SOD1 modulating composition and method of use thereof

Abstract

Aspects of this disclosure provide compounds, compositions, and methods for regulating the expression or activity of superoxide dismutase 1 (SOD1). In some aspects, the compounds, compositions, and methods of this disclosure can be used to reduce the expression of SOD1 mRNA in cells or animals. In some aspects, the compounds, compositions, and methods of this disclosure can be used to reduce the expression of SOD1 protein in cells or animals. In certain embodiments, the animal has a CNS-related disease, disorder, or condition.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 63 / 504,692, filed on 26 May 2023, U.S. Provisional Application No. 63 / 510,090, filed on 23 June 2023, and U.S. Provisional Application No. 63 / 613,687, filed on 21 December 2023, pursuant to Section 119(e) of the U.S. Patent Act. The disclosures of each of these prior applications are deemed to be part of the disclosures of this application and are incorporated into the disclosures of this application by reference. [Overview of the project] [Means for solving the problem]

[0002] This disclosure provides compounds, compositions, and methods for regulating the expression or activity of superoxide dismutase 1 (SOD1). In certain embodiments, these compounds, compositions, and methods can be used to reduce the expression of SOD1 mRNA in cells or animals. In certain embodiments, these compounds, compositions, and methods can be used to reduce the amount of SOD1 protein in cells or animals.

[0003] In certain embodiments, the animal has a CNS-related disease, disorder, or condition. In certain embodiments, the disease, disorder, or condition is a neurodegenerative disease (such as amyotrophic lateral sclerosis (ALS) or its symptoms, e.g., loss of motor function or neuronal death). The specific compounds, compositions, and methods provided in this disclosure are for the purpose of alleviating CNS-related diseases, disorders, or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in animals. In certain embodiments, the compounds and compositions provided in this disclosure are potent and tolerable, inhibit SOD1 expression, and can be used to treat, prevent, improve, or slow the progression of CNS-related diseases, disorders, or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death).

[0004] In certain embodiments, the compound and composition include one or more features that are effective in enhancing potency. In certain embodiments, the compound and composition include one or more features that are effective in enhancing tolerability. In certain embodiments, the compound and composition include one or more features that are effective in delivering the compound or composition to cells or tissues. In certain embodiments, the compound and composition are more potent, have a longer duration of action, or have greater therapeutic significance than publicly disclosed compounds. [Modes for carrying out the invention]

[0005] It should be understood that the above summary and the embodiments for carrying out the invention described below are merely illustrative and descriptive, and do not limit the embodiments claimed. The section headings used herein are for illustrative purposes only and should not be construed as limiting the subject matter described.

[0006] All documents or portions of documents cited in this application (including, but not limited to, patents, patent applications, articles, books, papers, GenBank, NCBI, and other sequence reference records) are expressly incorporated herein by reference with respect to the document portions discussed herein and the entirety of this application as of the filing date.

[0007] It should be understood that the sequences shown in each sequence number included herein, even when shown in relation to a modified compound, are independent of any modification to the sugar moiety, nucleoside bond, or nucleic acid base. Therefore, the compounds defined by sequence numbers may independently contain one or more modifications to the sugar moiety, nucleoside bond, or nucleic acid base. The oligomeric compounds referred to by compound numbers or reference numbers indicate a combination of nucleic acid base sequence, chemical modification, and motif.

[0008] In this specification, the use of the singular form includes the plural form unless otherwise specifically indicated. For example, the articles “a” and “an” are used to refer to one or more than one (i.e., at least one) grammatical object of the article. For example, “an + element” means one or more elements, e.g., multiple elements. In this specification, the use of “or” means “and / or” unless otherwise indicated. Furthermore, the use of the term “including,” as well as forms such as “includes” and “included,” is not limiting and is used synonymously with the phrase “including, but not limited to, these.”

[0009] definition Unless otherwise specified, the following terms have the following meanings:

[0010] The term "superoxide dismutase 1" is used synonymously with "SOD1" and refers to either the nucleic acid or protein of SOD1. Exemplary nucleotide and amino acid sequences of SOD1 can be found, for example, in nucleotides 5001-14310 of GenBank accession numbers NM_000454.5 (incorporated herein as SEQ ID NO: 1) and NG_008689.1 (incorporated herein as SEQ ID NO: 2). 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). "SOD1 mRNA" refers to the mRNA encoding the SOD1 protein. SOD1 may be referred to in either uppercase or lowercase.

[0011] A "SOD1-specific inhibitor" refers to any drug that can specifically inhibit the expression or activity of SOD1 RNA and / or SOD1 protein at the molecular level. For example, SOD1-specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules, and other drugs that can inhibit the expression of SOD1 RNA and / or SOD1 protein.

[0012] "2'-O-methoxyethyl" or "2'-MOE" refers to the modification 2'-O(CH2)2-OCH3. 2'-O-methoxyethyl modified sugars are modified sugars that have 2'-O(CH2)2-OCH3 instead of the 2'-OH group on the ribosyl ring.

[0013] The "5' start site" refers to the nucleotide in the target nucleic acid or target region that aligns with the 3' nucleoside of the antisense oligonucleotide.

[0014] The "3' termination site" refers to the nucleotide in the target nucleic acid or target region that aligns with the furthest 5' nucleoside of the antisense oligonucleotide.

[0015] "Approximately" means a value within ±10%. For example, if it says "a compound that achieved an SOD1 inhibition rate of approximately 70%", it implies that the compound inhibits SOD1 levels within the range of 60% to 80%. When "approximately" precedes a series of numbers or ranges, it should be understood that "approximately" can modify each of those numbers or ranges.

[0016] "Administering" or "administering" refers to a route through which the compounds or compositions provided in this disclosure are introduced into an organism to exert their intended function. Examples of usable administration routes include, but are not limited to, intrathecal (IT) administration, intraventricular (ICV) administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intra-arterial, intraperitoneal, or intracranial administration, such as intrathecal or intraventricular administration.

[0017] "Improvement" means improvement or reduction of at least one indicator, sign, or symptom of the associated disease, disorder, or condition. In certain embodiments, improvement includes delaying or slowing the progression or worsening of one or more indicators of the condition or disease. The progression or worsening of an indicator may be determined by subjective or objective scales known to those skilled in the art.

[0018] "Animals" refers to humans or non-human animals. Non-human animals include, but are not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates. Non-human primates include, but are not limited to, monkeys and chimpanzees.

[0019] "Antisense oligonucleotide" or "antisense strand" means an oligonucleotide that contains a region complementary to the target nucleic acid, such as SOD1 RNA or its region.

[0020] "Complementarity," in the case of oligonucleotides, means one or more nucleic acid base sequences of the oligonucleotide or region, which, when aligned in opposite directions, are complementary to one or more nucleic acid base sequences of the other oligonucleotide or nucleic acid or region. Complementary nucleic acid bases are limited to the pairs adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G), as described herein, unless otherwise specified. Complementary oligonucleotides and / or nucleic acids do not need to have nucleic acid base complementarity at each nucleoside and may contain one or more nucleic acid base mismatches. In contrast, "perfectly complementary" or "100% complementary," in the case of oligonucleotides, means that the oligonucleotide has nucleic acid base matches at each nucleoside, with no nucleic acid base mismatches whatsoever.

[0021] "Composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to an individual. For example, a composition may contain one or more compounds or salts thereof and a sterile aqueous solution.

[0022] "Concomitant administration" means administering two or more compounds in any form that allows both pharmacological effects to manifest in the patient. Concomitant administration does not require both compounds to be administered in a single pharmaceutical composition, in the same dosage form, via the same route of administration, or simultaneously. The effects of both compounds do not need to manifest simultaneously. Their effects only need to overlap over a period of time and do not need to have the same extent. Concomitant administration includes parallel or sequential administration of one or more compounds.

[0023] A "conjugate group" refers to an atomic group bonded to an oligonucleotide. The conjugate group is optionally bonded to the oligonucleotide via a conjugate linker. The conjugate group may, for example, alter the distribution, targeting, or half-life of the compound in which it is incorporated. Examples of conjugate groups include lipids (or lipophilic moieties), ligands, and other targeting moieties.

[0024] A "conjugate linker" refers to a group of atoms that contains at least one bond connecting the linking portion to an oligonucleotide.

[0025] "Identity," in the case of oligonucleotides, means that one or more nucleic acid base sequences within the oligonucleotide or region of that oligonucleotide or region match one or more nucleic acid base sequences within the other oligonucleotide or nucleic acid. Identity between an oligonucleotide and another oligonucleotide or nucleic acid does not require that every nucleic acid base be identical; it may contain one or more different nucleic acid bases. In contrast, "completely identical" or "100% identity," in the case of oligonucleotides, means that the oligonucleotide has the same nucleic acid bases at each corresponding position over its length as the other oligonucleotide or nucleic acid.

[0026] "Individual" refers to a human or non-human animal selected for treatment or therapy.

[0027] "Inhibiting expression or activity" means, with respect to a target nucleic acid or target protein, reducing or blocking the expression or activity of the target compared to the expression or activity in the untreated or control sample, and does not necessarily mean a complete elimination of expression or activity.

[0028] As used herein, the term “nucleoside bond” refers to a covalent bond between adjacent nucleosides in an oligonucleotide. As used herein, “modified nucleoside bond” refers to any nucleoside bond other than a phosphodiester nucleoside bond. “Phosphothioate nucleoside bond” is a modified nucleoside bond in which one of the non-bridged oxygen atoms of a phosphodiester nucleoside bond is replaced by a sulfur atom.

[0029] Representative nucleoside bonds containing a chiral center include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides containing a chiral nucleoside bond can be prepared as a group of modified oligonucleotides containing a stereorandom nucleoside bond, or as a group of modified oligonucleotides containing a phosphorothioate bond in specific stereochemical configurations, as further described below. Unless otherwise indicated, the chiral nucleoside bonds of the modified oligonucleotides described herein may be stereorandom or in specific stereochemical configurations.

[0030] The compounds of this disclosure may also contain one or more atomic isotopes in non-natural proportions of the atoms constituting such compounds. For example, the compounds may contain radioactive isotopes, such as tritium. 3 H), Iodine-125( 125 I) or carbon-14 ( 14 C) may be radioactively labeled. All isotopic variants of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure.

[0031] The term “isotope variant” refers to a therapeutic agent (e.g., compounds and / or modified oligonucleotides disclosed herein) that contains one or more isotopes in non-natural proportions of the atoms constituting such therapeutic agents. In certain embodiments, the “isotope variant” of a therapeutic agent contains one or more isotopes in non-natural proportions, such as hydrogen (H), deuterium ( 2H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine 123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I) and iodine-131 ( 131 I) are included, but not limited thereto. In certain embodiments, an "isotope variant" of a therapeutic agent contains one or more isotopes in a non-natural proportion, and the isotopes include hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14N), Nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), phosphorus-31( 31 P), phosphorus-32( 32 P), Lin-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), Sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123 ( 123 I) Iodine-125 125 I) Iodine-127( 127 I) Iodine-129( 129 I) and Iodine-131 ( 131 I) is one example, but it is not limited to these.

[0032] In therapeutic agents (e.g., compounds and / or modified oligonucleotides disclosed herein), where feasible according to the judgment of those skilled in the art, for example, any hydrogen 2 It can be H, and for example, any carbon 13 It can be C, and for example, any nitrogen 15 It can be N, or for example, any oxygen 18 It should be understood that it can be O. In certain embodiments, the “isotope variant” of the therapeutic agent contains a non-natural proportion of deuterium (D).

[0033] "Lipid" or "lipophilic moiety" refers to an aliphatic, cyclic (such as alicyclic) or polycyclic (such as polyalicyclic) compound, for example, a steroid (such as sterol) or a straight-chain or branched-chain aliphatic hydrocarbon. The term lipid includes cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl) glycerol, geranyloxy hexanol, hexadecyl glycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) chenodeoxycholic acid, ibuprofen, naproxen, dimethoxytrityl or phenoxazine. The term lipid includes saturated or unsaturated C4-C 30 hydrocarbon chains (such as C4-C 30 alkyl or alkenyl). In certain embodiments, the lipophilic moiety includes a saturated or unsaturated C5-C 20 hydrocarbon chain (such as a straight-chain C5-C 20 alkyl or alkenyl). In certain embodiments, the lipophilic moiety includes a saturated or unsaturated C 14- C 20 hydrocarbon chain (such as a straight-chain C 14- C 20 alkyl or alkenyl). In certain embodiments, the lipophilic moiety includes a saturated or unsaturated C6-C 18 hydrocarbon chain (such as a straight-chain C6-C 18 alkyl or alkenyl). In certain embodiments, the lipophilic moiety includes a saturated or unsaturated C 16 hydrocarbon chain (such as a straight-chain C 16 alkyl or alkenyl). In certain embodiments, the lipophilic moiety includes a saturated or unsaturated C 17 hydrocarbon chain (such as a straight-chain C 17 alkyl or alkenyl). In certain embodiments, the lipophilic moiety includes a saturated or unsaturated C 18 hydrocarbon chain (such as a straight-chain C 18 alkyl or alkenyl). In certain embodiments, the lipophilic moiety includes a saturated or unsaturated C 22Hydrocarbon chains (for example, straight chains of carbon) 22 Contains alkyl or alkenyl compounds.

[0034] "Mismatched" or "non-complementary" means that when a first oligonucleotide / or nucleic acid is aligned with a second oligonucleotide / nucleic acid in an antiparallel orientation, the nucleic acid bases of the first oligonucleotide / nucleic acid are not complementary to the corresponding nucleic acid bases of the second oligonucleotide / nucleic acid. For example, a nucleic acid base (including, but not limited to, universal nucleic acid bases, inosine, and hypoxanthine) can hybridize with at least one nucleic acid base, but is still mismatched or non-complementary with respect to the nucleic acid bases that those nucleic acid bases hybridize with. As another example, when a first oligonucleotide / nucleic acid is aligned with a second oligonucleotide in an antiparallel orientation, any nucleic acid bases of the first oligonucleotide / nucleic acid that cannot hybridize with the corresponding nucleic acid bases of the second oligonucleotide / nucleic acid are mismatched or non-complementary nucleic acid bases.

[0035] A "modified oligonucleotide" refers to an oligonucleotide in which at least one sugar, nucleic acid base, or nucleoside bond has been modified.

[0036] "To regulate" refers to altering or modulating characteristics in cells, tissues, organs, or organisms. For example, regulating SOD1 RNA can mean increasing or decreasing the levels of SOD1 RNA and / or SOD1 protein in cells, tissues, organs, or organisms. A "modulator" brings about a change in cells, tissues, organs, or organisms. For example, an SOD1 compound can be a modulator that decreases the amount of SOD1 RNA and / or SOD1 protein in cells, tissues, organs, or organisms.

[0037] "Motif" refers to the pattern of unmodified and modified sugar moieties, nucleic acid bases, and / or nucleoside bonds in oligonucleotides.

[0038] "Nucleic acid" refers to a molecule composed of monomeric nucleotides. Examples of nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0039] "Nucleic acid base" refers to a heterocyclic portion that can pair with a base of another nucleic acid. As used herein, "natural nucleic acid bases" are adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). "Modified nucleic acid bases" are naturally occurring nucleic acid bases that have been chemically modified. "Universal bases" or "universal nucleic acid bases" are nucleic acid bases other than natural and modified nucleic acid bases that can pair with any of them.

[0040] "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.

[0041] A "nucleoside" refers to a compound containing a nucleic acid base and a sugar moiety. The nucleic acid base and sugar moiety are either independently unmodified or modified. A "modified nucleoside" refers to a nucleoside containing a modified nucleic acid base and / or a modified sugar moiety. Modified nucleosides include debasic nucleosides, in which a nucleic acid base is missing.

[0042] An "oligomeric compound" means a compound comprising one or more oligonucleotides and optionally one or more additional features, such as a conjugate group or a terminal group. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNAs that target oligonucleotides, occupation-based compounds (e.g., compounds that block mRNA processing or translation, and splicing compounds). RNAi compounds include double-stranded compounds (e.g., small interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimetic compounds), which act at least partially 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, such as interfering RNA (iRNA), iRNA agents, RNAi agents, small interfering oligonucleotides, small interfering nucleic acids, small interfering modified oligonucleotides, and chemically modified siRNA. In addition, the term "RNAi" is intended to be equivalent to other terms used to describe sequence-specific RNA interference.

[0043] An "oligomeric double-stranded compound" refers to a double-stranded compound formed by two oligomeric compounds having complementary nucleic acid base sequences. Each oligomeric compound in an oligomeric double-stranded compound is sometimes referred to as a "double-stranded oligomeric compound." Each oligomeric compound in an oligomeric double-stranded compound may contain a non-complementary overhang nucleoside. In some embodiments, the terms "double-stranded oligomeric compound" and "modified oligonucleotide" are used synonymously. In other embodiments, the terms "oligomeric double-stranded compound" and "compound" are used synonymously.

[0044] "Oligonucleotide" means a polymer of linked nucleosides, each of which can be independently modified or unmodified.

[0045] "Parenteral administration" means administration via injection or infusion. Examples of parenteral administration include subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration or intracranial administration, for example, intrathecal administration or intraventricular administration.

[0046] "Pharmaceutically acceptable carrier or diluent" means any substance suitable for use in administration to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent can be included in the compositions of the present disclosure to assist in the administration of the compound to an individual and in its absorption by the individual, without exerting unduly harmful toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline, etc. For example, a pharmaceutically acceptable carrier can be a sterile aqueous solution, for example, PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0047] "Pharmaceutically acceptable salt" means or refers to a salt of a compound, for example, an oligomeric compound or an oligonucleotide, that is physiologically and pharmaceutically acceptable, i.e., a salt that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects.

[0048] "Tropomyosin receptor kinase B" or "TrkB" may be used synonymously herein and means a receptor for the brain-derived neurotrophic factor (BDNF) protein, which is encoded by the NTRK2 gene. TrkB is also known as receptor tyrosine kinase B, growth factor BDNF / NT-3 receptor and neurotrophic tyrosine kinase receptor type 2.

[0049] "Cannabinoid receptor type 1" or "CB1" refers to a G protein-coupled receptor for cannabinoids. In humans, CB1 is encoded by the CNR1 gene. CB1 is also known as cannabinoid receptor 1.

[0050] "α4β 1 / 7 The term "integrin receptor" refers to a heterodimeric integrin receptor formed by the binding of integrin α4 and integrin β1 (i.e., α4β1 integrin receptor), and a heterodimeric integrin receptor formed by the binding of integrin α4 and integrin β7 (i.e., α4β7 integrin receptor). In certain embodiments, the α4β 1 / 7 Integrin receptor ligands have a higher binding affinity to the α4β1 integrin receptor than to the α4β7 integrin receptor. In certain embodiments, the α4β 1 / 7 Integrin receptor ligands have a higher binding affinity to the α4β7 integrin receptor than to the α4β1 integrin receptor.

[0051] "N-methyl-D-aspartate receptors" or "NMDA receptors" refer to glutamate receptors and ion channels found, for example, in human neurons. Many ligands for NMDA receptors are known in the art and are disclosed, for example, in Neuropharmacology 2007, 53(6), 699-723, J.Med.Chem. 1990, 33(2), 789-808, Neuroscience 2001, 105(3), 663-669, J.Med.Chem. 2022, 65(13), 9063-9075, Drugs Fut. 2004, 29(10), 992, Drugs Fut. 2004, 29(10), 993, and British Journal of Pharmacology 2022, 179(6), 1146-1187, each of which is incorporated herein by reference.

[0052] For use herein, a pharmaceutically acceptable salt is any salt of the compounds provided herein that retains its biological properties, is non-toxic, or has no particular undesirability for pharmaceutical use. Examples of pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds or modified oligonucleotides described herein.

[0053] When the compounds of the present disclosure contain relatively acidic functional groups, the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either in its original form or in a suitable inert solvent.

[0054] When the compounds of the present disclosure contain relatively basic functional groups, the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either in its original form or in a suitable inert solvent.

[0055] Accordingly, the compounds of this disclosure may exist as salts, for example, salts with pharmaceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counterions well known in the art. Such salts include (1) organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2) Acid addition salts formed with acids such as octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, and muconic acid, or (2) acid protons present in the parent compound are (a) metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions, or hydroxides of alkali metals or alkaline earth metals, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and water Examples of salts formed when (b) a base is substituted with barium oxide or ammonia, or when it coordinates with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucaminepiperazine, tris(hydroxymethyl)aminomethane, or tetramethylammonium hydroxide, etc. (see, for example, Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0056] Pharmaceutically acceptable salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and, when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides, such as hydrochlorides and hydrobroms, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propions, hexanoates, cyclopentylpropions, glycolates, glutarates, pyruvates, lactates, malons, succinates, sorbates, ascorbicates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates. Examples include picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-octa-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, glucuronate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, and muconate. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium or potassium salts. In some embodiments, the pharmaceutically acceptable salts of the compounds and modified oligonucleotides disclosed herein are sodium salts.

[0057] The neutral form of the compound is preferably regenerated by contacting its salt with a base or acid and isolating the parent compound in its conventional form. The parent form of the compound may differ in various salt forms and in specific physical properties, such as solubility in polar solvents. In embodiments, the compounds of this disclosure contain both basic and acidic functional groups that convert the compound to either a base-addition salt or an acid-addition salt. The neutral form of the compound may be regenerated by contacting its salt with a base or acid and isolating the parent compound in its conventional form. The parent form of the compound may differ in various salt forms and in specific physical properties, such as solubility in polar solvents, but unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of this disclosure.

[0058] "Pharmaceutical agents" refer to compounds that produce a therapeutic effect when administered to an individual.

[0059] A "phosphorothioate bond" refers to a modified phosphate bond in which one of the non-bridged oxygen atoms is replaced by a sulfur atom.

[0060] A "part" refers to a defined number of consecutive (i.e., linked) nucleic acid bases of a nucleic acid. In certain embodiments, a part is a defined number of consecutive nucleic acid bases of a target nucleic acid. In certain embodiments, a part is a defined number of consecutive nucleic acid bases of an oligonucleotide.

[0061] "Prevention" means delaying or preventing the onset, progression, or progression of a disease, disability, or condition over a period of time.

[0062] "RNA interference compounds" or "RNAi compounds" refer to compounds that act, at least in part, via the RNA-induced silencing complex (RISC) pathway or Ago2, rather than via RNase H, to modulate target nucleic acids and / or target proteins encoded by the target nucleic acid. Examples of RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA (including microRNA mimetic compounds).

[0063] "Sense oligonucleotide" or "sense chain" means a chain of a double-stranded compound that includes a region substantially complementary to the antisense chain region of the compound of the present invention.

[0064] "Specifically inhibiting" means reducing or blocking the expression or activity of a target nucleic acid or target protein while minimizing or eliminating its effects on non-target nucleic acids or proteins.

[0065] With respect to oligonucleotides, “subunit” means a nucleotide, nucleoside, nucleic acid base or sugar, or a modified nucleotide, modified nucleoside, modified nucleic acid base or modified sugar, as provided in this disclosure.

[0066] "Target nucleic acid," "target RNA," and "nucleic acid target" all refer to nucleic acids that can derive the compounds described herein.

[0067] The "target region" refers to the portion of a target nucleic acid into which one or more compounds are directed.

[0068] The "targeting portion" refers to a conjugate group that increases the affinity for a given target, such as a molecule, cell or cell type, compartment, such as a compartment of a cell or organ, tissue, organ or region, compared to a compound in which such portion does not exist.

[0069] "Terminal-side group" means a chemical group or atomic group covalently bonded to the terminus of an oligonucleotide.

[0070] "Therapeutically effective amount" or "effective amount" means an amount of a compound, pharmaceutical agent or composition that produces a therapeutic effect in an individual. "Therapeutically effective amount" or "effective amount" is an amount sufficient for the compound to achieve the indicated purpose (e.g., effect of administering the compound, effect of treating, preventing or ameliorating a disease, or effect of reducing one or more symptoms of a disease or condition) compared to the case where the compound is absent. Examples of "therapeutically effective amount" or "effective amount" are amounts sufficient to contribute to the treatment, prevention, amelioration or reduction of symptoms (s) of a disease. "Reduction" of symptoms (s) (and terms grammatically equivalent to this phrase) means reducing the severity or frequency of the symptoms (s), or eliminating the symptoms (s). The "preventively effective amount" of a drug is an amount of the drug that, when administered to a subject, has the intended preventive effect, e.g., an effect of preventing or delaying the onset (or recurrence) of a disorder, disease, medical condition or condition, or an effect of reducing the likelihood of onset (or recurrence) of a disorder, disease, medical condition or condition, or their symptoms. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent sufficient to produce a therapeutic effect in an individual, e.g., an effect of treating, preventing or ameliorating a disease or disorder, or its symptoms, as described above. For example, with a therapeutically effective amount, an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90% or at least 100% can be seen for a given parameter. Therapeutic efficacy can also be expressed as an increase or decrease of "~ fold". For example, with a therapeutically effective amount, an effect of at least 1.2-fold, 1.5-fold, 2-fold, 5-fold or more than 5-fold compared to the control can be achieved.

