y is 1 or 2.

[0550] In some implementation schemes, R 3Y It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 3Y It is hydrogen. In some implementations, R 3Y It is a halogen. In some implementations, R 4Y It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 4Y It is hydrogen. In some implementations, R 4Y It is a halogen. In some implementations, R 5Y It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 5Y It is hydrogen. In some implementations, R 5Y It is a halogen. In some implementations, R 6Y It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 6Y It is hydrogen. In some implementations, R 6Y It is a halogen. In some implementations, R 7Y It is hydrogen, an optionally substituted alkyl group, an optionally substituted heteroalkyl group, or –C(O)R 7YD In some implementations, R 7Y For –C(O)R 7YD In some implementations, R 7YD It is an optionally substituted aryl group or an optionally substituted heteroaryl group. In some embodiments, R 7YD The aryl group is optionally substituted. In some embodiments, R 8Y It is hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 8Y R is an optionally substituted heteroalkyl group. In some embodiments, R 8Y For substituted heteroalkyl groups. In some embodiments, R 9Y It is hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group. In some embodiments, R 9Y It is hydrogen.

[0551] In some embodiments, at least one group of the CB1 ligand has the following formula:

[0552] , ,

[0553] or .

[0554] In some embodiments, at least one CB1 ligand is a compound of the following formula:

[0555] ,

[0556] R 16Y Hydrogen, halogen, –CN, –N3, –NO2, –NR 16YB R 16YC –C(O)R 16YD –C(O)OR 16YD –C(O)NR 16YB R 16YC –OR 16YA –NR 16YB C(O)R 16YD Optionally substituted alkyl groups, optionally substituted heteroalkyl groups, optionally substituted cycloalkyl groups, optionally substituted heterocycloalkyl groups, optionally substituted aryl groups, or optionally substituted heteroaryl groups; and

[0557] R 16YA R 16YB R 16YC and R 16YD Each of these elements is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; or R bonded to the same nitrogen atom. 16YB and R 16YC Linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups.

[0558] In some implementation schemes, R 16Y It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 16Y It is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0559] In some embodiments, at least one group of the CB1 ligand has the following formula: .

[0560] In some embodiments, at least one CB1 ligand is a compound of the following formula:

[0561] , ,

[0562] or .

[0563] In some embodiments, at least one NMDA receptor ligand is a compound of the following formula:

[0564] , , , ,

[0565] , , ,

[0566] , , , or .

[0567] In some embodiments, at least one group of the NMDA receptor ligand has the following formula: In some embodiments, at least one group of the NMDA receptor ligand has the following formula: or In some embodiments, at least one group of the NMDA receptor ligand has the following formula: In some embodiments, at least one group of the NMDA receptor ligand has the following formula: In some embodiments, at least one group of the NMDA receptor ligand has the following formula: In some embodiments, at least one group of the NMDA receptor ligand has the following formula: or In some embodiments, at least one group of the NMDA receptor ligand has the following formula: In some embodiments, at least one group of the NMDA receptor ligand has the following formula: In some embodiments, at least one group of the NMDA receptor ligand has the following formula: In some embodiments, at least one group of the NMDA receptor ligand has the following formula: or In some embodiments, at least one group of the NMDA receptor ligand has the following formula: .

[0568] In some implementations, the ligand is an antibody (e.g., anti-TrkB, anti-CB1, anti-α4β). 1 / 7(Integrin or anti-NMDA receptor antibody). In some embodiments, the ligand is an antibody fragment or antibody variant. "Anti-TrkB receptor antibody", "Anti-CB1 receptor antibody", "Anti-α4β..." 1 / 7 "Integrin receptor antibody" or "anti-NMDA receptor antibody" refers to antibodies that recognize and bind to TrkB, CB1, and α4β, respectively. 1 / 7 Integrins or NMDA receptors, or immune system proteins that interact with them in other ways.

[0569] In some embodiments, the oligonucleotide contains at least two ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 ligands). In some embodiments, the oligonucleotide contains two ligands. In some embodiments, the oligonucleotide contains three ligands. In some embodiments, the oligonucleotide also contains an additional ligand conjugated to the 5′ end. In some embodiments, the oligonucleotide also contains an additional ligand conjugated to the 3′ end. In some embodiments, the oligonucleotide also contains an additional ligand conjugated to both the 5′ end and the 3′ end. In some embodiments, at least two ligands belong to the same ligand type. In some embodiments, each ligand belongs to the same ligand type. In some embodiments, at least two ligands are identical. In some embodiments, at least two ligands are different ligands of the same ligand type. In some embodiments, at least two ligands belong to different ligand types. In some embodiments, all ligands do not belong to the same ligand type. In some embodiments, when the ligands belong to the same ligand type, they bind to the same target. In some implementations, at least one ligand is a small molecule, peptide, or protein.

[0570] In some implementation schemes, A 4 Each instance is a group of the same ligand type. In some embodiments, A 4 Each instance is the same group of the ligand. In some embodiments, A 4 At least two instances are groups of different ligand types. In some embodiments, A 4 At least two instances are groups of different ligands of the same ligand type. In some embodiments, A 4 At least two instances are groups of different ligands of different ligand types.

[0571] In some implementation schemes, A 5 Each instance is a group of the same ligand type. In some embodiments, A 5 Each instance is the same group of the ligand. In some embodiments, A 5 At least two instances are groups of different ligand types. In some embodiments, A 5At least two instances are groups of different ligands of the same ligand type. In some embodiments, A 5 At least two instances are groups of different ligands of different ligand types.

[0572] In some implementation schemes, A 6 Each instance is a group of the same ligand type. In some embodiments, A 6 Each instance is the same group of the ligand. In some embodiments, A 6 At least two instances are groups of different ligand types. In some embodiments, A 6 At least two instances are groups of different ligands of the same ligand type. In some embodiments, A 6 At least two instances are groups of different ligands of different ligand types.

[0573] In some implementation schemes, A 4 At least one instance and A 5 At least one instance is a group of the same ligand type. In some embodiments, A 4 At least one instance and A 5 At least one instance is the same group as the ligand. In some embodiments, A 4 At least one instance and A 5 At least one instance is a group of different ligand types. In some embodiments, A 4 At least one instance and A 5 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 4 At least one instance and A 5 At least one instance is a group of different ligands of different ligand types. In some embodiments, A 4 At least one instance and A 6 At least one instance is a group of the same ligand type. In some embodiments, A 4 At least one instance and A 6 At least one instance is the same group as the ligand. In some embodiments, A 4 At least one instance and A 6 At least one instance is a group of different ligand types. In some embodiments, A 4 At least one instance and A 6 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 4 At least one instance and A 6 At least one instance is a group of different ligands of different ligand types. In some embodiments, A 5At least one instance and A 6 At least one instance is a group of the same ligand type. In some embodiments, A 5 At least one instance and A 6 At least one instance is the same group as the ligand. In some embodiments, A 5 At least one instance and A 6 At least one instance is a group of different ligand types. In some embodiments, A 5 At least one instance and A 6 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 5 At least one instance and A 6 At least one instance is a group of different ligands of different ligand types.

[0574] In some implementation schemes, A 4 A 5 and A 6 Each instance is the same group of the ligand. In some embodiments, A is compared to any other group of the ligand in the oligonucleotide. 4 A 5 and A 6 Each instance is a different group of the ligand. In some embodiments, A 4 A 5 and A 6 Each instance is the same group of the TrkB ligand. In some embodiments, A 4 A 5 and A 6 Each instance is the same group of the CB1 receptor ligand. In some embodiments, A 4 A 5 and A 6 Each instance is α4β 1 / 7 The same group as the integrin receptor ligand. In some embodiments, A 4 A 5 and A 6 Each instance is the same group of the NMDA receptor ligand. In some embodiments, A 4 A 5 and A 6 Each instance is a TrkB ligand, a CB1 receptor ligand, or an α4β ligand. 1 / 7 Different groups of integrin receptor ligands and / or NMDA receptor ligands.

[0575] lipids

[0576] In the oligonucleotides disclosed herein, if present, then A 5 and A 6Each of these groups is independently a ligand or a lipid group. In some embodiments, A 5 A is a lipid group. In some embodiments, A 6 A is a lipid group. In some embodiments, A 5 and A 6 Each of these groups is an independent lipid component.

[0577] In some implementation schemes, A 4 Each instance is the same group of lipid. In some embodiments, A 5 Each instance is the same group of lipid. In some embodiments, A 6 Each instance is the same group of lipid.

[0578] In some implementation schemes, A 4 At least one instance and A 5 At least one instance is the same group as a lipid. In some embodiments, A 4 At least one instance and A 6 At least one instance is the same group as a lipid. In some embodiments, A 5 At least one instance and A 6 At least one instance is the same group as lipids.

[0579] In some implementation schemes, A 5 and A 6 Each instance is the same group of lipid. In some embodiments, A is compared to any other group of lipid in the oligonucleotide. 5 and A 6 Each instance is a different group of lipid.

[0580] In some embodiments, at least one lipid is a fatty acyl, glycerol, glycerophospholipid, sphingolipid, glycolipid, polyketide, sterol lipid, or isopentenol lipid. In some embodiments, at least one lipid is a fatty acid or conjugate, octadecanoic acid, eicosanoic acid, docosanoic acid, fatty alcohol, fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon, or fatty acyl glycoside.

[0581] In some embodiments, at least one lipid is a hydrocarbon. In some embodiments, the hydrocarbon chain is saturated or unsaturated. In some embodiments, the unsaturated hydrocarbon chain contains one, two, three, four, five, or six carbon-carbon double bonds (e.g., cis double bonds and / or trans double bonds). In some embodiments, at least one group of the lipid is an unsubstituted C. 7-36 Alkyl groups, C16 groups substituted with one or more fluorinated groups where the valence allows. 7-36 Alkyl, unsubstituted C 7-36Alkenyl, or C substituted with one or more fluorinated groups where the valence allows. 7-36 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 7-36 Alkyl or unsubstituted C 7-36 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 7-36 Alkyl group. In some embodiments, at least one group of the lipid is an unsubstituted C10 group. 7-20 Alkyl groups, C16 groups substituted with one or more fluorinated groups where the valence allows. 7-20 Alkyl, unsubstituted C 7-20 Alkenyl, or C substituted with one or more fluorinated groups where the valence allows. 7-20 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 7-20 Alkyl or unsubstituted C 7-20 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 7-20 Alkyl group. In some embodiments, at least one group of the lipid is an unsubstituted C10 group. 21-28 Alkyl groups, C16 groups substituted with one or more fluorinated groups where the valence allows. 21-28 Alkyl, unsubstituted C 21-28 Alkenyl, or C substituted with one or more fluorinated groups where the valence allows. 21-28 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 21-28 Alkyl or unsubstituted C 21-28 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 21-28 Alkyl group. In some embodiments, at least one group of the lipid is an unsubstituted C10 group. 29-36 Alkyl groups, C16 groups substituted with one or more fluorinated groups where the valence allows. 29-36 Alkyl, unsubstituted C 29-36 Alkenyl, or C substituted with one or more fluorinated groups where the valence allows. 29-36 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 29-36 Alkyl or unsubstituted C 29-36 Alkenyl group. In some embodiments, at least one group of the lipid is an unsubstituted C group. 29-36 Alkyl group. In some embodiments, at least one group of the lipid is an unsubstituted C10 group. 16-28 Alkyl or unsubstituted C 16-28The alkenyl group, each of which is independently unbranched, bibranched, or tribranched. In some embodiments, the alkenyl group described in this paragraph contains one C=C bond. In some embodiments, the alkenyl group described in this paragraph contains two, three, or four C=C bonds, where the valence allows. In some embodiments, at least one group of the lipid is an unbranched, unsubstituted C=C group. 18-26 Alkyl group. In some embodiments, at least one group of the lipid is –(CH2). 17 CH3, –(CH2) 18 CH3, –(CH2) 19 CH3, –(CH2) 20 CH3, –(CH2) 21 CH3, –(CH2) 22 CH3, –(CH2) 23 CH3, –(CH2) 24 CH3 or –(CH2) 25 CH3. In some embodiments, at least one group of the lipid is –(CH2). 21 CH3. In some embodiments, at least one group of the lipid is an unbranched, unsubstituted C. 18-26 Alkenyl group. In some embodiments, at least one group of the lipid is an unbranched, unsubstituted C- group containing a C=C bond. 18-26 Alkenyl group.

[0582] In some embodiments, at least one lipid is a monosubstituted glycerol, a disubstituted glycerol, a trisubstituted glycerol, a glycosyl monosubstituted glycerol, a glycosyl disubstituted glycerol, a betaine monosubstituted glycerol, or a betaine disubstituted glycerol.

[0583] In some embodiments, at least one lipid is glycerophosphate choline, glycerophosphate ethanolamine, glycerophosphate serine, glycerophosphate glycerol, glycerophosphate glycerophosphate ester, glycerophosphate inositol, glycerophosphate inositol monophosphate, glycerophosphate inositol diphosphate, glycerophosphate inositol triphosphate, glycerophosphate ester, glycerophosphate pyrophosphate, glycerophosphate glycerophosphate glycerol, CDP-glycerol, glycosyl glycerophospholipid, glycerophosphate inositol polysaccharide, glycerophosphate choline, glycerophosphate ethanolamine, diglycerophosphate tetraether phospholipid, glycero-noniol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphate ethanolamine polysaccharide, dihydroxyacetone phosphate, glycerophosphate ethanol, glycerophosphate threonine, or cyclic glycerophosphatidic acid.

[0584] In some embodiments, at least one lipid is a sphingosine base, ceramide, phosphospholipid, phosphonate sphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenic sphingolipid.

