Alkyl alkyl groups containing ligands in their internal position

Abstract

This disclosure provides oligonucleotides containing ligand radicals at an internal position. The disclosure also provides pharmaceutical compositions and kits comprising such oligonucleotides, methods for delivering such oligonucleotides, methods for modulating protein activity using such oligonucleotides, and methods for treating, preventing, or diagnosing diseases (e.g., central nervous system diseases, neurodegenerative diseases, and neurocognitive diseases) in subjects requiring such treatment, prevention, or diagnosis, using such oligonucleotides or pharmaceutical compositions. The disclosure also provides pharmaceutical compositions and kits, each comprising the oligonucleotides disclosed herein.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 520,337, filed on 17 August 2023 under Section 119(e) of the U.S. Patent Act, the contents of which are incorporated herein by reference. [Background technology]

[0002] When using compounds (e.g., oligonucleotides) for therapeutic, preventive, or diagnostic purposes, it is often desirable to deliver them to specific locations (e.g., desired cells, organs or tissues, or specific sites within a target) to enhance therapeutic or preventive effects, or to be advantageous for diagnostic purposes. This is especially true when attempting to deliver therapeutic compounds in vivo. Furthermore, efficient delivery of compounds to specific locations can limit or potentially eliminate unintended consequences (such as off-target effects) that may result from the administration of the compound. One strategy for facilitating the delivery of compounds (such as therapeutic, preventive, or diagnostic compounds) to desired locations in vivo is to link or attach them to targeting ligands.

[0003] One class of compounds that can be targeted using targeting ligands are oligomeric compounds (e.g., proteins, peptides, antibodies, and oligonucleotides). Oligomer compounds containing a nucleotide sequence (e.g., oligonucleotide) that is at least partially complementary to the target nucleic acid have been shown to alter the function and activity of the target both in vitro and in vivo. Oligonucleotides have been shown to modulate the expression or activity of the target nucleic acid (e.g., mRNA or premRNA) when delivered to cells containing that target nucleic acid. In certain cases, the oligonucleotide can reduce the expression of its gene by inhibiting the translation of its nucleic acid target and / or inducing the degradation of that target nucleic acid.

[0004] When the target nucleic acid is mRNA, oligonucleotides can regulate the expression of the target mRNA through one mechanism, RNA interference. RNA interference is a biological process through which RNA or RNA-like compounds (such as chemically modified RNA compounds) can at least partially silence gene expression via the RNA-induced silencing complex (RISC) pathway. In addition, 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 may be single-stranded or double-stranded. Oligonucleotides may include DNA, RNA, and RNA-like compounds, and may also include modified nucleosides containing one or more modified sugars, modified nucleic acid bases, and modified nucleoside-to-nucleoside bonds.

[0005] Novel compounds are needed for delivering pharmaceuticals (e.g., therapeutic, preventive, and diagnostic agents). [Overview of the project]

[0006] In one embodiment, the disclosure provides an oligonucleotide chain comprising an oligonucleotide chain modified with at least one ligand at an internal position. In one embodiment, the disclosure provides a modified oligonucleotide chain of formula I: [ka] The purpose is to provide oligonucleotides or pharmaceutically acceptable salts or prodrugs thereof, and here, [ka] It is a divalent radical of an oligonucleotide chain, [ka] One example of a nucleoside linker is independently [Chemical] is replaced by, s1 is 1, 2, 3, 4, 5, or 6, each L A and L 4 are each independently a linker, each A 4 is independently a ligand or a lipid radical, provided that at least one A 4 is a ligand radical, each of y5 and y6 is independently 0 or 1, when y5 is 0, L 5 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or an oxygen protecting group, or when y5 is 1, L 5 is a linker, when y6 is 0, L 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or an oxygen protecting group, or when y6 is 1, L 6 is a linker, A 5 and A 6 , when present, are each independently a ligand or a lipid radical, and each ligand is different from each lipid.

[0007] The oligonucleotide comprises one or more ligand radicals conjugated at one or more internal positions of the oligonucleotide (e.g., at a position of the oligonucleotide other than the 5' or 3' end). In some embodiments, the ligand is not a lipid. In some embodiments, the oligonucleotide further comprises one or more lipid radicals at one or more internal positions. In some embodiments, the oligonucleotide further comprises one or more ligand radicals and / or lipid radicals at the 5' terminus and / or 3' terminus.

[0008] The oligonucleotide may be useful for delivering a drug to a target (e.g., a human). In some embodiments, at least one example of the drug is an oligonucleotide chain. In some embodiments, the ligand can selectively target a location within a target (e.g., the brain of the target, or a region of the brain of the target). In some embodiments, the ligand can selectively target a specific cell type (e.g., cells of the central nervous system, such as neurons). In some embodiments, the ligand can selectively bind to one or more receptors, or otherwise selectively recognize one or more receptors. In some embodiments, the oligonucleotide can selectively target an oligonucleotide chain to a location within a target (e.g., the brain of the target, or a region of the brain of the target). In some embodiments, the oligonucleotide can selectively deliver an oligonucleotide chain to cells (e.g., cells of the central nervous system, such as neurons). In certain embodiments, the oligonucleotide can selectively bind to one or more receptors, or otherwise selectively recognize one or more receptors. The oligonucleotide may be useful for treating, preventing, or diagnosing diseases. The oligonucleotide in question may be advantageous over pharmaceuticals and certain known oligonucleotides (e.g., certain known oligonucleotides that do not contain radicals of one or more ligands conjugated at one or more internal positions). This is because the former may exhibit higher potency, efficacy, bioavailability, safety, and / or patient adherence rates, a wider therapeutic time range, fewer and / or milder side effects, and / or lower toxicity and / or treatment resistance than the latter. One or more of these advantages may be at least in part due to the oligonucleotide containing radicals of one or more ligands conjugated at one or more internal positions.

[0009] This disclosure also provides pharmaceutical compositions and kits, each of which comprises oligonucleotides disclosed herein. This disclosure also provides methods for using such oligonucleotides, pharmaceutical compositions, and kits.

[0010] In another aspect, the present disclosure provides a method for delivering any of the oligonucleotides or pharmaceutical compositions provided herein.

[0011] In another aspect, the Disclosure provides an oligonucleotide or pharmaceutical composition for manufacturing a drug for delivery to any of the oligonucleotides or pharmaceutical compositions provided herein.

[0012] In another aspect, the Disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for use in delivering any of such oligonucleotides or pharmaceutical compositions to a target.

[0013] In another aspect, the Disclosure provides a method for treating a disease in an object requiring treatment of the disease using any of the oligonucleotides or pharmaceutical compositions provided herein.

[0014] In another aspect, the disclosure provides the use of any oligonucleotide or pharmaceutical composition provided herein for manufacturing a drug for treating a disease in a subject requiring treatment of the disease.

[0015] In another aspect, the Disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for use in treating diseases in subjects requiring treatment of the disease.

[0016] In another aspect, the Disclosure provides a method for preventing disease in a subject requiring disease prevention using any of the oligonucleotides or pharmaceutical compositions provided herein.

[0017] In another aspect, the disclosure provides the use of any oligonucleotide or pharmaceutical composition provided herein for manufacturing a drug for preventing disease in subjects requiring disease prevention.

[0018] In another aspect, the Disclosure provides any of the oligonucleotides or pharmaceutical compositions provided herein for use in the prevention of disease in subjects requiring disease prevention.

[0019] In another embodiment, this disclosure relates to a compound of formula A-1: [ka] or its salt, the compound of formula A-2: L 4E2 -L 4D2 -A 4 (A-2) The present invention provides a method for producing any of the oligonucleotides provided herein, comprising contacting them with a salt thereof under appropriate conditions, M 1 and M 2 Each of them is independently a fragment of an oligonucleotide chain or a nucleoside radical. L 4D1 and L 4D2 Each of them is independently a single bond or a linker. L 4E1 This is the first reactive part, L 4E2 This is the second reactive part, L 4E1 and L 4E2 Under appropriate conditions, they react with each other and L 4E3 It can form L 4D1 -L 4E3 -L 4D2 L 4 That is the case.

[0020] The embodiments provided herein for preferred variable selections may be treated individually or in combination with one or more embodiments or other preferred variable selections provided herein, and each combination may be treated as if it were explicitly enumerated herein.

[0021] It should be acknowledged that the aforementioned concepts and additional concepts described later may be arranged in any suitable combination, as this disclosure is not limited in this respect. Furthermore, other advantages and novel features of this disclosure will become apparent from the detailed description of the various non-limiting embodiments below.

[0022] definition The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th Identification is made according to the Ed. (title page), and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional parts and reactivity, are referred to Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, and Michael B. Smith, March's Advanced Organic Chemistry, 7 th 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, 3 rd This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0023] The compounds described herein (e.g., oligonucleotides) may contain one or more chiral centers and therefore may exist in various stereoisomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of a single enantiomer, diastereomer or geometric isomer, or in the form of a stereoisomeric mixture, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers may be isolated 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, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further encompasses compounds as a single isomer substantially free of other isomers, or as a mixture of various isomers.

[0024] Unless otherwise indicated, the formulas and structures represented herein include compounds that do not contain isotopically enriched atoms, as well as compounds that do contain isotopically enriched atoms. For example, hydrogen may be replaced with deuterium or tritium. 19 F 18 It is replaced by F, or carbon is 13 C or 14Compounds having this structure, except in which carbon-enriched carbon is replaced, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0025] When a range of values ​​("Range") is listed, that range includes each value and its subranges. Unless otherwise indicated, a range includes the values ​​at both ends of that range. For example, "C 1-6 "Alkyl" includes 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 is included.

[0026] The term "alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 100 carbon atoms ("C"). 1-100 ("alkyl"). In some embodiments, the alkyl group has 1 to 20 carbon atoms ("C"). 1-20 (alkyl). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C"). 1-12 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1-10 (alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1-9 (alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1-8 (alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1-7 ("alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6(alkyl). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5 (alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 Alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3 ("alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 2-6 Alkyl). 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-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and n-dodecyl (C 12 Examples include ), and similar groups. Unless otherwise specified, each example of an alkyl group is either unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as fluorine) ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-12 Alkyl (unsubstituted C) 1-6 Alkyl groups include, for example, -CH3(Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), and unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), and unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is substituted C 1-12 Alkyl (substituted C) 1-6 Alkyl, for example, These are -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn).

[0027] The term "heteroalkyl" refers to an alkyl group further comprising at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorus, wherein the heteroatom is located within the matrix chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the matrix chain. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 100 carbon atoms and one or more heteroatoms located within the matrix chain ("heteroC"). 1-100 ("Alkyl"). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms inside the parent chain ("hetero C"). 1-20 ("Alkyl"). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms inside the parent chain ("hetero C"). 1-12 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and one or more heteroatoms inside the matrix chain ("hetero C"). 1-11 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms inside the matrix chain ("hetero C"). 1-10 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and one or more heteroatoms inside the matrix chain ("hetero C 1-9 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms inside the matrix chain ("hetero C"). 1-8 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms inside the matrix chain ("hetero C"). 1-7("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms inside the matrix chain ("hetero C"). 1-6 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms inside the matrix chain ("hetero C"). 1-5 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms inside the matrix chain ("hetero C"). 1-4 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom inside the parent chain ("hetero C"). 1-3 ("Alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom inside the matrix chain ("heteroC"). 1-2 ("Alkyl"). 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 2 to 6 carbon atoms and 1 or 2 heteroatoms inside the parent chain ("heteroC1 alkyl"). 2-6 Unless otherwise specified, each heteroalkyl group is an example of either unsubstituted ("unsubstituted heteroalkyl") or with one or more substituents (e.g., oxo, substituted or unsubstituted C). 1-6 It is substituted with an alkyl group (e.g., -CH3) ("substituted heteroalkyl"). In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-12 It is alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-12 It is alkyl. In some embodiments, the unsubstituted hetero C1 alkyl is -OCH3 or -CH2OH. In some embodiments, the substituted hetero C1 alkyl is -C(=O)NH2. In some embodiments, the unsubstituted hetero C2 alkyl is -OCH2CH3, -CH2OCH3, or -CH2CH2OH. "Hetero C z1-z2The terms "alkyl" and "C z1-z2 heteroalkyl" are used interchangeably herein, wherein each of z1 and z2 is independently an integer.

[0028] The term "alkenyl" refers to a radical of 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, an alkenyl group has 1 to 100 carbon atoms ("C 1-100 alkenyl"). In some embodiments, an alkenyl group has at least 2 carbon atoms. In some embodiments, an alkenyl group has 1 to 20 carbon atoms ("C 1-20 alkenyl"). In some embodiments, an alkenyl group has 1 to 12 carbon atoms ("C 1-12 alkenyl"). In some embodiments, an alkenyl group has 1 to 11 carbon atoms ("C 1-11 alkenyl"). In some embodiments, an alkenyl group has 1 to 10 carbon atoms ("C 1-10 alkenyl"). In some embodiments, an alkenyl group has 1 to 9 carbon atoms ("C 1-9 alkenyl"). In some embodiments, an alkenyl group has 1 to 8 carbon atoms ("C 1-8 alkenyl"). In some embodiments, an alkenyl group has 1 to 7 carbon atoms ("C 1-7 alkenyl"). In some embodiments, an alkenyl group has 1 to 6 carbon atoms ("C 1-6 alkenyl"). In some embodiments, an alkenyl group has 1 to 5 carbon atoms ("C 1-5 alkenyl"). In some embodiments, an alkenyl group has 1 to 4 carbon atoms ("C 1-4 alkenyl"). In some embodiments, an alkenyl group has 1 to 3 carbon atoms ("C 1-3 alkenyl"). In some embodiments, an alkenyl group has 1 to 2 carbon atoms ("C 1-2"Alkenyl"). In some embodiments, the alkenyl group has one carbon atom ("C1 alkenyl"). In certain embodiments, the alkenyl group has C 2-3 Alkenil, C 2-4 Alkenil, C 2-5 Alkenil, C 2-6 Alkenil, C 2-7 Alkenil, C 2-8 Alkenil, C 2-9 Alkenil, C 2-10 Alkenil, C 2-12 Alkenil, C 2-16 Alkenil, C 2-20 Alkenil, C 2-30 Alkenil, C 2-40 Alkenil, C 2-50 Alkenil, C 2-60 Alkenil, C 2-70 Alkenil, C 2-80 Alkenil, C 2-90 Alkenyl, or C 2-100 It is an alkenyl. One or more carbon-carbon double bonds can be located internally (e.g., in 2-butenyl) or at the terminal (e.g., in 1-butenyl). C 1-4 Examples of alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and similar groups. 1-6 An example of an alkenyl group is the aforementioned C 2-4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each example of an alkenyl group is independently either unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C 1-20 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C 1-20It is an alkenyl. In the alkenyl group, the stereochemistry is not specified for the C=C double bond (for example, -CH=CHCH3 or [ka] ) may be in (E) configuration or (Z) configuration.

[0029] The term "heteroalkenyl" refers to an alkenyl group further comprising at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorus, wherein the heteroatom is located within the matrix chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the matrix chain. In certain embodiments, a heteroalkenyl group refers to a group having 1 to 100 carbon atoms, at least one double bond, and one or more heteroatoms located within the matrix chain ("hetero C"). 1-100 ("hetero-alkenyl"). In some embodiments, the hetero-alkenyl group has at least two carbon atoms. In certain embodiments, the hetero-alkenyl group refers to a group having 1 to 20 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero-C"). 1-20 ("Alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having 1 to 12 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-12 ("Alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having 1 to 11 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-11 ("Alkenyl"). In certain embodiments, a heteroalkenyl group refers to a group having 1 to 10 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-10 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 9 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-9("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 8 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-8 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 7 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-7 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-6 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 5 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms inside the parent chain ("hetero C"). 1-5 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms inside the parent chain ("hetero C"). 1-4 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 3 carbon atoms, at least one double bond, and one heteroatom inside the parent chain ("hetero C"). 1-3 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1-2 carbon atoms, at least 1 double bond, and 1 heteroatom inside the parent chain ("hetero C"). 1-2 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 1 to 6 carbon atoms, at least one double bond, and one or two heteroatoms inside the parent chain ("hetero C"). 1-6 (Alkenyl). In certain embodiments, the heteroalkenyl group is C 2-3 Heteralkenyl, C 2-4 Heteralkenyl, C 2-5 Heteralkenyl, C 2-6 Heteralkenyl, C 2-7 Heteralkenyl, C 2-8 Heteralkenyl, C 2-9 Heteralkenyl, C 2-10Heteralkenyl, C 2-12 Heteralkenyl, C 2-16 Heteralkenyl, C 2-20 Heteralkenyl, C 2-30 Heteralkenyl, C 2-40 Heteralkenyl, C 2-50 Heteralkenyl, C 2-60 Heteralkenyl, C 2-70 Heteralkenyl, C 2-80 Heteralkenyl, C 2-90 Heteralkenyl, or C 2-100 It is a heteroalkenyl. Unless otherwise specified, each example of a heteroalkenyl group is independently either unsubstituted ("unsubstituted heteroalkenyl") or with one or more substituents (e.g., oxo, substituted or unsubstituted C). 1-6 It is substituted with an alkyl group (e.g., -CH3) ("substituted heteroalkenyl"). In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 1-20 It is an alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 1-20 It is an alkenyl. In some embodiments, the unsubstituted hetero C1 alkenyl is -CH=NH or =N-CH3. z1-z2 The term "Alkenil" and "C z1-z2 The term "heteroalkenyl" is used interchangeably, where z1 and z2 are independent integers.

[0030] The term "alkynyl" refers to a linear or branched hydrocarbon group radical having 1 to 100 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C1-100 alkynyl"). In some embodiments, the alkynyl group has 1 to 20 carbon atoms ("C 1-20 In some embodiments, the alkynyl group has at least two carbon atoms. In some embodiments, the alkynyl group has 1 to 10 carbon atoms ("C"). 1-10 In some embodiments, the alkynyl group has 1 to 9 carbon atoms ("C"). 1-9In some embodiments, the alkynyl group has 1 to 8 carbon atoms ("C"). 1-8 ("Alkynyl"). In some embodiments, the alkynyl group has 1 to 7 carbon atoms ("C"). 1-7 In some embodiments, the alkynyl group has 1 to 6 carbon atoms ("C"). 1-6 In some embodiments, the alkynyl group has 1 to 5 carbon atoms ("C"). 1-5 In some embodiments, the alkynyl group has 1 to 4 carbon atoms ("C"). 1-4 In some embodiments, the alkynyl group has 1 to 3 carbon atoms ("C"). 1-3 In some embodiments, the alkynyl group has 1 to 2 carbon atoms ("C"). 1-2 In some embodiments, the alkynyl group has one carbon atom ("C1 alkynyl"). In certain embodiments, the alkynyl group has C 2-3 Alkinyl, C 2-4 Alkinyl, C 2-5 Alkinyl, C 2-6 Alkinyl, C 2-7 Alkinyl, C 2-8 Alkinyl, C 2-9 Alkinyl, C 2-10 Alkinyl, C 2-12 Alkinyl, C 2-16 Alkinyl, C 2-20 Alkinyl, C 2-30 Alkinyl, C 2-40 Alkinyl, C 2-50 Alkinyl, C 2-60 Alkinyl, C 2-70 Alkinyl, C 2-80 Alkinyl, C 2-90 Alkinyl, or C 2-100 It is an alkynyl. One or more carbon-carbon triple bonds can be located internally (e.g., in 2-butynyl) or at the terminal (e.g., in 1-butynyl). C 1-4Examples of alkynyl groups include, but are not limited to, methylidinyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and similar groups. 1-6 An example of an alkenyl group is the aforementioned C 2-4 Examples of alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyls include heptynyl (C7), octinyl (C8), and the like. Unless otherwise specified, each example of an alkynyl group is independently either unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 1-20 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 1-20 It is alkinyl.

[0031] The term "heteroalkynyl" refers to an alkynyl group further comprising at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, and phosphorus, wherein the heteroatom is located within the matrix chain (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the matrix chain. In certain embodiments, a heteroalkynyl group refers to a group having 1 to 100 carbon atoms, at least one triple bond, and one or more heteroatoms located within the matrix chain ("hetero-C"). 1-100 ("Alkynyl"). In some embodiments, the heteroalkynyl group has at least two carbon atoms. In certain embodiments, the heteroalkynyl group refers to a group having 1 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-20 ("Alkynyl"). In certain embodiments, a heteroalkynyl group refers to a group having 1 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-10("Alkynyl"). In some embodiments, the heteroalkynyl group has 1 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-9 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 1 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-8 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 1 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-7 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms inside the parent chain ("hetero C"). 1-6 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms inside the parent chain ("hetero C"). 1-5 In some embodiments, the heteroalkynyl group has 1 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms inside the parent chain ("hetero C"). 1-4 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 1 to 3 carbon atoms, at least one triple bond, and one heteroatom inside the parent chain ("hetero C"). 1-3 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 1-2 carbon atoms, at least one triple bond, and one heteroatom inside the parent chain ("hetero C"). 1-2 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms inside the parent chain ("hetero C"). 1-6 (Alkynyl). In certain embodiments, the heteroalkynyl group is C 2-3 Heteroalkynyl, C 2-4 Heteroalkynyl, C 2-5 Heteroalkynyl, C2-6 Heteroalkynyl, C 2-7 Heteroalkynyl, C 2-8 Heteroalkynyl, C 2-9 Heteroalkynyl, C 2-10 Heteroalkynyl, C 2-12 Heteroalkynyl, C 2-16 Heteroalkynyl, C 2-20 Heteroalkynyl, C 2-30 Heteroalkynyl, C 2-40 Heteroalkynyl, C 2-50 Heteroalkynyl, C 2-60 Heteroalkynyl, C 2-70 Heteroalkynyl, C 2-80 Heteroalkynyl, C 2-90 Heteroalkynyl, or C 2-100 It is a heteroalkynyl. Unless otherwise specified, each example of a heteroalkynyl group is independently either unsubstituted ("unsubstituted heteroalkynyl") or with one or more substituents (e.g., oxo, substituted or unsubstituted C). 1-6 It is substituted with an alkyl group (e.g., -CH3) ("substituted heteroalkynyl"). In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 1-20 It is an alkynyl group. In certain embodiments, the heteroalkynyl group is a substituted heteroC 1-20 It is an alkynyl. In some embodiments, the unsubstituted hetero C1 alkynyl is -C≡N. z1-z2 The term "Alkinyl" and "C z1-z2 The term "heteroalkynyl" is used interchangeably, where z1 and z2 are independent integers.

[0032] The term "carbocykrill" or "carbocyclic" refers to a ring containing 3 to 14 carbon atoms ("C"). 3-14 A "carbocyclyl" group refers to a radical of a non-aromatic cyclic hydrocarbon group in which there are zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group has 3 to 14 ring carbon atoms ("C"). 3-14 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 13 ring carbon atoms ("C"). 3-13Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 12 ring carbon atoms ("C"). 3-12 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 11 ring carbon atoms ("C"). 3-11 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 10 ring carbon atoms ("C"). 3-10 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C"). 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C"). 3-7 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C"). 4-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5-6 ring carbon atoms ("C"). 5-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6 Examples of carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and similar groups. 3-8 As for the carbocyclyl group, the aforementioned C 3-6 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and similar groups. Exemplary C 3-10 As for the carbocyclyl group, the aforementioned C 3-8Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include ), and similar ones. Exemplary C 3-8 As for the carbocyclyl group, the aforementioned C 3-10 Carbocyclyl group, and cycloundecyl (C 11 ), spiro[5.5]undecanyl(C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 Examples include, and similarly. As illustrated in the above examples, in certain embodiments, the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., including condensed, cross-linked, or spirocyclic systems such as bicyclic ("bicyclic carbocyclyl") or tricyclic ("tricyclic carbocyclyl") systems), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes cyclic systems in which the carbocyclyl ring is condensed with one or more aryl or heteroaryl groups, with the attachment site on the carbocyclyl ring, in which case the carbon number is simply the carbon number of the carbocyclyl cyclic system. Unless otherwise specified, each example of a carbocyclyl group is independently either unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-14 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is carbocyclyl.

[0033] In some embodiments, "carbocyrill" is a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C"). 3-10 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3-8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3-6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C"). 4-6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C"). 5-6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include, as mentioned earlier, C 5-6 Examples include cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include, as mentioned earlier, C 3-6 Examples include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3-14 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is a cycloalkyl group. In certain embodiments, the carbocyclyl ring system contains 0, 1, or 2 C=C double bonds, as long as the valence allows.

[0034] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the attachment site can be a carbon or nitrogen atom, as long as the valence allows. Heterocyclyl groups can be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., condensed, bridging, or spirocyclic systems such as bicyclic (“bicyclic heterocyclyl”) or tricyclic (“tricyclic heterocyclyl”)), and can be saturated or may contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. A "heterocyclyl" includes, as defined above, a ring system in which a heterocyclyl ring is fused with one or more carbocyrill groups, with the attachment site either on the carbocyrill ring or the heterocyclyl ring, or, as defined above, a ring system in which a heterocyclyl ring is fused with one or more aryl or heteroaryl groups, with the attachment site on the heterocyclyl ring, in which case the ring member count is simply the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each example of a heterocyclyl is independently either unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 member heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 member heterocyclyl. In certain embodiments, the heterocyclyl is a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, where one, two, or three atoms of the heterocyclyl ring system are, independently, oxygen, nitrogen, or sulfur, as their valences allow.

[0035] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0036] Examples of three-membered heterocyclyl groups containing one heteroatom include azilidinyl, oxylanyl, and thiiranyl. Examples of four-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxathiolanyl, and dithiolanyl. Examples of five-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanil. An example of a six-membered heterocyclyl group containing three heteroatoms is triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include azocanyl, oxecanyl, and thiocanyl.Examples of bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydroclomenyl, octahydroisoclomenyl, decahydronaphthilidinyl, decahydro-1,8-naphthilidinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthaliumidyl, naphthaliumidyl, chromanyl, clomenyl, and 1H-benzo[e][1,4]diazepinyl Examples include 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-floo[3,2-b]pyrrolyl, 6,7-dihydro-5H-floo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofloo[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofloo[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthilidinyl, and similar compounds.

[0037] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic arrangement) that has 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system ("C 6-14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten 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 ("C"). 14"Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring is condensed with one or more carbocyrillic or heterocyclyl groups, as defined above, and the radical or attachment site is on the aryl ring, in which case the number of carbon atoms is simply the number of carbon atoms in the aryl ring system. Unless otherwise specified, each example of an aryl group is independently either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C 6-14 It is aryl. In certain embodiments, the aryl group is substituted C 6-14 It is Ariel.

[0038] 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 π electrons shared in the cyclic arrangement) radical having a ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the attachment site can be a carbon atom or a nitrogen atom, as long as the valence allows. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring is fused with one or more carbocykyl or heterocyclyl groups, as defined above, and the attachment site lies on the heteroaryl ring, in which case the ring membership number is simply the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring is fused with one or more aryl groups, as defined above, and the attachment site is on either the aryl ring or the heteroaryl ring, in which case the ring member number specifies the ring member number of the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and similar), the attachment site may be on either ring (e.g., either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl)). In certain embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, where 1, 2, 3, or 4 atoms of the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, where 1, 2, 3, or 4 atoms of the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0039] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms present in the aromatic ring system, where 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 ring carbon atom and 1-4 ring heteroatoms present in the aromatic ring system, where 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 ring carbon atom and 1-4 ring heteroatoms present in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each example of a heteroaryl group is independently either unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0040] Exemplary five-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetradinyl, respectively. Exemplary seven-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include naphthylidinyl, pteridinyl, quinolinil, isoquinolinil, sinnolinil, quinoxalinil, phthalazinyl, and quinazolinil. Examples of tricyclic heteroaryl groups include phenanthidinyl, dibenzofuranil, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0041] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0042] The term "alkoxy" refers to an -O-alkyl substituent.

[0043] The suffix "-ene" indicates that the resulting group is a polyvalent (e.g., divalent, trivalent, or tetravalent) part. For example, alkylene is the polyvalent part of alkyl, alkenylene is the polyvalent part of alkenyl, alkynylene is the polyvalent part of alkynyl, heteroalkylene is the polyvalent part of heteroalkyl, heteroalkenylene is the polyvalent part of heteroalkenyl, heteroalkynylene is the polyvalent part of heteroalkynyl, carbocyclylene is the polyvalent part of carbocyclyl, heterocyclylene is the polyvalent part of heterocyclyl, arylene is the polyvalent part of aryl, and heteroarylene is the polyvalent part of heteroaryl. 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 heteroalkylene is -(OCH2CH2)2- or -(CH2CH2O)2-. In some embodiments, the unsubstituted C6 heteroalkylene is -(OCH2CH2)3- or -(CH2CH2O)3-. In some embodiments, the unsubstituted C8 heteroalkylene is -(OCH2CH2)4- or -(CH2CH2O)4-. In some embodiments, the unsubstituted C 10 The heteroalkylene is -(OCH2CH2)5- or -(CH2CH2O)5-. In some embodiments, unsubstituted C 12 Heteroalkylenes are -(OCH2CH2)6- or -(CH2CH2O)6-.

[0044] Unless otherwise expressly indicated, the groups are optionally substituted. The term “optionally substituted” means either substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” means either a substituted or unsubstituted group (e.g., “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” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl group). Generally, the term “substituted” means that at least one hydrogen present in the group is replaced by an acceptable substituent, such as a substituent that simultaneously produces a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions of the group, and if more than one position is substituted in any given structure, the substituents are either the same or different at each position. The term “substituted” is intended to include substituent substitutions of all acceptable organic compounds and includes substitutions at any of the substituents described herein that result in the formation of a stable compound. This disclosure intends for all such combinations to arrive at a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen may have any suitable substituents as described herein that satisfy the hydrogen substituent and / or the valence of the heteroatom and result in the formation of a stable moiety. This disclosure is not limited in any way by the exemplary substituents described herein.