[0071] The terms “treating” or “treatment” refer to any sign of success in the therapy or improvement of an injury, disease, condition, or state, which may include any objective or subjective parameter, such as reduction, remission, decrease in symptoms, or increased patient tolerance to the injury, condition, or state, a slower rate of deterioration or decline, a decrease in the degree of debilitation at the end of deterioration, or an improvement in the patient’s physical or mental condition. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination. The terms “treating” and their inflections may include the prevention of injury, condition, state, or disease. In embodiments, treating is prevention. In embodiments, treating does not include prevention.

[0072] As used herein (and as is well understood in the art), “to treat” or “treatment” broadly includes any approach to obtain a beneficial or desired outcome (including clinical outcomes) in the condition in question. Beneficial or desired clinical outcomes include, but are not limited to, relief or improvement of one or more symptoms or conditions, whether partial or complete, and whether detectable or undetectable; a reduction in the severity of the disease; stabilization of the disease state (i.e., prevention of exacerbation); prevention of disease transmission or spread; delay or slowing of disease progression; improvement or relief of the disease state; reduction of disease relapses; and remission. In other words, as used herein, “treatment” includes curing, improving, or preventing the disease. Treatment may prevent the onset of the disease, inhibit the spread of the disease, reduce the symptoms of the disease, completely or partially eliminate the underlying cause of the disease, shorten the duration of the disease, or a combination of these events.

[0073] As used herein, “to treat” and “treatment” include prophylactic treatment. Treatment involves administering to a subject a therapeutically effective dose of the compounds described herein. This administration step may consist of a single dose or include a series of doses. The duration of treatment depends on various factors, such as the severity of the condition, the patient’s age, the concentration of the compound, the activity of the composition used in treatment, or a combination thereof. It will also be apparent that the effective dose of the drug used for treatment or prevention may increase or decrease over a particular treatment or prophylactic regimen. In some cases, chronic administration may be required. For example, the composition is administered to a subject in an amount and duration sufficient to treat the patient. “To treat” means to administer a compound or pharmaceutical composition to an animal in order to modify or improve a disease, disorder or condition in that animal.

[0074] Certain compounds in this disclosure have an asymmetric carbon atom (optical or chiral center) or a double bond, and the scope of this disclosure includes enantiomers, racemic compounds, diastereomers, tautomers, geometric isomers, stereoisomer forms that may be defined in terms of absolute stereochemistry, such as (R) or (S) or (D) or (L) forms for amino acids, and individual isomers. The compounds in this disclosure do not include compounds that are known in the art to be unstable and unsynthesizable and / or unisolated. This disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R) and (S) or (D) and (L) isomers may be prepared using chiral synthons or chiral reagents, or divided using conventional techniques. When a compound described herein contains an olefin bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0075] As used herein, the term "isomer" refers to a compound having the same number and types of atoms, i.e., the same molecular weight, but differing in the structural arrangement or composition of its atoms.

[0076] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to the other.

[0077] It will be apparent to those skilled in the art that specific compounds of the present disclosure can exist in tautomeric forms, and all such tautomeric forms of the compound are within the scope of the present disclosure.

[0078] Unless otherwise indicated, the structures depicted herein are intended to also include all stereochemical forms of the structure (i.e., the R and S configurations for each asymmetric center). Thus, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and mixtures of diastereomers, are within the scope of the present disclosure.

[0079] As used herein, a "chirally enriched population" means a plurality of molecules having the same molecular formula, where, when a particular chiral center is stereorandom, the number or percentage of molecules within the population that contain a particular stereochemical configuration at that particular chiral center is greater than the number or percentage of molecules within the population that are thought to contain the same particular stereochemical configuration at the same particular chiral center. A population of molecules that are chirally enriched and have a plurality of chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecule is a modified oligonucleotide. In certain embodiments, the molecule is a compound that includes a modified oligonucleotide.

[0080] Unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of the present disclosure unless hydrogen is replaced with deuterium or tritium, or carbon is replaced with 13 C-enriched carbon or 14 C-enriched carbon.

[0081] As used herein, “stereorandom chiral center” means a chiral center having a random stereochemical configuration with respect to a group of molecules with the same molecular formula. For example, in a group of molecules containing stereorandom chiral centers, the number of molecules having stereorandom chiral centers in (S) configuration may be the same as, but not necessarily the same as, the number of molecules having stereorandom chiral centers in (R) configuration. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method not designed to control its stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate nucleoside bond.

[0082] Specific Embodiments In certain embodiments, this disclosure relates to methods, compounds, and compositions for inhibiting SOD1. In certain embodiments, SOD1 is specifically inhibited. In certain embodiments, SOD1 is specifically degraded. In certain embodiments, the expression of SOD1 is inhibited. In certain embodiments, the translation of SOD1 is inhibited. In certain embodiments, the activity of SOD1 is inhibited. In certain embodiments, the expression, translation, or activity of SOD1 is reduced by at least 10% compared to the expression, translation, or activity in an untreated or control sample. For example, in certain embodiments, the expression, translation, or activity of SOD1 is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% compared to the expression, translation, or activity in an untreated or control sample. In certain embodiments, SOD1 expression, translation, or activity is reduced when measured by any suitable assay, which may include, but is not limited to, immunoassays, hybridization-based assays, or sequencing-based assays (e.g., RNA-Seq).

[0083] In certain embodiments, this disclosure relates to compounds that target SOD1 nucleic acid. In certain embodiments, the SOD1 nucleic acid has the sequence shown in GenBank accession numbers NM_000454.5 (incorporated herein as SEQ ID NO: 1) and NG_008689.1, nucleotides 5001 to 14310 (incorporated herein as SEQ ID NO: 2).

[0084] In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound is single-stranded. In certain embodiments, the compound is double-stranded.

[0085] A particular embodiment provides a compound comprising a modified oligonucleotide (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23) having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223.

[0086] A particular embodiment provides a compound comprising a modified oligonucleotide having a nucleic acid base sequence (for example, a modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23) which includes the nucleic acid base sequence described in any one of SEQ ID NOs: 11 to 18, 28 to 106, 184 to 187, 196 to 202, or 214 to 223.

[0087] A particular embodiment provides a compound comprising a modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.

[0088] In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1 or 2. In certain embodiments, the modified oligonucleotide comprises at least one modification selected from modified nucleoside bonds, modified sugars, and modified nucleic acid bases. In certain embodiments, the compound is double-stranded.

[0089] A particular embodiment provides a compound comprising a first modified oligonucleotide (for example, a first modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a region complementary to the first modified oligonucleotide having a length of 14 to 30, for example, 14 to 23).

[0090] In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as shown in any of the nucleic acid base sequences in Tables 2 and 3 (for example, a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23).

[0091] A particular embodiment provides a compound comprising a first modified oligonucleotide having a nucleic acid base sequence including the nucleic acid base sequence described in any one of SEQ ID NOs: 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23).

[0092] A particular embodiment provides a compound comprising a first modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23, wherein the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.

[0093] A particular embodiment comprises a first modified oligonucleotide containing a 5'-phosphonate modification (the first modified oligonucleotide being at least 80% complementary to the region of SEQ ID NO: 1 or 2) and one or more ligands described herein (e.g., one or more tropomyosin receptor B (TrkB) ligands, one or more cannabinoid receptor type 1 (CB1) ligands, one or more α4β ligands). 1 / 7 The present invention provides a compound comprising a first modified oligonucleotide containing an integrin ligand or one or more N-methyl-D-aspartate receptor (NMDA) ligands. In certain embodiments, the first modified oligonucleotide comprises a 5'-terminal nucleoside containing a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

[0094] In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213.

[0095] In certain embodiments, the modified oligonucleotide or first modified oligonucleotide of either the prior compound has complementarity or identity with SEQ ID NO: 1 or 2 of at least 80%, at least 85%, at least 90%, or at least 95% over its length. In certain embodiments, the modified oligonucleotide or first modified oligonucleotide has at least one, at least two, or at least three mismatches with the region of SEQ ID NO: 1 or 2. In certain embodiments, the complementary region between the first modified oligonucleotide or first chain and the second modified oligonucleotide or second chain has a linked nucleoside length of 14 to 30. In certain embodiments, the complementary region between the first modified oligonucleotide or first chain and the second modified oligonucleotide or second chain has a linked nucleoside length of 14 to 23. In certain embodiments, the complementary region between the first modified oligonucleotide or first chain and the second modified oligonucleotide or second chain has a linked nucleoside length of 19 to 23. In certain embodiments, the complementary region between the first modified oligonucleotide or first chain and the second modified oligonucleotide or second chain is such that the length of the linked nucleoside is 21 to 23. In certain embodiments, the first modified oligonucleotide is perfectly complementary to the second modified oligonucleotide.

[0096] In certain embodiments, the modified oligonucleotide of any of the prior compounds or the first modified oligonucleotide includes at least one modification selected from modified nucleoside bonds, modified sugars, and modified nucleic acid bases. In certain embodiments, the second modified oligonucleotide of any of the prior compounds includes at least one modification selected from the group consisting of modified nucleoside bonds, modified sugars, and modified nucleic acid bases. In certain embodiments, the modified nucleoside bond is a phosphorothioate nucleoside bond or a methylphosphonate nucleoside bond. In certain embodiments, the phosphorothioate nucleoside bond or methylphosphonate nucleoside bond is located at the 3' end of the first or second modified oligonucleotide, or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar includes a modification selected from the group consisting of halogens, alkoxy groups, and bicyclic sugars. In certain embodiments, the modified sugar includes a 2'-F modification. In certain embodiments, the modified sugar includes a 2'-OMe modification. In certain embodiments, each nucleoside of the first modified oligonucleotide contains a modified sugar. In certain embodiments, each nucleoside of the second modified oligonucleotide contains a modified sugar. In certain embodiments, the modified sugar includes modifications selected from the group consisting of halogens, alkoxy groups, and bicyclic sugars, or combinations thereof. In certain embodiments, the modified sugar includes modifications selected from the group consisting of 2'-MOE, 2'-F, and 2'-OMe, or combinations thereof. In certain embodiments, the first modified oligonucleotide contains 10 or fewer 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide contains 5 or fewer 2'-F sugar modifications.

[0097] In certain embodiments, the compound of any of the prior embodiments includes a conjugate group. In certain embodiments, the conjugate group is bonded to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety includes one or more TrkB ligands. In certain embodiments, the targeting moiety includes one or more CB1 ligands. In certain embodiments, the targeting moiety includes one or more α4β 1 / 7 Contains an integrin ligand. In certain embodiments, the targeting moiety contains one or more NMDA ligands. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In certain embodiments, one or more TrkB ligands are bound to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, one or more CB1 ligands are bound to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, one or more α4β 1 / 7 The integrin ligand is bound to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, one or more NMDA ligands are bound to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide.

[0098] In certain embodiments, the TrkB ligand of the modified oligonucleotide is of the following formula (I), or a salt, solvate, or hydrate thereof: [ka] During the ceremony, R 1 This is a modified oligonucleotide of the present invention, L 1 , L 2 , L 3and L 4 This is as described herein, R 2 is hydrogen, -OR 7 , -SR 8 or -NR 9 R 10 And, R 3 is hydrogen, -OR 11 , -SR 12 or -NR 13 R 14 And, R 4 is hydrogen, -OR 15 , -SR 16 or -NR 17 R 18 And, R 5 is hydrogen, -OR 19 , -SR 20 or -NR 21 R 22 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 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 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 CH2, NH, S, or O. Z is an arbitrarily substituted aryl or arbitrarily substituted heteroaryl.

[0099] In a particular embodiment, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 Each of these is independently an optionally substituted unsaturated or partially unsaturated alkyl group. In certain embodiments, R 7 , R 8 , R 9 and R 10 Each of these is an alkenil independently. In certain embodiments, R 7 , R 8 , R 9 and R 10 Each of them is independently an alkinnil.

[0100] In a particular embodiment, R 2 is OR 7 In a particular embodiment, R 3 is OR 11 In a particular embodiment, R 7 and R 11 Each is independently hydrogen, optionally substituted alkyl or

[0101] It is an optionally substituted alkenyl. In certain embodiments, one or both R 7 and R 11 Each of these is independently hydrogen. In certain embodiments, one or both R 7 and R 11 Each of these is independently an optionally substituted alkyl group. In certain embodiments, one or both R 7 and R 11 Each of these is independently an optionally substituted unsaturated or partially unsaturated alkyl. In certain embodiments, one or both R 7 and R11 Each of these is an alkenil independently. In certain embodiments, R 7 is an optionally substituted alkyl, and R 11 is hydrogen. In certain embodiments, R 7 is hydrogen, R 11 R is an optionally substituted alkyl group. In certain embodiments, R 7 is an alkenil, and R 11 is hydrogen. In certain embodiments, R 7 is hydrogen, R 11 is an arbitrarily substituted alkenyl.

[0102] In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R 1 This is a modified oligonucleotide of the present invention, L 1 , L 2 , L 3 and L 4 This is as described herein.

[0103] In certain embodiments, the TrkB ligand of the modified oligonucleotide is of the following formula (XXX), or a salt, solvate, or hydrate thereof. [ka] During the ceremony, L 1 , L 2 , L 3 , L 4 and R 1 This is as described herein, 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 14and 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, or R bonded to the same nitrogen atom. 16B and R 16C The substituents may optionally join to form substituted or unsubstituted heterocycloalkyl groups, or substituted or unsubstituted heteroaryl groups. z3 is 0, 1, 2, 3, 4, or 5. n16 is 0, 1, 2, 3, or 4. v16 and m16 are independently either 1 or 2.

[0104] In a particular embodiment, the modified oligonucleotide α4β 1 / 7 Integrin ligands are those of the following formula (XXXI), or their salts, solvates, or hydrates: [ka] During the ceremony, L 1 , L 2 , L 3 , L 4 and R 1 This is as described herein, R2 , R 3 , R 4 and R 5 Each of these is independently either H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl, or absent. R 8 is an arbitrarily substituted C 1- C5 alkyl, optionally substituted C 1- C5 alkylene-(C3-C6)-cycloalkyl, or optionally substituted (C 1- C4)-Alkilen-(C 1- It is a C4)-alkoxy, R 6 and R 7 Each of these independently consists of H, halogen, alkyl or optionally substituted alkyl, and optionally substituted heteroalkyl. [ka] That is the case.

[0105] In a particular embodiment, the modified oligonucleotide α4β 1 / 7 The integrin ligand is of the following formula (XXXII), or its salt, solvate, or hydrate: [ka] During the ceremony, L 1 , L 2 , L 3 , L 4 and R 1 This is as described herein, R 2 is H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl. R 3 and R 4 Each of these is independently H, a halogen, an optionally substituted alkyl, or an optionally substituted -O-alkyl.

[0106] In a particular embodiment, L1 , L 2 , L 3 and L 4 Each of these is independently either absent, bonded, optionally substituted alkyl linker, optionally substituted polyethylene glycol (PEG) linker, optionally substituted heteroalkyl linker, or optionally substituted heteroaryl linker.

[0107] In a particular embodiment, L 1 This is an arbitrarily substituted heteroaryl linker.

[0108] In a particular embodiment, L 1 This is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

[0109] In a particular embodiment, L 1 teeth, [ka] It includes the structure.

[0110] In a particular embodiment, L 1 is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or an optionally substituted C 1-10 It is an alkyl chain (one or more carbon atoms are replaced by O, N, or S).

[0111] In a particular embodiment, L 1 teeth, [ka] It includes the structure.

[0112] In a particular embodiment, L 1 teeth, [ka] Or it includes the -N(CH3)- structure.

[0113] In a particular embodiment, L 2 This is an arbitrarily substituted PEG linker.

[0114] In certain embodiments, the PEG linker has a PEG unit length of 5. In certain embodiments, the PEG linker has a PEG unit length of 4. In certain embodiments, the PEG linker has a PEG unit length of 3.

[0115] In a particular embodiment, L 2 is an optionally substituted alkyl linker. In certain embodiments, L 2 is an arbitrarily substituted C 1-20 It is an alkyl linker. In certain embodiments, L 2 is an optionally substituted C8 alkyl linker. In certain embodiments, L 3 This is an arbitrarily substituted heteroaryl linker.

[0116] In a particular embodiment, L 3 This is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

[0117] In a particular embodiment, L 3 teeth, [ka] It includes the structure.

[0118] In a particular embodiment, L 4 This is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =O substituents.

[0119] In certain embodiments, the heteroalkyl linker contains two integral substituents to form an optionally substituted carbocyclyl ring.

[0120] In a particular embodiment, L 4 teeth, [ka] The formula includes the structure of either or a salt thereof, where X is O or S.

[0121] In a particular embodiment, L 4 teeth, [ka] The formula includes the structure of either or a salt thereof, where X is O or S.

[0122] In a particular embodiment, L 1 -L 2 -L 3 -L 4 teeth, [ka] [ka] [ka] [ka] The formula includes the structure of either or a salt thereof, where X is O or S.

[0123] In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0124] In certain embodiments, the CB1 ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0125] In a particular embodiment, the modified oligonucleotide α4β 1 / 7 The integrin ligand is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0126] In certain embodiments, the NMDA ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0127] In certain embodiments, the compound of any of the prior embodiments contains a lipid. In certain embodiments, the lipid is bound to the nucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide contains one or more lipids. In certain embodiments, the one or more lipids are bound to one or more nucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or sense oligonucleotide.

[0128] In certain embodiments, the compound of any of the prior embodiments comprises one or more substituted or unsubstituted alkyl or alkenyls. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl is bonded to an internucleoside bond of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyls. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl is bonded to one or more internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or sense oligonucleotide.

[0129] In certain embodiments, the substituted or unsubstituted alkyl or alkenyl is saturated or unsaturated C 4- C 30 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C5-C 20 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 14- C 20 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 16Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 17 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 18 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 22 Contains hydrocarbon chains.

[0130] In certain embodiments, a substituted or unsubstituted alkyl or alkenyl is bonded to an internucleoside bond of a modified oligonucleotide (e.g., a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the internucleoside bond is between nucleosides within 10 positions (e.g., within 8, 6, 5, 4, 3, 2) from the terminal end (e.g., 5' and / or 3') of the modified oligonucleotide. In certain embodiments, the internucleoside bond is between nucleosides within 5 positions from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside bond is between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

[0131] In certain embodiments, the nucleoside linkage is between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside linkage is between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside linkage is between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

[0132] In certain embodiments, the nucleoside bonds of the modified oligonucleotide are selected from one of the formulas XXI-XXIV and XXXIII-XXXV.

[0133] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXI), or its salt, solvate, or hydrate: [ka] During the ceremony, Y is -C(=O)N(R C )- or -N(R C )C(=O)-, Q 1 and Q 3 These are independent of each other: -H, -OR4 , ligand, linker or lipid, Q 2 and Q 4 Each is independent, and combined, [ka] It is a ligand, linker, or lipid. R C These are independently -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Each R 2 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 6 , -N(R 6 ), or -SR 6 And, Each R 3 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 7 , -N(R 7 ), or -SR 7 And, R 4 and R 5 Whether they are independently oligonucleotides or R 4 and R 5 However, they combine to form a single oligonucleotide, Each R 6 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 7 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 8 These are independently substituted or unsubstituted heteroaryl compounds. Each R 9 These are independently substituted or unsubstituted heteroaryl compounds. Z 1 or Z 2 Each example is independent, combined, C 1- It is a C6 alkylene or a C2-C6 alkenylene. Each X is independently either O or S. Formula (XXI), or its salts, solvates, or hydrates, or salts thereof.

[0134] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXII), or its salt, solvate, or hydrate: [ka] During the ceremony, R C However, it is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, Each R 2 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 6 , -N(R 6 ), or -SR 6 And, Each R 3 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 7 , -N(R 7 ), or -SR 7 And, R 4 and R 5 Whether they are independently oligonucleotides or R 4 and R 5 However, they combine to form a single oligonucleotide, Each R 6 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 7These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 8 These are independently substituted or unsubstituted heteroaryl rings, Each R 9 These are independently substituted or unsubstituted heteroaryl rings, Each X is independently either O or S. Formula (XXII), or its salts, solvates or hydrates, or salts or prodrugs thereof.

[0135] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXIII), or its salt, solvate, or hydrate: [ka] During the ceremony, Each R 2 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 6 , -N(R 6 ), or -SR 6 And, Each R 3 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 7 , -N(R 7 ), or -SR 7 And, R 4 and R 5 Whether they are independently oligonucleotides or R 4 and R 5 However, they combine to form a single oligonucleotide, Each R 6 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 7 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 8 These are independently substituted or unsubstituted heteroaryl rings, Each R 9 These are independently substituted or unsubstituted heteroaryl rings, Each X is independently either O or S. Formula (XXIII), or its salts, solvates or hydrates, or salts or prodrugs thereof.

[0136] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXIV), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4 and R 5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0137] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXXIII), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4 and R 5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0138] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXXIV), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4 and R 5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0139] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXXV), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4 and R 5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0140] In certain embodiments, the compound of any of the prior embodiments includes a 5'-phosphonate modification. For example, in certain embodiments, the modified oligonucleotide includes one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide includes a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide includes a 5'-terminal nucleoside (e.g., the 5' end) containing the 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylenephosphonate modification. In certain embodiments, the modified oligonucleotide is a first modified oligonucleotide or an antisense oligonucleotide.

[0141] A particular embodiment provides a compound comprising a first modified oligonucleotide containing a 5'-phosphonate modification (the first modified oligonucleotide being at least 80% complementary to the region of SEQ ID NO: 1 or 2) and a second modified oligonucleotide containing one or more ligands.

[0142] In some embodiments, the first modified oligonucleotide comprises a 5'-terminal nucleoside with a 5'-phosphonate modification. In some embodiments, the 5'-phosphonate modification is either a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-ethylenephosphonate modification.

[0143] In some embodiments, the second modified oligonucleotide comprises one or more TrkB ligands, one or more CB1 ligands, and one or more α4β ligands. 1 / 7 It comprises an integrin ligand and one or more ligands selected from one or more NMDA ligands. In some embodiments, it comprises one or more TrkB ligands, one or more CB1 ligands, and one or more α4β ligands. 1 / 7 The integrin ligand, or one or more NMDA ligands, are bound to the 5' end of the second modified oligonucleotide. In some embodiments, one or more TrkB ligands, one or more CB1 ligands, and one or more α4β ligands are also present. 1 / 7 An integrin ligand, or one or more NMDA ligands, is bound to the 3' end of its second modified oligonucleotide. In some embodiments, it is bound to one or more TrkB ligands, one or more CB1 ligands, and one or more α4β ligands. 1 / 7The integrin ligand, or one or more NMDA ligands, are bound to the 5' and 3' ends of the second modified oligonucleotide. In some embodiments, one or more TrkB ligands are selected from one of formulas I-XX, XXV, and XXX, one or more CB1 ligands are of formula XXVI, and one or more α4β 1 / 7 The integrin ligand is selected from one of the following formulas: XXVII, XXVIII, XXXI, and XXXII, and one or more of its NMDA ligands are of formula XXIX.

[0144] In some embodiments, the second modified oligonucleotide comprises one or more TrkB ligands. In some embodiments, the one or more TrkB ligands are selected from one of the formulas I-XX, XXV, and XXX. In some embodiments, the second modified oligonucleotide comprises one TrkB ligand. In some embodiments, the second modified oligonucleotide comprises two TrkB ligands. In some embodiments, the second modified oligonucleotide comprises at least two TrkB ligands. In some embodiments, at least two of the TrkB ligands are the same. In some embodiments, at least two of the TrkB ligands are different.

[0145] In some embodiments, the second modified oligonucleotide comprises one or more CB1 ligands. In some embodiments, the one or more CB1 ligands are of formula XXVI. In some embodiments, the second modified oligonucleotide comprises one CB1 ligand. In some embodiments, the second modified oligonucleotide comprises two CB1 ligands. In some embodiments, the second modified oligonucleotide comprises at least two CB1 ligands. In some embodiments, the at least two CB1 ligands are the same. In some embodiments, the at least two CB1 ligands are different.

[0146] In some embodiments, the second modified oligonucleotide is one or more α4β 1 / 7 It contains an integrin ligand. In some embodiments, one or more of these α4β ligands. 1 / 7 The integrin ligand is selected from one of the formulas XXVII, XXVIII, XXXI, and XXXII. In some embodiments, the second modified oligonucleotide is one α4β 1 / 7 It contains an integrin ligand. In some embodiments, the second modified oligonucleotide is two α4β 1 / 7 It contains an integrin ligand. In some embodiments, the second modified oligonucleotide is at least two α4β 1 / 7 It contains an integrin ligand. In some embodiments, it contains at least two α4β 1 / 7 The integrin ligands are the same. In some embodiments, at least two of them are α4β 1 / 7 The integrin ligands are different.