[0585] In some embodiments, at least one lipid is a sterol, a steroid, an open-ring steroid, a bile acid or a derivative thereof, or a steroid conjugate. In some embodiments, at least one lipid is cholesterol. In some embodiments, at least one group of the lipid has the following formula:

[0586] .

[0587] In some embodiments, at least one lipid is lithocholic acid. In some embodiments, at least one group of the lipid has the following formula:

[0588] ,

[0589] In some embodiments, at least one group of the lipid has the following formula:

[0590] ,

[0591] Optionally, the unsubstituted C 7-30 Alkyl groups are unbranched, unsubstituted C14 groups. 11-23 Alkyl group, and unsubstituted C 7-30 The alkenyl group is an unbranched, unsubstituted C. 11-23 The alkenyl group (optionally containing one C=C bond, or optionally containing two, three, or four C=C bonds). In some embodiments, at least one group of the lipid has the following formula:

[0592] .

[0593] In some embodiments, at least one lipid is an isoprene, quinone, hydroquinone, polyisoprene alcohol, or hopane.

[0594] In some embodiments, at least one lipid is an acylamino sugar, an acylamino glycosyl, an acyltrehalose, or an acyltrehalose.

[0595] In some embodiments, at least one lipid is a linear polyketide, a halogenated lactone, anomeric lactone, a macrolide, a lactone polyketide, ansarmycin, a polyene, a linear tetracycline, a keratocycline, a polyether antibiotic, aflatoxin, cytochalasin, flavonoids, aromatic polyketides, nonribosomal peptide / polyketide hybrids, or a phenolic lipid.

[0596] Other oligonucleotide chain modifications

[0597] The modified oligonucleotide chain may also contain further modifications. In some embodiments, the modified oligonucleotide chain further comprises at least one modified sugar, at least one modified nucleobase, at least one modified internucleotide bond, or a combination thereof. In some embodiments, the modified oligonucleotide chain further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100 (inclusive) modified nucleosides. In some embodiments, the modified oligonucleotide chain further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100 (inclusive) modified sugars. In some embodiments, the modified oligonucleotide chain further comprises 1, 2, 3, 4, 5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, or 96-100 (inclusive) modified nucleoside linkages.

[0598] When an oligonucleotide contains an additional oligonucleotide chain, such as an antisense oligonucleotide chain, the additional oligonucleotide chain may independently contain one or more of the additional modifications described herein.

[0599] Sugar modification

[0600] Any modifications known in the art may be used in the oligonucleotides disclosed herein. In some embodiments, modified sugars are used in the oligonucleotides disclosed herein. In some embodiments, the modified sugar is a substituted furanyl sugar or a non-bicyclic modified sugar. In some embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In some embodiments, the modified sugar is a sugar substitute. The sugar substitute may contain one or more substitutions described herein.

[0601] In some embodiments, the modified sugar is a substituted furanyl sugar or a non-bicyclic modified sugar. In some embodiments, the furanyl sugar is a ribosyl sugar. In some embodiments, the furanyl sugar contains one or more substituents, including but not limited to substituents at the 2', 3', 4', and 5' positions.

[0602] In some embodiments, the substituents at the 2' position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl”, or “methoxy”). In some embodiments, the substituents suitable for the 2' position of non-bicyclic modified sugars include, but are not limited to, halogens, allyl groups, amino groups, azides, –SH, –CN, –OCN, –CF3, –OCF3, –F, –Cl, –Br, –SCH3, –SOCH3, –SO2CH3, –ONO2, –ON2, –N3, and –NH2. In some embodiments, the substituents at the 2' position include, but are not limited to, –O-(C1-C...). 10 Alkoxy, alkoxyalkyl, –O-alkyl, –S-alkyl, –N-alkyl, –O-alkenyl, –S-alkenyl, –N-alkenyl, –O-ynyl, –S-ynyl, –N-ynyl, –O-alkyl-O-alkyl, ynyl, wherein the alkyl, alkenyl, and ynyl groups may be substituted or unsubstituted C1 to C2 groups. 10 Alkyl or C2 to C 10 Alkenyl and alkynyl groups. In some embodiments, the substituents at the 2' position include, but are not limited to, alkylaryl, aralkyl, -O-alkylaryl, and -O-aralkyl. In some embodiments, these 2' substituents may be further substituted by one or more substituents independently selected from: hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro(–NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In some embodiments, the substituents at the 2' position include, but are not limited to, –O[(CH2)] h O] j CH3, –O(CH2) h OCH3, –O(CH2) h CH3, –O(CH2) h ONH2, –O(CH2) h NH2, –O(CH2) h SCH3 and –O(CH2) h ON[(CH2) h CH3)]2, where h and j are independently 1 to 10. In some embodiments, the substituents at the 2′ position include, but are not limited to, –OCH2CH2OCH3 (“MOE”), –O(CH2)2ON(CH3)2 (“DMAOE”), –O(CH2)2O(CH2)2N(CH3)2 (“DMAEOE”) and –OCH2C(=O)-N(H)CH3 (“NMA”).

[0603] In some embodiments, the substituents suitable for the 4′ position of the non-bicyclic modified sugar include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In some embodiments, the substituents suitable for the 5′ position of the non-bicyclic modified sugar include, but are not limited to, methyl (“Me”) (R or S), vinyl, and methoxy. 在In some embodiments, the 5' nucleotide is modified as a 5'-monophosphate ((HO)2(O)PO-5'); a 5'-diphosphate ((HO)2(O)POP(HO)(O)-O-5'); a 5'-triphosphate ((HO)2(O)PO-(HO)(O)POP(HO)(O)-O-5'); a 5'-guanosine cap (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); a 5'-adenosine cap (Appp); and any modified or unmodified nucleotide cap structure (NO). -5'(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); 5'-monothiophosphate (thiophosphate; (HO)2(S)PO-5'); 5'-monodithiophosphate (dithiophosphate; (HO)(HS)(S)PO-5'), 5'-thiophosphate ((HO)2(O)PS-5'); any other combination of oxygen / sulfur-substituted monophosphates, diphosphates, and triphosphates (e.g., 5'-α-thiotriphosphate, 5'-γ-thiotriphosphate, etc.), 5'-aminophosphate ((HO)2(O)P-NH-5', (HO)(NH2)(O)PO-5'), 5'-alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-5'-), 5'-alkenylphosphonates (i.e., vinyl, substituted vinyl), (OH)2(O)P-5'-CH2-), 5'-alkyl ether phosphonates (R=alkyl ether=methoxymethyl(MeOCH2-), ethoxymethyl, etc., e.g., RP(OH)(O)-O-5'-). In some embodiments, one or more sugars contain a 5'-vinylphosphonate modification. In some embodiments, one or more sugars contain a 5'-ethylidenephosphonate modification. In some embodiments, the 5' modification is located at the end of the oligonucleotide. In some embodiments, the 5' modification is located at the end of the antisense oligonucleotide. In some embodiments, the substituents described herein for the 2', 4', and 5' positions can be added to other specific positions on the sugar. In some embodiments, such substituents can be added to the 3' position of the sugar on the 3'-terminal nucleotide or the 5' position of the 5'-terminal nucleotide. In some embodiments, the non-bicyclic modified sugar may contain more than one non-bridging sugar substituent. In some such embodiments, the non-bicyclic modified sugar substituent includes, but is not limited to, 5'-Me-2'-F and 5'-Me-2'-OMe (including both the R and S isomers). In some embodiments, the modified sugar substituent includes those described in Migawa et al., WO 2008 / 101157.

[0604] In some embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In some embodiments, the bicyclic sugar contains a bridging substituent that bridges two atoms of the furanyl ring to form the second ring. In some embodiments, the bicyclic sugar does not contain a furanyl moiety. A “bicyclic nucleoside” (“BNA”) is a nucleoside having a bicyclic sugar. In some embodiments, the bicyclic sugar contains a bridge between the 4' and 2' furanyl ring atoms. In some embodiments, the bicyclic sugar contains a bridge between the 5' and 3' furanyl ring atoms. In some such embodiments, the furanyl ring is a ribose ring. In some embodiments, the 4′ to 2′ bridging substituents include, but are not limited to, 4′-CH2-2′, 4′-(CH2)2-2′, 4′-(CH2)3-2′, 4′-CH2-O-2′ (“LNA”), 4′-CH2-S-2′, 4′-(CH2)2-O-2′ (“ENA”), 4′-CH(CH3)-O-2′ (“constrained ethyl” or “cEt” when in the S configuration), 4′-CH2-O-CH2-2′, 4′-CH2-N(R)-2′, 4′- CH(CH2OCH3)-O-2' (“constrained MOE” or “cMOE”) and its analogues (e.g., U.S. Patent No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and its analogues (e.g., U.S. Patent No. 8,278,283), 4'-CH2-N(OCH3)-2' and its analogues (e.g., U.S. Patent No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., U.S. Patent Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2' (where R is H, C1-C) 12Alkyl groups or protecting groups (e.g., U.S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134), and 4'-CH2-C(=CH2)-2' and their analogues (e.g., U.S. Patent No. 8,278,426). Other representative U.S. patents and U.S. patent publications teaching the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; US 2009 / 0012281; US 2013 / 0190383; and WO 2013 / 036868. Any of the aforementioned bicyclic nucleosides can be prepared to have one or more stereochemical sugar configurations, including, for example, α-L-ribofranose and β-D-ribofranose (see, for example, WO 99 / 14226). Unless otherwise specified, the bicyclic nucleosides specified herein are in the β-D configuration.

[0605] In some embodiments, the modified sugar is a sugar substitute. In some embodiments, the oxygen atom of the sugar substitute is replaced by, for example, a sulfur, carbon, or nitrogen atom. In some such embodiments, the sugar substitute may also contain bridging and / or non-bridging substituents as described herein. In some embodiments, the sugar substitute comprises a ring having more than five atoms. In some such embodiments, the sugar substitute comprises a cyclobutyl moiety replacing the furanopentose sugar. In some embodiments, the sugar substitute comprises a six-membered ring replacing the furanopentose sugar. In some embodiments, the sugar substitute comprises tetrahydropyran (“THP”) replacing the furanopentose sugar. In some embodiments, the sugar substitute comprises morphine replacing the furanopentose sugar. Representative U.S. patents teaching the preparation of such modified sugar structures include, but are not limited to, U.S. patent numbers 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,5 19,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677; 8,088,904; 8,440,803; and 9,005,906.

[0606] In some embodiments, the sugar substitute comprises an acyclic moiety. In some embodiments, the sugar substitute is an unlocking nucleic acid (“UNA”). An UNA is an unlocking acyclic nucleic acid in which any bonds in the sugar have been removed, thereby forming an unlocking “sugar” residue. In one example, the UNA also encompasses a monomer in which the C1'-C4' bond (i.e., the covalent carbon-oxygen-carbon bond between the C1' and C4' carbons) has been removed. In another example, the C2'-C3' bond of the sugar (i.e., the covalent carbon-carbon bond between the C2' and C3' carbons) has been removed. Representative U.S. publications teaching the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publications Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020. In some embodiments, sugar substitutes include peptide nucleic acids (“PNA”), acyclic butyl nucleic acids (see, for example, Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US 2013 / 130378. Many other bicyclic and tricyclic sugars and sugar substitute ring systems are known in the art for use in modified nucleosides.

[0607] In some embodiments, modified and / or unmodified sugars are arranged in a defined pattern or “glycomotif” along a region of the modified oligonucleotide chain or thereof. In some cases, such glycomotifs include, but are not limited to, any of the sugar modification patterns described herein.

[0608] In some embodiments, the oligonucleotide chain includes a gapmer glycosidic motif. The gapmer oligonucleotide chain includes, or is composed of, a region having two outer “wing” regions and a central or inner “gap” region. The gap and wing regions form adjacent sequences of nucleosides, wherein the majority of the nucleoside sugar in each wing differs from the majority of the nucleoside sugar in the gap. In some embodiments, the wing regions contain the majority of modified sugars, and the gap contains the majority of unmodified sugars. In some embodiments, the nucleoside of the gap is a deoxynucleoside. Oligonucleotides having a gapmer glycosidic motif are described, for example, in U.S. Patent No. 8,790,919.

[0609] In some embodiments, one or both strands of the double-stranded oligonucleotide contain a triplet glycosidic motif. The oligonucleotide chain with the triplet glycosidic motif contains three identical sugar modifications on three consecutive nucleotides. In some embodiments, the triplet is located at or near the cleavage site of the oligonucleotide (e.g., where a ribonuclease such as Dicer or Drosha cleaves the oligonucleotide). In some embodiments, the double-stranded oligonucleotide chain may contain more than one triplet glycosidic motif. In some embodiments, the identical sugar modification of the triplet glycosidic motif is a 2'-F modification. Oligonucleotides with triplet glycosidic motifs are disclosed, for example, in U.S. Patent No. 10,668,170.

[0610] In some embodiments, one or both strands of the double-stranded oligonucleotide contain a tetrad glycosidic motif. The oligonucleotide chain with the tetrad glycosidic motif contains four identical sugar modifications on four consecutive nucleotides. In some embodiments, the tetrad is located at or near a cleavage site. In some embodiments, the double-stranded oligonucleotide chain may contain more than one tetrad glycosidic motif. In some embodiments, the identical sugar modification of the tetrad glycosidic motif is a 2'-F modification. For double-stranded oligonucleotides having a double-stranded region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide chain is typically located near positions 10, 11, and 12, starting from the 5' end. In some embodiments, counting begins with the first nucleotide at the 5' end of the positive oligonucleotide chain, or with the first paired nucleotide in the double-stranded region at the 5' end of the positive oligonucleotide chain, with the tetrameric glycomotif located at positions 8, 9, 10, and 11; 9, 10, 11, and 12; 10, 11, 12, and 13; 11, 12, 13, and 14; or 12, 13, 14, and 15 of the positive oligonucleotide chain. In some embodiments, counting begins with the first nucleotide at the 5' end of the negative oligonucleotide chain, or with the first paired nucleotide in the double-stranded region at the 5' end of the negative oligonucleotide chain, with the tetrameric glycomotif located at positions 8, 9, 10, and 11; 9, 10, 11, and 12; 10, 11, 12, and 13; 11, 12, 13, and 14; or 12, 13, 14, and 15 of the negative oligonucleotide chain. The cleavage site can vary depending on the length of the double-stranded region of the double-stranded oligonucleotide, and the position of the tetrad can be changed accordingly.

