Ligand-containing oligonucleotides at nucleobase, 2'position or 3 'position

Abstract

The present disclosure provides oligonucleotides comprising at least one group of a central nervous system receptor ligand at the nucleobase, the 2'position of the nucleoside, or the 3 'position of the nucleoside. 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). The present disclosure also provides oligonucleosides useful in the preparation of the oligonucleotides.

Description

Related applications

[0001] This application is based on 35 USC 119(e) claims priority to U.S. Provisional Application USSN 63 / 520,093, filed August 17, 2023, the contents of which are incorporated herein by reference. Background Technology

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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

[0006] In one aspect, this disclosure provides oligonucleotides that contain at least one group of a central nervous system receptor ligand at the 2′ position of a nucleobase, a nucleoside, or the 3′ position of a nucleoside.

[0007] On the other hand, this disclosure relates to oligonucleotides comprising modified oligonucleotide chains, said modified oligonucleotide chains comprising s1 examples of modified nucleosides independently comprising a portion of Formula I: (I); and The v1 instances of the nucleoside intermolecular heads of the modified oligonucleotide chains were independently... Substitute; in: s1 can be 1, 2, 3, 4, 5, or 6; N 1 Each instance is independently a group or bond of nucleobases; Each instance of t1 is independently 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a ligand or lipid group, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b、–S(=O)SR b 、–S(=O)N(R b )2、–S(=O)2R b 、–S(=O)2OR b 、–S(=O)2SR b 、–S(=O)2N(R b )2、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b )2、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b )2、–OS(=O)2R b 、–OS(=O)2OR b 、–OS(=O)2SR b 、–OS(=O)2N(R b )2、–ON(R b )2、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b )2、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b )2、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR b S(=O)N(R b )2、–NR b S(=O)2R b 、–NR b S(=O)2OR b 、–NR b S(=O)2SR b 、–NR b S(=O)2N(R b)2、–Si(R b 3、–Si(R) b )2OR b 、–Si(R b (OR) b )2、–Si(OR b 3. –OSi(R) b 3. –OSi(R) b )2OR b –OSi(R b (OR) b )2 or –OSi(OR b )3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R b Each instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; when When y2 of an instance is 0, its L 2 For –OH, –OR h , halogen, –CN or –N3; or when When the instance's y2 is 1, 2, 3, 4, 5, or 6, its L 2 For connectors; R h Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; When a portion of Formula I is part of an instance of the modified nucleoside at the 5' end or internal position of the modified oligonucleotide chain: its y3 is 0, and its L 3 For nucleoside indirect linking; or When a portion of Formula I is part of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain: When its y3 is 0: its L 3 For –OH, –OR d halogen, –CN or –N3, and R d Each instance is independently of substituted or unsubstituted C.1-6 Alkyl or oxygen protecting group; or When its y3 is 1, 2, 3, 4, 5, or 6, its L3 For connectors; v1 is 0, 1, 2, 3, 4, 5, or 6; When it exists, L A and L 4 Each instance is a connector independently; When present, each instance of y4 is independently 1, 2, 3, 4, 5, or 6; and When it exists, A 4 Each instance is independently a ligand or lipid group.

[0008] On the other hand, this disclosure relates to oligonucleotides comprising modified oligonucleotide chains, said modified oligonucleotide chains comprising s1 examples of modified nucleosides independently comprising a portion of Formula I: (I); and The v1 instances of the nucleoside intermolecular heads of the modified oligonucleotide chains were independently... Substitute; in: s1 can be 1, 2, 3, 4, 5, or 6; N 1 Each instance is independently a group or bond of nucleobases; Each instance of t1 is independently 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a group of central nervous system receptor ligands or lipids, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b、–SSR b 、–N3、–NO、–N(R b )2、–NO2、–C(=O)R b 、–C(=O)OR b 、–C(=O)SR b 、–C(=O)N(R b )2、–S(=O)R b 、–S(=O)OR b 、–S(=O)SR b 、–S(=O)N(R b )2、–S(=O)2R b 、–S(=O)2OR b 、–S(=O)2SR b 、–S(=O)2N(R b )2、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b )2、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b )2、–OS(=O)2R b 、–OS(=O)2OR b 、–OS(=O)2SR b 、–OS(=O)2N(R b )2、–ON(R b )2、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b )2、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b )2、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR bS(=O)N(R b )2、–NR b S(=O)2R b –NR b S(=O)2OR b –NR b S(=O)2SR b –NR b S(=O)2N(R b )2、–Si(R b 3、–Si(R) b )2OR b 、–Si(R b (OR) b )2、–Si(OR b 3. –OSi(R) b 3. –OSi(R) b )2OR b –OSi(R b (OR) b )2 or –OSi(OR b )3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R b Each instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; when When y2 of an instance is 0, its L 2 For –OH, –OR h , halogen, –CN or –N3; or when When the instance's y2 is 1, 2, 3, 4, 5, or 6, its L 2 For connectors; R h Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; When a portion of Formula I is part of an instance of the modified nucleoside at the 5' end or internal position of the modified oligonucleotide chain: its y3 is 0, and its L3 For nucleoside indirect linking; or When a portion of Formula I is part of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain: When its y3 is 0: its L 3 For –OH, –OR d halogen, –CN or –N3, and R d Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; or When its y3 is 1, 2, 3, 4, 5, or 6, its L3 For connectors; v1 is 0, 1, 2, 3, 4, 5, or 6; When it exists, L A and L 4 Each instance is a connector independently; When present, each instance of y4 is independently 1, 2, 3, 4, 5, or 6; and When it exists, A 4 Each instance is independently a ligand or lipid group.

[0009] 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 at least one group of a central nervous system receptor ligand at the 2′ or 3′ position of a nucleobase, nucleoside, or nucleoside) because the former 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 due to the oligonucleotide containing at least one group of a central nervous system receptor ligand at the 2′ or 3′ position of a nucleobase, nucleoside, or nucleoside.

[0010] 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.

[0011] In another respect, this disclosure provides methods for delivering any oligonucleotide or pharmaceutical composition provided herein to a subject.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] On the other hand, this disclosure provides any oligonucleotide or pharmaceutical composition provided herein for the prevention of disease in subjects in need.

[0020] On the other hand, this disclosure provides nucleosides comprising the portion of the following formula: , in: N 1 A group or bond that is a nucleobase; t1 is 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a ligand or lipid group, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)Rb 、–C(=O)OR b 、–C(=O)SR b 、–C(=O)N(R b )2、–S(=O)R b 、–S(=O)OR b 、–S(=O)SR b 、–S(=O)N(R b )2、–S(=O)2R b 、–S(=O)2OR b 、–S(=O)2SR b 、–S(=O)2N(R b )2、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b )2、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b )2、–OS(=O)2R b 、–OS(=O)2OR b 、–OS(=O)2SR b 、–OS(=O)2N(R b )2、–ON(R b )2、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b )2、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b )2、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR b S(=O)N(R b )2、–NR b S(=O)2R b–NR b S(=O)2OR b –NR b S(=O)2SR b –NR b S(=O)2N(R b )2、–Si(R b 3、–Si(R) b )2OR b 、–Si(R b (OR) b )2、–Si(OR b 3. –OSi(R) b 3. –OSi(R) b )2OR b –OSi(R b (OR) b )2 or –OSi(OR b )3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R b Each instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; When y2 is 0, L 2 For –OH, –OR h Halogen, –CN or –N3; or when y2 is 1, 2, 3, 4, 5 or 6, L 2 For connectors; R h For substituted or unsubstituted C 1-6 Alkyl or oxygen protecting group; When y3 is 0, L 3 For –OH, –OR d Halogen, –CN or –N3; or when y3 is 1, 2, 3, 4, 5 or 6, L 3 For connectors; and R d For substituted or unsubstituted C 1-6 Alkyl or oxygen protecting group.

[0021] On the other hand, this disclosure provides nucleosides comprising the portion of the following formula: , in: N 1 A group or bond that is a nucleobase; t1 is 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a group of central nervous system receptor ligands or lipids, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b)2, –OS(=O)R b , –OS(=O)OR b , –OS(=O)SR b , –OS(=O)N(R b )2, –OS(=O)2R b , –OS(=O)2OR b , –OS(=O)2SR b , –OS(=O)2N(R b , –ON(R b )2, –SC(=O)R b , –SC(=O)OR b , –SC(=O)SR b , –SC(=O)N(R b )2, –NR b C(=O)R b , –NR b C(=O)OR b , –NR b C(=O)SR b , –NR b C(=O)N(R b )2, –NR b S(=O)R b , –NR b S(=O)OR b , –NR b S(=O)SR b , –NR b S(=O)N(R b )2, –NR b S(=O)2R<00??337>, –NR b S(=O)2OR b , –NR b S(=O)2SR b , –NR b S(=O)2N(R b )2, –Si(R b )3, –Si(R b )2OR b , –Si(R b )(OR b )2, –Si(OR b )3, –OSi(R b )3, –OSi(R b )2OR b , –OSi(R b )(OR b )2 or –OSi(OR b)3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R b Each instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; When y2 is 0, L 2 For –OH, –OR h Halogen, –CN or –N3; or when y2 is 1, 2, 3, 4, 5 or 6, L 2 For connectors; R h For substituted or unsubstituted C 1-6 Alkyl or oxygen protecting group; When y3 is 0, L 3 For –OH, –OR d Halogen, –CN or –N3; or when y3 is 1, 2, 3, 4, 5 or 6, L 3 For connectors; and R d For substituted or unsubstituted C 1-6 Alkyl or oxygen protecting group.

[0022] The nucleosides described in this article can be used to prepare the oligonucleotides described in this article.

[0023] 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.

[0024] 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.

[0025] definition The definitions of specific functional groups and chemical terms are described in more detail below. Based on the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics The 75th edition, inside cover, is used to identify chemical elements and generally defines specific functional groups as described. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell's work. 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 ed., Cambridge University Press, Cambridge, 1987.

[0026] 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 can be separated from the mixture 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 Page 268 (edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure also covers compounds as single isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0027] 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.

[0028] 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 C 1–2 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.

[0029] 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”). 1-4Alkyl 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 groups (Et), unsubstituted propyl groups (Pr, such as unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (... i -Pr)), unsubstituted butyl (Bu, for example, 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)).

[0030] 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. 1-100Alkyl 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”). 1-7 Alkyl 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. 1-12Alkyl 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.

[0031] 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”). 1-12 Alkenyl 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 (“C6”). In some embodiments, the alkenyl group has 1 to 6 carbon atoms (“C6”). 1-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 1 to 5 carbon atoms (“C”). 1-5 Alkenyl group (“C”). 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, C2–9 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 2-4 Alkenyl 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 ...). ) can be ( E )or( Z ) configuration.

[0032] 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, C2–60 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.

[0033] 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, C2–7 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 1-4 Examples 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.

[0034] 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 The heteroynyl group ("heterynyl group") has 1 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms ("heterynyl group") within the parent chain in some embodiments. 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 1-20Alkynyl 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.

[0035] 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). In some embodiments, the carbocyclic group has 4 to 6 cyclic carbon atoms (“C”). 4-6 The carbocyclic group (“CCR”) has 5 to 6 cyclic carbon atoms in some embodiments. 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 3-8Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 Octahydro-1 H -Indanyl (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 14 As 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.

[0036] 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 5-6Examples 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] The term “halogen” or “halogen” refers to fluorine (fluorinated group, -F), chlorine (chloroinated group, -Cl), bromine (brominated group, -Br) or iodine (iodolated group, -I).

[0045] The term "alkoxy" refers to an -O-alkyl substituent.

[0046] 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–.

[0047] 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.

[0048] Exemplary carbon substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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; 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 =NR bbor = NOR cc Substitute; 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; 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 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14aryl 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; 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; 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(R ff )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; R ee Each instance is independently selected from C 1-10 Alkyl, C 1-10 All-halogenated alkyl, C 1-10 alkenyl, C 1-10 alkynyl, hetero-C 1-10Alkyl, 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; 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; 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 groups, -NH(OH), -SH, -SC 1–6 Alkyl, -SS(C 1–6 Alkyl), -C(=O)(C 1–6 Alkyl group, -CO2H, -CO2(C 1–6 Alkyl), -OC (=O)(C1–6 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 group), -OC (=NH)(C 1–6 Alkyl group), -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) 1–6 Alkyl)2、-P(=O)(C 1–6 Alkyl)2、-OP(=O)(C 1–6 Alkyl)2、-OP(=O)(OC 1–6 Alkyl)2, 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 heterocyclic or 5-10 heteroaryl; or two geminal Rs gg Substituents can link to form =O or =S; and Each X - To counteract ions.

[0049] In some embodiments, each carbon atom substituent is independently a halogen, substituted (e.g., substituted by one or more halogens), or unsubstituted C. 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(R) bb )2、-NR bb C(=O)R aa -NR bb CO2R aa or -NR bb C(=O)N(Rbb )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. 1–10 Alkyl groups, or nitrogen-protecting groups (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0050] 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.

[0051] 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 C 1–10 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 6-14Aryl 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 Protecting Groups in Organic Synthesis Those described in detail in TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999.

[0052] 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 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 it is attached, is independently selected from the group consisting of: formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, 2-picolinamide, 3-pyridinecarboxamide, N -Benzoylphenylalanyl derivatives, 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 derivatives, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0053] 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-oxybenzyl 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-nitrophenyl)methyl ester of carbamate, tert-amyl ester of 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 1,1-Dimethyl-3-(dimethylformamido)benzyl ester, carbamate N , N 1,1-Dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinamide carbamate, p-( p’ 1-Methoxyphenylazo)benzyl ester, 1-methylcyclobutyl ester of carbamate, 1-methylcyclohexyl ester of carbamate, 1-methyl-1-cyclopropylmethyl ester of carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl ester of carbamate, 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.