[0147] In some embodiments, the second modified oligonucleotide comprises one or more NMDA ligands. In some embodiments, the one or more NMDA ligands are of formula XXIX. In some embodiments, the second modified oligonucleotide comprises one NMDA ligand. In some embodiments, the second modified oligonucleotide comprises two NMDA ligands. In some embodiments, the second modified oligonucleotide comprises at least two NMDA ligands. In some embodiments, the at least two NMDA ligands are the same. In some embodiments, the at least two NMDA ligands are different.

[0148] In some embodiments, the second modified oligonucleotide comprises one or more lipids. In some embodiments, the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise saturated or unsaturated C4-C4 groups. 30Contains hydrocarbon chains. In some embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C5-C 20 It contains a hydrocarbon chain. In some embodiments, one or more substituted or unsubstituted alkyl or alkenyl atoms are saturated or unsaturated C 14 -C 20 Contains hydrocarbon chains. In some embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 16 Hydrocarbon chains, saturated or unsaturated carbon 17 Hydrocarbon chains, saturated or unsaturated carbon 18 Hydrocarbon chains, or saturated or unsaturated C 22 Contains hydrocarbon chains.

[0149] In some embodiments, the substituted or unsubstituted alkyl or alkenyl is bonded to the nucleoside bond of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is between nucleosides within 10 positions (e.g., within 8, 6, 5, 4, 3, 2) from the terminal end (e.g., 5' and / or 3') of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is between nucleosides within 5 positions from the 5' end of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is between nucleosides within 5 positions from the 3' end of the second modified oligonucleotide.

[0150] In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 2 and 3 from the 5' end of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 3' end of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 3' end of the second modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 2 and 3 from the 3' end of the second modified oligonucleotide.

[0151] In some embodiments, the nucleoside bond of the second modified oligonucleotide is selected from one of formulas XXI-XXIV and XXXIII-XXXV.

[0152] In some embodiments, the first modified oligonucleotide has a linked nucleoside with a length of 14 to 30. In some embodiments, the second modified oligonucleotide is a nucleoside with a linked nucleoside with a length of 14 to 30 and has a region complementary to the first modified oligonucleotide. In some embodiments, the first modified oligonucleotide has a nucleic acid base sequence containing at least 14 consecutive nucleic acid bases as described in one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In some embodiments, the second modified oligonucleotide has a nucleic acid base sequence containing at least 14 consecutive nucleic acid bases as described in one of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In some embodiments, the first modified oligonucleotide is selected from one of the IA reference numbers in Table 3. In some embodiments, the second modified oligonucleotide is selected from any of the IS reference numbers in Table 3.

[0153] A particular embodiment provides a compound comprising a first modified oligonucleotide selected from the group consisting of any one of the reference numerals listed in Table 3, and a second modified oligonucleotide having a linked nucleoside length of 14 to 21, which is completely complementary to the first modified oligonucleotide.

[0154] A particular embodiment provides a compound comprising a first modified oligonucleotide selected from the group consisting of any one of the IA reference numbers listed in Table 3, and a second modified oligonucleotide selected from the group consisting of any one of the IS reference numbers listed in Table 3.

[0155] In certain embodiments, the pharmaceutically acceptable salts of the modified oligonucleotides provided in this disclosure are sodium salts or potassium salts.

[0156] In certain embodiments, the present disclosure provides a group of modified oligonucleotides in which all phosphorothioate nucleoside bonds are stereorandom. In certain embodiments, the present disclosure provides a group of compounds in which all phosphorothioate nucleoside bonds are stereorandom.

[0157] In certain embodiments, the compound of any of the above embodiments is in a pharmaceutically acceptable salt form. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt.

[0158] A particular embodiment provides a composition comprising the compound described in any one of the above embodiments and a pharmaceutically acceptable carrier.

[0159] A particular embodiment provides a composition comprising a compound from any of the prior embodiments for use in therapy.

[0160] A particular embodiment provides a method for treating, preventing or improving a disease, disorder or condition associated with SOD1 in an individual, comprising administering individual compounds that target SOD1 to treat, prevent or improve the disease.

[0161] In certain embodiments, one of the compounds or compositions of the above embodiments is administered to an individual. In certain embodiments, the disease, disorder, or condition is a CNS-related disease, disorder, or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death).

[0162] In certain embodiments, administration of the compound inhibits, reduces, or improves CNS-related diseases, disorders, or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, including loss of motor function or neuronal death).

[0163] In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to an individual in a therapeutically effective dose. In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to an individual at a dose level sufficient to deliver about 1 to 100 mg per kg of body weight of the individual. In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to an individual at a constant dose of about 25 mg to about 1,000 mg. In certain embodiments, the compound or composition is administered to the individual at a maximum dose level or constant dose once or twice a day.

[0164] In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to the individual once daily, once weekly, once monthly, once quarterly, or once a year. In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to the individual about once quarterly (i.e., about once every three months) to about once a year. In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to the individual about once quarterly, about once every six months, or about once a year.

[0165] A particular embodiment provides a method for inhibiting SOD1 expression in a cell, comprising contacting the cell with a compound that targets SOD1 to inhibit SOD1 expression in that cell. In a particular embodiment, the cell is located in the liver of an individual. In a particular embodiment, the individual has or is at risk of having a CNS-related disease, disorder or condition, or symptoms thereof, or a neurodegenerative disease or symptoms thereof (such as ALS or symptoms thereof, e.g., loss of motor function or neuronal death).

[0166] A particular embodiment provides a method for mitigating or inhibiting a CNS-related disease, disorder or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in an individual, comprising administering a compound targeting SOD1 to the individual to mitigate or inhibit the CNS-related disease, disorder or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in the individual. In a particular embodiment, the individual has or is at risk of having a CNS-related disease, disorder or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In a particular embodiment, the compound is a compound targeting SOD1. In a particular embodiment, the compound is one of the above compounds. In a particular embodiment, the compound or composition is administered parenterally. In a particular embodiment, the compound or composition is administered intrathecally (IT).

[0167] Certain embodiments provide the use of compounds targeting SOD1 for the treatment, prevention, or improvement of diseases, disorders, or conditions associated with SOD1. In certain embodiments, the disease, disorder, or condition is a CNS-related disease, disorder, or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In certain embodiments, the compound is a compound targeting SOD1. In certain embodiments, the compound is any of the above compounds.

[0168] A particular embodiment provides the use of a compound that targets SOD1 in the manufacture of a pharmaceutical product for treating, preventing or improving a disease, disorder, or condition associated with SOD1. In a particular embodiment, the disease, disorder, or condition is a CNS-related disease, disorder, or condition, or a symptom thereof, or a neurodegenerative disease or a symptom thereof (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In a particular embodiment, the compound is a compound that targets SOD1. In a particular embodiment, the compound is any of the above compounds.

[0169] Specific adaptations In certain embodiments, the disclosure relates to a method for inhibiting SOD1 expression, which may be useful in treating, preventing or improving SOD1-related diseases in an individual by administration of a compound targeting SOD1. In certain embodiments, the compound may be a SOD1-specific inhibitor. In certain embodiments, the compound may be an antisense oligonucleotide, oligomeric compound, or oligonucleotide targeting SOD1.

[0170] In certain embodiments, this disclosure relates to the treatment, prevention, or improvement of diseases, disorders, or conditions associated with SOD1. In certain embodiments, diseases, disorders, or conditions associated with SOD1 that are treatable, preventable, and / or improveable by the methods provided in this disclosure include CNS-related diseases, disorders, or conditions, or their symptoms, or neurodegenerative diseases or their symptoms, such as ALS or its symptoms, e.g., loss of motor function or neuronal death. The specific compounds provided in this disclosure are for compounds and compositions that alleviate CNS-related diseases, disorders, or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in animals.

[0171] In certain embodiments, a method for treating, preventing, or improving a disease associated with SOD1 in an individual includes treating, preventing, or improving the disease by administering a compound comprising a SOD1-specific inhibitor to the individual. In certain embodiments, the individual is identified as having or being at risk of having a disease associated with SOD1. In certain embodiments, the disease is a CNS-related disease. In certain embodiments, the compound comprises an antisense oligonucleotide that targets SOD1. In certain embodiments, the compound comprises an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide having a linked nucleoside length of 14-23, and having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded. In certain embodiments, the single-stranded compound may have linked nucleoside lengths of 14-30, 14-23, 14-20, 16-20, or 14-16.In certain embodiments, the single-stranded compound may have linked nucleosides of lengths 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In certain embodiments, the double-stranded compound may include two oligonucleotides of the same or different lengths, as described elsewhere in this specification. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, and at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence comprising the nucleic acid sequence described in any one of SEQ ID NOs: 11 to 223 (e.g., a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23 and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intrathecal (IT) administration.In certain embodiments, administration of the compound improves, maintains, or prevents CNS-related diseases, disorders, or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, including loss of motor function or neuronal death) in animals.

[0172] In certain embodiments, a method for treating, preventing or improving CNS-related diseases, disorders or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in an animal comprises administering to the individual a compound comprising an SOD1-specific inhibitor to treat, prevent or improve CNS-related diseases, disorders or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In certain embodiments, the compound comprises an antisense oligonucleotide that targets SOD1. In certain embodiments, the compound comprises an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide having a linked nucleoside length of 14-23, and having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, or 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, and at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence comprising the nucleic acid sequence described in any one of SEQ ID NOs: 11 to 223 (e.g., a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23 and having a region complementary to the first modified oligonucleotide. In certain embodiments, administration of the compound improves, maintains, or prevents CNS-related diseases, disorders or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in animals. In certain embodiments, the individual is identified as having or being at risk of having a disease associated with SOD1.

[0173] In certain embodiments, a method for inhibiting SOD1 expression in an individual who has or is at risk of having a disease associated with SOD1 includes inhibiting SOD1 expression in that individual by administering a compound comprising a SOD1-specific inhibitor to that individual. In certain embodiments, administration of the compound inhibits SOD1 expression in the liver. In certain embodiments, the disease is a CNS-related disease. In certain embodiments, the individual has or is at risk of having a CNS-related disease, disorder or condition, or symptoms thereof, or a neurodegenerative disease or symptoms thereof (such as ALS or symptoms thereof, e.g., loss of motor function or neuronal death). In certain embodiments, the compound comprises an antisense oligonucleotide that targets SOD1. In certain embodiments, the compound comprises an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide having a linked nucleoside length of 14-23, and having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, and at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence comprising the nucleic acid sequence described in any one of SEQ ID NOs: 11 to 223 (e.g., a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23 and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intrathecal (IT) administration. In certain embodiments, administration of the compound improves, maintains, or prevents CNS-related diseases, disorders, or conditions, or their symptoms, neurodegenerative diseases or their symptoms (such as ALS or its symptoms, including loss of motor function or neuronal death).

[0174] In certain embodiments, a method for inhibiting SOD1 expression in cells includes inhibiting SOD1 expression in those cells by contacting the cells with a compound comprising a SOD1-specific inhibitor. In certain embodiments, the cells are hepatocytes. In certain embodiments, the cells are located in the liver. In certain embodiments, the cells are located in the liver of an individual who has or is at risk of CNS-related disease, disorder or condition, or symptoms thereof, or neurodegenerative disease or symptoms thereof (such as ALS or symptoms thereof, e.g., loss of motor function or neuronal death). In certain embodiments, the compound comprises an antisense oligonucleotide that targets SOD1. In certain embodiments, the compound comprises an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide having a linked nucleoside length of 14-23, and having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, and at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising the nucleic acid base sequence described in any one of SEQ ID NOs: 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23, and having a region complementary to the first modified oligonucleotide.

[0175] In certain embodiments, a method for mitigating or inhibiting a CNS-related disease, disorder or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in an individual who has or is at risk of having a SOD1-related disease includes administering a compound comprising a SOD1-specific inhibitor to mitigate or inhibit the CNS-related disease, disorder or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death) in that individual. In certain embodiments, the individual has or is at risk of having a CNS-related disease, disorder or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In certain embodiments, the compound comprises an antisense oligonucleotide that targets SOD1. In certain embodiments, the compound comprises an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide having a linked nucleoside length of 14-23, and having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23).In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases described in any of the nucleic acid base sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, or 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded.In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence comprising the nucleic acid sequence described in any one of SEQ ID NOs: 11 to 223 (e.g., a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23 and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intrathecal (IT) administration. In certain embodiments, the individual is identified as having or being at risk of having a disease associated with SOD1.

[0176] Certain embodiments relate to compounds comprising SOD1-specific inhibitors for use in the treatment of diseases, disorders, or conditions associated with SOD1. In certain embodiments, the disease, disorder, or condition is a CNS-related disease, disorder, or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In certain embodiments, the compound comprises an antisense oligonucleotide that targets SOD1. In certain embodiments, the compound comprises an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide having a linked nucleoside length of 14-23, and having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, or 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, and at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence comprising the nucleic acid sequence described in any one of SEQ ID NOs: 11 to 223 (e.g., a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23) and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (e.g., a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23). In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23 and having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to the individual parenterally. In certain embodiments, the compound is administered to the individual by intrathecal (IT) administration.

[0177] Specific embodiments include compounds comprising SOD1-specific inhibitors for use in reducing or inhibiting CNS-related diseases, disorders or conditions, or their symptoms, or neurodegenerative diseases or their symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In specific embodiments, the compound comprises an antisense oligonucleotide targeting SOD1. In specific embodiments, the compound comprises an oligonucleotide targeting SOD1. In specific embodiments, the compound comprises a modified oligonucleotide having a nucleic acid sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence comprising a nucleic acid base sequence described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a nucleic acid base sequence of 14-30, e.g., 14-23, of linked nucleosides). In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, and at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising the nucleic acid base sequence described in any one of SEQ ID NOs: 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23, and having a region complementary to the first modified oligonucleotide.

[0178] A particular embodiment relates to the use of a compound comprising a SOD1-specific inhibitor in the manufacture or preparation of a pharmaceutical for the treatment of a disease associated with SOD1. A particular embodiment relates to the use of a compound comprising a SOD1-specific inhibitor in the preparation of a pharmaceutical for the treatment of a disease, disorder, or condition associated with SOD1. In a particular embodiment, the disease, disorder, or condition is a CNS-related disease, disorder, or condition, or a symptom thereof. In a particular embodiment, the disease, disorder, or condition is a neurodegenerative disease or a symptom thereof (such as ALS or a symptom thereof, e.g., loss of motor function or neuronal death). In a particular embodiment, the compound comprises an antisense oligonucleotide that targets SOD1. In a particular embodiment, the compound comprises an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide having a linked nucleoside length of 14-23, and having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, or 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded. In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound.In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, and at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising the nucleic acid base sequence described in any one of SEQ ID NOs: 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23, and having a region complementary to the first modified oligonucleotide.

[0179] A particular embodiment relates to the use of a compound containing a SOD1-specific inhibitor in the manufacture or preparation of a pharmaceutical for reducing or inhibiting a CNS-related disease, disorder, or condition, or its symptoms (associated with SOD1), in an individual who has or is at risk of such a disease. In a particular embodiment, the CNS-related disease, disorder, or condition is a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). A particular embodiment relates to the use of a compound containing a SOD1-specific inhibitor in the preparation of a pharmaceutical for treating a disease, disorder, or condition associated with SOD1. In a particular embodiment, the disease, disorder, or condition is a CNS-related disease, disorder, or condition, or its symptoms, or a neurodegenerative disease or its symptoms (such as ALS or its symptoms, e.g., loss of motor function or neuronal death). In a particular embodiment, the compound contains an antisense oligonucleotide that targets SOD1. In a particular embodiment, the compound contains an oligonucleotide that targets SOD1. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound is a modified oligonucleotide having a nucleic acid base sequence comprising a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide having a nucleic acid base sequence of 14-30, e.g., 14-23, of linked nucleosides).In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences described in any one of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases described in any of the nucleic acid base sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). In certain embodiments, the compound includes a modified oligonucleotide having a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213 (for example, a modified oligonucleotide with a linked nucleoside length of 14-30, e.g., 14-23). ​​In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound includes a modified oligonucleotide selected from the group consisting of nucleic acid base sequences of SEQ ID NOs. 19-27, 107-183, 188-195, and 203-213. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223, and a second modified oligonucleotide having a nucleic acid sequence selected from the group consisting of the nucleic acid sequences of SEQ ID NOs: 19-27, 107-183, 188-195, and 203-213. In any of the above embodiments, the compound may be single-stranded or double-stranded.In any of the above embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223 (for example, a first modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide with a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence comprising the nucleic acid base sequence described in any one of SEQ ID NOs: 11 to 223 (for example, a first modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23), and a second modified oligonucleotide having a region complementary to the first modified oligonucleotide (for example, a second modified oligonucleotide having a linked nucleoside length of 14 to 30, e.g., 14 to 23). In a particular embodiment, the compound comprises a first modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23, and having a region complementary to the first modified oligonucleotide.

[0180] In any of the above methods or uses, the compound may be an oligomeric compound. In any of the above methods or uses, the compound may be single-stranded or double-stranded. In any of the above methods or uses, the compound may target SOD1. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a linked nucleoside length of 8 to 80, 10 to 30, 14 to 30, 14 to 23, or 19 to 23. In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the nucleic acid sequence shown in Sequence ID No. 1 over its length. In certain embodiments, the modified oligonucleotide comprises at least one modified nucleoside linkage, at least one modified sugar, and / or at least one modified nucleic acid base. In certain embodiments, the modified nucleoside linkage is a phosphorothioate nucleoside linkage. In certain embodiments, the modified sugar is a bicyclic sugar, 2'-MOE, 2'-F, or 2'-OMe. In certain embodiments, the modified nucleic acid base is 5-methylcytosine. In any of the above embodiments, each modified oligonucleotide independently has a linked nucleoside length of 12-30, 14-30, 14-25, 14-24, 14-23, 16-23, 17-23, 18-23, 19-23, 19-22, or 19-20. In certain embodiments, the modified oligonucleotide has at least one, at least two, or at least three mismatches with the region of SEQ ID NO: 1 or 2.

[0181] In any of the above methods or uses, the compound comprises a first and a second modified oligonucleotide, with a complementary region between the first and second modified oligonucleotides. In certain embodiments, the complementary region between the first and second oligonucleotides is such that the length of the linked nucleosides is 14–23, 19–23, or 21–23. In certain embodiments, the first modified oligonucleotide is perfectly complementary to the second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide comprises at least one modification selected from modified nucleoside bonds, modified sugars, and modified nucleic acid bases. In certain embodiments, the second modified oligonucleotide comprises at least one modification selected from the group consisting of modified nucleoside bonds, modified sugars, and modified nucleic acid bases. In certain embodiments, the modified nucleoside bond is a phosphorothioate nucleoside bond or a methylphosphonate nucleoside bond. In certain embodiments, the inter-nucleoside bond of the modified oligonucleotide is located at the 3' end of the first or second modified oligonucleotide, or at the 5' end of the first or second modified oligonucleotide. In certain embodiments, the first or second modified oligonucleotide contains one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide contains a modified sugar. In certain embodiments, the modified sugar includes modifications selected from the group consisting of halogens, alkoxy groups, and bicyclic sugars. In certain embodiments, the modified sugar includes modifications selected from the group consisting of 2'-MOE, 2'-F, and 2'-OMe, or combinations thereof. In certain embodiments, the first or second modified oligonucleotide contains 10 or fewer 2'-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide contains 5 or fewer 2'-F sugar modifications.

[0182] In any of the above methods or uses, the compound comprises a conjugate group. In certain embodiments, the conjugate group is bonded to the 5' end of the modified oligonucleotide. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more TrkB ligands. In certain embodiments, the one or more TrkB ligands are bonded to the 5' end or 3' end of the oligonucleotide, or to both the 5' end and 3' end of the oligonucleotide. In certain embodiments, the TrkB ligand is selected from formulas I-XX, XXV, and XXX, or their salts, solvates, or hydrates, where R is the modified oligonucleotide of the present invention. In certain embodiments, the modified oligonucleotide is bonded to the TrkB ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is bonded to the TrkB ligand via a phosphorothioate group. In certain embodiments, the targeting moiety comprises one or more CB1 ligands. In certain embodiments, one or more CB1 ligands are bound to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, the CB1 ligand is selected from formula XXVI, or a salt, solvate, or hydrate thereof, where R is the modified oligonucleotide of the present invention. In certain embodiments, the modified oligonucleotide is bound to the CB1 ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is bound to the CB1 ligand via a phosphorothioate group. In certain embodiments, the targeting moiety is one or more α4β 1 / 7 Contains an integrin ligand. In certain embodiments, one or more α4β 1 / 7 The integrin ligand is bound to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, its α4β 1 / 7The integrin ligand is selected from formulas XXVII, XXVIII, XXXI, and XXXII, or their salts, solvates, or hydrates, where R is the modified oligonucleotide of the present invention. In certain embodiments, the modified oligonucleotide is its α4β 1 / 7 It is bound to the integrin ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is its α4β 1 / 7 The integrin ligand is conjugated via a phosphorothioate group. In certain embodiments, the targeting moiety comprises one or more NMDA ligands. In certain embodiments, the one or more NMDA ligands are conjugated to the 5' or 3' end of the oligonucleotide, or to both the 5' and 3' ends of the oligonucleotide. In certain embodiments, the NMDA ligand is of formula XXIX, or a salt, solvate, or hydrate thereof, where R is the modified oligonucleotide of the present invention. In certain embodiments, the modified oligonucleotide is conjugated to the NMDA ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is conjugated to the NMDA ligand via a phosphorothioate group. In certain embodiments, the conjugate group comprises one or more lipids. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide of the present invention. In certain embodiments, the one or more lipids are conjugated to the nucleoside bond of the modified oligonucleotide. In certain embodiments, the nucleoside-to-nucleoside bond of the modified oligonucleotide is selected from one of formulas XXI-XXIV and XXXIII-XXXV, or a salt, solvate, or hydrate thereof, where R is the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more TrkB ligands and one or more lipids. In certain embodiments, the modified oligonucleotide comprises one or more CB1 ligands and one or more lipids. In certain embodiments, the modified oligonucleotide comprises one or more α4β 1 / 7It comprises an integrin ligand and one or more lipids. In certain embodiments, the modified oligonucleotide comprises one or more NMDA ligands and one or more lipids. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide of the present invention. In certain embodiments, one or more TrkB ligands are bound to the 5' end of the modified oligonucleotide. In certain embodiments, one or more TrkB ligands are bound to the 3' end of the modified oligonucleotide. In certain embodiments, one or more TrkB ligands are bound to both the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more lipids are bound to the nucleoside bonds of the modified oligonucleotide. In certain embodiments, one or more TrkB ligands are selected from any one of formulas I-XX, XXV, and XXX, or their salts, solvates, or hydrates, where R is the modified oligonucleotide of the present invention, and the nucleoside linkage of the modified oligonucleotide is selected from any one of formulas XXI-XXIV and XXXIII-XXXV, or their salts, solvates, or hydrates, where R is the modified oligonucleotide of the present invention. In certain embodiments, one or more CB1 ligands are bound to the 5' end of the modified oligonucleotide. In certain embodiments, one or more CB1 ligands are bound to the 3' end of the modified oligonucleotide. In certain embodiments, one or more CB1 ligands are bound to the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more lipids are bound to the nucleoside linkage of the modified oligonucleotide. In certain embodiments, one or more CB1 ligands are of formula XXVI, or a salt, solvate, or hydrate thereof, where R is a modified oligonucleotide of the present invention, and the nucleoside bond of the modified oligonucleotide is selected from any one of formulas XXI-XXIV and XXXIII-XXXV, or a salt, solvate, or hydrate thereof, where R is a modified oligonucleotide of the present invention. In certain embodiments, one or more α4β 1 / 7The integrin ligand is bound to the 5' end of its modified oligonucleotide. In certain embodiments, one or more α4β 1 / 7 The integrin ligand is bound to the 3' end of its modified oligonucleotide. In certain embodiments, one or more α4β 1 / 7 The integrin ligand is bound to the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more lipids are bound to the nucleoside bonds of the modified oligonucleotide. In certain embodiments, one or more α4β 1 / 7 The integrin ligand is selected from one of formulas XXVII, XXVIII, XXXI, and XXXII, or a salt, solvate, or hydrate thereof, where R is the modified oligonucleotide of the present invention, and the nucleoside bond of the modified oligonucleotide is selected from one of formulas XXI-XXIV and XXXIII-XXXV, or a salt, solvate, or hydrate thereof, where R is the modified oligonucleotide of the present invention. In certain embodiments, one or more NMDA ligands are bound to the 5' end of the modified oligonucleotide. In certain embodiments, one or more NMDA ligands are bound to the 3' end of the modified oligonucleotide. In certain embodiments, one or more NMDA ligands are bound to the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more lipids are bound to the nucleoside bond of the modified oligonucleotide. In certain embodiments, one or more NMDA ligands are of formula XXIX, or a salt, solvate, or hydrate thereof, where R is a modified oligonucleotide of the present invention, and the nucleoside linkage of the modified oligonucleotide is selected from any one of formulas XXI-XXIV and XXXIII-XXXV, or a salt, solvate, or hydrate thereof, where R is a modified oligonucleotide of the present invention.