[0611] In some embodiments, the oligonucleotide chain contains alternating glycomotifs. In some embodiments, one or both chains of the double-stranded oligonucleotide contain alternating glycomotifs. The oligonucleotide with alternating glycomotifs contains at least two different sugar modifications, including alternating sequences of one or more consecutive nucleotides containing a first sugar modification with alternating sequences of one or more consecutive nucleotides containing a second sugar modification and one or more consecutive nucleotides containing a third sugar modification. For example, if A, B, and C each represent a type of modification to a nucleotide, the alternating motifs could be “ABABABABABAB…”, “AABBAABBAABB…”, “AABAABAABAAB…”, “AAABAAABAAAB…”, “AAABBBAAABBB…”, or “ABCABCABCABC…”, etc. In some embodiments, the alternating glycomotif is repeated along the oligonucleotide chain for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases. In some embodiments, the alternating glycomotif comprises two different sugar modifications. In some embodiments, the alternating glycomotif comprises 2′-OMe and 2′-F sugar modifications.

[0612] In some embodiments, each nucleoside of the oligonucleotide chain is independently modified with one or more sugar modifications provided herein. In some embodiments, each strand of the double-stranded oligonucleotide independently has one or more sugar modifications provided herein. In some embodiments, the oligonucleotide chain containing the sugar motif is fully modified because each nucleoside contains a sugar modification.

[0613] In some embodiments, the modified sugar is 2′-fluoro-2′-deoxyribose, 2′-O-methylribose, 2′-thioribose, 2′,3′-dideoxyribose, 2′-amino-2′-deoxyribose, 2′-deoxyribose, 2′-azido-2′-deoxyribose, 2′-O-methyldeoxyribose, 3′-amino-2′,3′-dideoxyribose, 3′-azido-2′,3′-dideoxyribose, 3′-deoxyribose, 3′-O-(2-nitrobenzyl)-2′- Deoxyribose, 3′-O-methylribose, 5′-aminoribose, 5′-thioribose, 5-nitro-1-indolyl-2′-deoxyribose, 5′-biotin-ribose, 2′-O,4′-C-amino-linked ribose, 2′-O,4′-C-thio-linked ribose, 2′-O-methoxyethylribose, 2′-O,4′-C-methylene-linked ribose, 2′-O,4′-C-ethylidene-linked ribose, 2′,4′-restricted ethylribose, locked sugars, or bicyclic sugars.

[0614] In some embodiments, the modified sugar is located at the 3' end of the oligonucleotide chain. In some embodiments, the modified sugar is located within three nucleotides at the 3' end of the oligonucleotide chain. In some embodiments, the modified sugar is located at the 5' end of the oligonucleotide chain. In some embodiments, the modified sugar is located within three nucleotides at the 5' end of the oligonucleotide chain. In some embodiments, the modified sugar is located at an internal position on the oligonucleotide chain. In some embodiments, the modified sugar is located at a position more than three nucleotides away from the 3' end of the oligonucleotide chain. In some embodiments, the modified sugar is located at a position more than three nucleotides away from the 5' end of the oligonucleotide chain. In some embodiments, the modified sugar is located on a block of modified nucleobases. In some such embodiments, the block is located at the 3' end of the oligonucleotide chain. In some embodiments, the block is located within three nucleotides at the 3' end of the oligonucleotide chain. In some embodiments, the block is located at the 5' end of the oligonucleotide chain. In some embodiments, the block is located within three nucleotides at the 5' end of the oligonucleotide chain. In some embodiments, the block is located inside the oligonucleotide chain. In some embodiments, the block is located more than three nucleotides from the 3' end of the oligonucleotide chain. In some embodiments, the block is located more than three nucleotides from the 5' end of the oligonucleotide chain.

[0615] In some embodiments, the modified sugar is 2′-O-methylribose, 2′-F-ribose, or reverse abase-free deoxyribose. In some embodiments, the modified nucleoside is 2′-O-methyladenosine, 2′-O-methylguanosine, 2′-O-methylcytosine, 2′-O-methyluracil, 2′-F-adenosine, 2′-F-guanosine, 2′-F-cytosine, or 2′-F-uracil.

[0616] Nucleobase modification

[0617] Any modified nucleobases known in the art can be used in the oligonucleotides provided herein. In some embodiments, the modified oligonucleotides comprise one or more nucleosides containing modified nucleobases. In some embodiments, the modified oligonucleotides comprise one or more nucleosides that do not contain nucleobases, referred to as base-free nucleosides.

[0618] In some embodiments, the modified nucleobase is selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl-substituted pyrimidines, alkyl-substituted purines, and N-2, N-6, and O-6-substituted purines. In some embodiments, the modified nucleobase is selected from: 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymidine and 2-thiocytosine, 5-propynyl(C≡C-CH3)uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymidine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogen, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy. 8-aza and other 8-substituted purines, 5-halogens (especially 5-bromine), 5-trifluoromethyl, 5-haloururacil and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deadenine, 7-deadenine, 3-deadenine, 3-deadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl4-N-benzoylcytosine, 5-methyl4-N-benzoyluracil, universal bases, hydrophobic bases, hybrid bases, size-enlarged bases and fluorinated bases. Other modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenthiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G-clast). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles such as 7-deadenine, 7-deadenine, and 2-aminopyridine and 2-pyridone.

[0619] In some embodiments, the modified nucleobases are xanthine, allylaminouracil, allylaminothymidine, hypoxanthine, digoxigeninated adenine, digoxigeninated cytosine, digoxigeninated guanine, digoxigeninated uracil, 6-chloropurine nucleoside, N6-methyladenine, methylpseudorazine, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-Dihydrouracil, 5-[(3-Indolyl)propionamide-N-allyl]uracil, 5-aminoallyl cytosine, 5-aminoallyl uracil, 5-bromouracil, 5-bromocytosine, 5-carboxycytosine, 5-carboxymethyl ester uracil, 5-carboxyuracil, 5-fluorouracil, 5-formylcytosine, 5-formyluracil, 5-hydroxycytosine, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, 5-hydroxyuracil, 5-iodocytosine, 5-iodouracil, 5-methoxycytosine, 5-methoxyuracil, 5-methylcytosine, 5-methyluracil, 5-propyneamino Cytosine, 5-propynylaminouracil, 5-propynylcytosine, 5-propynyluracil, 6-azacytosine, 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deadenine, 7-deadenine, 7-deadenine, 7-deaden-7-propynylaminoadenine, 7-deaden-7-propynylaminoguanine, 8-azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine, aracytosine, araguanine, araadenine Araracil, Biotin-16-7-denitro-7-propyneaminoguanine, Biotin-16-aminoallylcytosine, Biotin-16-aminoallyluracil, Cyanide 3-5-propyneaminocytosine, Cyanide 3-6-propyneaminocytosine, Cyanide 3-aminoallylcytosine, Cyanide 3-aminoallyluracil, Cyanide 5-6-propyneaminocytosine, Cyanide 5-6-propyneaminocytosine, Cyanide 5-aminoallylcytosine, Cyanide 5-aminoallyluracil, Cyanide 7-aminoallyluracil, Dabcyl-5-3-aminoallyl Brutouridine, desulfobiotin-16-aminoallyl-uracil, desulfobiotin-6-aminoallylcytosine, isoguanine, N1-ethylpseudouracil, N1-methoxymethylpseudouracil, N1-methyladenine, N1-methylpseudouracil, N1-propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6-methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthine nucleoside, 3-deadenine, 2,6-diaminoadenine, 2,6-Diaminoguanine, 5-Formamide-uracil, 5-Ethynyluracil, N6-Isopentenyladenine (i6A), 2-Methyl-Thio-N6-Isopentenyladenine (ms2i6A), 2-Methyl-Thio-N6-Methyladenine (ms2m6A), N6-(cis-hydroxyisopentenyl)adenine (io6A), 2-Methyl-Thio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-Glycylcarbamoyladenine (g6A), N 6-Threonylcarbamoyladenine (t6A), 2-methylthio-N6-threonylcarbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxyn-valinecarbamoyladenine (hn6A), 2-methylthio-N6-hydroxyn-valinecarbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

[0620] Other nucleobases include those disclosed in the following literature: US Patent No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. (ed.), Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science and Engineering, pp. 858-859; Kroschwitz, JL. (ed.), John Wiley & Sons, 1990, pp. 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, YS., Chapter 15, dsRNA Research and Applications, pp. 289-302; Antisense Research and Applications, Crooke, ST. and Lebleu, B. (ed.), CRC Press, 1993, pp. 273-288; Antisense Drug Technology, Crooke, ST. (ed.), CRC Press. 2008, 163-166 and 442-443 (Chapters 6 and 15).

[0621] Publications teaching the preparation of certain modified nucleobases mentioned above, as well as other modified nucleobases, include, but are not limited to, U.S. Patent Application Publications Nos. 2003 / 0158403 and 2003 / 0175906; U.S. Patent Nos. 4,845,205, 5,130,302, 5,134,066, 5,175,273, 5,367,066, 5,432,272, 5,434,257, 5,457,187, 5,459,255, 5,484,908, 5,502,177, 5,525,711, 5,552,540, 5,587,469, 5,594,121, 5,596,091, and 5,614. 617, 5,645,985, 5,681,941, 5,811,534, 5,750,692, 5,948,903, 5,587,470, 5,457,191, 5,763,588, 5,830,653, 5,808,027, 6,005,096, 6,015,886 6,147,200, 6,166,197, 6,166,199, 6,222,025, 6,235,887, 6,380,368, 6,528,640, 6,639,062, 6,617,438, 7,045,610, 7,427,672, and 7,495,088.

[0622] In some embodiments, the oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along one or both strands of the oligonucleotide or a region thereof. In some embodiments, each nucleobase is modified. In some embodiments, none of the nucleobases are modified. In some embodiments, each purine or each pyrimidine is modified. In some embodiments, each adenine is modified. In some embodiments, each guanine is modified. In some embodiments, each thymine is modified. In some embodiments, each uracil is modified. In some embodiments, each cytosine is modified. In some embodiments, some or all of the cytosine nucleobases in the modified oligonucleotide chain are 5-methylcytosine.

[0623] In some embodiments, the modified nucleotide is located at the 3' end of the oligonucleotide chain. In some embodiments, the modified nucleotide is located within three nucleotides at the 3' end of the oligonucleotide chain. In some embodiments, the modified nucleotide is located at the 5' end of the oligonucleotide chain. In some embodiments, the modified nucleotide is located within three nucleotides at the 5' end of the oligonucleotide chain. In some embodiments, the modified nucleotide is located at an internal position on the oligonucleotide chain. In some embodiments, the modified nucleotide is located at a position more than three nucleotides away from the 3' end of the oligonucleotide chain. In some embodiments, the modified nucleotide is located at a position more than three nucleotides away from the 5' end of the oligonucleotide chain. In some embodiments, the modified oligonucleotide comprises a block of the modified nucleotide. In some such embodiments, the block is located at the 3' end of the oligonucleotide chain. In some embodiments, the block is located within three nucleotides at the 3' end of the oligonucleotide chain. In some embodiments, the block is located at the 5' end of the oligonucleotide chain. In some embodiments, the block is located within three nucleosides at the 5' end of the oligonucleotide chain. In some embodiments, the block is located internally within the oligonucleotide chain. In some embodiments, the block is located more than three nucleosides from the 3' end of the oligonucleotide chain. In some embodiments, the block is located more than three nucleosides from the 5' end of the oligonucleotide chain.

[0624] Nucleoside inter-linking modification

[0625] Any modified nucleoside interlinking can be used in the oligonucleotides provided herein. 3' to 5' phosphodiester links are naturally occurring nucleoside interlinkings in RNA and DNA. In some embodiments, the oligonucleotide chain has one or more modified (i.e., non-naturally occurring) nucleoside interlinkings. Certain non-naturally occurring nucleoside interlinkings can confer desired properties, such as enhanced cellular uptake, increased affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative phosphorus-containing modified nucleoside interlinkings include, but are not limited to, phosphate triesters, alkyl phosphonates (e.g., methylphosphonates), aminophosphates, thiophosphates (“P=S”), dithiophosphates (“HS-P=S”), and thiophosphates (“HS-P=O”). Representative phosphorus-free internucleotide linking groups include, but are not limited to, methylene methylimino (-CH2-N(CH3)-O-CH2), thiodiester, thiocarbamate (-OC(=O)(NH)-S-); siloxane (-O-SiH2-O-); and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and phosphorus-free internucleotide linkages are well known to those skilled in the art. Neutral internucleotide linkages include, but are not limited to, phosphate triesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), and amide-3 (3'-CH2 -C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), methyl acetal (3'-O-CH2-O-5'), methoxypropyl, and thiomethyl acetal (3'-S-CH2-O-5'). Other neutral nucleoside linkages include nonionic linkages involving siloxanes (dialkylsiloxanes), carboxylic esters, carboxamides, sulfides, sulfonates, and amides (see, for example: Carbohydrate Modifications in Antisense Research; edited by YS Sanghvi and PD Cook, ACS Symposium Series 580; Chapters 3 and 4, 40–65). Further neutral nucleoside linkages include nonionic linkages involving mixed N, O, S, and CH2 components.