[0054] 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.

[0055] In some 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: phenothiazinyl-(10)-acyl derivatives, N' -p-Toluenesulfonylaminoacyl derivatives, N’ -Phenylanthioacyl derivatives N -Benzoylphenylalanyl derivative, 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-Tetramethyldimethylsilylazacyclopentane adduct (STABASE), 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 salt N -Benzylamine, N -Di(4-methoxyphenyl)methylamine, N -5-Dibenzocycloheptylamine, N-Triphenylmethylamine (Tr) N -[(4-methoxyphenyl)diphenylmethyl]amine (MMTr) N -9-Phenylenylfluoreneamine (PhF) N -2,7-Dichloro-9-fluorenylmethyleneamine, N -Ferrocenylmethylamino (Fcm) N -2-pyridinemethylamino N’ -Oxides, N -1,1-Dimethylthiomethyleneamine, N -Benzylamine, N -p-Methoxybenzylamine, N -Diphenylmethyleneamine, N -[(2-pyridyl)trimethylmethyl]methyleneamine, N -( N’ , N’ -Dimethylaminomethylene)amine, N -p-Nitrobenzylidene, N - Salicylic acid, N -5-Chlorosalicylic acid, N -(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N -cyclohexylamine, N -(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N -borane derivatives, N -Diphenylboronic acid derivatives, N -[phenyl(pentacylchromium or tungsten)acyl]amine, N - Copper chelates, N -Zinc chelate, N -Nitroamine, N - Nitrosamines, amines N -Oxides, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkylaminophosphate, dibenzylaminophosphate, diphenylaminophosphate, benzylsulfonamide, o-nitrobenzenesulfonamide (Nps), 2,4-dinitrobenzenesulfonamide, pentachlorobenzenesulfonamide, 2-nitro-4-methoxybenzenesulfonamide, triphenylmethylsulfonamide, and 3-nitropyridinesulfonamide (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 diamine.

[0056] In some embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0057] 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.

[0058] 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... Protecting Groups in Organic Synthesis Those described in detail in TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999.

[0059] 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), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silanoxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), 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-benzyl 2-Fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyselenoethyl)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 -Oxygen anion group (oxido), diphenylmethyl, p ,p’ -Dinitrodiphenylmethyl, 5-Dibenzocycloheptanyl, Triphenylmethyl, 4,4′-Dimethoxytriphenylmethyl (4,4′-Dimethoxytriphenylmethyl 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 anion group, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl tert-hexyl silyl, tert-butyl dimethylsilyl (TBDMS), tert-butyl diphenylsilyl (TBDPS), tribenzyl silyl, tri-p-xylyl silyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butyl methoxyphenyl silyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxovalerate (levulinic acid) Esters), 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-(triphenylphosphonium)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, thiocarbonateS Benzyl ester, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 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 ester, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid ester, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid ester, dichlorophenylacetic acid ester, isobutyrate, monosuccinate, ( E 2-Methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthyl ester, nitrate ester, N , N , N’ , N’ alkyl tetramethyldiaminophosphate, N Alkyl phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate, benzyl sulfonate and toluenesulfonate (Ts).

[0060] 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.

[0061] 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.

[0062] 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(=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 R aa R bb and R cc As defined herein, sulfur protecting groups are well known in the art and include... Protecting Groups in Organic Synthesis Those described in detail in TW Greene and PGMUTS, 3rd edition, John Wiley & Sons, 1999.

[0063] 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.

[0064] "Click chemistry" is a chemical method first proposed by K. Barry Sharpless in 2001 and is meticulously 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, 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).

[0065] 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.

[0066] The term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in... J. Pharmaceutical SciencesPharmaceutically acceptable salts are described in detail in 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.

[0067] 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 rate, 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,” A.C.S. Symposium Series The concept of a prodrug is discussed in Volume 14 and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 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-bound moiety, such as a substituted or unsubstituted alkyl or substituted or unsubstituted phenyl). Prodrugs containing –OPG, –NPG2, –SPG, –C(=O)OPG, –OP(=O)(OPG)O–, –SP(=O)(OPG)O–, –OP(=O)(OPG)S–, or –OP(=O)(SPG)O– can be converted to –OH, –NH2, –SH, –C(=O)OH, –OP(=O)(OH)O–, –SP(=O)(OH)O–, –OP(=O)(OH)S–, or –OP(=O)(SH)O– under physiological conditions or through solvent decomposition. 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 of prodrugs described herein.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] The terms “symptoms,” “disease,” and “symptoms” are used interchangeably.

[0073] 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).

[0074] 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.

[0075] 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.

[0076] The term "composition" refers to a mixture of substances. The term "pharmaceutical composition" refers to a composition suitable for administration to a subject.

[0077] symbol" "" indicates the attachment point between the chemical part and the rest of the compound or chemical formula.

[0078] 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.

[0079] 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 can be naturally occurring, recombinant, synthetic, or combinations thereof. Peptides, polypeptides, or proteins can be fragments of naturally occurring peptides, polypeptides, or proteins.

[0080] 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.

[0081] 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).

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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).

[0087] The terms “internucleoside linkage”, “internucleoside linker”, “internucleosidic linkage”, and “internucleosidic linker” are used interchangeably.

[0088] 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.

[0089] "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).

[0090] "Terminal group" refers to a chemical group or atomic group covalently attached to the end of an oligonucleotide.

[0091] 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.

[0092] 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).

[0093] 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 (miRNA precursor) 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*) products. The mature miRNA is 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 results in 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 causing 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).

[0094] 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).

[0095] 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.

[0096] "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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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).

[0101] "Modified oligonucleotides" refers to oligonucleotides in which at least one sugar, nucleobase, or nucleoside link is modified.

[0102] "Nucleobase sequence" refers to the sequence of adjacent nucleobases in a nucleic acid or oligonucleotide that is independent of any sugar or nucleoside bond.

[0103] 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.

[0104] "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.

[0105] "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.

[0106] 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 integrin receptors or N -Methyl-D-aspartate (NMDA) receptor binding. In some embodiments, the ligand is capable of selectively targeting oligonucleotides (e.g., their oligonucleotide chains) to body regions or cells. In some embodiments, the ligand is capable of targeting oligonucleotides (e.g., their oligonucleotide chains) 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 oligonucleotides (e.g., their oligonucleotide chains) to central nervous system (CNS) cells (e.g., neurons). In some embodiments, the ligand is not a lipid.

[0107] 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."

[0108] 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).

[0109] The term "unsaturated" or "partially unsaturated" refers to a portion that includes at least one double or triple bond.

[0110] 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

[0111] In one aspect, this disclosure provides oligonucleotides that contain at least one group of a central nervous system receptor ligand at the 2′ or 3′ position of a nucleobase, nucleoside, or nucleoside. 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.

[0112] Oligonucleotide On the other hand, this disclosure provides oligonucleotides comprising modified oligonucleotide chains, said modified oligonucleotide chains comprising s1 examples of modified nucleosides independently comprising a portion of Formula I: (I); and The v1 instances of the nucleoside intermolecular heads of the modified oligonucleotide chains were independently... Substitute; in: s1 can be 1, 2, 3, 4, 5, or 6; N 1 Each instance is independently a group or bond of nucleobases; Each instance of t1 is independently 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a ligand or lipid group, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2R b –OS(=O)2OR b –OS(=O)2SR b–OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b –NR b C(=O)OR b –NR b C(=O)SR b –NR b C(=O)N(R b )2、–NR b S(=O)R b –NR b S(=O)OR b –NR b S(=O)SR b –NR b S(=O)N(R b )2、–NR b S(=O)2R b –NR b S(=O)2OR b –NR b S(=O)2SR b –NR b S(=O)2N(R b )2、–Si(R b 3、–Si(R) b )2OR b 、–Si(R b (OR) b )2、–Si(OR b 3. –OSi(R) b 3. –OSi(R) b )2OR b –OSi(R b (OR) b )2 or –OSi(OR b )3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R bEach instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; when When y2 of an instance is 0, its L 2 For –OH, –OR h , halogen, –CN or –N3; or when When the instance's y2 is 1, 2, 3, 4, 5, or 6, its L 2 For connectors; R h Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; When a portion of Formula I is part of an instance of the modified nucleoside at the 5' end or internal position of the modified oligonucleotide chain: its y3 is 0, and its L 3 For nucleoside indirect linking; or When a portion of Formula I is part of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain: When its y3 is 0: its L 3 For –OH, –OR d halogen, –CN or –N3, and R d Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; or When its y3 is 1, 2, 3, 4, 5, or 6, its L 3 For connectors; v1 is 0, 1, 2, 3, 4, 5, or 6; When it exists, L A and L 4 Each instance is a connector independently; When present, each instance of y4 is independently 1, 2, 3, 4, 5, or 6; and When it exists, A 4 Each instance is independently a ligand or lipid group.

[0113] In some implementations, if present, then A 1 A 2 and A3 Each instance is independently a group of central nervous system receptor ligands or lipids, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand.

[0114] In one aspect, this disclosure provides oligonucleotides comprising modified oligonucleotide chains, said modified oligonucleotide chains comprising s1 examples of modified nucleosides independently comprising a portion of Formula I: (I); and The v1 instances of the nucleoside intermolecular heads of the modified oligonucleotide chains were independently... Substitute; in: s1 can be 1, 2, 3, 4, 5, or 6; N 1 Each instance is independently a group or bond of nucleobases; Each instance of t1 is independently 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a group of central nervous system receptor ligands or lipids, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)Rb 、–S(=O)OR b 、–S(=O)SR b 、–S(=O)N(R b )2、–S(=O)2R b 、–S(=O)2OR b 、–S(=O)2SR b 、–S(=O)2N(R b )2、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b )2、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b )2、–OS(=O)2R b 、–OS(=O)2OR b 、–OS(=O)2SR b 、–OS(=O)2N(R b )2、–ON(R b )2、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b )2、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b )2、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR b S(=O)N(R b )2、–NR b S(=O)2R b 、–NR b S(=O)2OR b 、–NR b S(=O)2SR b 、–NRb S(=O)2N(R b )2、–Si(R b 3、–Si(R) b )2OR b 、–Si(R b (OR) b )2、–Si(OR b 3. –OSi(R) b 3. –OSi(R) b )2OR b –OSi(R b (OR) b )2 or –OSi(OR b )3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R b Each instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; when When y2 of an instance is 0, its L 2 For –OH, –OR h , halogen, –CN or –N3; or when When the instance's y2 is 1, 2, 3, 4, 5, or 6, its L 2 For connectors; R h Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; When a portion of Formula I is part of an instance of the modified nucleoside at the 5' end or internal position of the modified oligonucleotide chain: its y3 is 0, and its L 3 For nucleoside indirect linking; or When a portion of Formula I is part of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain: When its y3 is 0: its L 3 For –OH, –OR d halogen, –CN or –N3, and Rd Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; or When its y3 is 1, 2, 3, 4, 5, or 6, its L3 For connectors; v1 is 0, 1, 2, 3, 4, 5, or 6; When it exists, L A and L 4 Each instance is a connector independently; When present, each instance of y4 is independently 1, 2, 3, 4, 5, or 6; and When it exists, A 4 Each instance is independently a ligand or lipid group.

[0115] In some embodiments, s1 is 1, and the modified nucleoside is located at the 5' end of the modified oligonucleotide chain. In some embodiments, s1 is 1, and the modified nucleoside is located at an internal position in the modified oligonucleotide chain. In some embodiments, s1 is 1, and the modified nucleoside is located at the 3' end of the modified oligonucleotide chain.

[0116] In some embodiments, s1 is 2; one instance of the modified nucleoside is located at the 5' end of the modified oligonucleotide chain; and another instance of the modified nucleoside is located at an internal position within the modified oligonucleotide chain. In some embodiments, s1 is 2, and one instance of the modified nucleoside is located at the 3' end of the modified oligonucleotide chain; and Another instance of the modified nucleoside is located within the modified oligonucleotide chain. In some embodiments, s1 is 2; and each instance of the modified nucleoside is located within the modified oligonucleotide chain. In some embodiments, s1 is 3, 4, 5, or 6.

[0117] In some embodiments, at least one instance of the internal position is the nth nucleoside of the modified oligonucleotide chain, counted from the 5' end; and where the number of nucleosides in the modified oligonucleotide chain allows, n is an integer between 2 and 20 (inclusive). In some embodiments, at least one instance of the internal position is the nth nucleoside of the modified oligonucleotide chain, counted from the 3' end; and where the number of nucleosides in the modified oligonucleotide chain allows, n is an integer between 2 and 20 (inclusive).

[0118] In some implementation schemes, N 1 At least one instance is a nucleobase group. In some embodiments, N 1At least one example is a group of adenine, cytosine, guanine, or uracil. In some embodiments, N 1 At least one instance of it is a key.

[0119] In some embodiments, at least one instance of t1 is 1. In some embodiments, v1 is 0. In some embodiments, v1 is 1. In some embodiments, v1 is 2, 3, 4, 5, or 6. In some embodiments, at least one instance of y1 is 0. In some embodiments, at least one instance of y1 is 1. In some embodiments, at least one instance of y1 is 2. In some embodiments, at least one instance of y1 is 3, 4, 5, or 6. In some embodiments, at least one instance of y2 is 0. In some embodiments, at least one instance of y2 is 1. In some embodiments, at least one instance of y2 is 2. In some embodiments, at least one instance of y2 is 3, 4, 5, or 6. In some embodiments, at least one instance of y3 is 0. In some embodiments, at least one instance of y3 is 1. In some embodiments, at least one instance of y3 is 2. In some embodiments, at least one instance of y3 is 3, 4, 5, or 6. In some embodiments, when present, at least one instance of y4 is 1. In some implementations, when present, at least one instance of y4 is 2, 3, 4, 5, or 6.