[0183] In any of the above methods or uses, in certain embodiments, the compound comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl groups are bonded to the internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl groups are bonded to one or more internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or sense oligonucleotide. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C1 4- C 30 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C5-C 20 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 14- C 20 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 16 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 17 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 18 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 22 Contains hydrocarbon chains.

[0184] In certain embodiments, a substituted or unsubstituted alkyl or alkenyl is bonded to an internucleoside bond of a modified oligonucleotide (e.g., a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the internucleoside bond is between nucleosides within 10 positions (e.g., within 8, 6, 5, 4, 3, 2) from the terminal end (e.g., 5' and / or 3') of the modified oligonucleotide. In certain embodiments, the internucleoside bond is between nucleosides within 5 positions from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside bond is between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

[0185] In certain embodiments, the nucleoside linkage is between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside linkage is between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside linkage is between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

[0186] In certain embodiments, the nucleoside bonds of the modified oligonucleotide are selected from one of the formulas XXI-XXIV and XXXIII-XXXV.

[0187] In any of the above methods or uses, in certain embodiments, the compound comprises a 5'-phosphonate modification. For example, in certain embodiments, the modified oligonucleotide comprises one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., 5' end) containing the 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylenephosphonate modification. In certain embodiments, the modified oligonucleotide is a first modified oligonucleotide or an antisense oligonucleotide.

[0188] In any of the above methods or uses, the compound comprises a first modified oligonucleotide selected from the group consisting of any one of the IA reference numbers in Table 3, and a second modified oligonucleotide having a linked nucleoside length of 14 to 23, which is completely complementary to the first modified oligonucleotide. In a particular embodiment, the compound comprises a first modified oligonucleotide selected from any one of the IA reference numbers in Table 3, and a second modified oligonucleotide selected from any one of the IS reference numbers in Table 3. In a particular embodiment, the compound is in a pharmaceutically acceptable salt form. In a particular embodiment, the pharmaceutically acceptable salt is a sodium salt. In a particular embodiment, the pharmaceutically acceptable salt is a potassium salt. In a particular embodiment, the composition comprises the compound described in any one of the above embodiments and a pharmaceutically acceptable carrier.

[0189] In any of the above methods or uses, the compound of any of the prior embodiments or a composition containing that compound is administered to an individual in a therapeutically effective dose. In certain embodiments, the compound of any of the prior embodiments or a composition containing that compound is administered to an individual at a dose level sufficient to deliver about 1 to 100 mg per kg of the individual's body weight. In certain embodiments, the compound of any of the prior embodiments or a composition containing that compound is administered to an individual at a constant dose of about 25 mg to about 1,000 mg. In certain embodiments, the composition is administered to the individual at a maximum dose level or constant dose once or twice a day.

[0190] In any of the above methods or uses, the compound of any prior embodiment or a composition containing that compound is administered to the individual once daily, once weekly, once monthly, once quarterly, or once a year. In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to the individual about once quarterly (i.e., about once every three months) to about once a year. In certain embodiments, the compound of any prior embodiment or a composition containing that compound is administered to the individual about once quarterly, about once every six months, or about once a year.

[0191] Specific compounds In certain embodiments, the disclosure relates to compounds comprising or consisting of oligomeric compounds. In certain embodiments, the oligomeric compound comprises a nucleic acid base sequence complementary to the nucleic acid base sequence of a target nucleic acid.

[0192] In certain embodiments, the disclosure relates to compounds comprising or consisting of modified oligonucleotides. In certain embodiments, the modified oligonucleotide has a nucleic acid base sequence complementary to the nucleic acid base sequence of a target nucleic acid.

[0193] In certain embodiments, the disclosure relates to compounds comprising or consisting of antisense oligonucleotides. In certain embodiments, the antisense oligonucleotide has a nucleic acid base sequence complementary to the nucleic acid base sequence of a target nucleic acid.

[0194] In certain embodiments, the disclosure relates to compounds that are single-chain compounds. In certain embodiments, the single-chain compound comprises or consists of an oligomeric compound. In certain embodiments, such an oligomeric compound comprises or consists of an oligonucleotide and an optional conjugate group. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, the oligonucleotide or modified oligonucleotide of the single-chain compound comprises a self-complementary nucleic acid base sequence.

[0195] In certain embodiments, the disclosure relates to a compound that is a double-stranded compound. In certain embodiments, the double-stranded compound comprises or consists of an oligomeric compound. In certain embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In certain embodiments, the first oligonucleotide has a region complementary to the target nucleic acid, and the second oligonucleotide has a region complementary to the first modified oligonucleotide. In certain embodiments, the double-stranded compound comprises a modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a region complementary to the target nucleic acid. In certain embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the first modified oligonucleotide has a region complementary to the target nucleic acid, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide. In certain embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound is an RNA oligonucleotide. In such embodiments, the thymine nucleic acid base in the modified oligonucleotide is replaced by a uracil nucleic acid base.

[0196] In certain embodiments, the compounds described herein include a conjugate group. In certain embodiments, the first oligonucleotide or first modified oligonucleotide of the double-stranded compound includes a conjugate group. In certain embodiments, the second oligonucleotide or second modified oligonucleotide of the double-stranded compound includes a conjugate group. In certain embodiments, the first oligonucleotide or first modified oligonucleotide and the second oligonucleotide or second modified oligonucleotide of the double-stranded compound each include a conjugate group.

[0197] In certain embodiments, the compound has a linked nucleoside length of 14 to 30. In certain embodiments, the first oligonucleotide or first modified oligonucleotide of the double-stranded compound has a linked nucleoside length of 14 to 30. In certain embodiments, the second oligonucleotide or second modified oligonucleotide has a linked nucleoside length of 14 to 30. In certain embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound has a blunt end at one or both ends of the compound. In certain embodiments, the oligonucleotide or modified oligonucleotide of the double-stranded compound contains a non-complementary overhang nucleoside at one or both ends of the compound.

[0198] In certain embodiments, the compound has a nucleic acid base sequence comprising at least 14 consecutive nucleic acid bases as described in any of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of the double-stranded compound has a nucleic acid base sequence comprising at least 14 consecutive nucleic acid bases as described in any of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.

[0199] Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, oligonucleotides targeting microRNAs, occupation-based compounds (e.g., compounds that block mRNA processing or translation, and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNA (shRNA), single-stranded siRNA (ssRNA), and microRNA mimetic compounds).

[0200] In certain embodiments, the compounds described herein have a nucleic acid base sequence that, when written in the 5'→3' direction, includes the reverse complement of the target region of the target nucleic acid targeted by the compound.

[0201] In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 12 to 30. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 12 to 23. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 14 to 30. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 14 to 23. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 15 to 30. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 15 to 23. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 16 to 30. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 16 to 23. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 17 to 30. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 17 to 23. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 18 to 30. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 18 to 23. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 19 to 30. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 19 to 23.In other words, each of these oligonucleotides has 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits, or 19 to 23 linked subunits. In certain embodiments, the compounds described herein include oligonucleotides with a linked subunit length of 14. In certain embodiments, the compounds described herein include oligonucleotides with a linked subunit length of 16. In certain embodiments, the compounds described herein include oligonucleotides with a linked subunit length of 17. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 18. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 19. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 20. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 21. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 22. In certain embodiments, the compounds described herein include oligonucleotides having a linked subunit length of 23.In other embodiments, the compounds described herein include oligonucleotides having 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 23, 18 to 24, 18 to 25, 18 to 50, 19 to 23, 19 to 30, 19 to 50, 20 to 23, or 20 to 30 linked subunits. In certain such embodiments, the compounds described herein include oligonucleotides in which the length of the linked subunits is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, or within a range defined by any two of the above values.

[0202] In certain embodiments, the compound may further comprise additional parts, such as a conjugate group or a delivery group. In certain embodiments, such a compound is an oligomeric compound, and its additional part is bonded to an oligonucleotide. In certain embodiments, the conjugate group is bonded to a nucleoside of the oligonucleotide.

[0203] In certain embodiments, the compound may be in a truncated or truncated form. For example, one or more subunits may be deleted from the 5' end of the oligonucleotide (5' truncation) or from its 3' end (3' truncation).

[0204] In certain embodiments, the compound may be elongated. For example, one or more subunits may be attached to the 3' or 5' end of the oligonucleotide. In certain embodiments, at least one subunit (for example, 1, 2, 3, 4, 5, 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, or 50 or more subunits) is attached to the 5' end of the oligonucleotide. In certain embodiments, at least one subunit (for example, 1, 2, 3, 4, 5, 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, or 50 or more subunits) is attached to the 3' end of the oligonucleotide. In certain embodiments, at least one subunit may be attached to the 3' or 5' end of the oligonucleotide of the double-stranded compound to create a 3' and / or 5' end overhang. In certain embodiments, at least one subunit (for example, 1, 2, 3, 4, 5, 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, or 50 or more subunits) is attached to the 5' ends of both oligonucleotides of the double-stranded compound.In certain embodiments, at least one subunit (for example, 1, 2, 3, 4, 5, 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, or 50 or more subunits) is attached to the 3' ends of both oligonucleotides of the double-stranded compound. In certain embodiments, the subunit is bound to both oligonucleotides of the double-stranded compound at the same end (for example, the subunit is bound to the 3' end of one oligonucleotide and to the 5' end of the other oligonucleotide). In certain embodiments, when the subunit is bound to both oligonucleotides of the double-stranded compound at the same end, the number of subunits bound to each oligonucleotide may be the same or different. In certain embodiments, when the subunit is bound to both oligonucleotides of the double-stranded compound at the same end, the number of subunits bound to each oligonucleotide is the same. In certain embodiments, when the subunit is bound to both oligonucleotides of the double-stranded compound at the same end, the number of subunits bound to each oligonucleotide is different. This scenario, where the subunit is bound to both oligonucleotides of the double-stranded compound at the same end, may occur at one or both ends of the double-stranded compound. In certain embodiments, the subunits bound to its 3' and / or 5' ends are modified.

[0205] In certain embodiments, the compounds described herein are oligonucleotides. In certain embodiments, the compounds described herein are modified oligonucleotides. In certain embodiments, the compounds described herein are antisense oligonucleotides. In certain embodiments, the compounds described herein are oligomeric compounds. In certain embodiments, the compounds described herein are RNAi compounds. In certain embodiments, the compounds described herein are siRNA compounds.

[0206] In certain embodiments, the compounds described herein may include any of the SOD1-targeting oligonucleotide sequences described herein. In certain embodiments, the compounds may be double-stranded.

[0207] In certain embodiments, the compound comprises an oligonucleotide containing at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleic acid base portions described in any one of SEQ ID NOs. 11-18, 28-106, 184-187, 196-202, or 214-223. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleic acid base portions described in any one of SEQ ID NOs. 19-27, 107-183, 188-195, or 203-213.

[0208] In certain embodiments, the compound comprises a ribonucleotide in which the oligonucleotide has uracil (U) instead of thymine (T) in any of the sequences shown herein. In certain embodiments, the compound comprises a deoxyribonucleotide in which the oligonucleotide has thymine (T) instead of uracil (U) in any of the sequences shown herein.

[0209] Specific mechanism In certain embodiments, the compounds described herein include or consist of modified oligonucleotides. In certain embodiments, the compounds described herein include or consist of antisense oligonucleotides. In certain embodiments, the compounds include or consist of oligomeric compounds. In certain embodiments, the compounds described herein can hybridize to target nucleic acids. In certain embodiments, the compounds described herein selectively affect one or more target nucleic acids. Such compounds include nucleic acid base sequences that hybridize to one or more target nucleic acids, resulting in one or more desired activities, and not hybridizing to one or more non-target nucleic acids, or not hybridizing to one or more non-target nucleic acids in a manner that results in one or more undesirable activities.

[0210] In certain embodiments, when a compound described herein hybridizes to a target nucleic acid, one or more proteins that cause cleavage of the target nucleic acid are recruited. For example, when a particular compound described herein, or a portion thereof, is loaded onto an RNA-induced silencing complex (RISC), the target nucleic acid is ultimately cleaved. For example, a particular compound described herein causes the target nucleic acid to be cleaved by an Argonaut. The compound loaded onto the RISC is an RNAi compound. The RNAi compound may be double-stranded (siRNA) or single-stranded (ssRNA).

[0211] In certain embodiments, when a compound described herein hybridizes to a target nucleic acid, the proteins that cleave the target nucleic acid are not recruited. In certain such embodiments, when the compound hybridizes to a target nucleic acid, the splicing of the target nucleic acid is modified. In certain embodiments, when the compound hybridizes to a target nucleic acid, the binding interactions between the target nucleic acid and proteins or other nucleic acids are inhibited. In certain such embodiments, when the compound hybridizes to a target nucleic acid, RNA processing is modified. In certain such embodiments, when the compound hybridizes to a target nucleic acid, the translation of the target nucleic acid is modified.

[0212] The activity resulting from the compound hybridizing to the target nucleic acid can be observed directly or indirectly. In certain embodiments, observation or detection of activity includes observing or detecting changes in the amount of the target nucleic acid or the protein encoded by such target nucleic acid, changes in the ratio of splice variants of the nucleic acid or protein, and / or changes in phenotype in cells or animals.

[0213] Specific modifications In certain embodiments, the disclosure relates to compounds comprising or consisting of oligonucleotides. Oligonucleotides consist of linked nucleosides. In certain embodiments, the oligonucleotide may be unmodified RNA or DNA, or it may be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide contains at least one modified sugar, modified nucleic acid base, or modified nucleoside bond with respect to the unmodified RNA or DNA. In certain embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may contain a modified sugar, a modified nucleic acid base, or both a modified sugar and a modified nucleic acid base. The modified oligonucleotide may also contain terminal modifications, such as 5'-terminal modifications and 3'-terminal modifications.

[0214] Sugar modification and motifs 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 an alternative sugar. The alternative sugar may contain one or more substitutions described herein.

[0215] 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.

[0216] In certain embodiments, the substituent at the 2' position may include, but is not limited to, F and OCH3 ("OMe", "O-methyl", or "methoxy"). In certain embodiments, the substituent at the 2' position that is suitable 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, ONE2, NO2, N3, and NH2. In certain embodiments, the substituent at the 2' position may include O-(C 1- C 10 Examples include, but are not limited to, 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, and the alkyl, alkenyl and alkynyl are substituted or unsubstituted C1-C 10 Alkyl, or C2-C 10It can be an alkenyl or alkynyl. In certain embodiments, the substituent at the 2' position may be alkaryl, aralkyl, O-alkaryl and O-aralkyl, but is not limited to these. In certain embodiments, these 2' substituents may be further independently substituted 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 substituent at the 2' position may be O[(CH2) n O] m CH3, O(CH2) n OCH3, O(CH2) n CH3, O(CH2) n ONH2, O(CH2) n NH2, O(CH2) n SCH3 and O(CH2) n ON[(CH2) n Examples of substituents at the 2' position include, but are not limited to, OCH2CH2OCH3 ("MOE"), O(CH2)2ON(CH3)2 ("DMAOE"), O(CH2)2O(CH2)2N(CH3)2 ("DMAEOE"), and OCH2C(=O)-N(H)CH3 ("NMA"), but are not limited to these.

[0217] In certain embodiments, the substituent at the 4' position suitable for non-bicyclic modified sugars includes, but is not limited to, alkoxy (e.g., methoxy), alkyl, and groups described in Manoharan et al. WO2015 / 106128. In certain embodiments, the substituent at the 5' position suitable for non-bicyclic modified sugars includes, but is not limited to, methyl ("Me" or "CH3") (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)P O-(HO)(O)POP(HO)(O)-O-5'), 5' adenosine cap (Appp), and either modified or unmodified nucleotide cap structures (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) These include (S)PO-5'), 5'-phosphorothioates ((HO)2(O)PS-5'), any additional combination of monophosphates, diphosphates, and triphosphates in which oxygen is replaced by sulfur (e.g., 5'-alpha-thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 5'-phosphoamidates ((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'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is either a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification. 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 at the terminus of an oligonucleotide. In certain embodiments, the 5' modification is at the terminus of an antisense oligonucleotide. In certain embodiments, the substituents described herein, for their 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'-terminus nucleoside at the 3' position of the sugar, or to the 5' position of the 5'-terminus nucleoside. In certain embodiments, a non-bicyclic modified sugar may contain more than one non-crosslinked sugar substituent. In certain such embodiments, substituents on the non-bicyclic modified sugar include, but are not limited to, 5'-Me-2'-F and 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, substituents on the modified sugar include the groups described in WO2008 / 101157 by Migawa et al. and US2013 / 0203836 by Rajeev et al.

[0218] 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, the 4' and 2' crosslinkable substituents include 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" when in S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 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 Application Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2' (wherein R is H, C is H) 1- C 12Examples include, but are not limited to, alkyl or protecting groups (e.g., U.S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya el 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). The entire contents of each of the above are incorporated herein by reference. Additional representative U.S. patents and U.S. patent application publications teaching the preparation of bicyclic nucleic acid nucleotides include U.S. Patents No. 6,268,490, 6,525,191, 6,670,461, 6,770,748, 6,794,499, 6,998,484, 7,053,207, 7,034,133, 7,084,125, 7,399,845, 7,427,672, and 7 Examples include, but are not limited to, US2008 / 0039618, US2009 / 0012281, US2013 / 0190383, and WO2013 / 036868, the entire contents of which are incorporated herein by reference. Any of the above bicyclic nucleosides having one or more stereochemical sugar configurations (e.g., including α-L-ribofuranose and β-D-ribofuranose) can be prepared (see, for example, WO99 / 14226). Unless otherwise specified, the specific bicyclic nucleoside in this invention has a β-D configuration.

[0219] 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 U.S. Patents No. 4,981,957, No. 5,118,800, No. 5,166,315, No. 5,185,444, No. 5,319,080, No. 5,359,044, No. 5,393,878, No. 5,446,137, No. 5,466,786, No. 5,514,785, No. 5,519,134, No. 5,567,811, No. 5,576,427, No. 5,591,722, and Nos. 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 are examples of, but are not limited to, the overall contents of each of the above are incorporated herein by reference.

[0220] 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 acyclic nucleic acid of unlocked, in which one of the bonds of its sugar is removed to form the "sugar" residue of unlocked. In one example, a UNA also includes a monomer in which the bond between C1' and C4' (i.e., the carbon-oxygen-carbon covalent bond between the C1' and C4' carbons) is removed. In another example, the bond between C2' and C3' of the sugar (i.e., the carbon-carbon covalent bond between the C2' and C3' carbons) is 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 Application Publications 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of these are incorporated herein by reference. In certain embodiments, alternative sugars include peptide nucleic acids ("PNAs"), 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., U.S. 2013 / 130378, the entire contents of these are incorporated herein by reference. Many other bicyclic and tricyclic sugars, as well as cyclic systems of alternative sugars, that can be used with modified nucleosides are known in the art.

[0221] In certain embodiments, the disclosure relates to a compound comprising at least one oligonucleotide, the nucleoside of such oligonucleotide comprising one or more types of modified sugars and / or unmodified sugars arranged along the oligonucleotide or region thereof in a defined pattern, i.e., a “sugar motif”. In certain cases, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0222] In certain embodiments, the oligonucleotide contains a gapmer sugar motif. The gapmer oligonucleotide contains, 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 differ from the majority of the nucleoside sugars in the gap. In certain embodiments, the wing regions contain mostly modified sugars, and the gap contains mostly unmodified sugars. In certain embodiments, the nucleosides in the gap are deoxynucleosides. Compounds having a gapmer sugar motif are described, for example, in U.S. Patent No. 8,790,919, the entire contents of which are incorporated herein by reference.

[0223] In certain embodiments, one or both oligonucleotides of a double-stranded compound contain a triple sugar motif. An oligonucleotide having a triple sugar motif contains three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triple sugar is located at or near the cleavage site of the oligonucleotide. In certain embodiments, an oligonucleotide of a double-stranded compound may contain more than one triple sugar motif. In certain embodiments, the identical sugar modifications of the triple sugar motif are 2'-F modifications. Compounds having triple sugar motifs are disclosed, for example, in U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0224] In certain embodiments, one or both oligonucleotides of a double-stranded compound contain a quadruple sugar motif. An oligonucleotide having a quadruple sugar motif contains four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruple sugar is located at or near its cleavage site. In certain embodiments, an oligonucleotide of a double-stranded compound may contain more than one quadruple sugar motif. In certain embodiments, the identical sugar modifications on the quadruple sugar motif are 2'-F modifications. In double-stranded compounds having a double-stranded region with nucleotide lengths of 19–23, the cleavage sites of the antisense oligonucleotide are typically located around positions 10, 11, and 12 from its 5' end. In certain embodiments, the quadruple sugar motif is located at positions 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14, or 12, 13, 14, 15 of the sense oligonucleotide, counting from the first nucleoside at the 5' end of the sense oligonucleotide, or counting from the first paired nucleotide in the double-stranded region at the 5' end of the sense oligonucleotide. In certain embodiments, the quadruple sugar motif is located at positions 8, 9, 10, 11; 9, 10, 11, 12; 10, 11, 12; 10, 11, 12, 13; 11, 12, 13, 14, or 12, 13, 14, 15 of the antisense oligonucleotide, counting from the first nucleoside at the 5' end of the antisense oligonucleotide, or counting from the first paired nucleotide in the double-stranded region from the 5' end of the antisense oligonucleotide. The cleavage sites may vary depending on the length of the double-stranded region of the double-stranded compound, and the position of the quadruple sugar may change accordingly.

[0225] In certain embodiments, the oligonucleotide contains alternating sugar motifs. In certain embodiments, one or both oligonucleotides of a double-chain compound contain alternating sugar motifs. The oligonucleotide having alternating sugar motifs contains at least two different sugar modifications, wherein one or more consecutive nucleosides containing a first sugar modification are alternated with, for example, 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 the nucleoside, the alternating motifs could be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC...". In certain embodiments, the alternating sugar motif is repeated along an oligonucleotide 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 is composed of two different sugar modifications. In certain embodiments, the alternating sugar motif includes 2'-OMe and 2'-F sugar modifications.

[0226] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided in this disclosure. In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs provided in this disclosure. In certain embodiments, an oligonucleotide containing a sugar motif is fully modified in such a way that each nucleoside other than the nucleoside containing the sugar motif contains a sugar modification.

[0227] Nucleic acid base modification and motifs In certain embodiments, the compounds described herein include modified oligonucleotides. In certain embodiments, the modified oligonucleotide includes one or more nucleosides containing modified nucleic acid bases. In certain embodiments, the modified oligonucleotide includes one or more nucleosides that do not contain nucleic acid bases (referred to as debasalized nucleosides).

[0228] 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). Other modified nucleic acid bases may include bases in which the purine base or pyrimidine base is replaced by another heterocycle, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0229] Further nucleic acid bases can be found in 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, pages 858-859, Kroschwitz, JL, Ed., John Wiley & Sons, 1990, 858-859, Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pages 289-302, Antisense Research and Applications, Crooke, ST and Lebleu, B., Eds., CRC Press, 1993, 273-288, Antisense Drug Technology, Crooke ST, Ed., CRC The bases disclosed in Press, 2008, pp. 163-166 and pp. 442-443 (Chapters 6 and 15) are listed, each incorporated herein by reference.

[0230] Publications teaching the preparation of specific modified nucleic acid bases shown above, as well as other modified nucleic acid bases, include 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, 5,367,066, 5,432,272, and the same. No. 5,434,257, No. 5,457,187, No. 5,459,255, No. 5,484,908, No. 5,502,177, No. 5,525,711, No. 5,552 ,540, 5,587,469, 5,594,121, 5,596,091, 5,614,617, 5,645,985, 5,681,941, No. 5,811,534, No. 5,750,692, No. 5,948,903, No. 5,587,470, No. 5,457,191, No. 5,763,588, No. 5,830 , 653, 5,808,027, 6,005,096, 6,015,886, 6,147,200, 6,166,197, 6,166,199, Nos. 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, among others, are included herein by reference, and the entire contents of each of them are incorporated herein by reference.