[0626] In some embodiments, the oligonucleotide chain includes at least one modified internucleotide link. The modified internucleotide link can be located at any position on the oligonucleotide chain. For double-stranded oligonucleotides, the modified internucleotide link can be located within the sense oligonucleotide chain, the antisense oligonucleotide chain, or both oligonucleotide chains.

[0627] In some embodiments, internucleotide linking modification may occur on each nucleoside of the oligonucleotide chain. In some embodiments, internucleotide linking modification may occur in an alternating pattern along the oligonucleotide chain. In some embodiments, substantially each internucleotide linking group is a phosphate ester internucleotide linker (P=O). In some embodiments, each internucleotide linking group of the modified oligonucleotide chain is a phosphate thioester (P=S). In some embodiments, each internucleotide linking group of the modified oligonucleotide chain is independently selected from phosphate thioester and phosphate ester internucleotide links. In some embodiments, the internucleotide linking modification pattern is the same on each chain of the double-stranded oligonucleotide. In some embodiments, the internucleotide linking modification pattern is different on each chain of the double-stranded oligonucleotide. In some embodiments, the double-stranded oligonucleotide contains 6-8 modified internucleotide links. In some embodiments, the 6-8 modified internucleotide links are phosphate thioester internucleotide links or alkylphosphonate internucleotide links. In some embodiments, the sense oligonucleotide chain contains at least two modified internucleotide links at either or both of the 5' and 3' ends. In some such embodiments, the modified internucleotide links are phosphate thioester internucleotide links or alkylphosphonate internucleotide links. In some embodiments, the antisense oligonucleotide chain contains at least two modified internucleotide links at either or both of the 5' and 3' ends. In some such embodiments, the modified internucleotide links are phosphate thioester internucleotide links or alkylphosphonate internucleotide links.

[0628] In some embodiments, the double-stranded oligonucleotide includes a dangling region. In some embodiments, the double-stranded oligonucleotide includes an inter-nucleotide linker of phosphate thioester or alkylphosphonate in the dangling region. In some embodiments, the double-stranded oligonucleotide includes an inter-nucleotide linker of phosphate thioester or alkylphosphonate linker connecting the dangling nucleotide to a pairing nucleotide adjacent to the dangling nucleotide. For example, at least two phosphate thioester inter-nucleotide links may be present between the three terminal nucleotides, wherein two of the three nucleotides are dangling nucleotides and the third is a pairing nucleotide adjacent to the dangling nucleotide. The three terminal nucleotides may be located at the 3' end of the antisense oligonucleotide chain, the 3' end of the sense oligonucleotide chain, the 5' end of the antisense oligonucleotide chain, or the 5' end of the sense oligonucleotide chain.

[0629] In some embodiments, the modified oligonucleotide chain comprises one or more internucleotide links having a chiral center. Representative chiral internucleotide links include, but are not limited to, alkylphosphonates and thiophosphates. Modified oligonucleotide chains comprising internucleotide links having a chiral center can be prepared into a population of modified oligonucleotide chains comprising stereorandom internucleotide links, or into a population of modified oligonucleotide chains comprising thiophosphate links having a specific stereochemical configuration. In some embodiments, the population of modified oligonucleotide chains comprises thiophosphate internucleotide links, wherein all such thiophosphate internucleotide links are stereorandom. Such modified oligonucleotide chains can be generated using synthetic methods that result in the random selection of the stereochemical configuration of each thiophosphate link. As will be well understood by those skilled in the art, each individual thiophosphate of each individual oligonucleotide compound has a defined stereochemical configuration. In some embodiments, the population of modified oligonucleotide chains is enriched with modified oligonucleotide chains comprising one or more modified thiophosphate internucleotide links having a specific, independently selected stereochemical configuration. In some embodiments, at least 65% of the molecules in the population contain the specific thiophosphate-linked configuration. In some embodiments, at least 70% of the molecules in the population contain the specific thiophosphate-linked configuration. In some embodiments, at least 80% of the molecules in the population contain the specific thiophosphate-linked configuration. In some embodiments, at least 90% of the molecules in the population contain the specific thiophosphate-linked configuration. In some embodiments, at least 99% of the molecules in the population contain the specific thiophosphate-linked configuration. Such enriched populations of modified oligonucleotide chains can be generated using synthetic methods known in the art, such as those described in the following literature: Oka et al., JACS 125, 8307 (2003), Wan et al., Nuc. Acid. Res. 42, 13456 (2014), and WO 2017 / 015555. In some embodiments, the modified oligonucleotide chain population is enriched with modified oligonucleotide chains having at least one indicated thiophosphate in the (Sp) configuration. In some embodiments, the modified oligonucleotide chain population is enriched with modified oligonucleotide chains having at least one indicated thiophosphate in the (Rp) configuration.

[0630] In some embodiments, the modified internucleotide link is located at the 3' end of the oligonucleotide chain. In some embodiments, the modified internucleotide link is located within three nucleotides at the 3' end of the oligonucleotide chain. In some embodiments, the modified internucleotide link is located at the 5' end of the oligonucleotide chain. In some embodiments, the modified internucleotide link is located within three nucleotides at the 5' end of the oligonucleotide chain. In some embodiments, the modified internucleotide link is located at an internal position on the oligonucleotide chain. In some embodiments, the modified internucleotide link is located at a position more than three nucleotides away from the 3' end of the oligonucleotide chain. In some embodiments, the modified internucleotide link is located at a position more than three nucleotides away from the 5' end of the oligonucleotide chain. In some embodiments, the modified oligonucleotide comprises a block of modified internucleotide links. In some such embodiments, the block is located at the 3' end of the oligonucleotide chain. In some embodiments, the block is located within three nucleotides at the 3' end of the oligonucleotide chain. In some embodiments, the block is located at the 5' end of the oligonucleotide chain. In some embodiments, the block is located within three nucleotides at the 5' end of the oligonucleotide chain. In some embodiments, the block is located internally within the oligonucleotide chain. In some embodiments, the block is located more than three nucleotides from the 3' end of the oligonucleotide chain. In some embodiments, the block is located more than three nucleotides from the 5' end of the oligonucleotide chain.

[0631] In some embodiments, the modified nucleoside-to-nucleotide linkage comprises 5′-ethylidene phosphonate, thiophosphate, or amide.

[0632] In some embodiments, this disclosure provides an oligonucleotide of any of the formulas described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the oligonucleotide described herein comprises a pharmaceutically acceptable salt thereof and a prodrug. In some embodiments, the oligonucleotide described herein comprises a pharmaceutically acceptable salt thereof.

[0633] Pharmaceutical Compositions, Administration and Kits

[0634] On the other hand, pharmaceutical compositions are provided that comprise any oligonucleotides described herein and optionally pharmaceutically acceptable excipients.

[0635] The oligonucleotide or pharmaceutical composition described herein may be administered in combination with one or more other pharmaceutical agents. In some embodiments, the pharmaceutical agent is a therapeutic agent. In some embodiments, the pharmaceutical agent is a preventative agent. In some embodiments, the pharmaceutical agent is a diagnostic agent. The oligonucleotide or pharmaceutical composition may be administered in combination with other pharmaceutical agents to improve its activity (e.g., activity that treats, prevents, or reduces the risk of developing disease in a subject in need (e.g., potency and / or efficacy)), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject, cell, tissue, or biological sample. The combination may achieve an improvement in the same desired effect and / or may achieve different desired effects. In some embodiments, the combination exhibits a synergistic effect that is not present in pharmaceutical compositions containing one but not both of the oligonucleotides described herein or other pharmaceutical agents.

[0636] Oligonucleotides or pharmaceutical compositions may be administered simultaneously, before, or after one or more other pharmaceutical agents, for example, as a combination. Therapeutic agents include small molecules, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In some embodiments, the other pharmaceutical agent is a drug approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for human or veterinary use. In some embodiments, the other pharmaceutical agent is a therapeutic agent for treating a disease. In some embodiments, the other pharmaceutical agent is a preventative agent for preventing a disease. Each other pharmaceutical agent may be administered at a dose and / or schedule determined for the pharmaceutical agent. The other pharmaceutical agents may also be administered in a single dose or separately in different doses with each other and / or with the oligonucleotides or pharmaceutical compositions described herein. The specific combinations to be used in the protocol will take into account the compatibility of the oligonucleotides described herein with other pharmaceutical agents, and / or the desired effects to be achieved (e.g., therapeutic and / or preventative effects). Generally, the levels of the other pharmaceutical agents to be used in combination are expected to be no higher than the levels when used alone. In some embodiments, the levels used in combination will be lower than the levels when used alone.

[0637] In some embodiments, the pharmaceutical composition comprises an effective amount of the oligonucleotide described herein and a pharmaceutically acceptable excipient. In some embodiments, the oligonucleotide described herein is administered to a subject using a pharmaceutically acceptable formulation. For example, after administration of the pharmaceutically acceptable formulation to a subject, the pharmaceutically acceptable formulation provides continuous delivery of the oligonucleotide to the subject for at least 12 hours, 24 hours, 36 hours, 48 ​​hours, one week, two weeks, three weeks, or four weeks.

[0638] The actual dose level and administration time of the active ingredient in the pharmaceutical compositions disclosed herein may vary in order to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a specific subject, pharmaceutical composition, and administration method, while being acceptable to the subject.

[0639] In one embodiment, the oligonucleotides of this disclosure are administered acutely. Therefore, the oligonucleotides of this disclosure can be administered for a short duration of treatment, such as from about one day to about one week. In another embodiment, the oligonucleotides of this disclosure can be administered for a longer period of time to improve chronic conditions, such as from about one week to several months, depending on the condition being treated.

[0640] Oligonucleotides can be administered in any convenient manner, such as via intrathecal, intravenous, intramuscular, subcutaneous, oral, or intraventricular injection, or by topical application, such as in the form of creams or gels. Depending on the route of administration, the active ingredient (e.g., the oligonucleotide of this disclosure) may need to be coated in a material to protect the oligonucleotide from enzymes, acids, and other natural conditions that may inactivate or otherwise degrade it. For administration of the oligonucleotide of this disclosure by means other than parenteral administration, the oligonucleotide may be coated with a material or administered together with the material to prevent inactivation.

[0641] Oligonucleotides can be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycol and mixtures thereof, and in oils.

[0642] Some examples of substances that can be used as pharmaceutical excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; glycols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer solutions; skim milk powder; and other non-toxic and compatible substances used in pharmaceutical preparations, such as, for example, vitamin C, estrogens, and echinacea. Wetting agents and lubricants (such as sodium dodecyl sulfate), as well as colorants, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. Solubilizers, including, for example, castor oil polyoxyethylene ether (cremaphore) and β-cyclodextrin, may also be used in the pharmaceutical compositions described herein.

[0643] Pharmaceutical compositions can be manufactured through conventional processes such as mixing, dissolving, granulation, drage-making, milling, emulsification, encapsulation, embedding, or lyophilization. One or more physiologically acceptable excipients that facilitate the processing of oligonucleotides into pharmaceutical formulations can be used to formulate pharmaceutical compositions in a conventional manner. Pharmaceutical compositions described herein can be prepared by combining the oligonucleotides described herein with one or more suitable excipients (including those described herein) (e.g., for pharmaceutical, agricultural, or veterinary use) through processes such as contacting, mixing, dissolving, granulation, drage-making, milling, emulsification, encapsulation, embedding, or lyophilization.

[0644] The pharmaceutical compositions disclosed herein are available in forms suitable for virtually any method of administration (including, for example, intrathecal, local, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc.), or in forms suitable for administration by inhalation or blowing.

[0645] Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0646] Available injectable formulations include sterile suspensions, solutions, or emulsions of oligonucleotides in aqueous or oily media. Pharmaceutical compositions may also contain formulations such as suspending agents, stabilizers, and / or dispersants. Formulations for injection may be available in single dosage forms (e.g., in ampoules or multi-dose containers) and may contain added preservatives.

[0647] Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable medium, including but not limited to sterile pyrogen-free water, buffer, dextran solution, etc., prior to use. For this purpose, the oligonucleotides can be dried using any technique known in the art, such as lyophilization, and reconstituted prior to use.

[0648] To prolong delivery, oligonucleotides can be formulated as reservoir formulations for administration via implantation or intramuscular injection. Oligonucleotides can be formulated using suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils), ion exchange resins, or as sparingly soluble derivatives (e.g., as sparingly soluble salts).

[0649] Alternatively, other drug delivery systems may be used. Liposomes and emulsions are well-known examples of delivery media that can be used to deliver oligonucleotides. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used.

[0650] The pharmaceutical composition may be present, as desired, in a packaging or dispenser device, which may include one or more unit dosage forms containing oligonucleotides. The packaging may include, for example, metal or plastic foil, such as blister packs. Instructions for use may be included with the packaging or dispenser device.

[0651] Oligonucleotides or pharmaceutical compositions are typically used in amounts that effectively achieve the desired outcome, such as amounts that effectively treat or prevent a specific disease being treated. Oligonucleotides may be administered therapeutically to achieve a beneficial therapeutic effect or preventively to achieve a beneficial preventative effect. A beneficial therapeutic effect means the eradication or improvement of an underlying disease being treated, and / or the eradication or improvement of one or more symptoms associated with the underlying disease, resulting in an improvement in the patient's feeling or condition, even if the patient may still have the underlying disease. A beneficial therapeutic effect also includes stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

[0652] For prophylactic administration, oligonucleotides may be administered to subjects at risk of developing one of the aforementioned diseases. Subjects at risk of developing a disease may be those with characteristics that would lead to their placement in a designated group of at-risk subjects, as defined by an appropriate medical expert ...