[0120] In some embodiments, in at least one instance of a portion of Formula I: each instance of y1 is 0; y2 is 0; and y3 is 1. In some embodiments, in at least one instance of a portion of Formula I: each instance of y1 is 0; y2 is 0; and y3 is 2. In some embodiments, in at least one instance of a portion of Formula I: t1 is 1; y1 is 1; y2 is 0; and y3 is 1. In some embodiments, in at least one instance of a portion of Formula I: each instance of y1 is 0; y2 is 1; and y3 is 1. In some embodiments, in at least one instance of a portion of Formula I, each of t1, y1, y2, and y3 is 1. In some embodiments, in at least one instance of a portion of Formula I: y1 is 0; y2 is 2; and y3 is 1.

[0121] In some implementations, Formula I includes: , , , , , , , , , , , , , , or .

[0122] 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).

[0123] 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 and / or NMDA receptor ligand are linked. In some embodiments, the second oligonucleotide chain is linked to a ligand (e.g., TrkB, CB1, α4β). 1 / 7One or more groups of an integrin and / 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. In some embodiments, the oligonucleotide contains one or more groups of the ligand at a nucleobase. In some embodiments, the oligonucleotide contains one or more groups of the ligand at the 2′ position of the nucleoside. In some embodiments, the oligonucleotide contains one or more groups of the ligand at the 3′ position of the nucleoside.

[0124] 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.

[0125] 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.

[0126] In some implementations, the oligonucleotide chain is about 14 nucleotides to about 23 nucleotides in length.

[0127] 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.

[0128] In some implementations, the miRNA is a precursor, primary, and / or mature miRNA.

[0129] 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.

[0130] 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.

[0131] In some embodiments, the oligonucleotide comprises an oligonucleotide chain containing at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity to 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 thereof) associated with a disease (e.g., a CNS disease). In some embodiments, the disease is associated with gene overexpression. In some embodiments, "associated with" means "at least partially caused by".

[0132] 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 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). Exemplary nucleotide sequences of the human MAPT gene can be found, for example, in GenBank accession numbers 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)).

[0133] In some embodiments, the oligonucleotide comprises a positive 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 with 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). 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)).

[0134] In some embodiments, the oligonucleotide comprises a positive 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 with 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). Exemplary nucleotide sequences of the human LRRK2 gene can be found, for example, in GenBank accession numbers 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)).

[0135] connector In some embodiments, the oligonucleotides provided herein contain one or more adapters (e.g., L... 1 L 2 L 3 L A and L 4 ).

[0136] 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.

[0137] 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.

[0138] In some implementations, the connector is a key (e.g., a single key).

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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: , , , , , , , , 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).

[0144] 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 direction.

[0145] In some embodiments, the substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms has the following formula: , , , , , , , , or .

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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... .

[0150] 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: 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 The connector does not include O–O, O–N, N–O, or N–N.

[0151] 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: The number of main chain atoms in the connector is between 7 and 70 (inclusive); and The connector does not include O–O, O–N, N–O, or N–N.

[0152] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, and The combination of these conditions is conditional upon: 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). The connector does not contain O–O, O–N, N–O, or N–N; and The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0153] In some implementations, the connector is –CH2–. , , –O–, –CH2CH2O–, –OCH2CH2–, –C(=O)NH–, –NHC(=O)–, and The combination of these conditions is conditional upon: The number of main chain atoms in the connector is between 7 and 70 (inclusive); The connector does not contain O–O, O–N, N–O, or N–N; and The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0154] 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: 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 The connector does not include O–O, O–N, N–O, or N–N.

[0155] 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: The number of main chain atoms in the connector is between 7 and 70 (inclusive); and The connector does not include O–O, O–N, N–O, or N–N.

[0156] 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: 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). The connector does not contain O–O, O–N, N–O, or N–N; and The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0157] 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: The number of main chain atoms in the connector is between 7 and 70 (inclusive); The connector does not contain O–O, O–N, N–O, or N–N; and The connector's –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] In some implementation schemes, The instance y1 is 0, and its L 1 For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6Heteroalkyl, substituted or unsubstituted monocyclic carbocyclic, substituted or unsubstituted monocyclic heterocyclic, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2R b –OS(=O)2OR b –OS(=O)2SR b –OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b –NR b C(=O)OR b –NR b C(=O)SR b –NR b C(=O)N(R b )2、–NR b S(=O)Rb –NR b S(=O)OR b –NR b S(=O)SR b –NR b S(=O)N(R b )2、–NR b S(=O)2R b –NR b S(=O)2OR b –NR b S(=O)2SR b Or –NR b S(=O)2N(R b )2.

[0163] In some implementation schemes, The instance y1 is 0, and its L 1 For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Heteroalkyl, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2Rb –OS(=O)2OR b –OS(=O)2SR b –OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b –NR b C(=O)OR b –NR b C(=O)SR b –NR b C(=O)N(R b )2、–NR b S(=O)R b –NR b S(=O)OR b –NR b S(=O)SR b –NR b S(=O)N(R b )2、–NR b S(=O)2R b –NR b S(=O)2OR b –NR b S(=O)2SR b Or –NR b S(=O)2N(R b )2.

[0164] In some implementations, The instance y1 is 0, and its L 1 For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, –OR b or –N(R) b 2. In some implementations, The instance y1 is 0, and its L 1 It is hydrogen, halogen, or substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, The instance y1 is 0, and its L 1 It is hydrogen. In some implementations, R b Each instance is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, Rb Each instance is independently hydrogen. In some implementations, R b Each instance is independently an unsubstituted alkyl group. In some embodiments, R b Each instance is independently CH3, CH2CH3, or CH2CH2CH3.

[0165] In some implementations, if present, then At least one instance of it has the following formula: ; –L 1A1 –L 1A2 –、–L 1A3 –L 1A4 –、–L 1A5 –L 1A6 – and – L 1A7 –L 1A8 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 aC(=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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 1B1 and L 1B2 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 1C1 It 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 1A Attach to A 1 .

[0166] In some implementations, –L 1A1 –L 1A2 –、–L 1A3 –L 1A4 –、–L 1A5 –L 1A6 – and – L 1A7 –L 1A8 Each of the – symbols is independently a single bond, –O–, –NR. a –、–C(=O)NR a – or R a C(=O) –. In some implementations, –L 1A1 –L 1A2 –、–L 1A3 –L1A4 –、–L 1A5 –L 1A6 – and – L 1A7 –L 1A8 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 1A1 –L 1A2 –、–L 1A3 –L 1A4 –、–L 1A5 –L 1A6 – and – L 1A7 –L 1A8 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 1A1 –L 1A2 –、–L 1A3 –L 1A4 –、–L 1A5 –L 1A6 – and – L 1A7 –L 1A8 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 1A1 –L 1A2 –、–L 1A3 –L 1A4 –、–L 1A5 –L 1A6 – and – L 1A7 –L 1A8 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 1A1 –L 1A2 –、–L 1A3 –L 1A4 –、–L 1A5 –L 1A6 – and – L 1A7 –L 1A8 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–.

[0167] 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.

[0168] In some implementations, L 1B1 and L 1B2 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 1B1 and L 1B2 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 1B1 and L 1B2 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 1B1 and L 1B2 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0169] In some implementations, L 1C1 It is a single bond. In some implementations, L 1C1 This refers to a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms. In some embodiments, L 1C1 for (It can be attached in either direction).

[0170] In some implementations, its L 1 It has the following formula: .

[0171] In some implementations, –L 1A7 –L 1A8 At least one instance of – is –NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 1A7 –L 1A8 At least one instance of – is –NH–C(=O)– or –C(=O)–NH–. In some embodiments, –L 1A7 –L1A8 At least one instance of – is –O–C(=O)– or –C(=O)–O–. In some implementations, –L 1A7 –L 1A8 At least one instance of – is –O–. In some implementations, –L 1A7 –L 1A8 At least one instance of – is –NH–. In some implementations, –L 1A7 –L 1A8 At least one instance of – is –C(=O) –. In some implementations, –L 1A7 –L 1A8 At least one instance of – is a single key.

[0172] In some implementations, its L 1 It has the following formula: or .

[0173] In some implementations, The instance y1 is 1, 2, 3, 4, 5, or 6, and its L 1 For substituted or unsubstituted C 7-70 Heteroalkyl groups.

[0174] In some implementation schemes, At least one instance of it has the following formula: ; –L 2A1 –L 2A2 –、–L 2A3 –L 2A4 –、–L 2A5 –L 2A6 – and – L 2A7 –L 2A8 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 2B1 and L 2B2 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 2C1 It 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 2A Attach to A 2 .

[0175] In some implementations, –L 2A1 –L 2A2 –、–L 2A3 –L 2A4 –、–L 2A5 –L 2A6 – and – L 2A7 –L 2A8 Each of the – symbols is independently a single bond, –O–, –NR. a –、–C(=O)NR a – or R a C(=O) –. In some implementations, –L 2A1 –L 2A2 –、–L 2A3 –L 2A4 –、–L 2A5 –L 2A6 – and – L 2A7 –L 2A8 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 2A1 –L 2A2 –、–L 2A3 –L 2A4 –、–L 2A5 –L 2A6 – and – L 2A7 –L 2A8 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 2A1 –L 2A2 –、–L 2A3 –L 2A4 –、–L 2A5 –L 2A6 – and – L 2A7 –L 2A8 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 2A1 –L 2A2 –、–L 2A3 –L 2A4 –、–L 2A5 –L 2A6 – and – L 2A7 –L 2A8 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 2A1 –L 2A2 –、–L 2A3 –L 2A4 –、–L 2A5 –L 2A6 – and – L 2A7 –L 2A8 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–.

[0176] 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.

[0177] In some implementations, L 2B1 and L 2B2 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 2B1 and L 2B2 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 2B1 and L 2B2 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 2B1 and L 2B2 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0178] In some implementations, L 2C1 It is a single bond. In some implementations, L 2C1 This refers to a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms. In some embodiments, L2C1 for (It can be attached in either direction).

[0179] In some implementation schemes, At least one instance of it has the following formula: .

[0180] In some implementations, –L 2A7 –L 2A8 At least one instance of – is –NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 2A7 –L 2A8 At least one instance of – is –NH–C(=O)– or –C(=O)–NH–. In some embodiments, –L 2A7 –L 2A8 At least one instance of – is –O–C(=O)– or –C(=O)–O–. In some implementations, –L 2A7 –L 2A8 At least one instance of – is –O–. In some implementations, –L 2A7 –L 2A8 At least one instance of – is –NH–. In some implementations, –L 2A7 –L 2A8 At least one instance of – is –C(=O) –. In some implementations, –L 2A7 –L 2A8 At least one instance of – is a single key.

[0181] In some implementations, At least one instance of it has the following formula: In some implementations, At least one instance of it has the following formula: .

[0182] In some implementations, At least one instance of it has the following formula: .

[0183] In some implementation schemes, At least one instance of it has the following formula: ; –L 2A9 –L 2A10 –、–L 2A11 –L 2A12 –、–L 2A13 –L 2A14–、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 2B3 L 2B4 L 2B5 L 2B6 L 2B7 and L 2B8 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 2C2 and L 2C3 Each of them is independently a single bond, a substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms, or a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms; Key C 2B Attach to A 2 The first instance; and Key C 2C Attach to A 2 The second instance.

[0184] In some implementations, –L 2A9 –L 2A10 –、–L 2A11 –L 2A12 –、–L 2A13 –L 2A14 –、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 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 2A9 –L 2A10 –、–L 2A11 –L 2A12 –、–L 2A13 –L 2A14 –、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 2A9 –L 2A10 –、–L 2A11 –L 2A12 –、–L 2A13 –L 2A14 –、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 2A9 –L 2A10 –、–L 2A11 –L 2A12 –、–L 2A13 –L 2A14 –、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 2A9 –L 2A10 –、–L2A11 –L 2A12 –、–L 2A13 –L 2A14 –、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 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 2A9 –L 2A10 –、–L 2A11 –L 2A12 –、–L 2A13 –L 2A14 –、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 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–.

[0185] 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.

[0186] In some implementations, L 2B3 L 2B4 L 2B5 L 2B6 L2B7 and L 2B8 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 2B3 L 2B4 L 2B5 L 2B6 L 2B7 and L 2B8 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 2B3 L 2B4 L 2B5 L 2B6 L 2B7 and L 2B8 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 2B3 L 2B4 L 2B5 L 2B6 L 2B7 and L 2B8 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0187] In some implementations, L 2C2 and L 2C3 Each of them is an independent single bond. In some implementations, L 2C2 and L 2C3 Each of them is independently a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms. In some embodiments, L 2C2 and L 2C3 Each of them independently (It can be attached in either direction).

[0188] In some implementation schemes, At least one instance of it has the following formula: .

[0189] In some implementations, –L 2A17 –L 2A18 At least one instance of – is –NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 2A17 –L 2A18At least one instance of – is –NH–C(=O)– or –C(=O)–NH–. In some embodiments, –L 2A17 –L 2A18 At least one instance of – is –O–C(=O)– or –C(=O)–O–. In some implementations, –L 2A17 –L 2A18 At least one instance of – is –O–. In some implementations, –L 2A17 –L 2A18 At least one instance of – is –NH–. In some implementations, –L 2A17 –L 2A18 At least one instance of – is –C(=O) –. In some implementations, –L 2A17 –L 2A18 At least one instance of – is a single key.