[0231] In certain embodiments, the compounds described herein include oligonucleotides. In certain embodiments, the oligonucleotide includes modified and / or unmodified nucleic acid bases arranged along the oligonucleotide or its region in a defined pattern or motif. 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 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 are 5-methylcytosine.

[0232] 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. In certain embodiments, the block is within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is located at the 5' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5' end of the oligonucleotide.

[0233] Modification and motifs of internucleoside bonds The 3'→5' phosphodiester bond is a natural nucleoside bond in RNA and DNA. In certain embodiments, the compounds described herein have one or more modified nucleoside bonds, i.e., unnatural nucleoside bonds. Certain unnatural nucleoside bonds may confer desirable properties, such as enhanced cellular uptake, increased affinity for target nucleic acids, and improved stability in the presence of nucleases. Representative phosphorus-containing modified nucleoside bonds include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative non-phosphorus-containing internucleoside bonds 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 non-phosphorus-containing internucleoside bonds are well known to those skilled in the art. Examples of neutral internucleoside bonds include phosphotriesters, methylphosphonates, and MMI(3'-CH2-N(C Examples of neutral internucleoside bonds include, but are not limited to, H3)-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 examples of neutral internucleoside bonds include nonionic bonds, such as 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 examples of neutral nucleoside bonds include nonionic bonds containing mixed N, O, S, and CH2 component parts.

[0234] In certain embodiments, the compounds provided in this disclosure include at least one modified nucleoside bond. The modified nucleoside bond may be located at any of the oligonucleotide positions. In double-stranded compounds, the modified nucleoside bond may be located within the sense oligonucleotide, the antisense oligonucleotide, or both of the oligonucleotides of the double-stranded compound.

[0235] In certain embodiments, the nucleoside-to-nucleoside modification may occur on all nucleosides of the oligonucleotide. In certain embodiments, the nucleoside-to-nucleoside modification may occur in an alternating pattern along the oligonucleotide. In certain embodiments, each nucleoside-to-nucleoside bond is essentially a phosphate nucleoside bond (P=O). In certain embodiments, each nucleoside-to-nucleoside bond in the modified oligonucleotide is a phosphorothioate (P=S). In certain embodiments, each nucleoside-to-nucleoside bond in the modified oligonucleotide is independently selected from phosphorothioate and phosphate nucleoside bonds. In certain embodiments, the pattern of nucleoside-to-nucleoside modification is the same in each oligonucleotide of the double-stranded compound. In certain embodiments, the pattern of nucleoside-to-nucleoside modification is different in each oligonucleotide of the double-stranded compound. In certain embodiments, the double-stranded compound contains 6 to 8 modified nucleoside bonds. In certain embodiments, the 6 to 8 modified nucleoside bonds are phosphorothioate nucleoside bonds or alkylphosphonate nucleoside bonds. In certain embodiments, the sense oligonucleotide contains at least two modified nucleoside bonds at either or both of its 5' and 3' ends. In certain such embodiments, the modified nucleoside bonds are phosphorothioate nucleoside bonds or alkylphosphonate nucleoside bonds. In certain embodiments, the antisense oligonucleotide contains at least two modified nucleoside bonds at either or both of its 5' and 3' ends. In certain such embodiments, the modified nucleoside bonds are phosphorothioate nucleoside bonds or alkylphosphonate nucleoside bonds.

[0236] In certain embodiments, the double-stranded compound includes an overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or alkylphosphonate nucleoside linkage modification in its overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate nucleotide linkage or alkylphosphonate nucleotide linkage that links its overhang nucleotide to the adjacent paired 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 the adjacent paired nucleoside. These three terminal nucleosides may be at the 3' end of the antisense oligonucleotide, the 3' end of the sense oligonucleotide, the 5' end of the antisense oligonucleotide, or the 5' end of the antisense oligonucleotide.

[0237] In certain embodiments, the modified oligonucleotide contains one or more nucleoside bonds having a chiral center. Typical chiral nucleoside bonds include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides containing nucleoside bonds having a chiral center can be prepared in a specific stereochemical configuration as a group of modified oligonucleotides containing stereorandom nucleoside bonds or as a group of modified oligonucleotides containing phosphorothioate bonds. In certain embodiments, the group of modified oligonucleotides contains phosphorothioate nucleoside bonds, all of which are stereorandom. Such modified oligonucleotides can be produced using a synthetic method that randomly selects the stereochemical configuration of each phosphorothioate bond. As will be well understood by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereochemical configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides containing one or more specific phosphorothioate nucleoside bonds in a specific, independently selected stereochemical configuration. In certain embodiments, the specific configuration of the particular phosphorothioate bond is present in at least 65% of the molecules in the population. In certain embodiments, the specific configuration of the particular phosphorothioate bond is present in at least 70% of the molecules in the population. In certain embodiments, the specific configuration of the particular phosphorothioate bond is present in at least 80% of the molecules in the population. In certain embodiments, the specific configuration of the particular phosphorothioate bond is present in at least 90% of the molecules in the population. In certain embodiments, the specific configuration of the particular phosphorothioate bond is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotides can be produced using synthetic methods known in the art, for example, the methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO2017 / 015555.In certain embodiments, the population of modified oligonucleotides is enriched with respect to modified oligonucleotides having at least one phosphorothioate in the (Sp) conformation. In certain embodiments, the population of modified oligonucleotides is enriched with respect to modified oligonucleotides having at least one phosphorothioate in the (Rp) conformation.

[0238] conjugate group In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and optionally one or more conjugate groups. The conjugate groups may be bonded to either or both ends of the oligonucleotide, and / or to either internal position. In certain embodiments, the conjugate groups are bonded to the 3' end of the oligonucleotide. In certain embodiments, the conjugate groups are bonded to the 5' end of the oligonucleotide. In certain embodiments, the oligonucleotide is covalently bonded to one or more conjugate groups.

[0239] In certain embodiments, the conjugate group is a terminal group bonded to either or both ends of an oligonucleotide. In certain such embodiments, the terminal group is bonded to the 3' end of the oligonucleotide. In certain such embodiments, the terminal group is bonded to the 5' end of the oligonucleotide. In certain embodiments, the terminal group may be, but is not limited to, a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, or two or more independently modified or unmodified nucleosides, such as an overhang.

[0240] In certain embodiments, the conjugate group modifies one or more properties of the conjugated oligonucleotide, including, but not limited to, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cell distribution, cell uptake, charge, and clearance. In certain embodiments, the conjugate group enhances the affinity of the compound to a given target, such as a molecule, cell or cell type, compartment, such as an intracellular or organelle compartment, body tissue, organ or region, compared to, for example, a compound without such a conjugate group. In certain embodiments, the conjugate group imparts a novel property to the conjugated oligonucleotide, such as a fluorophore or reporter group that enables the detection of the oligonucleotide.

[0241] In certain embodiments, conjugate groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, sugar chains, vitamin moieties, polyethylene glycol, thioethers, polyethers, cholesterol, thiocholesterol, cholic acid moieties, folic acid, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescein, rhodamine, coumarin, fluorophores, and pigments.

[0242] In certain embodiments, the conjugate group may be an active drug substance, such as aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansyl sarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, benzothiadiazide, chlorothiazide, diazepine, indomethacin, barbiturates, cephalosporins, sulfonamides, antidiabetic drugs, antibacterial agents, or antibiotics.

[0243] In certain embodiments, the conjugate group is the targeting moiety. In certain embodiments, the targeting moiety may include, but is not limited to, lectins, glycoproteins, lipids, proteins, peptides, peptide mimetic compounds, receptor ligands, antibodies, tyrotropin, melanotropin, surfactant protein A, glycans, glycan derivatives, modified glycans, glycan clusters, polysaccharides, modified polysaccharides or polysaccharide derivatives, mucin glycans, polyvalent lactose, polyvalent galactose, N-acetyl-galactosamine (GalNAc), N-acetylglucosamine, polyvalent mannose, polyvalent fucose, glycated polyamino acids, polyvalent galactose, transferrin, bisphosphonates, polyglutamic acid, polyaspartic acid, lipids, cholesterol, steroids, bile acids, folic acid, vitamin B12, vitamin A, biotin, or RGD peptides or RGD peptide mimetic compounds.

[0244] In certain embodiments, the conjugate group may be cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86:6553-6556), cholic acid (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060), thioethers, such as hexyl-S-tritylthiol (e.g., Manoharan et al., Ann. NY. Acad. Sci., 1992, 660:306-309, Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), or thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res.,1992,20:533-538), aliphatic chains, e.g., dodecane-diol residues or undecyl residues (e.g., Saison-Behmoaras et al.,EMBO J,1991,10:1111-1118, Kabanov et al.,FEBS Lett.,1990,259:327-330, Svinarchuk et al.,Biochimie,1993,75:49-54), phospholipids, e.g., dihexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (e.g., Manoharan et al.,Tetrahedron Lett.,1995,36:3651-3654, Shea et al.,Nucl.Acids Res., 1990, 18:3777-3783), polyamine chains or polyethylene glycol chains (e.g., Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), adamantane acetate (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), palmityl (e.g., Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), octadecylamine or hexylamino-carbonyloxycholesterol moiety (e.g., Crooke et al. J. Pharmacol. Exp. Ther.,1996,277:923-937), tocopherol (e.g., Nishina et al., Molecular Therapy Nucleic Acids, 2015,4, e220 and Nishina et al., Molecular Therapy, 2008,16:734-740), GalNAc and other glycans (e.g., Maier et al., Bioconjugate Chemistry, 2003,14,18-29, Rensen et al.) Examples of conjugate groups listed in the references include, but are not limited to, those described in *al., J. Med. Chem. 2004, 47, 5798-5808, WO2009 / 073809, U.S. Patents 8,106,022, 8,450,467, 8,828,957, WO2014 / 179445, WO2014 / 179620, U.S. Patents 9,127,276, 9,181,549, and 10,844,379), and are included herein by reference in their entirety.

[0245] The conjugate group may be linked to the oligonucleotide via a conjugate linker. In certain embodiments, the conjugate linker includes a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units or a combination of such repeating units. In certain embodiments, the conjugate linker includes one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, the conjugate linker includes at least one phosphate group. In certain embodiments, the conjugate linker includes at least one phosphate base. In certain embodiments, the conjugate linker may include at least one neutral linking group. In certain embodiments, the conjugate linker may include, but is not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (HEC or AHA). Other conjugate linkers include substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, or substituted or unsubstituted C2-C 10Examples of preferred substituents include, but are not limited to, alkynyl substituents, and a non-limiting list of preferred substituents includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl substituents. In certain embodiments, the conjugate linker comprises 1 to 10 linker-nucleosides. In certain embodiments, such linker-nucleosides may be modified or unmodified nucleosides. It is typically desirable that the linker-nucleosides be cleaved from the compound once the compound reaches the target tissue. Thus, the linker-nucleosides in the present invention can be linked to each other and to the remainder of the compound via cleavable bonds. In the present invention, linker-nucleosides are not considered to be part of their oligonucleotides. Therefore, in embodiments in which a compound comprises an oligonucleotide consisting of a predetermined number or range of linked nucleosides and / or an oligonucleotide having a predetermined complementarity percentage to a reference nucleic acid, and in embodiments in which the compound also comprises a conjugate group including a conjugate linker containing a linker nucleoside, these linker nucleosides are not counted in relation to the length of the oligonucleotide and are not used when determining the complementarity percentage of the oligonucleotide with respect to the reference nucleic acid.

[0246] The rest of the house is a slightly less expensive one The price tag is US5,994.5 17 US6,300,319 US6,660,720 US6,906,182 US7,262,177 US7 491,805 US8,106,022 US7,723,509 US9,127,276 US2006 / 0148740 US2011 / 0123520 WO2013 / 033230 WO2012 / 037254 Biessen et al.,J.Med.Chem.1995,38,1846-1852;Lee et al.,Bioorganic & Medicinal Chemistry 2011,19,2494-2500;Rensen et al.,J.Biol.Chem.2001,276,37577-37584; al.,J.Med.Chem.2004,47,5798-5808;Sliedregt et al.,J.Med.Chem.1999,42,609-618;Valentijn et al.,Tetrahedron,1997,53,759-770;Lee,Carhohydr 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 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; Chem,1997,8,762-765;Kato et al.,Glycohiol,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、Leeorg Me et al.,Bio Lett,2006,16(19),5132-5135、Maierhofer et al.,Bioorg Med Chem,2007,15,7661-7676、Khorev et al.,Bioorg Med Chem,2008,16,5216-Meorg et.5231、 Chem,2011,19,2494-2500、Kornilova et al.,Analyt Biochem,2012,425,43-46、Pujol et al.,Angew Chemie Int Ed Engl,2012,51,7445-7448 et.al.,Biessen、 Chem,1995,38,1846-1852、Sliedregt et al.,J Med Chem,1999,42,609-618、Rensen et al.,J Med Chem,2004,47,5798-5808、Rensense et al.,Throm Varterios Biol,2006,26,169-175、van Rossenberg et al.,Gene Ther,2004,11,457-464、Sato et al.,Jam Chem Soc,2004,126,14013-14022、Lee et al.,J Org. Chem,2012,77,7564-7571、Biessen et al.,FASEB J,2000,14,1784-1792、Rajur et al.,Bioconjug Chem,1997,8,935-940、Duff et al.,Methods Enzymol,2000,313,297-321、Maier et al.,Bioconjug Chem,2003,14,18-29、Jayaprakash et al.,Org Lett,2010,12,5410-5413、Ac02se Nucleic Devic,Antisen12,103-128, Merwin et al., Bioconjug Chem, 1994, 5, 612-620, Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281, International Publication No. 1998 / 01338, same as No. 12011 / 038356, same as No. 1997 / 046098, same as No. 2008 / 098788, same as No. 2004 / 101619, same as No. 2 No. 012 / 037254, same as No. 2011 / 120053, same as No. 2011 / 100131, same as No. 2011 / 163121, same as No. 2012 / 177947, same as No. 2013 / 033230, same as No. 2013 / 075035, same as No. 2 No. 012 / 083185, No. 2012 / 083046, No. 2009 / 082607, No. 2009 / 134487, No. 2010 / 144740, No. 2010 / 148013, No. 1997 / 020563, No. 2010 / 088537, No. 2002 / 043771, No. 2010 / 129709, No. 2012 / 068187, No. 2009 / 126933, No. 2004 / 024757, No. 2010 / 054406, and so on. No. 2012 / 089352, the same No. 2012 / 089602, the same No. 2013 / 166121, the same No. 2013 / 165816, the same U.S. Patent No. 4,751,219, the same No. 7,582,744, the same No. 8,552,163, the same No. 8,1 No. 37,695, same as No. 6,908,903, same as No. 6,383,812, same as No. 7,262,177, same as No. 6,525,031, same as No. 5,994,517, same as No. 6,660,720, same as No. 6,300,319, same as No. 7,72 No. 3,509, same as No. 8,106,022, same as No. 7,491,805, same as No. 7,491,805, same as No. 8,541,548, same as No. 8,344,125, same as No. 8,313,772, same as No. 8,349,308, same as No. 8,450,467, same as No. 8,501,930, same as No. 8,158,601, same as No. 7,262,177, same as No. 6,906,182, same as No. 6,620,916, same as No. 8,435,491, same as No. 8,404,862, same as No. 7,851U.S. Patent Application Publication Nos. 615, 2011 / 0097264, 2011 / 0097265, 2013 / 0004427, 2003 / 0119724, 2011 / 0207799, 2012 / 0035115, 2012 / 0230938, 2005 / 0164235, 2006 / 0183886, 2012 / 0136042, 2012 / 0095075, 2013 / 0109817, and 2 References include, but are not limited to, those listed in Nos. 006 / 0148740, 2008 / 0206869, 2012 / 0165393, 2012 / 0101148, 2013 / 0121954, 2011 / 0123520, 2003 / 0077829, 2008 / 0108801, and 2009 / 0203132, each of which is incorporated herein by reference in its entirety.

[0247] specific conjugate groups In certain embodiments, the compounds provided in this disclosure include a conjugate group. In certain embodiments, the oligonucleotides provided in this disclosure include a conjugate group. In certain embodiments, the conjugate group is a targeting moiety. In certain embodiments, the targeting moiety includes one or more TrkB ligands. In certain embodiments, the targeting moiety includes one or more CB1 ligands. In certain embodiments, the targeting moiety includes one or more α4β 1 / 7 It contains an integrin ligand. In certain embodiments, the targeting portion contains one or more NMDA ligands.

[0248] In certain embodiments, the TrkB ligand of the modified oligonucleotide is of the following formula (I), or a salt, solvate, or hydrate thereof: [ka] During the ceremony, R 1 This is a modified oligonucleotide of the present invention, L 1 , L 2 , L 3 and L 4 This is as described herein, R 2 is hydrogen, -OR 7 , -SR 8 or -NR 9 R 10 And, R 3 is hydrogen, -OR 11 , -SR 12 or -NR 13 R 14 And, R 4 is hydrogen, -OR 15 , -SR 16 or -NR 17 R 18 And, R 5 is hydrogen, -OR 19 , -SR 20 or -NR 21 R 22 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 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 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 CH2, NH, S, or O. Z is an arbitrarily substituted aryl or arbitrarily substituted heteroaryl.

[0249] In a particular embodiment, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 Each of these is independently an optionally substituted unsaturated or partially unsaturated alkyl group. In certain embodiments, R 7 , R 8 , R 9 and R 10 Each of these is an alkenil independently. In certain embodiments, R 7 , R 8 , R 9 and R 10 Each of them is independently an alkinnil.

[0250] In a particular embodiment, R 2 is OR 7 In a particular embodiment, R 3 is OR 11 In a particular embodiment, R 7 and R 11 Each of these is independently hydrogen, an optionally substituted alkyl, or an optionally substituted alkenyl. In certain embodiments, one or both R 7 and R 11 Each of these is independently hydrogen. In certain embodiments, one or both R 7 and R 11 Each of these is independently an optionally substituted alkyl group. In certain embodiments, one or both R 7 and R 11 Each of these is independently an optionally substituted unsaturated or partially unsaturated alkyl. In certain embodiments, one or both R7 and R 11 Each of these is an alkenil independently. In certain embodiments, R 7 is an optionally substituted alkyl, and R 11 is hydrogen. In certain embodiments, R 7 is hydrogen, R 11 R is an optionally substituted alkyl group. In certain embodiments, R 7 is an alkenil, and R 11 is hydrogen. In certain embodiments, R 7 is hydrogen, R 11 is an arbitrarily substituted alkenyl.

[0251] In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R 1 This is a modified oligonucleotide of the present invention, L 1 , L 2 , L 3 and L 4 This is as described herein.

[0252] In certain embodiments, the TrkB ligand of the modified oligonucleotide is of the following formula (XXX), or a salt, solvate, or hydrate thereof. [ka] During the ceremony, L 1 , L 2 , L 3 , L 4 and R 1 This is as described herein, 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, or R bonded to the same nitrogen atom. 16B and R 16C The substituents may optionally join to form substituted or unsubstituted heterocycloalkyl groups, or substituted or unsubstituted heteroaryl groups. z3 is 0, 1, 2, 3, 4, or 5. n16 is 0, 1, 2, 3, or 4. v16 and m16 are independently either 1 or 2.

[0253] In a particular embodiment, the modified oligonucleotide α4β 1 / 7 Integrin ligands are those of the following formula (XXXI), or their salts, solvates, or hydrates: [ka] During the ceremony, L 1 , L 2 , L 3 , L 4 and R 1 This is as described herein, R 2 , R 3 , R 4 and R 5 Each of these is independently either H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl, or absent. R 8 is an arbitrarily substituted C 1- C5 alkyl, optionally substituted C 1- C5 alkylene-(C3-C6)-cycloalkyl, or optionally substituted (C 1- C4)-Alkilen-(C 1- It is a C4)-alkoxy, R 6 and R 7 Each of these independently consists of H, halogen, alkyl or optionally substituted alkyl, and optionally substituted heteroalkyl. [ka] That is the case.

[0254] In a particular embodiment, the modified oligonucleotide α4β 1 / 7 The integrin ligand is of the following formula (XXXII), or its salt, solvate, or hydrate: [ka] During the ceremony, L 1 , L 2 , L 3 , L 4 and R 1 This is as described herein, R 2 is H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl. R 3 and R 4 Each of these is independently H, a halogen, an optionally substituted alkyl, or an optionally substituted -O-alkyl.

[0255] In a particular embodiment, L1 , L 2 , L 3 and L 4 Each of these is independently either absent, bonded, optionally substituted alkyl linker, optionally substituted polyethylene glycol (PEG) linker, optionally substituted heteroalkyl linker, or optionally substituted heteroaryl linker.

[0256] In a particular embodiment, L 1 This is an arbitrarily substituted heteroaryl linker.

[0257] In a particular embodiment, L 1 This is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

[0258] In a particular embodiment, L 1 teeth, [ka] It includes the structure.

[0259] In a particular embodiment, L 1 is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or an optionally substituted C 1- C 10 It is an alkyl chain (one or more carbon atoms are replaced by O, N, or S).

[0260] In a particular embodiment, L 1 teeth, [ka] It includes the structure.

[0261] In a particular embodiment, L 1 teeth, [ka] Or it includes the -N(CH3)- structure.

[0262] In a particular embodiment, L 2 This is an arbitrarily substituted PEG linker.

[0263] In certain embodiments, the PEG linker has a PEG unit length of 5. In certain embodiments, the PEG linker has a PEG unit length of 4. In certain embodiments, the PEG linker has a PEG unit length of 3.

[0264] In a particular embodiment, L 2 is an optionally substituted alkyl linker. In certain embodiments, L 2 is an arbitrarily substituted C 1-20 It is an alkyl linker. In certain embodiments, L 2 is an optionally substituted C8 alkyl linker. In certain embodiments, L 3 This is an arbitrarily substituted heteroaryl linker.

[0265] In a particular embodiment, L 3 This is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

[0266] In a particular embodiment, L 3 teeth, [ka] It includes the structure.

[0267] In a particular embodiment, L 4 This is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =O substituents.

[0268] In certain embodiments, the heteroalkyl linker contains two integral substituents to form an optionally substituted carbocyclyl ring.

[0269] In a particular embodiment, L 4 teeth, [ka] The formula includes the structure of either or a salt thereof, where X is O or S.

[0270] In a particular embodiment, L 4 teeth, [ka] The formula includes the structure of either or a salt thereof, where X is O or S.

[0271] In a particular embodiment, L 1 -L 2 -L 3 -L 4 teeth, [ka] [ka] [ka] [ka] The formula includes the structure of either or a salt thereof, where X is O or S.

[0272] In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0273] In certain embodiments, the CB1 ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0274] In a particular embodiment, the modified oligonucleotide α4β 1 / 7 The integrin ligand is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0275] In certain embodiments, the NMDA ligand of the modified oligonucleotide is selected from the following formulas, or its salts, solvates, or hydrates: [ka] During the ceremony, R is a modified oligonucleotide of the present invention, X is either S or O.

[0276] In certain embodiments, the compounds provided in this disclosure include a conjugate group. In certain embodiments, the oligonucleotides provided in this disclosure include a conjugate group. In certain embodiments, the conjugate group is a lipid. In certain embodiments, the nucleoside bonds of the modified oligonucleotides provided in this disclosure include one or more lipids.

[0277] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXI), or its salt, solvate, or hydrate: [ka] During the ceremony, Y is -C(=O)N(R C )- or -N(R C )C(=O)-, Q 1 and Q 3 These are independent of each other: -H, -OR 4 , ligand, linker or lipid, Q 2 and Q 4 Each is independent, and combined, [ka] It is a ligand, linker, or lipid. R C These are independently -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Each R 2 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 6 , -N(R 6 ), or -SR 6 And, Each R 3These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 7 , -N(R 7 ), or -SR 7 And, R 4 and R 5 Whether they are independently oligonucleotides or R 4 and R 5 However, they combine to form a single oligonucleotide, Each R 6 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 7 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 8 These are independently substituted or unsubstituted heteroaryl compounds. Each R 9 These are independently substituted or unsubstituted heteroaryl compounds. Z 1 or Z 2 Each example is independent, combined, C 1- It is a C6 alkylene or a C2-C6 alkenylene. Each X is independently either O or S. Formula (XXI), or its salts, solvates, or hydrates, or salts thereof.

[0278] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXII), or its salt, solvate, or hydrate: [ka] During the ceremony, R C However, it is -H, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, Each R 2 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 6 , -N(R 6 ), or -SR 6 And, Each R 3 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 7 , -N(R 7 ), or -SR 7 And, R 4 and R 5 Whether they are independently oligonucleotides or R 4 and R 5 However, they combine to form a single oligonucleotide, Each R 6 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 7 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 8 These are independently substituted or unsubstituted heteroaryl rings, Each R 9 These are independently substituted or unsubstituted heteroaryl rings, Each X is independently either O or S. Formula (XXII), or its salts, solvates or hydrates, or salts or prodrugs thereof.

