Alpha 4 beta 1 / 7 integrin ligand conjugate compounds and uses thereof

Abstract

Provided herein are α4β 1 / 7 Integrin receptor ligand-containing compounds, methods of delivering the compounds, and methods of using the compounds to treat diseases, disorders, and conditions in a subject (e.g., diseases, disorders, and conditions of the central nervous system). 1 / 7 The present invention relates to compounds (eg, any of those defined herein) and methods for targeting cells expressing integrin receptors (collectively referred to as "integrin receptors").

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 327,334, filed April 4, 2022. The disclosure of the prior application is considered part of the disclosure of this application and is incorporated by reference in its entirety into the disclosure of this application. [Background technology]

[0002] In using compounds in therapeutic, prophylactic, or diagnostic applications, it is often desirable to deliver the compound to a specific location (e.g., to a desired cell(s)) to enhance therapeutic or prophylactic efficacy or to be advantageous for diagnostic purposes. This frequently occurs when attempting to deliver therapeutic compounds in vivo. Furthermore, the ability to efficiently deliver a compound to a specific location can limit or potentially eliminate unintended consequences (such as off-target effects) that may result from administration of the compound. One strategy to facilitate delivery of a compound, such as a therapeutic, prophylactic, or diagnostic compound, to a desired location in vivo is to link or bind the compound to a targeting ligand.

[0003] One type of compound that can be targeted using a targeting ligand is an oligomeric compound, such as a protein, peptide, antibody, and oligonucleotide. Oligomeric compounds containing a nucleotide sequence (e.g., an oligonucleotide) at least partially complementary to a target nucleic acid have been shown to alter the function and activity of the target both in vitro and in vivo. Oligonucleotides have been shown to regulate the expression or activity of the target nucleic acid when delivered to cells containing the target nucleic acid (e.g., mRNA or pre-mRNA). In certain cases, oligonucleotides can reduce gene expression by inhibiting the translation of the nucleic acid target and / or inducing the degradation of the target nucleic acid.

[0004] When the target nucleic acid is mRNA, one mechanism by which oligonucleotides can regulate the expression of mRNA targets is via RNA interference. RNA interference is a biological process in which RNA or RNA-like molecules (such as chemically modified RNA molecules) can silence gene expression, at least in part, through the RNA-induced silencing complex (RISC) pathway. Furthermore, oligonucleotides can regulate the expression of target nucleic acids, such as target mRNAs, through RNase recruitment mechanisms, microRNA mechanisms, occupancy-based mechanisms, and editing mechanisms. Oligonucleotides can be single-stranded or double-stranded. Oligonucleotides can include DNA, RNA, and RNA-like molecules, and can also include modified nucleosides containing one or more modified sugars, modified nucleobases, and modified internucleoside linkages.

[0005] Another type of compound that can be targeted using targeting ligand is small molecule compound.Small molecule compounds (for example, organic compounds with a molecular weight of less than about 1000 Daltons) have typically been shown to change the function and / or activity of target, and thus regulate or improve disease and / or disease symptoms, or when localized at target, are typically useful as diagnostic markers.More efficiently deliver compounds to specific locations can limit or potentially eliminate the unintended consequences (such as off-target effects) that may occur due to the administration of compounds, and can improve the localization of diagnostic compounds. Summary of the Invention [Means for solving the problem]

[0006] The embodiments provided herein relate to α4β1 integrin receptor and / or α4β7 integrin receptor (referred to herein as "α4β"). 1 / 7 The present invention relates to compounds (e.g., any of those defined herein) and methods for targeting cells expressing α4β integrin receptors (collectively referred to as "integrin receptors"). Certain embodiments provided herein relate to compounds (e.g., any of those defined herein) and methods for targeting cells expressing α4β integrin receptors (collectively referred to as "α4β integrin receptors"). 1 / 7The present invention relates to compounds and methods for delivering an agent to a cell that expresses an integrin receptor. In certain embodiments, the cell is in the brain. In certain embodiments, the cell is in the frontal lobe. In certain embodiments, the cell is in the striatum. In certain embodiments, the cell is in the cerebellum. In certain embodiments, the cell is in the brainstem. In certain embodiments, the cell is in the hippocampus. In certain embodiments, the cell is in the spinal cord. In certain embodiments, the agent is a therapeutic compound. In certain embodiments, delivery of the agent is for the treatment of diseases, disorders, and symptoms in a subject. In certain embodiments, the agent is a diagnostic compound. In certain embodiments, the compound is an α4β 1 / 7 In certain embodiments, the compound comprises an α4β integrin receptor ligand and one or more linker moieties for attachment to a therapeutic, prophylactic, or diagnostic agent. 1 / 7 The α4β ligand comprises an integrin receptor ligand, one or more linker moieties, and a therapeutic agent. In certain embodiments, the therapeutic agent is selected from a small molecule or an oligomeric compound. In certain embodiments, the oligomeric compound is a protein, a peptide, an antibody, an oligonucleotide, or a combination thereof. In certain embodiments, the α4β ligand comprises an integrin receptor ligand, one or more linker moieties, and a therapeutic agent. In certain embodiments, the therapeutic agent is selected from a small molecule or an oligomeric compound. In certain embodiments, the oligomeric compound is a protein, a peptide, an antibody, an oligonucleotide, or a combination thereof. 1 / 7 Integrin receptor ligands are α4β 1 / 7 In certain embodiments, the α4β 1 / 7 Integrin receptor ligands are α4β 1 / 7 In certain embodiments, the α4β 1 / 7 The integrin receptor ligand is a small molecule, an aptamer, a peptide, or an antibody. 1 / 7 The integrin receptor ligand is any of those defined herein, or a derivative or prodrug thereof.

[0007] In certain embodiments, α4β cells, such as brain cells, 1 / 7When a cell expressing an integrin receptor is contacted with a compound provided herein, the agent is delivered to the cell. In certain embodiments, the agent is delivered to an α4β receptor, such as a brain cell. 1 / 7 Contacting a cell expressing an integrin receptor with a compound provided herein treats a disease, disorder, or condition in a subject. 1 / 7 Compounds containing integrin receptor ligands are 1 / 7 Compared with cells that do not express integrin receptors, 1 / 7 In certain embodiments, the α4β integrin receptor is selectively or preferentially targeted to cells expressing the α4β integrin receptor. 1 / 7 Compounds containing integrin receptor ligands are 1 / 7 α4β compared with cells that do not express integrin receptor ligands 1 / 7 Selectively or preferentially target cells expressing integrin receptors.

[0008] Certain embodiments provided herein are directed to α4β 1 / 7 The present invention relates to compounds and methods for modulating expression of nucleic acid targets in cells expressing integrin receptors. In certain embodiments, the cells are in the brain. In certain embodiments, the cells are in the frontal lobe. In certain embodiments, the cells are in the striatum. In certain embodiments, the cells are in the cerebellum. In certain embodiments, the cells are in the brainstem. In certain embodiments, the cells are in the hippocampus. In certain embodiments, the cells are in the spinal cord. In certain embodiments, the cells are α4β, such as brain cells. 1 / 7 Contacting a cell that expresses an integrin receptor with a compound provided herein modulates the expression or activity of a nucleic acid target within the cell. In certain embodiments, the compound modulates the expression or activity of an α4β 1 / 7 It comprises an integrin receptor ligand, one or more linker moieties, and an oligonucleotide.

[0009] The embodiments provided herein with respect to the selection of preferred variables may be employed alone or in combination with one or more embodiments or other preferred variable selections provided herein, as if each combination were explicitly recited herein.

[0010] In one aspect, the disclosure provides compounds comprising the structure of formula (I'), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] Each of the α4β 1 / 7 is an integrin ligand, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; z1 is either 0 or 1).

[0011] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (I″): [ka] (In the formula, [ka] are oligonucleotides, and L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0012] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (I): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0013] In some embodiments, α4β 1 / 7 Integrin ligands are α4β 1 / 7 In some embodiments, the α4β 1 / 7 Integrin ligands are α4β 1 / 7 In certain embodiments, the α4β 1 / 7 The integrin ligand is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein each instance of R is independently [ka] Anti-α4β 1 / 7 integrin antibodies and their derivatives).

[0014] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (II'): [ka] (In the formula, R 2 and R 2A are each independently H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl; R 3 , R 3A , R 4 , and R 4A are each independently H, halogen, optionally substituted alkyl, or optionally substituted —O-alkyl; R 1 , z1, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0015] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (II″): [ka] (In the formula, L1, L2, L3, L4, R 1 , R 2 , R 3 , and R 4 is as defined herein).

[0016] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (II''-a): [ka] (In the formula, L1, L2, L3, L4, R 1 , R 2 , R 3 , and R 4 is as defined herein).

[0017] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (II''-a-1): [ka] (In the formula, L1, L2, L3, L4, R 1 , R 2 , R 3 , and R 4 is as defined herein).

[0018] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (II''-a-2): [ka] (In the formula, L1, L2, L3, L4, R 1 , R 3 , and R 4 is as defined herein).

[0019] In some embodiments, α4β 1 / 7 Integrin ligands have the structure [ka] or derivatives thereof.

[0020] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (II): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0021] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (II-a): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0022] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (III'): [ka] (In the formula, R 2 and R 2A are each independently H, halogen, polyethylene glycol (PEG), optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl; R 3 and R 3A are each independently an optionally substituted heteroalkyl or an optionally substituted heterocyclyl; n and n A are each independently 1, 2, or 3; z1 is 0 or 1, R 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0023] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (III): [ka] (where n, R 1 , R 2 , R 3 , L1, L2, L3, and L4 are as defined herein).

[0024] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (III-a): [ka] (where n, R 1 , R 2 , R 3 , L1, L2, L3, and L4 are as defined herein).

[0025] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (III-b): [ka] (where n, R 1 , R 3 , L1, L2, L3, and L4 are as defined herein).

[0026] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (IV'): [ka] (In the formula, R 2 and R 2A are each independently H, -OH, -NH2, or -NHR 3 , -OR 3 , or absent, R 3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; z1, R 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0027] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (IV): [ka] (In the formula, R 1 , R 2 , L1, L2, L3, and L4 are as described herein).

[0028] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (IV-a): [ka] (In the formula, R 1 , R 2 , L1, L2, L3, and L4 are as described herein).

[0029] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (IV-b): [ka] (In the formula, R 1 , R 2 , L1, L2, L3, and L4 are as described herein).

[0030] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (IV-c): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0031] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (V'): [ka] (In the formula, n and n A are each independently 0, 1, 2, or 3; z 1 , R 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0032] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (V'-a): [ka] (In the formula, R 1 , n, z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0033] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (V): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0034] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (Va): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0035] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (Vb): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0036] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (Vc): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0037] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (Vd): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0038] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (Ve): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0039] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of formula (VI'): [ka] (In the formula, n and n A are each independently 0, 1, 2, or 3; z 1 , R 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0040] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VI'-a): [ka] (In the formula, R 1 , n, n A , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0041] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VI): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0042] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VI-a): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0043] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VI-b): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0044] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VI-c): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0045] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VI-d): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0046] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII'): [ka] (In the formula, R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , and R 5A are each independently H, halogen, optionally substituted alkyl, optionally substituted —O-alkyl, cycloalkyl, or absent; R 8 and R 8Aare each independently optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl, or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy; R 6 , R 6A , R 7 , and R 7A are each independently H, halogen, alkyl, optionally substituted alkyl, optionally substituted heteroalkyl, [ka] and R 1 , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0047] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VII'-a): [ka] (In the formula, R 1 , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0048] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII'-a-1): [ka] (In the formula, R 1 , z 1, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0049] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII'-a-2): [ka] (In the formula, R 1 , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0050] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VII): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , L1, L2, L3, and L4 are as defined herein).

[0051] In certain embodiments, R 6 is F, CF3, or CH3, and R 7 teeth, [ka] In certain embodiments, R 7 is F, CF3, or CH3, and R 6 teeth, [ka] is.

[0052] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VII-a): [ka] (In the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , L1, L2, L3, and L4 are as defined herein).

[0053] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-b): [ka] (In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , L1, L2, L3, and L4 are as defined herein).

[0054] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-c): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, L1, L2, L3, and L4 are as defined herein).

[0055] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-c-1): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , L1, L2, L3, and L4 are as defined herein).

[0056] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-c-2): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , L1, L2, L3, and L4 are as defined herein).

[0057] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0058] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-1): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0059] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-2): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0060] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-3): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0061] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-4): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0062] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-5): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0063] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-6): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0064] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-7): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0065] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-8): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0066] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-9): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0067] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VII-d-10): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0068] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VIII'): [ka] (In the formula, R 2 and R 2A are each independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or absent; R 3 , R 3A , R 4 , and R 4A are each independently H, halogen, optionally substituted alkyl, or optionally substituted —O-alkyl; R 5 and R 5A are each independently -OH or absent, Y and Y Aare each independently -CH- or -(CH)-; R 1 , z1, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0069] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VIII'-a): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , Y, R 2A , R 3A , R 4A , R 5A , Y A , z1, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0070] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VIII): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , Y, L1, L2, L3, and L4 are as defined herein).

[0071] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VIII-a): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , Y, L1, L2, L3, and L4 are as defined herein).

[0072] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VIII-a-1): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , Y, L1, L2, L3, and L4 are as defined herein).

[0073] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (VIII-a-2): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , Y, L1, L2, L3, and L4 are as defined herein).

[0074] In some embodiments, the compound comprises the structure of formula (VIII-a-3): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , Y, L1, L2, L3, and L4 are as defined herein).

[0075] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (IX'): [ka] (In the formula, R 2 and R 2A each independently represents H, -OH, -NH2, -NHR 3 , -OR 3 , or -CONHR 3 and R 3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; n and n A each of is independently 1 or 2, R 1 , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0076] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (IX): [ka] (In the formula, R 1 , R 2 , n, L1, L2, L3, and L4 are as defined herein).

[0077] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (IX-a): [ka] (In the formula, R1 , R 2 , n, L1, L2, L3, and L4 are as defined herein).

[0078] In some embodiments, the compound comprises the structure of formula (IX-b): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0079] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (X'): [ka] (In the formula, R 2 and R 2A are each independently H, -CH2OR 3 , -(CH2)2OR 3 , -CH2NHCOR 3 , or -OR 3 and R 3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 1 , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0080] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (X): [ka] (In the formula, R 1 , R 2 , L1, L2, L3, and L4 are as described herein).

[0081] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (Xa): [ka] (In the formula, R 1 , R 2 , L1, L2, L3, and L4 are as described herein).

[0082] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (Xb): [ka] (In the formula, R 1 , L1, L2, L3, and L4 are as defined herein).

[0083] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XI'): [ka] (In the formula, R 2 and R 2A each of which is independently H, -CONHR 3 , -CH2OR 3 , -(CH2)2OR 3 , -CH2NHCOR 3 , or -OR 3 and R 3is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; X and X A each is independently H or a halogen; R 1 , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0084] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XI): [ka] (In the formula, R 1 , R 2 , X, L1, L2, L3, and L4 are as defined herein).

[0085] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XI-a): [ka] (In the formula, R 1 , R 2 , X, L1, L2, L3, and L4 are as defined herein).

[0086] A compound, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of formula (XI-b): [ka] (In the formula, R 1 , X, L1, L2, L3, and L4 are as defined herein).

[0087] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XII'): [ka] (In the formula, R 2 and R 2A each of which is independently H, -CONHR 4 , -CH2OR 4 , -(CH2)2OR 4 , -CH2NHCOR 4 , or -OR 4 and R 3 and R 3A each is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 4 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 5 and R 5A each of is independently —OH or absent, n and n A are independently 0, 1, 2, or 3, n1 and n1 A is independently 1, 2, or 3, R 1 , z 1 , L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0088] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XII): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n, n1, L1, L2, L3, and L4 are as defined herein).

[0089] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XII-a): [ka] (In the formula, R 1 , R 2 , R 4 , n, L1, L2, L3, and L4 are as defined herein).

[0090] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XII-b): [ka] (In the formula, R 1 , n, L1, L2, L3, and L4 are as defined herein).

[0091] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XIII'): [ka] (In the formula, R 2 and R 2A each of which is independently H, -CONHR 4 , -CH2OR 4 , -(CH2)2OR 4 , -CH2NHCOR 4 , or -OR4 and R 3 and R 3A each is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 4 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 5 and R 5A each of is independently —OH or absent, X and X A each is independently H, optionally substituted CH, optionally substituted NH, or cycloalkyl; R 1 , z1, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0092] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XIII): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X, L1, L2, L3, and L4 are as defined herein).

[0093] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XIII-a): [ka] (In the formula, R1 , R 2 , R 3 , R 4 , X, L1, L2, L3, and L4 are as defined herein).

[0094] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XIII-b): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , X, L1, L2, L3, and L4 are as defined herein).

[0095] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XIII-c): [ka] (In the formula, R 1 , X, L1, L2, L3, and L4 are as defined herein).

[0096] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XIV'): [ka] (In the formula, R 2 and R 2A each of which is independently H, -CH2OR 4 , -(CH2)2OR 4 , -CH2NHCOR 4 , or -OR 4 and R 3 and R 3Aeach independently represents H, -OH, -NH2, -NHR 5 , or -OR 5 and R 4 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 5 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; n and n A each of is independently 1, 2, or 3; R 1 , z1, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is as defined herein).

[0097] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XIV): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n, L1, L2, L3, and L4 are as defined herein).

[0098] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XIV-a): [ka] (In the formula, R 1 , R 2, n, L1, L2, L3, and L4 are as defined herein).

[0099] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of formula (XIV-b): [ka] (In the formula, R 1 , R 3 , n, L1, L2, L3, and L4 are as defined herein).

[0100] In some embodiments, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A each is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, an optionally substituted saturated or partially unsaturated heterocycloalkyl linker, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester linkage, or a phosphorothioate linkage.

[0101] In certain embodiments, L and / or L 1A is a bond.

[0102] In some embodiments, L and / or L 2A is an optionally substituted PEG linker. In some embodiments, the PEG linker is 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length. In certain embodiments, L and / or L 2A is the structure [ka] Includes.

[0103] In some embodiments, L3 and / or L 3A is an optionally substituted heteroaryl linker. In some embodiments, L and / or L 3A is an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, L and / or L 3A is the structure [ka] Includes.

[0104] In some embodiments, L4 and / or L 4A is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In some embodiments, the heteroalkyl linker comprises two substituents bonded together to form an optionally substituted carbocyclyl ring. In certain embodiments, L and / or L 4A is the structure [ka] wherein X is O or S. In certain embodiments, L and / or L 4A is the structure [ka] wherein X is O or S.

[0105] In certain embodiments, L1, L2, L3, and L4 and / or L 1A , L 2A , L 3A , and L 4A Together, the structure [ka] [ka] wherein X is O or S.

[0106] In certain embodiments, the compound comprises the following structure: [ka] [ka] [ka] [ka] [ka] [ka] wherein X is O or S.

[0107] In certain embodiments, X is O. In certain embodiments, X is S.

[0108] In some embodiments, R 1 comprises an oligonucleotide. In some embodiments, the oligonucleotide is attached at its 5' end. In some embodiments, the oligonucleotide is attached at its 3' end. In some embodiments, the oligonucleotide is attached at an internal position of the oligonucleotide. In certain embodiments, the internal position is an internucleoside linkage. In some embodiments, R 1 one or more additional α4β 1 / 7In some embodiments, the oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional α4β ligands. 1 / 7 In certain embodiments, the additional α4β 1 / 7 The ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, one or more internal positions of the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0109] In another aspect, the present disclosure provides a composition comprising any of the compounds disclosed herein, or a stereoisomer, tautomer, prodrug, or salt thereof, and a pharmaceutically acceptable excipient.

[0110] In another aspect, the present disclosure provides a method for delivering a therapeutic oligonucleotide to the brain of a subject, comprising administering to the subject any of the compounds provided herein, or a stereoisomer, tautomer, prodrug, or salt thereof, or any of the compositions provided herein. In some embodiments, the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal lobe, and spinal cord.

[0111] In another aspect, the present disclosure provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject, comprising administering to the subject any of the compounds disclosed herein, or a stereoisomer, tautomer, prodrug, or salt thereof, or any of the compositions disclosed herein. In some embodiments, the disease, disorder, or symptom thereof is a disease, disorder, or symptom thereof of the central nervous system (CNS). In certain embodiments, the disease, disorder, or symptom thereof is Alzheimer's disease, or a symptom thereof. In certain embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, is administered intrathecally to the subject.

[0112] In another aspect, the disclosure provides methods of making any of the compounds disclosed herein, or stereoisomers, tautomers, prodrugs, or salts thereof, comprising one or more compounds, including Examples 1-13, and chemical transformations described herein. [Brief explanation of the drawings]

[0113] [Figure 1] 1H NMR of Compound 2 in Example 1 is shown.

[0114] [Figure 2] 1H NMR of Compound 5 of Example 1 is shown.

[0115] [Figure 3] 1H NMR of Compound 6 in Example 1 is shown.

[0116] [Figure 4] 1H NMR of Compound 7 of Example 1 is shown.

[0117] [Figure 5] 1H NMR of Compound 8 of Example 1 is shown.

[0118] [Figure 6]1H NMR of Compound 10 of Example 1 is shown.

[0119] [Figure 7A] The characterization of compound 11 of Example 1 is shown. 1H NMR is shown. [Figure 7B] 1 shows the characterization of compound 11 of Example 1. LC / MS is shown. [Figure 7C] 1 shows the characterization of compound 11 of Example 1. Mass spectrometry data is shown. DETAILED DESCRIPTION OF THE INVENTION

[0120] definition It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed embodiments. As used herein, the use of the singular includes the plural unless expressly stated otherwise. As used herein, the use of "or" means "and / or" unless otherwise indicated. Furthermore, the use of the term "including" and other forms, such as "includes" and "included," is not limiting. The section headings used herein are merely organizational and should not be construed as limiting the subject matter described.

[0121] Unless otherwise indicated, the following terms have the following meanings:

[0122] As used herein, the term "treating" a disorder includes ameliorating, alleviating, and / or managing the disorder and / or conditions that may cause the disorder. The terms "treating" and "treatment" refer to a method of alleviating or reducing a disease and / or its associated symptoms. According to the present disclosure, "treating" includes, for example, blocking, inhibiting, attenuating, protecting against, modulating, reversing, or reducing the occurrence of the deleterious effects of a disorder. As used herein, "inhibiting" includes preventing, alleviating, and halting progression.

[0123] The terms "isolated," "purified," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it when found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography (HPLC). In particular, in certain embodiments, the compounds are at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0124] The term "administration" or "administering" includes routes of introducing a compound(s) into a subject to perform its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0125] The term "effective amount" includes an amount effective at dosages and for periods of time necessary to achieve the desired result. The effective amount of a compound can vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide an optimal therapeutic response. An effective amount is also an amount in which any intolerable or adverse effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.

[0126] As used herein, the terms "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered" refer to administration of a compound(s), oligonucleotide(s), drug, or other substance such that it enters the patient's circulatory system and undergoes metabolism and other similar processes.

[0127] The term "therapeutically effective amount" refers to that amount of compound being administered that is sufficient to prevent the occurrence of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.