[0190] In some implementations, –L 2A23 –L 2A24 At least one instance of – is –NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 2A23 –L 2A24 At least one instance of – is –NH–C(=O)– or –C(=O)–NH–. In some embodiments, –L 2A23 –L 2A24 At least one instance of – is –O–C(=O)– or –C(=O)–O–. In some implementations, –L 2A23 –L 2A24 At least one instance of – is –O–. In some implementations, –L 2A23 –L 2A24 At least one instance of – is –NH–. In some implementations, –L 2A23 –L 2A24 At least one instance of – is –C(=O) –. In some implementations, –L 2A23 –L 2A24 At least one instance of – is a single key.

[0191] In some implementations, At least one instance of it has the following formula: .

[0192] In some implementations, The instances of y2 are 1, 2, 3, 4, 5, or 6, and their L 2 For substituted or unsubstituted C 7-70 Heteroalkyl groups.

[0193] In some embodiments, a portion of Formula I is a portion of an example of a modified nucleoside located at the 5' end or internal position of a modified oligonucleotide chain; its y3 is 0; and its L 3 This is a nucleoside inverse junction, for example, a phosphate ester nucleoside inverse junction, a thiophosphate ester nucleoside inverse junction, or a methylphosphonate nucleoside inverse junction. In some embodiments, a portion of Formula I is a portion of an example of a modified nucleoside at the 3' end of a modified oligonucleotide chain; where y3 is 0; where L... 3 For –OH, –OR d , halogen, –CN or –N3; and R d Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group. In some embodiments, L 3 It is –OH, –OCH3, or F. In some embodiments, part of Formula I is part of an example of a modified nucleoside at the 3' end of a modified oligonucleotide chain; where y3 is 1, 2, 3, 4, 5, or 6; and where L 3 For connectors.

[0194] In some implementation schemes, At least one instance of it has the following formula: In some implementation schemes, At least one instance of it has the following formula: .

[0195] In some implementation schemes, At least one instance of it has the following formula: ; –L 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L 3A8 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–, –NRa 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 3B1 and L 3B2 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 3C1It 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 3A Attach to A 3 .

[0196] In some implementations, –L 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L 3A8 Each of the – symbols is independently a single bond, –O–, –NR. a –、–C(=O)NR a – or R a C(=O) –. In some implementations, –L 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L 3A8 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L 3A8 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L 3A8 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L3A8 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 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L 3A8 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–.

[0197] 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.

[0198] In some implementations, L 3B1 and L 3B2 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 3B1 and L 3B2 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 3B1 and L 3B2 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 3B1 and L 3B2 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0199] In some implementations, L 3C1It is a single bond. In some implementations, L 3C1 This refers to a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms. In some embodiments, L 3C1 for (It can be attached in either direction).

[0200] In some implementation schemes, At least one instance of it has the following formula: .

[0201] In some implementations, –L 3A7 –L 3A8 At least one instance of – is –NR a –C(=O)– or –C(=O)–NR a –. In some implementations, –L 3A7 –L 3A8 At least one instance of – is –NH–C(=O)– or –C(=O)–NH–. In some embodiments, –L 3A7 –L 3A8 At least one instance of – is –O–C(=O)– or –C(=O)–O–. In some implementations, –L 3A7 –L 3A8 At least one instance of – is –O–. In some implementations, –L 3A7 –L 3A8 At least one instance of – is –NH–. In some implementations, –L 3A7 –L 3A8 At least one instance of – is –C(=O) –. In some implementations, –L 3A7 –L 3A8 At least one instance of – is a single key.

[0202] In some implementations, At least one instance of it has the following formula: .

[0203] In some implementations, y3 is 1; and its for ; –L 3A1 –L 3A2 –、–L 3A3 –L 3A4 –、–L 3A5 –L 3A6 – and – L 3A7 –L 3A8 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. 1-6Alkyl 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 3B1 and L 3B2 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 3C1 It is a single bond, a substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms, or a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms.

[0204] In some implementations, y3 is 2; and its for ; –L 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L 3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 3B3 L 3B4 L 3B5 L 3B6 and L 3B7 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; and L 3C2 and L 3C3 Each of them is independently 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.

[0205] In some implementations, –L 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L 3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 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 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L 3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L 3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L 3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 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 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L 3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 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–.

[0206] 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, Ra Each instance is independently either hydrogen or unsubstituted C. 1-6 alkyl.

[0207] In some implementations, L 3B3 L 3B4 L 3B5 L 3B6 and L 3B7 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 3B3 L 3B4 L 3B5 L 3B6 and L 3B7 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 3B3 L 3B4 L 3B5 L 3B6 and L 3B7 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 3B3 L 3B4 L 3B5 L 3B6 and L 3B7 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0208] In some implementations, L 3C2 and L 3C3 Each of them is an independent single bond. In some implementations, L 3C2 and L 3C3 Each of them is independently a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms. In some embodiments, L 3C2 and L 3C3 Each of them independently (It can be attached in either direction).

[0209] In some implementations, y3 is 2; and its for , or .

[0210] In some implementations, when present, At least one instance is located between the first and second nucleotides of the modified oligonucleotide chain, counted starting from the 5' end. In some embodiments, when present, At least one instance is located between the nth and (n+1)th nucleotides of the modified oligonucleotide chain, counting from the 5' end; and where the number of nucleotides in the modified oligonucleotide chain allows, n is an integer between 2 and 20 (inclusive).

[0211] In some implementations, when present, 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, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heteroalkenyl group, a substituted or unsubstituted heteroalkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a nitrogen-protecting group when attached to a nitrogen atom, or an oxygen-protecting group when attached to an oxygen atom, or two R groups. C Examples of linkages form substituted or unsubstituted heterocyclic rings or substituted or unsubstituted heteroaryl rings; and Key C 4A Attach to L 4 .

[0212] 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.

[0213] 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)-.

[0214] In some implementation schemes, R c Each instance is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0215] In some implementations, when present, L A At least one instance of has the formula or In some implementations, L, when present, A At least one instance of has the formula .

[0216] In some implementations, when present, L A At least one instance of has the formula , , , , or .

[0217] In some implementations, at least one instance of y4 is 1; and its for ; –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 aC(=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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 4B1 L 4B2 and L 4B3 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 4A Attach to A 4 .

[0218] 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 aC(=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 –、–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, –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–.

[0219] 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.

[0220] In some implementations, L 4B1 L 4B2 and L 4B3 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 4B3 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 4B3 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 4B1 L 4B2 and L 4B3Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0221] 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).

[0222] In some implementations, at least one instance of y4 is 2; and its for ; –L 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L 4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L 4A47 –L 4A48 – and – L 4A49 –L 4A50 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 4B4 L4B5 L 4B6 L 4B7 L 4B8 L 4B9 L 4B10 L 4B11 and L 4B12 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 4C3 L 4C4 L 4C5 L 4C6 L 4C7 and L 4C8 Each of them is a single bond, a substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms, or a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms; Key C 4B Attach to A 4 The first instance; and Key C 4C Attach to A 4 The second instance.

[0223] In some implementations, –L 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L 4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L 4A47 –L 4A48 – and – L 4A49 –L 4A50 Each of the – symbols is independently a single bond, –O–, –NR. a –、–C(=O)NRa –or–NR a C(=O) –. In some implementations, –L 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L 4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L 4A47 –L 4A48 – and – L 4A49 –L 4A50 Each of the – is independently a single bond, –O–, –NH–, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L 4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L4A47 –L 4A48 – and – L 4A49 –L 4A50 Each of the following is an independent single bond, –C(=O)NR a –or–NR a C(=O) –. In some implementations, –L 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L 4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L 4A47 –L 4A48 – and – L 4A49 –L 4A50 Each of the – is independently a single bond, –C(=O)NH–, or –NHC(=O)–. In some implementations, –L 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L 4A47 –L 4A48 – and – L 4A49 –L 4A50 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 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L 4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L 4A47 –L 4A48 – and – L 4A49 –L 4A50 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–.

[0224] 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 aEach instance is independently either hydrogen or unsubstituted C. 1-6 alkyl.

[0225] In some implementations, L 4B4 L 4B5 L 4B6 L 4B7 L 4B8 L 4B9 L 4B10 L 4B11 and L 4B12 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 4B4 L 4B5 L 4B6 L 4B7 L 4B8 L 4B9 L 4B10 L 4B11 and L 4B12 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 4B4 L 4B5 L 4B6 L 4B7 L 4B8 L 4B9 L 4B10 L 4B11 and L 4B12 Each of them is an unsubstituted C. 1-10 Alkylene. In some embodiments, L 4B4 L 4B5 L 4B6 L 4B7 L 4B8 L 4B9 L 4B10 L 4B11 and L 4B12 Each of them is independently composed of one, two, three, four, five, six, seven, eight, nine or ten PEG repeats.

[0226] In some implementations, L 4C3 L 4C4 L 4C5 L 4C6 L 4C7 and L 4C8 Each of them is an independent single bond. In some implementations, L 4C3 L4C4 L 4C5 L 4C6 L 4C7 and L 4C8 Each of them is independently a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms. In some embodiments, L 4C3 L 4C4 L 4C5 L 4C6 L 4C7 and L 4C8 Each of them independently (It can be attached in either direction).

[0227] 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 Applications 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; U.S. 2012 / 0035115; U.S. 2012 / 0230938; U.S. 2005 / 0164235; U.S. 2006 / 0183886; U.S. 2012 / 0136042; U.S. 2012 / 0095075; U.S. 2013 / 0109817; U.S.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. .

[0228] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , , , , 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.

[0229] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , 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.

[0230] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , , , , , , , 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.

[0231] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , , , , , , , 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.

[0232] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , , , , , , , , , , , , 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.

[0233] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , , , , , , , , , , , 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.

[0234] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , , , , , , 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.

[0235] In some embodiments, the connector comprises a structure selected from the following: , , , , , , , , , , , , , , , , , , , 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.

[0236] In some embodiments, the connector comprises a structure selected from the following: 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.

[0237] In some embodiments, the connector comprises a structure selected from the following: , 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.

[0238] In some embodiments, the connector comprises a structure selected from the following: 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.

[0239] In some embodiments, the connector comprises a structure selected from the following: 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.

[0240] In some implementations, the connector includes a structure: , where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0241] In some implementations, the connector includes a structure: , 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.

[0242] ligands In the oligonucleotides disclosed herein, if present, then A 1 A 2 A 3 and A 4 Each instance of each of them can be an independent group of the ligand.

[0243] Where valence permits, two or more ligands can attach to the same or different sites on the corresponding junction. For example, when When y1 is 2, A, under the condition that the oxidation state allows, 1 Two instances can be attached to L 1 The same position or L 1 Two different positions.

[0244] In some implementations, if present, then A 1 At least one instance is a ligand group. In some embodiments, if present, then A 1 At least two instances are groups that are ligands. In some embodiments, if present, then A 2 At least one instance is a ligand group. In some embodiments, if present, then A 2 At least two instances are groups that are ligands. In some embodiments, if present, then A 3 At least one instance is a ligand group. In some embodiments, if present, then A 3 At least two instances are groups that are ligands. In some embodiments, if present, then A 4 At least one instance is a ligand group. In some embodiments, if present, then A 4 At least two instances are groups that are ligands. 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... 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.

[0245] 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.

[0246] 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).

[0247] 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: , , , , , , 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 -SR40 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 them is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or 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 21DOptionally 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 24DEach 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.

[0248] 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 -OR 31 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 4For -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.

[0249] 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 37 R 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 R38 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.

[0250] In some implementations, Y is NH or O. In some implementations, Y is O.

[0251] 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.

[0252] 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 .

[0253] In some implementation schemes, R 11 and R 13Each 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 12 For –CH3. In some implementations, 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. In some embodiments, R 16 It is –NHCH3.

[0254] 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.

[0255] In some implementation schemes, R 20 It is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 20 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, R22 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.

[0256] 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.

[0257] In some embodiments, at least one group of the TrkB ligand has the formula , , , , , , , , or .

[0258] In some embodiments, at least one group of the TrkB ligand has the following formula: or .

[0259] In some embodiments, at least one group of the TrkB ligand has the following formula: , , or or .

[0260] 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.

[0261] In some implementations, at least one α4β 1 / 7 Integrin ligands are compounds of the following formula: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Each instance of R is .

[0262] In some implementations, 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 R4Z Each of them is independently hydrogen, halogen, optionally substituted alkyl, or optionally substituted –O–alkyl.

[0263] 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.

[0264] In some implementations, at least one α4β 1 / 7 Integrin ligands have the following formula: .

[0265] In some implementations, 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.

[0266] 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.

[0267] In some implementations, 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 7ZIt can be hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heteroaryl.

[0268] 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.

[0269] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula: , , , or ; n2Z can be 0, 1, 2, or 3.

[0270] In some implementations, n²Z is 0 or 1. In some implementations, n²Z is 0.

[0271] In some implementations, 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.

[0272] In some implementations, n3Z is 0 or 1. In some implementations, n3Z is 0.

[0273] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula: , , , or ; R 8Z R 9Z R 10Z and R11Z 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 hydrogen, 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.

[0274] 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.

[0275] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula: or .

[0276] In some implementations, 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–.

[0277] 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–.

[0278] In some implementations, 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.

[0279] 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 19ZEach instance is independently H or an unsubstituted alkyl group. In some embodiments, n4Z is 1. In some embodiments, n4Z is 2.

[0280] In some implementations, 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.

[0281] 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.

[0282] In some implementations, 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.

[0283] 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.

[0284] In some implementations, 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.

[0285] 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.

[0286] In some implementations, α4β 1 / 7 At least one group of the integrin ligand has the following formula:

[0287] 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; R27Z 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.