Claims

1. An oligonucleotide comprising a modified oligonucleotide chain of formula I: (I)， Or a pharmaceutically acceptable salt or prodrug, wherein: It is a divalent group of an oligonucleotide chain; The s1 instances of the nucleoside indirect head were independently... Substitute; s1 can be 1, 2, 3, 4, 5, or 6; L A and L 4 Each instance is a connector independently; A 4 Each instance is independently a ligand or lipid group, provided that A 4 At least one instance is a group of a ligand; Each of y5 and y6 is independently 0 or 1; When y5 is 0, L 5 C is hydrogen, substituted or unsubstituted 1-6 Alkyl or oxygen protecting group; or when y5 is 1, L 5 For connectors; When y6 is 0, L 6 C is hydrogen, substituted or unsubstituted 1-6 Alkyl or oxygen protecting group; or when y6 is 1, L 6 For connectors; If it exists, then A 5 and A 6 Each of these groups is independently a ligand or a lipid group; and Each of the ligands is different from each of the lipids.

2. The oligonucleotide of claim 1, wherein... It contains between 6 and 100 nucleosides.

3. The oligonucleotide of claim 1, wherein... It contains between 10 and 30 nucleosides.

4. The oligonucleotide of claim 1, wherein... It contains between 14 and 23 nucleosides.

5. The oligonucleotide according to any one of claims 1-4, wherein s1 is 1.

6. The oligonucleotide of any one of claims 1-5, wherein s1 is 2, 3, 4, 5 or 6.

7. The oligonucleotide of any one of claims 1-6, wherein L A At least one instance is Nucleoside junctions between the first and second nucleosides, starting from the 5' end.

8. The oligonucleotide according to any one of claims 1-7, wherein: L A for Nucleoside junctions between the nth nucleotide and the (n+1)th nucleotide, starting from the 5' end; and exist If the number of nucleotides is allowed, n is an integer between 2 and 20 (inclusive).

9. The oligonucleotide of any one of claims 1-8, wherein the oligonucleotide comprises RNA.

10. The oligonucleotide of any one of claims 1-9, wherein the oligonucleotide is RNA.

11. The oligonucleotide according to any one of claims 1-10, wherein It is siRNA.

12. The oligonucleotide according to any one of claims 1-11, wherein: L A At least one instance of it has the following formula: ; Z A1 and Z A2 Each instance is independently a single-bonded, substituted, or unsubstituted C 1-6 Alkylene, or substituted or unsubstituted C 2-6 alkenyl; W A Each instance is independently, where the valence allows, a group consisting of: substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -O-, -OP(=O)(OR c )O-、-N(R c )-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NR c -、-NR c C(=O)-、-C(=O)R c -、-NR c C(=O)O-、-NR c C(=O)NR c -, -OC(=O)-, -OC(=O)O-, -OC(=O)N(R c )-、-S(=O)2NR c -、-NR c S(=O)2- or combinations thereof; R c Each instance is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen-protecting group when attached to a nitrogen atom, or oxygen-protecting group when attached to an oxygen atom, or R C Two instances are linked to form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring; and Key C 4A Attach to L 4 .

13. The oligonucleotide according to any one of claims 1-12, wherein: L A At least one instance of it has the following formula: or .

14. The oligonucleotide of any one of claims 1-13, wherein L A At least one instance of it has the following formula: .

15. The oligonucleotide of any one of claims 1-14, wherein L A At least one instance of it has the following formula: , , , , or .

16. The oligonucleotide of any one of claims 1-15, wherein Z A1 At least one instance is unsubstituted C 1-3 Alkylene.

17. The oligonucleotide of any one of claims 1-16, wherein Z A2 At least one instance is unsubstituted C 1-3 Alkylene.

18. The oligonucleotide of any one of claims 1-17, wherein L 4 At least one instance is substituted or unsubstituted C 1-100 Alkylene, substituted or unsubstituted C 2-100 alkenyl, substituted or unsubstituted C 2-100 alkyne-based, substituted or unsubstituted C 1-100 Heteroalkyl, substituted or unsubstituted C 2-100 Hesperidin-based or substituted or unsubstituted C 2-100 Hypo-heyne group; Optionally, where the valence allows, the C 1-100 Alkylene, C 2-100 imidene group, C 2-100 Ethyne group, C 1-100 Heteroalkyl, C 2-100 Hesperyl or C 2-100 One or more main chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, a substituted or unsubstituted aryl group, or a heterocyclic group.

19. The oligonucleotide of any one of claims 1-18, wherein L 4 At least one instance is substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 alkenyl, substituted or unsubstituted C 7-70 alkyne-based, substituted or unsubstituted C 7-70 Heteroalkyl, substituted or unsubstituted C 7-70 Hesperidin-based or substituted or unsubstituted C 7-70 Hypo-heyne group; Optionally, where the valence allows, the C 7-70 Alkylene, C 7-70 imidene group, C 7-70 Ethyne group, C 7-70 Heteroalkyl, C 7-70 Hesperyl or C 7-70 One or two main chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, a substituted or unsubstituted aryl group, or a heterocyclic group.

20. The oligonucleotide of any one of claims 1-19, wherein L 4 At least one instance is substituted or unsubstituted C 7-70 Alkylene or substituted or unsubstituted C 7-70 Heteroalkyl; and Where the valence allows, the C 7-70 Alkylene or C 7-70 One or two main chain atoms of a heteroalkyl group are independently substituted or unsubstituted carbocyclic group, substituted or unsubstituted heteroalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroalkyl group.

21. The oligonucleotide according to any one of claims 1-20, wherein: L 4 At least one instance is ； –L 4A1 –L 4A2 –、–L 4A3 –L 4A4 –、–L 4A5 –L 4A6 –、–L 4A7 –L 4A8 –、–L 4A17 –L 4A18 – and – L 4A19 –L 4A20 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –, –C(=O)–, –C(=NR a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–, –SP(=O)(OR a )O–, –OP(=O)(OR a )S– or –OP(=O)(SR a )O–; R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R group attached to a nitrogen atom. a Two instances of this form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 4B1 L 4B2 and L 4B6 Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-100 Alkylene, or substituted or unsubstituted C 1-100 Heteroalkyl; L 4C1 and L 4C2 Each of these is a single bond, a substituted or unsubstituted heterocyclic group replacing one of the main chain atoms, or a substituted or unsubstituted heteroaryl group replacing one of the main chain atoms; and Key C 4B Attach to A 4 .

22. The oligonucleotide according to any one of claims 1-21, wherein: L 4 At least one instance is ; Each of p1 and p2 is an independent integer from 1 to 10 (inclusive); Each of p3 and p5 is an independent integer from 0 to 10 (inclusive); –L 4A21 –L 4A22 –Each instance of – is independently a single bond, –O–, –S–, –S–S–, –NR a –, –C(=O)O–, –C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –, –C(=NR a )NR a –, –S(=O)NR a –, –S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted phenyl, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R-group attached to a nitrogen atom. a Two instances are linked by nitrogen atoms to form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups; and Key C 4B Attach to A 4 .

23. The oligonucleotide of any one of claims 1-22, wherein –L 4A21 –L 4A22 At least one instance of – is –NR a –C(=O)– or –C(=O)–NR a – 24. The oligonucleotide of any one of claims 1-23, wherein L 4 At least one instance is substituted or unsubstituted C 7-70 Heteroalkyl groups.

25. The oligonucleotide of any one of claims 1-24, wherein L 4 At least one instance of is –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)– or –N(CH3)C(=O)–, or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that: L 4 The number of main chain atoms in the examples is between 7 and 70 (inclusive); and L 4 Instances do not contain O–O, O–N, N–O, or N–N.

26. The oligonucleotide of any one of claims 1-25, wherein L 4 At least one instance is –CH2–, –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH– or –NHC(=O)–, or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that: L 4 The number of main chain atoms in the examples is between 7 and 70 (inclusive); L 4 Instances do not contain O–O, O–N, N–O, or N–N; and L 4 The total number of instances of –C(=O)NH– and –NHC(=O)– is between 0 and 4 (inclusive).

27. The oligonucleotide of any one of claims 1-26, wherein y5 is 0.

28. The oligonucleotide of any one of claims 1-27, wherein y5 is 1, and A 5 The group that is a ligand.

29. The oligonucleotide of any one of claims 1-28, wherein y5 is 1, and A 5 It is a lipid group.

30. The oligonucleotide of any one of claims 1-29, wherein L 5 For substituted or unsubstituted C 1-100 Alkylene, substituted or unsubstituted C 2-100 alkenyl, substituted or unsubstituted C 2-100 alkyne-based, substituted or unsubstituted C 1-100 Heteroalkyl, substituted or unsubstituted C 2-100 Hesperidin-based or substituted or unsubstituted C 2-100 Hypo-heyne group; Optionally, where the valence allows, the C 1-100 Alkylene, C 2-100 imidene group, C 2-100 Ethyne group, C 1-100 Heteroalkyl, C 2-100 Hesperyl or C 2-100 One or more main chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, a substituted or unsubstituted aryl group, or a heterocyclic group.

31. The oligonucleotide of any one of claims 1-30, wherein L 5 For substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 alkenyl, substituted or unsubstituted C 7-70 alkyne-based, substituted or unsubstituted C 7-70 Heteroalkyl, substituted or unsubstituted C 7-70 Hesperidin-based or substituted or unsubstituted C 7-70 Hypo-heyne group; Optionally, where the valence allows, the C 7-70 Alkylene, C 7-70 imidene group, C 7-70 Ethyne group, C 7-70 Heteroalkyl, C 7-70 Hesperyl or C 7-70 One or two main chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, a substituted or unsubstituted aryl group, or a heterocyclic group.

32. The oligonucleotide of any one of claims 1-31, wherein L 5 For substituted or unsubstituted C 7-70 Alkylene or substituted or unsubstituted C 7-70 Heteroalkyl; and Where the valence allows, the C 7-70 Alkylene or C 7-70 One or two main chain atoms of a heteroalkyl group are independently substituted or unsubstituted carbocyclic group, substituted or unsubstituted heteroalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroalkyl group.

33. The oligonucleotide according to any one of claims 1-32, wherein: L 5 for ; –L 5A1 –L 5A2 –、–L 5A3 –L 5A4 –、–L 5A5 –L 5A6 –、–L 5A7 –L 5A8 –、–L 5A17 –L 5A18 – and – L 5A19 –L 5A20 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –, –C(=O)–, –C(=NR a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–, –SP(=O)(OR a )O–, –OP(=O)(OR a )S– or –OP(=O)(SR a )O–; R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R group attached to a nitrogen atom. a Two instances of this form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 5B1 L 5B2 and L 5B6 Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-100 Alkylene, or substituted or unsubstituted C 1-100 Heteroalkyl; L 5C1 and L 5C2 Each of these is a single bond, a substituted or unsubstituted heterocyclic group replacing one of the main chain atoms, or a substituted or unsubstituted heteroaryl group replacing one of the main chain atoms; and Key C 5B Attach to A 5 .

34. The oligonucleotide according to any one of claims 1-33, wherein: L 5 for or ; k21 is 0, 1, 2, 3 or 4; If it exists, then R d Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl); k22 is 0, 1, 2, 3 or 4; If it exists, then R e Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl); Each of q1, q2, q4, q5, q8, and q9 is an independent integer from 0 to 10 (inclusive); Each of q3, q6, and q7 is an independent integer from 1 to 10 (inclusive); –L 5A21 –L 5A22 –, –L 5A23 –L 5A24 – and –L 5A25 –L 5A26 Each of – in – is independently a single bond, –O–, –S–, –S–S–, –NR a –, –C(=O)O–, –C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –, –C(=NR a )NR a –, –S(=O)NR a –, –S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–, –NR a C(=NR a )–, –NR a S(=O)–, –NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–, –NR a C(=NR a )O–, –NR a S(=O)O–, –NR a S(=O)2O–, –OC(=O)NR a –, –OC(=NR a )NR a –, –OS(=O)NR a –, –OS(=O)2NR a –, –NR a C(=O)NR a –, –NR a C(=NR a )NR a –, –NR a S(=O)NR a –, –NR a S(=O)2NR a –, –C(=O)–, –C(=NR a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–, –SP(=O)(OR a )O–, –OP(=O)(OR a )S– or –OP(=O)(SR a )O–; R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted phenyl, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R-group attached to a nitrogen atom. a Two instances are linked by nitrogen atoms to form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups; and Key C 5A Attach to A 5 .

35. The oligonucleotide of any one of claims 1-34, wherein –L 5A23 –L 5A24 – and – L 5A25 –L 5A26 Each of – is independently –NR a –C(=O)– or –C(=O)–NR a – 36. The oligonucleotide of any one of claims 1-35, wherein –L 5A21 –L 5A22 –for–OP(=O)(OR a )O–、–SP(=O)(OR a )O–、–OP(=O)(OR a )S–or–OP(=O)(SR a )O–.

37. The oligonucleotide of any one of claims 1-36, wherein L 5 For substituted or unsubstituted C 7-70 Heteroalkyl groups.

38. The oligonucleotide of any one of claims 1-37, wherein L 5 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that: L 5 The number of main chain atoms is between 7 and 70 (inclusive); and L 5 It does not include O–O, O–N, N–O, or N–N.

39. The oligonucleotide of any one of claims 1-38, wherein L 5 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that: L 5 The number of main chain atoms is between 7 and 70 (inclusive); L 5 It does not contain O–O, O–N, N–O, or N–N; and L 5 –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

40. The oligonucleotide of any one of claims 1-39, wherein y6 is 0.

41. The oligonucleotide of any one of claims 1-40, wherein y6 is 1, and A 6 The group that is a ligand.

42. The oligonucleotide of any one of claims 1-41, wherein y6 is 1, and A 6 It is a lipid group.

43. The oligonucleotide according to any one of claims 1-42, wherein L 6 For substituted or unsubstituted C 1-100 Alkylene, substituted or unsubstituted C 2-100 alkenyl, substituted or unsubstituted C 2-100 alkyne-based, substituted or unsubstituted C 1-100 Heteroalkyl, substituted or unsubstituted C 2-100 Hesperidin-based or substituted or unsubstituted C 2-100 Hypo-heyne group; Optionally, where the valence allows, the C 1-100 Alkylene, C 2-100 imidene group, C 2-100 Ethyne group, C 1-100 Heteroalkyl, C 2-100 Hesperyl or C 2-100 One or more main chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, a substituted or unsubstituted aryl group, or a heterocyclic group.