[0045] Examples of carbon atom substituents include halogens, -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(R bb )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 bb P(=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 アルキル、C 1-20 ペルハロアルキル、C 1-20 アルケニル、C 1-20Alkinyl, HeteroC 1-20 Alkyl, hetero C 1-20 Alkenyl, HeteroC 1-20 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Examples include aryls and 5-14 member heteroaryls, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd It is substituted with X - It is a counterion, Alternatively, the two geminal hydrogens on a carbon atom form the group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb , or =NOR cc Replaced by, Each R aa The example is independent of C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenil, C 1-20 Alkinyl, HeteroC 1-20 Alkyl, hetero C 1-20 Alkenyl, HeteroC 1-20 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base, Each R bbExamples of these are hydrogen, -OH, and -OR, independently. 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 Perhaloalkyl, C 1-20 Alkenil, C 1-20 Alkinyl, HeteroC 1-20 Alkyl, hetero C 1-20 Alkenyl, HeteroC 1-20 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R bb The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base, Each R cc Examples include hydrogen and C, which are independent of each other. 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenil, C 1-20 Alkinyl, HeteroC 1-20 Alkyl, hetero C1-20 Alkenyl, HeteroC 1-20 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base, Each R dd Examples of these are halogen, -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 ffC(=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 Perhaloalkyl, C 1-10 Alkenil, C 1-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 1-10 Alkenyl, HeteroC 1-10 Alkinyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by or two geminal R dd Substituents are attached to form =O or =S, X - It is a counterion, Each R ee The example is independent of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenil, C 1-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 1-10 Alkenyl, HeteroC1-10 Alkinyl, C 3-10 Carbocyclyl, C 6-10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg It is substituted with the base, Each R ff Examples include hydrogen and C, which are independent of each other. 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenil, C 1-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 1-10 Alkenyl, HeteroC 1-10 Alkinyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups are linked to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg It is substituted with the base, Each R gg Examples of these are halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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(OC1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -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), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -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), -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(C1-6 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 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenil, C 1-10 Alkinyl, HeteroC 1-10 Alkyl, hetero C 1-10 Alkenyl, HeteroC 1-10 Alkinyl, C 3-10 Carbocyclyl, C 6-10 It is an aryl, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl, or two geminal Rs. gg Substituents can be attached to form =O or =S, each X - It is a counterion.

[0046] In certain embodiments, each carbon atom substituent can be a halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C1-6 alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, -NO2, -C(=O)R aa , -CO 2 R aa -C(=O)N(R bb ) 2 -OC(=O)R aa , -OCO 2 R aa , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 Raa , or -NR bb C(=O)N(R bb ) 2 In certain embodiments, each carbon atom substituent can be halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C. 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(R bb )2, and here, R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 The R groups are alkyl groups, oxygen protecting groups attached to oxygen atoms (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or sulfur protecting groups attached to sulfur atoms (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each R is an oxygen protecting group attached to an alkyl or oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), and each R is an oxygen protecting group attached to an oxygen atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl). bb These are independently hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 Alkyl or nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 alkyl, -OR aa , -SR aa , -N(R bb ) 2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1-10 alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, or -NO2, where R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 The Rbb is an alkyl group, an oxygen protecting group attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or a sulfur protecting group attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl), and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C. 1-10 It is an alkyl group or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0047] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 alkyl, -C(=O)R aa , -CO 2 R aa -C(=O)N(R bb ) 2 , or nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogens) or unsubstituted C1-10 alkyl, -C(=O)R aa , -CO 2 R aa -C(=O)N(R bb ) 2 , or a nitrogen protecting group, where R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C1-10 An oxygen protecting group when attached to an alkyl or oxygen atom, where each Rbb independently supports hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 It is an alkyl or nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 alkyl or nitrogen protecting group.

[0048] In certain embodiments, substituents on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Examples of nitrogen protecting groups include -OH and -OR. 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), C1-20 alkenyl, C 1-20 Alkinyl, HeteroC 1-20 Alkyl, hetero C 1-20 Alkenyl, HeteroC 1-20 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14Examples include aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocykrill, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd It is substituted with R aa , R bb , R cc , and R dd This is as defined herein. Nitrogen protecting groups are well known in the art, and examples of nitrogen protecting groups include Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd This is detailed in edition, John Wiley & Sons, 1999.

[0049] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., -C(=O)R aa(The portion containing the nitrogen atom to which the nitrogen protecting group is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, independently includes formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetamide, (N'-dithiobenzyl The following are selected from the group consisting of xyacilamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazofenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0050] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a nitrogen protecting group (e.g., -C(=O)OR aa) is a portion containing a nitrogen atom to which the nitrogen protecting group is directly attached. In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, independently includes methyl carbamate, ethyl carbamate, 9-fluorenyl methyl carbamate (Fmoc), 9-(2-sulfo)fluorenyl methyl carbamate, 9-(2,7-dibromo)fluorenyl methyl carbamate, and 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxantyl)]methyl carbamate (DBD-Tmoc). ), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2-trichloroethylcarbamate (Troc), 2-trimethylsilylethylcarbamate (Teoc), 2-phenylethylcarbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethylcarbamate, 1,1-dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl Carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamide)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc ), allylcarbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamylcarbamate (Coc), 4-nitrocinnamylcarbamate (Noc), 8-quinolylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, benzylcarbamate (Cbz), p-methoxybenzylcarbamate (Moz), p-nitrobenzylcarbamate, p-bromobenzylcarbamate, p-chlorobenzylcarbamate, 2,4-Dichlorobenzylcarbamate, 4-Methylsulfinylbenzylcarbamate (Msz), 9-Anthrylmethylcarbamate, Diphenylmethylcarbamate, 2-Methylthioethylcarbamate, 2-Methylsulfonylethylcarbamate, 2-(p-Toluenesulfonyl)ethylcarbamate, [2-(1,3-Dithianyl)]methylcarbamate (Dmoc), 4-Methylthiophenylcarbamate (Mtpc), 2,4-Dimethylthiophenylcarbamate (Bmpc), 2-Phosphosphoethylcarbamate Peoc, 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzoisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethyl Toxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxyamide)benzylcarbamate, 1,1-dimethyl-3-(N,N- Dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,Selected from the group consisting of 5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0051] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a portion containing a nitrogen atom to which the nitrogen protecting group (e.g., -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, along with the nitrogen atom to which the nitrogen protecting group is attached, independently includes 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), and 2,4,6-tri The following are selected from the group consisting of methylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0052] In certain embodiments, each nitrogen protecting group, along with the nitrogen atom to which the nitrogen protecting group is attached, independently comprises phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, and N-2,5-dimethyl Pyrrole, N-1,1,4,4-tetramethyldisilyl azacyclopentane 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-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4 -Nitro-2-oxo-3-pyrroline-3-yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocerylmethylamino (Fcm), N-2-picolylamine N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyllideneamine, N-(5,The following are selected from the group consisting of 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboric acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramide, dibenzylphosphoramide, diphenylphosphoramide, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two examples of nitrogen protecting groups, along with the nitrogen atom to which the nitrogen protecting group is attached, are N,N'-isopropylidenediamine.

[0053] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0054] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogens) or unsubstituted C1-10 alkyl, -C(=O)R aa , -CO 2 R aa -C(=O)N(R bb ) 2 , or an oxygen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 alkyl, -C(=O)R aa , -CO 2 R aa -C(=O)N(R bb ) 2 , or an oxygen protecting group, where R aaC is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 An oxygen protecting group when attached to an alkyl or oxygen atom, where each Rbb independently supports hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 It is an alkyl or nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 alkyl or oxygen protecting group.

[0055] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Examples of oxygen protecting groups include -Raa, -N(R bb ) 2 -C(=O)SR aa -C(=O)R aa , -CO 2 R 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 , -SO 2 R 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 is given, and here, X - , R aa , R bb , and R cc This is defined herein. Oxygen protecting groups are well known in the art, and examples of oxygen protecting groups include Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd This is detailed in edition, John Wiley & Sons, 1999.

[0056] In certain embodiments, each oxygen protecting group, along with the oxygen atom to which the oxygen protecting group is attached, is methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (M EM), 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-methoxypiperidine-4-yl (CT MP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-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-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-Dimethoxytriphenylmethyl (or DMT), α-Naphthyldiphenylmethyl, p-Methoxyphenyldiphenylmethyl, Di(p-Methoxyphenyl)phenylmethyl, Tri(p-Methoxyphenyl)methyl, 4-(4'-Bromophenacyloxyphenyl)diphenylmethyl, 4,4',4″-Tris(4,5-Dichlorophthalimidophenyl)methyl, 4,4',4″-Tris(Lebrinoyloxyphenyl)methyl, 4,4',4″-Tris(Benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3″'-[N-(Imidazolylmethyl [I] Trityl ether (IDTr-OR), 4,4'-dimethoxy-3″'-[N-(imidazolylethyl)carbamoyl]trityl ether (IETr-OR), 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Dimethyltexylsilyl, t-Butyldimethylsilyl (TBDMS), t-Butyldiphenylsilyl (TBDPS), Tribenzylsilyl, Tri-p-Xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl (DPMS), t-Butylmethoxyphenylsilyl (TBMPS), Formate, Benzoylformate, Acetate, Chloroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Fe Noxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (rebrinate), 4,4-(ethylenedithio)pentanoate (rebrinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxyben Zyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate -Bonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenyl acetate, isobutyrate, monosuccinoate Selected from the group consisting of (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphodiamide, alkyl N-phenylcarbamate, borate, dimethylphosphinthiole, alkyl 2,4-dinitrophenyl sulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0057] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0058] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogens) or unsubstituted C1-10 alkyl, -C(=O)R aa , -CO 2 R aa -C(=O)N(R bb ) 2 , or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogens) or unsubstituted C1-10 alkyl, -C(=O)R aa , -CO 2 R aa -C(=O)N(R bb ) 2 , or a sulfur protecting group, where R aa C is hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 An oxygen protecting group when attached to an alkyl or oxygen atom, where each Rbb independently supports hydrogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 It is an alkyl or nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C1-6 alkyl or sulfur protecting group.

[0059] In certain embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also called "thiol protecting groups"). In some embodiments, each sulfur protecting group is -Raa, -N(R bb ) 2 -C(=O)SR aa -C(=O)R aa , -CO 2 R 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 , -SO 2R 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 ) Selected from the group consisting of 2, where R aa , R bb , and R cc This is as defined herein. Sulfur protecting groups are well known in the art, and examples of sulfur protecting groups include Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd This is detailed in edition, John Wiley & Sons, 1999.

[0060] In certain embodiments, the molecular weight of the substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, the substituent includes 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, the substituent includes 0, 1, 2, or 3 hydrogen bond acceptors.

[0061] Click chemistry, first introduced in 2001 by K. Barry Sharpless, is a chemical approach designed to rapidly and reliably generate substances by linking small units together through coupling reactions. See, for example, Kolb, Finn and Sharpless, Angewandte Chemie International Edition (2001) 40:2004-2021, and Evans, Australian Journal of Chemistry (2007) 60:384-395). Exemplary coupling reactions include, but are not limited to, the formation of esters, thioesters, and amides from activated acids or acyl halides (e.g., peptide coupling), nucleophilic substitution reactions (e.g., nucleophilic substitution of halides or ring opening of strained ring systems), azido-alkyne Huisgen cycloaddition, thiol-in addition, imine formation, Michael addition (e.g., maleimide addition), and Diels-Alder reactions (e.g., tetrazine[4+2] cycloaddition).

[0062] As used herein, the term “salt” refers to all salts, including pharmaceutically acceptable salts. Examples of salts include ionic compounds resulting from the neutralization reaction of acids and bases. Salts consist of one or more cations (positively charged ions) and one or more anions (negatively charged ions), and are therefore electrically neutral (have no net charge). Salts of the compounds of this disclosure include those derived from inorganic acids and organic acids, as well as inorganic bases and organic bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods known in the art, such as ion exchange. Other salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate. Examples of suitable salts include lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and similar salts. Suitable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar compounds. Further salts include those formed using ammonium, quaternary ammonium, and amine cations with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0063] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues, is free from excessive toxicity, irritation, allergic reactions, and similar effects, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, describe pharmaceutically acceptable salts in detail. Examples of pharmaceutically acceptable salts of the compounds of this disclosure include those derived from appropriate inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and lac. Examples of suitable salts include tobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, valersates, and similar salts. Suitable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts may be formed using non-toxic ammonium, quaternary ammonium, and amine cations with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0064] The term "prodrug" refers to a compound that can be converted to an oligonucleotide described herein under physiological conditions or by solvolysis. Prodrugs may be precursors to oligonucleotides and may be pharmaceutically acceptable. Prodrugs may be inactive at the time of administration to a subject, but at least one of the conversion products (e.g., oligonucleotides) may be active. Compared to oligonucleotides, prodrugs may offer advantages such as higher solubility, higher permeability, higher absorption, improved distribution, improved metabolism, improved excretion, higher exposure, higher histocompatibility, slower-acting delivery, more sustained-release delivery, lower toxicity, and / or a wider therapeutic time range (see, for example, Bundgard, H., DESIGN OF PRODRUGS (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). The prodrugs have been discussed in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol.14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. Prodrugs are oligonucleotides with -OH, -NH2, -SH, -C(=O)OH, The compounds may be those in which a hydrogen atom of -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O- is replaced by a protecting group ("PG", for example, a carbon-bonded 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- may be converted under physiological conditions or by solvolysis to form -OH, -NH2, -SH, -C(=O)OH, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-. Examples of prodrugs, but not limited to, include phosphorus-modified nucleic acid glutathione, acyloxy, thioacyloxy, 2-carbokkiethyl, disulfide, thiaminal, and enol ester derivatives. Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., “Prodrugs or phosphonates and phosphates: crossing the membrane,” Top. Curr. Chem., 2015, 360:115-160. In certain embodiments, the prodrug is one of the prodrugs of the formulas described herein.

[0065] The “subjects” to which the administration is intended refers to humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, or adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) or non-human animals. In certain embodiments, non-human animals are mammals (e.g., primates (e.g., crab-eating macaques or rhesus macaques), commercially relevant mammals (e.g., cattle, pigs, horses, sheep, goats, cats, or dogs), or birds (e.g., commercially relevant birds such as chickens, ducks, geese, or turkeys)). In certain embodiments, non-human animals are fish, reptiles, or amphibians. Non-human animals may be male or female at any developmental stage. Non-human animals may be transgenic animals or genetically modified animals. The term “patient” refers to a human subject requiring treatment for a disease.

[0066] The terms “administer,” “dosing,” or “administer” refer to the act of implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or pharmaceutical composition described herein into or onto a subject.

[0067] The terms “treatment,” “to treat,” and “to treat” refer to restoring, alleviating, delaying the onset of, or inhibiting the progression of any disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have appeared 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 symptoms appear (e.g., considering a history of symptoms and / or exposure to the pathogen). Treatment may also be continued after symptoms have subsided (e.g., to delay or prevent recurrence).

[0068] The terms “prevent,” “prevention,” or “prevention” refer to preventive measures for individuals who do not currently have, and have not had, the disease, but are at risk of developing the disease, or individuals who have had the disease in the past, are not currently diseased, but are at risk of disease recurrence. In certain embodiments, individuals are at a higher risk of developing or experiencing disease recurrence than the average healthy member of the target population.

[0069] The terms "medical condition," "disease," and "disorder" are used interchangeably.

[0070] The “effective dose” of the compounds described herein refers to an amount sufficient to elicit a desired biological response. The effective dose of the compounds described herein may vary depending on factors such as the desired biological endpoint, the severity of the side effect, disease, or disorder, the uniqueness of the particular compound, pharmacokinetics, and pharmacodynamics, the medical condition being treated, the method and route of administration, and the desired or required frequency, the species, age, and health or general condition of the subject. In certain embodiments, the effective dose is a therapeutic effective dose. In certain embodiments, the effective dose is a prophylactic dose. In certain embodiments, the effective dose is the amount in a single dose of the compound described herein. In certain embodiments, the effective dose is the total amount in multiple doses of the compound described herein. In certain embodiments, the desired dose is delivered three times a day, twice a day, once a day, once every two days, once every three days, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the desired dose is delivered by multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more doses).

[0071] The "therapeutic dose" of a compound is an amount sufficient to produce a therapeutic effect in the treatment of a medical condition, or sufficient to delay or minimize one or more signs and / or symptoms associated with that condition. In certain embodiments, the therapeutic dose is an amount that improves the overall treatment, reduces or avoids the symptoms, signs, or causes of a medical condition, and / or enhances the therapeutic effect of another therapeutic agent.

[0072] The “preventive effective dose” of a compound is the amount sufficient to prevent a disease or one or more signs and / or symptoms associated with that disease, or sufficient to prevent their recurrence. In certain embodiments, the preventive effective dose is the amount that improves overall prevention and / or enhances the preventive effect of another preventive agent.

[0073] The term "composition" refers to a mixture of substances. The term "pharmaceutical composition" refers to a composition suitable for administration to a subject.

[0074] [ka] The symbol indicates the attachment point of the chemically active part to the rest of the compound or chemical formula.

[0075] The term "small molecule" refers to a molecule with a relatively small molecular weight, whether of natural origin or artificially created (e.g., by chemical synthesis). Typically, small molecules are organic compounds (i.e., they contain carbon). Small molecules may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, and heterocyclic rings). In certain embodiments, the molecular weight of a small molecule is 2,000 g / mol or less. In certain embodiments, the molecular weight of a small molecule is 1,500 g / mol or less. In certain embodiments, the molecular weight of a small molecule is 1,000 g / mol or less, 900 g / mol or less, 800 g / mol or less, 700 g / mol or less, 600 g / mol or less, 500 g / mol or less, 400 g / mol or less, 300 g / mol or less, 200 g / mol or less, or 100 g / mol or less. In certain embodiments, the molecular weight of the small molecule is 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 500 g / mol or less) are also possible. In certain embodiments, the small molecule is a therapeutic agent such as a drug (e.g., a molecule approved by the US Food and Drug Administration as shown in the Code of Federal Regulations (CFR)). The small molecule may also form complexes with one or more metal atoms and / or metal ions. In this example, the small molecule is also called an “organometallic small molecule”. Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. It is preferable, but not always, that the drug has already been deemed safe and effective for use in humans or animals by a suitable government agency or regulatory authority.For example, drugs approved for human use are defined by the FDA under 21 C. FR Sections 330.5, 331 through 361, and 440 through 460, and drugs approved for veterinary use are defined by the FDA under 21 C. FR Sections 500 through 589. All defined drugs are considered to be available for use in accordance with this disclosure.

[0076] The terms “peptide,” “polypeptide,” or “protein” refer to oligomers or polymers of amino acid residues covalently linked to one another by peptide bonds. Peptides, polypeptides, or proteins can be of any size, structure, and function, and may be a single peptide, polypeptide, or protein, or a collection (e.g., complex) of peptides, polypeptides, and proteins, and optionally small molecules and / or metal ions. In certain embodiments, a peptide contains 2 to 10, 11 to 20, 21 to 30, 31 to 40, or 41 to 50 amino acid residues (including both ends). In certain embodiments, a polypeptide or protein contains 51 to 100, 101 to 200, 201 to 300, 301 to 500, 501 to 1,000, 1,001 to 3,000, 3,001 to 10,000, or 10,001 to 30,000 amino acid residues (including both ends). Peptides, polypeptides, or proteins may contain only natural amino acids and no unnatural amino acids, only unnatural amino acids and no natural amino acids, or both natural and unnatural amino acids. Peptides, polypeptides, or proteins may contain only amino acid analogs, or may contain amino acid analogs in addition to natural and / or unnatural amino acids. In certain embodiments, the amino acid residues of a peptide, polypeptide, or protein are alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and / or valine residues, and are D- and / or L-forms (e.g., L-form). One or more amino acid residues in a peptide, polypeptide, or protein may be alpha-amino acid residues or their homologs (e.g., beta-amino acid residues). One or more amino acid residues in a peptide, polypeptide, or protein may or may not be protected.One or more (e.g., two) ends of a peptide, polypeptide, or protein may be protected (e.g., to form an ester or amide) or not (e.g., -NH2, -NH3). + -C(=O)OH, or -C(=O)O - (As such). One or more amino acid residues in a peptide, polypeptide, or protein may or may not be modified. Modifications to amino acid residues in a peptide, polypeptide, or protein may include the addition of a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, or a linker for conjugation or functionalization. Peptides, polypeptides, or proteins may be of natural origin, recombinant, synthetic, or a combination thereof. Peptides, polypeptides, or proteins may be fragments of naturally occurring peptides, polypeptides, or proteins.

[0077] The term "nucleic acid" refers to a compound composed of linked monomeric nucleotides or nucleosides. Examples of nucleic acids, though not limited to them, include ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0078] The terms “oligomeric compound” or “oligomer” refer to a compound consisting of a small number of linked (e.g., covalently linked) subunits. With respect to proteins, peptides, polypeptides, or antibodies, “subunit” refers to an amino acid (e.g., a protected or unprotected amino acid) or a peptide bond. With respect to oligonucleotides, “subunit” refers to a nucleotide, nucleoside, nucleic acid base, internucleoside linker, or sugar, or a modified nucleotide, nucleoside, nucleic acid base, internucleoside linker, or sugar, or a combination thereof (e.g., a combination of nucleic acid base, internucleoside linker, or sugar, each of which may or may not be modified). A small number can be between 6 and 100 (including both ends). In some embodiments, a minority is 6-9, 10-13, 14-18, 19-23, 24-30, 31-40, 41-50, 51-60, 61-80, or 81-100 (including both ends).

[0079] The term "oligonucleotide" means an oligomer of linked (e.g., covalently linked) nucleotides and / or nucleosides (e.g., a nucleic acid that is an oligomer of a nucleotide), where each nucleotide and / or nucleoside may be independently modified or unmodified. Oligonucleotides may consist of, but are not limited to, ribonucleic acid (e.g., composed of ribonucleosides), deoxyribonucleic acid (e.g., composed of deoxyribonucleosides), modified nucleic acid (e.g., composed of modified nucleic acid bases, sugars and / or phosphate groups), or combinations thereof. Oligonucleotides may contain one or more loops within their structure (e.g., stem loops, hairpin loops, or internal loops in an RNA structure). Oligonucleotides may be single-stranded or double-stranded and may be RNA, DNA, or hybrids thereof.Oligonucleotides 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, lysogenic bacteria, repetitive DNA, satellite DNA, viral DNA, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), messenger RNA (mRNA), messenger RNA precursor (premRNA), transfer RNA (tRNA), heteronuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, and viral satellite RN. A may include signal recognition particle RNA, low molecular weight cytoplasmic RNA, low molecular weight nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-binding RNA (piRNA), polyinosinic acid, ribozymes, flexizymes, nucleolar low molecular weight RNA (snoRNA), splice reader RNA, viral RNA, antisense oligonucleotides (e.g., antisense DNA and antisense RNA), RNA interference compounds (RNAi compounds), circular RNA (circRNA) compounds, oligonucleotides targeting microRNA (miRNA), miRNA mimes, occupation-based compounds (e.g., compounds that block mRNA processing or translation and splicing compounds), and editing compounds (e.g., ADAR recruiting 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), small hairpin RNA (shRNA), and microRNA mimes). RNAi compounds act, at least in part, via the RNA-induced silencing complex (RISC) pathway, resulting in sequence-specific degradation and / or sequestration of target nucleic acids 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 that can mediate sequence-specific RNA interference (e.g., interfering RNA (iRNA), iRNA activators, RNAi activators, small interfering RNA, short interfering RNA, short interfering oligonucleotides, short interfering nucleic acids, short interfering modified oligonucleotides, chemically modified siRNAs, and others). In addition, the term “RNAi” is intended to be equivalent to other terms used to describe sequence-specific RNA interference. In some embodiments, the oligonucleotide contains 6–100 nucleotides and nucleosides. In some embodiments, the oligonucleotide contains 10–50 nucleotides and nucleosides. In some embodiments, the oligonucleotide contains 14–30 nucleotides and nucleosides. In some embodiments, the oligonucleotide contains 20–23 nucleotides and nucleosides. In certain embodiments, the oligonucleotide contains 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides and nucleosides.

[0080] Double-stranded oligonucleotides may have "blunt ends" or "overhangs." In blunt-ended oligonucleotides, both strands are of equal length, terminate at the same base position, and neither end has any unpaired bases. In contrast, oligonucleotides with overhangs (or "sticky ends") contain unpaired nucleotides at each end. In some embodiments, oligonucleotides have blunt ends at both ends. In some embodiments, oligonucleotides have overhangs at each end. In some embodiments, oligonucleotides have a blunt end at one end and an overhang at the other end. In certain embodiments, oligonucleotides contain 6-8, 9-11, 12-14, 15-17, 18-20, 21-24, 25-28, 29-32, 33-36, or 37-40 paired base pairs (including both ends).

[0081] The term "nucleic acid base" refers to the nitrogen-containing portion at the 1' position of a nucleoside. Nucleic acid bases can include purine bases and pyrimidine bases. Five nucleic acid bases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are called the major or standard nucleic acid bases. Nucleic acid bases can include unmodified and modified nucleic acid bases. When a nucleic acid base is mentioned in a formula definition, it refers to the portion covalently bonded to the detailed formula.

[0082] The term "nucleic acid base sequence" refers to the sequence of nucleic acid bases in a nucleic acid or oligonucleotide, independently of any sugar or nucleoside bond.

[0083] The term "nucleoside" refers to a compound containing a nucleic acid base and a sugar moiety. The nucleic acid base and sugar moiety can be independently unmodified or modified. A nucleoside can be unmodified or modified. A "modified nucleoside" refers to a nucleoside containing a modified nucleic acid base and / or a modified sugar moiety. Examples of modified nucleosides include debasic nucleosides, which lack a nucleic acid base and optionally contain a non-nucleic acid base moiety at the corresponding position (e.g., the 1' position).

[0084] The terms "nucleoside bond," "nucleoside linker," "nucleoside bond," and "nucleoside linker" are used interchangeably.

[0085] The terms “target nucleic acid,” “target RNA,” and “nucleic acid target” all mean nucleic acids that can be targeted by oligonucleotides (e.g., the ligand radicals contained in such oligonucleotides) as described herein.

[0086] The "target region" refers to a portion of the target nucleic acid targeted by one or more oligonucleotides (for example, the ligand radicals contained within those oligonucleotides).

[0087] A "terminal group" refers to a chemical group or atomic group that is covalently bonded to the end of an oligonucleotide.

[0088] The terms “sense oligonucleotide,” “sense oligonucleotide chain,” or “sense chain” refer to a chain of a double-stranded oligonucleotide that contains a region substantially complementary to a region of the antisense chain of the double-stranded oligonucleotide. The sense chain may contain a code that is translatable in the 5' to 3' direction.

[0089] The terms “antisense oligonucleotide,” “antisense oligonucleotide chain,” or “antisense chain” mean an oligonucleotide that includes a region that is complementary, or at least partially complementary, to the sense chain of the target nucleic acid or nucleic acid. In some embodiments, the antisense chain does not possess a code that is translatable in the 5' to 3' direction. In some embodiments, the antisense chain and the sense chain or target nucleic acid are complementary to each other by 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%. In certain embodiments, the antisense chain and the sense chain or target nucleic acid are perfectly complementary (100% complementary).

[0090] The terms “microRNA” and “miRNA,” which may be used interchangeably herein, refer to short-chain (e.g., about 20 to 24 nucleotides long) non-coding ribonucleic acid (RNA) that are involved in the post-transcriptional regulation of gene expression in multicellular organisms by affecting both mRNA stability and translation. miRNAs are transcribed by RNA polymerase II as part of a capped and polyadenylated primary transcript (pri-miRNA), which may or may not encode proteins. This primary transcript is cleaved by the enzyme Drosha ribonuclease III to produce stem-loop precursor miRNAs (pre-miRNAs) approximately 70 nucleosides long, which are further processed in the RNAi pathway. As part of this pathway, the pre-miRNA is cleaved by cytoplasmic dicer ribonucleases to produce mature miRNAs and antisense miRNA stars (miRNA*) products. The mature miRNA is incorporated into the RNA-induced silencing complex (RISC), which recognizes the target mRNA through incomplete base pairing (i.e., partial complementarity) with the miRNA, most commonly resulting in the inhibition or destabilization of the translation of the target mRNA. This mechanism is most often seen through the fact that the miRNA can reduce gene expression by either binding to the 3' untranslated region (UTR) of the target mRNA and inhibiting translation (e.g., by blocking ribosomes from reaching it for translation) or by directly degrading the transcript. The term (i.e., miRNA) may be used herein to refer to any form of the target miRNA (e.g., miRNA precursor, primary miRNA, and / or mature miRNA).

[0091] The terms “small interfering RNA,” “short interfering RNA,” and “siRNA,” which may be used interchangeably herein, refer to RNA compounds that exist as non-coding single-stranded or double-stranded RNA (dsRNA) compounds having a chain (may be one or more) of approximately 20 to approximately 24 nucleotides in length and are useful for RNA interference (RNAi). siRNAs are often found with a phosphorylated 5' end and a hydroxylated 3' end, the 3' end typically having a 2-nucleotide overhang 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 complementary target sequence (e.g., a target nucleic acid sequence) and promoting (e.g., promoting, inducing, initiating) mRNA degradation, thereby interfering with (e.g., inhibiting, silencing, interfering with) translation. RNAi modulates target nucleic acids and / or proteins encoded by target nucleic acids, at least in part, through the RNA-induced silencing complex (RISC) pathway or Ago2, rather than through RNase H. After integration into and separation from the RISC complex, the siRNA forms base pairs with its target mRNA (e.g., complete complementarity) and cleaves the target mRNA, thereby preventing it from being used as a translation template. As described herein, the RISC complex loaded with miRNA is also part of the RNAi pathway, scanning cytoplasmic mRNA for potential complementarity (e.g., partial complementarity).

[0092] The term "circular RNA" ("circRNA") refers to RNA that is covalently closed to form a continuous loop (i.e., its 5' and 3' ends are connected to each other). CircRNAs are resistant to exonuclease degradation and are often far more stable than their corresponding linear RNA sequences. Consequently, circRNAs typically have a longer half-life than linear RNAs. CircRNAs have diverse biological functions, for example, they are known to act as transcription factors, microRNA sponges, and protein templates. CircRNAs are also known to interact with proteins, for example, by mediating or altering protein-protein interactions, sequestering proteins, recruiting proteins to chromatin, and facilitating protein translocation.

[0093] "Small hairpin RNA" ("shRNA") refers to RNA compounds that have tight hairpin-shaped folds and can be used, for example, to silence the expression of target genes via RNAi. Due to the presence of the hairpin structure, shRNAs often have lower degradation and turnover rates compared to other RNAi agents.