[0128] A therapeutically effective amount (i.e., an effective dosage) of a compound may range from about 0.005 μg / kg body weight to about 200 mg / kg body weight, preferably from about 0.01 mg / kg body weight to about 200 mg / kg body weight, and more preferably from about 0.015 mg / kg body weight to about 30 mg / kg body weight. In other embodiments, a therapeutically effective amount may range from about 1.0 pM to about 10 μM. One of ordinary skill in the art will recognize that certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's overall health and / or age, and other diseases present, may influence the dosage required to effectively treat a subject. Furthermore, treatment of a subject with a therapeutically effective amount of a compound may include a single treatment or, preferably, may include a series of treatments. In one example, a subject is treated daily, weekly, monthly, quarterly, or yearly with a compound in the range of about 0.005 μg / kg body weight to about 200 mg / kg body weight. In another example, a subject may be treated daily, weekly, monthly, quarterly, or yearly for several years in the case of a chronic condition or disease. It will also be appreciated that the effective dosage of the compound used for treatment may increase or decrease over a particular course of treatment.

[0129] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, and the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0130] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds, and their enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids, (D)- or (L)-, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure form. Optically active (R)- and (S)-isomers, or (D)- and (L)-isomers, can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other center of geometric asymmetry, unless otherwise specified, it is intended that the compound include both the E and Z geometric isomers.

[0131] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0132] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0133] Unless otherwise specified, structures depicted herein are also meant to include all stereochemical forms (i.e., the R and S configurations at each asymmetric center). Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0134] As used herein, "chirally enriched population" refers to a plurality of molecules of the same molecular formula, wherein the number or percentage of molecules in the population that contain a specific stereochemical configuration at a specific chiral center is greater than the number or percentage of molecules that would be expected to contain the same specific stereochemical configuration at the same specific chiral center in the population if the specific chiral center were stereorandom. A chirally enriched molecular population with multiple 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.

[0135] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, a hydrogen atom is replaced by deuterium or tritium, or a carbon atom is replaced by an isotopically enriched atom. 13 C or 14 Compounds having this structure except for the replacement by a C-enriched carbon are within the scope of this disclosure.

[0136] As used herein, "stereorandom chiral centers" in the context of a population of molecules of the same molecular formula refers to chiral centers having random stereochemical configurations. For example, in a population of molecules containing stereorandom chiral centers, the number of molecules having stereorandom chiral centers in the (S) configuration may be, but is not necessarily, the same as the number of molecules having stereorandom chiral centers in the (R) configuration. The stereochemical configuration of a chiral center is considered random if it is the result of a synthetic method not designed to control the stereochemical configuration. In certain embodiments, the stereorandom chiral centers are stereorandom phosphorothioate internucleoside linkages.

[0137] The term "diastereomer" refers to a stereoisomer with two or more centers of asymmetry and whose molecules are not mirror images of one another.

[0138] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate."

[0139] The term "isomer" or "stereoisomer" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.

[0140] The term "prodrug" is intended to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active form of a compound (e.g., a biologically active form of a nucleic acid) or an analog thereof as described herein. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound (e.g., a nucleic acid) or an analog thereof. A prodrug may be inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions regarding prodrugs are found in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying functional groups present in the active compound such that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent active compound. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group is bonded to any group that is cleaved to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of suitable prodrugs include, but are not limited to, glutathione, acyloxy, thioacyloxy, 2-carbalkoxyethyl, disulfide, thiaminal, and enol ester derivatives of phosphorus atom-modified nucleic acids. The term "prooligonucleotide" or "pronucleotide" or "nucleic acid prodrug" refers to an oligonucleotide modified to be a prodrug of an oligonucleotide. Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., "Prodrugs or phosphonates and phosphates: crossing the membrane" Top. Curr. Chem. 2015, 360:115-160, the entire contents of which are incorporated herein by reference. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In embodiments, the compounds of the present disclosure are prodrugs of any of the formulas herein.

[0141] The term "prodrug" includes compounds having a moiety that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to become active drugs. Examples of prodrugs and their uses are well known in the art (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of a compound, or they can be prepared by separately reacting a purified compound, in its free acid form or at a hydroxyl group, with a suitable esterifying agent. A hydroxyl group can be converted to an ester by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionate esters and acyl esters. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In an embodiment, the compounds of the present disclosure are prodrugs of any of the formulas herein.

[0142] The term "subject" refers to an animal, e.g., a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human.

[0143] The terms "a," "an," and "the" as used in this application, including the claims, refer to "one or more." Thus, for example, a reference to "a sample" includes multiple samples unless the context clearly dictates otherwise (e.g., multiple samples), and so forth.

[0144] Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in a non-exclusive sense unless the context otherwise requires.

[0145] As used herein, the term "about," when referring to a value, is meant to encompass variations of, in some embodiments, ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, where such variations are appropriate for practicing the disclosed methods or utilizing the disclosed compositions.

[0146] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon) having the specified number of carbon atoms, or combinations thereof, which may be fully saturated, monounsaturated (e.g., alkene or alkenyl), or polyunsaturated (e.g., alkyne or alkynyl), and may include monovalent, divalent, and polyvalent radicals, such as C1-C 24 means 1 to 24 carbon atoms. Specific numbers of carbon atoms within this range include, for example, C1-C 20 Alkyl (having 1 to 20 carbon atoms), C1-C 12 Includes alkyl (having 1 to 12 carbon atoms) and C1-C4 alkyl (having 1 to 4 carbon atoms).

[0147] The term "alkenyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups can be optionally substituted with one or more substituents.

[0148] The term "alkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups can be optionally substituted with one or more substituents.

[0149] The term "lower alkyl" refers to a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups can be optionally substituted with one or more substituents.

[0150] The term "haloalkyl" refers to an alkyl group substituted by one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl. The term "arylalkenyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, and wherein the sp of the alkenyl unit is 0 or 1. 2 One or more of the hybridized carbons is attached to an aryl moiety. Alkenyl groups can be optionally substituted with one or more substituents.

[0151] The term "arylalkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond, in which one or more of the sp hybridized carbons of the alkynyl unit is attached to an aryl moiety. The alkynyl group can be optionally substituted with one or more substituents.

[0152] sp of alkenyl and alkynyl groups 2The hybridized or sp hybridized carbon may optionally be the point of attachment of an alkenyl or alkynyl group, respectively.

[0153] The term "alkoxy" refers to an --O-alkyl substituent.

[0154] As used herein, the terms "halogen," "hal," or "halo" mean -F, -Cl, -Br, or -I.

[0155] The term "alkylthio" refers to an --S-alkyl substituent.

[0156] The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

[0157] The term "haloalkoxy" refers to an -O-alkyl substituted by one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0158] The term "haloalkoxyalkyl" refers to alkyl-O-alkyl', where the alkyl' is substituted with one or more halo substituents.

[0159] The term "haloalkylaminocarbonyl" refers to -C(O)-amino-alkyl, where the alkyl is substituted by one or more halo substituents.

[0160] The term "haloalkylthio" refers to an -S-alkyl substituted by one or more halo substituents. Examples of haloalkylthio groups include trifluoromethylthio and 2,2,2-trifluoroethylthio.

[0161] The term "haloalkylcarbonyl" refers to -C(O)-alkyl substituted by one or more halo substituents. An example of a haloalkylcarbonyl group is trifluoroacetyl.

[0162] The term "cycloalkyl" refers to a 3- to 8-membered monocyclic or 7- to 14-membered bicyclic hydrocarbon ring system having at least one saturated ring or at least one non-aromatic ring, where the non-aromatic ring may have some degree of unsaturation. A cycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0163] The term "cycloalkoxy" refers to an --O-cycloalkyl substituent.

[0164] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0165] The term "cycloalkylalkoxy" refers to an --O-alkyl-cycloalkyl substituent.

[0166] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0167] The term "aryl" refers to a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. An aryl group can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of an aryl group can be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0168] The term "aryloxy" refers to an --O-aryl substituent.

[0169] The term "arylalkoxy" refers to an --O-alkyl-aryl substituent.

[0170] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.

[0171] The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.

[0172] The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0173] The term "arylalkylsulfonyl" refers to an -S(O)2-alkyl-aryl substituent.

[0174] The term "arylalkylsulfinyl" refers to an -S(O)-alkyl-aryl substituent.

[0175] The term "aryloxyalkyl" refers to an alkyl-O-aryl substituent.

[0176] The term "alkylaryl" refers to an -aryl-alkyl substituent.

[0177] The term "arylalkyl" refers to an -alkyl-aryl substituent.

[0178] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and / or S), wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) (e.g., O, N, P, Si, and / or S) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. A heteroalkyl is a non-cyclized chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety can include two, optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety can include three, optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety can include four, optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety can include five, optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). A heteroalkyl moiety can include up to eight or more, optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P).

[0179] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is dictated by the direction written in the formula of the linking group. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups as used herein include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -S0R'. When "heteroalkyl" is shown and followed by a list of specific heteroalkyl groups, such as -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are listed for clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R''.

[0180] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified, but not limited to, -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkene.

[0181] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Furthermore, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0182] The term "heteroaryl" refers to a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic aromatic ring system having 1-4 ring heteroatoms in the monocyclic ring, 1-6 heteroatoms in the bicyclic ring, or 1-9 heteroatoms in the tricyclic ring, wherein the heteroatoms are selected from O, N, or S, and the remaining ring atoms are carbon (with appropriate hydrogen atoms unless otherwise specified). Heteroaryl groups can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group can be substituted by a substituent. Heteroaryl groups can be fully unsaturated or partially unsaturated and partially saturated. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolylthiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0183] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0184] The term "heteroaryloxy" refers to an --O-heteroaryl substituent.

[0185] The term "heteroarylalkoxy" refers to an --O-alkyl-heteroaryl substituent.

[0186] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0187] The term "nitrogen-containing heteroaryl" refers to a heteroaryl group having 1 to 4 ring nitrogen heteroatoms if monocyclic, 1 to 6 ring nitrogen heteroatoms if bicyclic, or 1 to 9 ring nitrogen heteroatoms if tricyclic.

[0188] The term "heterocycloalkyl" refers to a 3- to 8-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 14-membered tricyclic non-aromatic ring system containing 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic ring, wherein the heteroatoms are selected from O, N, S, B, P, or Si, and the non-aromatic ring system is fully saturated. Heterocycloalkyl groups can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group can be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thiirenyl, and the like.

[0189] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0190] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl further substituted with one or more amino groups. The terms "hydroxyalkyl" or "hydroxylalkyl" refer to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl or aryl portions of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl can be optionally substituted with one or more substituents.

[0191] [ka] The symbol indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0192] The term "nucleobase" refers to nitrogen-containing biological compounds that form nucleosides. Nucleobases include purine bases and pyrimidine bases. The five nucleobases, adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), are referred to as primary or canonical nucleobases. When a nucleobase is listed in a formula definition, it refers to the moiety that is covalently attached to the listed formula.

[0193] The term "modified nucleobase" refers to a derivative of a nucleobase. Examples of modified nucleobases include, but are not limited to, xanthine, hypoxanthine, 7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, 5-hydroxymethylcytosine, purine, 2,6-diaminopurine, and 6,8-diaminopurine. When a modified nucleobase is listed in a formula definition, it refers to a moiety that is covalently linked to the listed formula.

[0194] The terms "substituent" and "substituent group" refer to an atom or group that replaces an atom or group in a specified parent compound. For example, a substituent in a modified nucleoside is an atom or group that is different from the atom or group found in a naturally occurring nucleoside (e.g., a modified 2'-substituent is any atom or group other than H or OH at the 2' position of a nucleoside). Substituents can be protected or unprotected. Substituents can also be further substituted with other substituents, attached to the parent compound directly or through a linking group such as an alkyl or hydrocarbyl group. Similarly, as used herein, "substituent" in reference to a chemical functional group refers to an atom or group of atoms that is different from the atom or group of atoms normally present in the specified functional group. In certain embodiments, substituents on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be at any atom of the group, and any group that can be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, etc.) can be optionally substituted with one or more substituents (which can be the same or different) that each replace a hydrogen atom.Examples of suitable substituents include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, Examples include, but are not limited to, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido, carbamyl, thioureido, thiocyanato, sulfamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N'-aryl, N''-hydroxyamidinyl.In certain embodiments, substituents on any group include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, thiocarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl, or amido. In certain embodiments, substituents on any group include alkyl, halogen, haloalkyl, cyano, nitro, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, thio, mercapto, mercaptoalkyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkylamino.

[0195] The term "protecting group" or "protecting moiety" refers to a substituent commonly employed to block or protect a particular functionality while allowing reactions of other functional groups on a compound, its derivatives, or conjugates, including nitrogen protecting groups when attached to a nitrogen atom and oxygen protecting groups when attached to an oxygen atom. Nitrogen protecting groups and oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0196] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups, and each R aa , R bb , and R cc are independently alkyl, cycloalkyl, aryl, or heteroaryl, each of which is selected from 1 to 3 independent R dd and each R ddare independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoa Nitrogen protecting groups are well known in the art and are described in, for example, Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 30, 1999, pp. 111-114, 1999. Nitrogen protecting groups are well known in the art and are described in, for example, Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M.Wut ... rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0197] Amide nitrogen protecting groups (e.g., -C(=O)R aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0198] Carbamate nitrogen protecting groups (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl ethyl carbamate (Troc), and 2-trimethylsilyl ethyl carbamate (Tmoc). Tyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bum eoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl Dithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitribenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 -methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzylcarbamate.

[0199] Sulfonamide nitrogen protecting groups (e.g., -S(=O)R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- These include, but are not limited to, dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0200] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacylate 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, N-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl ... amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorsalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,These include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenylphosphoramidate benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0201] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2(wherein, R aa , R bb , and Rcc Oxygen protecting groups include, but are not limited to, oxygen protecting groups (as defined herein). Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0202] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM). , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3- (Imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS) ), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophen noxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), t-butyl carbonate (BOC), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate benzoate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl These include, but are not limited to, methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0203] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa, -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2(wherein, R aa , R bb , and R cc Sulfur protecting groups include, but are not limited to, aryl, aryl- ... rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0204] The term "antisense oligonucleotide" or "antisense strand" means an oligonucleotide that contains a region that is complementary to a target nucleic acid.

[0205] The term "composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to a subject. For example, a composition can include one or more compounds or salts thereof and a sterile aqueous solution.

[0206] The term "nucleic acid" refers to a molecule composed of linked monomeric nucleotides or nucleosides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0207] The term "nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkages.

[0208] The term "nucleoside" refers to a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. A "modified nucleoside" refers to a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

[0209] The term "oligomeric compound" refers to a polymer of linked subunits. With respect to a protein, peptide, polypeptide, or antibody, "subunit" refers to an amino acid or peptide bond. With respect to an oligonucleotide, "subunit" refers to a nucleotide, nucleoside, nucleobase, or sugar, or a modified nucleotide, nucleoside, nucleobase, or sugar, as provided herein.

[0210] The term "oligonucleotide" refers to a polymer of linked nucleosides (e.g., polynucleotide, nucleic acid, polymer of nucleotides), each of which may be modified or unmodified, independently of the other. Without limitation, an oligonucleotide may be composed of ribonucleic acid (e.g., composed of ribonucleosides), deoxyribonucleic acid (e.g., composed of deoxyribonucleosides), modified nucleic acid (e.g., composed of modified nucleobases, sugars, and / or phosphate groups), or a combination thereof. Examples of oligonucleotide compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), oligonucleotides targeting microRNA (miRNA), miRNA mimics, occupancy-based compounds (e.g., compounds that block mRNA processing or translation and splicing compounds), and editing compounds (e.g., ADAR recruiting molecules, ADAR targeting molecules, single-stranded guide nucleic acids, or combinations thereof). 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 mimics), which act, at least in part, through the RNA-induced silencing complex (RISC) pathway, resulting in sequence-specific degradation and / or sequestering 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 capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, small interfering RNA, small interfering oligonucleotide, small interfering nucleic acid, small interfering modified oligonucleotide, chemically modified siRNA, etc. Furthermore, the term "RNAi" is intended to be equivalent to other terms used to describe sequence-specific RNA interference.

[0211] The terms "target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

[0212] The term "therapeutic compound" includes any pharmaceutical agent or compound that provides a therapeutic benefit to a subject. Therapeutic compounds include nucleic acids, oligomeric compounds, oligonucleotides, proteins, peptides, antibodies, small molecules, and other such agents.

[0213] "Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

[0214] "Targeting moiety" means a conjugate group that enhances affinity for a selected target, e.g., a molecule, a cell or cell type, a compartment, e.g., a cellular or organ compartment, a tissue, an organ, or a region of the body, e.g., compared to the compound in the absence of the moiety.

[0215] "Terminal group" means a chemical group or group of atoms covalently attached to the end of an oligonucleotide.

[0216] "Derivative" means a molecule or compound described herein that has been transformed by a chemical reaction.

[0217] The term "ligand" refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biological molecule. In some embodiments, a ligand is a small molecule. In some embodiments, a ligand binds to a protein (e.g., a receptor). In certain embodiments, a ligand binds to an α4β 1 / 7 Binds to integrin receptors.

[0218] "α4β 1 / 7The term "integrin receptor" refers to the heterodimeric integrin receptor formed by the association of integrin α4 with integrin β1 (i.e., α4β1 integrin receptor) and the heterodimeric integrin receptor formed by the association of integrin α4 with integrin β7 (i.e., α4β7 integrin receptor). In certain embodiments, the α4β 1 / 7 The integrin receptor ligand has a higher binding affinity for the α4β1 integrin receptor than for the α4β7 integrin receptor. 1 / 7 Integrin receptor ligands have a higher binding affinity for the α4β7 integrin receptor than for the α4β1 integrin receptor.

[0219] The terms "sense oligonucleotide" or "sense strand" refer to the strand of a double-stranded compound that includes a region that is substantially complementary to a region of the antisense strand of the double-stranded compound.

[0220] The terms "microRNA" and "miRNA," which may be used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides in length) non-coding ribonucleic acid (RNA) that is involved in the post-transcriptional control of gene expression in multicellular organisms by influencing both mRNA stability and translation. miRNAs are transcribed by RNA polymerase II as capped and polyadenylated primary transcripts (pri-miRNAs), which may or may not encode proteins. The primary transcripts are cleaved by the Drosha ribonuclease III enzyme to generate approximately 70-nucleotide-long stem-loop precursor miRNAs (pre-miRNAs), which are further processed in the RNAi pathway. As part of this pathway, the pre-miRNAs are cleaved by the cytoplasmic Dicer ribonuclease to generate mature miRNA products and antisense miRNA star (miRNA*) products. Mature miRNAs are incorporated into RNA-induced silencing complexes (RISCs), which recognize target mRNAs through imperfect base pairing (i.e., partial complementarity) with the miRNA, most commonly resulting in translational inhibition or destabilization of the target mRNA. This mechanism most often occurs through binding of the miRNA to the 3' untranslated region (UTR) of the target mRNA, which can reduce gene expression by either inhibiting translation (e.g., by blocking ribosomal access required for translation) or directly causing transcript degradation. The term (i.e., miRNA) can be used herein to refer to any form of the miRNA of interest (e.g., precursor miRNA, primary miRNA, and / or mature miRNA).

[0221] The terms "small interfering RNA," "small interfering RNA," and "siRNA," which may be used interchangeably herein, refer to RNA molecules that exist as non-coding double-stranded RNA (dsRNA) molecules about 20 to about 24 nucleotides in length and are useful for RNA interference (RNAi). siRNAs are often found to have a phosphorylated 5' end and a hydroxylated 3' end, with the 3' end typically having an overhang that extends two nucleotides beyond the 5' end of the antiparallel strand (e.g., the complementary strand of the dsRNA molecule). siRNAs can interfere with the expression of specific genes by binding to a complementary target sequence (e.g., a target nucleic acid sequence) and inducing (e.g., promoting, inducing, or initiating) mRNA degradation, thereby inhibiting (e.g., suppressing, silencing, or interfering with) translation. After incorporation into and segregation into the RISC complex, siRNAs base-pair (e.g., perfect complementarity) with and cleave their target mRNA, thereby preventing it from being used as a translation template. As described herein above, also part of the RNAi pathway, the miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity (eg, partial complementarity).

[0222] The term " ADAR recruiting molecule " as used herein refers to nucleic acid that is configured to increase the concentration of adenosine deaminase (ADAR) enzyme acting on ribonucleic acid in the area around nucleic acid.In some embodiments, the increase in concentration is compared with the concentration in a given area where no ADAR recruiting molecule is present.In some embodiments, the ADAR recruiting molecule comprises a double-stranded RNA duplex.

[0223] The term "ADAR targeting molecule" as used herein refers to a nucleic acid configured to guide an ADAR molecule to a desired location (e.g., local). As used herein, the term "guide" refers to increasing the concentration of ADAR at a desired location compared to the concentration in the absence of the ADAR targeting molecule. In some embodiments, the ADAR targeting molecule can be configured to control the desired location by changing the sequence and / or properties of the nucleic acid (e.g., by modifying the nucleobase, sugar, internucleoside linkage, or other components). In some embodiments, the ADAR targeting molecule comprises an ADAR recruiting molecule and a single-stranded guide nucleic acid. In some embodiments, the ADAR targeting molecule comprises a double-stranded RNA duplex and a single-stranded guide nucleic acid.

[0224] As used herein, the term " single-stranded guide nucleic acid " or " guide RNA " refers to a single-stranded nucleic acid, which comprises a specific sequence that is at least partially complementary to a target sequence.In some embodiments, the target sequence is located in, adjacent to, or close to the desired local area where ADAR concentration is to be adjusted.In some embodiments, the degree of complementarity is sufficient to promote the single-stranded guide nucleic acid to bind (for example, anneal) to the target sequence.

[0225] The compounds of the present disclosure may also contain proportions of atomic isotopes not found in nature at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0226] The term "isotopic variant" refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains a proportion of isotopes not found in nature at one or more of the atoms that make up the therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains a proportion of one or more isotopes not found in nature, including 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( 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( 131In certain embodiments, an "isotopic variant" of a therapeutic agent contains one or more isotopes in proportions not found in nature, including, but not limited to, 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( 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) include, but are not limited to:

[0227] In a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), if feasible according to the judgment of one of skill in the art, for example, any hydrogen atom may be 2H, for example, any carbon 13 C, for example, any nitrogen 15 N, for example, any oxygen 18 It will be understood that the isotope may be O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains deuterium (D) in proportions not found in nature.

[0228] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase, or internucleoside linkage is modified.

[0229] "Nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkages.

[0230] The term "oligomeric duplex" refers to a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may also be referred to as a "duplex oligomeric compound." The oligonucleotides of each oligomeric compound of an oligomeric duplex may contain non-complementary overhanging nucleosides. In some embodiments, the terms "duplex oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligomeric duplex" and "compound" are used interchangeably.

[0231] By "phosphorothioate linkage" is meant a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom.

[0232] The terms "RNA interference compound," "RNAi compound," and / or "iRNA agent" refer to a compound that acts, at least in part, through the RNA-induced silencing complex (RISC) pathway or Ago2, rather than RNase H, to regulate a target nucleic acid and / or a protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNAs, including microRNA mimics.

[0233] Certain embodiments In certain embodiments, the compound is an α4β 1 / 7 In certain embodiments, the compound comprises a ligand and one or more linker moieties. In certain embodiments, the compound is selected from any of the formulas provided herein. In certain embodiments, the compound comprises one or more linker moieties (L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, 1A , L 2A , L 3A , L 4A etc.) are α4β 1 / 7 The ligand is linked to a therapeutic, prophylactic, or diagnostic agent. In certain embodiments, the compound further comprises one or more therapeutic, prophylactic, or diagnostic agents. In certain embodiments, the therapeutic, prophylactic, or diagnostic agent is a small molecule or an oligomeric compound. In certain embodiments, the oligomeric compound comprises a protein, peptide, antibody, oligonucleotide, or a combination thereof.