44. The oligonucleotide of any one of claims 1-43, wherein L 6 For substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 alkenyl, substituted or unsubstituted C 7-70 alkyne-based, substituted or unsubstituted C 7-70 Heteroalkyl, substituted or unsubstituted C 7-70 Hesperidin-based or substituted or unsubstituted C 7-70 Hypo-heyne group; Optionally, where the valence allows, the C 7-70 Alkylene, C 7-70 imidene group, C 7-70 Ethyne group, C 7-70 Heteroalkyl, C 7-70 Hesperyl or C 7-70 One or two main chain atoms of the heterocyclic group are independently substituted or unsubstituted with a carbocyclic group, a heterocyclic group, a substituted or unsubstituted aryl group, or a heterocyclic group.

45. The oligonucleotide of any one of claims 1-44, wherein L 6 For substituted or unsubstituted C 7-70 Alkylene or substituted or unsubstituted C 7-70 Heteroalkyl; and Where the valence allows, the C 7-70 Alkylene or C 7-70 One or two main chain atoms of a heteroalkyl group are independently substituted or unsubstituted carbocyclic group, substituted or unsubstituted heteroalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroalkyl group.

46. ​​The oligonucleotide according to any one of claims 1-45, wherein: L 6 for ; –L 6A1 –L 6A2 –、–L 6A3 –L 6A4 –、–L 6A5 –L 6A6 –、–L 6A7 –L 6A8 –、–L 6A17 –L 6A18 – and – L 6A19 –L 6A20 Each of the following is independently a single bond: –O–, –S–, –S–S–, –NR. a –、–C(=O)O–、–C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –、–C(=NR a )NR a –、–S(=O)NR a –、–S(=O)2NR a –, –OC(=O)–, –OC(=NR a )–, –OS(=O)–, –OS(=O)2–, –NR a C(=O)–、–NR a C(=NR a )–、–NR a S(=O)–、–NR a S(=O)2–, –OC(=O)O–, –OC(=NR a )O–, –OS(=O)O–, –OS(=O)2O–, –NR a C(=O)O–、–NR a C(=NR a )O–、–NR a S(=O)O–、–NR a S(=O)2O–、–OC(=O)NR a –、–OC(=NR a )NR a –、–OS(=O)NR a –、–OS(=O)2NR a –、–NR a C(=O)NR a –、–NR a C(=NR a )NR a –、–NR a S(=O)NR a –、–NR a S(=O)2NR a –, –C(=O)–, –C(=NR a )–, –S(=O)–, –S(=O)2–, –OP(=O)(OR a )O–, –SP(=O)(OR a )O–, –OP(=O)(OR a )S– or –OP(=O)(SR a )O–; R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl group, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R group attached to a nitrogen atom. a Two instances of this form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 6B1 L 6B2 and L 6B6 Each of the C atoms in the equation is independently a single bond, substituted, or unsubstituted. 1-100 Alkylene or substituted or unsubstituted C 1-100 Heteroalkyl; L 6C1 and L 6C2 Each of these is a single bond, a substituted or unsubstituted heterocyclic group replacing one of the main chain atoms, or a substituted or unsubstituted heteroaryl group replacing one of the main chain atoms; and Key C 6B Attach to A 6 .

47. The oligonucleotide according to any one of claims 1-46, wherein: The substituted or unsubstituted heteroaryl group or substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms has the following formula: , , , , , , , , or ; k21 is 0, 1, 2, 3 or 4; If it exists, then R d Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl); k22 is 0, 1, 2, 3 or 4; If it exists, then R e Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl); k23 is an integer between 0 and 11 (inclusive); If it exists, then R f Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 Alkyl); and R g For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl).

48. The oligonucleotide of any one of claims 1-47, wherein the substituted or unsubstituted heteroaryl group replacing one of the main chain atoms has the following formula: 、 、 、 、 、 、 、 , or .

49. The oligonucleotide according to any one of claims 1-48, wherein: L 6 for or ； Each of r1, r2, r4, r5, r8, and r9 is an independent integer from 0 to 10 (inclusive); Each of r3, r6, and r7 is an independent integer from 1 to 10 (inclusive); –L 6A21 –L 6A22 –, –L 6A23 –L 6A24 – and –L 6A25 –L 6A26 Each of –, –O–, –S–, –S–S–, –NR a –, –C(=O)O–, –C(=NR a )O–, –S(=O)O–, –S(=O)2O–, –C(=O)NR a –, –C(=NR a )NR a –, –S(=O)NR a –, –S(=O)2NR a ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​)O–, –OP(=O)(OR a )S– or –OP(=O)(SR a )O–; R a Each instance is independently hydrogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted phenyl, nitrogen-protecting group when attached to a nitrogen atom, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or R-group attached to a nitrogen atom. a Two instances are linked by nitrogen atoms to form substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups; and Key C 6A Attach to A 6 .

50. The oligonucleotide of any one of claims 1-49, wherein –L 6A23 –L 6A24 – and – L 6A25 –L 6A26 Each of – is independently –NR a –C(=O)– or –C(=O)–NR a – 51. The oligonucleotide of any one of claims 1-50, wherein –L 6A21 –L 6A22 –for –O–.

52. The oligonucleotide of any one of claims 1-51, wherein L 6 For substituted or unsubstituted C 7-70 Heteroalkyl groups.

53. The oligonucleotide of any one of claims 1-52, wherein L 6 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –C(=O)N(CH3)–, –NHC(=O)–, –N(CH3)C(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that: L 6 The number of main chain atoms is between 7 and 70 (inclusive); and L 6 It does not include O–O, O–N, N–O, or N–N.

54. The oligonucleotide of any one of claims 1-53, wherein L 6 For –CH2–, , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, or or a combination of two or more instances of each of the foregoing, or a combination of two or more of the foregoing, provided that: L 6 The number of main chain atoms is between 7 and 70 (inclusive); L 6 It does not contain O–O, O–N, N–O, or N–N; and L 6 –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

55. The oligonucleotide of any one of claims 1-54, further comprising one or more modifications, said one or more modifications being independently selected from modified sugars, modified nucleobases and modified nucleoside junctions.

56. The oligonucleotide of any one of claims 1-55, wherein at least two ligands belong to the same ligand type.

57. The oligonucleotide of any one of claims 1-56, wherein at least two ligands are identical.

58. The oligonucleotide of any one of claims 1-57, wherein at least two ligands are different ligands of the same ligand type.

59. The oligonucleotide of any one of claims 1-58, wherein at least two ligands belong to different ligand types.

60. The oligonucleotide of any one of claims 1-59, wherein at least one ligand is a small molecule, peptide, or protein.

61. The oligonucleotide of any one of claims 1-60, wherein at least one example of the modified sugar is 2′-fluoro-2′-deoxyribose, 2′-O-methylribose, 2′-thioribose, 2′,3′-dideoxyribose, 2′-amino-2′-deoxyribose, 2′-deoxyribose, 2′-azido-2′-deoxyribose, 2′-O-methyldeoxyribose, 3′-amino-2′,3′-dideoxyribose, 3′-azido-2′,3′-dideoxyribose, 3′-deoxyribose, 3′-O -(2-nitrobenzyl)-2′-deoxyribose, 3′-O-methylribose, 5′-aminoribose, 5′-thioribose, 5-nitro-1-indolyl-2′-deoxyribose, 5′-biotin-ribose, 2′-O,4′-C-amino-linked ribose, 2′-O,4′-C-thio-linked ribose, 2′-O-methoxyethylribose, 2′-O,4′-C-methylene-linked ribose, 2′-O,4′-C-ethylidene-linked ribose, 2′,4′-restricted ethylribose, locked sugar, or bicyclic sugar.

62. The oligonucleotide of any one of claims 1-61, wherein at least one example of the modified nucleobase is xanthine, allylaminouracil, allylaminothymidine, hypoxanthine, digoxigenin-labeled adenine, digoxigenin-labeled cytosine, digoxigenin-labeled guanine, digoxigenin-labeled uracil, 6-chloropurine nucleoside, N6-methyladenine, methylpseudorazine, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-dihydrouracil, 5-[(3-indolyl)propionamide-N-allyl]uracil, 5-aminoallylcytosine, 5-aminoallyluracil. 5-Bromouracil, 5-Bromocytosine, 5-Carboxycytosine, 5-Carboxymethyl ester uracil, 5-Carboxyuracil, 5-Fluorouracil, 5-Formylcytosine, 5-Formyluracil, 5-Hydroxycytosine, 5-Hydroxymethylcytosine, 5-Hydroxyuracil, 5-Iodocytosine, 5-Iodouracil, 5-Methoxycytosine, 5-Methoxyuracil, 5-Methylcytosine, 5-Methyluracil, 5-Protyrylaminocytosine, 5-Protyrylaminouracil, 5-Protyrylcytosine, 5-Protyryluracil, 6-azacytosine, 6-azauracil, 6-Chloropurinine, 6-Thioguanine, 7-Deadenine, 7-Deadenine, 7-Deadenine, 7-Deaden-7-Protyrylamino Adenine, 7-deazo-7-propyneaminoguanine, 8-azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, vidarabine, vidarabine cytosine, vidarabine guanine, vidarabine uracil, biotin-16-7-deazo-7-propyneaminoguanine, biotin-16-aminoallylcytosine, biotin-16-aminoallyluracil, cyanine 3-5-propyneaminoguanine, cyanine 3-6-propyneaminoguanine, cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6-propyneaminoguanine, cyanine 5-aminoallylcytosine, cyanine 5-amino Allyluracil, cyanine 7-aminoallyluracil, dabcyl-5-3-aminoallyluracil, desulfobiotin-16-aminoallyl-uracil, desulfobiotin-6-aminoallylcytosine, isoguanine, N1-ethylpseudouracil, N1-methoxymethylpseudouracil, N1-methyladenine, N1-methylpseudouracil, N1-propylpseudouracil, N2-methylguanine, N4-biotin-OBEA-cytosine, N4-methylcytosine, N6-methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienoguanine, thienouracil, xanthine nucleoside, 3-deadenine, 2,6-diaminoadenine, 2,6-Diaminoguanine, 5-Formamide-uracil, 5-Ethynyluracil, N6-Isopentenyladenine (i6A), 2-Methyl-Thio-N6-Isopentenyladenine (ms2i6A), 2-Methyl-Thio-N6-Methyladenine (ms2m6A), N6-(cis-hydroxyisopentenyl)adenine (io6A), 2-Methyl-Thio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-Glycylcarbamoyladenine (g6A), N 6-Threonylcarbamoyladenine (t6A), 2-methylthio-N6-threonylcarbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxyn-valinecarbamoyladenine (hn6A), 2-methylthio-N6-hydroxyn-valinecarbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

63. The oligonucleotide of any one of claims 1-62, wherein at least one example of the modified nucleoside linker is a phosphate triester, alkyl phosphonate, aminophosphate, thiophosphate, dithiophosphate, or thiophosphate.

64. The oligonucleotide of any one of claims 1-63, wherein at least one ligand is a central nervous system receptor ligand.

65. The oligonucleotide of any one of claims 1-64, wherein at least one ligand is a tropomyosin receptor B (TrkB) ligand.

66. The oligonucleotide of any one of claims 1-65, wherein: At least one TrkB ligand is a compound of the following formula: 、 、 、 、 、 , or R 2 For hydrogen, -OR 7 -SR 8 or -NR 9 R 10 ; R 3 For hydrogen, -OR 31 -SR 32 or -NR 33 R 34 ; R 4 For hydrogen, -OR 35 -SR 36 or -NR 37 R 38 ; R 5 For hydrogen, -OR 39 -SR 40 or -NR 41 R 42 ; R 6 It can be hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH2, optionally substituted -NHAc, -SH or =O; R 7 R 8 R 9 R 10 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 39 R 40 R 41 and R 42 Each of the following is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is CH2, NH, S, or O; Z is an aryl group with optional substitution or a heteroaryl group with optional substitution; R 11 and R 13 Each is independently an alkyl group that is absent, hydrogen-rich, or optionally substituted; R 12 R 14 and R 15 Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 16 Hydrogen, halogen, –CN, –N3, –SO n16 R 1A –SO v16 NR 16B R 16C –NHNR 16B R 16C –ONR 16B R 16C –NHC(O)NHNR 16B R 16C –NHC(O)NR 16B R 16C –N(O) m16 –NR 16B R 16C –C(O)R 16D –C(O)OR 16D –C(O)NR 16B R 16C –OR 16A -NR 16B SO2R 16A -NR 16B C(O)R 16D -NR 16B C(O)OR 16D –NR 16B OR 16D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and Each can be a single bond or a double bond independently, where if If it is a single bond, then It is a double bond and R 13 It does not exist; and further, if If it is a single bond, then It is a double bond and R 11 It does not exist; R 16A R 16B R 16C R 16D Each is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; R bonded to the same nitrogen atom 16B and R 16C The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; R 17 R 18 and R 19 Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 20 Hydrogen, halogen, –CN, –N3, –SO n20 R 1A –SO v20 NR 20B R 20C –NHNR 20B R 20C –ONR 20B R 20C –NHC(O)NHNR 20B R 20C –NHC(O)NR 20B R 20C –N(O) m20 –NR 20B R 20C –C(O)R 20D –C(O)OR 20D –C(O)NR 20B R 20C –OR 20A -NR 20B SO2R 20A -NR 20B C(O)R 20D -NR 20B C(O)OR 20D –NR 20B OR 20D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 21 Hydrogen, halogen, –CN, –N3, –SO n21 R 1A –SO v21 NR 21B R 21C –NHNR 21B R 21C –ONR 21B R 21C –NHC(O)NHNR 21B R 21C –NHC(O)NR 21B R 21C –N(O) m21 –NR 21B R 21C –C(O)R 21D –C(O)OR 21D –C(O)NR 21B R 21C –OR 21A -NR 21B SO2R 21A -NR 21B C(O)R 21D -NR 21B C(O)OR 21D –NR 21B OR 21D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 22 and R 23 Each of them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 24 Hydrogen, halogen, –CN, –N3, –SO n24 R 1A –SO v24 NR 24B R 24C –NHNR 24B R 24C –ONR 24B R 24C –NHC(O)NHNR 24B R 24C –NHC(O)NR 24B R 24C –N(O) m24 –NR 24B R 24C –C(O)R 24D –C(O)OR 24D –C(O)NR 24B R 24C –OR 24A -NR 24B SO2R 24A -NR 24B C(O)R 24D –NR 24B C(O)OR 24D –NR 24B OR 24D Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 20A R 20B R 20C R 20D R 21A R 21B R 21C R 21D R 24A R 24B R 24C and R 24D Each is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; R bonded to the same nitrogen atom 20B R 20C R 21B R 21C R 24B R 24C R 24B and R 24C The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; n16, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, 2, 3, or 4; v16, v20, v21, m16, m20, m21 and m24 are each independently 1 or 2; z3 is 0, 1, 2, 3, 4 or 5; z4 and z7 are each independently 0, 1 or 2; z5 is 0, 1, 2, or 3; and z6 and z8 are each independently 0, 1, 2, 3 or 4.