[0279] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXIII), or its salt, solvate, or hydrate: [ka] During the ceremony, Each R 2These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 6 , -N(R 6 ), or -SR 6 And, Each R 3 These independently include -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and -OR 7 , -N(R 7 ), or -SR 7 And, R 4 and R 5 Whether they are independently oligonucleotides or R 4 and R 5 However, they combine to form a single oligonucleotide, Each R 6 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 7 These are independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted heteroalkyl group. Each R 8 These are independently substituted or unsubstituted heteroaryl rings, Each R 9 These are independently substituted or unsubstituted heteroaryl rings, Each X is independently either O or S. Formula (XXIII), or its salts, solvates or hydrates, or salts or prodrugs thereof.

[0280] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXIV), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4and R 5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0281] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXXIII), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4 and R 5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0282] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXXIV), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4 and R 5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0283] In certain embodiments, the nucleoside bond of the modified oligonucleotide is of the following formula (XXXV), or its salt, solvate, or hydrate: [ka] During the ceremony, R 4 and R 5 These are independently oligonucleotides or R 4 and R5 They combine to form a single oligonucleotide, Each X is independently either O or S.

[0284] In certain embodiments, the compound of any prior embodiment contains one or more lipid conjugate groups. In certain embodiments, the one or more lipid conjugate groups are bonded to one or more nucleoside bonds of the modified oligonucleotide. In certain embodiments, the one or more lipid conjugate groups are bonded to the 5' or 3' end of the modified oligonucleotide. In certain embodiments, the one or more lipid conjugate groups are bonded to the nucleoside bond of the modified oligonucleotide and to the 5' or 3' end. In certain embodiments, the one or more lipid conjugate groups are bonded to the nucleoside bond of the modified oligonucleotide and to both the 5' and 3' ends. In certain embodiments, the one or more TrkB ligands are bonded to the 5' or 3' end of the modified oligonucleotide, or to both the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, one or more conjugate groups comprise at least one TrkB ligand bonded to the 5' or 3' end of the modified oligonucleotide, or to both the 5' and 3' ends of the modified oligonucleotide, and at least one lipid. In certain embodiments, one or more conjugate groups comprise at least one TrkB ligand bonded to the 5' or 3' end of the modified oligonucleotide, or to both the 5' and 3' ends of the modified oligonucleotide, and one or more lipid conjugate groups bonded to one or more internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises a TrkB ligand and a lipid. In certain embodiments, the modified oligonucleotide comprises one or more TrkB ligands and one or more lipids. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or sense oligonucleotide.

[0285] In certain embodiments, the compound of any of the prior embodiments comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl groups are bonded to the internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl groups are bonded to one or more internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or sense oligonucleotide. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C1 4- C 30 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C5-C 20 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 14- C 20 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 16 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 17 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 18 Contains hydrocarbon chains. In certain embodiments, one or more substituted or unsubstituted alkyl or alkenyl groups are saturated or unsaturated C 22 Contains hydrocarbon chains.

[0286] In certain embodiments, a substituted or unsubstituted alkyl or alkenyl is bonded to an internucleoside bond of a modified oligonucleotide (e.g., a second modified oligonucleotide or sense oligonucleotide). In certain embodiments, the internucleoside bond is between nucleosides within 10 positions (e.g., within 8, 6, 5, 4, 3, 2) from the terminal end (e.g., 5' and / or 3') of the modified oligonucleotide. In certain embodiments, the internucleoside bond is between nucleosides within 5 positions from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside bond is between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

[0287] In certain embodiments, the nucleoside linkage is between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside linkage is between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside linkage is between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the nucleoside bond is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

[0288] In certain embodiments, the nucleoside bonds of the modified oligonucleotide are selected from one of the formulas XXI-XXIV and XXXIII-XXXV.

[0289] Target nucleic acids and target regions In certain embodiments, the compounds described herein include or consist of an oligonucleotide containing a region complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid codes for a protein. In certain embodiments, the target nucleic acid is non-coding. In certain such embodiments, the target nucleic acid is selected from mRNA and premRNA (including intron, exon, and untranslated regions). In certain embodiments, the target RNA is mRNA. In certain embodiments, the target nucleic acid is premRNA. In certain such embodiments, the target region is entirely within an exon. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region extends to an intron junction / exon junction. In certain embodiments, at least 50% of the target region is within an intron.

[0290] In certain embodiments, the compounds disclosed herein hybridize with the SOD1 nucleic acid. The most common hybridization mechanism involves hydrogen bonding between complementary nucleic acid bases of those nucleic acid molecules. Hybridization can occur under a variety of conditions. The hybridization conditions are sequence-dependent and are determined by the properties and composition of the nucleic acid molecules hybridizing. Methods for determining whether a sequence specifically hybridizes with a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein specifically hybridize with the SOD1 nucleic acid.

[0291] Examples of nucleotide sequences encoding SOD1 include, but are not limited to, GenBank accession number NM_000454.5 (incorporated herein as SEQ ID NO: 1) and nucleotides 5001-14310 of NG_008689.1 (incorporated herein as SEQ ID NO: 2).

[0292] Complementarity Oligonucleotides provided in this disclosure may have defined percentages of complementarity to specific nucleic acids, target regions, oligonucleotides, or parts thereof. Non-complementary nucleic acid bases may be permitted, provided that the oligonucleotide remains capable of specifically hybridizing to the nucleic acid, oligonucleotide, or part thereof. In certain embodiments, an oligonucleotide or a given part thereof provided in this disclosure is at least 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a target nucleic acid, target region, oligonucleotide, or a given part thereof. In certain embodiments, an oligonucleotide or a specified portion thereof provided in this disclosure is complementary to a target nucleic acid, target region, oligonucleotide or a specified portion thereof by 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-100%, or any number in between these ranges. The complementarity percentage between an oligonucleotide and a target nucleic acid, target region, oligonucleotide or a specified portion thereof can be determined by a conventional method. For example, an oligonucleotide that specifically hybridizes because 18-20 nucleic acid bases of that oligonucleotide are complementary to the target region will have a complementarity percentage of 90. In this example, the remaining non-complementary nucleic acid bases may be clustered with complementary nucleic acid bases or scattered among complementary nucleic acid bases, and do not need to be consecutive with each other or with complementary nucleic acid bases. Therefore, an oligonucleotide with a nucleic acid base length of 18 and four non-complementary nucleic acid bases flanked by two regions that are perfectly complementary to the target nucleic acid will have an overall complementarity of 77.8% with respect to the target nucleic acid. The complementarity percentage of an oligonucleotide with respect to the target nucleic acid, target region, oligonucleotide, or a predetermined region of the oligonucleotide can be determined by a standard method using the BLAST program (Basic Local Alignment Search Tool), which is known in the art.In certain embodiments, an oligonucleotide or a given portion thereof described herein is fully complementary (i.e., 100% complementary) to a target nucleic acid, a target region, an oligonucleotide, or a given portion thereof. For example, an oligonucleotide may be fully complementary to a target nucleic acid, a target region, an oligonucleotide, or a given portion thereof. As used herein, “fully complementary” means that each nucleic acid base of the oligonucleotide is complementary to the corresponding nucleic acid base of the target nucleic acid, a target region, an oligonucleotide, or a given portion thereof. For example, a 20-nucleotide oligonucleotide is fully complementary to a 400-nucleotide-length target sequence, as long as there are 20 corresponding nucleic acid base portions of the target nucleic acid that are fully complementary to the compound. “Fully complementary” can also be used with respect to a given portion of the first and / or second nucleic acid. For example, a 20-nucleotide portion of a 30-nucleotide oligonucleotide may be “fully complementary” to a 20-nucleotide region of a 400-nucleotide-length target sequence. The 20-nucleotide portion of the 30-nucleotide compound is perfectly complementary to its target sequence if the target sequence has a corresponding 20-nucleotide portion and each nucleotide is complementary to the 20-nucleotide portion of the compound. At the same time, the entire 30-nucleotide compound may or may not be perfectly complementary to its target sequence, depending on whether the remaining 10 nucleotides of the compound are also complementary to its target sequence.

[0293] In certain embodiments, the oligonucleotides described herein contain one or more mismatched nucleic acid bases with respect to a target nucleic acid, a target region, an oligonucleotide, or a predetermined portion thereof. In certain embodiments, oligonucleotides described herein that have a nucleic acid base length of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, or at most 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, contain four or fewer, three or fewer, two or fewer, or one or fewer nucleic acid bases that are non-complementary to the target nucleic acid or a predetermined portion thereof. In certain embodiments, oligonucleotides described herein having a nucleic acid base length of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, or at most 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, contain 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer nucleic acid bases that are non-complementary to the target nucleic acid, target region, oligonucleotide, or a given portion thereof. In certain embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 5' end of the oligonucleotide. In certain embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 3' end of the oligonucleotide. In certain embodiments, the mismatch forms a fluctuating base pair with the corresponding nucleic acid base on the target nucleic acid. For example, in certain embodiments, the mismatch forms a fluctuating base pair selected from hypoxanthine (the nucleic acid base of inosine) and uracil (I:U base pair), guanine and uracil (G:U base pair), hypoxanthine and adenine (I:A base pair), and hypoxanthine and cytosine (I:C base pair). Thus, in certain embodiments, the nucleic acid base of the mismatch on the oligonucleotide includes hypoxanthine, guanine, or uracil.

[0294] In certain embodiments, the oligonucleotides described herein may be complementary to a portion of a nucleic acid. As used herein, “portion” refers to a predetermined number of consecutive nucleic acid bases within a region of the nucleic acid. “Portion” may also refer to a predetermined number of consecutive nucleic acid bases within an oligonucleotide. In certain embodiments, the oligonucleotide is complementary to at least an 8-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least a 9-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least a 10-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least an 11-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least a 12-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least a 13-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least a 14-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least a 15-base portion of the nucleic acid. In certain embodiments, the oligonucleotide is complementary to at least a 16-base portion of the nucleic acid. The assumed oligonucleotide is complementary to at least 9, 10, 17, 18, 19, 20, 21, 22, or 23 or more nucleic acid base portions of the nucleic acid, or to a range defined by any two of these values. In certain embodiments, the oligonucleotide is an antisense oligonucleotide. In certain embodiments, a portion of the antisense oligonucleotide is compared to a portion of the target nucleic acid of the same length. In certain embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleic acid bases is compared to a portion of the target nucleic acid of the same length. In certain embodiments, the oligonucleotide is a sense oligonucleotide.In certain embodiments, a portion of the sense oligonucleotide is compared with a portion of the antisense oligonucleotide of the same length. In certain embodiments, portions of the sense oligonucleotide at 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleic acid bases are compared with a portion of the antisense oligonucleotide of the same length.

[0295] identity Oligonucleotides provided herein may have defined identity percentages with respect to specific nucleic acids, target regions, oligonucleotides, or predetermined portions thereof. For use herein, oligonucleotides are identical to sequences disclosed herein if they have the same nucleic acid base-pairing ability. For example, a DNA containing thymidine instead of uracil in the disclosed RNA sequence will be considered identical to the RNA sequence because both uracil and thymidine pair with adenine. Shortened and extended forms of the compounds described herein, as well as compounds having bases that are not identical to the compounds provided herein, are also envisioned. These non-identical bases may be adjacent to each other or scattered throughout the compound. The identity percentage of an oligonucleotide is calculated according to the number of bases that have identical base-pairing properties with respect to the sequence being compared. In certain embodiments, an oligonucleotide or a portion thereof described herein is 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more nucleic acids, oligonucleotides or portions thereof disclosed herein, or at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical. In certain embodiments, the oligonucleotides described herein are identical to a particular nucleic acid or oligonucleotide, or a portion thereof, by about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, or any percentage between such values.

[0296] In certain embodiments, the oligonucleotide may have one or more mismatched nucleic acid bases. In certain such embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 5' end of the oligonucleotide. In certain such embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 3' end of the oligonucleotide. In certain embodiments, a portion of the oligonucleotide is compared to a portion of the target nucleic acid of the same length. In certain embodiments, portions of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleic acid bases are compared with portions of the target nucleic acid of the same length. In certain embodiments, the oligonucleotide is a sense oligonucleotide. In certain embodiments, portions of the sense oligonucleotide are compared with portions of the target nucleic acid of the same length. In certain embodiments, portions of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleic acid bases are compared with portions of the target nucleic acid of the same length.

[0297] Pharmaceutical compositions and preparations For the preparation of pharmaceutical compositions or formulations, pharmaceutically acceptable active or inactive substances may be added to and mixed with the compounds described herein. The compositions and methods for compounding pharmaceutical compositions depend on a number of criteria, including, but not limited to, the route of administration, the severity of the disease, or the dose to be administered. Certain embodiments provide a pharmaceutical composition comprising one or more compounds or salts thereof. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises one or more modified oligonucleotides or consists of one or more modified oligonucleotides. In certain such embodiments, the pharmaceutical composition comprises one or more compounds and a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition comprises one or more compounds and sterile saline. In certain embodiments, such a pharmaceutical composition consists of one compound and sterile saline. In certain embodiments, the sterile saline is pharmaceutical-grade saline. In certain embodiments, the pharmaceutical composition comprises one or more compounds and sterile water. In certain embodiments, the pharmaceutical composition consists of one compound and sterile water. In certain embodiments, the sterile water is pharmaceutical-grade water. In certain embodiments, the pharmaceutical composition comprises one or more compounds and phosphate-buffered saline (PBS). In certain embodiments, the pharmaceutical composition consists of one compound and sterile PBS. In certain embodiments, the sterile PBS is pharmaceutical-grade PBS.

[0298] Compounds described herein that target SOD1 can be used in pharmaceutical compositions by combining the compound with a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutically acceptable diluent is water, for example, sterile water suitable for injection. Thus, in one embodiment, the method described herein uses a pharmaceutical composition comprising a compound that targets SOD1 and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides provided herein.

[0299] Pharmaceutical compositions comprising the compounds provided in this disclosure include any pharmaceutically acceptable salt, ester, or salt of such ester, or any other oligonucleotide that, when administered to an animal (including a human), can (directly or indirectly) supply its bioactive metabolite or residue. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. Thus, for example, this disclosure also applies to pharmaceutically acceptable salts of the compound, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalent substances. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts, and prodrugs may include incorporating an additional nucleoside at one or both ends of the compound, which is then cleaved by an endogenous nuclease in the body to form the active compound. In certain embodiments, the compound or composition further comprises a pharmaceutically acceptable carrier or diluent. [Examples]

[0300] The following examples describe a process for identifying lead compounds that target SOD1. Specific compounds are identified based on their high potency and tolerability.

[0301] The following examples are intended to illustrate the compounds described herein and are not intended to limit them. The following examples and the related sequence listings attached to this application may identify sequences as either "RNA" or "DNA," but these sequences may be modified by any combination of chemical modifications as disclosed herein. It will be readily apparent to those skilled in the art that, in certain cases, it is arbitrary to refer to a sequence as "RNA" or "DNA." For example, an oligonucleotide containing a nucleoside with a 2'-OH sugar moiety and a thymine base can be called DNA with a modified sugar (2'-OH relative to the natural 2'-H of DNA) or RNA with a modified base (methylated uracil relative to the natural uracil of RNA). Thus, the nucleic acid sequences provided herein, including but not limited to those in the sequence listings, are intended to encompass nucleic acids including any combination of natural or modified RNA and / or DNA, such nucleic acids including, but not limited to, those having modified nucleic acid bases.

[0302] Each of the references listed in this application is incorporated herein by reference in its entirety. [Table 1-1] [Table 1-2] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21] [Table 3-22]

[0303] Example 1: Preparation of N-(17-azido-3,6,9,12,15-pentaoxaheptadecyl)-4-(7,8-dihydroxy-4-oxochroman-2-yl)benzamide [ka] A solution of 2,5-dioxopyrrolidine-1-yl 4-(7,8-dihydroxy-4-oxochroman-2-yl)benzoate (144 mg, 0.365 mmol, 1 equivalent) and 17-azido-3,6,9,12,15-pentaoxaheptadecane-1-amine (223 mg, 0.73 mmol, 2 equivalents) in DMF (2 mL) was heated at 60°C for 20 minutes. Subsequently, the mixture was concentrated, and the crude substance was purified by flash chromatography (ethyl acetate / methanol, 0→5% eluate) to obtain the title compound (160 mg, 75%) as a brown solid. LCMS m / z587(M+1) 1 H NMR(499MHz,DMSO-d6)δ8.71(t,J=5.6Hz,1H),8.25(d,J=8.6Hz,2H),8.02(d,J=8.6Hz,2H),7.41(d,J=8. 6Hz,1H),6.99(s,1H),6.96(d,J=8.6Hz,1H),3.60-3.48(m,20H),3.45(q,J=5.8Hz,2H),3.40-3.34(m,2H)

[0304] Example 2: Preparation of N-(17-azido-3,6,9,12,15-pentaoxaheptadecyl)-4-(7,8-dimethoxy-4-oxochroman-2-yl)benzamide [ka] To a stirred suspension of N-(17-azido-3,6,9,12,15-pentaoxaheptadecyl)-4-(7,8-dihydroxy-4-oxochroman-2-yl)benzamide (400 mg, 0.683 mmol, 1 equivalent) and K2CO3 (188 mg, 1.365 mmol, 2 equivalents) in DMF (10 mL), iodomethane (0.043 mL, 0.683 mmol, 1 equivalent) was added, and the mixture was stirred overnight at room temperature. LC-MS revealed a mixture of starting materials for monomethylation and dimethylation. The mixture was concentrated and purified by reverse-phase column chromatography using 0→60% water / MeCN with 0.1% formic acid as the eluent to obtain the following three products as yellow viscous solids. (100mg, yield 24%) 100% purity LCMS: m / z = 615[M+1] 1 H NMR(500MHz,DMSO-d6)δ8.71(t,J=5.6Hz,1H),8.16(d,J=8.5Hz,2H),8.04(d,J=8.5Hz,2H),7.80(d,J=9.0H z,1H),7.30(d,J=9.0Hz,1H),7.07(s,1H),3.97(s,3H),3.96(s,3H),3.60-3.42(m,22H),3.40-3.34(m,2H).

[0305] Example 3: Preparation of N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-4-(7,8-dihydroxy-4-oxochroman-2-yl)benzamide [ka] A suspension of 2,5-dioxopyrrolidine-1-yl 4-(7,8-dihydroxy-4-oxochroman-2-yl)benzoate (665 mg, 1.684 mmol, 1 equivalent) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethane-1-amine (440 mg, 2 mmol, 1.2 equivalents), and DIPEA (0.5 ml, 3.7 mmol, 2.2 equivalents) in THF (20 mL) were heated at 60°C for 3 hours. The mixture was concentrated, the resulting solid was triturated with methanol, and filtered to obtain the title compound (595 mg, 71%) as a beige solid with a purity of >95% by HPLC. LCMS m / z521(M+Na) 1 H NMR(499MHz,DMSO-d6)δ8.71(t,J=5.6Hz,1H),8.25(d,8.6Hz,2H),8.02(d,8.6Hz,2H),7.41(d,J=8.6H z,1H),6.99(s,1H),6.96(d,J=8.7Hz,1H),3.61-3.51(m,12H),3.45(q,J=5.8Hz,2H),3.39-3.35(m,2H)

[0306] Example 4: Preparation of 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazole-6(3H)-one [ka] Step 1: 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazole-6(3H)-one To a solution of 7,8-diamino-2-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecyl)(methyl)amino)phenyl)-4H-chromen-4-one (700 mg, 1.28 mmol, 1 equivalent) in acetonitrile (15 mL), 1,1,1-trimethoxymethane (169.55 mg, 1.41 mmol, 1.1 equivalent) and iodine (32.56 mg, 128.29 μmol, 25.84 μL, 0.1 equivalent) were added. The mixture was stirred at 25°C for 1 hour, then quenched by adding aqueous solution of NaHSO3 (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (40 mL x 1), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluate of 0-15% MeOH / DCM gradient @ 100 mL / min) to obtain the title compound (470 mg, 64%) as a brown gum. MS ES + :570.2

[0307] Step 2: 8-(4-((17-chloro-3,6,9,12,15-pentaoxaheptadecyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazole-6(3H)-one To a solution of 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazole-6(3H)-one (400 mg, 702.19 µl, 1 equivalent) in DCM (6 mL), SOCl2 (835.40 mg, 7.02 mmol, 509.39 μL, 10 equivalents) was added. The mixture was stirred at 25°C for 4 hours, then poured into saturated NaHCO3 aqueous solution (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic extract was washed with brine (80 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound as a mixture of tautomers (320 mg, 71%) as a brown gum. MS ES + :588.3 1 H NMR(400MHz,DMSO-d6)δ=8.08-7.85(m,2H),7.76(d,J=8.5Hz,1H),7.50(br d,J=8.3Hz,1H),6.87(br d,J=8.9Hz,2H),6.79(s,1H),3.70-3.66(m,2H),3.66-3.60(m,6H),3.54-3.47(m,16H),3.05(s,3H),2.61(s,3H).

[0308] Step 3: 8-(4-((17-azido-3,6,9,12,15-pentaoxaheptadecyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazole-6(3H)-one 8-(4-((17-chloro-3,6,9,12,15-pentaoxaheptadecyl)(methyl)amino)phenyl)-2-methylchromeno[7,8-d]imidazole-6(3H)-one (310 mg, 0.527 mmol, 1 equivalent) and sodium azide (171 mg, 2.63 mmol, 5 equivalents) were heated at 70°C for 12 hours in dry DMF (2 mL). The mixture was cooled, diluted with water (20 mL), and extracted with DCM (100 mL). The organic extract was dried over Na2SO4, filtered, concentrated, and purified by column chromatography (0 → 20% MeOH / DCM) to obtain the title compound as a 1:2 (30:70) (120 mg, 38%) mixture of tautomers as a dark orange gum with a purity of >95%. LCMS m / z=595(M+1)

[0309] The tautomer structures are as follows: 1 This was confirmed by HNMR. Isomer 1 (its 7-NH proton appears at an even lower magnetic field of δ13.38) Isomer 2 (its 9-NH proton appears at a high magnetic field with a δ of 12.98)

[0310] A tautomorphic mixture (80 mg) with isomer 1 was further purified by flash column chromatography to obtain pure substance 2 (50 mg) as a dark orange gum.

[0311] Isomer 1: 1 H NMR:(499MHz,DMSO-d6)δ13.38,12.85(2s,1H),8.09,7.94(d,J=8.7Hz,2H),7.77,7.72(d,J=8.5Hz,1H),7.54,7.47(d,J=8.5Hz,1H),6.88,6.85(d, J=9.0Hz,2H),6.81,6.79(s,1H),3.67-3.62(m,2H),3.58-3.54(m,2H),3. 54-3.45(m,16H),3.38-3.35(m,2H),3.06,3.05(s,3H),2.63,2.60(s,3H). Isomer 2: 1H NMR(499MHz,DMSO-d6)δ12.98(s,1H),7.98(d,J=8.7Hz,2H),7.76(d,J=8.5Hz,1H),7.50(d,J=8.5Hz,1H),6.87(d,J=9. 0Hz,2H),6.80(s,1H),3.62(m,4H),3.58-3.54(m,2H),3.54-3.45(m,16H),3.40-3.34(m,2H),3.05(s,3H),2.61(s,3H).