[0234] In certain embodiments, the oligomeric compound is any of those described herein. In certain embodiments, the oligomeric compound is about 10-50 subunits in length. In certain embodiments, the oligomeric compound is an oligonucleotide. In certain embodiments, the oligonucleotide is any of those described herein. In certain embodiments, the oligonucleotide is 8-80 linked nucleosides in length, 12-50 linked nucleosides in length, 12-30 linked nucleosides in length, or 15-30 linked nucleosides in length.

[0235] In certain embodiments, the oligonucleotide is a modified oligonucleotide comprising at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.

[0236] In certain embodiments, the oligonucleotide is single-stranded.In certain embodiments, the oligonucleotide is double-stranded.In certain embodiments, the oligonucleotide is double-stranded over a portion of its length.In certain embodiments, the oligonucleotide comprises ribonucleic acid (for example, composed of ribonucleosides), deoxyribonucleic acid (for example, composed of deoxyribonucleosides), or a combination thereof.In certain embodiments, the oligonucleotide is small interfering RNA (siRNA), microRNA (miRNA) antagonist, miRNA mimic, ADAR recruiting molecule, ADAR targeting molecule, guide RNA, antisense oligonucleotide, short hairpin RNA (shRNA), or a combination thereof.

[0237] In some embodiments, the linker is a bond. In some embodiments, the linker is an optionally substituted PEG linker. In some embodiments, the linker is 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length. In certain embodiments, the linker has the structure [ka] Includes.

[0238] In some embodiments, the linker is an optionally substituted heteroaryl linker. In some embodiments, the linker is an optionally substituted partially unsaturated heteroaryl linker. In some embodiments, the linker has the structure [ka] Includes.

[0239] In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the linker is substituted with one or more =0 substituents. In some embodiments, the linker comprises two substituents bonded together to form an optionally substituted carbocyclyl ring. In certain embodiments, the linker has the structure [ka] wherein X is O or S. In certain embodiments, the linker comprises the structure [ka] wherein X is O or S.

[0240] In some embodiments, the linker has the structure [ka] [ka] wherein X is O or S.

[0241] In certain embodiments, the compound has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] or a salt thereof (wherein X is O or S).

[0242] In some embodiments, X is O. In some embodiments, X is S.

[0243] In some embodiments, R 1 comprises an oligonucleotide. In some embodiments, the oligonucleotide is attached at its 5' end. In some embodiments, the oligonucleotide is attached at its 3' end. In some embodiments, the oligonucleotide is attached at an internal position of the oligonucleotide. In some embodiments, the internal position is at an internucleoside linkage. In some embodiments, R 1 one or more additional α4β 1 / 7 In some embodiments, the oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional α4β integrin receptor ligands. 1 / 7 In certain embodiments, the additional α4β is conjugated to an integrin receptor ligand. 1 / 7 The integrin receptor ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, one or more internal positions of the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0244] Certain embodiments provide compositions comprising a compound of any of the embodiments herein and a pharmaceutically acceptable carrier or excipient.

[0245] Certain embodiments provide a composition comprising a compound of any embodiment anywhere herein for use in therapy.

[0246] In certain embodiments, a method for delivering an agent to a cell comprises contacting the cell with a compound of any of the embodiments herein, thereby delivering the agent to the cell. In certain embodiments, the cell contains α4β 1 / 7 In certain embodiments, the cell expresses an integrin receptor. In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a frontal lobe cell. In certain embodiments, the cell is a striatum cell. In certain embodiments, the cell is a cerebellum cell. In certain embodiments, the cell is a brainstem cell. In certain embodiments, the cell is a hippocampus cell. In certain embodiments, the cell is a spinal cord cell. In certain embodiments, the agent is a therapeutic or diagnostic agent. In certain embodiments, the cell is within an animal.

[0247] In certain embodiments, a method of modulating expression of a nucleic acid target in a cell comprises contacting the cell with a compound of any of the embodiments herein, thereby modulating expression of a nucleic acid target in the cell. In certain embodiments, the cell contains α4β on the surface of the cell. 1 / 7The cell expresses an integrin receptor. In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a cell of the frontal lobe. In certain embodiments, the cell is a cell of the striatum. In certain embodiments, the cell is a cell of the cerebellum. In certain embodiments, the cell is a cell of the brainstem. In certain embodiments, the cell is a cell of the hippocampus. In certain embodiments, the cell is a cell of the spinal cord. In certain embodiments, the agent is a therapeutic or diagnostic agent. In certain embodiments, contacting the cell with a compound of any of the embodiments herein inhibits expression of the nucleic acid target. In certain embodiments, the nucleic acid target is pre-mRNA, mRNA, non-coding RNA, or miRNA. In certain embodiments, the cell is in an animal.

[0248] In certain embodiments, a method for modulating expression of a nucleic acid target in a subject comprises administering to the subject any of the compounds or compositions provided herein, thereby modulating expression of the nucleic acid target in the subject. In certain embodiments, expression of the nucleic acid is α4β on the surface of a cell. 1 / 7 In certain embodiments, the expression of the nucleic acid is regulated in cells of the subject that express the integrin receptor. In certain embodiments, the expression of the nucleic acid is regulated in brain cells. In certain embodiments, the expression of the nucleic acid is regulated in brain cells that express the α4β receptor on their surface. 1 / 7 The cell expressing an integrin receptor is a brain cell. In certain embodiments, the brain cell is a cell of the frontal lobe. In certain embodiments, the brain cell is a cell of the striatum. In certain embodiments, the brain cell is a cell of the cerebellum. In certain embodiments, the brain cell is a cell of the brainstem. In certain embodiments, the brain cell is a cell of the hippocampus. In certain embodiments, the brain cell is a cell of the spinal cord. In certain embodiments, the nucleic acid target is pre-mRNA, mRNA, non-coding RNA, or miRNA. In certain embodiments, the compound is administered intrathecally to the subject.

[0249] In certain embodiments, a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject comprises administering any of the compounds or compositions provided herein to the subject, thereby treating, preventing, or ameliorating the disease, disorder, or symptom thereof in the subject. In certain embodiments, the disease, disorder, or symptom thereof is a disease, disorder, or symptom thereof of the central nervous system (CNS). In certain embodiments, the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof. In certain embodiments, the compound is administered intrathecally to the subject. In certain embodiments, the compound or composition is administered to the subject in a therapeutically effective amount.

[0250] In certain embodiments, α4β 1 / 7 Compounds containing integrin receptor ligands are 1 / 7 Compared with cells that do not express integrin receptors, 1 / 7 In certain embodiments, the α4β integrin receptor is selectively or preferentially targeted to cells expressing the α4β integrin receptor. 1 / 7 Compounds containing integrin receptor ligands are 1 / 7 α4β compared with cells that do not express integrin receptor ligands 1 / 7 Selectively or preferentially target cells expressing integrin receptors.

[0251] Also provided is the use of a compound described herein for the manufacture of a medicament in the treatment of a disease or disorder.

[0252] In another aspect, the disclosure provides methods for making any of the compounds provided herein, including one or more of the compounds and chemical transformations described herein, including Examples 1-13.

[0253] Certain compounds containing oligonucleotides In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotides have a nucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., a target nucleic acid expressed in a cell). In some embodiments, the oligonucleotides, when delivered to a cell expressing a target nucleic acid, can alter expression of the underlying gene. In some embodiments, the oligonucleotides, when delivered to a cell expressing a target nucleic acid, can inhibit expression of the underlying gene. Gene expression can be altered or inhibited in vitro or in vivo. In certain embodiments, the oligonucleotides comprise one or more ribonucleic acids (e.g., one or more ribonucleosides), deoxyribonucleic acids (e.g., one or more deoxyribonucleosides), modified nucleic acids (e.g., one or more modified nucleobases, sugars, and / or internucleoside linkages), or combinations thereof. In some embodiments, the oligonucleotides comprise ribonucleic acids (RNA). In some embodiments, the oligonucleotides comprise deoxyribonucleic acids (DNA). In some embodiments, the oligonucleotides comprise a modification (e.g., a modified nucleobase, a modified sugar, or a modified internucleoside linkage).

[0254] In certain embodiments, the oligonucleotide is single-stranded. In some embodiments, the single-stranded oligonucleotide is single-stranded RNA (ssRNA), ssDNA, or ssRNA / DNA hybrid (e.g., a single-stranded oligonucleotide composed of both ribonucleosides (modified or unmodified) and deoxyribonucleosides (modified or unmodified)). In some embodiments, the oligonucleotide is double-stranded (e.g., composed of two single-stranded nucleic acids). Such a double-stranded oligonucleotide comprises a first oligonucleotide having a region complementary to a target nucleic acid and a second oligonucleotide having a region complementary to the first oligonucleotide. The first and second oligonucleotides may be independently modified. In certain embodiments, the first oligonucleotide comprises one or more α4β1 / 7 In certain embodiments, the second oligonucleotide is linked to one or more α4β integrin receptor ligands. 1 / 7 It is linked to an integrin receptor ligand.

[0255] In some embodiments, an oligonucleotide comprises at least two nucleotides (e.g., 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, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 12 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, or more). In some embodiments, the oligonucleotide is at least 5 nucleotides in length. In some embodiments, the oligonucleotide is at least 10 nucleotides in length. In some embodiments, the oligonucleotide is at least 15 nucleotides in length. In some embodiments, the oligonucleotide is at least 16 nucleotides in length. In some embodiments, the oligonucleotide is at least 17 nucleotides in length. In some embodiments, the oligonucleotide is at least 18 nucleotides in length. In some embodiments, the oligonucleotide is at least 19 nucleotides in length. In some embodiments, the oligonucleotide is at least 20 nucleotides in length. In some embodiments, the oligonucleotide is at least 21 nucleotides in length. In some embodiments, the oligonucleotide is at least 22 nucleotides in length.In some embodiments, the oligonucleotide is at least 23 nucleotides in length. In some embodiments, the oligonucleotide is at least 24 nucleotides in length. In some embodiments, the oligonucleotide is at least 25 nucleotides in length. In some embodiments, the oligonucleotide is at least 26 nucleotides in length. In some embodiments, the oligonucleotide is at least 27 nucleotides in length. In some embodiments, the oligonucleotide is at least 28 nucleotides in length. In some embodiments, the oligonucleotide is at least 29 nucleotides in length. In some embodiments, the oligonucleotide is at least 30 nucleotides in length. In some embodiments, the oligonucleotide is at least 40 nucleotides in length. In some embodiments, the oligonucleotide is at least 50 nucleotides in length. In some embodiments, the oligonucleotide is at least 60 nucleotides in length. In some embodiments, the oligonucleotide is at least 70 nucleotides in length. In some embodiments, the oligonucleotide is at least 80 nucleotides in length. In some embodiments, the oligonucleotide is at least 90 nucleotides in length. In some embodiments, the oligonucleotide is at least 100 nucleotides in length. In some embodiments, the oligonucleotide is at least 150 nucleotides in length.

[0256] In some embodiments, the oligonucleotide is 150 nucleotides or less (e.g., 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, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 , 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150). In some embodiments, the oligonucleotide is 150 nucleotides or less in length. In some embodiments, the oligonucleotide is 100 nucleotides or less in length. In some embodiments, the oligonucleotide is 90 nucleotides or less in length. In some embodiments, the oligonucleotide is 80 nucleotides or less in length. In some embodiments, the oligonucleotide is 70 nucleotides or less in length. In some embodiments, the oligonucleotide is 60 nucleotides or less in length. In some embodiments, the oligonucleotide is 50 nucleotides or less in length. In some embodiments, the oligonucleotide is 40 nucleotides or less in length. In some embodiments, the oligonucleotide is 30 nucleotides or less in length. In some embodiments, the oligonucleotide is 29 nucleotides or less in length.In some embodiments, the oligonucleotide is 28 nucleotides or less in length. In some embodiments, the oligonucleotide is 27 nucleotides or less in length. In some embodiments, the oligonucleotide is 26 nucleotides or less in length. In some embodiments, the oligonucleotide is 25 nucleotides or less in length. In some embodiments, the oligonucleotide is 24 nucleotides or less in length. In some embodiments, the oligonucleotide is 23 nucleotides or less in length. In some embodiments, the oligonucleotide is 22 nucleotides or less in length. In some embodiments, the oligonucleotide is 21 nucleotides or less in length. In some embodiments, the oligonucleotide is 20 nucleotides or less in length. In some embodiments, the oligonucleotide is 19 nucleotides or less in length. In some embodiments, the oligonucleotide is 18 nucleotides or less in length. In some embodiments, the oligonucleotide is 17 nucleotides or less in length. In some embodiments, the oligonucleotide is 16 nucleotides or less in length. In some embodiments, the oligonucleotide is 15 nucleotides or less in length. In some embodiments, the oligonucleotide is 10 nucleotides or less in length. In some embodiments, the oligonucleotide is 5 nucleotides or less in length.

[0257] In some embodiments, the oligonucleotide is about 5 to about 150 nucleotides in length. In some embodiments, the oligonucleotide is about 10 to about 100 nucleotides in length. In some embodiments, the oligonucleotide is about 20 to about 90 nucleotides in length. In some embodiments, the oligonucleotide is about 30 to about 80 nucleotides in length. In some embodiments, the oligonucleotide is about 40 to about 70 nucleotides in length. In some embodiments, the oligonucleotide is about 50 to about 60 nucleotides in length.

[0258] In some embodiments, the oligonucleotide is a therapeutic oligonucleotide.The therapeutic oligonucleotide can include, but is not limited to, small interfering RNA (siRNA), microRNA (miRNA) antagonist, miRNA mimic, ADAR recruiting molecule, ADAR targeting molecule, guide RNA, antisense oligonucleotide, short hairpin RNA (shRNA) or combinations thereof.

[0259] In certain embodiments, the miRNA is a precursor miRNA, a primary miRNA, and / or a mature miRNA.

[0260] In certain embodiments, the oligonucleotide comprises or consists of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide is complementary to mRNA. In certain embodiments, the antisense oligonucleotide is complementary to pre-mRNA. In certain embodiments, the antisense oligonucleotide blocks translation and promotes degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide recruits RNase H and promotes degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide targets miRNA, inhibits miRNA regulation of mRNA expression, and promotes miRNA degradation.

[0261] Certain modifications In certain aspects, the present disclosure relates to compounds comprising oligonucleotides. In certain embodiments, the oligonucleotides may be unmodified RNA or DNA, or may be modified. In certain embodiments, the oligonucleotides are modified oligonucleotides. In certain embodiments, the modified oligonucleotides contain at least one modified sugar, modified nucleobase, or modified internucleoside linkage compared to unmodified RNA or DNA. In certain embodiments, the oligonucleotides have modified nucleosides. The modified nucleosides may contain modified sugars, modified nucleobases, or both modified sugars and modified nucleobases. The modified oligonucleotides may also contain terminal modifications, such as 5'-terminal modifications and 3'-terminal modifications.

[0262] GlycosylationSugar modifications 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 a sugar substitute. The sugar substitute may include one or more of the substitutions described herein.

[0263] In certain embodiments, the modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar includes one or more substituents, including but not limited to, substituents at the 2', 3', 4', and 5' positions.

[0264] In certain embodiments, the 2'-position substituent includes, but is not limited to, F and OCH ("OMe," "O-methyl," or "methoxy"). In certain embodiments, suitable 2'-position substituents for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF, OCF, F, Cl, Br, SCH, SOCH, SOCH, ONO, NO, NH, and NH. In certain embodiments, the 2'-position substituent includes, but is not limited to, O-(C-C 10 ) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, where alkyl, alkenyl, and alkynyl are substituted or unsubstituted C1-C 10 Alkyl or C2-C 10 The substituents at the 2'-position may be alkenyl or alkynyl. In certain embodiments, the substituents at the 2'-position include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In certain embodiments, these 2'-substituents may be further substituted with one or more substituents independently selected from hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro(NO), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the substituent at the 2'-position may be O[(CH) 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 CH3)]2, where n and m are independently 1 to about 10. In certain embodiments, 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").

[0265] In certain embodiments, suitable 4'-position substituents for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, suitable 5'-position substituents for non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, the 2'-, 4'-, and 5'-position substituents described herein may be attached to other specific positions on the sugar. In certain embodiments, such substituents may be attached to the 3'-position of the sugar of the 3'-terminal nucleoside or the 5'-position of the 5'-terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may comprise two or more non-bridging sugar substituents. In certain such embodiments, substituents on non-bicyclic modified sugars include, but are not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, substituents on modified sugars include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US2013 / 0203836. In certain embodiments, suitable 5'-position substituents on non-bicyclic modified sugars include, but are not limited to, methyl ("Me" or "CH") (R or S), vinyl, and methoxy.In certain embodiments, the 5' modifications include 5'-monophosphate ((HO)2(O)PO-5'); 5'-diphosphate ((HO)2(O)POP(HO)(O)-O-5'); 5'-triphosphate ((HO)2(O)PO-(HO)(O)POP(HO)(O)-O-5'); 5'-guanosine cap (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); 5' adenosine cap (Appp), as well as any modified or unmodified nucleotide cap structure (NO-5'(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); 5'-monothiophosphate (phosphorothioate; (HO)2(S)PO-5'); 5'-monodithiophosphate (phosphorodithioate; (HO)(HS) (S)PO-5'), 5' phosphorothiolate ((HO)2(O)PS-5'); any additional combination of oxygen / sulfur substituted monophosphates, diphosphates, and triphosphates (e.g., 5'-alpha-thiotriphosphate, 5'-gamma thiotriphosphate, etc.), 5'-phosphoramidates ((HO)2(O)P-NH-5', (HO)(NH2)(O)PO-5'), 5' alkyl phosphonates (R = alkyl = methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-5'-, 5' alkenyl phosphonates (i.e., vinyl, substituted vinyl), (OH)2(O)P-5'-CH2-), 5' alkyl ether phosphonates (R = alkyl ether methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g., RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5'-vinyl phosphonate modification. In certain embodiments, the 5' modification is at the end of the oligonucleotide. In certain embodiments, the 5' modification is at the end of the antisense oligonucleotide.

[0266] In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, the second ring being formed via a bridge connecting two atoms of the first ring, thereby forming a bicyclic structure. In certain embodiments, the bicyclic sugar comprises a bridge substituent bridging two atoms of a furanosyl ring to form a second ring. In certain embodiments, the bicyclic sugar does not comprise a furanosyl moiety. A "bicyclic nucleoside" ("BNA") is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar comprises 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'-2' bridged 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' ("constrained ethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CHOCH3)-O-2' ("constrained MOE" or "cMOE") and analogs thereof (e.g., U.S. Pat. No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,283), 4'-CH2-N(OCH3)-2' and analogs thereof (e.g., U.S. Pat. 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, C1-C 12alkyl, or a protecting group) (e.g., U.S. Pat. No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134), and 4'-CH2-C(=CH2)-2' and analogs thereof (e.g., U.S. Pat. No. 8,278,426). The entire contents of each of the foregoing are incorporated herein by reference. Additional representative U.S. patents and publications that teach the preparation of bicyclic nucleic acid nucleotides include U.S. Patent Nos. 6,268,490, 6,525,191, 6,670,461, 6,770,748, 6,794,499, 6,998,484, 7,053,207, 7,034,133, 7,084,125, 7,399,845, 7,427,672, 7,

[0004] The following publications are not limited to: US 2008 / 0039618, US 2009 / 0012281, US 2013 / 0190383, and WO 2013 / 036868, the entire contents of each of which are incorporated herein by reference.

[0005] Any of the foregoing bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, e.g., WO 99 / 14226). Certain bicyclic nucleosides herein are in the β-D configuration unless otherwise specified.

[0267] In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the sugar substitute has an oxygen atom replaced with, for example, a sulfur atom, a carbon atom, or a nitrogen atom. In certain such embodiments, the sugar substitute may also include bridging and / or non-bridging substituents as described herein. In certain such embodiments, the sugar substitute includes a ring with more than five atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes tetrahydropyran ("THP") in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a morpholino in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include U.S. Patent Nos. 4,981,957, 5,118,800, 5,166,315, 5,185,444, 5,319,080, 5,359,044, 5,393,878, 5,446,137, 5,466,786, 5,514,785, 5,519,134, 5,567,811, 5,576,427, 5,591,722, 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, the entire contents of each of the foregoing are incorporated herein by reference.

[0268] In some embodiments, the surrogate sugar comprises an acyclic moiety. In certain embodiments, the surrogate sugar is an unlocked nucleic acid ("UNA"). A UNA is an acyclic unlocked nucleic acid in which one of its sugar bonds has been removed to form an unlocked "sugar" residue. In one example, a UNA also encompasses a monomer in which the C1'-C4' bond (i.e., the carbon-oxygen-carbon covalent bond between the C1' and C4' carbons) has been removed. In another example, the C2'-C3' bond (i.e., the carbon-carbon covalent bond between the C2' and C3' carbons) of the sugar has been removed. Representative U.S. publications teaching the preparation of UNAs include, but are not limited to, U.S. Patent No. 8,314,227, and U.S. Patent Application Publication Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of which are incorporated herein by reference. In certain embodiments, sugar substitutes include peptide nucleic acids ("PNAs"), acyclic butyl nucleic acids (see Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and the nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378, the entire contents of which are incorporated herein by reference. Many other bicyclic and tricyclic sugars and alternative sugar ring systems are known in the art that can be used in modified nucleosides.

[0269] In certain aspects, the present disclosure refers to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotide contain one or more modified and / or unmodified sugars arranged in a defined pattern or "sugar motif" along the oligonucleotide or region thereof. In certain instances, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0270] In certain embodiments, the oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two outer "wing" regions and a central or internal "gap" region. The gap and wing regions form a continuous sequence of nucleosides, with the majority of nucleoside sugars in each wing being different from the majority of nucleoside sugars in the gap. In certain embodiments, the wing regions comprise a majority of modified sugars, and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides in the gap are deoxynucleosides. Compounds containing gapmer sugar motifs are described, for example, in U.S. Pat. No. 8,790,919, the contents of which are incorporated herein by reference.

[0271] In certain embodiments, one or both of the oligonucleotides of a double-stranded compound contain a triplex sugar motif. An oligonucleotide with a triplex sugar motif contains three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplex is located at or near the cleavage site of the oligonucleotide. In certain embodiments, an oligonucleotide of a double-stranded compound may contain two or more triplex sugar motifs. In certain embodiments, the identical sugar modification of a triplex sugar motif is a 2'-F modification. Compounds with triplex sugar motifs are disclosed, for example, in U.S. Pat. No. 10,668,170, the contents of which are incorporated herein by reference.

[0272] In certain embodiments, one or both of the oligonucleotides in a double-stranded compound contain a quadruplex sugar motif. An oligonucleotide with a quadruplex sugar motif contains four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, an oligonucleotide in a double-stranded compound may contain two or more quadruplex sugar motifs. In certain embodiments, the identical sugar modifications in a quadruplex sugar motif are 2'-F modifications. For double-stranded compounds having a duplex region 19 to 23 nucleotides in length, the cleavage sites of the antisense oligonucleotide are typically located around positions 10, 11, and 12 from the 5' end. In certain embodiments, the quadruplex sugar motif is located at positions 8, 9, 10, 11; 9, 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 from the first paired nucleotide in the duplex region from the 5' end of the sense oligonucleotide. In certain embodiments, the quadruplex sugar motif is located at positions 8, 9, 10, 11; 9, 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 from the first paired nucleotide in the duplex region from the 5' end of the antisense oligonucleotide. The cleavage site may vary depending on the length of the duplex region of the double-stranded compound, and the position of the quadruplex may vary accordingly.