[0094] The terms "mRNA" or "mRNA molecule" refer to messenger RNA, or RNA that acts as a template for protein synthesis within a cell. The sequence of an mRNA strand is based on the complementary DNA strand sequence that contains the sequence that codes for the protein to be synthesized.

[0095] The term “ADAR recruiting compound” as used herein refers to a nucleic acid configured to increase the concentration of an RNA-acting adenosine deaminase (ADAR) enzyme in the vicinity of the nucleic acid. In some embodiments, the increase in concentration is compared to the concentration at a given location where the ADAR recruiting compound is not present. In some embodiments, the ADAR recruiting compound comprises a double-stranded RNA diluent.

[0096] As used herein, the term “ADAR-targeting compound” refers to a nucleic acid configured to guide (e.g., localize) an ADAR compound to a desired location. As used herein, the term “guide” refers to 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 nucleic acid bases, sugars, nucleoside bonds, or other components). In some embodiments, the ADAR-targeting compound comprises an ADAR recruiting compound and a single-stranded guide nucleic acid. In some embodiments, the ADAR-targeting compound comprises a double-stranded RNA didulo and a single-stranded guide nucleic acid.

[0097] The terms “single-stranded guide nucleic acid” or “guide RNA” as used herein refer to a single-stranded nucleic acid comprising a specific sequence that is at least partially complementary to the target sequence. In some embodiments, the target sequence is located at, adjacent to, or near a location where it is desirable to modulate ADAR concentration. In some embodiments, the level of complementarity is sufficient to facilitate the binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.

[0098] A "modified oligonucleotide" refers to an oligonucleotide in which at least one sugar, nucleic acid base, or nucleoside bond has been modified.

[0099] "Nucleic acid base sequence" refers to the sequence of consecutive nucleic acid bases in a nucleic acid or oligonucleotide, independent of any sugar or nucleoside bonds.

[0100] The term "oligomeric double-stranded" refers to a double-stranded structure formed by two oligomeric compounds having complementary nucleic acid base sequences. Each oligomeric compound in an oligomeric double-stranded structure is sometimes called a "double-stranded oligomeric compound." Each oligonucleotide compound in an oligomeric double-stranded structure may contain a non-complementary overhanging nucleoside. "Phosphothioate," "phosphorothioate bond," or "phosphorothioate linker" refers to a modified phosphate bond in which one of the non-bridged oxygen atoms is replaced by a sulfur atom.

[0101] "Phospholothiolate," "phospholothiolate bond," or "phospholothiolate linker" refers to a modified phosphate bond in which one or each of the bridging oxygen atoms is replaced by a sulfur atom.

[0102] A "linker" refers to a polyvalent (e.g., divalent, trivalent, or tetravalent) chemical part (e.g., a combination of atoms having a suitable valency according to known chemical principles) that covalently links two or more (e.g., three or four) components of the compounds (e.g., oligonucleotides) provided herein.

[0103] The term "ligand" refers to a substance that binds to or interacts with proteins, nucleic acids, or other biomolecules. In some embodiments, ligands are selected from the group consisting of small molecules, saccharins, oligosaccharides, polysaccharides, biomacromolecules (e.g., peptides, proteins, and peptide analogs and peptide derivatives), peptidomimetics, antibodies and their antigen-binding fragments, nucleic acids, nucleic acid analogs and nucleic acid derivatives, extracts obtained from biomolecules such as bacteria, plants, fungi, or animal cells, animal tissues, and compositions of natural or synthetic origin. In some embodiments, ligands are small molecules. In some embodiments, ligands bind to proteins (e.g., receptors). In certain embodiments, ligands are tropomyosin receptor kinase B (TrkB), cannabinoid receptor type 1 (CB1), α4β1 / 7 The ligand binds to an integrin receptor or an N-methyl-D-aspartate (NMDA) receptor. In some embodiments, the ligand can selectively target an oligonucleotide (e.g., its oligonucleotide chain) to a region or cell in the body. In some embodiments, the ligand can target an oligonucleotide (e.g., its oligonucleotide chain) to a target brain region (e.g., the striatum, cerebellum, brainstem, hippocampus, prefrontal cortex, or spinal cord). In some embodiments, the ligand can target a central nervous system (CNS) cell (e.g., a neuron). In some embodiments, the ligand is not a lipid.

[0104] The term “internal position” of an oligonucleotide chain refers to a position of the oligonucleotide chain other than the 5' nucleoside or 3' nucleoside. In some embodiments, internal positions are located at nucleosidic bonds (e.g., nucleosidic bonds between the 5' nucleoside and the second nucleoside from the 5' end, nucleosidic bonds between the 3' nucleoside and the second nucleoside from the 3' end, nucleosidic bonds between the nth nucleoside and the (n+1)th nucleoside from the 5' end, where n is an integer from 2 to 20 (including both ends), as long as the number of nucleosides in the oligonucleotide chain allows). In some embodiments, internal positions are the positions of “internal nucleosides” (nucleosides that are not 5' nucleosides or 3' nucleosides). Oligonucleotides that have modifications at internal positions (e.g., conjugation of ligand radicals) are sometimes also called “internally modified oligonucleotides.”

[0105] The terms "lipid" or "lipophilic portion" refer to organic compounds that are substantially insoluble in water at ambient temperature and pressure. Lipids may be those listed in the LIPID MAPS® Structure Database (LMSD). Lipids may be aliphatic acyls, glycerolipids, glycerophospholipids, sphingolipids, glycolipids, polyketides, sterollipids, or prenolipids. Aliphatic acyls may be fatty acids or conjugates, octadecanoids, eicosanoids, docosanoids, aliphatic alcohols, aliphatic aldehydes, aliphatic esters, aliphatic amides, aliphatic nitriles, aliphatic ethers, hydrocarbons, oxygenated hydrocarbons, or aliphatic acyl glycosides. Glycerolipids may be monoradilglycerol, diradilglycerol, triradilglycerol, glycosylmonradilglycerol, glycosyldiradylglycerol, betaine monoradilglycerol, or betaine diradilglycerol. Glycerophospholipids may be glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid, glycerophosphoinositol glycan, glycerophosphonocholine, glycerophosphonoethanolamine, diglycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetone phosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid. Sphingolipids can be sphingoid bases, ceramides, phosphosphingolipids, phosphonosphingolipids, neutral sphingoglycolipids, acidic sphingoglycolipids, basic sphingoglycolipids, amphoteric sphingoglycolipids, or arsenosphingolipids.Glycolipids may be acylamino sugars, acylaminoglycans, acyltrehaloses, or acyltrehalose glycans. Polyketides may be linear polyketides, halogenated acetogenins, Annonaceae acetogenins, macrolides, lactone polyketides, ansamycin, polyenes, linear tetracyclines, angucyclines, polyether antibiotics, aflatoxins, cytochalasins, flavonoids, aromatic polyketides, non-ribosomal peptide / polyketide hybrids, or phenolic lipids. Sterol lipids may be sterols, steroids, secosteroids, bile acids or their derivatives, or steroid conjugates. Prenolic lipids may be isoprenoids, quinones, hydroquinones, polyprennols, or hopanoids. The term lipids include, for example, cholesterol, retinoic acid, cholic acid, adamantane acetate, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. Lipids can be hydrocarbons (e.g., substituted or unsubstituted, saturated or unsaturated, branched or unbranched hydrocarbons). Hydrocarbons can be alkanes, alkenes, or alkynes. The size of unsubstituted hydrocarbons is C7-C. 36 This is possible (i.e., unsubstituted hydrocarbons contain a total of 7–36 carbon atoms in the main chain and branched chains (if any)). Substituted hydrocarbons can be hydrocarbons substituted with at least one halogen (e.g., F) atom, as long as their valence allows. In certain embodiments, each substituent of a substituted hydrocarbon is not another hydrocarbon. The size of a substituted hydrocarbon is C7–C 36 This is possible (i.e., substituted hydrocarbons contain a total of 7-36 carbon atoms in the main chain and branched chains (if any), excluding the substituent atoms).

[0106] The terms "unsaturated" or "partially unsaturated" refer to a portion containing at least one double or triple bond.

[0107] The term "saturated" refers to a portion that does not contain double or triple bonds (i.e., that portion contains only single bonds). [Modes for carrying out the invention]

[0108] In one embodiment, the Disclosure provides oligonucleotides comprising a ligand radical at an internal position. The Disclosure also provides pharmaceutical compositions and kits comprising any of the oligonucleotides disclosed herein. The Disclosure also provides methods for delivering any of the oligonucleotides disclosed herein to a target, methods for treating a disease in a subject requiring treatment of the disease using any of the oligonucleotides disclosed herein, methods for preventing a disease in a subject requiring prevention of the disease using any of the oligonucleotides disclosed herein, and methods for modulating the activity of a protein in a subject, cell, tissue, or biological sample. In certain embodiments, the disease is a CNS disease, a neurodegenerative disease, or a neurocognitive disorder.

[0109] oligonucleotides In one embodiment, the present disclosure relates to a modified oligonucleotide chain of formula I: [ka] We provide oligonucleotides or pharmaceutically acceptable salts or prodrugs containing, wherein [ka] It is a divalent radical of an oligonucleotide chain, [ka] One example of a nucleoside linker is independently [ka] Replaced by, s1 is 1, 2, 3, 4, 5, or 6. Each L A and L 4 An example of this is an independent linker, Each A 4 Examples include a ligand or lipid radical independently, but with at least one A 4 An example is the ligand radical, Each of y5 and y6 is independently either 0 or 1. If y5 is 0, L 5 C is hydrogen, substituted or unsubstituted. 1-6 If it is an alkyl group, or an oxygen protecting group, or if y5 is 1, L 5 It is a linker, If y6 is 0, L 6 C is hydrogen, substituted or unsubstituted. 1-6 If it is an alkyl group, or an oxygen protecting group, or if y6 is 1, L 6 It is a linker, A 5 and A 6 Each of these, if present, is independently a ligand or lipid radical. Each ligand is different from each lipid.

[0110] In certain embodiments, s1 is 1. In certain embodiments, s1 is 2, 3, 4, 5, or 6.

[0111] In certain embodiments, y5 is 0. In certain embodiments, y5 is 1. In certain embodiments, y6 is 0. In certain embodiments, y6 is 1.

[0112] In certain embodiments, the oligonucleotide chain has a nucleic acid base sequence that is at least partially complementary to the target nucleic acid sequence (e.g., the target nucleic acid to be expressed intracellularly). In some embodiments, the oligonucleotide can modify the expression of the original gene when delivered to a cell expressing the target nucleic acid. In some embodiments, the oligonucleotide can inhibit the expression of the original gene when delivered to a cell expressing the target nucleic acid. The gene expression can be modified or inhibited in vitro or in vivo. In certain embodiments, the oligonucleotide comprises one or more ribonucleic acids (e.g., one or more ribonucleosides), deoxyribonucleic acids (e.g., one or more deoxyribonucleosides), modified nucleic acids (e.g., one or more modified nucleic acid bases, modified sugars and / or modified nucleotide interbonds), or a combination 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 nucleic acid bases, modified sugars, or modified nucleoside interbonds).

[0113] 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 certain embodiments, the first oligonucleotide chain is composed of radicals of one or more ligands (e.g., TrkB, CB1, α4β). 1 / 7 It is linked to an integrin or NMDA receptor ligand. In certain embodiments, the second oligonucleotide chain is linked to the radical of one or more ligands (e.g., TrkB, CB1, α4β). 1 / 7It is linked to an integrin or an NMDA receptor ligand. In certain embodiments, the oligonucleotide contains one or more ligand radicals at one or more internal positions. In certain embodiments, the oligonucleotide contains one or more ligand radicals at one or more internal positions, and optionally further contains a ligand radical at the 5' terminus and / or further contains a ligand radical at the 3' terminus.

[0114] In some embodiments, the oligonucleotide chains are 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, 5 The length is 2, 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.

[0115] In some embodiments, the oligonucleotide chain has a nucleotide length of 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 of both ends). In some embodiments, the oligonucleotide chain is approximately 6 to approximately 100 nucleotides long (inclusive of both ends). In some embodiments, the oligonucleotide chain is approximately 20 to approximately 90 nucleotides long (inclusive of both ends). In some embodiments, the oligonucleotide chain is approximately 30 to approximately 80 nucleotides long (inclusive of both ends). In some embodiments, the oligonucleotide chain is approximately 40 to approximately 70 nucleotides long (inclusive of both ends). In some embodiments, the oligonucleotide chain is approximately 50 to 60 nucleotides long (including both ends).

[0116] In certain embodiments, the oligonucleotide chain is approximately 14 to 23 nucleotides long.

[0117] In some embodiments, the oligonucleotide is a therapeutic oligonucleotide. Therapeutic oligonucleotides may include, for example, RNA (e.g., small interfering RNA (siRNA), microRNA (miRNA) antagonists, miRNA mimes, ADAR recruiting compounds, ADAR targeting compounds, guide RNA, antisense oligonucleotides, small hairpin RNA (shRNA), circular RNA (circRNA)) or combinations thereof.

[0118] In certain embodiments, the miRNA is a miRNA precursor, a primary miRNA, and / or a mature miRNA.

[0119] In certain embodiments, the oligonucleotide comprises an antisense oligonucleotide chain. In certain 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 certain embodiments, the antisense oligonucleotide chain is complementary to premRNA. In certain embodiments, the antisense oligonucleotide chain blocks the translation of mRNA transcripts and promotes their degradation. In certain embodiments, the antisense oligonucleotide (alone or with a complementary sense oligonucleotide) can silence gene expression through the RNA-induced silencing complex (RISC) pathway. In certain embodiments, the antisense oligonucleotide chain recruits RNase H and promotes the degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide chain targets miRNAs, inhibits the regulation of their mRNA expression, and promotes their degradation. In certain embodiments, the oligonucleotide contains or recruits an editing complex for editing RNA.

[0120] Certain oligonucleotides in this disclosure may exist in solvated forms (including hydrated forms) as well as in non-solvated forms. Certain oligonucleotides in this disclosure may exist in crystalline or amorphous forms.

[0121] In certain embodiments, the oligonucleotide comprises an oligonucleotide chain 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) having at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity or complementarity with a gene (e.g., a human gene) associated with a disease (e.g., a CNS disease). In certain embodiments, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. In certain embodiments, the disease is associated with gene overexpression. In certain embodiments, "related to" means "at least partially caused by".

[0122] In certain embodiments, the oligonucleotide comprises an oligonucleotide chain 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) 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 microtubule-associated tau protein (MAPT) gene (e.g., the human MAPT gene). In certain embodiments, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human MAPT gene can be found, for example, in GenBank accession number NM_001377265.1 (incorporated herein as SEQ ID NO: 1) and nucleotides 2624000-2761000 of NT_010783.14 (incorporated herein as SEQ ID NO: 2). Additional examples of MAPT sequences are readily available through publicly available databases (e.g., GenBank, UniProt, and OMIM). Further information on 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 shown in SNP databases). Numerous sequence variations within the MAPT gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov / snp / ?term=MAPT).In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample. In certain embodiments, the oligonucleotide inhibits the expression, translation, or activity of MAPT in a subject, cell, tissue, or biological sample by 3–10%, 10–20%, 20–40%, 40–60%, 60–90%, or 90–99% compared to the expression, translation, or activity in a negative control (e.g., measured by immunoassay, hybridization-based assay, or sequencing-based assay (e.g., RNA-Seq)).

[0123] In certain embodiments, the oligonucleotide comprises an oligonucleotide chain 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) 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). In certain embodiments, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. Exemplary nucleotide sequences of the human SOD1 gene can be found, for example, nucleotides 5092-138872 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). Additional examples of SOD1 sequences are readily available through publicly available databases (e.g., GenBank, UniProt, and OMIM). Further information on 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 shown in SNP databases). Numerous sequence variations within the SOD1 gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, for example, www.ncbi.nlm.nih.gov / snp / ?term=SOD1).In certain embodiments, oligonucleotides inhibit the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample. In certain embodiments, oligonucleotides inhibit the expression, translation, or activity of SOD1 in a subject, cell, tissue, or biological sample by 3–10%, 10–20%, 20–40%, 40–60%, 60–90%, or 90–99% compared to the expression, translation, or activity in a negative control (e.g., measured by immunoassay, hybridization-based assay, or sequencing-based assay (e.g., RNA-Seq)).

[0124] In certain embodiments, the oligonucleotide comprises an oligonucleotide chain 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) 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). In certain embodiments, the oligonucleotide comprises an antisense oligonucleotide. In certain embodiments, the oligonucleotide comprises a sense oligonucleotide. In certain embodiments, the oligonucleotide is a single-stranded oligonucleotide. In certain embodiments, the oligonucleotide is a double-stranded oligonucleotide. 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 nucleotides 5002-149290 of NG_011709.2 (incorporated herein as SEQ ID NO: 6). Additional examples of LRRK2 sequences are readily available through publicly available databases (e.g., GenBank, UniProt, and OMIM). Further information on 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 shown in SNP databases).Numerous sequence variations within the LRRK2 gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, e.g., www.ncbi.nlm.nih.gov / snp / ?term=LRRK2). In certain embodiments, oligonucleotides inhibit the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample. In certain embodiments, oligonucleotides inhibit the expression, translation, or activity of LRRK2 in a subject, cell, tissue, or biological sample by 3–10%, 10–20%, 20–40%, 40–60%, 60–90%, or 90–99% compared to the expression, translation, or activity in a negative control (e.g., measured by immunoassay, hybridization-based assay, or sequencing-based assay (e.g., RNA-Seq)).

[0125] In a particular embodiment, [ka] is a sense oligonucleotide chain, and the oligonucleotide further comprises an antisense oligonucleotide chain. In a particular embodiment, [ka] The first is an antisense oligonucleotide chain, and the second oligonucleotide further contains a sense oligonucleotide chain.

[0126] Linker In some embodiments, the oligonucleotides provided herein include one or more linkers (e.g., L A , L 4 , L 5 , and L 6 ) includes.

[0127] In certain embodiments, the linker comprises a chain structure (such as a hydrocarbyl chain), an oligomer of repeating units, or a combination of such repeating units. In certain 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 repeating units (including both ends). In certain embodiments, the repeating unit is -CH2-. In certain embodiments, the repeating unit is -CH2CH2O- or -OCH2CH2-. In certain embodiments, the linker length is such that between any two of the attachment points there are 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 (including both ends).

[0128] In certain embodiments, the linker contains carbon atoms (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 carbon atoms (including both ends)) in its main chain. In certain embodiments, the linker 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 heteroatoms (including both ends)). In certain embodiments, the linker contains amides, esters, disulfides, or combinations thereof in its main chain. In certain embodiments, the linker contains hydrazones, oximes, imines, guanidines, ureas, carbamates, alkyls, sulfonamides, heterocycles, or combinations thereof in its main chain. In certain embodiments, the linker contains one or more groups independently selected from alkyls, aminos, oxos, amides, disulfides, polyethylene glycols, ethers, thioethers, and hydroxylaminos in its main chain. In certain embodiments, the linker contains at least one phosphorus atom in its main chain. In certain embodiments, the linker contains at least one nonpolar linking group. In certain embodiments, the linker contains at least one polar linking group. In certain embodiments, the linker contains at least one linking group formed by a click chemistry reaction between a first click chemistry reactive moiety and a second click chemistry reactive moiety. In certain embodiments, the linker is substituted. In certain 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, alkylthioether, thiol, ureido, or a combination thereof.As those skilled in the art will acknowledge, each of these groups can be further substituted. In some embodiments, the linker is substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 substituents.

[0129] In some embodiments, the linker is a bond (e.g., a single bond).

[0130] In some embodiments, the linker is an optionally substituted alkylene. In some embodiments, the terminal carbon atoms of the alkylene back chain are the attachment sites. In some embodiments, the internal carbon atoms of the alkylene back chain are the attachment sites. In some embodiments, the linker is an optionally substituted alkenylene. In some embodiments, the linker is an optionally substituted alkylylene. In some embodiments, the linker is a substituted or unsubstituted C 1-100 Alkylene, substituted or unsubstituted C 2-100 Alkenylene, or substituted or unsubstituted C 2-100 It is an alkylene. In certain embodiments, C1-100 alkylene, C 2-100 Alkenylene, or C 2-100 One or more atoms (e.g., two, three, or four) of the alkynylene backbone are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as long as their valence allows. In some embodiments, the linker is substituted or unsubstituted C 7-70 Alkylene, substituted or unsubstituted C 7-70 Alkenylene, or substituted or unsubstituted C 7-70 It is an alkylene. In certain embodiments, C7-70 alkylene, C 7-70 Alkenylene, or C 7-70 One or more atoms (e.g., two, three, or four) of the alkynylene backbone are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as long as their valence allows. In certain embodiments, C7-70 alkylene, C 7-70 alkenylene, or C 7-70 one or two atoms in the main chain of alkynylene may, as valence allows, be independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, the linker is 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 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 alkenylene, 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 , C 53-60 , or C 61-70 alkynylene. In certain embodiments, C1-6, 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 C61-70 Alkenylene, 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 atoms (e.g., two, three, or four) in the alkynylene backbone can be independently replaced by substituted or unsubstituted carbocyclylenes, substituted or unsubstituted heterocyclylenes, substituted or unsubstituted arylenes, or substituted or unsubstituted heteroarylenes, as long as their valence allows.

[0131] In some embodiments, the linker is an optionally substituted alkenylene containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 double bonds. In some embodiments, the linker is an optionally substituted alkynylene containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 triple bonds. In some embodiments, the linker is an optionally substituted alkylene, alkenylene, or alkynylene containing one or more (e.g., 2, 3, 4, 5) branching points. In certain embodiments, the linker contains 2, 3, 4, or 5 branching points.

[0132] In some embodiments, the linker is an optionally substituted heteroalkylene. In some embodiments, the end atoms of the heteroalkylene backbone are the attachment sites. In some embodiments, the internal atoms of the heteroalkylene backbone are the attachment sites. In some embodiments, the linker is an optionally substituted heteroalkenylene. In some embodiments, the linker is an optionally substituted heteroalkynylene. In some embodiments, the linker is a substituted or unsubstituted C 1-100 Heteroalkylene, substituted or unsubstituted C 2-100 Heteroalkenylenes, or substituted or unsubstituted C 2-100 It is a heteroalkylene. In certain embodiments, C1-100 heteroalkylene, C 2-100Heteroalkenylene, or C 2-100 One or more (e.g., two, three, or four) atoms in the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as long as their valence allows. In some embodiments, the linker is substituted or unsubstituted C 7-70 Heteroalkylene, substituted or unsubstituted C 7-70 Heteroalkenylenes, or substituted or unsubstituted C 7-70 It is a heteroalkylene. In certain embodiments, C7-70 heteroalkylene, C 7-70 Heteroalkenylene, or C 7-70 One or more (e.g., two, three, or four) atoms in the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as long as their valence allows. In certain embodiments, C 7-70 Heteroalkylene, C 7-70 Heteroalkenylene, or C 7-70 One or two atoms in the main chain of the heteroalkylene can be independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, as long as their valence allows. In some embodiments, the linker is 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 Heteroalkylene, 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 53-60or C 61-70 heteroalkenylene, 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 , C 53-60 or C 61-70 heteroalkynylene. In certain embodiments, C1-6, 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 heteroalkylene, 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 heteroalkenylene, 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., 2, 3, or 4) atoms in the main chain of heteroalkynylene are, as valence permits, independently replaced with substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0133] In some embodiments, the substituted or unsubstituted heteroarylene replacing one of the main chain atoms is a substituted or unsubstituted 5 or 6-membered monocyclic heteroarylene. In some embodiments, the substituted or unsubstituted heteroarylene replacing one of the main chain atoms is a substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl fused with a substituted or unsubstituted 7- to 9-membered monocyclic carbocyrill. In some embodiments, the substituted or unsubstituted heteroarylene replacing one of the main chain atoms is a substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl fused with a substituted or unsubstituted 7- to 9-membered monocyclic heterocyclil. In some embodiments, the substituted or unsubstituted heteroarylene replacing one of the main chain atoms is a substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl fused with a substituted or unsubstituted 7- to 9-membered monocyclic heterocyclil fused with one or two substituted or unsubstituted phenyl atoms. In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms is a substituted or unsubstituted 5 or 6-membered monocyclic heterocyclylene. In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms is a moiety formed by a click chemistry reaction between a first click chemistry-reactive moiety and a second click chemistry-reactive moiety.

[0134] In some embodiments, the substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms is of the following formula: [ka] And, k21 is 0, 1, 2, 3, or 4. Each R d Examples, if present, are halogens, substituted or unsubstituted C independently. 1-6 Alkyl, or -O-(substituted or unsubstituted C) 1-6 It is alkyl, k22 is 0, 1, 2, 3, or 4. Each R e Examples, if present, are halogens, substituted or unsubstituted C independently. 1-6 Alkyl, or -O-(substituted or unsubstituted C) 1-6 It is alkyl, k23 is an integer between 0 and 11, including both ends. Each R f Examples, if present, are halogens, substituted or unsubstituted C independently. 1-6 Alkyl, or -O-(substituted or unsubstituted C) 1-6 It is alkyl, R g C is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, or -O-(substituted or unsubstituted C) 1-6 It is alkyl.

[0135] In certain embodiments, a substituted or unsubstituted heteroarylene that replaces one of the main chain atoms has the following formula: [ka]

[0136] A substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms may be attached in any orientation.

[0137] In some embodiments, the linker is an optionally substituted heteroalkynylene containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 double bonds. In some embodiments, the linker is an optionally substituted heteroalkynylene containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 triple bonds. In some embodiments, the linker is an optionally substituted heteroalkylene, heteroalkynylene, or heteroalkynylene containing one or more (e.g., 2, 3, 4, or 5) branching points. In certain embodiments, the linker contains 2, 3, 4, or 5 branching points.

[0138] In some embodiments, the optionally substituted heteroalkylene is optionally substituted polyethylene glycol (optionally substituted PEG). In some embodiments, the end atoms of the PEG backbone are the attachment sites. In some embodiments, the internal atoms of the PEG backbone are the attachment sites. In some embodiments, the linker comprises one or more PEG repeating units (-OCH2CH2- or -CH2CH2O-). In certain embodiments, the linker comprises 2-3, 4-5, 6-7, 8-9, 10-11, 12-13, or 14-15 PEG repeating units. In certain 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., 2, 3, or 4) PEGs.

[0139] In some embodiments, the linker includes a moiety formed by a Michael addition reaction between a Michael donor and a Michael acceptor. In some embodiments, the Michael donor is an enolate. In some embodiments, the Michael acceptor is a moiety containing an α,β-unsaturated carbonyl. In some embodiments, the Michael donor is -SH. In some embodiments, the Michael acceptor is [ka] That is the case.

[0140] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] This is a combination, however, The number of main chain atoms in the linker is 2-6, 7-12, 13-20, 21-30, 31-40, 41-50, 51-60, 61-80, 81-100 (including both ends). The linker does not contain OO, ON, NO, or NN.

[0141] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] This is a combination, however, The number of main chain atoms in the linker is 7 to 70 (including both ends). The linker does not contain OO, ON, NO, or NN.

[0142] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] This is a combination, however, The number of main chain atoms in the linker is 2-6, 7-12, 13-20, 21-30, 31-40, 41-50, 51-60, 61-80, or 81-100 (including both ends). The linker does not include OO, ON, NO, or NN. Linker's -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0143] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] This is a combination, however, The number of main chain atoms in the linker is 7 to 70 (including both ends). The linker does not include OO, ON, NO, or NN. Linker's -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0144] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, The number of main chain atoms in the linker is 2-6, 7-12, 13-20, 21-30, 31-40, 41-50, 51-60, 61-80, 81-100 (including both ends). The linker does not contain OO, ON, NO, or NN.

[0145] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, The number of main chain atoms in the linker is 7 to 70 (including both ends). The linker does not contain OO, ON, NO, or NN.

[0146] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, The number of main chain atoms in the linker is 2-6, 7-12, 13-20, 21-30, 31-40, 41-50, 51-60, 61-80, or 81-100 (including both ends). The linker does not include OO, ON, NO, or NN. Linker's -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0147] In some embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, The number of main chain atoms in the linker is 7 to 70 (including both ends). The linker does not include OO, ON, NO, or NN. Linker's -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0148] 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 a combination of any two or more of -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, and -N(CH3)C(=O)- (e.g., 3, 4, 5, 6, 7, 8, 9, or 10), provided that the number of main chain atoms in the example linker is between 7 and 70 (including both ends), and the example linker does not include OO, ON, NO, or NN.

[0149] In certain embodiments, the linker includes cleavable bonds or portions. In certain embodiments, the linker does not include cleavable bonds or portions. In certain embodiments, the linker includes a covalent attachment to a solid support. In certain embodiments, the linker includes multiple sites for the attachment of ligand radicals.

[0150] In certain embodiments, the linker contains a peptide in its back chain. In certain embodiments, the peptide contains 1-5, 6-10, 11-15, 16-20, 21-25, 26-30, 31-35, or 36-40 amino acids (including both ends).

[0151] In certain embodiments, the linker includes pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), 6-aminohexanoic acid (HEC or AHA), or a combination thereof.

[0152] In some embodiments, at least one L A Examples include: [ka] It is an internucleoside linker located between the first and second nucleosides, counting from the 5' end. In certain embodiments, L A teeth, [ka] It is an internucleoside linker located between the nth nucleoside and the (n+1)th nucleoside, counting from the 5' end. [ka] n is an integer between 2 and 20 (inclusive), as long as the number of nucleosides allows. In some embodiments, at least one L A Examples include: [ka] It is an internucleoside linker located between the first and second nucleosides, counting from the 3' end. In certain embodiments, L A teeth, [ka] It is an internucleoside linker located between the nth nucleoside and the (n+1)th nucleoside, counting from the 3' end. [ka] n is an integer between 2 and 20 (including both ends), as long as the number of nucleosides allows.

[0153] In some embodiments, L A This is the one in the following formula: [ka] And, each Z A1 and Z A2 Examples of this can be found independently of single bonds, substitutions, or unsubstituted C. 1-6 Alkylene, or substituted or unsubstituted C 2-6 It is alkenylene, Each W A The examples are, independently, as long as the valence allows, substituted or unsubstituted alkylenes, substituted or unsubstituted heteroalkylenes, substituted or unsubstituted carbocyclylenes, substituted or unsubstituted heterocyclenes, substituted or unsubstituted arylenes, substituted or unsubstituted heteroarylenes, -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 radicals of combinations thereof, Each R c Examples of these independently include hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, or oxygen protecting group when attached to an oxygen atom, or two R C These examples are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring, join C 4A L 4 It is attached to it.