[0288] 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.

[0289] In some implementations, 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.

[0290] In some implementation schemes, R 28Z H, –CH2NHCOR 30Zor –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.

[0291] In some embodiments, 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)R19YD –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.

[0292] 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 19Y It is hydrogen, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group.

[0293] 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: or .

[0294] In some embodiments, at least one CB1 ligand is a compound of the following formula: , in: R 17Y For hydrogen, -SO n17Y R17YA –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.

[0295] 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 17YFor –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.

[0296] In some embodiments, at least one group of the CB1 ligand has the following formula: .

[0297] In some embodiments, at least one CB1 ligand is a compound of the following formula: In some embodiments, at least one group of the CB1 ligand has the following formula: .

[0298] In some embodiments, at least one CB1 ligand is 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)NR7YB 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.

[0299] 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 7YIt 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.

[0300] In some embodiments, at least one group of the CB1 ligand has the following formula: .

[0301] In some embodiments, 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.

[0302] 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.

[0303] In some embodiments, at least one group of the CB1 ligand has the following formula: .

[0304] In some embodiments, at least one CB1 ligand is a compound of the following formula: , , or .

[0305] In some embodiments, at least one NMDA receptor ligand is a compound of the following formula: , , , , , , , , , , or .

[0306] 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: .

[0307] 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.

[0308] In some embodiments, the oligonucleotide comprises at least two ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 ligands). In some embodiments, the oligonucleotide comprises two ligands. In some embodiments, the oligonucleotide comprises three ligands. In some embodiments, the oligonucleotide comprises at least one ligand conjugated to the 5′ end. In some embodiments, the oligonucleotide comprises at least one ligand conjugated to the 3′ end. In some embodiments, the oligonucleotide comprises at least one ligand conjugated to the 5′ end and at least one ligand conjugated to the 3′ end. In some embodiments, the oligonucleotide comprises at least two ligands conjugated to the 5′ end. In some embodiments, the oligonucleotide comprises at least two ligands conjugated to the 3′ end. In some embodiments, the oligonucleotide comprises at least two ligands conjugated to the 5′ end and at least two ligands conjugated to the 3′ end. In some embodiments, the oligonucleotide comprises at least one ligand conjugated to a nucleobase. In some embodiments, the oligonucleotide comprises at least two ligands conjugated to a nucleobase. In some embodiments, the oligonucleotide comprises at least one ligand conjugated to the 2′ position of the nucleoside. In some embodiments, the oligonucleotide comprises at least two ligands conjugated to the 2′ position of the nucleoside.

[0309] 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 ligands belong to the same ligand type, they bind to the same target. In some embodiments, at least one ligand is a small molecule, peptide, or protein.

[0310] In some implementation schemes, A 1 Each instance is a group of the same ligand type. In some embodiments, A 1 Each instance is the same group of the ligand. In some embodiments, A 1 At least two instances are groups of different ligand types. In some embodiments, A 1 At least two instances are groups of different ligands of the same ligand type. In some embodiments, A 1 At least two instances are groups of different ligands of different ligand types.

[0311] In some implementation schemes, A 2 Each instance is a group of the same ligand type. In some embodiments, A 2 Each instance is the same group of the ligand. In some embodiments, A 2 At least two instances are groups of different ligand types. In some embodiments, A 2 At least two instances are groups of different ligands of the same ligand type. In some embodiments, A 2 At least two instances are groups of different ligands of different ligand types.

[0312] In some implementation schemes, A 3 Each instance is a group of the same ligand type. In some embodiments, A 3 Each instance is the same group of the ligand. In some embodiments, A 3 At least two instances are groups of different ligand types. In some embodiments, A 3 At least two instances are groups of different ligands of the same ligand type. In some embodiments, A 3 At least two instances are groups of different ligands of different ligand types.

[0313] In some implementation schemes, A 4 Each instance is a group of the same ligand type. In some embodiments, A 4Each 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.

[0314] In some implementation schemes, A 1 At least one instance and A 2 At least one instance is a group of the same ligand type. In some embodiments, A 1 At least one instance and A 2 At least one instance is the same group as the ligand. In some embodiments, A 1 At least one instance and A 2 At least one instance is a group of different ligand types. In some embodiments, A 1 At least one instance and A 2 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 1 At least one instance and A 2 At least one instance is a group of different ligands of different ligand types. In some embodiments, A 1 At least one instance and A 3 At least one instance is a group of the same ligand type. In some embodiments, A 1 At least one instance and A 3 At least one instance is the same group as the ligand. In some embodiments, A 1 At least one instance and A 3 At least one instance is a group of different ligand types. In some embodiments, A 1 At least one instance and A 3 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 1 At least one instance and A 3 At least one instance is a group of different ligands of different ligand types. In some embodiments, A 1 At least one instance and A 4 At least one instance is a group of the same ligand type. In some embodiments, A 1 At least one instance and A 4 At least one instance is the same group as the ligand. In some embodiments, A 1 At least one instance and A 4At least one instance is a group of different ligand types. In some embodiments, A 1 At least one instance and A 4 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 1 At least one instance and A 4 At least one instance is a group of different ligands of different ligand types. In some embodiments, A 2 At least one instance and A 3 At least one instance is a group of the same ligand type. In some embodiments, A 2 At least one instance and A 3 At least one instance is the same group as the ligand. In some embodiments, A 2 At least one instance and A 3 At least one instance is a group of different ligand types. In some embodiments, A 2 At least one instance and A 3 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 2 At least one instance and A 3 At least one instance is a group of different ligands of different ligand types. In some embodiments, A 2 At least one instance and A 4 At least one instance is a group of the same ligand type. In some embodiments, A 2 At least one instance and A 4 At least one instance is the same group as the ligand. In some embodiments, A 2 At least one instance and A 4 At least one instance is a group of different ligand types. In some embodiments, A 2 At least one instance and A 4 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 2 At least one instance and A 4 At least one instance is a group of different ligands of different ligand types. In some embodiments, A 3 At least one instance and A 4 At least one instance is a group of the same ligand type. In some embodiments, A 3 At least one instance and A 4 At least one instance is the same group as the ligand. In some embodiments, A 3 At least one instance and A 4 At least one instance is a group of different ligand types. In some embodiments, A3 At least one instance and A 4 At least one instance is a group of different ligands of the same ligand type. In some embodiments, A 3 At least one instance and A 4 At least one instance is a group of different ligands of different ligand types.

[0315] In some implementation schemes, A 1 A 2 A 3 and A 4 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. 1 A 2 A 3 and A 4 Each instance is a different group of the ligand. In some embodiments, A 1 A 2 A 3 and A 4 Each instance is the same group of TrkB. In some embodiments, A 1 A 2 A 3 and A 4 Each instance is the same group of the CB1 receptor ligand. In some embodiments, A 1 A 2 A 3 and A 4 Each instance is α4β 1 / 7 The same group as the integrin receptor ligand. In some embodiments, A 1 A 2 A 3 and A 4 Each instance is the same group of the NMDA receptor ligand. In some embodiments, A 1 A 2 A 3 and A 4 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.

[0316] lipids In the oligonucleotides disclosed herein, if present, then A 1 A 2 A 3 and A 4 Each instance of [a group] is independently a ligand or lipid group. In some embodiments, A, if present, [is...]. 1At least one instance is a lipid group. In some embodiments, if present, then A 2 At least one instance is a lipid group. In some embodiments, if present, then A 3 At least one instance is a lipid group. In some embodiments, if present, then A 4 At least one instance is a lipid group. In some embodiments, if present, then A 1 A 2 A 3 and A 4 At least one instance is a lipid group independently.

[0317] In some implementation schemes, A 1 Each instance is the same group of lipid. In some embodiments, A 2 Each instance is the same group of lipid. In some embodiments, A 3 Each instance is the same group of lipid. In some embodiments, A 4 Each instance is the same group of lipid.

[0318] In some implementation schemes, A 1 At least one instance and A 2 At least one instance is the same group as a lipid. In some embodiments, A 1 At least one instance and A 3 At least one instance is the same group as a lipid. In some embodiments, A 1 At least one instance and A 4 At least one instance is the same group as a lipid. In some embodiments, A 2 At least one instance and A 3 At least one instance is the same group as lipids. In some embodiments, A 2 At least one instance and A 4 At least one instance is the same group as a lipid. In some embodiments, A 3 At least one instance and A 4 At least one instance is the same group as lipids.

[0319] In some implementation schemes, A 1 A 2 A 3 and A 4 Each instance is the same group of lipid. In some embodiments, A is compared to any other group of lipid in the oligonucleotide. 1 A 2 A 3 and A 4Each instance is a different group of lipid.

[0320] 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.

[0321] 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 7-36 Alkenyl, 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 16-28 The 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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: .

[0326] In some embodiments, at least one lipid is lithocholic acid. In some embodiments, at least one group of the lipid has the following formula: , In some embodiments, at least one group of the lipid has the following formula: , Optionally, the unsubstituted C 7-30 Alkyl groups are unbranched, unsubstituted C14 groups. 11-23 Alkyl groups, and unsubstituted C4 groups 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: .

[0327] In some embodiments, at least one lipid is an isoprene, quinone, hydroquinone, polyisoprene alcohol, or hopane.

[0328] In some embodiments, at least one lipid is an acylamino sugar, an acylamino glycosyl, an acyltrehalose, or an acyltrehalose.

[0329] 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.

[0330] Other oligonucleotide chain modifications 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.

[0331] 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.

[0332] Sugar modification 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.

[0333] 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.

[0334] 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) hSCH3 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”).

[0335] 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 oligon...

Claims

1. An oligonucleotide comprising a modified oligonucleotide chain, said modified oligonucleotide chain comprising: S1 examples of modified nucleosides that independently contain a portion of Formula I: (I); and The v1 instances of the nucleoside intermolecular heads of the modified oligonucleotide chains were independently... Substitute; in: s1 can be 1, 2, 3, 4, 5, or 6; N 1 Each instance is independently a group or bond of nucleobases; Each instance of t1 is independently 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a ligand or lipid group, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2R b –OS(=O)2OR b –OS(=O)2SR b –OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b –NR b C(=O)OR b –NR b C(=O)SR b –NR b C(=O)N(R b )2、–NR b S(=O)R b –NR b S(=O)OR b –NR b S(=O)SR b –NR b S(=O)N(R b )2、–NR b S(=O)2R b –NR b S(=O)2OR b –NR b S(=O)2SR b –NR b S(=O)2N(R b )2、–Si(R b 3、–Si(R) b )2OR b 、–Si(R b (OR) b )2、–Si(OR b 3. –OSi(R) b 3. –OSi(R) b )2OR b –OSi(R b (OR) b )2 or –OSi(OR b )3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R b Each instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; when When y2 of an instance is 0, its L 2 For –OH, –OR h , halogen, –CN or –N3; or when When the instance's y2 is 1, 2, 3, 4, 5, or 6, its L 2 For connectors; R h Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; When a portion of Formula I is part of an instance of the modified nucleoside at the 5' end or internal position of the modified oligonucleotide chain: its y3 is 0, and its L 3 For nucleoside indirect linking; or When a portion of Formula I is part of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain: When its y3 is 0: its L 3 For –OH, –OR d halogen, –CN or –N3, and R d Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group; or When its y3 is 1, 2, 3, 4, 5, or 6, its L3 For connectors; v1 is 0, 1, 2, 3, 4, 5, or 6; When it exists, L A and L 4 Each instance is a connector independently; When present, each instance of y4 is independently 1, 2, 3, 4, 5, or 6; and When it exists, A 4 Each instance is independently a ligand or lipid group.

2. A nucleoside comprising a portion of the following formula: ， in: N 1 A group or bond that is a nucleobase; t1 is 1, 2, or 3; Each instance of y1, y2, and y3 is independently 0, 1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; If it exists, then A 1 A 2 and A 3 Each instance is independently a ligand or lipid group, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand; when When y1 of an instance is 0, its L 1 Hydrogen, halogen, 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, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2R b –OS(=O)2OR b –OS(=O)2SR b –OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b –NR b C(=O)OR b –NR b C(=O)SR b –NR b C(=O)N(R b )2、–NR b S(=O)R b –NR b S(=O)OR b –NR b S(=O)SR b –NR b S(=O)N(R b )2、–NR b S(=O)2R b –NR b S(=O)2OR b –NR b S(=O)2SR b –NR b S(=O)2N(R b )2、–Si(R b 3、–Si(R) b )2OR b 、–Si(R b (OR) b )2、–Si(OR b 3. –OSi(R) b 3. –OSi(R) b )2OR b –OSi(R b (OR) b )2 or –OSi(OR b )3; or when When the instance y1 is 1, 2, 3, 4, 5, or 6, its L 1 For connectors; R b Each instance is independently hydrogen, 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, oxygen-protecting group when attached to an oxygen atom, or sulfur-protecting group when attached to a sulfur atom, or two R groups attached to the same intercalary atom. b Examples are linked together by intermediary atoms to form substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl rings; When y2 is 0, L 2 For –OH, –OR h Halogen, –CN or –N3; or when y2 is 1, 2, 3, 4, 5 or 6, L 2 For connectors; R h For substituted or unsubstituted C 1-6 Alkyl or oxygen protecting group; When y3 is 0, L 3 For –OH, –OR d Halogen, –CN or –N3; or when y3 is 1, 2, 3, 4, 5 or 6, L 3 For connectors; and R d For substituted or unsubstituted C 1-6 Alkyl or oxygen protecting group.

3. The oligonucleotide of claim 1 or the nucleoside of claim 2, wherein, if present, A 1 A 2 and A 3 Each instance is independently a group of central nervous system receptor ligands or lipids, provided that A 1 A 2 and A 3 At least one instance is a group of a central nervous system receptor ligand.