67. The oligonucleotide of any one of claims 1-66, wherein at least one group of the TrkB ligand has the following formula: , or .

68. The oligonucleotide of any one of claims 1-67, wherein at least one group of the TrkB ligand has the following formula: 、 、 、 or .

69. The oligonucleotide of any one of claims 1-68, wherein at least one group of the TrkB ligand has the following formula: 、 、 、 、 、 、 、 、 、 。 70. The oligonucleotide of any one of claims 1-69, wherein at least one TrkB ligand is 3,7-dihydroxyflavone, 3,7,8,2′-tetrahydroxyflavone, 7,3′-dihydroxyflavone, 7,8,2′-trihydroxyflavone, 7,8,3′-trihydroxyflavone, 7,8,4′-trihydroxyflavone, geraniol (5,7,3′-trihydroxy-4′-methoxyflavone), 7-hydroxy-4′-methoxyflavone, 8-hydroxy-7-methoxyflavone, protoflavin (4′-dimethylamino-7,8-dihydroxyflavone), norbaicalin (5,7,8-trihydroxyflavone), R7, R13, proflavin (7,8-dihydroxyflavone), 7,8-dimethoxyflavone, quercetin (3,3′,4′,5,7-pentahydroxyflavone), apigenin (4′,5,7-trihydroxyflavone), isocoumarin, gossypol (3,5,7,8,3′,4′-hexahydroxyflavone), 2-methyl-8-phenylchromene[7,8-d]imidazol-6(3H)-one, 8-phenylchromene[7,8-d]imidazol-6(3H)-one, 4-oxo-2-phenyl-4H-chromene-7,8-dimethyldiacetate, ANA-12 or anti-TrkB antibody.

71. The oligonucleotide according to any one of claims 1-70, wherein at least one ligand is α4β. 1 / 7 Integrin ligands.

72. The oligonucleotide of any one of claims 1-71, wherein at least one α4β 1 / 7 Integrin ligands are compounds of the following formula: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , or Each instance of R is , Or anti-α4β 1 / 7 The functional group of an integrin antibody.

73. The oligonucleotide according to any one of claims 1-72, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or , R 2Z It is hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heteroaryl; and R 3Z and R 4Z Each of them is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl.

74. The oligonucleotide according to any one of claims 1-73, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or ; R 4Z It can be hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted –O-alkyl or optionally substituted cycloalkyl; R 5Z It is an optionally substituted heteroalkyl or optionally substituted heterocyclic group; and n1Z is 1, 2, or 3.

75. The oligonucleotide according to any one of claims 1-74, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: 、 or ； R 6Z For hydrogen, –OH, –NH2, –NHR 7Z –OR 7Z Or it may not exist; and R 7Z It can be hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl.

76. The oligonucleotide of any one of claims 1-75, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: 、 、 、 or ； n2Z can be 0, 1, 2 or 3.

77. The oligonucleotide of any one of claims 1-76, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: 、 、 or ;and n3Z can be 0, 1, 2, or 3.

78. The oligonucleotide according to any one of claims 1-77, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: 、 、 , or ; R 8Z R 9Z R 10Z and R 11Z Each of them is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted –O-alkyl, or substituted or unsubstituted cycloalkyl; R 12Z and R 13Z Each of these is independently H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, , , , , or ;and R 14Z It is an optionally substituted C1-C5 alkyl, an optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl, or an optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy.

79. The oligonucleotide of any one of claims 1-78, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or .

80. The oligonucleotide of any one of claims 1-79, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: 、 or ； R 15Z H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 16Z and R 17Z Each of these is independently H, a halogen, an optionally substituted alkyl group, or an optionally substituted –O–alkyl group; and Y Z It is –CH2– or –(CH2)2–.

81. The oligonucleotide according to any one of claims 1-80, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or ； R 18Z For H, –OH, –NH2, –NHR 19Z –OR 19Z Or –CONHR 19Z ; R 19Z Each instance is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n4Z is 1 or 2.

82. The oligonucleotide according to any one of claims 1-81, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or ; R 19Z H, –CH2OR 20Z –(CH2)2OR 20Z –CH2NHCOR 20Z or –OR 20Z ;and R 20Z It can be H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

83. The oligonucleotide according to any one of claims 1-82, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or ; R 21Z For H, –CONHR 22Z –CH2OR 22Z –(CH2)2OR 22Z –CH2NHCOR 22Z or –OR 22Z ; R 22Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X 1Z It is H or halogen.

84. The oligonucleotide according to any one of claims 1-83, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or ； R 23Z For H, -CONHR 24Z -CH2OR 24Z -(CH2)2OR 24Z -CH2NHCOR 24Z or -OR 24Z ; R 24Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n5Z can be 0, 1, 2, or 3.

85. The oligonucleotide according to any one of claims 1-84, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: R 25Z For H, –CONHR 27Z –CH2OR 27Z –(CH2)2OR 27Z –CH2NHCOR 27Z or –OR 27Z ; R 26Z H, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group; R 27Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X 2Z CH2 or NH can be substituted with optional substitution.

86. The oligonucleotide of any one of claims 1-85, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or ; R 28Z H, –CH2OR 30Z –(CH2)2OR 30Z –CH2NHCOR 30Z or –OR 30Z ; R 29Z For H, –OH, –NH2, –NHR 31Z or –OR 31Z ; R 30Z H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 31Z It is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n3Z can be 1, 2, or 3.

87. The oligonucleotide of any one of claims 1-86, wherein at least one ligand is a cannabinoid receptor type 1 (CB1) ligand.

88. The oligonucleotide of any one of claims 1-87, wherein: At least one CB1 ligand is a compound of the following formula: ； X 1Y For NR 10Y or CR 11Y R 12Y ; R 10Y R 11Y and R 12Y Each of these is independently hydrogen, an optionally substituted alkyl group, an optionally substituted heteroalkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; R 19Y For hydrogen, -SO n19Y R 19YA –SO v19Y NR 19YB R 19YC –NHNR 19YB R 19YC –ONR 19YB R 19YC –NHC(O)NHNR 19YB R 19YC –NHC(O)NR 19YB R 19YC –NR 19YB R 19YC –C(O)R 19YD –C(O)OR 19YD –C(O)NR 19YB R 19YC –OR 19YA -NR 19YB SO2R 19YA -NR 19YB C(O)R 19YD –NR 19YB C(O)OR 19YD –NR 19YB OR 19YD Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 19YA R 19YB R 19YC and R 19YD Each of these elements is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; or R bonded to the same nitrogen atom. 19YB and R 19YC Linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; n19Y is 0, 1, 2, 3, or 4; and v19Y is 1 or 2.

89. The oligonucleotide of any one of claims 1-88, wherein: At least one group of the CB1 ligand has the following formula: 。 90. The oligonucleotide of any one of claims 1-89, wherein: At least one group of the CB1 ligand has the following formula: or .

91. The oligonucleotide according to any one of claims 1-90, wherein: At least one group of the CB1 ligand is a group of a compound of the following formula: ， in: R 17Y For hydrogen, -SO n17Y R 17YA –SO v17Y NR 17YB R 17YC –NHNR 17YB R 17YC –ONR 17YB R 17YC –NHC(O)NHNR 17YB R 17YC –NHC(O)NR 17YB R 17YC –NR 17YB R 17YC –C(O)R 17YD –C(O)OR 17YD –C(O)NR 17YB R 17YC –OR 17YA –NR 17YB SO2R 17YA –NR 17YB C(O)R 17YD –NR 17YB C(O)OR 17YD –NR 17YB OR 17YD Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 17YA R 17YB R 17YC and R 17YD Each of these is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; wherein R is bonded to the same nitrogen atom. 17YB and R 17YC The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; n17Y is 0, 1, 2, 3, or 4; and v17Y is 1 or 2.

92. The oligonucleotide according to any one of claims 1-91, wherein: At least one group of the CB1 ligand has the following formula: 。 93. The oligonucleotide according to any one of claims 1-92, wherein: At least one group of the CB1 ligand is a group of a compound of the following formula: 。 94. The oligonucleotide according to any one of claims 1-93, wherein: At least one group of the CB1 ligand has the following formula: 。 95. The oligonucleotide according to any one of claims 1-94, wherein: At least one group of the CB1 ligand is a group of a compound of the following formula: ， R 3Y R 4Y R 5Y R 6Y and R 8Y Each of them is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 9Y It is hydrogen, an optionally substituted alkyl group, or an optionally substituted heteroalkyl group; or R 6Y and R 9Y Substituents may link together to form optionally substituted heterocyclic alkyl groups or optionally substituted heteroaryl groups; R 7Y For hydrogen, -SO n7Y R 7YA –SO v7Y NR 7YB R 7YC –NHNR 7YB R 7YC –ONR 7YB R 7YC –NHC(O)NHNR 7YB R 7YC –NHC(O)NR 7YB R 7YC –NR 7YB R 7YC –C(O)R 7YD –C(O)OR 7YD –C(O)NR 7YB R 7YC –OR 7YA –NR 7YB SO2R 7YA –NR 7YB C(O)R 7YD –NR 7YB C(O)OR 7YD –NR 7YB OR 7YD Optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 7YA R 7YB R 7YC R 7YD Each is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; wherein R bonded to the same nitrogen atom 7YB and R 7YC The substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; n7Y is 0, 1, 2, 3, or 4; and v7Y is 1 or 2.

96. The oligonucleotide according to any one of claims 1-95, wherein: At least one group of the CB1 ligand has the following formula: 、 、 、 。 97. The oligonucleotide according to any one of claims 1-96, wherein: At least one CB1 ligand is a compound of the following formula: ， R 16Y Hydrogen, halogen, –CN, –N3, –NO2, –NR 16YB R 16YC –C(O)R 16YD –C(O)OR 16YD –C(O)NR 16YB R 16YC –OR 16YA –NR 16YB C(O)R 16YD Optionally substituted alkyl groups, optionally substituted heteroalkyl groups, optionally substituted cycloalkyl groups, optionally substituted heterocycloalkyl groups, optionally substituted aryl groups, or optionally substituted heteroaryl groups; and R 16YA R 16YB R 16YC and R 16YD Each of these elements is independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, 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; or R bonded to the same nitrogen atom. 16YB and R 16YC Linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups.

98. The oligonucleotide according to any one of claims 1-97, wherein: At least one group of the CB1 ligand has the following formula: 。 99. The oligonucleotide as described in any one of claims 1-98, wherein: At least one CB1 ligand is a compound of the following formula: 、 、 or .

100. The oligonucleotide of any one of claims 1-99, wherein at least one ligand is an N-methyl-D-aspartic acid (NMDA) receptor ligand.

101. The oligonucleotide of any one of claims 1-100, wherein at least one NMDA receptor ligand is a compound of the following formula: , , , , , , , , , , or , Or it could be a group of an anti-NMDA receptor antibody.

102. The oligonucleotide of any one of claims 1-101, wherein at least one group of the NMDA receptor ligand has the following formula: 。 103. The oligonucleotide of any one of claims 1-102, wherein at least one group of the NMDA receptor ligand has the following formula: or .

104. The oligonucleotide of any one of claims 1-103, wherein at least one group of the NMDA receptor ligand has the following formula: 。 105. The oligonucleotide of any one of claims 1-104, wherein at least one group of the NMDA receptor ligand has the following formula: 。 106. The oligonucleotide of any one of claims 1-105, wherein at least one group of the NMDA receptor ligand has the following formula: 。 107. The oligonucleotide of any one of claims 1-106, wherein at least one group of the NMDA receptor ligand has the following formula: or .

108. The oligonucleotide of any one of claims 1-107, wherein at least one group of the NMDA receptor ligand has the following formula: 。 109. The oligonucleotide of any one of claims 1-108, wherein at least one group of the NMDA receptor ligand has the following formula: 。 110. The oligonucleotide of any one of claims 1-109, wherein at least one group of the NMDA receptor ligand has the following formula: 。 111. The oligonucleotide of any one of claims 1-110, wherein at least one group of the NMDA receptor ligand has the following formula: or .