[0154] In some embodiments, at least one Z A1 Examples include substitution or non-substitution C. 1-6 It is an alkylene. In some embodiments, at least one Z A1 Examples include substitution or non-substitution C. 1-3 It is an alkylene. In certain embodiments, at least one Z A1 An example is non-substituted C 1-3 It is an alkylene. In some embodiments, at least one Z A2 Examples include substitution or non-substitution C. 1-6 It is an alkylene. In some embodiments, at least one Z A2 Examples include substitution or non-substitution C. 1-3 It is an alkylene. In certain embodiments, at least one Z A2 An example is non-substituted C 1-3 It is alkylene.

[0155] In some embodiments, W A is -N(R c )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NRc -, or -NR c C(=O)-. In a particular embodiment, W A is -N(R c )-,-C(=O)NR c -, or -NR c C(=O)-

[0156] Several embodiments, each R c Examples of these are, independently, hydrogen, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, or substituted or unsubstituted alkynyls.

[0157] In some embodiments, L A is, formula [ka] In some embodiments, L A is, formula [ka] It belongs to them.

[0158] In a particular embodiment, L A is, formula [ka] It belongs to them.

[0159] In some embodiments, L4 is [ka] And, -L 4A1 -L 4A2 -, -L 4A3 -L 4A4 -, -L 4A5 -L 4A6 -, -L 4A7 -L 4A8 -, -L 4A17 -L 4A18 -, and -L 4A19 -L 4A20each - 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-, and each R aExamples of this are, independently, hydrogen, substituted or unsubstituted C 1-6 Alkyl, 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 An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. L 4B1 , L 4B2 , and L 4B6 Each of these can be a single bond, a substitution, or an unsubstituted C, independently. 1-100 Alkylene, or substituted or unsubstituted C 1-100 It is a heteroalkylene, L 4C1 and L 4C2 Each of these is a single bond, a substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms, or a substituted or unsubstituted heteroarylene that replaces one of the main chain atoms. join C 4B is, A 4 It is attached to it.

[0160] In some embodiments, -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 these is independently a single bond, -O-, -NR a -, -C(=O)NR a -, or -NR a In some embodiments, C(=O)- 4A1 -L 4A2 -, -L 4A3 -L 4A4 -, -L 4A5 -L 4A6 -, -L 4A7 -L 4A8 -, -L 4A17 -L4A18 -, and -L 4A19 -L 4A20 Each of these is independently a single bond, -O-, -NH-, -C(=O)NH-, or -NHC(=O)-. In certain embodiments, -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 -s is independent, a single bond, -C(=O)NR a -, or -NR a It is C(=O)-. In certain embodiments, -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 these is independently a single bond, -C(=O)NH-, or -NHC(=O)-. In some embodiments, -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 these 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 )O-. In some embodiments, -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 these is independently -C(=O)O-, -OC(=O)-, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-.

[0161] In some embodiments, at least one R a Examples of this are, independently, hydrogen or substituted or unsubstituted C 1-6 It is alkyl. In some embodiments, each R a Examples of this are, independently, hydrogen or substituted or unsubstituted C 1-6 It is alkyl. In a particular embodiment, each R a Examples include hydrogen or unsubstituted C, independently. 1-6 It is alkyl.

[0162] In some embodiments, L 4B1 , L 4B2 , and L 4B6 Each of these can be a single bond, a substitution, or an unsubstituted C, independently. 1-20 Alkylene or substituted or unsubstituted C12 1-20 It is a heteroalkylene. In some embodiments, L 4B1 , L 4B2 , and L 4B6 Each of these can be independently substituted or non-substituted C 1-10 Alkylene or substituted or unsubstituted C12 1-10 It is a heteroalkylene. In certain embodiments, L 4B1 , L 4B2 , and L 4B6 Each of these is independently a non-substituted C 1-10 It is an alkylene. In certain embodiments, L 4B1 , L 4B2 , and L 4B6Each of these independently consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeats of PEG.

[0163] In a particular embodiment, L 4C1 and L 4C2 Each of them is independent and a single bond. In a particular embodiment, L 4C1 and L 4C2 Each of these is an independent substituted or unsubstituted heteroarylene that replaces one of the main chain atoms. In certain embodiments, L 4C1 and L 4C2 Each of them is independent, [ka] (It can be attached in either direction.)

[0164] In a particular embodiment, L4 is [ka] And, Each of p1 and p2 is an independent integer between 1 and 10 (including both ends). Each of p3 and p5 is an independent integer between 0 and 10 (including both ends). Each-L 4A21 -L 4A22 Examples of - are independent single bonds, -O-, -S-, -SS-, and -NR. a -, -C(=O)O-, -C(=NR a )O-, -S(=O)O-, -S(=O)2O-, -C(=O)NR a -, -C(=NR a )NR a -, -S(=O)NR a -, -S(=O)2NR a -, -OC(=O)-, -OC(=NR) a )-, -OS(=O)-, -OS(=O)2-, -NR a C(=O)-, -NR a C(=NR a )-, -NR a S(=O)-, -NR aS(=O)2-, -OC(=O)O-, -OC(=NR a )O-, -OS(=O)O-, -OS(=O)2O-, -NR a C(=O)O-, -NR a C(=NR a )O-, -NR a S(=O)O-, -NR a S(=O)2O-, -OC(=O)NR a -, -OC(=NR a )NR a -, -OS(=O)NR a -, -OS(=O)2NR a -, -NR a C(=O)NR a -, -NR a C(=NR a )NR a -, -NR a S(=O)NR a -, -NR a S(=O)2NR a -, -C(=O)-, -C(=NR) a )-, -S(=O)-, -S(=O)2-, -OP(=O)(OR a )O-, -SP(=O)(OR a )O-, -OP(=O)(OR a )S-, or -OP(=O)(SR a )O-, Each R a Examples of this are, independently, hydrogen, substituted or unsubstituted C 1-6 The R is an alkyl group, a substituted or unsubstituted phenyl group, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R groups attached to a nitrogen atom. a An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. join C 4B is, A 4 It is attached to it.

[0165] In certain embodiments, at least one -L 4A21 -L 4A22 - is an example of -NRa -C(=O)- or -C(=O)-NR a -In certain embodiments, at least one -L 4A21 -L 4A22 Examples of - are -NH-C(=O)- or -C(=O)-NH-. In certain embodiments, at least one -L 4A21 -L 4A22 Examples of - are -OC(=O)- or -C(=O)-O-. In certain embodiments, at least one -L 4A21 -L 4A22 An example of - is -O-. In certain embodiments, at least one -L 4A21 -L 4A22 An example of - is -NH-. In certain embodiments, at least one -L 4A21 -L 4A22 An example of - is -C(=O)-.

[0166] In some embodiments, L 4 The combinations are -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, and -N(CH3)C(=O)-, however, the number of main chain atoms in the example linker is 7 to 70 (including both ends), and the example linker does not contain OO, ON, NO, or NN. In certain embodiments, L 4 These are combinations of -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, and -NHC(=O)-, however, the L 4 In the example, the number of main chain atoms is 7 to 70 (including both ends), the example linker does not contain OO, ON, NO, or NN, and the number of -C(=O)NH- and -NHC(=O)- combinations in the example linker is 0 to 4 (including both ends). In some embodiments, L 4This includes -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, or -N(CH3)C(=O)-, or a combination of two or more of the above examples, or a combination of two or more of the above examples, provided that the number of main chain atoms in the linker example is 7 to 70 (including both ends), and the linker example does not include OO, ON, NO, or NN. In certain embodiments, L 4 -CH2-, -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, or -NHC(=O)-, or a combination of two or more of the above examples, or a combination of two or more of the above examples, however, the L 4 The number of main chain atoms in the example is 7 to 70 (including both ends), the example linker does not contain OO, ON, NO, or NN, and the number of combinations of -C(=O)NH- and -NHC(=O)- in the example linker is 0 to 4 (including both ends).

[0167] In a particular embodiment, [ka] The following is true: [ka]

[0168] In some embodiments, L 5 teeth [ka] And, -L 5A1 -L 5A2 -, -L 5A3 -L 5A4 -, -L 5A5 -L 5A6 -, -L 5A7 -L 5A8 -, -L 5A17 -L 5A18 -, and -L 5A19 -L5A20 each - 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-, and each Ra Examples of this are, independently, hydrogen, substituted or unsubstituted C 1-6 Alkyl, 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 An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. L 5B1 , L 5B2 , and L 5B6 Each of these can be a single bond, a substitution, or an unsubstituted C, independently. 1-100 Alkylene, or substituted or unsubstituted C 1-100 It is a heteroalkylene, L 5C1 and L 5C2 Each of these is a single bond, a substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms, or a substituted or unsubstituted heteroarylene that replaces one of the main chain atoms. join C 5B is, A 5 It is attached to it.

[0169] In some embodiments, -L 5A1 -L 5A2 -, -L 5A3 -L 5A4 -, -L 5A5 -L 5A6 -, -L 5A7 -L 5A8 -, -L 5A17 -L 5A18 -, and -L 5A19 -L 5A20 Each of these is independently a single bond, -O-, -NR a -, -C(=O)NR a -, or -NR a In some embodiments, C(=O)- 5A1 -L 5A2 -, -L 5A3 -L 5A4 -, -L 5A5 -L 5A6 -, -L 5A7 -L 5A8 -, -L5A17 -L 5A18 -, and -L 5A19 -L 5A20 Each of these is independently a single bond, -O-, -NH-, -C(=O)NH-, or -NHC(=O)-. In certain embodiments, -L 5A1 -L 5A2 -, -L 5A3 -L 5A4 -, -L 5A5 -L 5A6 -, -L 5A7 -L 5A8 -, -L 5A17 -L 5A18 -, and -L 5A19 -L 5A20 Each of the -s is independent, a single bond, -C(=O)NR a -, or -NR a It is C(=O)-. In certain embodiments, -L 5A1 -L 5A2 -, -L 5A3 -L 5A4 -, -L 5A5 -L 5A6 -, -L 5A7 -L 5A8 -, -L 5A17 -L 5A18 -, and -L 5A19 -L 5A20 Each of these is independently a single bond, -C(=O)NH-, or -NHC(=O)-. In some embodiments, -L 5A1 -L 5A2 -, -L 5A3 -L 5A4 -, -L 5A5 -L 5A6 -, -L 5A7 -L 5A8 -, -L 5A17 -L 5A18 -, and -L 5A19 -L 5A20 -At least one of these 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 )O-. In some embodiments, -L 5A1-L 5A2 -, -L 5A3 -L 5A4 -, -L 5A5 -L 5A6 -, -L 5A7 -L 5A8 -, -L 5A17 -L 5A18 -, and -L 5A19 -L 5A20 At least one of these is independently -C(=O)O-, -OC(=O)-, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-.

[0170] In some embodiments, at least one R a Examples of this are, independently, hydrogen or substituted or unsubstituted C 1-6 It is alkyl. In some embodiments, each R a Examples of this are, independently, hydrogen or substituted or unsubstituted C 1-6 It is alkyl. In a particular embodiment, each R a Examples include hydrogen or unsubstituted C, independently. 1-6 It is alkyl.

[0171] In some embodiments, L 5B1 , L 5B2 , and L 5B6 Each of these can be a single bond, a substitution, or an unsubstituted C, independently. 1-20 Alkylene or substituted or unsubstituted C12 1-20 It is a heteroalkylene. In some embodiments, L 5B1 , L 5B2 , and L 5B6 Each of these can be independently substituted or non-substituted C 1-10 Alkylene or substituted or unsubstituted C12 1-10 It is a heteroalkylene. In certain embodiments, L 5B1 , L 5B2 , and L 5B6 Each of these is independently a non-substituted C 1-10 It is an alkylene. In certain embodiments, L 5B1 , L 5B2 , and L 5B6Each of these independently consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeats of PEG.

[0172] In a particular embodiment, L 5C1 and L 5C2 Each of them is independent and a single bond. In a particular embodiment, L 5C1 and L 5C2 Each of these is an independent substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms. In certain embodiments, L 5C1 and L 5C2 Each of them is independent, [ka] (It can be attached in either direction.)

[0173] In some embodiments, L 5 teeth [ka] And, k21 is 0, 1, 2, 3, or 4. Each R d Examples, if present, are halogens, substituted or unsubstituted C independently. 1-6 Alkyl, or -O-(substituted or unsubstituted C) 1-6 It is alkyl, k22 is 0, 1, 2, 3, or 4. Each R e Examples, if present, are halogens, substituted or unsubstituted C independently. 1-6 Alkyl, or -O-(substituted or unsubstituted C) 1-6 It is alkyl, Each of q1, q2, q4, q5, q8, and q9 is an independent integer between 0 and 10 (including both ends). Each of q3, q6, and q7 is an integer between 1 and 10 (including the two endpoints), -L 5A21 -L 5A22 -, -L 5A23 -L 5A24 -, and -L5A25 -L 5A26 - each independently represents 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-, Each R a Examples of this are, independently, hydrogen, substituted or unsubstituted C 1-6 The R is an alkyl group, a substituted or unsubstituted phenyl group, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R groups attached to a nitrogen atom. a An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. join C 5A is, A 5 It is attached to it.

[0174] In certain embodiments, k21 is 0. In certain embodiments, k21 is 1. In certain embodiments, k21 is 2. In certain embodiments, k22 is 0. In certain embodiments, k22 is 1. In certain embodiments, k22 is 2.

[0175] Several embodiments, each R d Examples include, if present, independently of substitution or non-substitution C. 1-6 It is alkyl. In a particular embodiment, each R d If an example exists, it is an independent non-substitutive C. 1-6 It is alkyl. In some embodiments, each R e Examples include, if present, independently of substitution or non-substitution C. 1-6 It is alkyl. In a particular embodiment, each R e If an example exists, it is an independent non-substitutive C. 1-6 It is alkyl.

[0176] In a particular embodiment, each of q1, q2, q4, q5, q8, and q9 is independently 0. In a particular embodiment, each of q1, q2, q4, q5, q8, and q9 is independently 1. In a particular embodiment, each of q1, q2, q4, q5, q8, and q9 is independently 2. In a particular embodiment, each of q1, q2, q4, q5, q8, and q9 is independently 3. In a particular embodiment, each of q3, q6, and q7 is independently 0. In a particular embodiment, each of q3, q6, and q7 is independently 1. In a particular embodiment, each of q3, q6, and q7 is independently 2. In a particular embodiment, each of q3, q6, and q7 is independently 3.

[0177] In some embodiments, -L 5A23 -L 5A24 - and -L 5A25 -L 5A26 Each of these is independently a single bond, -O-, -NR a -, -NR a -C(=O)-, or -C(=O)-NR a - is. In certain embodiments, -L 5A23 -L 5A24 - and -L 5A25 -L 5A26 Each of these is independent of -NR a -C(=O)- or -C(=O)-NR a - is

[0178] In some embodiments, -L 5A21 -L 5A22 - is -OP(=O)(OR a )O-, -SP(=O)(OR a )O-, -OP(=O)(OR a )S-, or -OP(=O)(SR a )O-. In certain embodiments, -L 5A21 -L 5A22 is -OP(=O)(SR a )O-. In certain embodiments, -L 5A21 -L 5A22 - is -OP(=O)(SH)O-.

[0179] In a particular embodiment, L 5 -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] The combination is such that, however, the number of main chain atoms of the linker is 7 to 70 (including both ends), and the linker does not contain OO, ON, NO, or NN. In certain embodiments, L 5 -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] The combination is as follows, however, the number of main chain atoms of the linker is 7 to 70 (including both ends), and the linker does not contain OO, ON, NO, or NN, and the linker contains -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0180] In a particular embodiment, L 5 -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] Alternatively, a combination of two or more of the above-mentioned examples, or a combination of two or more of the above-mentioned examples, provided that the number of main chain atoms of the linker is 7 to 70 (including both ends), and the linker does not contain OO, ON, NO, or NN. In certain embodiments, L 5 -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] Alternatively, a combination of two or more of the above-mentioned examples, or a combination of two or more of the above-mentioned examples, provided that the number of main chain atoms of the linker is 7 to 70 (including both ends), the linker does not contain OO, ON, NO, or NN, and the linker contains -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0181] In a particular embodiment, [ka] teeth [ka] That is the case.

[0182] In some embodiments, L 6 teeth [ka] And, -L 6A1 -L 6A2 -, -L 6A3 -L 6A4-, -L 6A5 -L 6A6 -, -L 6A7 -L 6A8 -, -L 6A17 -L 6A18 - and -L 6A19 -L 6A20 - each 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)(ORa )O-, -SP(=O)(OR a )O-, -OP(=O)(OR a )S-, or -OP(=O)(SR a )O-, Each R a Examples of this are, independently, hydrogen, substituted or unsubstituted C 1-6 Alkyl, 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 An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. L 6B1 , L 6B2 , and L 6B6 Each of these can be a single bond, a substitution, or an unsubstituted C, independently. 1-100 Alkylene, or substituted or unsubstituted C 1-100 It is a heteroalkylene, L 6C1 and L 6C2 Each of these is a single bond, a substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms, or a substituted or unsubstituted heteroarylene that replaces one of the main chain atoms. join C 6B is, A 6 It is attached to it.

[0183] In some embodiments, -L 6A1 -L 6A2 -, -L 6A3 -L 6A4 -, -L 6A5 -L 6A6 -, -L 6A7 -L 6A8 -, -L 6A17 -L 6A18 -, and -L 6A19 -L 6A20 - At least one of these is independently a single bond, -O-, -NR a -, -C(=O)NR a -, or -NR a In some embodiments, C(=O)-6A1 -L 6A2 -, -L 6A3 -L 6A4 -, -L 6A5 -L 6A6 -, -L 6A7 -L 6A8 -, -L 6A17 -L 6A18 -, and -L 6A19 -L 6A20 Each of these is independently a single bond, -O-, -NH-, -C(=O)NH-, or -NHC(=O)-. In certain embodiments, -L 6A1 -L 6A2 -, -L 6A3 -L 6A4 -, -L 6A5 -L 6A6 -, -L 6A7 -L 6A8 -, -L 6A17 -L 6A18 -, and -L 6A19 -L 6A20 Each of the -s is independent, a single bond, -C(=O)NR a -, or -NR a It is C(=O)-. In certain embodiments, -L 6A1 -L 6A2 -, -L 6A3 -L 6A4 -, -L 6A5 -L 6A6 -, -L 6A7 -L 6A8 -, -L 6A17 -L 6A18 -, and -L 6A19 -L 6A20 Each of these is independently a single bond, -C(=O)NH-, or -NHC(=O)-. In some embodiments, -L 6A1 -L 6A2 -, -L 6A3 -L 6A4 -, -L 6A5 -L 6A6 -, -L 6A7 -L 6A8 -, -L 6A17 -L 6A18 -, and -L 6A19 -L 6A20 -At least one of these is independently -C(=O)O-, -OC(=O)-, -OP(=O)(ORa )O-, -SP(=O)(OR a )O-, -OP(=O)(OR a )S-, or -OP(=O)(SR a )O-. In some embodiments, -L 6A1 -L 6A2 -, -L 6A3 -L 6A4 -, -L 6A5 -L 6A6 -, -L 6A7 -L 6A8 -, -L 6A17 -L 6A18 -, and -L 6A19 -L 6A20 At least one of these is independently -C(=O)O-, -OC(=O)-, -OP(=O)(OH)O-, -SP(=O)(OH)O-, -OP(=O)(OH)S-, or -OP(=O)(SH)O-.

[0184] In some embodiments, at least one R a Examples of this are, independently, hydrogen or substituted or unsubstituted C 1-6 It is alkyl. In some embodiments, each R a Examples of this are, independently, hydrogen or substituted or unsubstituted C 1-6 It is alkyl. In a particular embodiment, each R a Examples include hydrogen or unsubstituted C, independently. 1-6 It is alkyl.

[0185] In some embodiments, L 6B1 , L 6B2 , and L 6B6 Each of these can be a single bond, a substitution, or an unsubstituted C, independently. 1-20 Alkylene or substituted or unsubstituted C12 1-20 It is a heteroalkylene. In some embodiments, L 6B1 , L 6B2 , and L 6B6 Each of these can be independently substituted or non-substituted C 1-10 Alkylene or substituted or unsubstituted C12 1-10 It is a heteroalkylene. In certain embodiments, L 6B1 , L 6B2, and L 6B6 Each of these is independently a non-substituted C 1-10 It is an alkylene. In certain embodiments, L 6B1 , L 6B2 , and L 6B6 Each of these independently consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeats of PEG.

[0186] In a particular embodiment, L 6C1 and L 6C2 Each of them is independent and a single bond. In a particular embodiment, L 6C1 and L 6C2 Each of these is an independent substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms. In certain embodiments, L 6C1 and L 6C2 Each of them is independent, [ka] (It can be attached in either direction.)

[0187] In some embodiments, L 6 teeth [ka] And, Each of r1, r2, r4, r5, r8, and r9 is an independent integer between 0 and 10 (including both ends). Each of r3, r6, and r7 is an integer between 1 and 10 (including the two endpoints), -L 6A21 -L 6A22 -, -L 6A23 -L 6A24 -, and -L 6A25 -L 6A26 Each of these is independently a single bond, -O-, -S-, -SS-, -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)NRa -, -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-, Each R a Examples of this are, independently, hydrogen, substituted or unsubstituted C 1-6 The R is an alkyl group, a substituted or unsubstituted phenyl group, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R groups attached to a nitrogen atom. aAn example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. join C 6A is, A 6 It is attached to it.

[0188] In certain embodiments, k21 is 0. In certain embodiments, k21 is 1. In certain embodiments, k21 is 2. In certain embodiments, k22 is 0. In certain embodiments, k22 is 1. In certain embodiments, k22 is 2.

[0189] Several embodiments, each R d Examples include, if present, independently of substitution or non-substitution C. 1-6 It is alkyl. In a particular embodiment, each R d If an example exists, it is an independent non-substitutive C. 1-6 It is alkyl. In some embodiments, each R e Examples include, if present, independently of substitution or non-substitution C. 1-6 It is alkyl. In a particular embodiment, each R e If an example exists, it is an independent non-substitutive C. 1-6 It is alkyl.

[0190] In a particular embodiment, each of r1, r2, r4, r5, r8, and r9 is independently 0. In a particular embodiment, each of r1, r2, r4, r5, r8, and r9 is independently 1. In a particular embodiment, each of r1, r2, r4, r5, r8, and r9 is independently 2. In a particular embodiment, each of r1, r2, r4, r5, r8, and r9 is independently 3. In a particular embodiment, each of r3, r6, and r7 is independently 0. In a particular embodiment, each of r3, r6, and r7 is independently 1. In a particular embodiment, each of r3, r6, and r7 is independently 2. In a particular embodiment, each of r3, r6, and r7 is independently 3.

[0191] In some embodiments, -L 6A23 -L6A24 - and -L 6A25 -L 6A26 Each of these is independently a single bond, -O-, -NR a -, -NR a -C(=O)-, or -C(=O)-NR a - is. In certain embodiments, -L 6A23 -L 6A24 - and -L 6A25 -L 6A26 Each of these is independent of -NR a -C(=O)- or -C(=O)-NR a - is

[0192] In some embodiments, -L 6A21 -L 6A22 - is -O-, -OP(=O)(OR a )O-, -SP(=O)(OR a )O-, -OP(=O)(OR a )S-, or -OP(=O)(SR a )O-. In certain embodiments, -L 6A21 -L 6A22 - is -O-.

[0193] In a particular embodiment, L 6 -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] The combination is as follows, however, the number of main chain atoms of the linker is 7 to 70 (including both ends), and the linker does not contain OO, ON, NO, or NN. In certain embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] The combination is as follows, however, the number of main chain atoms of the linker is 7 to 70 (including both ends), and the linker does not contain OO, ON, NO, or NN, and the linker contains -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0194] In a particular embodiment, L 6 -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-, [ka] Or a combination of two or more of the above-mentioned examples, or a combination of two or more of the above-mentioned examples, provided that the number of main chain atoms of the linker is 7 to 70 (including both ends), and the linker does not contain OO, ON, NO, or NN. In certain embodiments, the linker is -CH2-, [ka] -O-, -CH2CH2O-, -OCH2CH2-, -C(=O)NH-, -NHC(=O)-, [ka] The combination is as follows, however, the number of main chain atoms of the linker is 7 to 70 (including both ends), and the linker does not contain OO, ON, NO, or NN, and the linker contains -C(=O)NH-, -NHC(=O)-, [ka] The number of possible combinations is 0 to 4 (including both ends).

[0195] The snowflake is a snowflake Price to buy on the coin:US5,9 94,517, US6,300,319, US6,660,720, US6,906,182, US 7,262,177, US7,491,805, US8,106,022, US7,723,509, US9,127,276, US2006 / 0148740, US2011 / 0123520, WO 2013 / 033230, WO 2012 / 037254, Biessen et al., J.Med.Chem.1995,38,1846-1852;Lee et al.,Bioorganic & Medicinal Chemistry 2011,19,2494-2500; al.,J.Biol.Chem.2001,276,37577-37584;Rensen et al.,J.Med.Chem.2004,47,5798-5808;Sliedregt et al.,J.Med.Chem 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-56761,2076,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、425、 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.90-Red.6 et2,699、 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.2004,46,457、 al.,J.Am.Chem.Soc.2004,126,14013-14022、Lee et al.,J.Org.Chem.2012,77,7564-7571、Biessen et al.,FASEB J.2000g.14,1782 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.,Org2010,12,5410-5413, Manoharan,Antisense Nucleic Acid Drug Dev.2002,12,103-128, Merwin et al.,Bioconjug.Chem.1994,5,612-620, Tomiya et al. al.,Bioorg.Med.Chem.,2013,21,5275-5281, International Application WO 1998 / 013381, WO 2011 / 038356, WO 1997 / 046098, WO 2008 / 098788, WO 2004 / 101619, WO 2012 / 037254, WO 2011 / 120053, WO 2011 / 100131, WO 2011 / 163121, WO 2012 / 177947, WO 2013 / 033230, WO 2013 / 075035, WO 2012 / 083185, WO 2012 / 083046, WO 2009 / 082607, WO 2009 / 134487, WO 2010 / 144740, WO 2010 / 148013, WO 1997 / 020563, WO 2010 / 088537, WO 2002 / 043771, WO 2010 / 129709, WO 2012 / 068187, WO 2009 / 126933, WO 2004 / 024757, WO 2010 / 054406, WO 2012 / 089352, WO 2012 / 089602, WO 2013 / 166121, WO 2013 / 165816, US 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, No. 8,541,548, No. 8,344,125, No. 8,313,772, No. 8,349,308, No. 8,450,467, No. 8,501,930, No. 8,158,601, No. 7,26 No. 2,177, No. 6,906,182, No. 6,620,916, No. 8,435,491, No. 8,404,862, No. 7,851,615, U.S. Patent Application Publication No. US2011 / 0097264, No.No. 2011 / 0097265, No. US2013 / 0004427, No. US2003 / 0119724, No. US2011 / 0207799, No. US2012 / 0035115, No. U No. S2012 / 0230938, No. US2005 / 0164235, No. US2006 / 0183886, No. US2012 / 0136042, No. US2012 / 0095075, No. U Issues S2013 / 0109817, US2006 / 0148740, US2008 / 0206869, US2012 / 0165393, US2012 / 0101148, US2013 / 0121954, US2011 / 0123520, US2003 / 0077829, US2008 / 0108801, and US2009 / 0203132.

[0196] In a particular embodiment, the linker is as follows: [ka] [ka] The structure includes a selection from, 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.

[0197] In a particular embodiment, the linker is as follows: [ka] [ka] The structure includes a selection from, 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.

[0198] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, 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.

[0199] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, 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.

[0200] In a particular embodiment, the linker is as follows: [ka] The structure comprises a selection from, where each L is independently a phosphotryester, alkylphosphonate, phosphoramidate, phosphorothioate, phosphorodithioate, or phosphorothiolate, 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.

[0201] In a particular embodiment, the linker is as follows: [ka] [ka] [ka] The structure includes a selection from, 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.

[0202] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, 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.

[0203] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, 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.

[0204] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0205] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, 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.

[0206] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, 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.

[0207] In a particular embodiment, the linker is as follows: [ka] The structure includes a selection from, 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.

[0208] In a particular embodiment, the linker is as follows: [ka] The structure includes n, where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0209] In a particular embodiment, the linker is as follows: [ka] The structure includes, 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.

[0210] Ligand In the oligonucleotides of this disclosure, at least one A 4 An example is a ligand radical, A 5 and A 6Each of these, if present, is independently a ligand or lipid radical. In some embodiments, at least one ligand is a central nervous system receptor ligand. In certain embodiments, at least one ligand is a TrkB receptor ligand. In certain embodiments, at least one ligand is a selective TrkB modifier. In certain embodiments, at least one ligand is a non-selective TrkB modifier (i.e., a pan-TrkABC modifier). In certain embodiments, at least one ligand is a CB1 receptor ligand. In certain embodiments, at least one ligand is an α4β 1 / 7 It is an integrin receptor ligand. In certain embodiments, at least one ligand is an NMDA receptor ligand. In some embodiments, the ligand directs an oligonucleotide to a location within a target. In some embodiments, the ligand targets a 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 a cell.

[0211] In some embodiments, the ligand targets a cell receptor. In certain embodiments, the cell receptor is the TrkB receptor, CB1 receptor, or α4β receptor. 1 / 7The receptor is an integrin receptor, or NMDA receptor. In some embodiments, the receptor is located in the brain. In some embodiments, the receptor is located in the prefrontal cortex. In some embodiments, the receptor is located in the striatum. In some embodiments, the receptor is located in the cerebellum. In some embodiments, the receptor is located in the brainstem. In some embodiments, the receptor is located in the hippocampus. In some embodiments, the receptor is located in the spinal cord. In some embodiments, the ligand is used to target an oligonucleotide against a certain cell type. In some embodiments, the cell is a central nervous system cell. In certain embodiments, the cell is a neuron. In certain embodiments, the cell is a glial cell. In certain embodiments, the cell is an astrocyte. In certain embodiments, the cell is an oligodendrocyte. In certain embodiments, the cell is an ependymal cell. In certain embodiments, the cell is a microglia.