[0273] In certain embodiments, an oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both of the oligonucleotides in a double-stranded compound comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, where one or more consecutive nucleosides comprising a first sugar modification alternate with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, where A, B, and C each represent one type of modification on a nucleoside, the alternating motif can be "ABABABABABAB...," "AABBAABBAABB...," "AABAABAABAAB"AAABAAABAAAB...," "AAABBBAAABBB...," or "ABCABCABCABC...," etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobases along the oligonucleotide. In certain embodiments, the alternating sugar motif is composed of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises a 2'-OMe and a 2'-F sugar modification.

[0274] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications as provided herein.In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs as provided herein.In certain embodiments, the oligonucleotide that contains a sugar motif is fully modified, in that each nucleoside other than the nucleoside that comprises the sugar motif comprises a sugar modification.

[0275] Nucleobase modifications and motifs In certain embodiments, modified oligonucleotides comprise one or more nucleosides that comprise a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleosides that do not contain a nucleobase, referred to as abasic nucleosides.

[0276] In certain embodiments, the modified nucleobase is selected from 5-substituted pyrimidines, 6-azapyrimidines, alkyl- or alkynyl-substituted pyrimidines, alkyl-substituted purines, and N-2, N-6, and O-6 substituted purines. In certain embodiments, modified nucleobases include 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-azo uracil, 6-azo cytosine, 6-azo thymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-azapurine and other 8-substituted nucleobases. The bases are selected from substituted purines, 5-halo, particularly 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-Ν-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-Ν-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenothiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G-clamp). Modified nucleobases also include those in which the purine or pyrimidine base is replaced with other heterocycles, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0277] Further nucleobases include those described in U.S. Pat. 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 Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is incorporated herein by reference.

[0278] Publications that teach the preparation of some of the above and other modified nucleobases include, but are not limited to, U.S. Patent Application Publication Nos. 2003 / 0158403 and 2003 / 0175906, U.S. Patent Nos. 4,845,205, 5,130,302, 5,134,066, 5,175,273, 5,367,066, and 5,367,066. No. 5,432,272, No. 5,434,257, No. 5,457,187, No. 5,459,255, No. 5,484,908, No. 5,502,177, No. 5,52 No. 5,711, No. 5,552,540, No. 5,587,469, No. 5,594,121, No. 5,596,091, No. 5,614,617, No. 5,645,985 No. 5,681,941, No. 5,811,534, No. 5,750,692, No. 5,948,903, No. 5,587,470, No. 5,457,191, No. No. 5,763,588, No. 5,830,653, No. 5,808,027, No. 6,005,096, No. 6,015,886, No. 6,147,200, No. 6,166 ,197, 6,166,199, 6,222,025, 6,235,887, 6,380,368, 6,528,640, 6,639,062, 6,617,438, 7,045,610, 7,427,672 and 7,495,088, the contents of each of which are incorporated herein by reference.

[0279] In certain embodiments, an oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or a region thereof. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases is modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methylcytosine.

[0280] In certain embodiments, the modified oligonucleotide comprises a modified nucleobase block. In certain such embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides from the 3' end of the oligonucleotide. In certain embodiments, the block is at the 5' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides from the 5' end of the oligonucleotide.

[0281] Internucleoside linkage modifications and motifs A 3'-5' phosphodiester linkage is the natural internucleoside linkage of RNA and DNA. In certain embodiments, an oligonucleotide has one or more modified, i.e., non-natural, internucleoside linkages. Certain non-natural internucleoside linkages can 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 internucleoside linkages 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 linkages include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2), thiodiester, thionocarbamate (-OC(=O)(NH)-S-); siloxane (-O-SiH2-O-); and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriesters, methylphosphonates, MM 1(3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S-CH2-O-5'). Additional neutral internucleoside linkages include nonionic linkages including siloxanes (dialkylsiloxanes), carboxylate esters, carboxamides, sulfides, sulfonate esters, and amides (e.g., Carbohydrate (See, Modifications in Antisense Research; YS Sanghvi and PD Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65.) Additional neutral internucleoside linkages include nonionic linkages containing mixtures of N, O, S, and CH2 moieties.

[0282] In certain embodiments, oligonucleotide comprises at least one modified internucleoside linkage.Modified internucleoside linkage can be located in any part of oligonucleotide.In the case of double-stranded compound, modified internucleoside linkage can be located in the sense oligonucleotide, antisense oligonucleotide, or both oligonucleotides of double-stranded compound.

[0283] In certain embodiments, internucleoside linkage modifications may be present at every nucleoside of an oligonucleotide. In certain embodiments, internucleoside linkage modifications may be present in an alternating pattern along the oligonucleotide. In certain embodiments, essentially all internucleoside linkage groups are phosphate internucleoside linkages (P=O). In certain embodiments, each internucleoside linkage group of a modified oligonucleotide is phosphorothioate (P=S). In certain embodiments, each internucleoside linkage group of a modified oligonucleotide is independently selected from phosphorothioate internucleoside linkages and phosphate internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of a double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of a double-stranded compound is different. In certain embodiments, a double-stranded compound comprises 6 to 8 modified internucleoside linkages. In certain embodiments, the 6 to 8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5'-terminus and the 3'-terminus. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain such embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5'-terminus and the 3'-terminus. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0284] In certain embodiments, the double-stranded compound comprises an overhang region. In certain embodiments, the double-stranded compound comprises phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate internucleoside linkage or an alkylphosphonate internucleoside linkage connecting the overhang nucleotide and the paired nucleotide next to the overhang nucleotide. For example, there can be at least two phosphorothioate internucleoside linkages between the three terminal nucleosides, where two of the three nucleosides are overhang nucleosides, and the third nucleoside is the paired nucleoside next to the overhang nucleoside. These three terminal nucleosides can 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.

[0285] In certain embodiments, modified oligonucleotides contain one or more internucleoside linkages with a chiral center. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides containing internucleoside linkages with a chiral center can be prepared as a population of modified oligonucleotides containing stereorandom internucleoside linkages or as a population of modified oligonucleotides containing phosphorothioate linkages of a specific stereochemical configuration. In certain embodiments, a population of modified oligonucleotides contains phosphorothioate internucleoside linkages, and all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be produced using a synthetic method in which the stereochemical configuration of each phosphorothioate linkage is randomly selected. As will be appreciated by those skilled in the art, each individual phosphorothioate in each individual oligonucleotide molecule has a predetermined stereochemical configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides containing one or more specific phosphorothioate internucleoside linkages of independently selected specific stereochemical configurations. In certain embodiments, a particular arrangement of phosphorothioate linkages is present in at least 65% of the molecules in the population. In certain embodiments, a particular arrangement of phosphorothioate linkages is present in at least 70% of the molecules in the population. In certain embodiments, a particular arrangement of phosphorothioate linkages is present in at least 80% of the molecules in the population. In certain embodiments, a particular arrangement of phosphorothioate linkages is present in at least 90% of the molecules in the population. In certain embodiments, a particular arrangement of phosphorothioate linkages 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, such as those 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 for modified oligonucleotides having at least one designated phosphorothioate in the (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0286] α4β 1 / 7 Integrin Receptor Ligands In some embodiments, the compounds provided herein are 1 / 7 In some embodiments, the α4β 1 / 7 Integrin receptor ligands are useful for inducing therapeutic, prophylactic, or diagnostic agents. In certain embodiments, the therapeutic agent is an oligonucleotide (e.g., a therapeutic oligonucleotide). In some embodiments, α4β 1 / 7 The integrin receptor ligand targets the oligonucleotide to a localized location. 1 / 7 The integrin receptor ligand targets a tissue. In some embodiments, the tissue is brain tissue. In some embodiments, the α4β 1 / 7 The integrin receptor ligand targets a cellular receptor. In some embodiments, the cellular receptor is α4β 1 / 7 In some embodiments, the α4β 1 / 7 Integrin receptors are found in the brain. 1 / 7 Integrin receptors are found in the frontal lobe. 1 / 7 The integrin receptor is located in the striatum.1 / 7 Integrin receptors are found in the cerebellum. 1 / 7 Integrin receptors are found in the brainstem. 1 / 7 Integrin receptors are found in the hippocampus. 1 / 7 Integrin receptors are found in the spinal cord.

[0287] Any α4β in the compounds provided herein 1 / 7 The use of integrin receptor ligands is also contemplated by the present disclosure. 1 / 7 Integrin receptor ligands are known in the art, and one of ordinary skill in the art would be able to identify additional α4β ligands for use in the compounds described herein beyond those expressly provided in this disclosure. 1 / 7 The present disclosure also provides for the identification of any α4β integrin receptor ligands provided herein or known in the art. 1 / 7 Derivatives and prodrugs of integrin receptor ligands are also contemplated for use with the compounds described herein, and those of skill in the art would know how to make such derivatives and prodrugs.

[0288] In some embodiments, α4β 1 / 7 Integrin receptor ligands are α4β 1 / 7 In some embodiments, the α4β 1 / 7 Integrin receptor ligands are α4β 1 / 7 In some embodiments, the α4β 1 / 7 The integrin receptor ligand is any of those disclosed in International Patent Application Publication No. WO2019 / 246455, which is incorporated herein by reference. In some embodiments, the α4β 1 / 7Integrin receptor ligands are any of those disclosed in Baiula, M. et al. Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives. Front. Chem. 2019, 7, 489, incorporated herein by reference. Exemplary α4β1 receptor ligands for use in the present disclosure include: 1 / 7 Integrin receptor ligands include the following α4β 1 / 7 Integrin receptor ligands and any of their derivatives, including, but not limited to: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (Wherein, each case of R is [ka] (It is).

[0289] In certain embodiments, α4β 1 / 7 Integrin receptor ligands include: [ka] or a derivative thereof.

[0290] In some embodiments, α4β 1 / 7 Integrin receptor ligands include anti-α4β 1 / 7 In certain embodiments, the α4β 1 / 7 Integrin receptor ligands include anti-α4β 1 / 7 Integrin receptor antibody fragment, or anti-α4β 1 / 7 Integrin receptor antibody variant. "Anti-α4β 1 / 7 Integrin receptor antibodies" are α4β 1 / 7 Refers to immune system proteins that recognize, bind to, or otherwise interact with integrin receptors.

[0291] In certain embodiments, α4β 1 / 7 The integrin receptor ligand is conjugated (e.g., linked, connected, bound, associated) to one or more agent moieties. In certain embodiments, the agent moiety is a therapeutic agent, a prophylactic agent, a diagnostic agent, or an imaging agent. In certain embodiments, the agent is a small molecule or an oligomeric compound. In certain embodiments, the agent moiety is a protein, peptide, antibody, oligonucleotide, small molecule, macromolecule, or combination thereof.

[0292] In some embodiments, multiple α4β 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to an agent moiety. 1 / 7 Integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more α4β 1 / 7 In some embodiments, two α4β integrin receptor ligands are conjugated to the agent moiety. 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to an agent moiety. 1 / 7In some embodiments, the integrin receptor ligand is conjugated to the agent moiety. 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to the agent moiety. 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to an agent moiety. 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to an agent moiety. 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to an agent moiety. 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to an agent moiety. 1 / 7 In some embodiments, the integrin receptor ligand is conjugated to an agent moiety. 1 / 7 An integrin receptor ligand is conjugated to an agent moiety.

[0293] Multiple α4β 1 / 7 When conjugated to an integrin receptor ligand, α4β 1 / 7 The integrin receptor ligands may all be conjugated to or near the same position on the agent moiety, or the α4β 1 / 7 The integrin receptor ligand may be conjugated to multiple different positions on the agent moiety.

[0294] In some embodiments, the oligonucleotide comprises an α4β nucleotide linked via either the 5' and / or 3' end of the oligonucleotide, or at an internal position on the oligonucleotide (i.e., a nucleotide on the oligonucleotide other than the 5' or 3' nucleotide). 1 / 7 In some embodiments, the oligonucleotide is conjugated to (e.g., connected to, bound to, associated with) an integrin receptor ligand via the 5' end of the oligonucleotide. 1 / 7In some embodiments, the oligonucleotide is conjugated to an α4β integrin receptor ligand via the 3' end of the oligonucleotide. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an α4β integrin receptor ligand via both the 5' and 3' ends of the oligonucleotide. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an α4β integrin receptor ligand at an internal position within the oligonucleotide (e.g., an "internal modified oligonucleotide"). 1 / 7 Conjugated to an integrin receptor ligand.

[0295] In some embodiments, the oligonucleotide comprises multiple α4β 1 / 7 In some embodiments, the oligonucleotide is conjugated to at least two α4β1 / 7 integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more α4β1 / 7 integrin receptor ligands). 1 / 7 In some embodiments, the oligonucleotide is conjugated to two α4β integrin receptor ligands. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an integrin receptor ligand. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an integrin receptor ligand. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an integrin receptor ligand. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an integrin receptor ligand. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an integrin receptor ligand. 1 / 7In some embodiments, the oligonucleotide is conjugated to an integrin receptor ligand. 1 / 7 In some embodiments, the oligonucleotide is conjugated to an integrin receptor ligand. 1 / 7 In some embodiments, the oligonucleotide is conjugated to at least one to about two α4β integrin receptor ligands. 1 / 7 Conjugated to an integrin receptor ligand.

[0296] Multiple α4β oligonucleotides 1 / 7 When conjugated to an integrin receptor ligand, α4β 1 / 7 The integrin receptor ligands may all be conjugated to the same or nearby position on the oligonucleotide, or the α4β 1 / 7 The integrin receptor ligand may be conjugated to multiple different positions on the oligonucleotide. 1 / 7 Integrin receptor ligands (i.e., 2, 3, 4, 5, or more α4β 1 / 7 In some embodiments, a plurality of α4β integrin receptor ligands are conjugated to the 5' end of the oligonucleotide. 1 / 7 Integrin receptor ligands (i.e., 2, 3, 4, 5, or more α4β 1 / 7 In some embodiments, a plurality of α4β integrin receptor ligands are conjugated to the 3' end of the oligonucleotide. 1 / 7 Integrin receptor ligands (i.e., 2, 3, 4, 5, or more α4β 1 / 7 In some embodiments, the oligonucleotide is conjugated to one or more internal positions of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to one or more α4β integrin receptor ligands at the 5' end of the oligonucleotide. 1 / 7 to an integrin receptor ligand and / or one or more α4β 1 / 7at one or more α4β integrin receptor ligands and / or at an internal position or positions of the oligonucleotide 1 / 7 Conjugated to an integrin receptor ligand.

[0297] Linker In certain embodiments, conjugates of the compound formulas described herein are provided. In certain embodiments, the conjugates comprise an α4β covalently linked to an agent moiety. 1 / 7 In certain embodiments, the conjugates provided herein comprise one or more linker moieties. In certain embodiments, the one or more linker moieties are α4β 1 / 7 The integrin receptor ligand is linked to an agent moiety. In certain embodiments, the agent moiety is a protein, peptide, antibody, nucleic acid, small molecule, macromolecule, therapeutic agent, prophylactic agent, diagnostic agent, or imaging agent. In some embodiments, the compound is conjugated to an oligonucleotide. In certain embodiments, the α4β 1 / 7 In certain embodiments, the integrin receptor ligand is conjugated to one or more α4β 1 / 7 an integrin receptor ligand, one or more linker moieties, and one or more agent moieties, wherein 1 / 7 The integrin receptor ligand is conjugated (eg, linked, connected, bound, associated) to one or more agent moieties via one or more linker moieties.

[0298] The conjugates disclosed herein can be prepared using any available method. 1 / 7 When associating the integrin receptor ligand with the oligonucleotide, the moieties can be linked directly or indirectly (e.g., via a linker moiety, i.e., the linker can link the oligonucleotide and the α4β 1 / 7 and in some formulas herein, "-Ln - ", where n is a number (e.g., L1, L2, L3, L4, L 1A , L 2A , L 3A , L 4A )). For example, oligonucleotides and α4β 1 / 7 The integrin receptor ligands may be directly linked to one another, for example, by one or more covalent bonds, or may be linked via one or more linkers. A "linker" is a linker that connects two components of the compounds provided herein (e.g., α4β 1 / 7 The term "linker" refers to any chemical moiety (e.g., a combination of atoms having appropriate valences according to known chemical principles) used to conjugate an integrin receptor ligand and an oligonucleotide to one another. Each of the two components can be connected to any portion of any of the linkers provided herein. In some embodiments, one component of a compound provided herein (e.g., an α4β 1 / 7 The integrin receptor ligand or oligonucleotide) is connected by a bond to one end of the linker, and the other component is connected by a bond to the other end of the linker. In some embodiments, one or both components of the compounds provided herein can be connected by a bond to any internal position of the linker described herein. For example, in the context of an "alkyl linker," an α4β 1 / 7The integrin receptor ligand can be linked by a bond to a carbon at one end of an alkyl linker, and the oligonucleotide can be linked by a bond to a carbon at the other end of the alkyl linker. In some embodiments, the linker is a bond (e.g., including phosphodiester and phosphorothioate linkages). In some embodiments, the linker is an optionally substituted alkyl linker (i.e., two moieties are linked using an alkyl chain, and the two moieties may be conjugated to both ends of the alkyl linker, or one or both moieties may be conjugated to an internal carbon on the alkyl linker). In some embodiments, the linker is an optionally substituted polyethylene glycol (PEG) linker (i.e., two moieties are linked using a PEG chain, and the two moieties may be conjugated to both ends of the PEG linker, or one or both moieties may be conjugated to an internal position on the PEG linker). In some embodiments, the linker is an optionally substituted heteroalkyl linker (i.e., two moieties are joined using a heteroalkyl chain, and the two moieties may be conjugated to either end of the heteroalkyl linker, or one or both moieties may be conjugated to an internal position of the heteroalkyl linker). In some embodiments, the linker is an optionally substituted heteroaryl linker (i.e., two moieties are joined using a heteroaryl group, and the two moieties may be conjugated to any position on the heteroaryl group).

[0299] In certain embodiments, the compounds provided herein comprise one or more linking groups. In certain embodiments, each of L1, L2, L3, and L4 comprises a linking group. In certain embodiments, each of L1, L2, L3, and L4 comprises a linking group. In certain embodiments, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4AEach of the groups comprises a linking group. In certain embodiments, the linking group is 1 / 7 In certain embodiments, the linking group is covalently attached to an integrin receptor ligand. In certain embodiments, the linking group is covalently attached to an oligonucleotide. In certain embodiments, the linking group is covalently attached to a cleavable moiety. In certain embodiments, the linking group comprises a cleavable bond. In certain embodiments, the linking group does not comprise a cleavable moiety. In certain embodiments, the linking group comprises a covalent bond to a solid support. In certain embodiments, the linking group is α4β 1 / 7 It contains multiple sites for the binding of integrin receptor ligands.

[0300] In certain embodiments, the linking group comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units or combinations of such repeating units. In certain embodiments, the linking group comprises 1 to 50 repeating units, 1 to 40 repeating units, 1 to 25 repeating units, 1 to 20 repeating units, 1 to 15 repeating units, 1 to 10 repeating units, or 1 to 5 repeating units. In certain embodiments, the linking group is 1 to 50 atoms in length, 1 to 40 atoms in length, 1 to 25 atoms in length, 1 to 20 atoms in length, 1 to 15 atoms in length, 1 to 10 atoms in length, or 1 to 5 atoms in length.

[0301] In certain embodiments, the linking group contains a carbon atom. In certain embodiments, the linking group contains a heteroatom (e.g., nitrogen, oxygen, sulfur, etc.). In certain embodiments, the linking group forms an amide linkage, an ester linkage, or a disulfide linkage. In certain embodiments, the linking group forms a hydrazone linkage, an oxime linkage, an imine linkage, a guanidine linkage, a urea linkage, a carbamate linkage, an unsaturated alkyl linkage, a sulfonamide linkage, or a 4- to 8-membered heterocyclic linkage. In certain embodiments, the linking group comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, the linking group comprises at least one phosphorus group. In certain embodiments, the linking group comprises at least one phosphate group. In certain embodiments, the linking group comprises at least one neutral linking group. In certain embodiments, the linking group is substituted with a variety of substituents, including, but not limited to, hydrogen atoms, alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, halogen, aryl, heterocycle, heteroaromatic, cyano, amido, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, and ureido groups, each of which may in turn be substituted, as will be understood by those skilled in the art.

[0302] In certain embodiments, linking groups include, but are not limited to, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, or substituted or unsubstituted C2-C10 alkynyl, with a non-limiting list of preferred substituents including hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the linking group is aliphatic or heteroaliphatic. For example, the linking group can be a polyalkyl linking group. The linking group can be a polyether linking group. The linking group can be a polyethylene linking group, such as PEG.

[0303] In certain embodiments, the linking group is a short peptide chain, hi certain embodiments, the linking group comprises 1 to 40 amino acids, 1 to 25 amino acids, 1 to 20 amino acids, 1 to 15 amino acids, 1 to 10 amino acids, or 1 to 5 amino acids.

[0304] In certain embodiments, the linking group comprises a linker nucleoside. In certain embodiments, the linking group comprises 1 to 40 linker nucleosides, 1 to 25 linker nucleosides, 1 to 20 linker nucleosides, 1 to 15 linker nucleosides, 1 to 10 linker nucleosides, or 1 to 5 linker nucleosides. In certain embodiments, such linker nucleosides can be modified or unmodified nucleosides. Typically, it is desirable for the linker nucleosides to be cleaved from the compound after reaching the target tissue. Thus, the linker nucleosides herein can be linked to each other or to the remainder of the compound via a cleavable bond. As used herein, linker nucleosides are not considered part of the oligonucleotide payload. Thus, compounds may include oligonucleotides containing a specific number or range of linked nucleosides and / or a specific percent complementarity to a reference nucleic acid, and compounds may include α4β oligonucleotides containing linker-nucleoside-containing linking groups. 1 / 7In embodiments involving integrin receptor ligands, those linker nucleosides are not counted in the length of the oligonucleotide, nor are they used in determining the percent complementarity of the oligonucleotide to a reference nucleic acid.

[0305] In certain embodiments, the linking group comprises a protein-binding group. In certain embodiments, the protein-binding group is a lipid, such as, but not limited to, cholesterol, cholic acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholene. Examples of suitable protein-binding groups include: saccharides (e.g., saccharides, dimethoxytrityl, or phenoxazine), vitamins (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosomolytic components, steroids (e.g., uvaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, friedelin, epifriedelanol-derivatized lithocholic acid), or cationic lipids. In certain embodiments, the protein-binding group is a saturated or unsaturated fatty acid with a chain length of C16 to C22, cholesterol, cholic acid, vitamin E, adamantane, or 1-pentafluoropropyl.

[0306] In certain embodiments, linking groups include, but are not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA).