[0312] Example 5: Preparation of (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamide)propanoic acid [ka] Step 1: tert-butyl(S)-2-(3,5-dichloroisonicotinamide)-3-(4-(5-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate A solution of tert-butyl(S)-2-(3,5-dichloroisonicotinamide)-3-(4-(2-methyl-3-oxo-5-((1-phenyl-2,5,8,11-tetraoxatridecane-13-yl)oxy)-2,3-dihydropyridazine-4-yl)phenyl)propanoate (prepared as described in Gong et.al., “Synthesis and Biological Evaluation of Novel Pyridazinone-Based α4 Integrin Receptor Antagonists”, J.Med.Chem., 2006, 49, 11, 3402-3411, 0.81 g, 1.02 mmol) in methanol (17 ml) was stirred for 2 hours in a hydrogen atmosphere (1 atm) in the presence of Pd / C (0.11 g, 1.02 mmol). The catalyst was removed by filtration, the filtrate was concentrated, and purified by silica gel column chromatography using 0-5% MeOH in DCM to obtain the title compound (0.47 g, 66%). MS(ESI)m / z696.6[M+H] +

[0313] Step 2: tert-butyl(S)-2-(3,5-dichloroisonicotinamide)-3-(4-(2-methyl-5-(2-(2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate At 0°C, a solution of tert-butyl(S)-2-(3,5-dichloroisonicotinamide)-3-(4-(5-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazine-4-yl)phenyl)propanoate (0.10 g, 0.144 mmol) in pyridine (1.4 ml) was met with dropwise addition of methanesulfonyl chloride (17 µl, 0.216 mmol) in DCM (1.4 ml). The reaction mixture was stirred at room temperature for 16 hours, then quenched by adding water (10 ml), and extracted with DCM (3 × 10 ml). The organic layer was washed with a saturated solution of NaHCO3 (10 ml) and brine (10 ml). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated to obtain the title compound as brown oil (0.11 g, quantitative). MS(ESI)m / z773.5[M+H] +

[0314] Step 3: tert-butyl(S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamide)propanoate To a solution of tert-butyl(S)-2-(3,5-dichloroisonicotinamide)-3-(4-(2-methyl-5-(2-(2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate (0.11 mg, 0.143 mmol) in DMF (2.3 ml), NaN3 (21 mg, 0.316 mmol) was added, followed by the addition of one drop of water. The mixture was stirred at 80°C for 6 hours, then cooled to room temperature, and separated with ethyl acetate (20 ml) and water (20 ml). The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (2 × 15 ml). The combined organic extracts were washed with brine (x2), dried, filtered, concentrated, and purified by silica gel column chromatography using a gradient of ethyl acetate in hexane from 0 to 100% to obtain the title compound as a clear oil (85 mg, 82%). MS(ESI)m / z721.6[M+H] +

[0315] Step 4: (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamide)propanoic acid To a solution of tert-butyl(S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamide)propanoate (25 mg, 0.035 mmol) in DCM (0.3 ml), TFA (0.14 ml) was added dropwise at 0°C. The cooling bath was removed, and the mixture was stirred at room temperature for 17 hours, then concentrated. The mixture was purified by silica gel column chromatography using a 0 → 100% methanol gradient in DCM to obtain the title product (16 mg, 69%). MS(ESI)m / z687.8[M+Na] + 1 H NMR(500MHz,DMSO-d6)δ12.95(s,1H),9.31(d,J=10Hz,1H),8.63(s,2H),8.20(s,1H),7.42(d,J=10Hz,2H),7.29(d,J=10Hz,2H),4.78-4.72(m ,1H),4.36-4.32(m,2H),3.66(s,5H),3.57(t,J=5Hz,2H),3.36(t,J=5Hz,2H),3.53-3.47(m,8H),3.20(dd,J=10,5Hz,1H),2.93(q,J=10Hz,1H)

[0316] Example 6: Preparation of (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)-5-methylhexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid [ka] Step 1: Ethyl(E)-2-(4-(2-ethoxyvinyl)-2-oxopyridine-1(2H)-yl)-5-methylhexanoate To a stirred solution of ethyl 2-(4-bromo-2-oxopyridine-1-yl)-5-methylhexanoate (prepared according to the procedure described in WO2021076890, 4.8 g, 14.54 mmol) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.76 g, 29.081 mmol) in dioxane (50 ml) and water (5 ml), K2CO3 (4.02 g, 29.10 mmol) and Pd(PPh3)4 (1.68 g, 1.45 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 70°C under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched by adding water, and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography. Elution was performed with PE / EA (1:1) to obtain the title product (containing pinacol). The residue was further purified by reverse-phase flash chromatography (C18 silica gel column, mobile phase: acetonitrile in water, 10-100% gradient over 25 minutes, detector: 254 nm UV) to obtain the title product (4 g, 86%) as brown oil. MS(ESI)m / z322.1[M+H] + 1H NMR(300MHz,CDCl3)δ7.16(m,J=19.4,10.1Hz,2H),6.37(s,1H),6.19(d,J=7.4Hz,1H), 5.60(d,J=13.0Hz,1H),5.54(m,J=10.2,5.6Hz,1H),4.19(q,J=7.2Hz,2H),3.94(q,J=7. 1Hz,2H),2.29-2.03(m,1H),1.86(d,J=12.3Hz,1H),1.57(m,J=13.3,6.8Hz,1H),1.35(t ,J=7.0Hz,3H),1.24(m,J=8.5,7.8Hz,4H),1.14-1.04(m,1H),0.87(m,J=6.8,3.0Hz,6H)

[0317] Step 2: Ethyl 5-methyl-2-(2-oxo-4-(2-oxoethyl)pyridine-1(2H)-yl)hexanoate Ethyl(E)-2-(4-(2-ethoxyvinyl)-2-oxopyridine-1(2H)-yl)-5-methylhexanoate (3.9 g, 12.134 mmol) and TFA (40 ml) were stirred overnight at room temperature. The resulting mixture was concentrated and purified by silica gel column chromatography (elution with PE / EA(1 / 2)) to obtain the title compound (1.9 g, 53%) as a yellow oil. MS(ESI)m / z294.2 1 ¹H NMR (300MHz, chloroform-d) δ 9.76 (t, J=2.0Hz, 1H), 7.35 (d, J=7.1Hz, 1H), 6.54-6.47 (m, 1H), 6.14 (m, J=7.2, 2.0Hz, 1H), 5.56 (m, J=10.1, 5.6Hz, 1H), 4.21 (q, J=7.1Hz, 2H), 3.56 (d, J= 2.0,0.8Hz,2H),2.19(m,J=14.0,11.1,5.5Hz,1H),1.88(m,J=18.8,10.4,4.8Hz,1H),1.5 9(m,J=13.3,6.7Hz,1H),1.34-1.16(m,4H),1.16-0.98(m,1H),0.88(q,J=6.6,3.1Hz,6H)

[0318] Step 3: Ethyl 5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecane-18-yl)pyridine-1(2H)-yl)hexanoate To a stirred solution of ethyl 5-methyl-2-[2-oxo-4-(2-oxoethyl)pyridine-1(2H)-yl]hexanoate (1.8 g, 6.136 mmol) in DCM (27 ml), 15,15,16,16-tetramethyl-5,8,11,14-tetraoxa-2-aza-15-silaheptadecane (1.97 g, 6.127 mmol) and STAB (2.60 g, 12.268 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours, quenched by adding water (100 ml), and extracted with DCM (3 × 120 ml). The combined organic extracts were washed with brine (2 x 50 ml), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (elution with DCM / MeOH (10:1)) to obtain the title compound (1.6 g, 44%) as a yellowish-brown oil. MS(ESI)m / z599.3[M+H] + 1 1H NMR (300MHz, acetonitrile-d3) δ 7.25 (d, J=7.1Hz, 1H), 6.20 (s, 1H), 6.11 (m, J=7.1, 2.0Hz, 1H), 5.08 (m, J=10.2, 5.4Hz, 1H), 4.08 (q, J=7.1Hz, 2H), 3.66 (m, J=5.7, 4.4Hz, 2H), 3.57-3.47 (m, 11H), 3.47- 3.37(m,3H),2.68-2.48(m,4H),2.24(s,3H),2.15-1.99(m,1H),1.90(m,1H),1.48(m,J=13.4,6.8 Hz,1H),1.25-1.11(m,5H),1.07-0.88(m,1H),0.83(s,9H),0.79(m,J=6.6,3.0Hz,6H),0.02(s,6H)

[0319] Step 4: 5-Methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecane-18-yl)pyridine-1(2H)-yl)hexanoic acid To a stirred solution of ethyl 5-methyl-2-[2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecane-18-yl)pyridine-1-yl]hexanoate (1.4 g, 2.338 mmol) in THF (14 ml) and water (2.8 ml), lithium hydroxide (223.95 mg, 9.352 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. Acetic acid (0.71 g, 11.688 mmol) in water (14 ml) was added dropwise at 0°C, and the resulting mixture was extracted with CH3Cl (3 × 100 ml). The combined organic extracts were washed with brine (2 x 40 ml), dried over anhydrous MgSO4, filtered, and concentrated to obtain the title compound (0.90 g, 67%) as a yellow semi-solid, which was used in the next step without further purification. MS(ESI)m / z571.3[M+H] +

[0320] Step 5: Methyl(3S)-3-(5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecane-18-yl)pyridine-1(2H)-yl)hexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate In DMF (12 ml), methyl(3S)-3-amino-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-ylpropanoate (600 mg, 2.017 mmol) and 5-methyl-2-[2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecane-18-yl)pyridine-1-yl]hexanoic acid (1.15 g, 2.017 mmol) are mixed with DIEA (782.27 mg, 6.051 mmol). ), HBTU (765.13 mg, 2.017 mmol) and HOBT (27.26 mg, 0.202 mmol) were added, and the resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. The mixture was then purified by reverse-phase flash chromatography (C18 silica gel column, mobile phase: acetonitrile in water, gradient from 40% to 100% in 10 minutes, gradient to 100% in 20 minutes, detector: 220 nm / 305 nm UV) to obtain the title compound (509.0 mg, 29%) as brown oil. MS(ESI)m / z850.6[M+H] + 1 H NMR(300MHz,DMSO-d6)δ8.95(m,J=27.0,8.5,5.6Hz,1H),7.57(m,J=12.3,7.3,5.2Hz,1H),7.45-7.19(m,2H),7.12-6.86(m,4H) ),6.18(m,J=21.3,11.5,5.6Hz,2H),5.77(d,J=5.1Hz,1H),5.34(m,J=61.7,13.7,5.9Hz,2H),3.68(q,J=5.2Hz,2H),3.63-3.3 9(m,15H),3.32(s,2H),2.83(t,J=6.5Hz,2H),2.24(m,J=12.7,5.5Hz,6H),1.95-1.80(m,7H),1.70-1.57(m,1H),1.57-1.47(m ,1H),1.47-1.34(m,1H),1.24(d,J=5.5Hz,2H),1.15-0.96(m,1H),0.93-0.79(m,13H),0.72(t,J=6.0Hz,4H),0.08-0.01(m,6H)

[0321] Step 6: Methyl(3S)-3-(2-(4-(14-hydroxy-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)-5-methylhexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate To a solution of methyl(3S)-3-(5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecane-18-yl)pyridine-1(2H)-yl)hexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (0.25 g, 0.294 mmol) in THF (2 ml), TBAF (0.35 ml, 0.35 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred at room temperature under an inert atmosphere for 2 hours, then diluted with saturated ammonium chloride solution (15 ml), and extracted with ethyl acetate (3 × 15 ml). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (0-15% MeOH in DCM) to obtain the title compound as a clear oil (0.12 mg, 55%). MS(ESI)m / z759.1[M+Na] +

[0322] Step 7: Methyl(3S)-3-(5-methyl-2-(4-(3-methyl-14-((methylsulfonyl)oxy)-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)hexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate To a solution of methyl(3S)-3-(2-(4-(14-hydroxy-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)-5-methylhexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (0.12 g, 0.163 mmol) in DCM (1 ml), methanesulfonyl chloride (0.016 ml, 0.212 mmol) and triethylamine (0.045 ml, 0.33 mmol) were added. The reaction mixture was stirred at 0°C for 2 hours, then diluted with saturated sodium bicarbonate aqueous solution (10 ml), and extracted with DCM (3 × 20 ml). The combined organic extracts were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound as brown oil (0.11 g, 83%). MS(ESI)m / z815.1[M+H] +

[0323] Step 8: Methyl(3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)-5-methylhexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate To a solution of methyl(3S)-3-(5-methyl-2-(4-(3-methyl-14-((methylsulfonyl)oxy)-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)hexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (0.11 g, 0.135 mmol) in DMF (1 ml), sodium azide (24 mg, 0.37 mmol) was added. The reaction mixture was heated at 65°C for 2 hours, then diluted with water (15 ml), and extracted with ethyl acetate (3 × 15 ml). The combined organic extracts were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (0-15% MeOH in DCM) to obtain the title compound as a clear oil (45 mg, 44%). MS(ESI)m / z762.2[M+H]+

[0324] Step 9: (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)-5-methylhexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid To a solution of methyl(3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridine-1(2H)-yl)-5-methylhexaneamide)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (45 mg, 0.059 mmol) in methanol / water / dioxane (1.5 ml, 1:1:1), lithium hydroxide (4 mg, 0.177 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the resulting residue was treated with a 10% citric acid solution and extracted with ethyl acetate (3 × 15 ml). The combined organic extract was washed with brine (5 ml), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the title compound as a clear oil (30 mg, 75%). MS(ESI)m / z748.1[M+H] + 1 H NMR(500MHz,DMSO-d6)δ12.35(bs,1H),9.00(d,J=10Hz,1H),7.69(d,J=10Hz,1H),7.37(t,J=10Hz,1H),7.2 7(d,J=5Hz,1H),7.06(s,1H),6.99(d,J=5Hz,1H),6.91(s,2H),6.29(s,1H),6.18(d,J=5Hz,1H),5.47(q,J=5 Hz,1H),5.17(q,J=5Hz,1H),4.09(m,3H),2.64(t,5Hz,2H),3.61-3.57(m,13H),3.16(s,6H),2.26(s,3H),1 .90(s,6H),1.87-1.79(m,1H),1.68-1.64(m,1H),1.41-1.35(m,1H),0.95-0.82(m,3H),6.60(d,J=10Hz,6H)

[0325] Example 7: Synthesis of N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(2-chlorophenyl)pyrrolidine-1-carboxamide [ka] To a stirred solution of 2-[(8-azido-3,6-dioxaocto-1-yl)oxy]ethane-1-amine (300 mg, 1.375 mmol) in DCM (6 mL), disuccinimidyl carbonate (422.53 mg, 1.649 mmol) was added in fractions at 0°C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. DIEA (44.06 mg, 0.341 mmol) and 2-(2-chlorophenyl)tetrahydropyrrole (247.71 mg, 1.364 mmol) were added dropwise at 0°C, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched by adding a saturated NaHCO3 solution at 0°C, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC (SunFire C18 OBD Prep Column (19×150mm, 5m), mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 25 mL / min, gradient: isocratic 37-47, wavelength: 254 nm / 220 nm, RT1 (min): 8.26) to obtain the title compound (180 mg, 31%) as a colorless oil. MS(ESI)m / z=426.1[M+H] + 1 ¹H NMR (300MHz, chloroform-d) δ 7.36-7.24 (m,1H), 7.20-7.15 (m,1H), 7.15-7.07 (m,2H), 5.16-5.00 (m,1H), 4.01 (s,1H), 3.71-3.51 (m,8H), 3.50-3.38 (m,4H), 3.37-3.23 (m,5H), 2.43-2.26 (m,1H), 1.89-1.71 (m,3H)

[0326] Preparation of ligand-conjugate oligonucleotides Exemplary ligand-conjugate oligonucleotides that fall within the scope of this disclosure may be synthesized according to the following procedure.

[0327] In some cases, one ligand (ligand A in the general procedure below) is conjugated to the 5' end of the oligonucleotide.

[0328] In some cases, two identical ligands (ligand A and ligand A) are conjugated to the 5' and 3' ends of the oligonucleotide.

[0329] In some cases, two different ligands (ligand A and ligand B) are conjugated to the 5' and 3' ends of the oligonucleotide.

[0330] In some cases, one ligand (ligand A) is conjugated to the 3' end of the oligonucleotide.

[0331] Example 8: General procedure I-type A-sense chain conjugated ligand [ka] Step 1: 5'-DBCO functionalized sense chain Sodium phosphate buffer (10% (V / V), 1M, pH 7) and acetonitrile (20%-50% (V / V)) were added to an aqueous solution of 5'-amine-functionalized sense chains. Subsequently, a solution of DBCO-NHS (1.5-3 equivalents) in DMSO or acetonitrile was added, and the reaction was monitored by LC-MS and HPLC. Once complete, either precipitate was removed by centrifugation, the aqueous solution was purified by reverse-phase HPLC, dried by lyophilization, and the dried 5'-DBCO-functionalized sense chains were reconstituted with RNase-free water.

[0332] Step 2: 5'-ligand conjugate sense chain A solution of ligand A-N3 (2 equivalents) in DMSO or THF was added to a solution of a 5'-DBCO modified sense chain (1 equivalent), and the reaction was monitored by HPLC and LC-MS. Once complete, the 5'-conjugate sense chain was purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter.

[0333] Example 9: General Procedure I Ligand conjugated to the 5' end of a type B sense chain [ka] Step 1: 5'-DBCO functionalized sense chain Add sodium phosphate buffer (10% (V / V), 1M, pH 7) to an aqueous solution of 5'-(C6-SS-C6)-mC functionalized sense chain. Add tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 equivalents) in water (pH 7), and monitor the reaction by HPLC and LC-MS. Once complete, remove excess TCEP with sodium phosphate buffer (100 mM, pH 7, 3×) by molecular weight cutoff. Add a solution of DBCO-MAL (3 equivalents) in DMSO, and monitor the reaction by LC-MS and HPLC. Once complete, remove any solids by centrifugation, purify the solution by reverse-phase HPLC, dry by lyophilization, and reconstitute the dried product with RNase-free water.

[0334] Step 2: 5'-ligand conjugate sense chain A solution of ligand A-N3 (3 equivalents) in DMSO or THF is added to a solution of a 5'-DBCO-functionalized sense chain (1 equivalent), and the reaction is monitored by HPLC and LC-MS. Once complete, the 5'-conjugate sense chain is purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter.

[0335] Example 10: General Procedure Type II A-Bis-Homo-3',5'-Ligand Conjugate Sense Chain [ka] Step 1: 3',5'-bis-DBCO modified sense chain Sodium phosphate buffer (10% (V / V), 1M, pH 7) and acetonitrile (20%-50% (V / V)) were added to an aqueous solution of 3',5' amine-functionalized sense chains. Subsequently, a solution of DBCO-NHS (3 equivalents) in DMSO or CH3CN was added, and the reaction was monitored by LC-MS and HPLC. Upon completion, the product was purified by reverse-phase HPLC, dried by lyophilization, and reconstituted with RNase-free water.

[0336] Step 2: 3',5'-bis-conjugate sense chain A solution of 3',5'-bis-DBCO modified sense chain (1 equivalent) was added to a solution of ligand A-N3 (3 equivalents) in DMSO or CH3CN, and the reaction was monitored by HPLC and LC-MS. Once complete, the 3',5'-bis conjugate sense chain was purified by reverse-phase HPLC, dried by lyophilization, reconstituted with RNase-free water, and desalted using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes).

[0337] Example 11: General Procedure Type II Type B-Bis-Homo-5',3'-Ligand Conjugate Sense Chain [ka] Step 1: 3',5'-bis-DBCO modified sense chain Add sodium phosphate buffer (10% (V / V), 1M, pH 7) to an aqueous solution of 5',3'-bis(C6-SS-C6)-mC functionalized sense chain. Add tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 equivalents) in water (pH 7), and monitor the reaction by HPLC and LC-MS. Once complete, remove excess TCEP with sodium phosphate buffer (100 mM, pH 7, 3×) by MWCO. Add a solution of DBCO-MAL (3 equivalents) in DMSO, and monitor the reaction by LC-MS and HPLC. Once complete, remove any solids by centrifugation, purify the solution by reverse-phase HPLC, dry by lyophilization, and reconstitute the dried bis-DBCO modified sense chain with RNase-free water.

[0338] Step 2: 3',5'-bis-conjugate sense chain A solution of ligand A-N3 (3 equivalents) in DMSO or THF is added to a solution of a 5',3'-bis-DBCO functionalized sense chain (1 equivalent), and the reaction is monitored by HPLC and LC-MS. Once complete, the bis-homo-5'-,3' conjugate sense chain is purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter.

[0339] Example 12: General Procedure Type II C-Bis-Homo-5',3'-Ligand Conjugate Sense Chain [ka] Step 1: 5'-DBCO / 3'-(C6-SS-C6)-mC functionalized sense strand Sodium phosphate buffer (10% (V / V), 1M, pH 7) and acetonitrile (20%-50% (V / V)) were added to an aqueous solution of 5'-amine-functionalized sense chains. Subsequently, a solution of DBCO-NHS (1.5-3 equivalents) in DMSO or acetonitrile was added, and the reaction was monitored by LC-MS and HPLC. Once complete, either precipitate was removed by centrifugation, and the aqueous solution was purified by reverse-phase HPLC. The product fractions were combined and dried by lyophilization, and the dried N-DBCO-modified sense chains were reconstituted in RNase-free water for step 2.

[0340] Step 2: 5',3'-BisDBCO functionalized sense chain Sodium phosphate buffer (10% (V / V), 1M, pH 7) was added to an aqueous solution of 5'-DBCO / 3'-(C6-SS-C6)-mC functionalized sense chains. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 equivalents) in water (pH 7) was added, and the reaction was monitored by HPLC and LC-MS. Once complete, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 equivalents) in DMSO was added, and the reaction was monitored by LC-MS and HPLC. Once complete, any solids were removed by centrifugation, the solution was purified by reverse-phase HPLC, dried by lyophilization, and the dried bis-DBCO modified sense chains were reconstituted in RNase-free water for step 3.

[0341] Step 3: Bis-homo-5',3'-ligand conjugate sense chain A solution (1 equivalent) of a 5'-,3'-bis-DBCO-functionalized sense chain was added to a solution (3 equivalents) of ligand A-N3 in DMSO or THF, and the reaction was monitored by HPLC and LC-MS. Once complete, the bis-homo-5'-,3' conjugate sense chain was purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter. The product was confirmed by HPLC and LC-MS.

[0342] Example 13: General Procedure Type II D-bis-homo-5',3'-ligand conjugate sense chain [ka] Step 1: 5'-(C6-SS-C6)-mC / 3'-DBCO functionalized sense strand Sodium phosphate buffer (10% (V / V), 1M, pH 7) and acetonitrile (20%-50% (V / V)) were added to an aqueous solution of 5'-amine-functionalized sense chains. Subsequently, a solution of DBCO-NHS (1.5-3 equivalents) in DMSO or acetonitrile was added, and the reaction was monitored by LC-MS and HPLC. Once complete, either precipitate was removed by centrifugation, and the aqueous solution was purified by reverse-phase HPLC. The product fractions were combined and dried by lyophilization, and the dried N-DBCO-modified sense chains were reconstituted in RNase-free water for step 2.

[0343] Step 2: 5',3'-BisDBCO functionalized sense chain Sodium phosphate buffer (10% (V / V), 1M, pH 7) was added to an aqueous solution of 5'-DBCO / 3'-(C6-SS-C6)-mC functionalized sense chains. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 equivalents) in water (pH 7) was added, and the reaction was monitored by HPLC and LC-MS. Once complete, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 equivalents) in DMSO was added, and the reaction was monitored by LC-MS and HPLC. Once complete, any solids were removed by centrifugation, the solution was purified by reverse-phase HPLC, dried by lyophilization, and the dried bis-DBCO modified sense chains were reconstituted in RNase-free water for step 3.

[0344] Step 3: Bis-homo-5',3'-ligand conjugate sense chain A solution (1 equivalent) of a 5'-,3'-bis-DBCO-functionalized sense chain was added to a solution (3 equivalents) of ligand A-N3 in DMSO or THF, and the reaction was monitored by HPLC and LC-MS. Once complete, the bis-homo-5'-,3' conjugate sense chain was purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter. The product was confirmed by HPLC and LC-MS.

[0345] Example 14: General Procedure III Type A-Bis-Hetero-3',5'-Ligand Conjugate Sense Chain [ka] Step 1: 5'-Conjugate 3'-(C6-SS-C6)-mC Functionalized Sense Chain An aqueous solution of ligand A-N3 (2 equivalents) in DMSO was added to an aqueous solution of a 5'-DBCO-modified sense chain (1 equivalent; see above for preparation), and the reaction was monitored by HPLC and LC-MS. Once complete, the 5'-conjugate sense chain was purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter.

[0346] Step 2: 5'-Conjugate 3'-DBCO Modified Sense Chain To a solution of 5'-conjugate 3'-(C6-SS-C6)-mC functionalized sense chain (1 equivalent) in water, sodium phosphate buffer (10% (V / V), 1M, pH 7) was added. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP, 25 equivalents) in water (pH 7) was added, and the reaction was monitored by HPLC and LC-MS. Once complete, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 equivalents) in DMSO was added, and the reaction was monitored by HPLC and LC-MS. Once complete, the aqueous solution was purified by reverse-phase HPLC, dried by lyophilization, and the dried 5'-conjugate 3'-DBCO modified sense chain was reconstituted with sodium phosphate buffer (100 mM) for step 3.

[0347] Step 3: Bis-hetero-3',5'-ligand conjugate sense chain An aqueous solution of ligand B-N3 (2 equivalents) in DMSO was added to an aqueous solution of a 5'-conjugate 3'-DBCO-functionalized sense chain (1 equivalent), and the reaction was monitored by HPLC and LC-MS. After completion, the 5'-,3'-conjugate sense chain was purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter.

[0348] Example 15: General Procedure III Type B-Bis-Hetero-3',5'-Ligand Conjugate Sense Chain [ka] Step 1: 5'-(C6-SS-C6)-mC,3'-conjugate sense chain An aqueous solution of ligand A-N3 (2 equivalents) in DMSO was added to an aqueous solution of a 3'-DBCO-modified sense chain (1 equivalent; see above for preparation), and the reaction was monitored by HPLC and LC-MS. Once complete, the 3'-conjugate sense chain was purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifugal filter.