[0212] In some embodiments, the ligand is a receptor agonist (e.g., TrkB, CB1, α4β) 1 / 7 The ligand is an integrin or an NMDA receptor agonist. In some embodiments, the ligand is a receptor antagonist (e.g., TrkB, CB1, α4β). 1 / 7 It is an integrin, or an NMDA receptor antagonist.

[0213] In some embodiments, the oligonucleotides provided herein comprise at least one TrkB ligand, which is a radical of a compound of the following formula: [ka] And, R 2 is hydrogen, -OR 7 , -SR 8 , or -NR 9 R 10 And, R 3 is hydrogen, -OR 31 , -SR 32 , or -NR 33 R 34 And, R 4 is hydrogen, -OR 35 , -SR 36 , or -NR 37 R 38 And, R 5 is hydrogen, -OR 39 , -SR 40 , or -NR 41 R 42 And, R 6 is 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 these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. Y is CH2, NH, S, or O. Z is an arbitrarily substituted aryl or arbitrarily substituted heteroaryl, R 11 and R 13 Each of these is an alkyl group that is either absent, has hydrogen, or is optionally substituted. R 12 , R 14 and R 15 Each of these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R 16 These are hydrogen, halogens, -CN, -N3, and -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 Ure 16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, [ka] Each of these is independently a single bond or a double bond. [ka] If it is a single bond, [ka] It is a double bond, R 13 It does not exist, and furthermore [ka] If it is a single bond, [ka] It is a double bond, R 11 It does not exist. R 16A , R 16B , R 16C , R 16D 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, and R is bonded to the same nitrogen atom. 16B and R 16C The substituents can be optionally attached to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. R 17 , R 18 , and R 19 Each of these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R 20 These are hydrogen, halogens, -CN, -N3, and -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 Ure 20D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, R 21 These are hydrogen, halogens, -CN, -N3, and -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 Ure 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, R 22 and R 23Each of these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R 24 These are hydrogen, halogens, -CN, -N3, and -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 Ure 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 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, and R is bonded to the same nitrogen atom. 20B , R 20C , R 21B , R 21C , R 24B , R 24C , R 24B , and R 24C The substituents can be optionally attached to form substituted or unsubstituted heterocycloalkyl 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 independently 0, 1, or 2. z5 is 0, 1, 2, or 3. z6 and z8 are independently 0, 1, 2, 3, or 4.

[0214] In some embodiments, R 2 is hydrogen or -OR 7 In a particular embodiment, R 2 is hydrogen. In a particular embodiment, R 2 is, -OR 7 In a particular embodiment, R 2 is -OH. In a particular embodiment, R 2 is -OCH3. In some embodiments, R 3 is hydrogen or -OR 31 In a particular embodiment, R 3 is hydrogen. In a particular embodiment, R 3 is, -OR 31In a particular embodiment, R 3 is -OH. In a particular embodiment, R 3 is -OCH3. In some embodiments, R 4 is hydrogen or -OR 35 In a particular embodiment, R 4 is hydrogen. In a particular embodiment, R 4 is, -OR 35 In a particular embodiment, R 4 is -OH. In a particular embodiment, R 4 is -OCH3. In some embodiments, R 5 is hydrogen or -OR 39 In a particular embodiment, R 5 is hydrogen. In a particular embodiment, R 5 is, -OR 39 In a particular embodiment, R 5 is -OH. In a particular embodiment, R 5 is -OCH3. In some embodiments, R 6 R is hydrogen, -OH, or optionally substituted -O-alkyl. In certain embodiments, R 6 It is hydrogen.

[0215] 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 a hydrogen atom or an optionally substituted alkyl group. In certain embodiments, R 7 , R 8 , R 9 , R 10 , R 31 , R 32 , R 33 , R34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , and R 42 Each of these is independently hydrogen. In a particular embodiment, 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 these is an optionally substituted alkyl group, independently of the others. In certain 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 of these is independently an unsubstituted alkyl. In a particular embodiment, 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 these is independently -CH3.

[0216] In some embodiments, Y is NH or O. In certain embodiments, Y is O.

[0217] In some embodiments, Z is an optionally substituted aryl. In certain embodiments, Z is an optionally substituted phenyl. In certain embodiments, Z is an unsubstituted phenyl.

[0218] In certain embodiments, the radical of at least one TrkB ligand is of the formula [ka] In certain embodiments, the radical of at least one TrkB ligand is of the formula [ka] It belongs to them.

[0219] In some embodiments, R 11 and R 13 Each of these is either absent or hydrogen, independently of the others. In certain embodiments, R 11 and R 13 Each of them is independent and does not exist. In some embodiments, R 12 , R 14 , and R 15 Each of these is independently hydrogen, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 12 , R 14 , and R 15 Each of these is independently hydrogen. In a particular embodiment, R 12 , R 14 , and R 15 Each of these is an optionally substituted alkyl group, independently of the others. In certain embodiments, R 12 , R 14 , and R 15 Each of these is independently an unsubstituted alkyl. In some embodiments, R 16R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 16 This is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0220] In some embodiments, R 17 , R 18 , and R 19 Each of these is independently hydrogen, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 17 , R 18 , and R 19 Each of these is independently hydrogen, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group.

[0221] In some embodiments, R 20 R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 20 R is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R 20 is hydrogen. In some embodiments, R 21 R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 21 R is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R 21 is hydrogen. In some embodiments, R 22 and R 23 Each of these is independently hydrogen, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 22 and R 23 Each of these is independently hydrogen, an unsubstituted alkyl, or an unsubstituted heteroalkyl. In certain embodiments, R 22 and R 23 Each of these is independently hydrogen. In some embodiments, R 24R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 24 R is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl. In certain embodiments, R 24 It is hydrogen.

[0222] In some embodiments, n16, n20, n21, n23, n24, z6, and z8 are each independently 0, 1, and 2. In certain embodiments, n16, n20, n21, n23, n24, z6, and z8 are each independently 0. In certain embodiments, v16, v20, v21, m16, m20, m21, and m24 are each independently 1. In certain embodiments, v16, v20, v21, m16, m20, m21, and m24 are each independently 2. In some embodiments, z3 is 0, 1, 2, or 3. In certain embodiments, z3 is 0. In some embodiments, z4 and z7 are each independently 0 or 1. In certain embodiments, z4 and z7 are each independently 0. In some embodiments, z5 is 0, 1, or 2. In certain embodiments, z5 is 0. In some embodiments, z6 and z8 are independently 0, 1, or 2. In certain embodiments, z6 and z8 are independently 0.

[0223] In some embodiments, the radical of at least one TrkB ligand is expressed as follows: [ka] It belongs to them.

[0224] In certain embodiments, at least one TrkB ligand is a flavone, tropoflavone, or a derivative thereof. In certain 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, diosmetine (5,7,3'-trihydroxy-4'-methoxyflavone), 7-hydroxy-4'-methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavone (4'-dimethylamino-7,8-dihydroxyflavone), norwogonin (5,7,8-trihydroxy These are flavonoids, R7, R13, tropoflavone (7,8-dihydroxyflavone), 7,8-dimethoxyflavone, quercetin (3,3',4',5,7-pentahydroxyflavone), apigenin (4',5,7-trihydroxyflavone), isocoumarin, goshipetin (3,5,7,8,3',4'-hexahydroxyflavone), 2-methyl-8-phenylchromeno[7,8-d]imidazole-6(3H)-one, 8-phenylchromeno[7,8-d]imidazole-6(3H)-one, 4-oxo-2-phenyl-4H-chromen-7,8-diyldiacetate, or ANA-12.

[0225] In some embodiments, at least one α4β 1 / 7 Integrin ligands are compounds with the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] And here, the example for each R is, [ka] That is the case.

[0226] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 2Z These are hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl groups, or substituted or unsubstituted heteroaryl groups. R 3Z and R 4Z Each of these is independently hydrogen, a halogen, an optionally substituted alkyl, or an optionally substituted -O-alkyl.

[0227] In some embodiments, R 2Z R is hydrogen or a substituted or unsubstituted heteroalkyl. In certain embodiments, R 2Z is hydrogen. In some embodiments, R 3Z and R 4Z Each of them is independently hydrogen or a halogen. In certain embodiments, R 3Z and R 4Z Each of them is independently a halogen.

[0228] In a particular embodiment, at least one α4β 1 / 7 The integrin ligand is defined by the following formula: [ka]

[0229] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 4Z is hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl. R 5Z is an optionally substituted heteroalkyl or optionally substituted heterocycline, n1Z is 1, 2, or 3.

[0230] In some embodiments, R 4Z R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 4Z is hydrogen. In some embodiments, R 5Z n1Z is an optionally substituted heteroalkyl group. In some embodiments, n1Z is 1 or 2. In certain embodiments, n1Z is 1.

[0231] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 6Z These are hydrogen, -OH, -NH2, and -NHR 7Z , -OR 7Z is or does not exist, R 7ZThis is hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0232] In some embodiments, R 6Z is either hydrogen, -OH, -NH2, or absent. In certain embodiments, R 6Z is hydrogen. In a particular embodiment, R 6Z It does not exist. In some embodiments, R 7Z R is hydrogen or optionally substituted alkyl. In certain embodiments, R 7Z is hydrogen or an unsubstituted alkyl group.

[0233] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] [ka] And, n2Z is ​​0, 1, 2, or 3.

[0234] In some embodiments, n2Z is ​​0 or 1. In certain embodiments, n2Z is ​​0.

[0235] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, n3Z is 0, 1, 2, or 3.

[0236] In some embodiments, n3Z is 0 or 1. In certain embodiments, n3Z is 0.

[0237] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 8Z , R 9Z , R 10Z , and R 11Z Each of these is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, or substituted or unsubstituted cycloalkyl. R 12Z and R 13Z Each of these can independently be hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, [ka] And, R 14Z This 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.

[0238] In some embodiments, R 8Z , R 9Z , R 10Z , and R 11Z Each of them is independently hydrogen, halogen, or optionally substituted alkyl. In certain embodiments, R 8Z , R 9Z , R 10Z , and R 11Z Each of them is independently an optionally substituted alkyl group. In a particular embodiment, R 8Z , R 9Z , R 10Z , and R 11Z Each of them is independently an unsubstituted alkyl. In some embodiments, R 12Z and R 13Z Each of them independently produces hydrogen, [ka] In a particular embodiment, R 12Z and R 13Z Each of them independently is H or [ka] In some embodiments, R 14Z is an optionally substituted C1-C5 alkyl group. In certain embodiments, R 14Z This is an optionally substituted C4 alkyl group.

[0239] In a particular embodiment, at least one α4β 1 / 7 The radical of the integrin ligand is given by the following formula: [ka]

[0240] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 15Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, R 16Z and R 17Z Each of them is independently H, a halogen, an optionally substituted alkyl, or an optionally substituted -O-alkyl. Y Z It is -CH2- or -(CH2)2-.

[0241] In some embodiments, R 15Z is H, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 15Z H is H. In some embodiments, R 16Z and R17Z Each of them is independently H or an optionally substituted alkyl. In certain embodiments, R 16Z and R 17Z Each of them is independently H. In a particular embodiment, Y Z is -CH2-. In a particular embodiment, Y Z It is -(CH2)2-.

[0242] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 18Z H, -OH, -NH2, -NHR 19Z , -OR 19Z , or -CONHR 19Z And, Each R 19Z Examples of these are independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. n4Z is either 1 or 2.

[0243] In some embodiments, R 18Z is H, -OH, or -NH2. In certain embodiments, R 18Z is H. In some embodiments, each R 19Z Examples of these are independently H or optionally substituted alkyl groups. In a particular embodiment, each R 19Z Examples of n4Z are independently H or an unsubstituted alkyl. In certain embodiments, n4Z is 1. In certain embodiments, n4Z is 2.

[0244] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 19Z H, -CH2OR 20Z -(CH2)2OR 20Z -CH2NHCOR 20Z , or -OR 20Z And, R 20Z This is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0245] In some embodiments, R 19Z is H or -CH2NHCOR 20Z In a particular embodiment, R 19Z is -CH2NHCOR 20Z In some embodiments, R 20Z is H or an optionally substituted alkyl group. In certain embodiments, R 20Z is either H or an unsubstituted alkyl group.

[0246] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 21Z H, -CONHR 22Z -CH2OR 22Z -(CH2)2OR 22Z -CH2NHCOR 22Z , or -OR 22Z And, R 22Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, X 1Z This is H or a halogen.

[0247] In some embodiments, R21Z is H or -CH2NHCOR 22Z In a particular embodiment, R 21Z is -CH2NHCOR 22Z In some embodiments, R 22Z is H or an optionally substituted alkyl group. In certain embodiments, R 22Z is H or an unsubstituted alkyl group. In certain embodiments, X 1Z H is H. In certain embodiments, X 1Z It is a halogen.

[0248] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 23Z H, -CONHR 24Z -CH2OR 24Z -(CH2)2OR 24Z -CH2NHCOR 24Z , or -OR 24Z And, R 24Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, n5Z is 0, 1, 2, or 3.

[0249] In some embodiments, R 23Z is H or -CONHR 24Z In a particular embodiment, R 23Z -CONHR 24Z In some embodiments, R 24Z is H or an optionally substituted alkyl group. In certain embodiments, R 24Z n5Z is H or an unsubstituted alkyl group. In some embodiments, n5Z is 0, 1, or 2. In certain embodiments, n5Z is 1.

[0250] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 25Z H, -CONHR 27Z -CH2OR 27Z -(CH2)2OR 27Z -CH2NHCOR 27Z , or -OR 27Z And, R 26Z is H, an optionally substituted alkyl, or an optionally substituted cycloalkyl, R 27Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, X 2Z This is an optionally substituted CH2 or an optionally substituted NH.

[0251] In some embodiments, R 25Z is H or -CH2NHCOR 27Z In a particular embodiment, R 25Z is -CH2NHCOR 27Z In some embodiments, R 26Z is H or an optionally substituted alkyl group. In some embodiments, R 26Z is H or an unsubstituted alkyl. In certain embodiments, R 26Z is H or -CH3. In some embodiments, R 27Z is H, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 27Z is H, an unsubstituted alkyl, or an unsubstituted heteroalkyl. In some embodiments, X 2Z is an optionally substituted NH. In certain embodiments, X 2Z It is NH.

[0252] In a particular embodiment, at least one α4β 1 / 7 The radical of an integrin ligand has the following formula: [ka] And, R 28Z H, -CH2OR 30Z -(CH2)2OR 30Z -CH2NHCOR 30Z , or -OR 30Z And, R 29Z H, -OH, -NH2, -NHR 31Z , or -OR 31Z And, R 30Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, R 31Z is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, n3Z is 1, 2, or 3.

[0253] In some embodiments, R 28Z H, -CH2NHCOR 30Z , or -OR 30Z In a particular embodiment, R 28Z is -CH2NHCOR 30Z In some embodiments, R 29Z These are H, -OH, and -NH2. In some embodiments, R 30Z is H, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 30Z is H, an unsubstituted alkyl, or an unsubstituted heteroalkyl. In some embodiments, R 31Zis H, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 31Z n3Z is H, an unsubstituted alkyl, or an unsubstituted heteroalkyl. In certain embodiments, n3Z is 1. In certain embodiments, n3Z is 2.

[0254] In some embodiments, at least one CB1 ligand is a compound of the following formula: [ka] And, X 1Y , NR 10Y or CR 11Y R 12Y And, R 10Y , R 11Y , and R 12Y Each of these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R 19Y is 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)OR19YD , -NR 19YB Ure 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 them independently is 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 These are connected to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, n19Y is 0, 1, 2, 3, or 4. v19Y is either 1 or 2.

[0255] In some embodiments, X 1Y , NR 10Y In a particular embodiment, X 1Y is NH. In some embodiments, R 10Y R is hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 10Y R is hydrogen, an unsubstituted alkyl, or an unsubstituted heteroalkyl. In certain embodiments, R 10Y is hydrogen. In some embodiments, R 19Y R is hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 19Y is hydrogen, an unsubstituted alkyl group, or an unsubstituted heteroalkyl group.

[0256] In certain embodiments, the radical of at least one CB1 ligand has the following formula: [ka] In certain embodiments, the radical of at least one CB1 ligand has the following formula: [ka]

[0257] In certain embodiments, the radical of at least one CB1 ligand is the radical of a compound with the following formula: [ka] Here, R 17Y is 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 Ure 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 them 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, where R bonded to the same nitrogen atom 17YB and R 17YC The substituents can be optionally attached to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. n17Y is 0, 1, 2, 3, or 4. v17Y is either 1 or 2.

[0258] In some embodiments, R 17Y is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -NR 17YB R 17YC In a particular embodiment, R 17Y -NR 17YB R 17YC In a particular embodiment, R 17Y is -NH2. In some embodiments, R 17YB and R 17YC Each of these is independently hydrogen, an optionally substituted alkyl, or an optionally substituted heteroalkyl. In certain embodiments, R 17YB and R 17YC Each of them is independently a hydrogen atom.

[0259] In certain embodiments, the radical of at least one CB1 ligand has the following formula: [ka]

[0260] In certain embodiments, the radical of at least one CB1 ligand is the radical of a compound with the following formula: [ka] In certain embodiments, the radical of at least one CB1 ligand has the following formula: [ka]

[0261] In certain embodiments, the radical of at least one CB1 ligand is the radical of a compound of the following formula: [ka] And, R 3Y , R 4Y , R 5Y , R 6Y , and R 8Y Each of these 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 is hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl, or R 6Y and R 9Y The substituents may be linked together to form optionally substituted heterocycloalkyl or optionally substituted heteroaryl compounds. R 7Y is 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 , -NR7YB 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 Ure 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 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, where R is bonded to the same nitrogen atom. 7YB and R 7YC The substituents can be optionally attached to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. n7Y is 0, 1, 2, 3, or 4. v7Y is either 1 or 2.

[0262] In some embodiments, R 3Y R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 3Y is hydrogen. In a particular embodiment, R 3Y is a halogen. In some embodiments, R 4YR is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 4Y is hydrogen. In a particular embodiment, R 4Y is a halogen. In some embodiments, R 5Y R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 5Y is hydrogen. In a particular embodiment, R 5Y is a halogen. In some embodiments, R 6Y R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 6Y is hydrogen. In a particular embodiment, R 6Y is a halogen. In some embodiments, R 7Y is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or -C(O)R 7YD In a particular embodiment, R 7Y is -C(O)R 7YD In some embodiments, R 7YD R is an optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, R 7YD is an arbitrarily substituted aryl. In some embodiments, R 8Y R is hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 8Y is an optionally substituted heteroalkyl group. In certain embodiments, R 8Y is a substituted heteroalkyl. In some embodiments, R 9Y R is hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 9Y It is hydrogen.

[0263] In certain embodiments, the radical of at least one CB1 ligand has the following formula: [ka]

[0264] In certain embodiments, at least one CB1 ligand is a compound of the following formula: [ka] And, R 16Y These are 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, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, R 16YA , R 16YB , R 16YC , and R 16YD 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, or R bonded to the same nitrogen atom. 16YB and R 16YC These are connected to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl atoms.

[0265] In some embodiments, R 16Y R is hydrogen, halogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In certain embodiments, R 16Y This is hydrogen, halogen, unsubstituted alkyl, or unsubstituted heteroalkyl.

[0266] In certain embodiments, the radical of at least one CB1 ligand has the following formula: [ka]

[0267] In certain embodiments, at least one CB1 ligand is a compound of the following formula: [ka]

[0268] In some embodiments, at least one NMDA receptor ligand is a compound of the following formula: [ka]

[0269] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka] In certain embodiments, the radical of at least one NMDA receptor ligand is of the following formula: [ka]

[0270] In some embodiments, the ligand is an antibody (e.g., anti-TrkB, anti-CB1, anti-α4β). 1 / 7 The ligand is an integrin or an anti-NMDA receptor antibody. In certain embodiments, the ligand is an antibody fragment or antibody variant. Examples include "anti-TrkB receptor antibody," "anti-CB1 receptor antibody," and "anti-α4β receptor antibody." 1 / 7 Integrin receptor antibodies, or anti-NMDA receptor antibodies, are TrkB, CB1, and α4β, respectively. 1 / 7Integrins refer to immune system proteins that recognize, bind to, or otherwise interact with NMDA receptors.

[0271] 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 2 ligands. In some embodiments, the oligonucleotide comprises 3 ligands. In some embodiments, the oligonucleotide further comprises an additional ligand conjugated to the 5' end. In some embodiments, the oligonucleotide further comprises an additional ligand conjugated to the 3' end. In certain embodiments, the oligonucleotide further comprises an additional ligand conjugated to the 5' end and an additional ligand conjugated to the 3' end. In some embodiments, at least two ligands are of the same ligand type. In some embodiments, each ligand is of the same ligand type. In some embodiments, at least two ligands are the same. In some embodiments, at least two ligands are different ligands of the same ligand type. In some embodiments, at least two ligands are of different ligand types. In some embodiments, none of the ligands are of the same ligand type. In certain embodiments, if the ligands are of the same ligand type, they bind to the same target. In some embodiments, at least one ligand is a small molecule, peptide, or protein.

[0272] In some embodiments, each A 4 Examples include radicals of the same ligand type. In some embodiments, each A 4 An example is a radical of the same ligand. In some embodiments, at least two A 4 Examples include radicals of different ligand types. In some embodiments, at least two A 4An example is a radical of different ligands of the same ligand type. In some embodiments, at least two A 4 An example of this is a radical of different ligands of different ligand types.

[0273] In some embodiments, each A 5 Examples include radicals of the same ligand type. In some embodiments, each A 5 An example is a radical of the same ligand. In some embodiments, at least two A 5 Examples include radicals of different ligand types. In some embodiments, at least two A 5 An example is a radical of different ligands of the same ligand type. In some embodiments, at least two A 5 An example of this is a radical of different ligands of different ligand types.

[0274] In some embodiments, each A 6 Examples include radicals of the same ligand type. In some embodiments, each A 6 An example is a radical of the same ligand. In some embodiments, at least two A 6 Examples include radicals of different ligand types. In some embodiments, at least two A 6 An example is a radical of different ligands of the same ligand type. In some embodiments, at least two A 6 An example of this is a radical of different ligands of different ligand types.

[0275] In some embodiments, at least one A 4 Examples and at least one A 5 An example is a radical of the same ligand type. In some embodiments, at least one A 4 Examples and at least one A 5 An example is a radical of the same ligand. In some embodiments, at least one A 4 Examples and at least one A 5Examples include radicals of different ligand types. In some embodiments, at least one A 4 Examples and at least one A 5 An example is a radical of different ligands of the same ligand type. In some embodiments, at least one A 4 Examples and at least one A 5 An example is a radical of different ligands of different ligand types. In some embodiments, at least one A 4 Examples and at least one A 6 An example is a radical of the same ligand type. In some embodiments, at least one A 4 Examples and at least one A 6 An example is a radical of the same ligand. In some embodiments, at least one A 4 Examples and at least one A 6 Examples include radicals of different ligand types. In some embodiments, at least one A 4 Examples and at least one A 6 An example is a radical of different ligands of the same ligand type. In some embodiments, at least one A 4 Examples and at least one A 6 An example is a radical of different ligands of different ligand types. In some embodiments, at least one A 5 Examples and at least one A 6 An example is a radical of the same ligand type. In some embodiments, at least one A 5 Examples and at least one A 6 An example is a radical of the same ligand. In some embodiments, at least one A 5 Examples and at least one A 6 Examples include radicals of different ligand types. In some embodiments, at least one A 5 Examples and at least one A 6 An example is a radical of different ligands of the same ligand type. In some embodiments, at least one A 5Examples and at least one A 6 An example of this is a radical of different ligands of different ligand types.

[0276] In some embodiments, each A 4 , A 5 , and A 6 An example is a radical of the same ligand. In some embodiments, each A 4 , A 5 , and A 6 An example is a ligand radical that is different from any other ligand radical in the oligonucleotide. In some embodiments, each A 4 , A 5 , and A 6 An example is the radical of the same TrkB ligand. In some embodiments, each A 4 , A 5 , and A 6 An example is the radical of the same CB1 receptor ligand. In some embodiments, each A 4 , A 5 , and A 6 An example is the same α4β 1 / 7 It is a radical of an integrin receptor ligand. In some embodiments, each A 4 , A 5 , and A 6 An example is a radical of the same NMDA receptor ligand. In some embodiments, each A 4 , A 5 , and A 6 Examples include various TrkB ligands, CB1 receptor ligands, and α4β 1 / 7 It is a radical of an integrin receptor ligand and / or an NMDA receptor ligand.

[0277] Lipids In the oligonucleotides of this disclosure, A 5 and A 6 Each of these, if present, is independently a ligand or lipid radical. In some embodiments, A 5 A is a lipid radical. In some embodiments, A 6A is a lipid radical. In certain embodiments, A 5 and A 6 These are, independently, lipid radicals.

[0278] In some embodiments, each A 4 An example is the same lipid radical. In some embodiments, each A 5 An example is the same lipid radical. In some embodiments, each A 6 An example of this is a radical of the same lipid.

[0279] In some embodiments, at least one A 4 Examples and at least one A 5 An example is a radical of the same lipid. In some embodiments, at least one A 4 Examples and at least one A 6 An example is a radical of the same lipid. In some embodiments, at least one A 5 Examples and at least one A 6 An example of this is a radical of the same lipid.

[0280] In some embodiments, each A 5 and A 6 An example is the same lipid radical. In some embodiments, each A 5 and A 6 An example of this is a radical of a different lipid compared to any other lipid radical in an oligonucleotide.

[0281] In some embodiments, at least one lipid is an aliphatic acyl, glycerolipid, glycerophospholipid, sphingolipid, glycolipid, polyketide, sterollipid, or prenolipid. In some embodiments, at least one lipid is a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, aliphatic alcohol, aliphatic aldehyde, aliphatic ester, aliphatic amide, aliphatic nitrile, aliphatic ether, hydrocarbon, oxygen-containing hydrocarbon, or aliphatic acyl glycoside.

[0282] In some embodiments, at least one lipid is a hydrocarbon. In some embodiments, the hydrocarbon chain is saturated or unsaturated. In certain embodiments, the unsaturated hydrocarbon chain contains 1, 2, 3, 4, 5, or 6 carbon-carbon double bonds (e.g., cis double bonds and / or trans double bonds). In some embodiments, the radical of at least one lipid is an unsubstituted C 7-36 Alkyl, C substituted with one or more fluoro atoms as far as the valence allows. 7-36 Alkyl, unsubstituted C 7-36 C is substituted with an alkenyl or one or more fluoroions, as long as the valence allows. 7-36 It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 7-36 Alkyl or unsubstituted C 7-36 It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 7-36 It is alkyl. In some embodiments, at least one lipid radical is unsubstituted C 7-20 Alkyl, C substituted with one or more fluoro atoms as far as the valence allows. 7-20 Alkyl, unsubstituted C 7-20 C is substituted with an alkenyl or one or more fluoroions, as long as the valence allows. 7-20 It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 7-20 Alkyl or unsubstituted C 7-20 It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 7-20 It is alkyl. In some embodiments, at least one lipid radical is unsubstituted C 21-28 Alkyl, C substituted with one or more fluoro atoms as far as the valence allows. 21-28 Alkyl, unsubstituted C 21-28 C is substituted with an alkenyl or one or more fluoroions, as long as the valence allows. 21-28 It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 21-28 Alkyl or unsubstituted C 21-28It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 21-28 It is alkyl. In some embodiments, at least one lipid radical is unsubstituted C 29-36 Alkyl, C substituted with one or more fluoro atoms as far as the valence allows. 29-36 Alkyl, unsubstituted C 29-36 C is substituted with an alkenyl or one or more fluoroions, as long as the valence allows. 29-36 It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 29-36 Alkyl or unsubstituted C 29-36 It is an alkenyl. In certain embodiments, at least one lipid radical is an unsubstituted C 29-36 It is alkyl. In some embodiments, at least one lipid radical is unsubstituted C 16-28 Alkyl or unsubstituted C 16-28 These are alkenyls, each independently being unbranched, bibranched, or tribranched. In certain embodiments, the alkenyls described in this paragraph contain one C=C bond. In certain embodiments, the alkenyls described in this paragraph contain two, three, or four C=C bonds, as valence allows. In certain embodiments, at least one lipid radical is an unbranched unsubstituted C=C bond. 18-26 It is alkyl. In certain embodiments, at least one lipid radical 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 It is CH3. In certain embodiments, at least one lipid radical is -(CH2) 21 It is CH3. In certain embodiments, at least one lipid radical is an unbranched, unsubstituted C 18-26It is an alkenyl. In certain embodiments, the radical of at least one lipid is an unbranched, unsubstituted C100, containing one C=C bond. 18-26 It is Alkenil.

[0283] In certain embodiments, at least one lipid is monoradilglycerol, diradilglycerol, triradilglycerol, glycosylmonorasylglycerol, glycosyldirasylglycerol, betaine monoradilglycerol, or betaine diradilglycerol.

[0284] In certain embodiments, at least one lipid is glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosylglycerophospholipid, glycerophosphoinositol glycan, glycerophosphonocholine, glycerophosphonoethanolamine, diglycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetone phosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid.

[0285] In certain embodiments, at least one lipid is a sphingoid base, ceramide, phosphosphingolipid, phosphonosphingolipid, neutral sphingoglycolipid, acidic sphingoglycolipid, basic sphingoglycolipid, amphoteric sphingoglycolipid, or arsenosphingolipid.

[0286] In certain embodiments, at least one lipid is a sterol, steroid, secosteroid, bile acid, or a derivative thereof, or a steroid conjugate. In certain embodiments, at least one lipid is cholesterol. In certain embodiments, the radical of at least one lipid is of the following formula: [ka]

[0287] In certain embodiments, at least one lipid is lithocholic acid. In certain embodiments, the radical of at least one lipid is of the following formula: [ka]

[0288] In certain embodiments, at least one lipid radical is of the following formula: [ka] And, Optionally, non-substituted C 7-30 Alkyl is an unbranched, unsubstituted C 11-23 Alkyl and unsubstituted C 7-30 Alkenyls are unbranched, unsubstituted C 11-23 The alkenyl (which may contain one C=C bond or two, three, or four C=C bonds) is an alkenyl. In certain embodiments, at least one lipid radical is of the following formula: [ka]

[0289] In certain embodiments, at least one lipid is an isoprenoid, quinone, hydroquinone, polyprenol, or hopanoid.

[0290] In certain embodiments, at least one lipid is an acylamino sugar, an acylamino sugar glycan, an acyltrehalose, or an acyltrehalose glycan.