[0307] It's a nice selection of snowflakes It has a current assets:US5,994,517;US 6,300,319;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 al.,Tetrahedron,1997,53,759-770;Lee,Carbohydr.Res.1978,67,509-514;Connolly et al.,J.Biol.Chem.1982,257,939-945;Pavia et al.,Int.J.Pep.Protein Res.1983,22,539-548;Lee et al.,Biochem.1984,23,4255-4261;Lee et al.,Glycoconjugate J.1987,4,317-328;Toyokuni et al.,Tetrahedron Lett.1990,31,2673-2676;Biessen et al al.,J.Med.Chem.1995,38,1538-1546;Valentijn et al.,Tetrahedron,1997,53,759-770;Kim et al.,Tetrahedron Lett.1997,38,3487-3490;Lee et al al.,Bioconjug.Chem.1997,8,762-765;Kato et al.,Glycobiol.2001,11,821-829;Rensen et al.,J.Biol.Chem.2001,276,37577-37584;Lee et al.,Methods Enzymol.2003,362,38-43;Westerlind et al.,Glycoconj.J.2004,21,227-241;Lee et al.,Bioorg.Med.Chem.Lett.2006,16(19),5132-5135;Maierhofer et al.,Bioorg.Med.Chem.2007,15,7661-7676;Khorev et al.,Bioorg.Med.Chem.6e,2002 al.,Bioorg.Med.Chem.2011,19,2494-2500;Kornilova et al.,Analyt.Biochem.2012,425,43-46;Pujol et al.,Angew.Chemie Int.Essen.Engl.2042,51-Bie al.,J.Med.Chem.1995,38,1846-1852;Sliedregt et al.,J.Med.Chem.1999,42,609-618;Rensen et al.,J.Med.Chem.2004,47,5798-Rensen et5808; al.,Arterioscler.Thromh.Vase.Biol.2006,26,169-175;van Rossenberg et al.,Gene Ther.2004,11,457-464;Sato et al.,J.Am.Chem.Soc.2004,126,14022- 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.; Enzymol.2000,313,297-321;Maier et al.,Bioconjug.Chem.2003,14,18-29;Jayaprakash et al.,Org.Lett.2010,12,5410-5413;Manoharan,Antisense Nucleic Acid Drug Dev.2002,12,103-128;Merwin et al.,Bioconjug.Chem.1994,5,612-620;Tomiya et al. al.,Bioorg.Med.Chem.,2013,21,5275-5281;International Submission WO1998 / 013381;WO2011 / 038356;WO1997 / 046098;WO2008 / 098788;WO2004 / 1 01619;WO2012 / 037254;WO2011 / 120053;WO2011 / 100131;WO2011 / 163121;WO2012 / 177947;WO2013 / 033230;WO2013 / 075035;WO2 012 / 083185;WO2012 / 083046;WO2009 / 082607;WO2009 / 134487;WO2010 / 144740;WO2010 / 148013;WO1997 / 020563;WO2010 / 08853 7;WO2002 / 043771;WO2010 / 129709;WO2012 / 068187;WO2009 / 126933;WO2004 / 024757;WO2010 / 054406;WO2012 / 089352;WO2012 / 0 89602; WO2013 / 166121; WO2013 / 165816; U.S. Patent No. 4,751,219; same as No. 7,582,744; same as No. 8,552,163; same as No. 8,137,695; 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. 7,723,509; same as No. 8,106,022; same as No. 7,491,8 05; 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. 7,851,615; U.S. Patent Application Publication No. US2011 / 0097264; same as No.US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799; US2012 / 0035115; US2012 / 0230938; US2005 / 0164235; US2006 / 0183886; US2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2 006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132, each of which is incorporated herein by reference.

[0308] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka] wherein each n is independently 1 to 20, and p is 1 to 6.

[0309] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka] wherein each n is independently 1 to 20.

[0310] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka] wherein each n is independently 1 to 20.

[0311] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka] wherein each n is independently 1 to 20.

[0312] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka] wherein each L is independently a phosphorus linking group and each n is independently 1 to 20.

[0313] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka] [ka]

[0314] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka]

[0315] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka]

[0316] In certain embodiments, L1, L2, L3, and L4 independently or together comprise a structure selected from the following: [ka] (wherein n is 1 to 20).

[0317] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka]

[0318] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka]

[0319] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka]

[0320] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently comprise or together have the following structures: [ka]

[0321] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently comprise or together have the following structures: [ka]

[0322] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka]

[0323] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) independently or together comprise a structure selected from the following: [ka] wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

[0324] In some embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A) can independently be a linker (e.g., an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker). In some embodiments, any of L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) can independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). In some embodiments, any of L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A ) may independently be absent.

[0325] In some embodiments, L1 is a bond.

[0326] In some embodiments, L2 is an optionally substituted PEG linker. In some embodiments, the PEG linker is 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length. In certain embodiments, L2 has the structure [ka] Includes.

[0327] In some embodiments, L3 is an optionally substituted heteroaryl linker. In some embodiments, L3 is an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, L3 has the structure [ka] Includes.

[0328] In some embodiments, L4 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In some embodiments, the heteroalkyl linker comprises two substituents bonded together to form an optionally substituted carbocyclyl ring. In certain embodiments, L4 has the structure [ka] wherein X is O or S. In certain embodiments, L4 comprises the structure [ka] wherein X is O or S.

[0329] In some embodiments, L1, L2, L3, and L4 and / or L 1A , L 2A , L 3A , and L 4A Together, the structure [ka] [ka] wherein X is O or S.

[0330] Methods for making compounds In some embodiments, the present disclosure provides the α4β 1 / 7 The present invention relates to methods of making compounds and compositions that include integrin receptor ligands.

[0331] The compounds of the present disclosure can be made by means known in the art of organic synthesis. Methods for optimizing reaction conditions and, if necessary, minimizing competing by-products are known in the art. High-speed parallel synthesizers and computer-controlled microreactors can be advantageously utilized for reaction optimization and scale-up (see, e.g., Design and Optimization in Organic Synthesis, 2004). nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jaehnisch, K et al., Angew. Chem. Int. Ed. Engl. 2004 43:406; and references therein. Additional reaction schemes and protocols can be determined by one of skill in the art by use of publicly available structure search database software, such as SciFinder® (CAS division of the American Chemical Society) and Reaxys® (Elsevier), or by appropriate keyword searches using internet search engines such as Google® or keyword databases such as the U.S. Patent and Trademark Office text database.

[0332] As can be appreciated by those skilled in the art, methods for synthesizing compounds of the formulae herein, including the schemes and examples herein, will be apparent to those skilled in the art. Furthermore, the various synthetic steps may be performed in an alternate order or sequence to achieve the desired compounds. Additionally, solvents, temperatures, reaction times, and the like defined herein are for illustrative purposes only, and one skilled in the art will recognize that the reaction conditions can be varied to achieve the desired compounds of the present disclosure.

[0333] The compounds herein may also contain linkages (e.g., carbon-carbon bonds), and bond rotation is limited to that particular linkage, for example, limitations due to the presence of a ring or double bond. Accordingly, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomeric forms, and in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form is represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. All crystalline forms and polymorphs of the compounds described herein are also expressly included in the present disclosure. Extracts and fractions containing compounds of the present disclosure are also included in embodiments. The term "isomer" is intended to include diastereoisomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. For compounds containing one or more stereocenters, e.g., chiral compounds, the methods of the present disclosure can be practiced with enantiomerically enriched compounds, racemates, or mixtures of diastereomers. All isomers of the compounds defined herein are expressly included in the present disclosure.

[0334] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or greater. More preferably, the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, 99%, or greater. In preferred embodiments, only one enantiomer or diastereomer of a chiral compound of the present disclosure is administered to a cell or subject.

[0335] Treatment method In one aspect, a method of treating a subject suffering from or susceptible to a disorder or disease is provided, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

[0336] In another aspect, provided is a method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as needing modulation of protein function, comprising administering to said subject in need thereof an effective amount of a compound or pharmaceutical composition described herein, such that said disorder in said subject is treated.

[0337] In one aspect, a method for delivering a therapeutic oligonucleotide to the brain of a subject is provided, comprising contacting the subject with a compound or pharmaceutical composition described herein in an amount and under conditions sufficient to target the brain. In some embodiments, the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal lobe, and spinal cord.

[0338] In certain embodiments, methods for treating a disease, disorder, or symptom thereof are provided, wherein the disease is a central nervous system (CNS) disease, disorder, or symptom thereof. In some embodiments, the disease is a neurodegenerative disease, disorder, or symptom thereof. In some embodiments, the disease is Alzheimer's disease, or a symptom thereof.

[0339] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and drug addiction.

[0340] In certain embodiments, the CNS disorder is the result of, for example, neurotoxicity and / or neurotrauma, e.g., acute neuronal injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or chronic neurodegenerative disorders (e.g., multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease). In certain embodiments, the compounds of the present disclosure provide a neuroprotective effect, e.g., against acute neuronal injury or chronic neurodegenerative disorders.

[0341] In certain embodiments, the CNS disorder is stroke (eg, ischemic stroke).

[0342] In certain embodiments, the CNS disorder is multiple sclerosis.

[0343] In certain embodiments, the CNS disorder is a spinal cord injury.

[0344] In certain embodiments, the CNS disorder is epilepsy.

[0345] In certain embodiments, the CNS disorder is, for example, a psychiatric disorder, such as depression, anxiety or an anxiety-related condition, a learning disability, a somatic disorder, schizophrenia, or schizoaffective disorder.

[0346] In certain embodiments, the CNS disorder is depression. "Depression" includes, but is not limited to, depressive disorders or conditions, such as major depressive disorder (e.g., unipolar depression), treatment-resistant depression, dysthymic disorder (e.g., chronic mild depression), bipolar disorder (e.g., manic depression), seasonal affective disorder, and / or depression associated with substance abuse or substance abuse disorder (e.g., withdrawal). Depression can be clinical depression or pre-morbid depression. Depression can be associated with premenstrual syndrome and / or premenstrual dysphoric disorder.

[0347] In certain embodiments, the CNS disorder is anxiety. " Anxiety " includes, but is not limited to, anxiety and anxiety-related conditions, such as clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder (GAD), specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorder with anxiety features, anxiety disorder associated with depression, anxiety disorder due to general medical conditions, and substance-induced anxiety disorder, anxiety associated with substance abuse or substance use disorder (e.g., withdrawal, dependence, relapse) and anxiety associated with nausea and / or vomiting. The treatment can be to induce or promote sleep in a subject (e.g., a subject with anxiety).

[0348] In certain embodiments, the CNS disorder is a learning disorder (eg, attention deficit disorder (ADD)).

[0349] In certain embodiments, the CNS disorder is schizophrenia or schizoaffective disorder.

[0350] In certain embodiments, the CNS disorder is a sleep condition. "Sleep condition" includes, but is not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement disorder (RBD), shift work sleep disorder (SWSD), and sleep problems (e.g., parasomnia), such as nightmares, night terrors, sleep talking, head nodding, snoring, and jaw clenching and / or teeth grinding (bruxism).

[0351] In certain embodiments, the CNS disorder is a movement disorder, such as a basal ganglia disorder, including Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette syndrome, tardive dyskinesia, and dystonia.

[0352] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0353] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0354] In certain embodiments, the CNS disorder is nausea and / or vomiting.

[0355] In certain embodiments, the CNS disorder is drug addiction (eg, addiction to, for example, opiates, nicotine, cocaine, psychostimulants, or alcohol).

[0356] The term "neurological disease" (including, for example, "neurodegenerative disease") refers to any disease of the nervous system, including diseases involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (portions located in both the central and peripheral nervous systems). Neurodegenerative disease refers to a type of nervous system disorder characterized by the loss of nerve cells, including, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington's disease. Examples of nervous system disorders include, but are not limited to, headaches, impaired consciousness and coma, dementia, seizures, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmological, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of the peripheral nerves, muscles, and neuromuscular junction. Substance abuse or substance use disorders (SUDs) and psychiatric disorders, including, but not limited to, bipolar disorder, schizophrenia, and schizoaffective disorder, are also included in the definition of nervous system disorders. Further examples of neurological disorders include acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformations, Asperger's syndrome, ataxia-telangiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Batten disease, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Binswanger's disease, blepharospasm, and Bloch-Salzba syndrome. Agers syndrome; brachial plexus injury; brain abscess; brain injury; brain tumor (including glioblastoma multiforme); spinal cord tumor; Brown-Séquard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; head injury; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin-Lowry syndrome; coma, including persistent vegetative state; congenital bilateral facial palsy; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder;Cushing's syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes, dancing feet syndrome; Dandy-Walker syndrome; Dawson's disease; de ​​Morcher syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; autonomic neuropathy; dysgraphia; dyslexia; dystonia; early infantile epileptic encephalopathy; syringomyelia turcica syndrome; encephalitis; encephalocele; cerebral trigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; syncope; familial spastic paraparesis; febrile seizures; Fisher's syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barré syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head trauma; headache; hemifacial spasm; hereditary spastic paraplegia; hereditary polyneuropathic ataxia; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological symptoms of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat disorders; hydrocephalus; hydrocephalus; hypercalcaemia Hypercortisolism; Hypoxia; Immune-mediated encephalomyelitis; Inclusion body myositis; Incontinentia pigmenti; Infant; Phytanic acid storage disease; Infantile Refsum disease; Infantile spasms; Inflammatory myopathy; Intracranial cyst; Intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsborn syndrome; Klippel-Feil syndrome; Krabbe disease; Kugelberg-Welander disease; Kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; Lateral medullary (Wallenberg) syndrome; Learning disability; Leigh disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome syndrome; leukodystrophy; dementia with Lewy bodies; lissencephaly; locked-in syndrome; Lou Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis); lumbar discopathy; Lyme disease - neurological sequelae; Machado-Joseph disease; megaloencephaly; megalencephaly; Melkerson-Rosenthal syndrome; Meniere's disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller-Fisher syndrome; minor stroke; mitochondrial myopathy; Moebius syndrome; unilateral muscular atrophy; motor neuron disease; moyamoya disease; mucopolysaccharidosis; multi-infarct dementia;Multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; diffuse myelinating sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; congenital myotonia; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; intraneuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; sequelae of subclinical spinal dysraphism; Ohtahara syndrome; olivopontine stenosis Cerebral atrophy; opsoclonus-myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; congenital paramyotonia; paraneoplastic disorders; paroxysmal seizures; Parry-Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorder; photoresponsive sneeze reflex; phytanic acid storage disease; Pick's disease; radiculopathy; pituitary tumor; polymyositis; porencephaly; postpolio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postorthostatic hypotension; Prader-Willi syndrome; Primary lateral sclerosis; Prion disease; Progressive; Hemifacial atrophy; Progressive multifocal leukoencephalopathy; Progressive sclerosing poliodystrophy; Progressive supranuclear palsy; Pseudotumor cerebri; Ramsay-Hunt syndrome (Types I and II); Rasmussen's encephalitis; Reflex sympathetic dystrophy syndrome; Refsum's disease; Repetitive movement disorder; Repetitive stress injury; Restless legs syndrome; Retroviral-associated myelopathy; Rett syndrome; Reye's syndrome; St. Vitus' dance; Sandhoff disease; Schilder's disease; Schizencephaly; Septo-optic dysplasia; Shaken baby syndrome; Herpes zoster; Shy-Drager syndrome; She Glenn syndrome; sleep apnea; Sotos syndrome; spasticity; spina bifida; spinal cord injury; spinal tumor; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered cord syndrome; Thomsen's disease; thoracic outlet syndrome; painful tics; Todd's palsy; Tourette's syndrome; transient ischemic attack; transmissible spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraplegia; tuberous sclerosis;These include vascular dementia (multi-infarct dementia), vasculitis including temporal arteritis, von Hippel-Lindau disease (VHL), Wallenberg syndrome, Werdnig-Hoffmann disease, West syndrome, whiplash injury, Williams syndrome, Wilson disease, and Zellweger syndrome.

[0357] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0358] In another embodiment, the aforementioned method is provided, wherein the effective amount of the compound provided herein is as described above.

[0359] In another embodiment, the above method is provided, wherein the compound provided herein is administered intrathecally, intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically. In certain embodiments, the compound is administered intrathecally.

[0360] In other embodiments, the above methods are provided, wherein a compound of any of the formulae provided herein is administered alone or in combination with one or more other therapeutic agents. In further embodiments, the additional therapeutic agent is a central nervous system (CNS) disorder agent.

[0361] Another object of the present disclosure is the use of a compound described herein in the manufacture of a medicament for use in treating a disorder or disease.Another object of the present disclosure is the use of a compound described herein for use in treating a disorder or disease.

[0362] Pharmaceutical Composition In one aspect, a pharmaceutical composition is provided that includes any of the compounds described herein and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

[0363] The compounds or compositions described herein can be administered in combination with one or more additional therapeutic agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional therapeutic agents that improve their activity (e.g., activity (e.g., efficacy and / or effectiveness) in treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, and / or reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell. It will also be understood that the therapies employed may achieve desired effects for the same disorder and / or may achieve different effects. In certain embodiments, pharmaceutical compositions described herein comprising a compound described herein and an additional therapeutic agent exhibit a synergistic effect that is not present in pharmaceutical compositions comprising either a compound described herein or an additional therapeutic agent, but not both.

[0364] The compound or composition may be administered simultaneously with, before, or after one or more additional therapeutic agents, which may be useful, for example, as a combination therapy. Therapeutic agents include therapeutically active agents. Therapeutic agents also include prophylactically active agents. Therapeutic agents include drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration under the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules such as cells. In certain embodiments, the additional therapeutic agents are therapeutic agents useful for the treatment and / or prevention of diseases (e.g., CNS disorders). Each additional therapeutic agent may be administered at a dose and / or time schedule determined for that therapeutic agent. The additional therapeutic agents can also be administered in a single dose, together with each other and / or with the compounds or compositions described herein, or separately in different doses. The particular combination employed in a regimen will take into account compatibility of the compounds described herein with the additional therapeutic agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional therapeutic agent(s) of the combination will be utilized at levels that do not exceed the levels utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0365] In one aspect, a kit is provided that includes an effective amount of a compound provided herein in unit dosage form together with instructions for administering the compound to a subject suffering from or susceptible to a disease or disorder.

[0366] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents present in the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galactunolonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functional groups, allowing the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are also suitable for the present disclosure.

[0367] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for the purposes of this disclosure.

[0368] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0369] Certain compounds of the present disclosure can exist not only in unsolvated form but also in solvated form, including hydrated form.In general, solvated form is equivalent to unsolvated form and is intended to be included within the scope of the present disclosure.Certain compounds of the present disclosure may exist in multiple crystalline forms or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0370] The present disclosure also provides pharmaceutical compositions, comprising an effective amount of the compound described herein and pharmaceutically acceptable excipient.In one embodiment, the compound of any of the formulas provided herein is administered to subject using a pharmaceutically acceptable formulation, for example, after the pharmaceutically acceptable formulation is administered to subject, the pharmaceutically acceptable formulation is used to provide the sustained delivery of compound to subject for at least 12 hours, 24 hours, 36 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks or 4 weeks.

[0371] Actual dosage levels and times of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, while being tolerated acceptably by the subject.

[0372] In use, at least one compound according to the present disclosure is administered in a pharmaceutical carrier in a pharmaceutically effective amount by intravenous, intrathecal, intramuscular, subcutaneous, or intracerebroventricular injection, or by oral administration or topical application to a subject in need thereof. According to the present disclosure, the compound of the present disclosure can be administered alone or in combination with a second, different therapeutic agent. "In combination" means together, substantially simultaneously, or sequentially. In one embodiment, the compound of the present disclosure is administered acutely. Thus, the compound of the present disclosure can be administered for a short treatment period, such as from about one day to about one week. In another embodiment, the compound of the present disclosure can be administered over a long period, for example, from about one week to several months, to ameliorate a chronic disorder.

[0373] As used herein, a "pharmaceutically effective amount" refers to an amount of a compound of the present disclosure that is high enough to significantly positively alter the condition being treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio), within the scope of sound medical judgment. A pharmaceutically effective amount of a compound of the present disclosure may vary depending on the specific goal to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of treatment, the nature of any concurrent treatments, and the specific compound employed. For example, a therapeutically effective amount of a compound of the present disclosure administered to a child or neonate would be proportionally reduced, in accordance with sound medical judgment. Thus, an effective amount of a compound of the present disclosure would be the minimum amount that provides the desired effect.

[0374] A crucial practical advantage of the present disclosure is that the compound can be administered in a convenient manner, for example, by intrathecal, intravenous, intramuscular, subcutaneous, oral, or intracerebroventricular injection, or by local application such as cream or gel. Depending on the administration route, the active ingredient contained in the compound of the present disclosure may need to be coated with a material to protect the compound from the action of enzymes, acids, and other natural conditions that may inactivate the compound. To administer the compound of the present disclosure by a mode other than parenteral administration, the compound may be coated with or administered using a material to prevent inactivation.

[0375] The compounds can be administered parenterally or intraperitoneally.Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.

[0376] Some examples of substances that can function as pharmaceutical excipients or pharmaceutical carriers (these terms are used interchangeably herein) are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer; nonfat powdered milk; and other non-toxic compatible substances used in pharmaceutical formulations, such as vitamin C, estrogen, and echinacea. Wetting agents and lubricants such as sodium lauryl sulfate, as well as colorants, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. Solubilizing agents, including, for example, cremaphor and beta-cyclodextrin, may also be used in the pharmaceutical compositions herein.

[0377] Pharmaceutical compositions containing the active compounds of the present disclosure (or their derivatives or prodrugs) can be prepared by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing processes. The compositions can be formulated in a convenient manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliary agents that facilitate the processing of the active compounds into pharmaceutically usable preparations. The compositions herein can be prepared (e.g., for pharmaceutical, agricultural, or veterinary use) by mixing (e.g., contacting, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing) the compounds defined herein with one or more suitable carriers, diluents, excipients, or auxiliary agents, including those described herein.

[0378] The pharmaceutical compositions of the present disclosure may be in a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ophthalmic, oral, buccal, systemic, nasal, injectable, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0379] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0380] Useful injection preparations include sterile suspensions, solutions, or emulsions of active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. Injection preparations may be provided in unit dosage forms (e.g., ampoules or multi-dose containers) and may contain added preservatives.

[0381] Alternatively, the injectable formulations may be provided in powder form to be reconstituted before use with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc. To this end, the active compound(s) may be dried by any known technique, such as lyophilization, and reconstituted prior to use.

[0382] For long-term delivery, the active compound(s) or prodrug(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredients can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0383] Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compound(s), oligonucleotide(s), or prodrug(s). Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be utilized.

[0384] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0385] The active compound(s), or prodrug(s), or compositions thereof of the present disclosure are generally used in an amount effective to achieve the intended result, for example, an amount effective for treating or preventing the particular disease being treated. The compound(s) and oligonucleotide(s) can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying disorder being treated and / or eradication or amelioration of one or more symptoms associated with the underlying disorder, such that the patient reports an improvement in mood or condition, even if the patient is still suffering from the underlying disorder. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0386] In the case of prophylactic administration, the compound can be administered to patients at risk of developing any of the aforementioned diseases. Patients at risk of developing a disease can be patients with characteristics that place them in a designated risk patient group defined by appropriate medical professionals or organizations. At-risk patients can also be patients who are usually or regularly in an environment where the onset of the underlying disease may occur. In other words, at-risk patients are those who are usually or regularly exposed to a disease or disease-causing condition, or those who may have been acutely exposed for a limited time. Alternatively, prophylactic administration can be performed to prevent the onset of symptoms in patients diagnosed with an underlying disorder.

[0387] The amount of compound administered will depend on a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated, the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of one of ordinary skill in the art.

[0388] Effective dosages can be estimated initially from in vitro assays. For example, initial dosages for use in animals may be determined based on the IC50 or IC60 of a particular compound as measured by in vitro assays such as the in vitro fungal MIC or MFC, and other in vitro assays. 50 The active compound can be formulated to achieve a circulating or serum concentration of the active compound that is equal to or greater than 100 mg / kg. Calculating the dosage to achieve such a circulating or serum concentration, taking into account the bioavailability of a particular compound, is well within the ability of one skilled in the art. For guidance, see "General Principles," in: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-112, 13th ed., McGraw-Hill, and references therein, which are incorporated herein by reference.

[0389] Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds for treating or preventing the various diseases described above are well known in the art.

[0390] Dosages typically range from about 0.0001 mg or 0.001 mg or 0.01 mg / kg / day to about 100 mg / kg / day, but may be increased or decreased depending on, among other factors, the activity of the compound, its bioavailability, the mode of administration, and the various factors described above. Dosage amounts and administration intervals can be individually adjusted to provide plasma levels of the compound(s) sufficient to maintain therapeutic or prophylactic effect. In cases of local administration or selective uptake, e.g., local topical administration, the effective local concentration of the active compound(s) may not be related to plasma concentration. One of ordinary skill in the art will be able to optimize an effective local dosage without undue experimentation.