4. The nucleoside according to claim 2, wherein the nucleoside has the following formula: ， Or a pharmaceutically acceptable salt or prodrug, wherein E 1 For –OP(=O)(OR) b )2、–SP(=O)(OR b )2、–OP(=O)(OR b (SR) b –OR b –SR b –SSR b –N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2R b –OS(=O)2OR b –OS(=O)2SR b –OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b –NR b C(=O)OR b –NR b C(=O)SR b –NR b C(=O)N(R b )2、–NR b S(=O)R b –NR b S(=O)OR b –NR b S(=O)SR b –NR b S(=O)N(R b )2、–NR b S(=O)2R b –NR b S(=O)2OR b –NR b S(=O)2SR b Or –NR b S(=O)2N(R b )2.

5. The oligonucleotide of claim 1, wherein the oligonucleotide is a single-stranded oligonucleotide.

6. The oligonucleotide of claim 1, wherein the oligonucleotide is a double-stranded oligonucleotide comprising a sense oligonucleotide chain and an antisense oligonucleotide chain.

7. The oligonucleotide of any one of claims 1-6, wherein the modified oligonucleotide chain is the positive oligonucleotide chain.

8. The oligonucleotide of any one of claims 1-7, wherein the modified oligonucleotide chain is the antisense oligonucleotide chain.

9. The oligonucleotide of any one of claims 1-8, wherein the nucleobases of the antisense oligonucleotide chain are complementary to the nucleobases of the sense oligonucleotide chain.

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

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

12. The oligonucleotide of any one of claims 1-11, wherein the oligonucleotide is siRNA.

13. The oligonucleotide of any one of claims 1-12, wherein the modified oligonucleotide chain comprises between 6 and 100 nucleosides.

14. The oligonucleotide of any one of claims 1-13, wherein the modified oligonucleotide chain comprises between 10 and 30 nucleosides.

15. The oligonucleotide of any one of claims 1-14, wherein the modified oligonucleotide chain comprises between 14 and 23 nucleosides.

16. The oligonucleotide of any one of claims 1-15, wherein s1 is 1, and the modified nucleoside is located at the 5' end of the modified oligonucleotide chain.

17. The oligonucleotide of any one of claims 1-16, wherein s1 is 1, and the modified nucleoside is located inside the modified oligonucleotide chain.

18. The oligonucleotide of any one of claims 1-17, wherein s1 is 1, and the modified nucleoside is located at the 3' end of the modified oligonucleotide chain.

19. The oligonucleotide of any one of claims 1-18, wherein: s1 is 2; One example of the modified nucleoside is located at the 5' end of the modified oligonucleotide chain; and Another instance of the modified nucleoside is located inside the modified oligonucleotide chain.

20. The oligonucleotide of any one of claims 1-19, wherein: s1 is 2; One example of the modified nucleoside is located at the 3' end of the modified oligonucleotide chain; and Another instance of the modified nucleoside is located inside the modified oligonucleotide chain.

21. The oligonucleotide of any one of claims 1-20, wherein: s1 is 2; and Each instance of the modified nucleoside is located within the modified oligonucleotide chain.

22. The oligonucleotide of any one of claims 1-21, wherein: At least one instance of the internal position is the nth nucleotide of the modified oligonucleotide chain, counted from the 5' end; and Where the number of nucleosides in the modified oligonucleotide chain is permissible, n is an integer between 2 and 20 (inclusive).

23. The oligonucleotide of any one of claims 1-22, wherein s1 is 3, 4, 5 or 6.

24. The oligonucleotide or nucleoside according to any one of claims 1-23, wherein N 1 At least one instance is a nucleobase group.

25. The oligonucleotide or nucleoside according to any one of claims 1-24, wherein N 1 At least one instance is a group of adenine, cytosine, guanine or uracil.

26. The oligonucleotide or nucleoside according to any one of claims 1-25, wherein N 1 At least one instance of it is a key.

27. The oligonucleotide or nucleoside according to any one of claims 1-26, wherein at least one example of t1 is 1.

28. The oligonucleotide or nucleoside according to any one of claims 1-27, wherein at least one instance of y1 is 0.

29. The oligonucleotide or nucleoside according to any one of claims 1-28, wherein The instance y1 is 0, and its L 1 For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Heteroalkyl, substituted or unsubstituted monocyclic carbocyclic, substituted or unsubstituted monocyclic heterocyclic, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2R b –OS(=O)2OR b –OS(=O)2SR b –OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b , –NR b C(=O)OR b , –NR b C(=O)SR b , –NR b C(=O)N(R b )2, –NR b S(=O)R b , –NR b S(=O)OR b , –NR b S(=O)SR b , –NR b S(=O)N(R b )2, –NR b S(=O)2R b , –NR b S(=O)2OR b , –NR b S(=O)2SR b or –NR b S(=O)2N(R b )2.

30. The oligonucleotide or nucleoside according to any one of claims 1-29, wherein The instance y1 is 0, and its L 1 For hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Heteroalkyl, –CN, –OR b –SCN, –SR b –SSR b –N3, –NO, –N(R) b )2、–NO2、–C(=O)R b –C(=O)OR b –C(=O)SR b –C(=O)N(R) b )2、–S(=O)R b –S(=O)OR b –S(=O)SR b –S(=O)N(R) b )2、–S(=O)2R b –S(=O)2OR b –S(=O)2SR b –S(=O)2N(R) b )2、–OC(=O)R b –OC(=O)OR b –OC(=O)SR b –OC(=O)N(R) b )2、–OS(=O)R b –OS(=O)OR b –OS(=O)SR b –OS(=O)N(R) b )2、–OS(=O)2R b –OS(=O)2OR b –OS(=O)2SR b –OS(=O)2N(R) b )2、–ON(R b )2、–SC(=O)R b –SC(=O)OR b –SC(=O)SR b –SC(=O)N(R) b )2、–NR b C(=O)R b –NR b C(=O)OR b –NR b C(=O)SR b 、 –NR b C(=O)N(R b )2、 –NR b S(=O)R b 、 –NR b S(=O)OR b 、 –NR b S(=O)SR b 、 –NR b S(=O)N(R b )2、 –NR b S(=O)2R b 、 –NR b S(=O)2OR b 、 –NR b S(=O)2SR b or –NR b S(=O)2N(R b )2。 31. The oligonucleotide or nucleoside according to any one of claims 1-30, wherein at least one example of y1 is 1.

32. The oligonucleotide or nucleoside according to any one of claims 1-31, wherein at least one example of y1 is 2.

33. The oligonucleotide or nucleoside according to any one of claims 1-32, wherein at least one example of y1 is 3, 4, 5 or 6.

34. The oligonucleotide or nucleoside according to any one of claims 1-33, wherein A 1 Each instance is a group of the ligand.

35. The oligonucleotide or nucleoside according to any one of claims 1-34, wherein: A 1 At least one instance is a group of a ligand; and A 1 At least one instance is a lipid group.

36. The oligonucleotide or nucleoside according to any one of claims 1-35, wherein A 1 Each instance is a lipid group.

37. The oligonucleotide or nucleoside according to any one of claims 1-36, wherein The instance y1 is 1, 2, 3, 4, 5, or 6, and its L 1 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.

38. The oligonucleotide or nucleoside according to any one of claims 1-37, wherein The instance y1 is 1, 2, 3, 4, 5, or 6, and its L 1 For substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 alkenyl, substituted or unsubstituted C 7-70 Heteroalkyl, or substituted or unsubstituted C 7-70 Hesperyl; Optionally, where the valence allows, the C 7-70 Alkylene, C 7-70 imidene group, C 7-70 Heteroalkyl or C 7-70 One, two, three, or four main chain atoms of the heterocyclic group are independently replaced by a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group.

39. The oligonucleotide or nucleoside according to any one of claims 1-38, wherein The instance y1 is 1, 2, 3, 4, 5, or 6, and its L 1 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, two, three, or four main chain atoms of a heteroalkyl group are independently substituted or unsubstituted with a carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

40. The oligonucleotide or nucleoside according to any one of claims 1-39, wherein: If it exists, then At least one instance of it has the following formula: ； –L 1A1 –L 1A2 –, –L 1A3 –L 1A4 –, –L 1A5 –L 1A6 – and –L 1A7 –L 1A8 Each of – and –L 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<00004​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​)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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 1B1 and L 1B2 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 1C1 It 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 1A Attach to A 1 .

41. The oligonucleotide or nucleoside according to any one of claims 1-40, wherein its L 1 It has the following formula: 。 42. The oligonucleotide or nucleoside according to any one of claims 1-41, wherein its L 1 It has the following formula: or .

43. The oligonucleotide or nucleoside according to any one of claims 1-42, wherein The instance y1 is 1, 2, 3, 4, 5, or 6, and its L 1 For substituted or unsubstituted C 7-70 Heteroalkyl groups.

44. The oligonucleotide or nucleoside according to any one of claims 1-43, wherein... The instance y1 is 1, 2, 3, 4, 5, or 6, and its L 1 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: Its L 1 The number of main chain atoms is between 7 and 70 (inclusive); and Its L 1 It does not include O–O, O–N, N–O, or N–N.

45. The oligonucleotide or nucleoside according to any one of claims 1-44, wherein The instance y1 is 1, 2, 3, 4, 5, or 6, and its L 1 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: Its L 1 The number of main chain atoms is between 7 and 70 (inclusive); Its L 1 It does not contain O–O, O–N, N–O, or N–N; and Its L 1 –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

46. ​​The oligonucleotide or nucleoside according to any one of claims 1-45, wherein at least one instance of y2 is 0.

47. The oligonucleotide or nucleoside according to any one of claims 1-46, wherein The instance y2 is 0, and its L 2 It can be –OH, –OCH3, or F.

48. The oligonucleotide or nucleoside according to any one of claims 1-47, wherein at least one instance of y2 is 1.

49. The oligonucleotide or nucleoside according to any one of claims 1-48, wherein at least one example of y2 is 2.

50. The oligonucleotide or nucleoside according to any one of claims 1-49, wherein at least one example of y2 is 3, 4, 5 or 6.

51. The oligonucleotide or nucleoside according to any one of claims 1-50, wherein A 2 Each instance is a group of the ligand.

52. The oligonucleotide or nucleoside according to any one of claims 1-51, wherein: A 2 At least one instance is a group of a ligand; and A 2 At least one instance is a lipid group.

53. The oligonucleotide or nucleoside according to any one of claims 1-52, wherein A 2 Each instance is a lipid group.

54. The oligonucleotide or nucleoside according to any one of claims 1-53, wherein The instances of y2 are 1, 2, 3, 4, 5, or 6, and their L 2 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.

55. The oligonucleotide or nucleoside according to any one of claims 1-54, wherein The instances of y2 are 1, 2, 3, 4, 5, or 6, and their L 2 For substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 alkenyl, substituted or unsubstituted C 7-70 Heteroalkyl, or substituted or unsubstituted C 7-70 Hesperyl; Optionally, where the valence allows, the C 7-70 Alkylene, C 7-70 imidene group, C 7-70 Heteroalkyl or C 7-70 One, two, or three main chain atoms of the heterocyclic group are independently replaced by a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

56. The oligonucleotide or nucleoside according to any one of claims 1-55, wherein The instances of y2 are 1, 2, 3, 4, 5, or 6, and their L 2 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, two, or three main chain atoms of a heteroalkyl group are independently substituted or unsubstituted with a carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

57. The oligonucleotide or nucleoside according to any one of claims 1-56, wherein At least one instance of it has the following formula: .

58. The oligonucleotide or nucleoside according to any one of claims 1-57, wherein: At least one instance of it has the following formula: ； –L 2A1 –L 2A2 –, –L 2A3 –L 2A4 –, –L 2A5 –L 2A6 – and –L 2A7 –L 2A8 Each of – and –L 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 2B1 and L 2B2 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 2C1 It 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 2A Attach to A 2 .

59. The oligonucleotide or nucleoside according to any one of claims 1-58, wherein At least one instance of it has the following formula: 。 60. The oligonucleotide or nucleoside according to any one of claims 1-59, wherein At least one instance of it has the following formula: 。 61. The oligonucleotide or nucleoside according to any one of claims 1-60, wherein: At least one instance of it has the following formula: ； –L 2A9 –L 2A10 –、–L 2A11 –L 2A12 –、–L 2A13 –L 2A14 –、–L 2A15 –L 2A16 –、–L 2A17 –L 2A18 –、–L 2A19 –L 2A20 –、–L 2A21 –L 2A22 – and – L 2A23 –L 2A24 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 2B3 L 2B4 L 2B5 L 2B6 L 2B7 and L 2B8 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 2C2 and L 2C3 Each of them is independently a single bond, a substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms, or a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms; Key C 2B Attach to A 2 The first instance; and Key C 2C Attach to A 2 The second instance.

62. The oligonucleotide or nucleoside according to any one of claims 1-61, wherein At least one instance of it has the following formula: 。 63. The oligonucleotide or nucleoside according to any one of claims 1-62, wherein At least one instance of it has the following formula: 。 64. The oligonucleotide or nucleoside according to any one of claims 1-63, wherein The instances of y2 are 1, 2, 3, 4, 5, or 6, and their L 2 For substituted or unsubstituted C 7-70 Heteroalkyl groups.

65. The oligonucleotide or nucleoside according to any one of claims 1-64, wherein... The instances of y2 are 1, 2, 3, 4, 5, or 6, and their L 2 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: Its L 2 The number of main chain atoms is between 7 and 70 (inclusive); and Its L 2 It does not include O–O, O–N, N–O, or N–N.