[0291] In certain embodiments, at least one lipid is a linear polyketide, halogenated acetogenin, annonaceous acetogenin, macrolide, lactone polyketide, ansamycin, polyene, linear tetracycline, angucycline, polyether antibiotic, aflatoxin, cytochalasin, flavonoid, aromatic polyketide, non-ribosomal peptide / polyketide hybrid, or phenolic lipid.

[0292] Additional oligonucleotide chain modification The modified oligonucleotide chain may further include additional modifications. In certain embodiments, the modified oligonucleotide chain further includes at least one modified sugar, at least one modified nucleic acid base, at least one modified nucleoside bond, or a combination thereof. In certain embodiments, the modified oligonucleotide chain further includes 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 modified nucleosides (including both ends). In certain 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 modified sugars (including both ends). In certain 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 modified nucleoside bonds (including both ends).

[0293] If the oligonucleotide includes an additional oligonucleotide chain (e.g., an antisense oligonucleotide chain), such additional oligonucleotide chain may independently include one or more of the additional modifications described herein.

[0294] sugar modification Any modification 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 certain embodiments, the modified sugar is a substituted furanosyl sugar or a non-bicyclic modified sugar. In certain embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, the modified sugar is a substitute sugar. The substitute sugar may contain one or more substitutions described herein.

[0295] In certain embodiments, the modified sugar is a substituted furanosyl or a non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar contains one or more substituents, including but not limited to substituents at the 2', 3', 4', and 5' positions. In certain embodiments, the 2' substituent may include, but is not limited to, F and OCH3 ("OMe", "O-methyl", or "methoxy"). In certain embodiments, suitable 2' substituents for non-bicyclic modified sugars may include, but is not limited to, halo, allyl, amino, azide, -SH, -CN, -OCN, -CF3, -OCF3, -F, -Cl, -Br, -SCH3, -SOCH3, -SO2CH3, -ONO2, -NO2, -N3, and -NH2. In certain embodiments, the 2' substituent may include, but is not limited to, -O-(C1-C 10Examples include alkoxy, alkoxyalkyl, -O-alkyl, -S-alkyl, -N-alkyl, -O-alkenyl, -S-alkenyl, -N-alkenyl, -O-alkynyl, -S-alkynyl, -N-alkynyl, -O-alkyl-O-alkyl, and alkynyl, wherein the alkyl, alkenyl and alkynyl are substituted or unsubstituted C1-C 10 Alkyl or C2-C 10 These can be alkenyls and alkynyls. In certain embodiments, the 2' substituents may include, but are not limited to, alkalil, aralkyl, -O-alkaryl, and -O-aralkyl. In certain embodiments, these 2' substituents may be further substituted independently with one or more substituents selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro(-NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the 2' substituent may include, but is not limited to, -O[(CH2) h O] j CH3, -O(CH2) h OCH3, -O(CH2) h CH3, -O(CH2) h ONH2, -O(CH2) h NH2, -O(CH2) h SCH3 and -O(CH2) h ON[(CH2) h Examples include CH3)2, where h and j are independently 1 to 10. In certain embodiments, the substituent at the 2' position may 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").

[0296] In certain embodiments, suitable substituents at the 4' position for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, suitable substituents at the 5' position for non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, the 5' modification is 5'-monophosphate ((HO)2(O)PO-5'), 5'-diphosphate ((HO)2(O)POP(HO)(O)-O-5'), 5'-triphosphate ((HO)2(O)PO-(HO)(O)POP(HO)(O)-O-5'), 5'-guanosine cap (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)( O)POP(HO)(O)-O-5'), 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 (phosphorothioate, (HO)2(S)PO-5'), 5'-monoditithiophosphate (phosphorodithioate, (HO)(HS)(S)P These include (OH)(O)P-5'-5', 5'-phosphorothiolate ((HO)2(O)PS-5'), any additional combination of oxygen / sulfur-substituted monophosphates, diphosphates and triphosphates (e.g., 5'-alpha-thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 5'-phosphoamides ((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-), and 5'-alkyl ether phosphonates (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g., RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars include a 5'-vinylphosphonate modification. In certain embodiments, one or more sugars include a 5'-ethylenephosphonate modification.In certain embodiments, the 5' modification is located at the terminus of the oligonucleotide. In certain embodiments, the 5' modification is located at the terminus of the antisense oligonucleotide. In certain embodiments, the substituents described herein for the 2', 4', and 5' positions may be added to other specific positions of the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar at its 3'-terminal nucleoside, or to the 5' position of its 5'-terminal nucleoside. In certain embodiments, the non-bicyclic modified sugar may contain more than one non-crosslinked sugar substituent. In certain such embodiments, examples of non-bicyclic modified sugar substituents include, but are not limited to, 5'-Me-2'-F and 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, examples of modified sugar substituents include those described in Migawa et al., WO 2008 / 101157.

[0297] In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar containing two rings, the second ring forming a bicyclic structure by being formed via a bridge that links two atoms in the first ring. In certain embodiments, the bicyclic sugar contains a crosslinkable substituent that crosslinks two atoms of its furanosyl ring to form the second ring. In certain embodiments, the bicyclic sugar does not contain a furanosyl moiety. A "bicyclic nucleoside" ("BNA") is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar contains a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar contains a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, substituents that crosslink from 4' to 2' include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' ("LNA"), 4'-CH2-S-2', 4'-(CH2)2-O-2' ("ENA"), 4'-CH(CH3)-O-2' ("restricted ethyl" or "cEt" in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', and 4'-CH(CH2OCH3)-O-2'. ("Restricted MOE" or "cMOE") and its analogs (e.g., U.S. Patent No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and its analogs (e.g., U.S. Patent No. 8,278,283), 4'-CH2-N(OCH3)-2' and its analogs (e.g., U.S. Patent No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., U.S. Patent Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2', where R is H, C1-C 12Examples include alkyl groups or protecting groups (e.g., U.S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134), and 4'-CH2-C(=CH2)-2' and its analogues (e.g., U.S. Patent No. 8,278,426). Additional representative U.S. patents and publications teaching the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, U.S. Patents No. 6,268,490, No. 6,525,191, No. 6,670,461, No. 6,770,748, No. 6,794,499, No. 6,998,484, No. 7,053,2 Issues such as No. 07, No. 7,034,133, No. 7,084,125, No. 7,399,845, No. 7,427,672, No. 7,569,686, No. 7,741,457, No. 8,022,193, No. 8,030,467, No. 8,278,425, No. 8,278,426, No. 8,278,283, No. US 2008 / 0039618, No. US 2009 / 0012281, No. US 2013 / 0190383, and No. WO 2013 / 036868 are examples. Any of the aforementioned bicyclic nucleosides can be prepared to have one or more stereochemical sugar configurations (e.g., including α-L-ribofuranose and β-D-ribofuranose) (see, for example, WO 99 / 14226). Unless otherwise specified, the specific bicyclic nucleosides in this invention are in the β-D configuration.

[0298] In certain embodiments, the modified sugar is an alternative sugar. In certain embodiments, the alternative sugar has its oxygen atom replaced by, for example, a sulfur atom, a carbon atom, or a nitrogen atom. In certain such embodiments, the alternative sugar may also include crosslinkable substituents and / or non-crosslinkable substituents as described herein. In certain embodiments, the alternative sugar includes a ring having more than five atoms. In certain such embodiments, the alternative sugar includes a cyclobutyl moiety instead of pentofuranosyl sugar. In certain embodiments, the alternative sugar includes a six-membered ring instead of pentofuranosyl sugar. In certain embodiments, the alternative sugar includes tetrahydropyran ("THP") instead of pentofuranosyl sugar. In certain embodiments, the alternative sugar includes morpholino instead of pentofuranosyl sugar. Representative U.S. patents teaching the preparation of such modified sugar structures include, but are not limited to, U.S. Patents Nos. 4,981,957, 5,118,800, 5,166,315, 5,185,444, 5,319,080, 5,359,044, 5,393,878, 5,446,137, 5,466,786, 5,514,785, 5,519,134, and 5,567,811. Examples include Nos. 5,576,427, 5,591,722, 5,597,909, 5,610,300, 5,627,053, 5,639,873, 5,646,265, 5,658,873, 5,670,633, 5,700,920, 7,875,733, 7,939,677, 8,088,904, 8,440,803, and 9,005,906.

[0299] In some embodiments, the alternative sugar includes an acyclic moiety. In certain embodiments, the alternative sugar is an unlocked nucleic acid ("UNA"). A UNA is an unlocked acyclic nucleic acid in which one of the sugar bonds has been removed to form an unlocked "sugar" residue. In one example, a UNA also includes monomers in which the C1'-C4' bond (i.e., the covalent carbon-oxygen-carbon bond between the C1' and C4' carbons) has been removed. In another example, the C2'-C3' bond of the sugar (i.e., the covalent carbon-carbon bond between the C2' and C3' carbons) has been removed. Representative U.S. publications teaching the preparation of UNAs include, but are not limited to, U.S. Patent No. 8,314,227, and U.S. Patent Publications 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020. In certain embodiments, alternative sugars include peptide nucleic acids ("PNA"), acyclic butyl nucleic acids (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US 2013 / 130378. Many other bicyclic and tricyclic sugars and alternative sugar ring systems that can be used with modified nucleosides are known in the art.

[0300] In some embodiments, modified sugars and / or unmodified sugars are arranged along the modified oligonucleotide chain or region in a defined pattern or “sugar motif.” In certain cases, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0301] In certain embodiments, the oligonucleotide chain includes a gapmer sugar motif. The gapmer oligonucleotide chain includes, or comprises, a region having two outer "wing" regions and a central or inner "gap" region. The gap and wing regions form a continuous sequence of nucleosides, where the majority of the nucleoside sugars in each wing are different from the majority of the nucleoside sugars in the gap. In certain embodiments, the wing regions consist mostly of modified sugars, and the gap consists mostly of unmodified sugars. In certain embodiments, the nucleosides in the gap are deoxynucleosides. Oligonucleotides having a gapmer sugar motif are described, for example, in U.S. Patent No. 8,790,919.

[0302] In certain embodiments, one or both strands of a double-stranded oligonucleotide contain a triplet sugar motif. An oligonucleotide chain having a triplet sugar motif contains three identical sugar modifications in three consecutive nucleosides. In certain embodiments, the triplet is located at or near the cleavage site of the oligonucleotide (e.g., the site where a ribonuclease such as Dicer or Drosha cleaves the oligonucleotide). In certain embodiments, a strand of a double-stranded oligonucleotide may contain one or more triplet sugar motifs. In certain embodiments, the identical sugar modifications of the triplet sugar motif are 2'-F modifications. Oligonucleotides having triplet sugar motifs are disclosed, for example, in U.S. Patent No. 10,668,170.

[0303] In certain embodiments, one or both strands of a double-stranded oligonucleotide contain a quadruplet sugar motif. An oligonucleotide chain having a quadruplet sugar motif contains four identical sugar modifications in four consecutive nucleosides. In certain embodiments, the quadruplet is located at or near the cleavage site. In certain embodiments, a strand of a double-stranded oligonucleotide may contain more than one quadruplet sugar motif. In certain embodiments, the identical sugar modifications of the quadruplet sugar motif are 2'-F modifications. With respect to double-stranded oligonucleotides having a double-stranded region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide chain is typically located around positions 10, 11, and 12 from the 5' end. In certain embodiments, the quadruplet sugar motif is located at positions 8, 9, 10, and 11, 9, 11, and 12, 10, 11, 12, and 13, 11, 12, 13, and 14, or 12, 13, 14, and 15 of the sense oligonucleotide chain, counting from the first nucleoside at the 5' end of the sense oligonucleotide chain, or starting from the first nucleotide pair from the 5' end within the double-stranded region of the sense oligonucleotide chain. In certain embodiments, the quadruplet sugar motif is located at positions 8, 9, 10, and 11, 9, 11, and 12, 10, 11, and 13, 11, 12, 13, and 14, or 12, 13, 14, and 15 of the antisense oligonucleotide chain, counting from the first nucleoside at the 5' end of the antisense oligonucleotide chain, or starting from the first nucleotide pair from the 5' end within the double-stranded region of the antisense oligonucleotide chain. The cleavage sites may vary depending on the length of the double-stranded region of the double-stranded oligonucleotide, and therefore the position of the quadruplet may vary.

[0304] In certain embodiments, the oligonucleotide chain contains an alternating sugar motif. In certain embodiments, one or both chains of a double-stranded oligonucleotide contain an alternating sugar motif. The oligonucleotide having an alternating sugar motif contains at least two different sugar modifications, where one or more consecutive nucleosides containing a first sugar modification alternate with one or more consecutive nucleosides containing a second sugar modification and one or more consecutive nucleosides containing a third sugar modification, and so on. For example, if A, B, and C each represent one type of modification to a nucleoside, the alternating motif may be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC...", etc. In certain embodiments, the alternating sugar motif is repeated along the oligonucleotide chain over at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleic acid bases. In certain embodiments, the alternating sugar motif consists of two different sugar modifications. In certain embodiments, the alternating sugar motif includes 2'-OMe and 2'-F sugar modifications.

[0305] In certain embodiments, each nucleoside in an oligonucleotide chain is independently modified with one or more sugar modifications provided herein. In certain embodiments, each chain of a double-stranded oligonucleotide independently has one or more sugar modifications provided herein. In certain embodiments, an oligonucleotide chain containing a sugar motif is fully modified in such a way that each nucleoside contains a sugar modification.

[0306] In certain embodiments, the modified sugars are 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)- These are 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-ethylene-linked ribose, 2',4'-restricted ethylribose, locked sugars, or bicyclic sugars.

[0307] In certain embodiments, the modified sugar is located at the 3' end of the oligonucleotide chain. In certain embodiments, the modified sugar is located within 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the modified sugar is located at the 5' end of the oligonucleotide chain. In certain embodiments, the modified sugar is located within 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the modified sugar is located in an internal position within the oligonucleotide chain. In certain embodiments, the modified sugar is located more than 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the modified sugar is located more than 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the modified sugar is located in a block of modified nucleic acid bases. In certain such embodiments, the block is located at the 3' end of the oligonucleotide chain. In certain embodiments, the block is within 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the block is located at the 5' end of the oligonucleotide chain. In certain embodiments, the block is within 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the block is located internally within the oligonucleotide chain. In certain embodiments, the block is more than three nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the block is more than three nucleosides from the 5' end of the oligonucleotide chain.

[0308] In certain embodiments, the modified sugar is 2'-O-methylribose, 2'-F-ribose, or inverted debased deoxyribose. In certain embodiments, the modified nucleoside is 2'-O-methyladenosine, 2'-O-methylguanosine, 2'-O-methylcytosine, 2'-O-methyluracil, 2'-F-adenosine, 2'-F-guanosine, 2'-F-cytosine, or 2'-F-uracil.

[0309] Nucleic acid base modification Any modified nucleic acid base known in the art may be used in the oligonucleotides provided herein. In certain embodiments, the modified oligonucleotide comprises one or more nucleosides containing a modified nucleic acid base. In certain embodiments, the modified oligonucleotide comprises one or more nucleosides that do not contain a nucleic acid base (referred to as debased nucleosides).

[0310] In certain embodiments, the modified nucleic acid bases are selected from 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl-substituted pyrimidines, alkyl-substituted purines, and N-2, N-6, and O-6-substituted purines. In certain embodiments, the modified nucleic acid bases are 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl(C≡C-CH3)uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azocymine, 5-ribosyluracil (pseudracil), 4-thiouracil, 8-haloprin, 8-aminopurine, 8-thiolpurine, 8-thioalkylpurine, 8-hydroxylpurine, and 8-azocytosine. The bases are selected from purines and other 8-substituted purines, 5-halo (especially 5-bromo), 5-trifluoromethyl, 5-halouracil and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl4-N-benzoylcytosine, 5-methyl4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-extended bases, and fluorinated bases. Further modified nucleic acid bases include tricyclic pyrimidines (such as 1,3-diazaphenoxadin-2-one, 1,3-diazaphenothiazine-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxadin-2-one (G-clamp)). Modified nucleic acid bases can also include those in which a purine or pyrimidine base is replaced by another heterocycle (e.g., 7-deaza-adenine, 7-deazaguanosine, and 2-aminopyridine and 2-pyridone).

[0311] In certain embodiments, the modified nucleic acid bases are xanthine, allylaminouracil, allylaminothymidine, hypoxanthine, digoxigenylated adenine, digoxigenylated cytosine, digoxigenylated guanine, digoxigenylated uracil, 6-chloropurine riboside, N6-methyladenine, methylpseudolacil, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-dihydrouracil, 5-[(3-indolyl)propionamide-N-allyl] Racil, 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-hydroxymethyluracil, 5-hydroxyuracil, 5-iodocytosine, 5-iodouracil, 5-methoxycytosine, 5-methoxyuracil, 5-methylcytosine, 5-methyluracil, 5-propargyl Luaminocytosine, 5-propargylaminouracil, 5-propynylcytosine, 5-propynyluracil, 6-azacytosine, 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deazaadenine, 7-deazaguanine, 7-deaza-7-propargylaminoadenine, 7-deaza-7-propargylaminoguanine, 8-aziadenine, 8-azidodenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine, aracytosine, aragu anine), arauracil, biotin-16-7-deaza-7-propargylaminoguanine, biotin-16-aminoallylcytosine, biotin-16-aminoallyluracil, cyanine 3-5-propargylaminocytosine, cyanine 3-6-propargylaminouracil, cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6-propargylaminocytosine, cyanine 5-6-propargylaminouracil, cyanine 5-aminoallylcytosine, cyanine 5-aminoallyluracil,Cyanine 7-aminoallyluracil, dabucil-5-3-aminoallyluracil, desthiobiotin-16-aminoallyluracil, desthiobiotin-6-aminoallylcytosine, isoguanine, N1-ethylpsuduracil, N1-methoxymethylpsuduracil, N1-methyladenine, N1-methylpsuduracil, N1-propylpsuduracil, N2-methylguanine, N4- Otin-OBEA-cytosine, N4-methylcytosine, N6-methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienouranine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6-diaminoguanine, 5-carboxamide-uracil, 5-ethinyluracil, N6-isopentenyladenine (i6A), 2 -Methyl-thio-N6-isopentenyl adenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis-hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2- These are methylthio-N6-threonylcarbamoyladenine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalylcarbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

[0312] Further references to nucleic acid bases include U.S. Patent No. 3,687,808, Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008, The Concise Encyclopedia Of Polymer Science And Engineering, pp. 858-859; Kroschwitz, JL, Ed., John Wiley & Sons, 1990, pp. 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pp. 289-302; Antisense Research and Applications, Crooke, ST and Lebleu, B., Eds., CRC Press, 1993, pp. 273-288; Antisense Drug Technology, Crooke ST, Ed., CRC Examples include those disclosed in Press, 2008, pp. 163-166 and pp. 442-443 (Chapters 6 and 15).

[0313] Publications teaching the preparation of other modified nucleic acid bases, similar to the specific modified nucleic acid bases described above, include, but are not limited to, U.S. Patent Applications Publications 2003 / 0158403 and 2003 / 0175906, U.S. Patents 4,845,205, 5,130,302, 5,134,066, 5,175,273, and 5,367. ,066, No. 5,432,272, No. 5,434,257, No. 5,457,187, No. 5,459,255, No. 5,484,908, No. 5,502,1 No. 77, No. 5,525,711, No. 5,552,540, No. 5,587,469, No. 5,594,121, No. 5,596,091, No. 5,614,617 , No. 5,645,985, No. 5,681,941, No. 5,811,534, No. 5,750,692, No. 5,948,903, No. 5,587,470, No. No. 5,457,191, No. 5,763,588, No. 5,830,653, No. 5,808,027, No. 6,005,096, No. 6,015,886, No. 6, Examples include Nos. 147,200, 6,166,197, 6,166,199, 6,222,025, 6,235,887, 6,380,368, 6,528,640, 6,639,062, 6,617,438, 7,045,610, 7,427,672, and 7,495,088.

[0314] In certain embodiments, the oligonucleotide comprises modified and / or unmodified nucleic acid bases arranged in a defined pattern or motif along one or both chains or regions of the oligonucleotide. In certain embodiments, each nucleic acid base is modified. In certain embodiments, none of the nucleic acid bases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleic acid bases in the modified oligonucleotide chain are 5-methylcytosine.

[0315] In certain embodiments, the modified nucleic acid base is located at the 3' end of the oligonucleotide chain. In certain embodiments, the modified nucleic acid base is located within 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the modified nucleic acid base is located at the 5' end of the oligonucleotide chain. In certain embodiments, the modified nucleic acid base is located within 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the modified nucleic acid base is located in an internal position within the oligonucleotide chain. In certain embodiments, the modified nucleic acid base is located more than 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the modified nucleic acid base is located more than 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the modified oligonucleotide includes a block of modified nucleic acid bases. In certain such embodiments, the block is located at the 3' end of the oligonucleotide chain. In certain embodiments, the block is within 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the block is located at the 5' end of the oligonucleotide chain. In certain embodiments, the block is within 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the block is located internally within the oligonucleotide chain. In certain embodiments, the block is more than three nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the block is more than three nucleosides from the 5' end of the oligonucleotide chain.

[0316] Nucleoside bond modification Any modified nucleoside linkage may be used in the oligonucleotides provided herein. The 3' to 5' phosphodiester linkage is a naturally occurring nucleoside linkage in RNA and DNA. In certain embodiments, the oligonucleotide chain has one or more modified (i.e., non-naturally occurring) nucleoside links. Certain non-naturally occurring nucleoside links may confer desirable properties (e.g., enhanced cellular uptake, enhanced affinity to target nucleic acids, and improved stability in the presence of nucleases). Representative phosphorus-containing modified nucleoside links include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, phosphorothioates ("P=S"), phosphorodithioates ("HS-P=S"), and phosphorothiolates ("HS-P=O"). Representative phosphorus-free internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiesters, thionocarbamates (-OC(=O)(NH)-S-), siloxanes (-O-SiH2-O-), and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and phosphorus-free internucleoside links are available to those skilled in the art. It is well known that neutral internucleoside bonds include, but are not limited to, phosphotriesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S-CH2-O-5').Further neutral internucleoside bonds include nonionic bonds, which are composed of siloxanes (dialkylsiloxanes), carboxylic acid esters, carboxamides, sulfides, sulfonic acid esters, and amides (see, for example, Carbohydrate Modifications in Antisense Research; YSSanghvi and PDCook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside bonds include nonionic bonds, which are composed of mixed N, O, S, and CH2 constituent parts.

[0317] In certain embodiments, the oligonucleotide chain includes at least one modified nucleoside bond. The modified nucleoside bond can be located at any position on the oligonucleotide chain. With respect to double-stranded oligonucleotides, the modified nucleoside bond can be located within the sense oligonucleotide chain, the antisense oligonucleotide chain, or both oligonucleotide chains of the double-stranded oligonucleotide.

[0318] In certain embodiments, nucleoside linkage modification may occur at any nucleoside of the oligonucleotide chain. In certain embodiments, nucleoside linkage modification may occur in an alternating pattern along the oligonucleotide chain. In certain embodiments, each nucleoside linkage group is essentially a phosphate nucleoside linkage (P=O). In certain embodiments, each nucleoside linkage group of the modified oligonucleotide chain is a phosphorothioate (P=S). In certain embodiments, each nucleoside linkage group of the modified oligonucleotide chain is independently selected from phosphorothioate and phosphate nucleoside linkages. In certain embodiments, the pattern of nucleoside linkage modification is the same in each chain of a double-stranded oligonucleotide. In certain embodiments, the pattern of nucleoside linkage modification is different in each chain of a double-stranded oligonucleotide. In certain embodiments, the double-stranded oligonucleotide contains 6-8 modified nucleoside links. In certain embodiments, the 6-8 modified nucleoside bonds are either phosphorothioate nucleoside bonds or alkylphosphonate nucleoside bonds. In certain embodiments, the sense oligonucleotide chain contains at least two modified nucleoside bonds at either the 5' end and the 3' end or both. In certain such embodiments, the modified nucleoside bonds are either phosphorothioate nucleoside bonds or alkylphosphonate nucleoside bonds. In certain embodiments, the antisense oligonucleotide chain contains at least two modified nucleoside bonds at either the 5' end and the 3' end or both. In certain such embodiments, the modified nucleoside bonds are either phosphorothioate nucleoside bonds or alkylphosphonate nucleoside bonds.

[0319] In certain embodiments, the double-stranded oligonucleotide includes an overhang region. In certain embodiments, the double-stranded oligonucleotide includes a phosphorothioate or alkylphosphonate nucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded oligonucleotide includes a phosphorothioate or alkylphosphonate nucleoside linkage that links an overhang nucleotide to a nucleotide pair adjacent to the overhang nucleotide. For example, there may be at least two phosphorothioate nucleoside links between three terminal nucleosides, two of which are overhang nucleosides and the third is a nucleoside pair adjacent to the overhang nucleosides. These three terminal nucleosides may be at the 3' end of an antisense oligonucleotide chain, the 3' end of a sense oligonucleotide chain, the 5' end of an antisense oligonucleotide chain, or the 5' end of a sense oligonucleotide chain.

[0320] In certain embodiments, the modified oligonucleotide chain includes one or more nucleoside bonds having a chiral center. Typical chiral nucleoside bonds include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotide chains containing nucleoside bonds having a chiral center can be prepared as a group of modified oligonucleotide chains containing stereorandom nucleoside bonds, or as a group of modified oligonucleotide chains containing phosphorothioate bonds in a specific stereochemical configuration. In certain embodiments, the group of modified oligonucleotide chains contains phosphorothioate nucleoside bonds, all of which are stereorandom. Such modified oligonucleotide chains can be produced using a synthetic method in which the stereochemical configuration of each phosphorothioate bond is randomly selected. As is well understood by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide compound has a defined stereochemical configuration. In certain embodiments, the population of modified oligonucleotide chains is enriched with modified oligonucleotide chains that contain one or more specific phosphorothioate nucleoside bonds in a specific, independently selected stereochemical configuration. In certain embodiments, the specific configuration of the specific phosphorothioate bond is present in at least 65% of the molecules in the population. In certain embodiments, the specific configuration of the specific phosphorothioate bond is present in at least 70% of the molecules in the population. In certain embodiments, the specific configuration of the specific phosphorothioate bond is present in at least 80% of the molecules in the population. In certain embodiments, the specific configuration of the specific phosphorothioate bond is present in at least 90% of the molecules in the population. In certain embodiments, the specific configuration of the specific phosphorothioate bond is present in at least 99% of the molecules in the population. Such a population of enriched modified oligonucleotide chains can be produced using synthetic methods known in the art (e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al., Nuc. Acid. Res. 42, 13456 (2014), and WO 2017 / 015555).In certain embodiments, the population of modified oligonucleotide chains is enriched with modified oligonucleotide chains having at least one pointed phosphorothioate in (Sp) configuration. In certain embodiments, the population of modified oligonucleotide chains is enriched with modified oligonucleotide chains having at least one phosphorothioate in (Rp) configuration.

[0321] In certain embodiments, the modified nucleoside bond is located at the 3' end of the oligonucleotide chain. In certain embodiments, the modified nucleoside bond is located within 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the modified nucleoside bond is located at the 5' end of the oligonucleotide chain. In certain embodiments, the modified nucleoside bond is located within 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the modified nucleoside bond is located at an internal position within the oligonucleotide chain. In certain embodiments, the modified nucleoside bond is located more than 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the modified nucleoside bond is located more than 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the modified oligonucleotide includes a block of modified nucleoside bonds. In certain such embodiments, the block is located at the 3' end of the oligonucleotide chain. In certain embodiments, the block is within 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the block is at the 5' end of the oligonucleotide chain. In certain embodiments, the block is within 3 nucleosides from the 5' end of the oligonucleotide chain. In certain embodiments, the block is located internally within the oligonucleotide chain. In certain embodiments, the block is more than 3 nucleosides from the 3' end of the oligonucleotide chain. In certain embodiments, the block is more than 3 nucleosides from the 5' end of the oligonucleotide chain.

[0322] In certain embodiments, the modified nucleoside bond includes a 5'-ethylene phosphonate, phosphorothioate, or amide.

[0323] In certain embodiments, this disclosure provides an oligonucleotide of any one of the formulas described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the oligonucleotides described herein include pharmaceutically acceptable salts thereof and prodrugs. In certain embodiments, the oligonucleotides described herein include pharmaceutically acceptable salts thereof.

[0324] Pharmaceutical compositions, administrations, and kits In another embodiment, a pharmaceutical composition is provided comprising any of the oligonucleotides described herein and optionally a pharmaceutically acceptable excipient.

[0325] As described herein, oligonucleotides or pharmaceutical compositions may be administered in combination with one or more additional pharmaceuticals. In some embodiments, the pharmaceutical is a therapeutic agent. In some embodiments, the pharmaceutical is a prophylactic agent. In some embodiments, the pharmaceutical is a diagnostic agent. Oligonucleotides or pharmaceutical compositions may be administered in combination with additional pharmaceuticals that improve the activity of the oligonucleotide or pharmaceutical composition in a subject, cell, tissue, or biological sample (e.g., activity in treating a disease in a subject requiring treatment of the disease, in preventing a disease in a subject requiring prevention of the disease, and / or reducing the risk of developing a disease in a subject requiring a reduction in the risk of developing the disease (e.g., potency and / or effectiveness)), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution. The combination may result in the same desired improvement and / or different desired effects. In certain embodiments, the combination exhibits a synergistic effect that is not observed in pharmaceutical compositions that include one or more of the oligonucleotides described herein but not both.

[0326] Oligonucleotides or pharmaceutical compositions may be administered simultaneously with, or before or after, one or more additional pharmaceuticals, and such pharmaceuticals may be useful, for example, as combination drugs. Examples of therapeutic agents include small molecules, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or synthetic proteins, protein-linked small molecules, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceuticals are drugs approved for human or veterinary use by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). In certain embodiments, the additional pharmaceuticals are therapeutic agents useful for treating diseases. In certain embodiments, the additional pharmaceuticals are prophylactic agents useful for preventing diseases. Each additional pharmaceutical may be administered in a dose and / or time schedule determined for that pharmaceutical. Additional pharmaceuticals may be administered together and / or with the oligonucleotides or pharmaceutical compositions described herein in a single dose, or separately in different doses. When considering a particular combination for a regimen, the compatibility of the oligonucleotides described herein with the additional pharmaceutical(s), and / or the desired effects to be achieved (e.g., therapeutic and / or preventive effects) will be taken into account. Generally, the additional pharmaceutical(s) in a combination are expected to be used at levels no higher than those used individually. In some embodiments, the levels used in a combination are lower than those used individually.