[0391] Preferably, the compound(s) provide therapeutic or prophylactic benefit and have acceptable tolerability. The tolerability of the compound(s) and oligonucleotide(s) can be determined using standard pharmaceutical procedures. The dose ratio between intolerable effects and therapeutic effect (or prophylactic effect) is the therapeutic index. Compound(s) that exhibit a high therapeutic index are preferred.

[0392] The recitation of a list of chemical groups in any definition of a variable herein includes definitions of that variable of any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0393] Additional Embodiments Certain specific embodiments include the following embodiments P1 to P30.

[0394] Embodiment P1. A compound comprising the structure of Formula (I), or a salt thereof: [ka] (In the formula, [ka] is α4β 1 / 7 is an integrin ligand, each of L1, L2, L3, and L4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, or peptides).

[0395] Embodiment P2. The α4β 1 / 7 Integrin ligand is α4β 1 / 7 The compound of embodiment 1, or a salt thereof, which is an integrin agonist.

[0396] Embodiment P3. The α4β 1 / 7 Integrin ligand is α4β 1 / 7 2. The compound of embodiment 1, or a salt thereof, which is an integrin antagonist.

[0397] Embodiment P4. The α4β 1 / 7 The compound of embodiment 1, or a salt thereof, wherein the integrin ligand is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] (Wherein, each case of R is [ka] Anti-α4β 1 / 7 integrin antibodies and their derivatives).

[0398] Embodiment P5. The α4β 1 / 7 Integrin ligands have the structure [ka] or a derivative thereof, or a salt thereof.

[0399] Embodiment P6. The compound has the structure of Formula (II): [ka] or a salt thereof.

[0400] Embodiment P7. The compound has the structure of Formula (II-a): [ka] or a salt thereof.

[0401] Embodiment P8. The compound of any one of embodiments 1-7, or a salt thereof, wherein each of L1, L2, L3, and L4 is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, a phosphodiester linkage, or a phosphorothioate linkage.

[0402] Embodiment P9. The compound of embodiment 8, or a salt thereof, wherein L1 is a bond.

[0403] Embodiment P10. A compound according to embodiment 8 or 9, or a salt thereof, wherein L2 is an optionally substituted PEG linker.

[0404] Embodiment P11. The compound of embodiment 10, or a salt thereof, wherein the PEG linker is 5 PEG units in length.

[0405] Embodiment P12.L2 is a structure [ka] 12. The compound of any one of embodiments 8 to 11, or a salt thereof, comprising:

[0406] Embodiment P13. A compound according to any one of embodiments 8 to 12, or a salt thereof, wherein L3 is an optionally substituted heteroaryl linker.

[0407] Embodiment P14. A compound according to embodiment 13, or a salt thereof, wherein L3 is an optionally substituted partially unsaturated heteroaryl linker.

[0408] Embodiment P15.L3 is a structure [ka] 15. The compound of embodiment 13 or 14, or a salt thereof, comprising:

[0409] Embodiment P16. A compound according to any one of embodiments 8 to 15, or a salt thereof, wherein L4 is an optionally substituted heteroalkyl linker.

[0410] Embodiment P17. The compound of embodiment 16, or a salt thereof, wherein said heteroalkyl linker is substituted with one or more ═O substituents.

[0411] Embodiment P18.L4 is a structure [ka] wherein X is O or S, or a salt thereof.

[0412] Embodiment P19. L1, L2, L3, and L4 together form the structure [ka] wherein X is O or S; or a salt thereof.

[0413] Embodiment P20. The compound has the structure: [ka] or a salt thereof, wherein X is O or S.

[0414] Embodiment P21. A compound according to any one of embodiments 18 to 20, or a salt thereof, wherein X is O.

[0415] Embodiment P22. A compound according to any one of embodiments 18 to 20, or a salt thereof, wherein X is S.

[0416] Embodiment P23.R 1 23. The compound of any one of embodiments 1 to 22, or a salt thereof, wherein

[0417] Embodiment P24. The compound of embodiment 23, or a salt thereof, wherein said oligonucleotide is attached at its 5' end.

[0418] Embodiment P25. The compound of embodiment 23, or a salt thereof, wherein said oligonucleotide is linked at its 3' end.

[0419] Embodiment P26. The compound of embodiment 23, or a salt thereof, wherein said oligonucleotide is linked at an internal position of said oligonucleotide.

[0420] Embodiment P27. The compound of embodiment 26, or a salt thereof, wherein said internal position is an internucleoside linkage.

[0421] Embodiment P28.R 1 but one or more additional α4β 1 / 7 28. The compound of any one of embodiments 1 to 27, or a salt thereof, comprising an oligonucleotide conjugated to a ligand.

[0422] Embodiment P29. The oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional α4β 1 / 7 29. The compound of embodiment 28, or a salt thereof, conjugated to a ligand.

[0423] Embodiment P30. The additional α4β 1 / 7 30. The compound of embodiment 28 or 29, or a salt thereof, wherein the ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, one or more internal positions of the oligonucleotide, or any combination thereof.

[0424] Embodiment P31. The compound of any one of embodiments 23 to 30, or a salt thereof, wherein said oligonucleotide is a modified oligonucleotide.

[0425] Embodiment P32. A composition comprising a compound according to any one of embodiments 1 to 31, or a salt thereof, and a pharmaceutically acceptable excipient.

[0426] Embodiment P33. A method for delivering a therapeutic oligonucleotide to the brain of a subject, comprising administering to the subject a compound described in any one of embodiments 1-31, or a salt thereof, or a composition described in embodiment 32.

[0427] Embodiment P34. The method of embodiment 33, wherein said therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal lobe, and spinal cord.

[0428] Embodiment P35. A method for treating or ameliorating a disease, disorder, or a symptom thereof in a subject, comprising administering to the subject a compound described in any one of embodiments 1-31, or a salt thereof, or a composition described in embodiment 32.

[0429] Embodiment P36. The method of embodiment 35, wherein said disease, disorder, or symptom thereof is a disease, disorder, or symptom thereof of the central nervous system (CNS).

[0430] Embodiment P37. The method of embodiment 35 or 36, wherein said disease, disorder, or symptom thereof is Alzheimer's disease, or a symptom thereof.

[0431] Embodiment P38. The method of any one of embodiments 33-37, wherein said compound, or salt thereof, is administered to said subject intrathecally.

[0432] Embodiment P39. A method for making a compound of any one of embodiments 1-31, or a salt thereof, comprising one or more compounds and chemical transformations described herein, including Example 1.

[0433] Additional embodiments include the following embodiments 1 to 127.

[0434] Embodiment 1. A compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (I'): [ka] (In the formula, [ka] Each of the α4β 1 / 7 is an integrin ligand, L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; z1 is either 0 or 1).

[0435] Embodiment 2. The compound of embodiment 1, wherein the compound comprises the structure of formula (I″), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, [ka] is an oligonucleotide).

[0436] Embodiment 3. The compound of embodiment 1, wherein the compound comprises the structure of formula (I), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0437] Embodiment 4. The α4β 1 / 7 Integrin ligand is α4β 1 / 7 The compound of any one of embodiments 1-3, or a stereoisomer, tautomer, prodrug, or salt thereof, which is an integrin agonist.

[0438] Embodiment 5. The α4β 1 / 7 Integrin ligand is α4β 1 / 7 The compound of any one of embodiments 1-3, or a stereoisomer, tautomer, prodrug, or salt thereof, which is an integrin antagonist.

[0439] Embodiment 6. The α4β 1 / 7 4. The compound of any one of embodiments 1-3, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the integrin ligand is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (Wherein, each case of R is [ka] Anti-α4β 1 / 7 integrin antibodies and their derivatives).

[0440] Embodiment 7. The compound of embodiment 1, wherein the compound comprises the structure of formula (II'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A are each independently H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl; R 3 , R 3A , R 4 , and R 4A are each independently H, halogen, optionally substituted alkyl, or optionally substituted —O-alkyl).

[0441] Embodiment 8. The compound of embodiment 7, wherein the compound comprises the structure of formula (II″), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0442] Embodiment 9. The compound of embodiment 8, wherein the compound comprises the structure of formula (II″-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0443] Embodiment 10. The compound of embodiment 9, wherein the compound comprises the structure of formula (II''-a-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0444] Embodiment 11. The compound of embodiment 9, wherein the compound comprises the structure of formula (II''-a-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0445] Embodiment 12. The α4β 1 / 7 Integrin ligands have the structure [ka] 12. The compound of any one of embodiments 1-11, or a stereoisomer, tautomer, prodrug, or salt thereof, including a derivative thereof.

[0446] Embodiment 13. The compound of embodiment 8, wherein the compound comprises the structure of formula (II), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0447] Embodiment 14. The compound of embodiment 13, wherein the compound comprises the structure of formula (II-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0448] Embodiment 15. The compound of embodiment 1, wherein the compound comprises the structure of formula (III'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A are each independently H, halogen, polyethylene glycol (PEG), optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl; R 3 and R 3A are each independently an optionally substituted heteroalkyl or an optionally substituted heterocyclyl; n and n A are each independently 1, 2, or 3).

[0449] Embodiment 16. The compound of embodiment 15, wherein the compound comprises the structure of formula (III), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0450] Embodiment 17. The compound of embodiment 16, wherein the compound comprises the structure of formula (III-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0451] Embodiment 18. The compound of embodiment 16, wherein the compound comprises the structure of formula (III-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0452] Embodiment 19. The compound of embodiment 1, wherein the compound comprises the structure of formula (IV'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A are each independently H, -OH, -NH2, or -NHR 3 , -OR 3 , or absent, R 3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl).

[0453] Embodiment 20. The compound of embodiment 19, wherein the compound comprises the structure of formula (IV), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0454] Embodiment 21. The compound of embodiment 20, wherein the compound comprises the structure of formula (IV-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0455] Embodiment 22. The compound of embodiment 20, wherein the compound comprises the structure of formula (IV-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0456] Embodiment 23. The compound of embodiment 20, wherein the compound comprises the structure of formula (IV-c), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0457] Embodiment 24. The compound of embodiment 1, wherein the compound comprises the structure of formula (V'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, n and n A are each independently 0, 1, 2, or 3).

[0458] Embodiment 25. The compound of embodiment 24, wherein the compound comprises the structure of formula (V'-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0459] Embodiment 26. The compound of embodiment 24, wherein the compound comprises the structure of formula (V), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0460] Embodiment 27. The compound of embodiment 26, wherein the compound comprises the structure of formula (Va), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0461] Embodiment 28. The compound of embodiment 26, wherein the compound comprises the structure of formula (Vb), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0462] Embodiment 29. The compound of embodiment 26, wherein the compound comprises the structure of formula (Vc), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0463] Embodiment 30. The compound of embodiment 26, wherein the compound comprises the structure of formula (Vd), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0464] Embodiment 31. The compound of embodiment 26, wherein the compound comprises the structure of formula (Ve), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0465] Embodiment 32. The compound of embodiment 1, wherein the compound comprises the structure of formula (VI'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, n and n A are each independently 0, 1, 2, or 3).

[0466] Embodiment 33. The compound of embodiment 32, wherein the compound comprises the structure of formula (VI'-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0467] Embodiment 34. The compound of embodiment 32, wherein the compound comprises the structure of formula (VI), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0468] Embodiment 35. The compound of embodiment 34, wherein the compound comprises the structure of formula (VI-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0469] Embodiment 36. The compound of embodiment 34, wherein the compound comprises the structure of formula (VI-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0470] Embodiment 37. The compound of embodiment 34, wherein the compound comprises the structure of formula (VI-c), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0471] Embodiment 38. The compound of embodiment 34, wherein the compound comprises the structure of formula (VI-d), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0472] Embodiment 39. The compound of embodiment 1, wherein the compound comprises the structure of formula (VII'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 , and R 5A are each independently H, halogen, optionally substituted alkyl, optionally substituted —O-alkyl, cycloalkyl, or absent; R 8 and R 8A are each independently optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl, or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy; R 6 , R6A , R 7 , and R 7Aare each independently H, halogen, alkyl, or optionally substituted alkyl, optionally substituted heteroalkyl, [ka] (It is).

[0473] Embodiment 40. The compound of embodiment 39, wherein the compound comprises the structure of formula (VII'-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0474] Embodiment 41. The compound of embodiment 40, wherein the compound comprises the structure of formula (VII'-a-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0475] Embodiment 42. The compound of embodiment 40, wherein the compound comprises the structure of formula (VII'-a-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0476] Embodiment 43. The compound of embodiment 39, wherein the compound comprises the structure of formula (VII), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0477] Embodiment 44. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0478] Embodiment 45. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0479] Embodiment 46. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-c), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0480] Embodiment 47. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-c-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0481] Embodiment 48. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-c-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0482] Embodiment 49. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-d), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0483] Embodiment 50. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-d-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0484] Embodiment 51. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-d-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0485] Embodiment 52. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-d-3), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0486] Embodiment 53. The compound of embodiment 43, wherein the compound comprises the structure of formula (VII-d-4), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0487] Embodiment 54. The compound of embodiment 46, wherein the compound comprises the structure of formula (VII-d-5), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0488] Embodiment 55. The compound of embodiment 46, wherein the compound comprises the structure of formula (VII-d-6), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0489] Embodiment 56. The compound of embodiment 46, wherein the compound comprises the structure of formula (VII-d-7), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0490] Embodiment 57. The compound of embodiment 46, wherein the compound comprises the structure of formula (VII-d-8), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0491] Embodiment 58. The compound of embodiment 46, wherein the compound comprises the structure of formula (VII-d-9), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0492] Embodiment 59. The compound of embodiment 46, wherein the compound comprises the structure of formula (VII-d-10), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0493] Embodiment 60.R 6 is F, CF3, or CH3, and R 7 but, [ka] 40. The compound of embodiment 39, wherein

[0494] Embodiment 61.R 7 is F, CF3, or CH3, and R 6 but, [ka] 40. The compound of embodiment 39, wherein

[0495] Embodiment 62. The compound of embodiment 1, wherein the compound comprises the structure of formula (VIII'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A are each independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or absent; R 3 , R 3A , R 4 , and R 4A are each independently H, halogen, optionally substituted alkyl, or optionally substituted —O-alkyl; R 5 and R 5A are each independently -OH or absent, Y and Y A are each independently -CH2- or -(CH2)2-.

[0496] Embodiment 63. The compound of embodiment 62, wherein the compound comprises the structure of formula (VIII'-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0497] Embodiment 64. The compound of embodiment 62, wherein the compound comprises the structure of formula (VIII), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0498] Embodiment 65. The compound of embodiment 64, wherein the compound comprises the structure of formula (VIII-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0499] Embodiment 66. The compound of embodiment 65, wherein the compound comprises the structure of formula (VIII-a-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0500] Embodiment 67. The compound of embodiment 65, wherein the compound comprises the structure of formula (VIII-a-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0501] Embodiment 68. The compound of embodiment 65, wherein the compound comprises the structure of formula (VIII-a-3), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0502] Embodiment 69. The compound of embodiment 1, wherein the compound comprises the structure of formula (IX'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A each independently represents H, -OH, -NH2, -NHR 3 , -OR 3 , or -CONHR 3 and R 3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; n and n A each of which is independently 1 or 2).

[0503] Embodiment 70. The compound of embodiment 69, wherein the compound comprises the structure of formula (IX), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0504] Embodiment 71. The compound of embodiment 70, wherein the compound comprises the structure of formula (IX-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0505] Embodiment 72. The compound of embodiment 70, wherein the compound comprises the structure of formula (IX-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0506] Embodiment 73. The compound of embodiment 1, wherein the compound comprises the structure of formula (X'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A are each independently H, -CH2OR 3 , -(CH2)2OR 3 , -CH2NHCOR 3 , or -OR 3 and R 3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl).

[0507] Embodiment 74. The compound of embodiment 73, wherein the compound comprises the structure of formula (X), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0508] Embodiment 75. The compound of embodiment 74, wherein the compound comprises the structure of formula (Xa), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0509] Embodiment 76. The compound of embodiment 74, wherein the compound comprises the structure of formula (Xb), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0510] Embodiment 77. The compound of embodiment 1, wherein the compound comprises the structure of formula (XI'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A each of which is independently H, -CONHR 3 , -CH2OR 3 , -(CH2)2OR 3 , -CH2NHCOR 3 , or -OR 3 and R 3 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; X and X A each of which is independently H or a halogen.

[0511] Embodiment 78. The compound of embodiment 77, wherein the compound comprises the structure of formula (XI), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0512] Embodiment 79. The compound of embodiment 78, wherein the compound comprises the structure of formula (XI-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0513] Embodiment 80. The compound of embodiment 78, wherein the compound comprises the structure of formula (XI-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0514] Embodiment 81. The compound of embodiment 1, wherein the compound comprises the structure of formula (XII'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A each of which is independently H, -CONHR 4 , -CH2OR 4 , -(CH2)2OR 4 , -CH2NHCOR 4 , or -OR 4 and R 3 and R 3A each is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 4 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 5 and R 5A each of is independently —OH or absent, n and n A are independently 0, 1, 2, or 3, n1 and n1 A is independently 1, 2, or 3).

[0515] Embodiment 82. The compound of embodiment 81, wherein the compound comprises the structure of formula (XII), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0516] Embodiment 83. The compound of embodiment 82, wherein the compound comprises the structure of formula (XII-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0517] Embodiment 84. The compound of embodiment 82, wherein the compound comprises the structure of formula (XII-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0518] Embodiment 85. The compound of embodiment 1, wherein the compound comprises the structure of formula (XIII'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A each of which is independently H, -CONHR 4 , -CH2OR 4 , -(CH2)2OR 4, -CH2NHCOR 4 , or -OR 4 and R 3 and R 3A each is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl; R 4 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 5 and R 5A each of is independently —OH or absent, X and X A each is independently H, optionally substituted CH, optionally substituted NH, or cycloalkyl.

[0519] Embodiment 86. The compound of embodiment 85, wherein the compound comprises the structure of formula (XIII), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0520] Embodiment 87. The compound of embodiment 86, wherein the compound comprises the structure of formula (XIII-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0521] Embodiment 88. The compound of embodiment 86, wherein the compound comprises the structure of formula (XIII-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0522] Embodiment 89. The compound of embodiment 86, wherein the compound comprises the structure of formula (XIII-c), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0523] Embodiment 90. The compound of embodiment 1, wherein the compound comprises the structure of formula (XIV'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 2 and R 2A each of which is independently H, -CH2OR 4 , -(CH2)2OR 4 , -CH2NHCOR 4 , or -OR 4 and R 3 and R 3A each independently represents H, -OH, -NH2, -NHR 5 , or -OR 5 and R 4 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 5 is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; n and n A each of which is independently 1, 2, or 3).

[0524] Embodiment 91. The compound of embodiment 90, wherein the compound comprises the structure of formula (XIV), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0525] Embodiment 92. The compound of embodiment 91, wherein the compound comprises the structure of formula (XIV-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0526] Embodiment 93. The compound of embodiment 91, wherein the compound comprises the structure of formula (XIV-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0527] Embodiment 94. L1, L2, L3, L4, L 1A , L 2A , L 3A , and L 4A or a stereoisomer, tautomer, prodrug, or salt thereof.

[0528] Embodiment 95. L1 and / or L 1A is a bond, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0529] Embodiment 96. L2 and / or L 2A 96. The compound of embodiment 94 or 95, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted PEG linker.

[0530] Embodiment 97. The compound of embodiment 96, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the PEG linker is 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length.

[0531] Embodiment 98. L2 and / or L 2A But the structure [ka] 98. The compound of any one of embodiments 94-97, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising:

[0532] Embodiment 99. L3 and / or L 3A The compound of any one of embodiments 94-98, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted heteroaryl linker.

[0533] Embodiment 100. L3 and / or L 3A is an optionally substituted partially unsaturated heteroaryl linker, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0534] Embodiment 101. L3 and / or L 3A But the structure [ka] 101. The compound of embodiment 99 or 100, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising:

[0535] Embodiment 102. L4 and / or L 4A The compound of any one of embodiments 94-101, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted heteroalkyl linker.

[0536] Embodiment 103. The compound of embodiment 102, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the heteroalkyl linker is substituted with one or more ═O substituents.

[0537] Embodiment 104. The compound of embodiment 102 or 103, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the heteroalkyl linker comprises two substituents bonded together to form an optionally substituted carbocyclyl ring.

[0538] Embodiment 105. L4 and / or L 4A But the structure [ka] wherein X is O or S, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0539] Embodiment 106. L4 and / or L 4A But the structure [ka] wherein X is O or S, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0540] Embodiment 107. L1, L2, L3, and L4 and / or L 1A , L 2A , L 3A , and L4A But together, the structure [ka] [ka] wherein X is O or S, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0541] Embodiment 108. The compound of any one of embodiments 1 to 107, wherein the compound comprises the following structure: [ka] [ka] [ka] [ka] [ka] [ka] wherein X is O or S.

[0542] Embodiment 109. A compound according to any one of embodiments 105-108, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is O.

[0543] Embodiment 110. A compound according to any one of embodiments 105-108, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is S.

[0544] Embodiment 111.R 1 111. The compound of any one of embodiments 1-110, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein

[0545] Embodiment 112. The compound of embodiment 111, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the oligonucleotide is linked at its 5' end.

[0546] Embodiment 113. The compound of embodiment 111, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the oligonucleotide is linked at its 3' end.

[0547] Embodiment 114. The compound of embodiment 111, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the oligonucleotide is linked at an internal position of the oligonucleotide.

[0548] Embodiment 115. The compound of embodiment 114, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the internal position is an internucleoside linkage.

[0549] Embodiment 116.R 1 but one or more additional α4β 1 / 7 116. The compound of any one of embodiments 1-115, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising an oligonucleotide conjugated to a ligand.

[0550] Embodiment 117. The oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional α4β 1 / 7117. The compound of embodiment 116, or a stereoisomer, tautomer, prodrug, or salt thereof, conjugated to a ligand.

[0551] Embodiment 118. The additional α4β 1 / 7 118. The compound of embodiment 116 or 117, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, one or more internal positions of the oligonucleotide, or any combination thereof.

[0552] Embodiment 119. The compound of any one of embodiments 111 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the oligonucleotide is a modified oligonucleotide.

[0553] Embodiment 120. A composition comprising a compound according to any one of embodiments 1 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, and a pharmaceutically acceptable excipient.

[0554] Embodiment 121. A method for delivering a therapeutic oligonucleotide to the brain of a subject, comprising administering to the subject a compound described in any one of embodiments 1 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, or a composition described in embodiment 120.

[0555] Embodiment 122. The method of embodiment 121, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal lobe, and spinal cord.

[0556] Embodiment 123. A method for treating or ameliorating a disease, disorder, or a symptom thereof in a subject, comprising administering to the subject a compound described in any one of embodiments 1 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, or a composition described in embodiment 120.

[0557] Embodiment 124. The method of embodiment 123, wherein the disease, disorder, or symptom thereof is a disease, disorder, or symptom thereof of the central nervous system (CNS).

[0558] Embodiment 125. The method of embodiment 123 or 124, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

[0559] Embodiment 126 The method of any one of embodiments 123-125, wherein the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, is administered intrathecally to the subject.

[0560] Embodiment 127. A method for making a compound of any one of embodiments 1 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising one or more compounds and chemical transformations described herein, including Examples 1 to 13. [Example]

[0561] In order that the embodiments described herein may be more fully understood, the following examples are set forth: The examples described in this application are provided to illustrate the compounds, compositions, and methods provided herein, and should not be construed as limiting the scope thereof in any way.