[0349] Step 2: Sense chain of 5'-DBCO,3'-conjugate To a solution of 5'-conjugate 3'-(C6-SS-C6)-mC functionalized sense chain (1 equivalent) in water, sodium phosphate buffer (10% (V / V), 1M, pH 7) was added. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP, 25 equivalents) in water (pH 7) was added, and the reaction was monitored by HPLC and LC-MS. Once complete, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 equivalents) in DMSO was added, and the reaction was monitored by HPLC and LC-MS. Once complete, the aqueous solution was purified by reverse-phase HPLC, dried by lyophilization, and the dried 5'-conjugate 3'-DBCO modified sense chain was reconstituted with sodium phosphate buffer (100 mM) for step 3.

[0350] Step 3: Bis-hetero-3',5'-ligand conjugate sense chain An aqueous solution of ligand B-N3 (2 equivalents) in DMSO was added to an aqueous solution of a 5'-conjugate 3'-DBCO-functionalized sense chain (1 equivalent), and the reaction was monitored by HPLC and LC-MS. After completion, the 5'-,3'-conjugate sense chain was purified by reverse-phase HPLC or molecular weight cutoff (3K, 5 times) using an Amicon® Ultra-15 centrifug...

Claims

1. A compound comprising a modified oligonucleotide having a linked nucleoside length of 14 to 30, wherein the modified oligonucleotide has a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 18, 28 to 106, 184 to 187, 196 to 202, or 214 to 223.

2. A modified oligonucleotide having a length of 14 to 23 units of linked nucleosides, comprising a compound having a nucleic acid base sequence containing the nucleic acid base sequence described in any one of SEQ ID NOs: 11 to 18, 28 to 106, 184 to 187, 196 to 202, or 214 to 223.

3. A compound comprising a modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of SEQ ID NOs: 11-18, 28-106, 184-187, 196-202, or 214-223.

4. The compound according to any one of claims 1 to 3, wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1 or 2.

5. The compound according to any one of claims 1 to 4, wherein the modified oligonucleotide comprises at least one modification selected from modified nucleoside bonds, modified sugars, and modified nucleic acid bases.

6. A compound according to any one of claims 1 to 5, which is double-chain.

7. A compound comprising: a first modified oligonucleotide having a linked nucleoside length of 14 to 23, wherein the first modified oligonucleotide has a nucleic acid base sequence containing at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 consecutive nucleic acid bases as described in any of the nucleic acid base sequences of SEQ ID NOs. 11 to 223; and a second modified oligonucleotide having a linked nucleoside length of 14 to 23, wherein the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.

8. A compound comprising a first modified oligonucleotide having a nucleotide sequence comprising a nucleic acid sequence containing the nucleic acid sequence described in any one of SEQ ID NOs: 11 to 223, wherein the length of the linked nucleoside is 14 to 23, and a second modified oligonucleotide having a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleotide sequence comprising a nucleoside, wherein the region is complementary to the first modified oligonucleotide.

9. A compound comprising a first modified oligonucleotide having a nucleic acid base sequence selected from the group consisting of any one of SEQ ID NOs: 11 to 223, and a second modified oligonucleotide having a linked nucleoside length of 19 to 23, wherein the second modified oligonucleotide has a region complementary to the first modified oligonucleotide.

10. The compound according to any one of claims 7 to 9, wherein the first modified oligonucleotide has complementarity or identity with SEQ ID NO: 1 or 2 over its length of at least 80%, at least 85%, at least 90%, or at least 95%.

11. The compound according to any one of claims 7 to 10, wherein the first modified oligonucleotide has at least one, at least two, or at least three mismatches to the region of SEQ ID NO: 1 or 2, which is the same length as the first modified oligonucleotide.

12. The compound according to any one of claims 7 to 11, wherein the length of the linked nucleoside in the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 14 to 23.

13. The compound according to any one of claims 7 to 11, wherein the length of the linked nucleoside in the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 19 to 23.

14. The compound according to any one of claims 7 to 11, wherein the length of the linked nucleoside in the complementary region between the first modified oligonucleotide and the second modified oligonucleotide is 21 to 23.

15. The compound according to any one of claims 7 to 11, wherein the first modified oligonucleotide is completely complementary to the second modified oligonucleotide.

16. The compound according to any one of claims 7 to 15, wherein the first modified oligonucleotide comprises at least one modification selected from modified nucleoside bonds, modified sugars, and modified nucleic acid bases.

17. The compound according to any one of claims 7 to 16, wherein the second modified oligonucleotide comprises at least one modification selected from the group consisting of modified nucleoside bonds, modified sugars, and modified nucleic acid bases.

18. The compound according to any one of claims 5, 16, and 17, wherein the modified nucleoside bond is a phosphorothioate nucleoside bond or a methylphosphonate nucleoside bond.

19. The compound of claim 18, wherein the phosphorothioate nucleoside bond or methylphosphonate nucleoside bond is located at the 3' end of the first or second modified oligonucleotide, or at the 5' end of the first modified oligonucleotide.

20. The compound according to any one of claims 5, 16, and 17, wherein the modified sugar comprises a modification selected from the group consisting of halogens, alkoxy groups, and bicyclic sugars.

21. The compound of claim 20, wherein the modified sugar includes a 2'-F modification.

22. The compound of claim 20, wherein the modified sugar includes a 2'-OMe modification.

23. The compound according to any one of claims 7 to 15, wherein each nucleoside of the first modified oligonucleotide contains a modified sugar.

24. The compound according to any one of claims 7 to 15, wherein each nucleoside of the second modified oligonucleotide contains a modified sugar.

25. The compound according to claim 23 or 24, wherein the modified sugar comprises a modification selected from the group consisting of halogens, alkoxy groups, and bicyclic sugars, or combinations thereof.

26. The compound according to claim 25, wherein the modified sugar comprises a modification selected from the group consisting of LNA, cEt, 2'-MOE, 2'-F, 2'-OMe, and 2'-deoxy, or combinations thereof.

27. The compound according to claim 26, wherein the first modified oligonucleotide contains 10 or fewer 2'-F sugar modifications.

28. The compound according to claim 27, wherein the second modified oligonucleotide contains five or fewer 2'-F sugar modifications.

29. A compound according to any prior claim, comprising a conjugate group.

30. The compound according to claim 29, wherein the conjugate group is bonded to the 5' end of the modified oligonucleotide.

31. The compound according to claim 29 or 30, wherein the conjugate group includes a targeting moiety.

32. The targeting portion comprises one or more tropomyosin receptor B (TrκB) ligands and one or more cannabinoid receptor type 1 (CB) ligands. １ ) Ligand, one or more α ４ β １／７ The compound according to claim 31, comprising an integrin ligand and one or more ligands selected from one or more N-methyl-D-aspartate receptor (NMDA) ligands.

33. The compound according to claim 32, wherein the modified oligonucleotide is the second modified oligonucleotide.

34. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 33, wherein an integrin ligand, or one or more NMDA ligands, is bound to the 5' end of the modified oligonucleotide.

35. The one or more TrkB ligands, the one or more CB １ ligands, the one or more α ４ β １／７ integrin ligands, or the one or more NMDA ligands are attached to the 3'-end of the modified oligonucleotide, the compound according to claim 33.

36. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 33, wherein an integrin ligand, or one or more NMDA ligands, are bound to the 5' and 3' ends of the modified oligonucleotide.

37. The one or more TrkB ligands are selected from any one of formulas I to XX, XXV, and XXX. The one or more CBs １ The ligand is of formula XXVI, The one or more α ４ β １／７ The integrin ligand is selected from one of the following formulas: XXVII, XXVII, XXXI, and XXXII. The compound according to any one of claims 32 to 36, wherein one or more NMDA ligands are of formula XXIX.

38. The compound according to any one of claims 29 to 37, wherein the conjugate group comprises one or more lipids.

39. The compound according to claim 38, wherein the modified oligonucleotide is the second modified oligonucleotide.

40. The compound according to claim 38 or 39, wherein one or more lipids are bonded to the nucleoside bonds of the modified oligonucleotide.

41. The compound according to claim 40, wherein the nucleoside bond of the modified oligonucleotide is selected from any one of formulas XXI to XXIV and XXXIII to XXXV.

42. The modified oligonucleotide is, One or more TrkB ligands, one or more CBs １ ligand, one or more α ４ β １／７ An integrin ligand, or one or more NMDA ligands, One or more lipids, A compound according to any one of claims 32 to 41, comprising:

43. The compound according to claim 42, wherein the modified oligonucleotide is the second modified oligonucleotide.

44. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 42, wherein an integrin ligand, or one or more NMDA ligands, is bound to the 5' end of the modified oligonucleotide.

45. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 42, wherein an integrin ligand, or one or more NMDA ligands, is bound to the 3' end of the modified oligonucleotide.

46. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 42, wherein an integrin ligand or one or more NMDA ligands are bound to the 5' and 3' ends of the modified oligonucleotide.

47. The one or more TrkB ligands are selected from any one of formulas I to XX, XXV, and XXX. The one or more CBs １ The ligand is of formula XXVI, The one or more α ４ β １／７ The integrin ligand is selected from one of the following formulas: XXVII, XXVII, XXXI, and XXXII. The one or more NMDA ligands are of formula XXIX. The compound according to claim 42.

48. The compound according to any one of claims 42 to 47, wherein one or more lipids are bonded to the nucleoside bonds of the modified oligonucleotide.

49. The compound according to claim 48, wherein the nucleoside bond of the modified oligonucleotide is selected from any one of formulas XXI to XXIV and XXXIII to XXXV.

50. The compound according to any one of claims 1 to 49, wherein the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.

51. The substituted or unsubstituted one or more alkyl or alkenyl groups are saturated or unsaturated C ４ -C ３０ The compound according to claim 50, comprising a hydrocarbon chain.

52. The substituted or unsubstituted one or more alkyl or alkenyl groups are saturated or unsaturated C ５ -C ２０ The hydrocarbon chain comprises, optionally, one or more substituted or unsubstituted alkyl or alkenyl atoms, which are saturated or unsaturated C. １４ -C ２０ The compound according to claim 51, comprising a hydrocarbon chain.

53. The substituted or unsubstituted one or more alkyl or alkenyl groups are saturated or unsaturated C １６ Hydrocarbon chains, saturated or unsaturated carbon １７ Hydrocarbon chains, saturated or unsaturated carbon １８ Hydrocarbon chains, or saturated or unsaturated C ２２ The compound according to claim 52, comprising a hydrocarbon chain.

54. The compound according to any one of claims 50 to 53, wherein one or more substituted or unsubstituted alkyl or alkenyl groups are bonded to the internucleoside bonds of the modified oligonucleotide.

55. The compound according to claim 54, wherein the nucleoside bond of the modified oligonucleotide is selected from any one of formulas XXI to XXIV and XXXIII to XXXV.

56. The compound according to any one of claims 1 to 6, wherein the modified oligonucleotide includes a 5'-phosphonate modification.

57. The compound according to any one of claims 7 to 55, wherein the first modified oligonucleotide comprises a 5'-phosphonate modification.

58. The compound according to claim 56 or 57, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

59. A first modified alkyl group comprising a 5'-phosphonate modification, The first modified oligonucleotide is at least 80% complementary to the region of SEQ ID NO: 1 or 2, A second modified oligonucleotide containing one or more ligands, Compounds containing these compounds.

60. The compound according to claim 59, wherein the first modified oligonucleotide comprises a 5'-terminal nucleoside containing a 5'-phosphonate modification.

61. The compound according to claim 59 or 60, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylenephosphonate modification.

62. The compound according to any one of claims 59 to 61, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification.

63. The compound according to any one of claims 59 to 61, wherein the 5'-phosphonate modification is a 5'-ethylenephosphonate modification.

64. The second modified oligonucleotide comprises one or more TrkB ligands and one or more CBs. １ ligand, one or more α ４ β １／７ A compound according to any one of claims 59 to 63, comprising an integrin ligand and one or more ligands selected from one or more NMDA ligands.

65. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 64, wherein an integrin ligand, or one or more NMDA ligands, is bound to the 5' end of the second modified oligonucleotide.

66. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 64, wherein an integrin ligand, or one or more NMDA ligands, is bound to the 3' end of the second modified oligonucleotide.

67. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 64, wherein an integrin ligand, or one or more NMDA ligands, are bound to the 5' and 3' ends of the second modified oligonucleotide.

68. The one or more TrkB ligands are selected from any one of formulas I to XX, XXV, and XXX. The one or more CBs １ The ligand is of formula XXVI, The one or more α ４ β １／７ The integrin ligand is selected from one of the following formulas: XXVII, XXVII, XXXI, and XXXII. The one or more NMDA ligands are of formula XXIX. The compound according to claim 64.

69. The compound according to any one of claims 59 to 68, wherein the second modified oligonucleotide comprises one or more TrkB ligands.

70. The compound according to claim 69, wherein one or more TrkB ligands are selected from any one of formulas I to XX, XXV, and XXX.

71. The compound according to claim 69 or 70, wherein the second modified oligonucleotide comprises one TrkB ligand.

72. The compound according to claim 69 or 70, wherein the second modified oligonucleotide comprises at least two TrkB ligands.

73. The compound according to claim 72, wherein at least two of the aforementioned TrkB ligands are the same.

74. The compound according to claim 72, wherein at least two of the aforementioned TrkB ligands are different.

75. The second modified oligonucleotide is one or more CBs １ A compound according to any one of claims 59 to 68, comprising a ligand.

76. The one or more CBs １ The compound according to claim 75, wherein the ligand is of formula XXVI.

77. The second modified oligonucleotide is one CB １ The compound according to claim 75 or 76, comprising a ligand.

78. The second modified oligonucleotide has at least two CBs １ The compound according to claim 75 or 76, comprising a ligand.

79. The aforementioned at least two CBs １ The compound according to claim 78, wherein the ligand is the same.

80. The aforementioned at least two CBs １ The compound according to claim 78, wherein the ligand is different.

81. The second modified oligonucleotide contains one or more α ４ β １／７ A compound according to any one of claims 59 to 68, comprising an integrin ligand.

82. The one or more α ４ β １／７ The compound according to claim 81, wherein the integrin ligand is selected from one of the formulas XXVII, XXVII, XXXI, and XXXII.

83. The second modified oligonucleotide is one α ４ β １／７ The compound according to claim 81 or 82, comprising an integrin ligand.

84. The second modified oligonucleotide has at least two α ４ β １／７ The compound according to claim 81 or 82, comprising an integrin ligand.

85. The above at least two α ４ β １／７ The compound according to claim 84, wherein the integrin ligand is the same.

86. The above at least two α ４ β １／７ The compound according to claim 84, wherein the integrin ligand is different.

87. The compound according to any one of claims 59 to 68, wherein the second modified oligonucleotide comprises one or more NMDA ligands.

88. The compound according to claim 87, wherein one or more NMDA ligands are of formula XXIX.

89. The compound according to claim 87 or 88, wherein the second modified oligonucleotide comprises one NMDA ligand.

90. The compound according to claim 87 or 88, wherein the second modified oligonucleotide comprises at least two NMDA ligands.

91. The compound according to claim 90, wherein at least two of the NMDA ligands are the same.

92. The compound according to claim 90, wherein at least two of the NMDA ligands are different.

93. The compound according to any one of claims 59 to 92, wherein the second modified oligonucleotide comprises one or more lipids.

94. The compound according to any one of claims 59 to 93, wherein the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.

95. The substituted or unsubstituted one or more alkyl or alkenyl groups are saturated or unsaturated C ４ -C ３０ The compound according to claim 94, comprising a hydrocarbon chain.

96. The substituted or unsubstituted one or more alkyl or alkenyl groups are saturated or unsaturated C ５ -C ２０ The hydrocarbon chain comprises, optionally, one or more substituted or unsubstituted alkyl or alkenyl atoms, which are saturated or unsaturated C. １４ -C ２０ The compound according to claim 95, comprising a hydrocarbon chain.

97. The substituted or unsubstituted one or more alkyl or alkenyl groups are saturated or unsaturated C １６ Hydrocarbon chains, saturated or unsaturated carbon １７ Hydrocarbon chains, saturated or unsaturated carbon １８ Hydrocarbon chains, or saturated or unsaturated C ２２ The compound according to claim 96, comprising a hydrocarbon chain.

98. The compound according to any one of claims 94 to 97, wherein one or more substituted or unsubstituted alkyl or alkenyl groups are bonded to the internucleoside bond of the second modified oligonucleotide.

99. The compound according to claim 98, wherein the nucleoside bond of the second modified oligonucleotide is selected from any one of formulas XXI to XXIV and XXXIII to XXXV.

100. The compound according to any one of claims 59 to 99, wherein the length of the linked nucleoside in the first modified oligonucleotide is 14 to 30.

101. The compound according to any one of claims 59 to 100, wherein the second modified oligonucleotide has a length of 14 to 30 and has a region complementary to the first modified oligonucleotide.

102. The compound according to any one of claims 59 to 101, wherein the first modified oligonucleotide has a nucleic acid base sequence comprising at least 14 consecutive nucleic acid bases as described in any one of SEQ ID NOs: 11 to 18, 28 to 106, 184 to 187, 196 to 202, or 214 to 223.

103. The compound according to any one of claims 59 to 102, wherein the second modified oligonucleotide has a nucleic acid base sequence comprising at least 14 consecutive nucleic acid bases as described in any one of SEQ ID NOs: 19 to 27, 107 to 183, 188 to 195, and 203 to 213.

104. The compound according to any one of claims 59 to 103, wherein the first modified oligonucleotide is selected from any one of the IA reference numbers in Table 3.

105. The compound according to any one of claims 59 to 104, wherein the second modified oligonucleotide is selected from any one of the IS reference numbers in Table 3.

106. A compound comprising a first modified oligonucleotide selected from the group consisting of any one of the IA reference numbers in Table 3, and a second modified oligonucleotide having a linked nucleoside length of 14 to 21 and being completely complementary to the first modified oligonucleotide.

107. A compound comprising a first modified oligonucleotide selected from the group consisting of any one of the IA reference numbers in Table 3, and a second modified oligonucleotide selected from the group consisting of any one of the IS reference numbers in Table 3.

108. A compound comprising a first modified oligonucleotide selected from the group consisting of any one of the IA reference numbers in Table 3, and a second modified oligonucleotide selected from the group consisting of any one of the IS reference numbers in Table 3.

109. The compound according to claim 106, 107, or 108, comprising a conjugate group.

110. The compound according to claim 109, wherein the conjugate group is bonded to the 5' end of the modified oligonucleotide.

111. The compound according to claim 109 or 110, wherein the conjugate group includes a targeting moiety.

112. The targeting portion comprises one or more tropomyosin receptor B (TrκB) ligands and one or more cannabinoid receptor type 1 (CB) ligands. １ ) Ligand, one or more α ４ β １／７ The compound according to claim 111, comprising an integrin ligand and one or more ligands selected from one or more NMDA ligands.

113. The compound according to claim 112, wherein the modified oligonucleotide is the second modified oligonucleotide.

114. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 112 or 113, wherein an integrin ligand, or one or more NMDA ligands, is bound to the 5' end of the modified oligonucleotide.

115. The one or more TrkB ligands, the one or more CB １ ligands, the one or more α ４ β １／７ integrin ligands, or the one or more NMDA ligands are attached to the 3'-end of the modified oligonucleotide, the compound according to claim 112 or 113.

116. The one or more TrkB ligands, The one or more CBs １ ligand, the one or more α ４ β １／７ The compound according to claim 112 or 113, wherein an integrin ligand, or one or more NMDA ligands, are bound to the 5' and 3' ends of the modified oligonucleotide.

117. The one or more TrkB ligands mentioned above are selected from any one of the formulas I to XX, XXV and XXX. The one or more CBs １ The ligand is of formula XXVI, the above one or more α ４ β １／７ the integrin ligand is selected from any one of Formulas XXVII, XXVIII, XXXI and XXXII The one or more NMDA ligands are of formula XXIX. The compound according to any one of claims 112 to 116.

118. A compound according to any one of claims 1 to 117, which is a pharmaceutically acceptable salt form.

119. The compound according to claim 118, wherein the pharmaceutically acceptable salt is a sodium salt.

120. The compound according to claim 118, wherein the pharmaceutically acceptable salt is a potassium salt.

121. A composition comprising a compound according to any of the prior claims and a pharmaceutically acceptable carrier.

122. A composition comprising a compound described in any of the prior claims for use in therapy.

123. A method for treating, preventing or improving a disease, disorder or condition associated with SOD1 in an individual, comprising administering a compound targeting SOD1 to the individual to treat, prevent or improve the disease, disorder or condition.

124. A method for administering to an individual a compound according to any one of claims 1 to 120 or a composition according to claim 122.

125. The method according to claim 123 or 124, wherein the disease, disorder or condition is a neurodegenerative disease (ALS or its symptoms, such as loss of motor function or death of neurons).

126. The method according to any one of claims 123 to 125, wherein administration of the compound inhibits, reduces or improves neurodegenerative diseases, ALS or its symptoms, such as loss of motor function or neuronal death.

127. A method for inhibiting the expression of SOD1 in cells, comprising contacting the cells with a compound that targets SOD1 to inhibit the expression of SOD1 in the cells.

128. The method according to claim 127, wherein the cells are located in the brain of an individual.

129. The method according to claim 128, wherein the individual has a neurodegenerative disease (ALS or its symptoms, such as loss of motor function or death of neurons) or is at risk thereof.

130. A method for mitigating or inhibiting a neurodegenerative disease (ALS or its symptoms, such as loss of motor function or neuronal death) in an individual, comprising administering a compound targeting SOD1 to the individual to mitigate or inhibit the neurodegenerative disease (ALS or its symptoms, such as loss of motor function or neuronal death).

131. The method according to claim 130, wherein the individual has a neurodegenerative disease (ALS or its symptoms, such as loss of motor function or death of neurons) or is at risk thereof.

132. The method according to any one of claims 123 to 131, wherein the compound is a compound that targets SOD1.

133. The method according to any one of claims 123 to 132, wherein the compound is the compound described in any one of claims 1 to 120 or the composition described in claim 122.

134. The method according to claim 133, wherein the compound or composition is administered parenterally.

135. The method according to claim 133, wherein the compound or composition is administered by intrathecal administration.

136. The use of compounds that target SOD1 to treat, prevent or improve diseases, disorders, or conditions associated with SOD1.

137. The use according to claim 136, wherein the disease, disorder, or condition is a neurodegenerative disease (ALS or its symptoms, such as loss of motor function or death of neurons).

138. The use according to claim 136 or 137, wherein the compound is a compound that targets SOD1.

139. The use according to any one of claims 136 to 138, wherein the compound or modified oligonucleotide is the compound according to any one of claims 1 to 120 or the composition according to claim 122.

140. The manufacture of a pharmaceutical product for the treatment, prevention, or improvement of a disease, disorder, or condition associated with SOD1, using a compound that targets SOD1.

141. The use according to claim 140, wherein the disease is a neurodegenerative disease (ALS or its symptoms, such as loss of motor function or death of neurons).

142. The use according to claim 140 or 141, wherein the compound is a compound that targets SOD1.

143. The use according to any one of claims 140 to 142, wherein the compound or modified oligonucleotide is the compound according to any one of claims 1 to 120 or the composition according to claim 122.

144. The method or use according to any of the prior claims, wherein the compound or composition is administered to an individual approximately once every three months to approximately once a year.

145. The method or use according to any of the prior claims, wherein the compound or composition is administered to an individual about once every three months, about once every six months, or about once a year.

146. A method for delivering a therapeutic oligonucleotide to a target brain, comprising administering to the target a compound according to any one of claims 1 to 120, or a stereoisomer, tautomer, prodrug or salt thereof, or a composition according to claim 122.

147. The method according to claim 146, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, prefrontal cortex, and spinal cord.

148. A method for treating or improving a disease, disorder or symptoms thereof, comprising administering to the subject a compound according to any one of claims 1 to 120, or a stereoisomer, tautomer, prodrug or salt thereof, or a composition according to claim 122.

149. The method according to claim 148, wherein the disease, disorder or symptoms thereof are a disease, disorder or symptoms thereof of the central nervous system (CNS).

150. The method according to claim 148 or 149, wherein the disease, disorder or its symptoms are Alzheimer's disease or its symptoms.

151. The method according to any one of claims 146 to 150, wherein the administration is intrathecal administration or intraventricular (ICV) administration.

152. A method for delivering one or more cargo molecules in vivo to target cells or tissues, comprising administering to the target a compound according to any one of claims 1 to 120 or a composition according to claim 122.

153. The method according to claim 152, wherein the cells or tissue are cells or tissue of a CNS.

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