[0327] In some embodiments, the pharmaceutical composition comprises an effective amount of the oligonucleotide described herein and a pharmaceutically acceptable excipient. In some embodiments, the oligonucleotide described herein is administered to a subject using a pharmaceutically acceptable dosage form. For example, the pharmaceutically acceptable dosage form may deliver the oligonucleotide to the subject continuously for at least 12 hours, 24 hours, 36 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks, or 4 weeks after administration of the pharmaceutically acceptable dosage form to the subject.

[0328] The actual dose level and time course of administration of the active ingredient in the pharmaceutical composition of this disclosure may be modified to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response in a specific subject, pharmaceutical composition, and administration method, while being tolerable to the subject.

[0329] In one embodiment, the oligonucleotides of the Disclosure are administered acutely. Therefore, the oligonucleotides of the Disclosure may be administered for short-term treatment (e.g., about one day to about one week). In another embodiment, the oligonucleotides of the Disclosure may be administered over a long period (e.g., about one week to several months, depending on the condition being treated) to induce remission of a chronic disorder.

[0330] Oligonucleotides can be administered in any convenient manner, such as by intrathecal, intravenous, intramuscular, subcutaneous, oral, or intracerebroventricular injection, or by topical application as a cream or gel. Depending on the administration route, the active ingredient (e.g., the oligonucleotides of this disclosure) may need to be coated with a material to protect the oligonucleotide from the action of enzymes, acids, and other natural conditions that may inactivate or otherwise degrade the oligonucleotide. For administration of the oligonucleotides of this disclosure by means other than parenteral administration, the oligonucleotides may be coated with a material to prevent inactivation, or administered together with such a material.

[0331] Oligonucleotides can be administered parenterally or intraperitoneally. Dispersions can also be prepared with, for example, glycerol, liquid polyethylene glycol, and mixtures thereof, as well as oils.

[0332] Some examples of substances that can act as pharmaceutical excipients include, for example, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils (such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil), polyols (such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol), agar, alginic acid, pyrogen-free water, isotonic saline, and phosphate buffer, skim milk powder, and other non-toxic, suitable substances used in pharmaceutical formulations (such as vitamin C, estrogen, and echinacea). Humectants and lubricants (such as sodium lauryl sulfate), as well as colorants, fragrances, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. Solubilizers (including, for example, cremophor and beta-cyclodextrin) may also be used in the pharmaceutical compositions described herein.

[0333] Pharmaceutical compositions can be prepared by conventional mixing, dissolution, granulation, sugar-coated tablet formation, particle formation, emulsification, encapsulation, encapsulation, or lyophilization processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable excipients that facilitate the process of oligonucleotides into pharmaceutically usable preparations. Pharmaceutical compositions as described herein can be prepared by combining (e.g., contact, mixing, dissolution, granulation, sugar-coated tablet formation, particle formation, emulsification, encapsulation, encapsulation, or lyophilization) oligonucleotides as described herein with one or more suitable excipients (including those described herein) (e.g., for pharmaceutical, agricultural, or veterinary applications).

[0334] The pharmaceutical compositions of this disclosure may be in a form substantially suitable for any method of administration (e.g., including intrathecal, topical, ophthalmic, oral, buccal, systemic, nasal, injection, perdermal, transrectal, transvaginal, and similar) or in a form suitable for administration by inhalation or inhalation.

[0335] Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or transpulmonary administration.

[0336] Useful injectable preparations include sterile suspensions, solutions, or emulsions of oligonucleotides in aqueous or oily vehicles. Pharmaceutical compositions may also contain compounding agents (such as suspending agents, stabilizers, and / or dispersants). Injectable formulations can be presented in unit dosage forms (e.g., in ampoules or multi-dose containers) and may contain additional preservatives.

[0337] Alternatively, the injectable formulation may be provided in powder form for re-preparation with a suitable vehicle before use, which may include, but are not limited to, sterile pyrogen-free water, buffer solutions, glucose solutions, and the like. For this purpose, the oligonucleotide(s) may be dried by any technique known in the art (such as lyophilization) and re-prepared before use.

[0338] For sustained delivery, oligonucleotides can be formulated as depot preparations for implantation or intramuscular injection. Oligonucleotides can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils), with ion exchange resins, or as sparingly soluble derivatives (e.g., as sparingly soluble salts).

[0339] Alternatively, other drug delivery systems can be employed. Liposomes and emulsions are well-known examples of delivery media that can be used for the delivery of oligonucleotides. Certain organic solvents (such as dimethyl sulfoxide (DMSO)) can also be employed.

[0340] The pharmaceutical composition may be presented in a pack or dispenser device that may contain one or more unit dosage forms containing oligonucleotides, if desired. The pack may include, for example, metal foil or plastic foil (such as a blister pack). The pack or dispenser device may be accompanied by ...

Claims

1. Modified oligonucleotide chain of formula I: 【Chemical 217】 An oligonucleotide or a pharmaceutically acceptable salt or prodrug containing, [Formula 218] It is a divalent radical of an oligonucleotide chain, 【Chemical 219】 One example of a nucleoside linker s is independently 【Chemical 220】 Replaced by, s1 is 1, 2, 3, 4, 5, or 6. Each L Ａ and L ４ An example of this is an independent linker, Each A ４ Examples include a ligand or lipid radical independently, but with at least one A ４ An example is the ligand radical, Each of y5 and y6 is independently either 0 or 1. If y5 is 0, L ５ C is hydrogen, substituted or unsubstituted. １－６ If it is an alkyl group or an oxygen protecting group, or if y5 is 1, L ５ It is a linker, When y6 is 0, L ６ is hydrogen, substituted or unsubstituted C １－６ alkyl, or an oxygen protecting group; or when y6 is 1, L ６ is a linker, A ５ and A ６ Each of these, if present, is independently a ligand or lipid radical. Each of the ligands is different from each of the lipids. 【Request Item 2】 【Chemistry 221】 The oligonucleotide according to claim 1, comprising 6 to 100 nucleosides, including both ends. 【Request Item 3】 【Chemistry 222】 The oligonucleotide according to claim 1, comprising 10 to 30 nucleosides, including both ends. 【Request Item 4】 【Chemistry 223】 The oligonucleotide according to claim 1, comprising 14 to 23 nucleosides, including both ends.

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

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

7. at least one L Ａ Examples include: 【Chemistry 224】 The oligonucleotide according to any one of claims 1 to 6, wherein the oligonucleotide is an internucleoside linker located between the first nucleoside and the second nucleoside, counting from the 5' end.

8. L Ａ teeth, 【Chemical 225】 The internucleoside linker is located between the nth nucleoside and the (n+1)th nucleoside, counting from the 5' end. 【Chemistry 226】 The oligonucleotide according to any one of claims 1 to 7, wherein n is an integer from 2 to 20, including both ends, as long as the number of nucleosides allows.

9. The oligonucleotide according to any one of claims 1 to 8, wherein the oligonucleotide contains RNA.

10. The oligonucleotide according to any one of claims 1 to 9, wherein the oligonucleotide is RNA. 【Request Item 11】 【Chemistry 227】 The oligonucleotide according to any one of claims 1 to 10, wherein is siRNA.

12. at least one L Ａ An example is the following expression: 【Chemistry 228】 And, Each Z Ａ１ and Z Ａ２ Examples of single bonds, substitutions, or unsubstituted C are shown independently. １－６ Alkylene, or substituted or unsubstituted C ２－６ It is alkenylene, Each W Ａ The examples are, independently, as far as the valence allows, substituted or unsubstituted alkylenes, substituted or unsubstituted heteroalkylenes, substituted or unsubstituted carbocyclylenes, substituted or unsubstituted heterocyclenes, substituted or unsubstituted arylenes, substituted or unsubstituted heteroarylenes, -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) ２ NR ｃ -, -NR ｃ S (=O) ２ -, or radicals of a combination of these, Each R ｃ Examples of these independently include hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, or oxygen protecting group when attached to an oxygen atom, or two R Ｃ These examples are connected to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring, bond C ４Ａ is, L ４ An oligonucleotide according to any one of claims 1-11, which is attached to the above.

13. at least one L Ａ An example of this is the following expression: 【Chemistry 229】 The oligonucleotide according to any one of claims 1 to 12.

14. at least one L Ａ An example of this is the following expression: 【Chemistry 230】 The oligonucleotide according to any one of claims 1 to 13.

15. at least one L Ａ An example of this is the following expression: 【Chemistry 231】 The oligonucleotide according to any one of claims 1 to 14.

16. at least one Z Ａ１ An example is non-substituted C １－３ The oligonucleotide according to any one of claims 1 to 15, wherein the oligonucleotide is alkylene.

17. at least one Z Ａ２ An example is non-substituted C １－３ The oligonucleotide according to any one of claims 1-16, wherein the oligonucleotide is alkylene.

18. at least one L ４ Examples include substitution or non-substitution C. １－１００ Alkylene, substituted or unsubstituted C ２－１００ Alkenylenes, substituted or unsubstituted C11 ２－１００ Alkynylene, substituted or unsubstituted C １－１００ Heteroalkylene, substituted or unsubstituted C ２－１００ Heteroalkenylenes, or substituted or unsubstituted C ２－１００ It is a heteroalkylene, Optionally, C １－１００ Alkylene, C ２－１００ Alkenylene, C ２－１００ Alkinylene, C １－１００ Heteroalkylene, C ２－１００ Heteroalkenylene, or C ２－１００ The oligonucleotide according to any one of claims 1 to 17, wherein one or more atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences permit.

19. at least one L ４ Examples include substitution or non-substitution C. ７－７０ Alkylene, substituted or unsubstituted C ７－７０ Alkenylenes, substituted or unsubstituted C11 ７－７０ Alkynylene, substituted or unsubstituted C ７－７０ Heteroalkylene, substituted or unsubstituted C ７－７０ Heteroalkenylenes, or substituted or unsubstituted C ７－７０ It is a heteroalkylene, Optionally, C ７－７０ Alkylene, C ７－７０ Alkenylene, C ７－７０ Alkinylene, C ７－７０ Heteroalkylene, C ７－７０ Heteroalkenylene, or C ７－７０ The oligonucleotide according to any one of claims 1 to 18, wherein one or two atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences allow.

20. at least one L ４ Examples include substitution or non-substitution C. ７－７０ Alkylene or substituted or unsubstituted C ７－７０ It is a heteroalkylene, Said C ７－７０ Alkylene or C ７－７０ The oligonucleotide according to any one of claims 1 to 19, wherein one or two atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences allow.

21. at least one L ４ Examples are 【Chemistry 232】 And, -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 is independently a single bond, -O-, -S-, -S-S-, -NR ａ -, -C(=O)O-, -C(=NR ａ )O-, -S(=O)O-, -S(=O) ２ O-, -C(=O)NR ａ -, -C(=NR ａ )NR ａ -, -S(=O)NR ａ -, -S(=O) ２ NR 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) ２ O-, -NR ａ C(=O)O-, -NR ａ C(=NR ａ )O-, -NR ａ S(=O)O-, -NR ａ S(=O) ２ O-, -OC(=O)NR ａ -, -OC(=NR ａ )NR ａ -, -OS(=O)NR ａ -, -OS(=O) ２ NR ａ -, -NR ａ C(=O)NR ａ -, -NR ａ C(=NR ａ )NR ａ -, -NR ａ S(=O)NR ａ -, -NR ａ S (=O) ２ NR 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-, Each R ａ Examples include hydrogen, substituted or unsubstituted C, independently. １－６ An alkyl group, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R groups attached to a nitrogen atom ａ An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. L ４Ｂ１ , L ４Ｂ２ , and L ４Ｂ６ Each of these can independently be a single bond, a substituted or unsubstituted C １－１００ Alkylene, or substituted or unsubstituted C １－１００ It is a heteroalkylene, L ４Ｃ１ and L ４Ｃ２ Each of these is a single bond, a substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms, or a substituted or unsubstituted heteroarylene that replaces one of the main chain atoms. bond C ４Ｂ A ４ An oligonucleotide according to any one of claims 1 to 20, which is attached to the above.

22. at least one L ４ Examples are [Chem. 233] And, Each of p1 and p2 is an integer between 1 and 10, including both ends. Each of p3 and p5 is an integer between 0 and 10, including both endpoints. Each -L ４Ａ２１ -L ４Ａ２２ - examples are each independently a single bond, -O-, -S-, -S-S-, -NR ａ -, -C(=O)O-, -C(=NR ａ )O-, -S(=O)O-, -S(=O) ２ O-, -C(=O)NR ａ -, -C(=NR ａ )NR ａ -, -S(=O)NR ａ -, -S(=O) ２ NR 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) ２ O-, -NR ａ C(=O)O-, -NR ａ C(=NR ａ )O-, -NR ａ S(=O)O-, -NR ａ S(=O) ２ O-, -OC(=O)NR ａ -, -OC(=NR ａ )NR ａ -, -OS(=O)NR ａ -, -OS(=O) ２ NR ａ -, -NR ａ C(=O)NR ａ -, -NR ａ C(=NR ａ )NR ａ -, -NR ａ S(=O)NR ａ -, -NR ａ S(=O) ２ NR 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-, Each R ａ Examples include hydrogen, substituted or unsubstituted C, independently. １－６ The R group is an alkyl group, a substituted or unsubstituted phenyl group, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R groups attached to a nitrogen atom. ａ An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. bond C ４Ｂ A ４ An oligonucleotide according to any one of claims 1 or 21, which is attached to the above.

23. at least one -L ４Ａ２１ -L ４Ａ２２ Examples of - are -NR ａ -C(=O)- or -C(=O)-NR ａ - The oligonucleotide according to any one of claims 1 to 22.

24. at least one L ４ Examples include substitution or non-substitution C. ７－７０ An oligonucleotide according to any one of claims 1 to 23, wherein the oligonucleotide is a heteroalkylene.

25. at least one L ４ An example is -CH ２ -, -O-, -CH ２ CH ２ O-, -OCH ２ CH ２ -, -C(=O)NH-, -C(=O)N(CH ３ )-, -NHC(=O)-, or -N(CH ３ ) C (= O) -, or a combination of two or more of the above examples, or a combination of two or more of the above examples, however, Said L ４ The number of main chain atoms in this example is 7 to 70, including both ends. Said L ４ An example is the oligonucleotide according to any one of claims 1-24, which does not contain O-O, O-N, N-O, or N-N.

26. at least one L ４ An example is -CH ２ -, -O-, -CH ２ CH ２ O-, -OCH ２ CH ２ -, -C(=O)NH-, or -NHC(=O)-, or a combination of two or more of the above examples, or a combination of two or more of the above examples, however, Said L ４ The number of main chain atoms in this example is 7 to 70, including both ends. Said L ４ The examples do not include O-O, O-N, N-O, or N-N. Said L ４ The oligonucleotide according to any one of claims 1-25, wherein the number of combinations of -C(=O)NH- and -NHC(=O)- in the example is 0 to 4, including both ends.

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

28. y5 is 1, A ５ The oligonucleotide according to any one of claims 1 to 27, wherein is a ligand radical.

29. y5 is 1, A ５ The oligonucleotide according to any one of claims 1 to 28, wherein is a lipid radical.

30. L ５ is a substitution or non-substitution C １－１００ Alkylene, substituted or unsubstituted C ２－１００ Alkenylenes, substituted or unsubstituted C11 ２－１００ Alkynylene, substituted or unsubstituted C １－１００ Heteroalkylene, substituted or unsubstituted C ２－１００ Heteroalkenylenes, or substituted or unsubstituted C ２－１００ It is a heteroalkylene, Optionally, C １－１００ Alkylene, C ２－１００ Alkenylene, C ２－１００ Alkinylene, C １－１００ Heteroalkylene, C ２－１００ Heteroalkenylene, or C ２－１００ The oligonucleotide according to any one of claims 1 to 29, wherein one or more atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences permit.

31. L ５ is a substitution or non-substitution C ７－７０ Alkylene, substituted or unsubstituted C ７－７０ Alkenylenes, substituted or unsubstituted C11 ７－７０ Alkynylene, substituted or unsubstituted C ７－７０ Heteroalkylene, substituted or unsubstituted C ７－７０ Heteroalkenylenes, or substituted or unsubstituted C ７－７０ It is a heteroalkylene, Optionally, C ７－７０ Alkylene, C ７－７０ Alkenylene, C ７－７０ Alkinylene, C ７－７０ Heteroalkylene, C ７－７０ Heteroalkenylene, or C ７－７０ The oligonucleotide according to any one of claims 1 to 30, wherein one or two atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences allow.

32. L ５ is a substitution or non-substitution C ７－７０ Alkylene or substituted or unsubstituted C ７－７０ It is a heteroalkylene, Said C ７－７０ Alkylene or C ７－７０ The oligonucleotide according to any one of claims 1 to 31, wherein one or two atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences allow.

33. L ５ teeth 【Chemistry 234】 And, -L ５Ａ１ -L ５Ａ２ -, -L ５Ａ３ -L ５Ａ４ -, -L ５Ａ５ -L ５Ａ６ -, -L ５Ａ７ -L ５Ａ８ -, -L ５Ａ１７ -L ５Ａ１８ -, and -L ５Ａ１９ -L ５Ａ２０ - each is independently a single bond, -O-, -S-, -S-S-, -NR ａ -, -C(=O)O-, -C(=NR ａ )O-, -S(=O)O-, -S(=O) ２ O-, -C(=O)NR ａ -, -C(=NR ａ )NR ａ -, -S(=O)NR ａ -, -S(=O) ２ NR 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) ２ O-, -NR ａ C(=O)O-, -NR ａ C(=NR ａ )O-, -NR ａ S(=O)O-, -NR ａ S(=O) ２ O-, -OC(=O)NR ａ -, -OC(=NR ａ )NR ａ -, -OS(=O)NR ａ -, -OS(=O) ２ NR ａ -, -NR ａ C(=O)NR ａ -, -NR ａ C(=NR ａ )NR ａ -, -NR ａ S(=O)NR ａ -, -NR ａ S (=O) ２ NR 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-, Each R ａ Examples include hydrogen, substituted or unsubstituted C, independently. １－６ An alkyl group, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R groups attached to a nitrogen atom ａ An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. L ５Ｂ１ , L ５Ｂ２ , and L ５Ｂ６ Each of these can independently be a single bond, a substituted or unsubstituted C １－１００ Alkylene, or substituted or unsubstituted C １－１００ It is a heteroalkylene, L ５Ｃ１ and L ５Ｃ２ Each of these is a single bond, a substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms, or a substituted or unsubstituted heteroarylene that replaces one of the main chain atoms. bond C ５Ｂ A ５ An oligonucleotide according to any one of claims 1-32, which is attached to the above.

34. L ５ teeth 【Chemistry 235】 And, k21 is 0, 1, 2, 3, or 4. Each R ｄ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, k22 is 0, 1, 2, 3, or 4. Each R ｅ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, Each of q1, q2, q4, q5, q8, and q9 is an independent integer between 0 and 10, including both endpoints. Each of q3, q6, and q7 is an integer between 1 and 10, including both endpoints. -L ５Ａ２１ -L ５Ａ２２ -, -L ５Ａ２３ -L ５Ａ２４ -, and -L ５Ａ２５ -L ５Ａ２６ - each is independently a single bond, -O-, -S-, -S-S-, -NR ａ -, -C(=O)O-, -C(=NR ａ )O-, -S(=O)O-, -S(=O) ２ O-, -C(=O)NR ａ -, -C(=NR ａ )NR ａ -, -S(=O)NR ａ -, -S(=O) ２ NR 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) ２ O-, -NR ａ C(=O)O-, -NR ａ C(=NR ａ )O-, -NR ａ S(=O)O-, -NR ａ S(=O) ２ O-, -OC(=O)NR ａ -, -OC(=NR ａ )NR ａ -, -OS(=O)NR ａ -, -OS(=O) ２ NR ａ -, -NR ａ C(=O)NR ａ -, -NR ａ C(=NR ａ )NR ａ -, -NR ａ S(=O)NR ａ -, -NR ａ S(=O) ２ NR 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-, Each R ａ Examples include hydrogen, substituted or unsubstituted C, independently. １－６ The R group is an alkyl group, a substituted or unsubstituted phenyl group, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R groups attached to a nitrogen atom. ａ An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. bond C ５Ａ A ５ An oligonucleotide according to any one of claims 1-33, which is attached to the above.

35. -L ５Ａ２３ -L ５Ａ２４ - and -L ５Ａ２５ -L ５Ａ２６ Each of these is independent of -NR ａ -C(=O)- or -C(=O)-NR ａ - The oligonucleotide according to any one of claims 1 to 34.

36. -L ５Ａ２１ -L ５Ａ２２ - is -OP (=O) (OR ａ )O-,-SP(=O)(OR ａ )O-,-OP(=O)(OR ａ ) S-, or -OP (=O) (SR ａ The oligonucleotide according to any one of claims 1 to 35, wherein it is O-.

37. L ５ is a substitution or non-substitution C ７－７０ An oligonucleotide according to any one of claims 1 to 36, wherein the oligonucleotide is a heteroalkylene.

38. L ５ is, -CH ２ - 【Chemistry 236】 -O-、-CH ２ CH ２ O-OCH ２ CH ２ -、-C(=O)NH-、-C(=O)N(CH ３ )-、-NHC(=O)-、-N(CH ３ )C(=O)-、 【Chemistry 237】 Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, L ５ The number of main chain atoms is 7 to 70, including both ends. L ５ The oligonucleotide according to any one of claims 1 to 37, which does not contain O-O, O-N, N-O, or N-N.

39. L ５ is, -CH ２ - [Chemical 238] -O-、-CH ２ CH ２ O-OCH ２ CH ２ -、-C(=0)NH-、-NHC(=0)-、 【Chemistry 239】 Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, L ５ The number of main chain atoms is 7 to 70, including both ends. L ５ This does not include O-O, O-N, N-O, or N-N. L ５ の-C(=O)NH-、-NHC(=O)-、 【Chemistry 240】 The oligonucleotide according to any one of claims 1-38, wherein the number of combinations is 0 to 4, including both ends.

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

41. y6 is 1, A ６ The oligonucleotide according to any one of claims 1 to 40, wherein is a ligand radical.

42. y6 is 1, A ６ The oligonucleotide according to any one of claims 1 to 41, wherein is a lipid radical.

43. L ６ is a substitution or non-substitution C １－１００ Alkylene, substituted or unsubstituted C ２－１００ Alkenylenes, substituted or unsubstituted C11 ２－１００ Alkynylene, substituted or unsubstituted C １－１００ Heteroalkylene, substituted or unsubstituted C ２－１００ Heteroalkenylenes, or substituted or unsubstituted C ２－１００ It is a heteroalkylene, Optionally, C １－１００ Alkylene, C ２－１００ Alkenylene, C ２－１００ Alkinylene, C １－１００ Heteroalkylene, C ２－１００ Heteroalkenylene, or C ２－１００ The oligonucleotide according to any one of claims 1 to 42, wherein one or more atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences permit.

44. L ６ is a substitution or non-substitution C ７－７０ Alkylene, substituted or unsubstituted C ７－７０ Alkenylenes, substituted or unsubstituted C11 ７－７０ Alkynylene, substituted or unsubstituted C ７－７０ Heteroalkylene, substituted or unsubstituted C ７－７０ Heteroalkenylenes, or substituted or unsubstituted C ７－７０ It is a heteroalkylene, Optionally, C ７－７０ Alkylene, C ７－７０ Alkenylene, C ７－７０ Alkinylene, C ７－７０ Heteroalkylene, C ７－７０ Heteroalkenylene, or C ７－７０ The oligonucleotide according to any one of claims 1 to 43, wherein one or two atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences allow.

45. L ６ is a substitution or non-substitution C ７－７０ Alkylene or substituted or unsubstituted C ７－７０ It is a heteroalkylene, Said C ７－７０ Alkylene or C ７－７０ The oligonucleotide according to any one of claims 1 to 44, wherein one or two atoms of the main chain of the heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, to the extent that their valences allow.

46. L ６ teeth 【Chemistry 241】 And, -L ６Ａ１ -L ６Ａ２ -, -L ６Ａ３ -L ６Ａ４ -, -L ６Ａ５ -L ６Ａ６ -, -L ６Ａ７ -L ６Ａ８ -, -L ６Ａ１７ -L ６Ａ１８ -, and -L ６Ａ１９ -L ６Ａ２０ - each is independently a single bond, -O-, -S-, -S-S-, -NR ａ -, -C(=O)O-, -C(=NR ａ )O-, -S(=O)O-, -S(=O) ２ O-, -C(=O)NR ａ -, -C(=NR ａ )NR ａ -, -S(=O)NR ａ -, -S(=O) ２ NR 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) ２ O-, -NR ａ C(=O)O-, -NR ａ C(=NR ａ )O-, -NR ａ S(=O)O-, -NR ａ S(=O) ２ O-, -OC(=O)NR ａ -, -OC(=NR ａ )NR ａ -, -OS(=O)NR ａ -, -OS(=O) ２ NR ａ -, -NR ａ C(=O)NR ａ -, -NR ａ C(=NR ａ )NR ａ -, -NR ａ S(=O)NR ａ -, -NR ａ S (=O) ２ NR 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-, Each R ａ Examples include hydrogen, substituted or unsubstituted C, independently. １－６ An alkyl group, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R groups attached to a nitrogen atom ａ An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. L ６Ｂ１ , L ６Ｂ２ , and L ６Ｂ６ Each of these can independently be a single bond, a substituted or unsubstituted C １－１００ Alkylene, or substituted or unsubstituted C １－１００ It is a heteroalkylene, L ６Ｃ１ and L ６Ｃ２ Each of these is a single bond, a substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms, or a substituted or unsubstituted heteroarylene that replaces one of the main chain atoms. bond C ６Ｂ A ６ An oligonucleotide according to any one of claims 1-45, which is attached to the above.

47. The substituted or unsubstituted heteroarylene or substituted or unsubstituted heterocyclylene that replaces one of the main chain atoms is defined by the following formula: 【Chemistry 242】 And, k21 is 0, 1, 2, 3, or 4. Each R ｄ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, k22 is 0, 1, 2, 3, or 4. Each R ｅ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, k23 is an integer between 0 and 11, including both endpoints. Each R ｆ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, R ｇ C is hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ An oligonucleotide according to any one of claims 1 to 46, wherein it is an alkyl group.

48. The substituted or unsubstituted heteroarylene that replaces one of the main chain atoms has the following formula: 【Chemistry 243】 The oligonucleotide according to any one of claims 1 to 47.

49. L ６ teeth 【Chemistry 244】 And, Each of r1, r2, r4, r5, r8, and r9 is an independent integer between 0 and 10, including both endpoints. Each of r3, r6, and r7 is an integer between 1 and 10, including both endpoints. -L ６Ａ２１ -L ６Ａ２２ -, -L ６Ａ２３ -L ６Ａ２４ -, and -L ６Ａ２５ -L ６Ａ２６ - are each independently a single bond, -O-, -S-, -S-S-, -NR ａ -, -C(=O)O-, -C(=NR ａ )O-, -S(=O)O-, -S(=O) ２ O-, -C(=O)NR ａ -, -C(=NR ａ )NR ａ -, -S(=O)NR ａ -, -S(=O) ２ NR 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) ２ O-, -NR ａ C(=O)O-, -NR ａ C(=NR ａ )O-, -NR ａ S(=O)O-, -NR ａ S(=O) ２ O-, -OC(=O)NR ａ -, -OC(=NR ａ )NR ａ -, -OS(=O)NR ａ -, -OS(=O) ２ NR ａ -, -NR ａ C(=O)NR ａ -, -NR ａ C(=NR ａ )NR ａ -, -NR ａ S(=O)NR ａ -, -NR ａ S(=O) ２ NR 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-, Each R ａ Examples include hydrogen, substituted or unsubstituted C, independently. １－６ The R group is an alkyl group, a substituted or unsubstituted phenyl group, a nitrogen protecting group attached to a nitrogen atom, an oxygen protecting group attached to an oxygen atom, or a sulfur protecting group attached to a sulfur atom, or two R groups attached to a nitrogen atom. ａ An example is that it is linked together with the nitrogen atom to form a substituted or unsubstituted heterocycline or a substituted or unsubstituted heteroaryl. bond C ６Ａ A ６ An oligonucleotide according to any one of claims 1-48, which is attached to the above.

50. -L ６Ａ２３ -L ６Ａ２４ - and -L ６Ａ２５ -L ６Ａ２６ Each of these is independent of -NR ａ -C(=O)- or -C(=O)-NR ａ - The oligonucleotide according to any one of claims 1-49.

51. -L ６Ａ２１ -L ６Ａ２２ The oligonucleotide according to any one of claims 1 to 50, wherein - is -O-.

52. L ６ is a substitution or non-substitution C ７－７０ An oligonucleotide according to any one of claims 1 to 51, which is a heteroalkylene.

53. L ６ is, -CH ２ - 【Chemistry 245】 -O-、-CH ２ CH ２ O-OCH ２ CH ２ -、-C(=O)NH-、-C(=O)N(CH ３ )-、-NHC(=O)-、-N(CH ３ )C(=O)-、 【Chemistry 246】 Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, L ６ The number of main chain atoms is 7 to 70, including both ends. L ６ The oligonucleotide according to any one of claims 1 to 52, which does not contain O-O, O-N, N-O, or N-N.

54. L ６ is, -CH ２ - 【Chemistry 247】 -O-、-CH ２ CH ２ O-OCH ２ CH ２ -、-C(=0)NH-、-NHC(=0)-、 【Chemistry 248】 Alternatively, a combination of two or more of the examples mentioned above, or a combination of two or more of the examples mentioned above, however, L ６ The number of main chain atoms is 7 to 70, including both ends. L ６ This does not include O-O, O-N, N-O, or N-N. L ６ の-C(=O)NH-、-NHC(=O)-、 【Chemistry 249】 The oligonucleotide according to any one of claims 1-53, wherein the number of combinations is 0 to 4, including both ends.

55. The oligonucleotide according to any one of claims 1 to 54, further comprising one or more modifications independently selected from modified sugars, modified nucleic acid bases, and modified internucleoside linkers.