66. The oligonucleotide or nucleoside according to any one of claims 1-65, wherein The instances of y2 are 1, 2, 3, 4, 5, or 6, and their L 2 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: Its L 2 The number of main chain atoms is between 7 and 70 (inclusive); Its L 2 It does not contain O–O, O–N, N–O, or N–N; and Its L 2 –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

67. The oligonucleotide or nucleoside according to any one of claims 1-66, wherein at least one instance of y3 is 1.

68. The oligonucleotide or nucleoside according to any one of claims 1-67, wherein at least one instance of y3 is 2.

69. The oligonucleotide or nucleoside according to any one of claims 1-68, wherein at least one example of y3 is 3, 4, 5 or 6.

70. The oligonucleotide or nucleoside according to any one of claims 1-69, wherein A 3 Each instance is a group of the ligand.

71. The oligonucleotide or nucleoside according to any one of claims 1-70, wherein: A 3 At least one instance is a group of a ligand; and A 3 At least one instance is a lipid group.

72. The oligonucleotide or nucleoside according to any one of claims 1-71, wherein A 3 Each instance is a lipid group.

73. The oligonucleotide according to any one of claims 1-72, wherein: The portion of Formula I is a portion of an example of the modified nucleoside at the 5' end of the modified oligonucleotide chain; Its y3 is 0; and Its L 3 It is a nucleoside junction, such as a phosphate nucleoside junction, a thiophosphate nucleoside junction, or a methylphosphonate nucleoside junction.

74. The oligonucleotide according to any one of claims 1-73, wherein: The portion of Formula I is a portion of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain; Its y3 is 0; Its L 3 For –OH, –OR d , halogen, –CN or –N3; and R d Each instance is independently of substituted or unsubstituted C. 1-6 Alkyl or oxygen protecting group.

75. The oligonucleotide or nucleoside according to any one of claims 1-74, wherein L 3 It can be –OH, –OCH3, or F.

76. The oligonucleotide according to any one of claims 1-75, wherein: The portion of Formula I is a portion of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain; Its y3 is 1, 2, 3, 4, 5, or 6; and Its L 3 For connectors.

77. The oligonucleotide or nucleoside according to any one of claims 1-76, wherein its L 3 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.

78. The oligonucleotide or nucleoside according to any one of claims 1-77, wherein its L 3 For substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 alkenyl, substituted or unsubstituted C 7-70 Heteroalkyl, or substituted or unsubstituted C 7-70 Hesperyl; Optionally, where the valence allows, the C 7-70 Alkylene, C 7-70 imidene group, C 7-70 Heteroalkyl or C 7-70 One, two, or three main chain atoms of the heterocyclic group are independently replaced by a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

79. The oligonucleotide or nucleoside according to any one of claims 1-78, wherein its L 3 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, two, or three main chain atoms of a heteroalkyl group are independently substituted or unsubstituted with a carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

80. The oligonucleotide or nucleoside according to any one of claims 1-79, wherein At least one instance of it has the following formula: .

81. The oligonucleotide or nucleoside according to any one of claims 1-80, wherein: At least one instance of it has the following formula: ； –L 3A1 –L 3A2 –, –L 3A3 –L 3A4 –, –L 3A5 –L 3A6 – and –L 3A7 –L 3A8 Each of – and –L 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 3B1 and L 3B2 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 3C1 It 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 3A Attach to A 3 .

82. The oligonucleotide or nucleoside according to any one of claims 1-81, wherein At least one instance of it has the following formula: 。 83. The oligonucleotide or nucleoside according to any one of claims 1-82, wherein At least one instance of it has the following formula: 。 84. The oligonucleotide or nucleoside according to any one of claims 1-83, wherein its L 3 For substituted or unsubstituted C 7-70 Heteroalkyl groups.

85. The oligonucleotide or nucleoside according to any one of claims 1-84, wherein its L 3 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: Its L 3 The number of main chain atoms is between 7 and 70 (inclusive); and Its L 3 It does not include O–O, O–N, N–O, or N–N.

86. The oligonucleotide or nucleoside according to any one of claims 1-85, wherein its L 3 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: Its L 3 The number of main chain atoms is between 7 and 70 (inclusive); Its L 3 It does not contain O–O, O–N, N–O, or N–N; and Its L 3 –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

87. The oligonucleotide or nucleoside according to any one of claims 1-86, wherein: Its y3 is 1; That for ; –L 3A1 –L 3A2 –, –L 3A3 –L 3A4 –, –L 3A5 –L 3A6 – and –L 3A7 –L 3A8 Each of – and –L 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 [[ID=四十八]]C(=NR[[ID=四十九]] a [[ID=五十]]O–, –NR[[ID=五十一]] a [[ID=五十二]]S(=O)O–, –NR[[ID=五十三]] a [[ID=五十四]]S(=O)2O–, –OC(=O)NR[[ID=五十五]] a [[ID=五十六]]–, –OC(=NR[[ID=五十七]] a [[ID=五十八]]NR[[ID=五十九]] a [[ID=六十]]–, –OS(=O)NR[[ID=六十一]] a [[ID=六十二]]–, –OS(=O)2NR[[ID=六十三]] a [[ID=六十四]]–, –NR[[ID=六十五]] a [[ID=六十六]]C(=O)NR[[ID=六十七]] a [[ID=六十八]]–, –NR[[ID=六十九]] a [[ID=七十]]C(=NR[[ID=七十一]] a [[ID=七十二]]NR[[ID=七十三]] a [[ID=七十四]]–, –NR[[ID=七十五]] a [[ID=七十六]]S(=O)NR[[ID=七十七]] a [[ID=七十八]]–, –NR[[ID=七十九]] a [[ID=八十]]S(=O)2NR[[ID=八十一]] a [[ID=八十二]]–, –C(=O)–, –C(=NR[[ID=八十三]] a [[ID=八十四]])–, –S(=O)–, –S(=O)2–, –OP(=O)(OR[[ID=八十五]] 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 3B1 and L 3B2 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 3C1 It is a single bond, a substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms, or a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms.

88. The oligonucleotide or nucleoside according to any one of claims 1-87, wherein: Its y3 is 1; and That for .

89. The oligonucleotide or nucleoside according to any one of claims 1-88, wherein: Its y3 is 2; That for ; –L 3A9 –L 3A10 –、–L 3A11 –L 3A12 –、–L 3A13 –L 3A14 –、–L 3A15 –L 3A16 –、–L 3A17 –L 3A18 –、–L 3A19 –L 3A20 – and – L 3A21 –L 3A22 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 3B3 L 3B4 L 3B5 L 3B6 and L 3B7 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; and L 3C2 and L 3C3 Each of them is independently 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.

90. The oligonucleotide or nucleoside according to any one of claims 1-89, wherein: Its y3 is 2; and That for , or 。 91. The oligonucleotide of any one of claims 1-90, wherein v1 is 0.

92. The oligonucleotide of any one of claims 1-91, wherein v1 is 1.

93. The oligonucleotide of any one of claims 1-92, wherein v1 is 2, 3, 4, 5 or 6.

94. The oligonucleotide of any one of claims 1-93, wherein, when present, At least one instance is located between the first and second nucleotides of the modified oligonucleotide chain, counted from the 5' end.

95. The oligonucleotide according to any one of claims 1-94, wherein: When it exists At least one instance is located between the nth nucleotide and the (n+1)th nucleotide, counting from the 5' end of the modified oligonucleotide chain; and Where the number of nucleosides in the modified oligonucleotide chain is permissible, n is an integer between 2 and 20 (inclusive).

96. The oligonucleotide according to any one of claims 1-95, wherein: When it exists, 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, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heteroalkenyl group, a substituted or unsubstituted heteroalkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a nitrogen-protecting group when attached to a nitrogen atom, or an oxygen-protecting group when attached to an oxygen atom, or two R groups. c Examples of linkages form substituted or unsubstituted heterocyclic rings or substituted or unsubstituted heteroaryl rings; and Key C 4A Attach to L 4 .

97. The oligonucleotide of any one of claims 1-96, wherein, when present, L A At least one instance of it has the following formula: or .

98. The oligonucleotide of any one of claims 1-97, wherein, when present, L A At least one instance of it has the following formula: .

99. The oligonucleotide of any one of claims 1-98, wherein Z A1 For unreplaced C 1-3 Alkylene.

100. The oligonucleotide of any one of claims 1-99, wherein Z A2 For unreplaced C 1-3 Alkylene.

101. The oligonucleotide of any one of claims 1-100, wherein, when present, L A At least one instance of it has the following formula: , , , , or .

102. The oligonucleotide of any one of claims 1-101, wherein, when present, at least one instance of y4 is 1.

103. The oligonucleotide of any one of claims 1-102, wherein, when present, at least one instance of y4 is 2, 3, 4, 5 or 6.

104. The oligonucleotide of any one of claims 1-103, wherein, when present, 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.

105. The oligonucleotide of any one of claims 1-104, wherein, when present, 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, two, three, or four main chain atoms of the heterocyclic group are independently replaced by a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

106. The oligonucleotide of any one of claims 1-105, wherein, when present, 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, two, three, or four main chain atoms of a heteroalkyl group are independently substituted or unsubstituted with a carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

107. The oligonucleotide according to any one of claims 1-106, wherein: At least one instance of y4 is 1; That for ； –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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 4B1 L 4B2 and L 4B3 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 4A Attach to A 4 .

108. The oligonucleotide according to any one of claims 1-107, wherein: At least one instance of y4 is 2; That for ； –L 4A21 –L 4A22 –、–L 4A23 –L 4A24 –、–L 4A25 –L 4A26 –、–L 4A27 –L 4A28 –、–L 4A29 –L 4A30 –、–L 4A31 –L 4A32 –、–L 4A33 –L 4A34 –、–L 4A35 –L 4A36 –、–L 4A37 –L 4A38 –、–L 4A39 –L 4A40 –、–L 4A41 –L 4A42 –、–L 4A43 –L 4A44 –、–L 4A45 –L 4A46 –、–L 4A47 –L 4A48 – and – L 4A49 –L 4A50 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 two R groups attached to a nitrogen atom. a Examples include the formation of substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups through nitrogen atom linkage; L 4B4 L 4B5 L 4B6 L 4B7 L 4B8 L 4B9 L 4B10 L 4B11 and L 4B12 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 4C3 L 4C4 L 4C5 L 4C6 L 4C7 and L 4C8 Each of them is a single bond, a substituted or unsubstituted heterocyclic group that replaces one of the main chain atoms, or a substituted or unsubstituted heteroaryl group that replaces one of the main chain atoms; Key C 4B Attach to A 4 The first instance; and Key C 4C Attach to A 4 The second instance.

109. The oligonucleotide of any one of claims 1-108, wherein, when present, L 4 At least one instance is substituted or unsubstituted C 7-70 Heteroalkyl groups.

110. The oligonucleotide of any one of claims 1-109, wherein, when present, L 4 At least one instance 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: L 4 At least one instance of which has a main chain atom count between 10 and 100 (inclusive); and L 4 At least one instance does not contain O–O, O–N, N–O, or N–N.

111. The oligonucleotide of any one of claims 1-110, wherein, when present, L 4 At least one instance 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: L 4 At least one instance of the main chain has a main chain atom count between 10 and 100 (inclusive); L 4 At least one instance does not contain O–O, O–N, N–O, or N–N; and L 4 At least one instance of –C(=O)NH–, –NHC(=O)–, and The total number is between 0 and 4 (inclusive).

112. The oligonucleotide according to any one of claims 1-111, wherein A 4 Each instance is a group of the ligand.

113. The oligonucleotide according to any one of claims 1-112, wherein: A 4 At least one instance is a group of a ligand; and A 4 At least one instance is a lipid group.

114. The oligonucleotide of any one of claims 1-113, wherein A 4 Each instance is a lipid group.

115. The oligonucleotide or nucleoside according to any one of claims 1-114, 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).

116. The oligonucleotide of any one of claims 1-115, wherein in at least one instance of a portion of formula I: Each instance of y1 is 0; y2 is 0; and y3 is 1.

117. The oligonucleotide of any one of claims 1-116, wherein in at least one instance of a portion of Formula I: Each instance of y1 is 0; y2 is 0; and y3 is 2.

118. The oligonucleotide of any one of claims 1-117, wherein in at least one instance of a portion of Formula I: t1 is 1; y1 is 1; y2 is 0; and y3 is 1.

119. The oligonucleotide of any one of claims 1-118, wherein in at least one instance of a portion of Formula I: Each instance of y1 is 0; y2 is 1; and y3 is 1.

120. The oligonucleotide of any one of claims 1-119, wherein in at least one instance of the portion of Formula I, each of t1, y1, y2 and y3 is 1.

121. The oligonucleotide of any one of claims 1-120, wherein in at least one instance of a portion of formula I: y1 is 0; y2 is 2; and y3 is 1.

122. The oligonucleotide of any one of claims 1-121, further comprising one or more modifications, said one or more modifications being independently selected from modified sugars, modified nucleobases and modified nucleoside junctions.

123. The oligonucleotide of any one of claims 1-122, 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.

124. The oligonucleotide of any one of claims 1-123, 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-Protyrylaminocytosine, 5-Protyrylaminocytosine, 5-Protyryluracil, 6-azacytosine, 6-azauracil, 6-Chloropurine, 6-Thioguanine, 7-Deadenine, 7-Deadenine, 7-Deadenine, 7-Deaden-7-Protyrylamino Adenine, 7-deazo-7-propynylaminoguanine, 8-azaadenine, 8-azidoadenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, vidarabine, vidarabine cytosine, vidarabine guanine, vidarabine uracil, biotin-16-7-deazo-7-propynylaminoguanine, biotin-16-aminoallylcytosine, biotin-16-aminoallyluracil, cyanine 3-5-propynylaminoguanine, cyanine 3-6-propynylaminoguanine, cyanine 3-aminoallylcytosine, cyanine 3-aminoallylcytosine, cyanine 5-6-propynylaminoguanine, cyanine 5-aminoallylcytosine, cyanine 5-aminoallylcytosine, cyanine 5-aminoallylcytosine, cyanine 5-amino-... Allyl uridine, cyanocyanate 7-aminoallyl uridine, dabcyl-5-3-aminoallyl uridine, desulfobiotin-16-aminoallyl-uridine, desulfobiotin-6-aminoallyl cytosine, 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).