[0562] Basic experimental procedure The definitions of the variables in the structures in the schemes herein are the same as the definitions at the corresponding positions in the formulas defined herein. Common abbreviations: ACN Acetonitrile br Broad CDI Carbonyldiimidazole d doublet DCM dichloromethane dd double doublet dba Dibenzylideneacetone DBCO Azadibenzocyclooctyne DFAA Difluoroacetic anhydride DIPEA or DIEA Diisopropylethylamine DMF Dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-ferrocenediyl-bis(diphenylphosphine) EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc ethyl acetate h time HBTU Hexafluorophosphate Benzotriazole Tetramethyluronium HRMS high resolution mass spectrometry HPLC High Performance Liquid Chromatography LCMS Liquid Chromatography and Mass Spectrometry MS mass spectrometry MW Microwave m multiplet MeOH Methanol min mL milliliter MWCO Molecular Weight Cutoff m / z mass-to-charge ratio NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance ppm parts per million rt or RT room temperature s singlet t triplet TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride TLC thin layer chromatography

[0563] Examples 1A-1B: α4β 1 / 7 Synthesis of integrin ligand-conjugated oligonucleotides Exemplary compounds within the scope of this disclosure can be synthesized according to the following procedures.

[0564] Example 1A: General Procedure I: 5'-Conjugated Sense Strand

[0565] Step 1: To an aqueous solution of the 5'-amine-functionalized sense strand (I), 10% V / V 1 M sodium phosphate buffer (pH = 7) and 20%-50% V / V CH3CN were added. A solution of DBCO-NHS (II) (1.5-3 equivalents) in DMSO or CH3CN was added to the reaction. The reaction was monitored by LCMS and HPLC. Upon completion, the precipitate was removed using centrifugation, and the aqueous solution was purified by reverse-phase HPLC. The product fractions were combined and dried by lyophilization. For Step 2, the dried N-DBCO-modified sense strand (III) was reconstituted in RNase-free water. [ka]

[0566] Step 2: To a solution of 5'-DBCO-modified sense strand (III) (1 equivalent) was added a solution of Ligand-A-N3 (2 equivalents) in DMSO or THF. The reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand (IV) was purified by reverse-phase HPLC or by molecular weight cutoff using an Amicon® Ultra-15 centrifugal filter (3K, 5 times).

[0567] General Procedure II Type A: Bis-conjugated Sense Strand

[0568] Step 1: To an aqueous solution of the 5'-amine-functionalized sense strand (I), 10% V / V 1 M sodium phosphate buffer (pH = 7) and 20%-50% V / V CH3CN were added. A solution of DBCO-NHS (II) (1.5-3 equivalents) in DMSO or CH3CN was added to the reaction. The reaction was monitored by LCMS and HPLC. Upon completion, the precipitate was removed by centrifugation, and the aqueous solution was purified by reverse-phase HPLC. The product fractions were combined and dried by lyophilization. For Step 2, the 5'-DBCO-modified sense strand (III) was reconstituted in RNase-free water.

[0569] Step 2: To an aqueous solution of the 5'-DBCO-modified 3'-(C6-SS-C6)-mC-functionalized sense strand (III), 10% V / V 1 M sodium phosphate buffer (pH = 7) was added. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 equivalents) was dissolved in HO, and the pH of the solution was adjusted to 7 using 10 M NaOH. The aqueous TCEP solution was added to the solution of sense strand (III). The reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed using 100 mM sodium phosphate buffer (pH = 7) via MWCO (three times). To the disulfide-reduced sense strand solution, a solution of DBCO-MAL (V) (3 equivalents) in DMSO was added. The reaction was monitored by LCMS and HPLC. Upon completion, the solids were removed by centrifugation, and the solution was purified by reverse-phase HPLC and dried by lyophilization. For step 3, the dried bis-DBCO-modified sense strand (VI) was reconstituted in RNase-free water.

[0570] Step 3: To a solution of 5'-,3'-DBCO-functionalized sense strand (VI) (1 equivalent) was added a solution of Ligand-A-N3 (3 equivalents) in DMSO or THF. The reaction was monitored by HPLC and LCMS. Upon completion, the 5'-,3'-bis-conjugated sense strand (VII) was purified by reverse-phase HPLC or by molecular weight cutoff with an Amicon® Ultra-15 centrifugal filter (3K, 5 times). The product was confirmed by HPLC and LCMS. [ka]

[0571] General Procedure II Type B: 3',5'-conjugated sense strand

[0572] Step 1: To an aqueous solution of the 5'-amine, 3'-(C6-SS-C6)-mC functionalized sense strand (I), 10% V / V 1 M sodium phosphate buffer (pH = 7) and 20% to 50% V / V CH3CN were added. A solution of DBCO-NHS (II) (1.5 to 3 equivalents) in DMSO or CH3CN was added to the reaction. The reaction was monitored by LCMS and HPLC. Upon completion, the precipitate was removed by centrifugation, and the aqueous solution was purified by reverse-phase HPLC. The combined product fractions were collected and dried by lyophilization. For step 2, the 5'-DBCO-modified sense strand (III) was reconstituted in RNase-free water.

[0573] Step 2: To an aqueous solution of 5'-DBCO-modified sense strand (III) (1 equivalent) was added a solution of Ligand-A-N3 (2 equivalents) in DMSO. The reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand (IV) was purified by reverse-phase HPLC or by molecular weight cutoff using an Amicon® Ultra-15 centrifugal filter (3K, 5 times).

[0574] Step 3: To a solution of 5'-conjugated 3'-(C6-SS-C6)-mC-functionalized sense strand (IV) (1 equivalent) in HO, 10% V / V 1 M sodium phosphate buffer (pH = 7) was added. TCEP (V) (20 equivalents) was dissolved in HO, and the pH of the solution was adjusted to 7 using 10 M NaOH. Aqueous TCEP solution was added to the solution of sense strand (IV). The reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed (three times) using a MWCO with 100 mM sodium phosphate buffer (pH = 7). To the disulfide-reduced sense strand solution, a solution of DBCO-MAL (VI) (3 equivalents) in DMSO was added. The reaction was monitored by HPLC and LCMS. Upon completion, the aqueous solution was purified by reverse-phase HPLC. The product fractions were collected and dried by lyophilization. For the next step, the 5′-conjugated 3′-DBCO modified sense strand (VII) was reconstituted in 100 mM sodium phosphate buffer.

[0575] Step 4: To an aqueous solution of 5'-conjugated 3'-DBCO-functionalized sense strand (VII) (1 equivalent) was added a solution of Ligand-B-N3 (2 equivalents) in DMSO. The reaction was monitored by HPLC and LCMS. Upon completion, the 5'-,3'-conjugated sense strand (VIII) was purified by reverse-phase HPLC or by molecular weight cutoff using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes). [ka]

[0576] General Procedure III: 3'-Conjugated Sense Strand

[0577] Step 1: To an aqueous solution of 3'-(C6-SS-C6)-mC-functionalized sense strand (I), 10% V / V 1 M sodium phosphate buffer (pH = 7) was added. TCEP (II) (20 equivalents) was dissolved in HO, and the pH of the solution was adjusted to 7 using 10 M NaOH. The aqueous TCEP solution was added to the solution of sense strand (I). The reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with 100 mM sodium phosphate buffer (pH = 7) (three times). To the disulfide-reduced sense strand solution, a solution of DBCO-MAL (III) (3 equivalents) in DMSO was added. The reaction was monitored by LCMS and HPLC. Upon completion, the solids were removed by centrifugation, and the solution was purified by reverse-phase HPLC. The product fractions were collected and dried by lyophilization. For step 3, the dried 3'-DBCO-modified sense strand (IV) was reconstituted in 100 mM sodium phosphate buffer.

[0578] Step 3: To an aqueous solution of 3'-DBCO-functionalized sense strand (IV) (1 equivalent) was added a solution of Ligand-A-N3 (3 equivalents) in DMSO. The reaction was monitored by HPLC and LCMS. Upon completion, the 3'-conjugated sense strand (V) was purified by reverse-phase HPLC or by molecular weight cutoff with an Amicon® Ultra-15 centrifugal filter (3K, 5 times). The product was confirmed by HPLC and LCMS. [ka]

[0579] Example 1B: α4β 1 / 7 Synthesis of integrin ligand-conjugated oligonucleotides Basic scheme: [ka] Synthesis Procedure: [ka] To a mixture of pyridazinone (2 g, 11.173 mmol, 1 equiv.), finely ground K2CO3 (6.177 g, 44.693 mmol, 4 equiv.), and tetrabutylammonium bromide (0.36 g, 1.117 mmol, 0.1 equiv.) in dry acetonitrile (11 ml), BnO-(PEG)4-OH (4.766 g, 16.76 mmol, 4.332 ml, 1.5 equiv.) was added over 10 min at room temperature. The mixture was stirred overnight at room temperature, then the inorganics were filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography using a gradient of 0–40% acetonitrile / water (+0.1% formic acid) to give the desired product in 74% yield (3.52 g). MS ESI+ m / z = 449.0 [MNa]+.

[0580] [ka] To a solution of 3,5-dichloroisonicotinic acid (7 g, 36.458 mmol, 1 equiv) in DMF (102 ml) were added HBTU (15.209 g, 40.104 mmol, 1.1 equiv) and HOBt (1.159 g, 7.292 mmol, 0.2 equiv) sequentially, followed by the dropwise addition of DIEA (14.137 g, 109.375 mmol, 19.104 ml, 3 equiv) at 0 °C. The solution was stirred for 20 min, then tert-butyltyrosine (8.219 g, 34.635 mmol, 0.95 equiv) was added, and the reaction was stirred at room temperature for 3 h. The reaction was taken up in EtOAc and washed with water followed by brine. The EtOAc layer was dried, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-55% EtOAc / hexanes to give the desired product in 38% yield (5.72 g). MS ESI+ m / z = 411.4 [M−H]+.

[0581] [ka] To a solution of phenol (5.42 g, 13.178 mmol, 1 equiv) in DCM (14.5 mL) was added TfNPh (6.12 g, 17.132 mmol, 1.3 equiv), followed by DIEA (5.1 g, 39.535 mmol, 6.892 mL, 3 equiv) at 0 °C. The mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO and brine, dried over NaSO, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a 0-20% ethyl acetate / hexane gradient to give the desired product in 87% yield (6.2 g). MS ESI+ m / z = 543.3 [MH].

[0582] [ka] A solution of triflate (3.3 g, 6.07 mmol, 1 equiv.), diboron pinacol (2.31 g, 9.11 mmol, 1.5 equiv.), and KOAc (2.08 g, 21.25 mmol, 3.5 equiv.) in anhydrous DMF (33 mL) was degassed for 10 min by purging with argon under stirring. Pd(Dppf)Cl2 (889 mg, 1.21 mmol, 0.2 equiv.) was added under argon, and the mixture was degassed for an additional 5 min. The vial was sealed and stirred at 90 °C for 10 h. The mixture was cooled, and the catalyst was filtered off using Celite. The filtrate was concentrated, and the resulting residue was partitioned between EtOAc and brine. The organic phase was dried, filtered, concentrated, and then purified by silica gel column chromatography using 0–30% EtOAc / hexane to give the desired product in 84% yield (2.67 g). MS ESI+ m / z = 521.5 [M−H]+.

[0583] [ka] A mixture of boronic ester (2.2 g, 4.221 mmol, 1 equiv.), aryl chloride (1.802 g, 4.221 mmol, 1 equiv.), and 1M Na2CO3 (1.118 g, 10.552 mmol, 2.5 equiv.) in acetonitrile (10.5 mL) was degassed for 10 min by purging with argon while stirring. Pd(PPh3)2Cl2 (0.593 g, 0.844 mmol, 0.2 equiv.) was added, and the mixture was degassed for an additional 5 min. The vial was sealed and stirred at 150 °C for 4 h, then cooled to room temperature. The catalyst was removed by filtration through Celite, and the filtrate was concentrated. The resulting residue was purified by reverse-phase column chromatography (C18) using a gradient of 0–60% acetonitrile / water (+0.1% formic acid) to give the desired product in 53% yield (1.75 g). MS: ESI+ m / z = 785.6 [M−H]+.

[0584] [ka] A solution of the benzyl ether (308 mg, 0.39 mmol) in methanol (6.5 ml) was stirred under 1 atm H2 (gas) in the presence of Pd / C (42 mg, 0.39 mmol, 1 equiv.) for 6.5 h. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-5% methanol / ethyl acetate to give the desired product in 77% yield (209 mg). MS ESI+ m / z = 695.5 [MH]+.

[0585] [ka] MsCl (0.145 g, 1.266 mmol, 0.098 ml, 1.5 equiv) in DCM (8.5 ml) was added dropwise to a solution of the alcohol (0.587 g, 0.844 mmol, 1 equiv) in pyridine (8.5 ml) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, then quenched by the addition of water and extracted with DCM. The organic layer was washed with a saturated solution of NaHCO and brine. The organic layer was dried and then concentrated. The resulting residue (649 mg, 99%) was used in the next step without further purification. MS ESI+ m / z = 773.4 [MH].

[0586] [ka] To a solution of the mesylate (0.5 g, 0.646 mmol, 1 equiv.) in DMF (10 ml) was added NaN (0.092 g, 1.422 mmol, 2.2 equiv.), and the mixture was stirred at 80 °C overnight, then cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-80% EtOAc / hexanes to give the desired product in 67% yield (313 mg). MS ESI+ m / z = 720.5 [MH]+.

[0587] [ka] TFA (0.96 ml) was added dropwise to a solution of the tert-butyl ester (0.17 g, 0.236 mmol, 1 equiv.) in DCM (1.9 ml) at 0 °C. The cooling bath was removed, and the mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using a gradient of 0-100% acetonitrile / water (+0.1% formic acid). The resulting residue was repurified by silica gel column chromatography using a gradient of 0-20% methanol / EtOAc to give the desired product in 44% yield (69 mg). MS ESI+ m / z = 664.1 [MH]+.

[0588] [ka] To an aqueous solution of the AC6-functionalized sense strand, a solution of DCBO-NHS (12) (3 equiv.) in CHCN was added. The reaction was monitored by LCMS and HPLC. Upon completion of the reaction, the solid was filtered off, and the solution was purified by HPLC and lyophilized to dryness. The dried DCBO-modified sense strand was reconstituted in RNase-free water, and ligand 11 (2 equiv.) in THF was added. After the reaction was complete, the conjugate was purified by MWCO (5X).

[0589] Basic annealing steps: The concentrations of both the sense and antisense strands were determined using a Nanodrop. Double-stranded siRNA was prepared by mixing equimolar amounts of the sense and antisense strands. The annealing process was monitored by non-denaturing RP-HPLC. After annealing, the antisense strand in the double-stranded mixture was less than 5%. The concentration of the double strand was determined by measuring the absorbance of the solution using a Nanodrop.

[0590] Example 2: BA-128 conjugate [ka] (wherein X is O or S). BA-128: (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: (S)-tert-butyl 2-(3,5-dichloroisonicotinamido)-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 (S)-tert-butyl 2-(3,5-dichloroisonicotinamido)-3-(4-(2-methyl-3-oxo-5-((1-phenyl-2,5,8,11-tetraoxatridecan-13-yl)oxy)-2,3-dihydropyridazin-4-yl)phenyl)propanoate (0.81 g, 1.02 mmol) in MeOH (17 ml) was stirred under 1 atm H2 (gas) in the presence of Pd / C (0.11 g, 1.02 mmol) for 2 h. The catalyst was filtered off and the filtrate was concentrated. The crude material was purified by silica gel column chromatography using 0-5% MeOH / DCM to give the title compound (0.47 g, 66%). MS (ESI) m / z 696.6 [M+H] + .

[0591] Step 2: (S)-tert-butyl 2-(3,5-dichloroisonicotinamido)-3-(4-(2-methyl-5-(2-(2-(2-(2-((methylsulfonyl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate Methanesulfonyl chloride (17 μl, 0.216 mmol) in DCM (1.4 ml) was added dropwise to a solution of tert-butyl (S)-2-(3,5-dichloroisonicotinamido)-3-(4-(5-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate (0.10 g, 0.144 mmol) in pyridine (1.4 ml) at 0° C. The reaction mixture was stirred at room temperature for 16 hours, then quenched by the addition of water (10 ml) and extracted with DCM (3×10 ml). The organic layer was washed with a saturated solution of NaHCO (10 ml) and brine (10 ml). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound as a brown oil (0.11 g, quantitative). MS (ESI) m / z 773.5 [M+H] + .

[0592] Step 3: (S)-tert-butyl 3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoate To a solution of tert-butyl (S)-2-(3,5-dichloroisonicotinamido)-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) was added NaN (21 mg, 0.316 mmol), followed by one drop of water. The mixture was stirred at 80° C. for 6 h, then cooled to room temperature and partitioned between EtOAc (20 ml) and water (20 ml). The organic phase was separated and the aqueous phase was extracted twice with EtOAc (2×15 ml). The combined organic layers were washed twice with brine, dried, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc / hexanes to give the title compound as a clear oil (85 mg, 82%). MS (ESI) m / z 721.6 [M+H] + .

[0593] 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-dichloroisonicotinamido)propanoic acid TFA (0.14 ml) was added dropwise to a solution of (S)-tert-butyl 3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoate (25 mg, 0.035 mmol) in DCM (0.3 ml) at 0° C. The cooling bath was removed and the mixture was stirred at room temperature for 17 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient of 0-100% methanol / DCM to give the desired product (16 mg, 69%). MS (ESI) m / z 687.8 [M+Na] + . 1H NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.31 (d, J = 10 Hz, 1H), 8.63 (s, 2H), 8.20 (s, 1H), 7.42 (d, J = 10 Hz, 2H), 7.29 (d, J = 10 Hz, 2H), 4.78-4.72 (m, 1H), 4.36-4.32 (m, 2H), 3.66 (s, 5H), 3.57 (t, J = 5 Hz, 2H), 3.36 (t, J = 5 Hz, 2H), 3.53-3.47 (m, 8H), 3.20 (dd, J = 10, 5 Hz, 1H), 2.93 (q, J = 10 Hz, 1H).

[0594] BA-128 was conjugated to the oligosense strand according to General Procedure Type I. The product (MW: 8336.82 g / mol) was produced with 98% purity and was confirmed by HPLC and LCMS (m / z: 8335.56).

[0595] BA-128 was bis-conjugated to the sense strand of the oligonucleotide according to the general procedure Type IIB. The product (MW: 9483.37 g / mol) was produced with a purity of 96% and was confirmed by HPLC and LCMS (m / z: 9482.44).

[0596] Example 3: BA-148 conjugate [ka] (wherein X is O or S). BA-148: (S)-2-((S)-1-((4-(4-(2-(2-(azidoxy)ethoxy)ethoxy)butoxy)phenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(4-((pyrrolidine-1-carbonyl)oxy)phenyl)propanoic acid [ka] Step 1: 4-((S)-2-((S)-1-((4-hydroxyphenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-methoxy-3-oxopropyl)phenylpyrrolidine-1-carboxylate To a solution of 4-((S)-3-methoxy-3-oxo-2-((S)-pyrrolidine-2-carboxamido)propyl)phenylpyrrolidine-1-carboxylate hydrochloride (0.43 g, 1 mmol) in pyridine (3 ml) was added 4-hydroxybenzenesulfonyl chloride (0.23 g, 1.2 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 17 hours. Excess pyridine was removed under vacuum. The residue was dissolved in EtOAc (60 ml) and washed with saturated ammonium chloride (20 ml), water, and brine (10 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of 50-100% EtOAc / hexane to give the title compound as a yellow oil (0.16 g, 29%). MS (ESI) m / z 546.2 [M+H] + .

[0597] Step 2: 4-((S)-2-((S)-1-((4-(4-(2-(2-(azidoxy)ethoxy)ethoxy)butoxy)phenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-methoxy-3-oxopropyl)phenylpyrrolidine-1-carboxylate To a solution of 4-((S)-2-((S)-1-((4-hydroxyphenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-methoxy-3-oxopropyl)phenylpyrrolidine-1-carboxylate (0.16 g, 0.293 mmol) in anhydrous MeCN (5 ml) was added 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl methanesulfonate (0.11 g, 0.367 mmol), cesium carbonate (0.19 g, 0.587 mmol). The reaction mixture was stirred at 60° C. under an inert atmosphere for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3×25 ml). The combined organic extracts were washed with brine (10 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of 0-40% MeOH / EtOAc to give the title compound as a colorless oil (52 mg, 24%). MS (ESI) m / z 769.5 [M+Na] + .

[0598] Step 3: (S)-2-((S)-1-((4-(4-(2-(2-(azidoxy)ethoxy)ethoxy)butoxy)phenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(4-((pyrrolidine-1-carbonyl)oxy)phenyl)propanoic acid To a solution of 4-((S)-2-((S)-1-((4-hydroxyphenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-methoxy-3-oxopropyl)phenylpyrrolidine-1-carboxylate (50 mg, 0.70 mmol) in a mixture of THF (3 ml), MeOH (2 ml), and HO (0.5 ml), LiOH (11 mg, 0.27 mmol) was added and stirred at room temperature for 15 hours. The solvent was evaporated in vacuo. The residue was treated with 10% citric acid solution and purified by reverse-phase column chromatography (C18) using a gradient of 0-40% ACN / water (+0.1% formic acid) to give the title compound as a white solid (43 mg, 88%). MS (ESI) m / z 755.9 [M+Na] + . 1H NMR (400 MHz, DMSO-d6) δ 7.81 - 7.75 (m, 2H), 7.56 (m, 1H), 7.19 - 7.05 (m, 4H), 6.89 (dd, J = 8.5, 3.5 Hz, 2H), 4.22 - 4.16 (m, 2H), 4.13 - 3.91 (m, 3H), 3.76 (dq, J = 4.8, 2.4 Hz, 2H), 3.63 - 3.25 (m, 22H), 3.16 - 2.87 (m, 3H), 1.91 - 1.79 (m, 4H), 1.38 (m, 2H).

[0599] BA-148 was conjugated to the oligosense strand according to General Procedure Type I. The product (MW: 8032.88 g / mol) was produced with 98% purity and was confirmed by HPLC and LCMS (m / z: 8031.37).

[0600] Example 4: BA-149 conjugate [ka] (wherein X is O or S). BA-149: (S)-2-(4-(4-(2-(2-(azidoxy)ethoxy)ethoxy)butoxy)-2,6-dichlorobenzamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoic acid [ka] Step 1: (S)-2-(2,6-dichloro-4-hydroxybenzamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate methyl ester To a solution of methyl (S)-2-amino-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate (0.51 g, 1.45 mmol) in anhydrous DMA (3 ml) was added 2,6-dichloro-4-hydroxybenzoic acid (0.25 g, 1.2 mmol), HATU (0.69 g, 1.81 mmol), and DIPEA (0.42 ml, 2.42 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 17 hours. The reaction mixture was diluted with water (200 ml), resulting in the formation of a beige precipitate. The solid was collected by filtration, washed with water, and air-dried to give the title compound (0.38 g, 62%) as an off-white solid. MS (ESI) m / z 505.4 [M+H] + .

[0601] Step 2: (S)-2-(4-(4-(2-(2-(azidoxy)ethoxy)ethoxy)butoxy)-2,6-dichlorobenzamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate methyl ester To a solution of (S)-methyl 2-(2,6-dichloro-4-hydroxybenzamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate (0.19 g, 0.387 mmol) in anhydrous MeCN (5 ml) was added 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl methanesulfonate (0.13 g, 0.425 mmol) and cesium carbonate (0.25 g, 0.773 mmol). The reaction mixture was stirred at 60°C under an inert atmosphere for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (3 x 25 ml). The combined organic extracts were washed with brine (10 ml), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient of 50-100% EtOAc / hexanes to give the title compound as a colorless oil (0.18 g, 65%). MS (ESI) m / z 706.7 [M+H] + .