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

57. The oligonucleotide according to any one of claims 1 to 56, wherein at least two ligands are the same.

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

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

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

61. Examples of at least one of the modified sugars are 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 The oligonucleotide according to any one of claims 1 to 60, wherein the oligonucleotide is '-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-ethylene-linked ribose, 2',4'-restricted ethylribose, locked sugar, or bicyclic sugar.

62. Examples of at least one of the modified nucleic acid bases include xanthine, allylaminouracil, allylaminothymidine, hypoxanthine, digoxigenylated adenine, digoxigenylated cytosine, digoxigenylated guanine, digoxigenylated uracil, 6-chloropurine riboside, N6-methyladenine, methylpseudolacil, 2-thiocytosine, 2-thiouracil, 5-methyluracil, 4-thiothymidine, 4-thiouracil, 5,6-dihydro-5-methyluracil, 5,6-dihydrouracil, and 5-[(3-indolyl)propionamide-N-allyl] Uracil, 5-aminoallylcytosine, 5-aminoallyluracil, 5-bromouracil, 5-bromocytosine, 5-carboxycytosine, 5-carboxymethylesteruracil, 5-carboxyuracil, 5-fluorouracil, 5-formylcytosine, 5-formyluracil, 5-hydroxycytosine, 5-hydroxymethylcytosine, 5-hydroxymethyluracil, 5-hydroxyuracil, 5-iodocytosine, 5-iodouracil, 5-methoxycytosine, 5-methoxyuracil, 5-methylcytosine, 5-methyluracil, 5-propal Glyaminocytosine, 5-propargylaminouracil, 5-propynylcytosine, 5-propynyluracil, 6-azacytosine, 6-azauracil, 6-chloropurine, 6-thioguanine, 7-deazaadenine, 7-deazaguanine, 7-deaza-7-propargylaminoadenine, 7-deaza-7-propargylaminoguanine, 8-aziadenine, 8-azidodenine, 8-chloroadenine, 8-oxoadenine, 8-oxoguanine, araadenine, aracytosine, araguanine uanine), arauracil, biotin-16-7-deaza-7-propargylaminoguanine, biotin-16-aminoallylcytosine, biotin-16-aminoallyluracil, cyanine 3-5-propargylaminocytosine, cyanine 3-6-propargylaminouracil, cyanine 3-aminoallylcytosine, cyanine 3-aminoallyluracil, cyanine 5-6-propargylaminocytosine, cyanine 5-6-propargylaminouracil, cyanine 5-aminoallylcytosine, cyanine 5-aminoallyluracil,Cyanine 7-aminoallyluracil, dabucil-5-3-aminoallyluracil, desthiobiotin-16-aminoallyluracil, desthiobiotin-6-aminoallylcytosine, isoguanine, N1-ethylpsuduracil, N1-methoxymethylpsuduracil, N1-methyladenine, N1-methylpsuduracil, N1-propylpsuduracil, N2-methylguanine, N4-biotin-OBE A-cytosine, N4-methylcytosine, N6-methyladenine, O6-methylguanine, pseudoisocytosine, pseudouracil, thienocytosine, thienouranine, thienouracil, xanthosine, 3-deazaadenine, 2,6-diaminoadenine, 2,6-diaminoguanine, 5-carboxamideuracil, 5-ethinyluracil, N6-isopentenyladenine (i6A), 2-methylthio-N6-isopentenine N6-(cis-hydroxyisopentenyl)adenine (ms2i6A), 2-methylthio-N6-methyladenine (ms2m6A), N6-(cis-hydroxyisopentenyl)adenine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenine (ms2io6A), N6-glycinylcarbamoyladenine (g6A), N6-threonylcarbamoyladenine (t6A), 2-methylthio-N6-threonylcarbamoyl The oligonucleotide according to any one of claims 1 to 61, wherein the oligonucleotides are denine (ms2t6A), N6-methyl-N6-threonylcarbamoyladenine (m6t6A), N6-hydroxynorvalylcarbamoyladenine (hn6A), 2-methylthio-N6-hydroxynorvalylcarbamoyladenine (ms2hn6A), N6,N6-dimethyladenine (m62A), and N6-acetyladenine (ac6A).

63. The oligonucleotide according to any one of claims 1 to 62, wherein at least one example of the modified internucleoside linker is a phosphotriester, alkylphosphonate, phosphoramidate, phosphorothioate, phosphorodithioate, or phosphorothiolate.

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

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

66. At least one TrkB ligand is a compound with the following formula: [Chemical 250] And, R ２ is hydrogen, -OR ７ ,-SR ８ , or -NR ９ R １０ And, R ３ is hydrogen, -OR ３１ ,-SR ３２ , or -NR ３３ R ３４ And, R ４ is hydrogen, -OR ３５ ,-SR ３６ , or -NR ３７ R ３８ And, R ５ is hydrogen, -OR ３９ ,-SR ４０ , or -NR ４１ R ４２ And, R ６ These are hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH ２ , which are arbitrarily 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 these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl. Y is CH ２ , NH, S, or O, Z is an arbitrarily substituted aryl or arbitrarily substituted heteroaryl, R １１ and R １３ Each of these is an alkyl group that is either absent, has hydrogen, or is optionally substituted. R １２ , R １４ and R １５ Each of these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R １６ These are hydrogen, halogen, -CN, and -N ３ , -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 SO ２ R 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, 【Chemistry 251】 Each of these is independently a single bond or a double bond. 【Chemistry 252】 If it is a single bond, 【Chemistry 253】 It is a double bond, R １３ It does not exist, and furthermore 【Chemistry 254】 If it is a single bond, 【Chemistry 255】 It is a double bond, R １１ It does not exist. R １６Ａ , R １６Ｂ , R １６Ｃ , R １６Ｄ These are independently hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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, and R bonded to the same nitrogen atom １６Ｂ and R １６Ｃ The substituents can be optionally attached to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. R １７ , R １８ , and R １９ Each of these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R ２０ These are hydrogen, halogen, -CN, and -N ３ , -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 SO ２ R 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 These are hydrogen, halogen, -CN, and -N ３ , -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 SO ２ R 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 these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R ２４ These are hydrogen, halogen, -CN, and -N ３ , -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 SO ２ R 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 These are independently hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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, and 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 can be optionally attached to form substituted or unsubstituted heterocycloalkyl 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 independently 0, 1, or 2. z5 is 0, 1, 2, or 3. The oligonucleotide according to any one of claims 1 to 65, wherein z6 and z8 are each independently 0, 1, 2, 3, or 4.

67. At least one radical of the TrkB ligand is of the following formula: 【Chemistry 256】 The oligonucleotide according to any one of claims 1 to 66.

68. At least one radical of the TrkB ligand is of the following formula: 【Chemistry 257】 The oligonucleotide according to any one of claims 1 to 67.

69. At least one radical of the TrkB ligand is of the following formula: 【Chemistry 258】 The oligonucleotide according to any one of claims 1 to 68.

70. 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, diosmetin (5,7,3'-trihydroxy-4'-methoxyflavone), 7-hydroxy-4'-methoxyflavone, 8-hydroxy-7-methoxyflavone, eutropoflavone (4'-dimethylamino-7,8-dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone), R7, R13, tropoflavone (7, The oligonucleotide according to any one of claims 1 to 69, wherein the oligonucleotide is 8-dihydroxyflavone), 7,8-dimethoxyflavone, quercetin (3,3',4',5,7-pentahydroxyflavone), apigenin (4',5,7-trihydroxyflavone), isocoumarin, goshipetin (3,5,7,8,3',4'-hexahydroxyflavone), 2-methyl-8-phenylchromeno[7,8-d]imidazole-6(3H)-one, 8-phenylchromeno[7,8-d]imidazole-6(3H)-one, 4-oxo-2-phenyl-4H-chromen-7,8-diyldiaacetate, ANA-12, or an anti-TrkB antibody.

71. At least one ligand is α ４ β １／７ An oligonucleotide according to any one of claims 1 to 70, which is an integrin ligand.

72. at least one alpha ４ β １／７ Integrin ligands are compounds with the following formula: 【Chemistry 259-1】 【Chemistry 259-2】 【Chemistry 259-3】 【Chemistry 259-4】 【Chemistry 259-5】 【Chemistry 259-6】 【Chemistry 259-7】 【Chemistry 259-8】 【Chemistry 259-9】 Here, the examples of each R are: 【Chemistry 260】 It is either anti-alpha or anti-alpha ４ β １／７ An oligonucleotide according to any one of claims 1-71, which is a radical of an integrin antibody.

73. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 261】 And, R ２Ｚ These are hydrogen, polyethylene glycol, substituted or unsubstituted heteroalkyl groups, or substituted or unsubstituted heteroaryl groups. R ３Ｚ and R ４Ｚ The oligonucleotide according to any one of claims 1 to 72, wherein each of them is independently hydrogen, a halogen, an optionally substituted alkyl, or an optionally substituted -O-alkyl.

74. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 262】 And, R ４Ｚ This is hydrogen, halogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl. R ５Ｚ is an optionally substituted heteroalkyl or optionally substituted heterocycline, The oligonucleotide according to any one of claims 1-73, wherein n1Z is 1, 2, or 3.

75. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: [Chem. 263] And, R ６Ｚ is hydrogen, -OH, -NH ２ , - NHR ７Ｚ , -OR ７Ｚ is or does not exist, R ７Ｚ The oligonucleotide according to any one of claims 1 to 74, wherein is hydrogen, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

76. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 264-1】 【Chemistry 264-2】 And, The oligonucleotide according to any one of claims 1 to 75, wherein n2Z is ​​0, 1, 2, or 3.

77. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: [Chem. 265] And, The oligonucleotide according to any one of claims 1 to 76, wherein n3Z is 0, 1, 2, or 3.

78. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: [Chem. 266] And, R ８Ｚ , R ９Ｚ , R １０Ｚ , and R １１Ｚ Each of these is independently hydrogen, a halogen, an optionally substituted alkyl, an optionally substituted -O-alkyl, or a substituted or unsubstituted cycloalkyl. R １２Ｚ and R １３Ｚ Each of these can independently be H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, 【Chemistry 267】 And, R １４Ｚ is an arbitrarily substituted C １ -C ５ Alkyl, optionally substituted C １ -C ５ Alkylene-(C) ３ -C ６ )-cycloalkyl, or optionally substituted (C １ -C ４ )-Alkylene-(C １ -C ４ )-alkoxy, the oligonucleotide according to any one of claims 1-77.

79. at least one alpha ４ β １／７ The radical of the integrin ligand is given by the following formula: [Chem. 268] The oligonucleotide according to any one of claims 1 to 78.

80. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 269】 And, R １５Ｚ is 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, or an optionally substituted -O-alkyl. Y Ｚ is, -CH ２ - or - (CH ２ ) ２ - The oligonucleotide according to any one of claims 1-79.

81. at least one α ４ β １／７ The radical of an integrin ligand is of the following formula: 【Chemistry 270】 And, R １８Ｚ H, -OH, -NH ２ , - NHR １９Ｚ , -OR １９Ｚ , or -CONHR １９Ｚ And, Each R １９Ｚ Examples of these are independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. The oligonucleotide according to any one of claims 1 to 80, wherein n4Z is 1 or 2.

82. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 271】 And, R １９Ｚ H, -CH ２ OR ２０Ｚ ,-(CH ２ ) ２ OR ２０Ｚ ien-CH ２ NHCOR ２０Ｚ , or -OR ２０Ｚ And, R ２０Ｚ The oligonucleotide according to any one of claims 1 to 81, wherein is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

83. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 272】 And, R ２１Ｚ H, -CONHR ２２Ｚ ien-CH ２ OR ２２Ｚ ,-(CH ２ ) ２ OR ２２Ｚ ien-CH ２ NHCOR ２２Ｚ , or -OR ２２Ｚ And, R ２２Ｚ is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, X １Ｚ The oligonucleotide according to any one of claims 1 to 82, wherein is H or a halogen.

84. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 273】 And, R ２３Ｚ H, -CONHR ２４Ｚ ien-CH ２ OR ２４Ｚ ,-(CH ２ ) ２ OR ２４Ｚ ien-CH ２ NHCOR ２４Ｚ , or -OR ２４Ｚ And, R ２４Ｚ is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, The oligonucleotide according to any one of claims 1 to 83, wherein n5Z is 0, 1, 2, or 3.

85. at least one alpha ４ β １／７ The radical of an integrin ligand is given by the following formula: 【Chemistry 274】 And, R ２５Ｚ H, -CONHR ２７Ｚ ien-CH ２ OR ２７Ｚ ,-(CH ２ ) ２ OR ２７Ｚ ien-CH ２ NHCOR ２７Ｚ , or -OR ２７Ｚ And, R ２６Ｚ is H, an optionally substituted alkyl, or an optionally substituted cycloalkyl, R ２７Ｚ is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, X ２Ｚ is an arbitrarily substituted CH ２ The oligonucleotide according to any one of claims 1 to 84, or optionally substituted NH.

86. At least one α ４ β １／７ The radical of the integrin ligand is of the following formula: 【Chemistry 275】 And, R ２８Ｚ H, -CH ２ OR ３０Ｚ ,-(CH ２ ) ２ OR ３０Ｚ ien-CH ２ NHCOR ３０Ｚ , or -OR ３０Ｚ And, R ２９Ｚ H, -OH, -NH ２ , - NHR ３１Ｚ , or -OR ３１Ｚ And, R ３０Ｚ is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, R ３１Ｚ is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, The oligonucleotide according to any one of claims 1-85, wherein n3Z is 1, 2, or 3.

87. At least one ligand is cannabinoid receptor type 1 (CB １ ) An oligonucleotide according to any one of claims 1 to 86, which is a ligand.

88. at least one CB １ The ligand is a compound with the following formula: 【Chemistry 276】 And, X １Ｙ NR １０Ｙ or CR １１Ｙ R １２Ｙ And, R １０Ｙ , R １１Ｙ , and R １２Ｙ Each of these is independently hydrogen, an optionally substituted alkyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. R １９Ｙ is 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 SO ２ R 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 independently consists of hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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 These are connected to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, n19Y is 0, 1, 2, 3, or 4. The oligonucleotide according to any one of claims 1-87, wherein v19Y is 1 or 2.

89. at least one CB １ The ligand radical is given by the following formula: 【Chemistry 277】 The oligonucleotide according to any one of claims 1 to 88.

90. at least one CB １ The ligand radical is given by the following formula: 【Chemistry 278】 The oligonucleotide according to any one of claims 1 to 89.

91. at least one CB １ The ligand radical is the radical of the compound in the following formula: 【Chemistry 279】 And here, R １７Ｙ is 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 SO ２ R 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 independently consists of hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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, where R is bonded to the same nitrogen atom. １７ＹＢ and R １７ＹＣ The substituents can be optionally attached to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. n17Y is 0, 1, 2, 3, or 4. The oligonucleotide according to any one of claims 1-90, wherein v17Y is 1 or 2.

92. at least one CB １ The ligand radical is given by the following formula: 【Chemistry 280】 The oligonucleotide according to any one of claims 1 to 91.

93. at least one CB １ The ligand radical is the radical of the compound in the following formula: 【Chemistry 281】 The oligonucleotide according to any one of claims 1 to 92.

94. at least one CB １ The ligand radical is given by the following formula: 【Chemistry 282】 The oligonucleotide according to any one of claims 1 to 93.

95. at least one CB １ The ligand radical is the radical of the compound in the following formula: 【Chemistry 283】 And, R ３Ｙ , R ４Ｙ , R ５Ｙ , R ６Ｙ , and R ８Ｙ Each of these 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 is hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl, or R ６Ｙ and R ９Ｙ The substituents may be linked together to form optionally substituted heterocycloalkyl or optionally substituted heteroaryl compounds. R ７Ｙ is 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 SO ２ R 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 These are independently hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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, where R is bonded to the same nitrogen atom. ７ＹＢ and R ７ＹＣ The substituents can be optionally attached to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. n7Y is 0, 1, 2, 3, or 4. The oligonucleotide according to any one of claims 1-94, wherein v7Y is 1 or 2.

96. at least one CB １ The ligand radical is given by the following formula: 【Chemistry 284】 The oligonucleotide according to any one of claims 1 to 95.

97. at least one CB １ The ligand is a compound with the following formula: 【Chemistry 285】 And, R １６Ｙ These are hydrogen, halogen, -CN, and -N ３ , -NO ２ , -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, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, R １６ＹＡ , R １６ＹＢ , R １６ＹＣ , and R １６ＹＤ These are independently hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , 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 The oligonucleotide according to any one of claims 1-96, wherein the atoms are connected to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

98. at least one CB １ The ligand radical is given by the following formula: 【Chemistry 286】 The oligonucleotide according to any one of claims 1 to 97.

99. at least one CB １ The ligand is a compound with the following formula: 【Chemistry 287】 The oligonucleotide according to any one of claims 1 to 98.

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

101. At least one NMDA receptor ligand is a compound with the following formula: [Chem. 288] The oligonucleotide according to any one of claims 1-100, which is either or a radical of an anti-NMDA receptor antibody.

102. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 289】 The oligonucleotide according to any one of claims 1-101.

103. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 290】 The oligonucleotide according to any one of claims 1 to 102.

104. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 291】 The oligonucleotide according to any one of claims 1 to 103.

105. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 292】 The oligonucleotide according to any one of claims 1 to 104.

106. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 293】 The oligonucleotide according to any one of claims 1 to 105.

107. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 294】 The oligonucleotide according to any one of claims 1 to 106.

108. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 295】 The oligonucleotide according to any one of claims 1-107.

109. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 296】 The oligonucleotide according to any one of claims 1-108.

110. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 297】 The oligonucleotide according to any one of claims 1-109.

111. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 298】 The oligonucleotide according to any one of claims 1 to 110.

112. The radical of at least one NMDA receptor ligand is given by the following formula: 【Chemistry 299】 The alkyl group according to any one of claims 1 to 111.

113. The oligonucleotide according to any one of claims 1 to 112, wherein at least one lipid is an aliphatic acyl, glycerolipid, glycerophospholipid, sphingolipid, glycolipid, polyketide, sterollipid, or prenolipid.

114. The oligonucleotide according to any one of claims 1 to 113, wherein at least one lipid is a fatty acid or conjugate, octadecanoid, eicosanoid, docosanoid, aliphatic alcohol, aliphatic aldehyde, aliphatic ester, aliphatic amide, aliphatic nitrile, aliphatic ether, hydrocarbon, oxygen-containing hydrocarbon, or aliphatic acyl glycoside.

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

116. At least one lipid radical is an unsubstituted C ７－３６ Alkyl, C substituted with one or more fluoro atoms as far as the valency allows. ７－３６ Alkyl, unsubstituted C ７－３６ C is an alkenyl, or a carbon atom substituted with one or more fluoroions, as long as its valence allows. ７－３６ The oligonucleotide according to any one of claims 1-115, wherein the oligonucleotide is an alkenyl.

117. The oligonucleotide according to any one of claims 1 to 116, wherein at least one lipid radical comprises 1, 2, 3, 4, 5, or 6 carbon-carbon double bonds.

118. At least one lipid radical is an unsubstituted C １６－２８ Alkyl or unsubstituted C １６－２８ The oligonucleotide according to any one of claims 1 to 117, wherein each of them is an alkenyl, and each of them is independently unbranched, bibranched, or tribranched.

119. At least one lipid radical is an unbranched, unsubstituted C １８－２６ The alkyl group according to any one of claims 1-118, wherein the alkyl group is alkyl.

120. At least one lipid radical is -(CH ２ ) ２１ CH ３ The oligonucleotide according to any one of claims 1-119.

121. The oligonucleotide according to any one of claims 1 to 120, wherein at least one lipid is monoradilglycerol, diradilglycerol, triradilglycerol, glycosylmonorasylglycerol, glycosyldirasylglycerol, betaine monoradilglycerol, or betaine diradilglycerol.

122. At least one lipid is glycerophosphocholine, glycerophosphoethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphoglycerophosphate, glycerophosphoinositol, glycerophosphoinositol monophosphate, glycerophosphoinositol bisphosphate, glycerophosphoinositol trisphosphate, glycerophosphate, glyceropyrophosphate, glycerophosphoglycerophosphoglycerol, CDP-glycerol, glycosyl The oligonucleotide according to any one of claims 1-121, wherein the oligonucleotide is a glycerophospholipid, glycerophosphoinositol glycan, glycerophosphonocholine, glycerophosphonoethanolamine, diglycerol tetraether phospholipid, glycerol-nonitol tetraether phospholipid, oxidized glycerophospholipid, glycerophosphoethanolamine glycan, dihydroxyacetone phosphate, glycerophosphoethanol, glycerophosphothreonine, or cyclic glycerophosphatidic acid.

123. The oligonucleotide according to any one of claims 1 to 122, wherein at least one lipid is a sphingoid base, a ceramide, a phosphosphingolipid, a phosphonosphingolipid, a neutral sphingoglycolipid, an acidic sphingoglycolipid, a basic sphingoglycolipid, an amphoteric sphingoglycolipid, or an arsenosphingolipid.

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

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

126. The oligonucleotide according to any one of claims 1 to 25, wherein at least one lipid is an isoprenoid, a quinone, a hydroquinone, a polyprenol, or a hopanoid.

127. The oligonucleotide according to any one of claims 1 to 126, wherein at least one lipid is an acylaminosaccharide, an acylaminosaccharide glycan, an acyltrehalose, or an acyltrehalose glycan.

128. The oligonucleotide according to any one of claims 1 to 127, wherein at least one lipid is a linear polyketide, halogenated acetogenin, Annonaceae acetogenin, macrolide, lactone polyketide, ansamycin, polyene, linear tetracycline, angucycline, polyether antibiotic, aflatoxin, cytochalasin, flavonoid, aromatic polyketide, non-ribosomal peptide / polyketide hybrid, or phenolic lipid. 【Request Item 129】 【Chemical 300】 The following is true: 【Chemical 301】 The oligonucleotide according to any one of claims 1 to 128. 【Request Item 130】 【Chemical 302】 teeth 【Chemical 303】 The oligonucleotide according to any one of claims 1-129.

131. Equation I is as follows: 【Chemical 304-1】 【Chemical 304-2】 【Chemical 304-3】 【Chemical 304-4】 【Chemical 304-5】 An oligonucleotide according to any one of claims 1 to 130, or a pharmaceutically acceptable salt or prodrug thereof. 【Request Item 132】 【Chemistry 305】 The oligonucleotide according to any one of claims 1-131, wherein is a sense oligonucleotide chain, and the oligonucleotide further comprises an antisense oligonucleotide chain. 【Request Item 133】 【Chemistry 306】 The oligonucleotide according to any one of claims 1-132, wherein is an antisense oligonucleotide chain, and the oligonucleotide further comprises a sense oligonucleotide chain.

134. The oligonucleotide according to any one of claims 1-133, wherein the nucleic acid base of the antisense oligonucleotide chain is complementary to the nucleic acid base of the sense oligonucleotide chain.

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

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

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

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

139. The pharmaceutical composition according to claim 138, further comprising additional pharmaceuticals.

140. below: An oligonucleotide according to any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, and A kit comprising instructions for using the oligonucleotide, pharmaceutically acceptable salt, prodrug, or pharmaceutical composition.

141. Compound of formula A-1: 【Chemical 307】 or its salt, the compound of formula A-2: L ４Ｅ２ -8 ４Ｄ２ - ４ (A-2) A method for producing an oligonucleotide according to any one of claims 1-137, comprising contacting the oligonucleotide with a salt thereof under appropriate conditions, M １ and M ２ Each of these is independently a fragment of the oligonucleotide chain or a nucleoside radical, L ４Ｄ１ and L ４Ｄ２ Each of them is independently a single bond or a linker. L ４Ｅ１ This is the first reactive part, L ４Ｅ２ This is the second reactive part, L ４Ｅ１ and L ４Ｅ２ Under the aforementioned appropriate conditions, they react with each other to form L ４Ｅ３ It can form L ４Ｄ１ -L ４Ｅ３ -L ４Ｄ２ is, L ４ The method described above.

142. M １ and M ２ The method according to claim 141, wherein each of them is independently a nucleoside radical. 【Request Item 143】 【Chemistry 308】 The following is true: 【Chemical 309】 The method according to claim 141 or 142.

144. L ４Ｅ１ and L ４Ｅ２ The method according to any one of claims 141-143, wherein each of them is a click chemistry handle.

145. L ４Ｅ１ and L ４Ｅ２ One of them is -N ３ And L ４Ｅ１ and L ４Ｅ２ The method according to any one of claims 141-144, wherein the other of the two is -C≡CH.

146. L ４Ｅ１ and L ４Ｅ２ One of them is -N ３ And L ４Ｅ１ and L ４Ｅ２ The other of these was arbitrarily replaced. 【Chemical 310】 Arbitrarily replaced 【Chemical 311】 or optionally replaced 【Chemical 312】 The method according to any one of claims 141 to 145.

147. L ４Ｅ３ This is the one in the following formula: 【Chemistry 313】 And, k21 is 0, 1, 2, 3, or 4. Each R ｄ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, k22 is 0, 1, 2, 3, or 4. Each R ｅ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, k23 is an integer between 0 and 11, including both endpoints. Each R ｆ Examples, if present, include halogens, substituted or unsubstituted C independently. １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ It is alkyl, R ｇ C is hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, or -O- (substituted or unsubstituted C) １－６ The method according to any one of claims 141-146, wherein the alkyl group is...

148. L ４Ｅ３ This is the formula: 【Chemical 314】 The method according to any one of claims 141 to 147.

149. L ４Ｅ１ and L ４Ｅ２ One of them is -SH, L ４Ｅ１ and L ４Ｅ２ The other of the two is 【Chemical Industry 315】 The method according to any one of claims 141-148.

150. L ４Ｅ１ or L ４Ｅ２ One of them is Michael Donner, L ４Ｅ１ or L ４Ｅ２ The method according to any one of claims 141-149, wherein the other of the two is Michael Acceptor.

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

152. Use of an oligonucleotide according to any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, for producing a drug for delivering the oligonucleotide to a target.

153. An oligonucleotide according to any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, for use in delivering the oligonucleotide to a target.

154. The oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition thereof, is delivered to the brain of the subject, for the method according to claim 151, the use according to claim 152, and the use according to claim 153.

155. The oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition thereof, is delivered to the striatum, cerebellum, brainstem, hippocampus, prefrontal cortex, or spinal cord of the subject, for the method according to claim 151, the use according to claim 152, and the use according to claim 153.

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

157. Use of an oligonucleotide according to any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, for the manufacture of a drug for treating a disease in a subject requiring treatment of the disease.

158. An oligonucleotide according to any one of claims 1 to 137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, for use in treating a disease in a subject requiring treatment of the disease.

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

160. Use of an oligonucleotide according to any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, for the manufacture of a drug for preventing disease in subjects requiring disease prevention.

161. An oligonucleotide according to any one of claims 1 to 137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, for use in the prevention of disease in subjects requiring disease prevention.

162. The disease is related to microtubule-associated tau protein (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2), and the method according to claim 156 or 159, the use according to claim 157 or 160, and an oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition for the use according to claim 158 or 161.

163. The disease is a central nervous system disorder, and the oligonucleotide, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161.

164. Oligonucleotides, pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161, wherein the disease is a brain disease, Edwards syndrome, gliosis, hyperstimulus, Meckel syndrome, myoclonus epilepsy myopathy, sensory ataxia, narcolepsy, prion disease, serotonin syndrome, or spinal cord disease.

165. The disease is a neurodegenerative disease, and the oligonucleotide, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161.

166. The aforementioned diseases include ABr amyloidosis, aceruloplasminemia, acute neurodegenerative diseases, amyotrophic lateral sclerosis, vitamin E deficiency ataxia, atypical Rett syndrome, beta-propeller protein-related neurodegeneration, COASY protein-related neurodegeneration, central nervous system degenerative diseases, demyelination, fatty acid hydroxylase-related neurodegeneration, fragile X-related tremor ataxia syndrome, Gemignani syndrome, Gerstmann-Streusler syndrome, Huntington's disease, Huntington-like syndrome, hypomyelination with basal ganglia and cerebellar atrophy, infantile cerebellar-retinal degeneration, infantile neuronal axonal dystrophy, Kozaki hypergrowth syndrome, mitochondrial membrane protein-related neurodegeneration, multiple sclerosis, multiple system atrophy, and muscular dystrophy. Oligonucleotides, pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions according to claim 156 or 159, for use according to claim 157 or 160, and for use according to claim 158 or 161,

167. The disease is a neurocognitive disorder, and the oligonucleotide, a pharmaceutically acceptable salt thereof, or a prodrug, or a pharmaceutical composition for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161.

168. Oligonucleotides, pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161, wherein the disease is dementia, HIV-related neurocognitive disorder, or memory impairment.

169. Oligonucleotides, pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161, wherein the disease is Parkinson's disease.

170. Oligonucleotides, pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161, wherein the disease is amyotrophic lateral sclerosis.

171. Oligonucleotides, pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions for the method according to claim 156 or 159, the use according to claim 157 or 160, and the use according to claim 158 or 161, wherein the disease is Alzheimer's disease.

172. Oligonucleotides, pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions for the use described in claim 156 or 159, the use described in claim 157 or 160, and the use described in claim 158 or 161, wherein the disease is tauopathy, frontotemporal dementia (FTD), FTDP-17, progressive supranuclear palsy (PSP), chronic traumatic encephalopathy (CTE), corticobasal ganglia ganglion degeneration (CBD), epilepsy, or Dravet syndrome.

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

174. Use of an oligonucleotide according to any one of claims 1-137, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 138 or 139, for the production of a drug for inhibiting the expression of microtubule-associated tau protein (MAPT), superoxide dismutase type 1 (SOD1), or leucine-rich repeat kinase 2 (LRRK2) in a subject, biological sample, tissue, or cell.

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

176. The biological sample, tissue, or cell is in vitro, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or pharmaceutical composition for the method according to claim 173, the use according to claim 174, and the use according to claim 175.

177. An oligonucleotide, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition for the use described in claim 173, the use described in claim 174, and the use described in claim 175, further comprising administering an additional effective amount of the pharmacokinetic to the subject or contacting an effective amount thereof with the biological sample, tissue, or cells.

178. The oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition thereof, is administered parenterally to the subject according to the method of claim 173, the use according to claim 174, and the use according to claim 175.

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

180. The subject is a human, and the oligonucleotide, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition for the method according to claim 173, the use according to claim 174, and the use according to claim 175.

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