125. The oligonucleotide of any one of claims 1-124, wherein at least one example of the modified nucleoside junction is a thiophosphate nucleoside junction, a thiophosphate nucleoside junction, or a methylphosphonate nucleoside junction.

126. The oligonucleotide or nucleoside according to any one of claims 1-125, comprising at least two ligands, said at least two ligands belonging to the same ligand type.

127. The oligonucleotide or nucleoside according to any one of claims 1-126, comprising at least two ligands, wherein the at least two ligands are identical.

128. The oligonucleotide or nucleoside according to any one of claims 1-127, comprising at least two ligands, said at least two ligands being different ligands of the same ligand type.

129. The oligonucleotide or nucleoside according to any one of claims 1-128, comprising at least two ligands, said at least two ligands belonging to different ligand types.

130. The oligonucleotide or nucleoside according to any one of claims 1-129, wherein at least one ligand is a small molecule, peptide, or protein.

131. The oligonucleotide or nucleoside according to any one of claims 1-130, wherein at least one ligand is a central nervous system receptor ligand.

132. The oligonucleotide or nucleoside according to any one of claims 1-131, wherein at least one ligand is a tropomyosin receptor B (TrkB) ligand.

133. The oligonucleotide or nucleoside according to any one of claims 1-132, 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.

134. The oligonucleotide or nucleoside according to any one of claims 1-133, wherein at least one group of the TrkB ligand has the following formula: , or .

135. The oligonucleotide or nucleoside according to any one of claims 1-134, wherein at least one group of the TrkB ligand has the following formula: , , or .

136. The oligonucleotide or nucleoside according to any one of claims 1-135, wherein at least one group of the TrkB ligand has the following formula: 、 、 、 、 、 、 、 、 、 。 137. The oligonucleotide or nucleoside according to any one of claims 1-136, 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.

138. The oligonucleotide or nucleoside according to any one of claims 1-137, wherein at least one ligand is α4β. 1 / 7 Integrin ligands.

139. The oligonucleotide or nucleoside according to any one of claims 1-138, 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.

140. The oligonucleotide or nucleoside according to any one of claims 1-139, 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.

141. The oligonucleotide or nucleoside according to any one of claims 1-140, 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.

142. The oligonucleotide or nucleoside according to any one of claims 1-141, 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.

143. The oligonucleotide or nucleoside according to any one of claims 1-142, 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.

144. The oligonucleotide or nucleoside according to any one of claims 1-143, 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.

145. The oligonucleotide or nucleoside according to any one of claims 1-144, 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.

146. The oligonucleotide or nucleoside according to any one of claims 1-145, wherein: α4β 1 / 7 At least one group of the integrin ligand has the following formula: or .

147. The oligonucleotide or nucleoside according to any one of claims 1-146, 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–.

148. The oligonucleotide or nucleoside according to any one of claims 1-147, 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.

149. The oligonucleotide or nucleoside according to any one of claims 1-148, 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.

150. The oligonucleotide or nucleoside according to any one of claims 1-149, 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.

151. The oligonucleotide or nucleoside according to any one of claims 1-150, 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.

152. The oligonucleotide or nucleoside according to any one of claims 1-151, 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.

153. The oligonucleotide or nucleoside according to any one of claims 1-152, 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.

154. The oligonucleotide or nucleoside according to any one of claims 1-153, wherein at least one ligand is a cannabinoid receptor type 1 (CB1) ligand.

155. The oligonucleotide or nucleoside according to any one of claims 1-154, 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.

156. The oligonucleotide or nucleoside according to any one of claims 1-155, wherein: At least one group of the CB1 ligand has the following formula: 。 157. The oligonucleotide or nucleoside according to any one of claims 1-156, wherein: At least one group of the CB1 ligand has the following formula: or .

158. The oligonucleotide or nucleoside according to any one of claims 1-157, wherein: At least one CB1 ligand is 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.

159. The oligonucleotide or nucleoside according to any one of claims 1-158, wherein: At least one group of the CB1 ligand has the following formula: 。 160. The oligonucleotide or nucleoside according to any one of claims 1-159, wherein: At least one CB1 ligand is a compound of the following formula: 。 161. The oligonucleotide or nucleoside according to any one of claims 1-160, wherein: At least one group of the CB1 ligand has the following formula: 。 162. The oligonucleotide or nucleoside according to any one of claims 1-161, wherein: At least one CB1 ligand is 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.

163. The oligonucleotide or nucleoside according to any one of claims 1-162, wherein: At least one group of the CB1 ligand has the following formula: 。 164. The oligonucleotide or nucleoside according to any one of claims 1-163, 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.

165. The oligonucleotide or nucleoside according to any one of claims 1-164, wherein: At least one group of the CB1 ligand has the following formula: 。 166. The oligonucleotide or nucleoside according to any one of claims 1-165, wherein: At least one CB1 ligand is a compound of the following formula: 、 、 or .

167. The oligonucleotide or nucleoside according to any one of claims 1-166, wherein at least one ligand is N 2-Methyl-D-aspartate (NMDA) receptor ligand.

168. The oligonucleotide or nucleoside according to any one of claims 1-167, 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.

169. The oligonucleotide or nucleoside according to any one of claims 1-168, wherein at least one group of the NMDA receptor ligand has the following formula: 。 170. The oligonucleotide or nucleoside according to any one of claims 1-169, wherein at least one group of the NMDA receptor ligand has the following formula: or .

171. The oligonucleotide or nucleoside according to any one of claims 1-170, wherein at least one group of the NMDA receptor ligand has the following formula: 。 172. The oligonucleotide or nucleoside according to any one of claims 1-171, wherein at least one group of the NMDA receptor ligand has the following formula: 。 173. The oligonucleotide or nucleoside according to any one of claims 1-172, wherein at least one group of the NMDA receptor ligand has the following formula: 。 174. The oligonucleotide or nucleoside according to any one of claims 1-173, wherein at least one group of the NMDA receptor ligand has the following formula: or .

175. The oligonucleotide or nucleoside according to any one of claims 1-174, wherein at least one group of the NMDA receptor ligand has the following formula: 。 176. The oligonucleotide or nucleoside according to any one of claims 1-175, wherein at least one group of the NMDA receptor ligand has the following formula: 。 177. The oligonucleotide or nucleoside according to any one of claims 1-176, wherein at least one group of the NMDA receptor ligand has the following formula: 。 178. The oligonucleotide or nucleoside according to any one of claims 1-177, wherein at least one group of the NMDA receptor ligand has the following formula: or .

179. The oligonucleotide or nucleoside according to any one of claims 1-178, wherein at least one group of the NMDA receptor ligand has the following formula: 。 180. The oligonucleotide or nucleoside according to any one of claims 1-179, wherein at least one lipid is a group consisting of: fatty acyl, glycerol, glycerophospholipid, sphingolipid, glycolipid, polyketide, sterol lipid or isopentenol lipid.

181. The oligonucleotide or nucleoside according to any one of claims 1-180, wherein at least one lipid is a group consisting of: 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.

182. The oligonucleotide or nucleoside according to any one of claims 1-181, wherein at least one lipid is a hydrocarbon group.

183. The oligonucleotide or nucleoside according to any one of claims 1-182, wherein at least one lipid is an unsubstituted C6- 30 Alkyl groups, C6- substituted with one or more fluorinated groups where the valence allows. 30 Alkyl, unsubstituted C6- 30 Alkenyl, or C6- substituted with one or more fluorinated groups where the valence allows. 30 Alkenyl group.

184. The oligonucleotide or nucleoside according to any one of claims 1-183, wherein at least one lipid is an unsubstituted C 16-28 Alkyl or unsubstituted C 16-28 Alkenyl groups, each of which is independently unbranched, dibranched, or tribranched.

185. The oligonucleotide or nucleoside according to any one of claims 1-184, wherein at least one lipid is an unbranched, unsubstituted C14. 18-26 alkyl.

186. The oligonucleotide or nucleoside according to any one of claims 1-185, wherein at least one lipid is –(CH2). 21 CH3.

187. The oligonucleotide or nucleoside according to any one of claims 1-186, wherein at least one lipid is a group consisting of: monosubstituted glycerol, disubstituted glycerol, trisubstituted glycerol, glycosyl monosubstituted glycerol, glycosyl disubstituted glycerol, betaine monosubstituted glycerol, or betaine disubstituted glycerol.

188. The oligonucleotide or nucleoside according to any one of claims 1-187, wherein at least one lipid is a group comprising: 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.

189. The oligonucleotide or nucleoside according to any one of claims 1-188, wherein at least one lipid is a group consisting of: sphingosine base, ceramide, phosphospholipid, phosphonate sphingolipid, neutral glycosphingolipid, acidic glycosphingolipid, basic glycosphingolipid, amphoteric glycosphingolipid, or arsenic sphingolipid.

190. The oligonucleotide or nucleoside according to any one of claims 1-189, wherein at least one lipid is a group consisting of sterols, steroids, open-ring steroids, bile acids or derivatives thereof, or steroid conjugates.

191. The oligonucleotide or nucleoside according to any one of claims 1-190, wherein at least one lipid is a cholesterol group.

192. The oligonucleotide or nucleoside according to any one of claims 1-191, wherein at least one lipid is a group consisting of isoprene, quinone, hydroquinone, polyisoprene alcohol, or hopane.

193. The oligonucleotide or nucleoside according to any one of claims 1-192, wherein at least one lipid is an acylamino sugar, an acylamino glycosyl, an acyltrehalose, or an acyltrehalose.

194. The oligonucleotide or nucleoside according to any one of claims 1-193, 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.

195. The oligonucleotide according to any one of claims 1-194, wherein formula I is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or 。 196. The oligonucleotide of any one of claims 1-195, wherein the positive oligonucleotide chain has at least 80%, at least 85%, at least 90%, or at least 95% identity with SEQ ID NO: 1 or 2.

197. The oligonucleotide of any one of claims 1-196, wherein the positive oligonucleotide chain has at least 80%, at least 85%, at least 90%, or at least 95% identity with SEQ ID NO: 3 or 4.

198. The oligonucleotide of any one of claims 1-197, wherein the positive oligonucleotide chain has at least 80%, at least 85%, at least 90%, or at least 95% identity with SEQ ID NO: 5 or 6.

199. A pharmaceutical composition comprising any one of claims 1-198, an oligonucleotide or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

200. The pharmaceutical composition of claim 199, further comprising additional pharmaceutical agents.

201. A reagent kit comprising: The oligonucleotide of any one of claims 1-198 or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 199 or 200; and Instructions for use of the oligonucleotide, pharmaceutically acceptable salt, prodrug, or pharmaceutical composition thereof.

202. A method for delivering an oligonucleotide to a subject, comprising administering to the subject any oligonucleotide of any one of claims 1-198 or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 199 or 200.

203. Use of the oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-198, or the pharmaceutical composition of claim 199 or 200, for the manufacture of a medicament for the delivery of the oligonucleotide to a subject.

204. The oligonucleotide of any one of claims 1-198 or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of any one of claims 199 or 200, for delivery of the oligonucleotide to a subject.

205. The method of claim 202, the use of the method of claim 203, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 204, wherein the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof is delivered to the brain of the subject.

206. The method of claim 202, the use of the method of claim 203, and the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof used as described in claim 204, 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.

207. A method for treating a disease in a subject in need, comprising administering to the subject an effective amount of any one of claims 1-198, an oligonucleotide or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 199 or 200.

208. Use of any oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-198, or the pharmaceutical composition of any one of claims 199 or 200, for the manufacture of a medicament for treating a disease in a subject in need.

209. The oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-198, or the pharmaceutical composition of claim 199 or 200, for treating a disease in a subject in need.

210. A method for preventing disease in a subject in need, comprising administering to the subject an effective amount of any oligonucleotide of claims 1-198 or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of claim 199 or 200.

211. The use of any oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-198, or the pharmaceutical composition of any one of claims 199 or 200, in the manufacture of a medicament for the prevention of disease in a subject in need.

212. The oligonucleotide or pharmaceutically acceptable salt or prodrug of any one of claims 1-198, or the pharmaceutical composition of claim 199 or 200, for the prevention of disease in a subject of need.

213. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the disease is a central nervous system disease.

214. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein 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.

215. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the disease is a neurodegenerative disease.

216. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, 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, Demignani syndrome, Gerstmann-Straussler syndrome, Huntington's disease, Huntington's syndrome, myelination dysplasia 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.

217. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the disease is a neurocognitive disorder.

218. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the disease is dementia, HIV-related neurocognitive impairment or memory impairment.

219. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the disease is Parkinson's disease.

220. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the disease is amyotrophic lateral sclerosis (ALS).

221. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the disease is Alzheimer's disease.

222. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, 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 Dlaivé syndrome.

223. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof is administered parenterally to the subject.

224. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof is administered intrathecally, intraventricularly or intravenously to the subject.

225. The method of claim 207 or 210, the use of the oligonucleotide or pharmaceutically acceptable salt or prodrug or pharmaceutical composition thereof as described in claim 209 or 212, wherein the subject is a human.

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