[0602] Step 3: (S)-2-(4-(4-(2-(2-(azidoxy)ethoxy)ethoxy)butoxy)-2,6-dichlorobenzamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoic acid To a solution of (S)-methyl 2-(4-(4-(2-(2-(azidoxy)ethoxy)ethoxy)butoxy)-2,6-dichlorobenzamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate (0.175 g, 0.248 mmol) in a mixture of THF (4 ml), MeOH (3 ml), and HO (0.5 ml), LiOH (41 mg, 1 mmol) was added and stirred at room temperature for 15 h. The solvent was evaporated in vacuo. The residue was treated with 10% citric acid solution and purified by reverse-phase column chromatography (C18) using a gradient of 0-40% ACN / water (+0.1% formic acid) to give the title compound as a clear, colorless oil (96 mg, 56%). MS (ESI) m / z 692.6 [M+H] + .1H NMR data (500 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.98 (d, J = 8.3 Hz, 1H), 7.31 - 7.24 (m, 3H), 7.11 - 7.06 (m, 2H), 7.05 (s, 2H), 6.72 (d, J = 8.5 Hz, 2H), 4.69 (ddd, J = 10.4, 8.3, 4.4 Hz, 1H), 4.18 - 4.12 (m, 2H), 3.74 - 3.69 (m, 2H), 3.65 (s, 6H), 3.62 - 3.50 (m, 10H), 3.38 (dd, J = 5.5, 4.3 Hz, 2H), 3.16 (dd, J = 14.1, 4.4 Hz, 1H), 2.92 (dd, J = 14.1, 10.5 Hz, 1H).

[0603] BA-149 was conjugated to the oligosense strand according to General Procedure Type I. The product (MW: 7991.63 g / mol) was produced with a purity of 87% and was confirmed by HPLC and LCMS (m / z: 7990.46).

[0604] Example 5: BA-154 conjugate [ka] (wherein X is O or S). BA-154: (S)-4-(((S)-1-((S)-2-((2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-3-((S)-4-methyl-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)pentanamido)-4-oxobutanoic acid [ka] Step 1: (S)-4-(((S)-1-((S)-2-((4-(2-(2-(azidoxy)ethoxy)ethoxy)butyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-3-((S)-4-methyl-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)pentanamido)-4-oxobutanoate methyl To a solution of ((S)-4-methoxy-2-((S)-4-methyl-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)pentanamido)-4-oxobutanoyl)-L-valyl-L-proline (0.30 g, 0.415 mmol) in anhydrous DMA (5 ml) was added 4-(2-(2-(azidoxy)ethoxy)ethoxy)butan-1-amine (0.11 g, 0.519 mmol), HATU (0.32 g, 0.83 mmol), and DIPEA (0.22 mL, 1.25 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 15 hours. The reaction mixture was diluted with water (150 ml), resulting in the formation of an off-white precipitate. The solid was collected by filtration, washed with water, and air-dried. The crude was redissolved in DCM and purified by silica gel column chromatography using a gradient of 0-20% MeOH / EtOAc to give the title compound as a white solid (0.13 g, 34%). MS (ESI) m / z 924.1 [M+H]+ .

[0605] Step 2: (S)-4-(((S)-1-((S)-2-((4-(2-(2-(azidoxy)ethoxy)ethoxy)butyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-3-((S)-4-methyl-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)pentanamido)-4-oxobutanoic acid To a solution of methyl (S)-4-(((S)-1-((S)-2-((4-(2-(2-(azidoxy)ethoxy)ethoxy)butyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-3-((S)-4-methyl-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)pentanamido)-4-oxobutanoate (0.18 g, 0.195 mmol) in a mixture of THF (8 ml), MeOH (15 ml), and HO (2 ml), LiOH (12 mg, 0.49 mmol) was added and stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure. The residue was treated with HCl (1N, 5 ml). The resulting white precipitate was collected by filtration, washed with water, and air-dried to give the title compound as an off-white glass-like solid (0.17 g, 98%). MS (ESI) m / z 932.1 [M+Na] +.1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.09 (d, J = 2.9 Hz, 1H), 8.36 (d, J = 7.9 Hz, 1H), 8.15 (ddd, J = 20.1, 15.8, 8.4 Hz, 2H), 7.98 (s, 1H), 7.82 (dd, J = 10.4, 6.9 Hz, 2H), 7.52 (d, J = 8.6 Hz, 0H), 7.40 - 7.29 (m, 2H), 7.15 (q, J = 6.3, 5.6 Hz, 4H), 6.93 (t, J = 7.4 Hz, 1H), 4.51 (dq, J = 30.1, 6.9 Hz, 1H), 4.38 - 4.19 (m, 3H), 3.75 - 3.35 (m, 19H), 3.24 (dt, J = 12.3, 6.3 Hz, 1H), 3.18 - 3.06 (m, 1H), 2.74 - 2.56 (m, 1H), 2.24 (s, 3H), 2.08 - 1.68 (m, 3H), 1.56 (tt, J = 13.2, 6.7 Hz, 1H), 1.44 (ddt, J = 14.2, 10.3, 6.5 Hz, 2H), 0.92 - 0.73 (m, 12H).

[0606] BA-154 was conjugated to the oligosense strand according to General Procedure Type I. The product (MW: 8209.13 g / mol) was produced with 99% purity and was confirmed by HPLC and LCMS (m / z: 8207.66).

[0607] Example 6: BA-161 conjugate [ka] (wherein X is O or S). BA-161: (14S,17S)-1-azido-14-benzyl-13,16-dioxo-17-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)-3,6,9-trioxa-12,15-diazaicosan-20-oic acid [ka] Step 1: 1-(tert-butyl) 5-methyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-((E)-3-(pyridin-3-yl)acryloyl)-L-lysyl-L-glutamate A solution of (E)-N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(3-(pyridin-3-yl)acryloyl)-L-lysine (2.90 g, 5.805 mmol) and 1-tert-butyl 5-methyl(2S)-2-aminopentanedioate hydrochloride (1.47 g, 5.805 mmol) in DMF (29 ml) was treated with HATU (3.31 g, 8.707 mmol), followed by the dropwise addition of DIPEA (2.25 g, 17.415 mmol) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 1-tert-butyl 5-methyl(2S)-2-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-6-[(2E)-3-(pyridin-3-yl)prop-2-enamido]hexanamido]pentanedioate (3.9 g, 96%) as a white solid. MS (ESI) m / z 699.9 [M+H] + .

[0608] Step 2: (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((E)-3-(pyridin-3-yl)acrylamido)hexanamido)-5-methoxy-5-oxopentanoic acid A solution of 1-tert-butyl 5-methyl(2S)-2-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-6-[(2E)-3-(pyridin-3-yl)prop-2-enamido]hexanamido]pentanedioate (300 mg, 0.429 mmol) in DCM (1 ml) was treated with hydrogen chloride in dioxane (3 mL) at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. MS (ESI) m / z 643.6 [M+H] + .

[0609] Step 3: (5S,8S,11S)-11-benzyl-1-(9H-fluoren-9-yl)-8-(3-methoxy-3-oxopropyl)-3,6,9-trioxo-5-(4-((E)-3-(pyridin-3-yl)acrylamido)butyl)-2-oxa-4,7,10-triazadodecan-12-oate tert-butyl ester A solution of (2S)-2-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-6-[(2E)-3-(pyridin-3-yl)prop-2-enamido]hexanamido]-5-methoxy-5-oxopentanoic acid (3 g, 4.67 mmol) and (2S)-2-amino-3-phenylpropanoic acid tert-butyl hydrochloride (2.41 g, 9.34 mmol) in DMF (30 ml) was treated with HATU (3.55 g, 9.34 mmol) under a nitrogen atmosphere at room temperature, followed by the dropwise addition of DIPEA (6.03 g, 46.65 mmol). The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The residue was purified by trituration with diethyl ether. The precipitated solid was collected by filtration and washed with diethyl ether to give the title compound (3.8 g, 96%) as an off-white solid. MS (ESI) m / z 847.1 [M+H] + .

[0610] Step 4: (S)-4-((S)-2-amino-6-((E)-3-(pyridin-3-yl)acrylamido)hexanamido)-5-(((S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl)amino)-5-oxovalerate methyl ester A solution of methyl (4S)-4-{[(2S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl]carbamoyl}-4-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-6-[(2E)-3-(pyridin-3-yl)prop-2-enamido]hexanamido]butanoate (500 mg, 0.591 mmol) in DCM (20 ml) was treated with piperidine (4 ml). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water, 10% to 0% gradient in 35 min; detector: UV 254 nm. The resulting product was extracted with DCM (2 × 150 ml). The combined organic layers were washed with brine (2 × 30 ml) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give methyl (4S)-4-[(2S)-2-amino-6-[(2E)-3-(pyridin-3-yl)prop-2-enamido]hexanamido]-4-{[(2S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl]carbamoyl}butanoate (680 mg, 44%) as an off-white solid. MS (ESI) m / z 624.6 [M+H] + .

[0611] Step 5: (S)-5-(((S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl)amino)-5-oxo-4-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)methyl valerate To a solution of methyl (S)-4-((S)-2-amino-6-((E)-3-(pyridin-3-yl)acrylamido)hexanamido)-5-(((S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl)amino)-5-oxovalerate (0.33 g, 0.523 mmol) in anhydrous DMA (3 ml) was added 2-(4-(3-(o-tolyl)ureido)phenyl)acetic acid (0.14 g, 0.475 mmol), HATU (0.18 g, 0.475 mmol), and DIPEA (0.083 ml, 0.475 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 3 hours. The reaction mixture was diluted with water (120 ml). The resulting precipitate was filtered off, washed with water and air-dried to give the title compound as an off-white solid (0.32 g, 76%). MS (ESI) m / z 891.1 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.58 (dd, J = 4.8, 1.6 Hz, 1H), 8.25 (d, J = 7.3 Hz, 1H), 8.19 - 8.10 (m, 2H), 8.05 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.88 (s, 1H), 7.83 (dd, J = 8.2, 1.3 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.43 - 7.30 (m, 2H), 7.30 - 7.08 (m, 9H), 6.93 (td, J = 7.4, 1.3 Hz, 1H), 6.74 (d, J = 15.9 Hz, 1H), 4.38 - 4.17 (m, 3H), 3.58 (s, 3H), 3.43 (s, 2H), 3.21 - 3.02 (m, 2H), 3.02 - 2.86 (m, 3H), 2.29 (ddd, J = 12.7, 6.2, 3.1 Hz, 2H), 2.23 (s, 3H), 1.99 - 1.84 (m, 1H), 1.82 - 1.68 (m, 1H), 1.61 (s, 1H), 1.51 (dd, J = 9.3, 4.9 Hz, 1H), 1.43 (s, 2H), 1.29 (s, 11H).

[0612] Step 6: ((S)-5-Methoxy-5-oxo-2-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)pentanoyl)-L-phenylalanine To a solution of (S)-5-(((S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl)amino)-5-oxo-4-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)methyl valerate (0.3 g, 0.34 mmol) in trifluoroethanol (3 ml) was added formic acid (0.35 ml). The reaction mixture was heated at 60° C. for 15 hours. The reaction mixture was concentrated to dryness to quantitatively obtain the title compound as a yellow oil. MS (ESI) m / z 834.7 [M+H] + , 856.7 [M+Na] + .

[0613] Step 7: (14S,17S)-1-Azido-14-benzyl-13,16-dioxo-17-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)-3,6,9-trioxa-12,15-diazaicosan-20-oate methyl ester To a solution of ((S)-5-methoxy-5-oxo-2-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)pentanoyl)-L-phenylalanine (0.28 g, 0.34 mmol) in anhydrous DMA (3 mL) was added 4-(2-(2-(azidoxy)ethoxy)ethoxy)butan-1-amine (0.15 g, 0.67 mmol), HATU (0.32 g, 0.84 mmol), and DIPEA (0.24 mL, 1.34 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 18 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (15 ml), dried over anhydrous NaSO and concentrated under reduced pressure to give the title compound as a beige solid (0.25 g, 71%). MS (ESI) m / z 1035.2 [M+H] + .

[0614] Step 8: (14S,17S)-1-Azido-14-benzyl-13,16-dioxo-17-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)-3,6,9-trioxa-12,15-diazaicosan-20-oic acid To a solution of methyl (14S,17S)-1-azido-14-benzyl-13,16-dioxo-17-((S)-6-((E)-3-(pyridin-3-yl)acrylamido)-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanamido)-3,6,9-trioxa-12,15-diazaicosan-20-oate (0.24 g, 0.23 mmol) in a mixture of methanol / water / THF (6 ml, 1:1:1), LiOH (17 mg, 0.70 mmol) was added and stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure. The residue was treated with 10% citric acid solution and purified by reverse-phase column chromatography (C18) using a gradient of 0-40% ACN / water (+0.1% formic acid) to give the title compound as a white sponge-like solid (0.13 g, 55%). MS (ESI) m / z 1021.2 [M+H] + , 1043.1 [M+Na] + . 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.53 (dd, J = 4.7, 1.6 Hz, 1H), 8.26 (s, 4H), 8.23 ​​- 8.14 (m, 2H), 8.14 - 7.92 (m, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.50 - 7.32 (m, 4H), 7.27 - 7.08 (m, 8H), 6.93 (td, J = 7.5, 1.4 Hz, 1H), 6.73 (d, J = 15.9 Hz, 1H), 4.45 (td, J = 8.3, 5.3 Hz, 1H), 4.19 (dq, J = 13.1, 7.8 Hz, 2H), 3.63 - 3.29 (m, 18H), 3.21 (dt, J = 11.7, 6.3 Hz, 2H), 3.17 - 3.07 (m, 2H), 3.02 - 2.90 (m, 1H), 2.23 (s, 3H), 2.14 (tt, J = 16.6, 8.5 Hz, 2H), 1.83 (dt, J = 15.7, 6.9 Hz, 1H), 1.67 (ddd, J = 31.5, 16.3, 8.3 Hz, 2H), 1.43 (s, 2H), 1.36 - 1.13 (m, 2H).

[0615] BA-161 was conjugated to the oligosense strand according to General Procedure Type I. The product (MW: 8367.17 g / mol) was produced with 98% purity and was confirmed by HPLC and LCMS (m / z: 8365.37).

[0616] Example 7: BA-171 conjugate [ka] (wherein X is O or S). BA-171: (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid [ka] Step 1: (E)-2-(4-(2-ethoxyvinyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanoate ethyl ester To a stirred solution of ethyl 2-(4-bromo-2-oxopyridin-1-yl)-5-methylhexanoate (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 HO (5 ml) was added KCO (4.02 g, 29.10 mmol) and Pd(PPh) (1.68 g, 1.45 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 70 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched at room temperature by the addition of water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the product (containing pinacol). The residue was further purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN / water, 10-100% gradient in 25 min; detector: UV 254 nm. This gave ethyl 2-(4-[(E)-2-ethoxyethenyl]-2-oxopyridin-1-yl-5-methylhexanoate (4 g, 86%) as a brown oil. MS (ESI) m / z 322.1 [M+H] + . 1H NMR (300 MHz, CDCl3) δ 7.16 (m, J = 19.4, 10.1 Hz, 2H), 6.37 (s, 1H), 6.19 (d, J = 7.4 Hz, 1H), 5.60 (d, J = 13.0 Hz, 1H), 5.54 (m, J = 10.2, 5.6 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.94 (q, J = 7.1 Hz, 2H), 2.29 - 2.03 (m, 1H), 1.86 (d, J = 12.3 Hz, 1H), 1.57 (m, J = 13.3, 6.8 Hz, 1H), 1.35 (t, J = 7.0 Hz, 3H), 1.24 (m, J = 8.5, 7.8 Hz, 4H), 1.14 - 1.04 (m, 1H), 0.87 (m, J = 6.8, 3.0 Hz, 6H).

[0617] Step 2: Ethyl 5-methyl-2-(2-oxo-4-(2-oxoethyl)pyridin-1(2H)-yl)hexanoate To a 250 mL round-bottom flask were added ethyl 2-(4-[(E)-2-ethoxyethenyl]-2-oxopyridin-1-yl-5-methylhexanoate (3.9 g, 12.134 mmol) and TFA (40 ml) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give ethyl 5-methyl-2-[2-oxo-4-(2-oxoethyl)pyridin-1-yl]hexanoate (1.9 g, 53%) as a yellow oil. MS (ESI) m / z 294.2. 1H NMR (300 MHz, chloroform-d) δ 9.76 (t, J = 2.0 Hz, 1H), 7.35 (d, J = 7.1 Hz, 1H), 6.54 - 6.47 (m, 1H), 6.14 (m, J = 7.2, 2.0 Hz, 1H), 5.56 (m, J = 10.1, 5.6 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.56 (d, J = 2.0, 0.8 Hz, 2H), 2.19 (m, J = 14.0, 11.1, 5.5 Hz, 1H), 1.88 (m, J = 18.8, 10.4, 4.8Hz, 1H), 1.59 (m, J = 13.3, 6.7 Hz, 1H), 1.34 - 1.16 (m, 4H), 1.16 - 0.98 (m, 1H), 0.88 (q, J = 6.6, 3.1 Hz, 6H).

[0618] Step 3: Ethyl 5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadecan-18-yl)pyridin-1(2H)-yl)hexanoate To a stirred solution of ethyl 5-methyl-2-[2-oxo-4-(2-oxoethyl)pyridin-1-yl]hexanoate (1.8 g, 6.13...

Claims

1. Compounds, stereoisomers, tautomers, prodrugs, or salts thereof containing the structure of formula (I'): 【Chemistry 297】 (In the formula, 【Chemistry 298】 Each of these is independent of α ４ β １／７ It is an integrin ligand, L １ 、 L ２ 、 L ３ 、 L ４ 、 L １Ａ 、 L ２Ａ 、 L ３Ａ 、 and L ４Ａ each of which is, independently, a linker, a bond, or absent, R １ It comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides. z1 is either 0 or 1).

2. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (II'): 【Chemical 304】 (In the formula, R ２ and R ２Ａ Each of these is independently H, polyethylene glycol (PEG), an optionally substituted heteroalkyl, or an optionally substituted heteroaryl. R ３ , R ３Ａ , R ４ , and R ４Ａ Each of these is independently H, a halogen, an optionally substituted alkyl, or an optionally substituted -O-alkyl).

3. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (III'): 【Chemical 312】 (In the formula, R ２ and R ２Ａ Each of these is independently H, halogen, polyethylene glycol (PEG), optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl. R ３ and R ３Ａ Each is independently an optionally substituted heteroalkyl or optionally substituted heterocycline. n and n Ａ (Each of these is independently 1, 2, or 3).

4. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (IV'): 【Chemical 316】 (In the formula, R ２ and R ２Ａ These are H, -OH, and -NH, respectively, independently. ２ , - NHR ３ , -OR ３ , or absent, R ３ Each of these cases is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl).

5. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (V'): 【Chemistry 321】 (In the formula, n and n Ａ (Each of these values ​​is independently 0, 1, 2, or 3).

6. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (VI'): 【Chemistry 329】 (In the formula, n and n Ａ (Each of these values ​​is independently 0, 1, 2, or 3).

7. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (VII'): 【Chemistry 336】 (In the formula, R ２ , R ２Ａ , R ３ , R ３Ａ , R ４ , R ４Ａ , R ５ , and R ５Ａ Each of these is independently H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl, or absent. R ８ and R ８Ａ Each of these is independently replaced by C by arbitrary selection. １ -C ５ Alkyl, optionally substituted C １ -C ５ Alkylene-(C) ３ -C ６ )-cycloalkyl, or optionally substituted (C １ -C ４ )-Alkylene-(C １ -C ４ ) - It is an alkoxy, R ６ , Ｒ６Ａ , R ７ , and R ７Ａ Each of these independently comprises H, halogen, alkyl, or optionally substituted alkyl, or optionally substituted heteroalkyl. 【Chemistry 337】 (That is the case.)

8. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (VIII'): 【Chemical 360】 (In the formula, R ２ and R ２Ａ Each of these is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or absent. R ３ , R ３Ａ , R ４ , and R ４Ａ Each of these is independently H, a halogen, an optionally substituted alkyl, or an optionally substituted -O-alkyl. R ５ and R ５Ａ Each is independently either -OH or absent. Y and Y Ａ Each of them is independent of -CH ２ - or - (CH ２ ) ２ - is).

9. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (IX'): 【Chemical 367】 (In the formula, R ２ and R ２Ａ Each of these is independently H, -OH, and -NH ２ , - NHR ３ , -OR ３ , or -CONHR ３ And, R ３ Each of these cases independently comprises H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. n and n Ａ Each of these is independently either 1 or 2.

10. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (X'): 【Chemistry 371】 (In the formula, R ２ and R ２Ａ These are H and -CH, respectively, independently. ２ OR ３ ,-(CH ２ ) ２ OR ３ ien-CH ２ NHCOR ３ , or -OR ３ And, R ３ Each of these cases is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl).

11. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (XI'): 【Chemistry 375】 (In the formula, R ２ and R ２Ａ each independently is H, -CONHR ３ , -CH ２ OR ３ , -(CH ２ ) ２ OR ３ , -CH ２ NHCOR ３ , or -OR ３ and R ３ in each case, independently, is H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl, X and X Ａ Each of these is independently either H or a halogen.

12. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (XII'): 【Chemistry 379】 (In the formula, R ２ and R ２Ａ Each of these independently corresponds to H, -CONHR ４ ien-CH ２ OR ４ ,-(CH ２ ) ２ OR ４ ien-CH ２ NHCOR ４ , or -OR ４ And, R ３ and R ３Ａ Each of these is independently H, an optionally substituted alkyl, or an optionally substituted cycloalkyl. R ４ Each of these cases independently comprises H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. R ５ and R ５Ａ Each of them is independently -OH or absent, n and n Ａ Each of these cases is independently 0, 1, 2, or 3. n1 and n1 Ａ Each of these cases is independently 1, 2, or 3).

13. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (XIII'): 【Chemistry 383】 (In the formula, R ２ and R ２Ａ Each of these independently corresponds to H, -CONHR ４ ien-CH ２ OR ４ ,-(CH ２ ) ２ OR ４ ien-CH ２ NHCOR ４ , or -OR ４ And, R ３ and R ３Ａ Each of these is independently H, an optionally substituted alkyl, or an optionally substituted cycloalkyl. R ４ Each of these cases independently comprises H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. R ５ and R ５Ａ Each of them is independently -OH or absent, X and X Ａ Each of these is independently H, and CH which is substituted by any choice. ２ (The NH group is optionally substituted, or is a cycloalkyl group.)

14. The compound according to claim 1, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (XIV'): 【Chemical 388】 (In the formula, R ２ and R ２Ａ Each of them is independently H, -CH ２ OR ４ ,-(CH ２ ) ２ OR ４ ien-CH ２ NHCOR ４ , or -OR ４ And, R ３ and R ３Ａ Each of these is independently H, -OH, and -NH ２ , - NHR ５ , or -OR ５ And, R ４ Each of these cases independently comprises H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. R ５ Each of these cases independently comprises H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl. n and n Ａ Each of these is independently 1, 2, or 3.

15. A composition for use in the treatment of a disease, disorder, or symptom of the central nervous system (CNS), wherein the composition comprises a compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the disease, disorder, or symptom of the CNS is optionally Alzheimer's disease or a symptom thereof.

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