112. The oligonucleotide of any one of claims 1-111, wherein at least one group of the NMDA receptor ligand has the following formula: 。 113. The oligonucleotide according to any one of claims 1-112, wherein at least one lipid is a fatty acyl, glycerol, glycerophospholipid, sphingolipid, glycolipid, polyketide, sterol lipid or isopentenol lipid.

114. The oligonucleotide according to any one of claims 1-113, wherein at least one lipid is a fatty acid or conjugate, octadecanoic acid, eicosanoic acid, docosanoic acid, fatty alcohol, fatty aldehyde, fatty ester, fatty amide, fatty nitrile, fatty ether, hydrocarbon, oxygenated hydrocarbon or fatty acyl glycoside.

115. The oligonucleotide of any one of claims 1-114, wherein at least one lipid is a hydrocarbon.

116. The oligonucleotide of any one of claims 1-115, wherein at least one group of the lipid is an unsubstituted C. 7-36 Alkyl groups, C16 groups substituted with one or more fluorinated groups where the valence allows. 7-36 Alkyl, unsubstituted C 7-36 Alkenyl, or C substituted with one or more fluorinated groups where the valence allows. 7-36 Alkenyl group.

117. The oligonucleotide of any one of claims 1-116, wherein at least one group of the lipid comprises one, two, three, four, five or six carbon-carbon double bonds.

118. The oligonucleotide of any one of claims 1-117, wherein at least one group of the lipid is an unsubstituted C. 16-28 Alkyl or unsubstituted C 16-28 Alkenyl groups, each of which is independently unbranched, dibranched, or tribranched.

119. The oligonucleotide of any one of claims 1-118, wherein at least one group of the lipid is an unbranched, unsubstituted C-chain group. 18-26 alkyl.

120. The oligonucleotide of any one of claims 1-119, wherein at least one group of the lipid is –(CH2). 21 CH3.

121. The oligonucleotide of any one of claims 1-120, wherein at least one lipid is a monosubstituted glycerol, a disubstituted glycerol, a trisubstituted glycerol, a glycosyl monosubstituted glycerol, a glycosyl disubstituted glycerol, a betaine monosubstituted glycerol, or a betaine disubstituted glycerol.

122. The oligonucleotide according to any one of claims 1-121, wherein at least one lipid is glycerophosphate choline, glycerophosphate ethanolamine, glycerophosphate serine, glycerophosphate glycerol, glycerophosphate glycerophosphate ester, glycerophosphate inositol, glycerophosphate inositol monophosphate, glycerophosphate inositol diphosphate, glycerophosphate inositol triphosphate, glycerophosphate ester, glycerophosphate pyrophosphate, glycerophosphate glycerophosphate glycerol, CDP-glycerol, glycosyl glycerophospholipid, glycerophosphate inositol polysaccharide, glycerophosphate choline, glycerophosphate ethanolamine, diglycerophosphate tetraether phospholipid, glycero-noniol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphate ethanolamine polysaccharide, dihydroxyacetone phosphate, glycerophosphate ethanol, glycerophosphate threonine, or cyclic glycerophosphatidic acid.

123. The oligonucleotide according to any one of claims 1-122, wherein at least one lipid is a sphingosine base, ceramide, phosphospholipid, phosphonate sphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenic sphingolipid.

124. The oligonucleotide according to any one of claims 1-123, wherein at least one lipid is a sterol, steroid, open-ring steroid, bile acid or a derivative thereof, or a steroid conjugate.

125. The oligonucleotide of any one of claims 1-124, wherein at least one lipid is cholesterol.

126. The oligonucleotide according to any one of claims 1-25, wherein at least one lipid is an isoprene, quinone, hydroquinone, polyisoprene alcohol, or hopane.

127. The oligonucleotide of any one of claims 1-126, wherein at least one lipid is an acylamino sugar, an acylamino glycosyl, an acyltrehalose, or an acyltrehalose.

128. The oligonucleotide according to any one of claims 1-127, wherein at least one lipid is a linear polyketide, a halogenated lactone, an anthocyanin, a macrolide, a lactone polyketide, ansarmycin, a polyene, a linear tetracycline, a keratocycline, a polyether antibiotic, aflatoxin, a cytochalasin, a flavonoid, an aromatic polyketide, a nonribosomal peptide / polyketide hybrid, or a phenolic lipid.

129. The oligonucleotide of any one of claims 1-128, wherein for: 。 130. The oligonucleotide of any one of claims 1-129, wherein for 。 131. The oligonucleotide of any one of claims 1-130, or a pharmaceutically acceptable salt or prodrug thereof, wherein formula I is: 、 、 、 、 、 、 、 、 、 、 or 。 132. The oligonucleotide according to any one of claims 1-131, wherein It is a sense oligonucleotide chain, and the oligonucleotide also contains an antisense oligonucleotide chain.

133. The oligonucleotide according to any one of claims 1-132, wherein It is an antisense oligonucleotide chain, and the oligonucleotide also contains a sense oligonucleotide chain.

134. The oligonucleotide of any one of claims 1-133, wherein the nucleobases of the antisense oligonucleotide chain are complementary to the nucleobases of the sense oligonucleotide chain.

135. The oligonucleotide of any one of claims 1-134, wherein the positive oligonucleotide chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity with SEQ ID NO: 1 or 2.

136. The oligonucleotide of any one of claims 1-135, wherein the positive oligonucleotide chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity with SEQ ID NO: 3 or 4.

137. The oligonucleotide of any one of claims 1-136, wherein the positive oligonucleotide chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity with SEQ ID NO: 5 or 6.

138. A pharmaceutical composition comprising any one of claims 1-137, an oligonucleotide or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

139. The pharmaceutical composition of claim 138, further comprising additional pharmaceutical agents.

140. A reagent kit comprising: The oligonucleotide of any one of claims 1-137 or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 138 or 139; and Instructions for use of the oligonucleotide, pharmaceutically acceptable salt, prodrug, or pharmaceutical composition thereof.

141. A method for preparing the oligonucleotide of any one of claims 1-137, comprising subjecting the compound of formula A-1 to suitable conditions: (A-1)， Or its salts, and compounds of formula A-2: L 4E2 -L 4D2 -HAS 4 (A-2)， or its salt in contact, wherein: M 1 and M 2 Each of these groups is independently a fragment of an oligonucleotide chain or a nucleoside; L 4D1 and L 4D2 Each of them is independently a single key or connector; L 4E1 The first reactive component; L 4E2 This is the second reactive component; L 4E1 and L 4E2 They can react with each other under suitable conditions to form L 4E3 ;and L 4D1 –L 4E3 –L 4D2 For L 4 .

142. The method of claim 141, wherein M 1 and M 2 Each of the groups in the group is an independent nucleoside group.

143. The method of claim 141 or 142, wherein for: 、 、 、 、 、 、 、 、 or .

144. The method of any one of claims 141-143, wherein L 4E1 and L 4E2 Each of these is a clickable chemical handle.

145. The method of any one of claims 141-144, wherein L 4E1 and L 4E2 One of them is –N3, and L 4E1 and L 4E2 The other one is –C≡CH.

146. The method of any one of claims 141-145, wherein L 4E1 and L 4E2 One of them is –N3, and L 4E1 and L 4E2 The other one is an optional replacement. Optional replacement Or optional replacement .

147. The method of any one of claims 141-146, wherein L 4E3 It has the following formula: , , , , , , , , or ; k21 is 0, 1, 2, 3 or 4; If it exists, then R d Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl); k22 is 0, 1, 2, 3 or 4; If it exists, then R e Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl); k23 is an integer between 0 and 11 (inclusive); If it exists, then R f Each instance is independently halogenated, substituted, or unsubstituted C. 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 Alkyl); and R g For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl or –O– (substituted or unsubstituted C) 1-6 alkyl).

148. The method of any one of claims 141-147, wherein L 4E3 It has the following formula: 、 、 、 、 、 、 、 , or .

149. The method of any one of claims 141-148, wherein L 4E1 and L 4E2 One of them is –SH, and L 4E1 and L 4E2 The other one is .

150. The method of any one of claims 141-149, wherein L 4E1 or L 4E2 One of them was Michael's donor, and L 4E1 or L 4E2 Another one is the Michael receptor.

151. A method for delivering an oligonucleotide to a subject, comprising administering to the subject any oligonucleotide of any one of claims 1-137 or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 138 or 139.

152. Use of the oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-137, or the pharmaceutical composition of claims 138 or 139, for the manufacture of a medicament for delivery of the oligonucleotide to a subject.

153. The oligonucleotide of any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claims 138 or 139, for delivering the oligonucleotide to a subject.

154. The method of claim 151, the use of claim 152, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 153, wherein the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof is delivered to the brain of the subject.

155. The method of claim 151, the use of claim 152, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 153, wherein the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof is delivered to the striatum, cerebellum, brainstem, hippocampus, frontal cortex or spinal cord of the subject.

156. A method for treating a disease in a subject in need, comprising administering to the subject an effective amount of any one of claims 1-137, an oligonucleotide or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 138 or 139.

157. The use of any oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-137, or the pharmaceutical composition of claims 138 or 139, for the manufacture of a medicament for treating a disease in a subject in need.

158. The oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-137, or the pharmaceutical composition of claim 138 or 139, for treating a disease in a subject in need.

159. A method for preventing disease in a subject in need, comprising administering to the subject an effective amount of any oligonucleotide of claims 1-137 or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 138 or 139.

160. The use of any oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-137, or the pharmaceutical composition of claims 138 or 139, for the manufacture of a medicament for the prevention of disease in a subject in need.

161. The oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-137, or the pharmaceutical composition of claim 138 or 139, for the prevention of disease in a subject of need.

162. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 158 or 161, wherein the disease is associated with microtubule-associated protein Tau (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2).

163. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as claimed in claim 158 or 161, wherein the disease is a central nervous system disease.

164. The method of claim 156 or 159, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 157 or 160, and the disease is a brain disease, Edwards syndrome, gliosis, excessive panic, Meckel syndrome, myoclonic epilepsy, myopathy, sensory ataxia, narcolepsy, prion disease, serotonin syndrome, or spinal cord disease.

165. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as claimed in claim 158 or 161, wherein the disease is a neurodegenerative disease.

166. The method of claim 156 or 159, the use of the oligonucleotide or a pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as used in claim 158 or 161, wherein the disease is ABri amyloidosis, aceruloplasminemia, acute neurodegenerative disease, amyotrophic lateral sclerosis, ataxia with vitamin E deficiency, atypical Rett syndrome, β-propeller protein-associated neurodegeneration, COASY protein-associated neurodegeneration, central nervous system degenerative disease, demyelination, fatty acid hydroxylase-associated neurodegeneration, fragile X-chromosome-related tremor / ataxia syndrome, Geminin's syndrome, Gerstmann-Straussler syndrome, Huntington's disease. Huntington's disease, Huntington's syndrome, myelination failure with basal ganglia and cerebellar atrophy, infantile cerebellar-retinal degeneration, infantile axonal dystrophy, Ozaki overgrowth syndrome, mitochondrial membrane protein-related neurodegeneration, multiple sclerosis, multiple system atrophy, muscular dystrophy, Nassu-Hacola disease, neuroacanthosis, neurogenic ataxia and retinitis pigmentosa syndrome, neuronal ceroid lipofuscin deposition disease, neuronal intranuclear inclusion body disease, neurofilament, pantothenic acid kinase-related neurodegeneration, Parkinson's disease, posterior column ataxia, pure autonomic dysfunction, retrograde degeneration, Rett syndrome, Spoan syndrome, Sara disease, spinocerebellar ataxia, subacute combined degeneration, tabes dorsalis, tau proteinosis, or Wolfram syndrome.

167. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as claimed in claim 158 or 161, wherein the disease is a neurocognitive disorder.

168. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as claimed in claim 158 or 161, wherein the disease is dementia, HIV-related neurocognitive impairment, or memory impairment.

169. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as claimed in claim 158 or 161, wherein the disease is Parkinson's disease.

170. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as claimed in claim 158 or 161, wherein the disease is amyotrophic lateral sclerosis (ALS).

171. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as claimed in claim 158 or 161, wherein the disease is Alzheimer's disease.

172. The method of claim 156 or 159, the use of the method of claim 157 or 160, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 158 or 161, wherein the disease is tau proteinosis, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglia degeneration (CBD), epilepsy, or Dlavis syndrome.

173. A method for inhibiting the expression of microtubule-associated protein Tau (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2) in a subject, biological sample, tissue, or cell, the method comprising administering to the subject or exposing the biological sample, tissue, or cell to an effective amount of any one of claims 1-137, an oligonucleotide or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 138 or 139.

174. Use of any oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-137, or of any pharmaceutical composition of claim 139, for the manufacture of a medicament for inhibiting the expression of microtubule-associated protein Tau (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2) in a subject, biological sample, tissue, or cell.

175. The oligonucleotide of any one of claims 1-137 or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claims 138 or 139, for inhibiting the expression of microtubule-associated protein Tau (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2) in a subject, biological sample, tissue, or cell.

176. The method of claim 173, the use of claim 174, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 175, wherein the biological sample, tissue, or cell is in vitro.

177. The method of claim 173, the use of the method of claim 174, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 175, further comprising administering or exposing the biological sample, tissue or cell to an effective amount of the agent.

178. The method of claim 173, the use of claim 174, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 175, wherein the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof is administered parenterally to the subject.

179. The method of claim 173, the use of claim 174, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 175, wherein the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof is administered intrathecally, intraventricularly, or intravenously to the subject.

180. The method of claim 173, the use of the method of claim 174, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 175, wherein the subject is a human.

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