Alpha4beta1 / 7 integrin ligand conjugated compounds and uses thereof

Abstract

Provided herein are [alpha] 4 [beta] 1 / 7 integrin receptor ligand-containing compounds, methods of delivering the compounds, and methods of using the compounds to treat diseases, disorders, and symptoms (e.g., central nervous system diseases, disorders, and symptoms) in a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 327,334, filed on April 4, 2022. The disclosure of the prior application is considered part of the disclosure of the present application and is incorporated by reference in its entirety into the disclosure of the present application. Background Art

[0003] In the use of compounds in therapeutic, preventive or diagnostic applications, it is generally desirable to deliver the compound to a specific location (e.g., to a desired cell) to enhance the therapeutic or preventive effect or to facilitate diagnostic purposes. This is often the case when attempting to deliver a therapeutic compound in vivo. In addition, being able to effectively deliver the compound to a specific location can limit or potentially eliminate the unintended consequences (such as off-target effects) that may be caused by the administration of the compound. One strategy to facilitate the delivery of a compound (such as a therapeutic, preventive or diagnostic compound) to a desired location in vivo is by connecting or attaching the compound to a targeting ligand.

[0004] The class compound that can use targeting ligand targeting is oligomeric compound, such as protein, peptide, antibody and oligonucleotide.The oligomeric compound comprising the nucleotide sequence (for example, oligonucleotide) that is at least partially complementary to target nucleic acid has been shown to change the function and activity of target in vitro and in vivo.When being delivered to the cell containing target nucleic acid (such as mRNA or pre-mRNA), oligonucleotide has been shown to regulate the expression or activity of target nucleic acid.In some cases, oligonucleotide can reduce the expression of gene by suppressing the translation of nucleic acid target and / or triggering the degradation of target nucleic acid.

[0005] If the target nucleic acid is mRNA, one mechanism by which the expression of the oligonucleotide-regulated mRNA target is through 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 an RNA-induced silencing complex (RISC) pathway. In addition, oligonucleotides can regulate the expression of target nucleic acids (such as target mRNA) through RNA enzyme recruitment mechanisms, microRNA mechanisms, placeholder mechanisms, and editing mechanisms. Oligonucleotides can be single-stranded or double-stranded. Oligonucleotides can comprise DNA, RNA, and RNA-like molecules, which may further comprise modified nucleosides, which comprise one or more modified sugars, modified core bases, and modified internucleoside bonds.

[0006] Another class of compounds that can be targeted using targeting ligands is small molecule compounds. Small molecule compounds (e.g., organic compounds with a molecular weight of about 1000 Daltons or less) are generally shown to be able to change the function and / or activity of the target, so that the disease and / or disease symptoms are regulated or improved or are generally used as diagnostic markers when positioned to the target. More effectively delivering the compound to a specific location can limit or potentially eliminate the unexpected consequences (such as off-target effects) that may be caused by the administration of the compound and provide improved positioning of the diagnostic compound. Summary of the Invention

[0007] The embodiments provided herein relate to methods for targeting the expression of the α4β1 integrin receptor and / or the α4β7 integrin receptor (collectively referred to herein as "α4β 1 / 7 Certain embodiments provided herein relate to compounds (e.g., any of those described herein) and methods for delivering an agent to cells expressing α4β 1 / 7 Compounds and methods for delivering cells that express integrin receptors. In certain embodiments, the cells are in the brain. In certain embodiments, the cells are in the frontal cortex. 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 agent is a therapeutic compound. In certain embodiments, the delivery of the agent is for treating a disease, disorder, or symptom in a subject. In certain embodiments, the agent is a diagnostic compound. In certain embodiments, the compound comprises α4β 1 / 7 Integrin receptor ligands and one or more linker moieties for attachment to therapeutic, prophylactic, or diagnostic agents. In certain embodiments, the compound comprises α4β 1 / 7 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, α4β 1 / 7 The integrin receptor ligand is α4β 1 / 7 Integrin receptor agonists. In certain embodiments, α4β 1 / 7 The integrin receptor ligand is α4β 1 / 7 Integrin receptor antagonists. In certain embodiments, α4β 1 / 7 Integrin receptor ligands are small molecules, aptamers, peptides, or antibodies. 1 / 7 The integrin receptor ligand is any of those described herein, or a derivative or prodrug thereof.

[0008] In certain embodiments, expression of α4β1 / 7 Contacting cells expressing integrin receptors, such as brain cells, with a compound provided herein delivers the agent to the cell. In certain embodiments, the α4β 1 / 7 In certain embodiments, cells expressing integrin receptors, such as brain cells, are contacted with a compound provided herein to treat a disease, disorder, or symptom in a subject. 1 / 7 Compared to cells with integrin receptors, cells containing α4β 1 / 7 Compounds that are ligands for integrin receptors selectively or preferentially target α4β 1 / 7 In certain embodiments, cells that do not contain α4β 1 / 7 Compared to compounds containing α4β integrin receptor ligands 1 / 7 Compounds that are ligands for integrin receptors selectively or preferentially target α4β 1 / 7 Integrin receptors on cells.

[0009] Certain embodiments provided herein relate to methods for regulating the expression of α4β 1 / 7 Compounds and methods for inhibiting expression of a nucleic acid target of an integrin receptor in a cell. In certain embodiments, the cell is in the brain. In certain embodiments, the cell is in the frontal cortex. 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 expression of α4β isoforms is inhibited. 1 / 7 Contacting cells that express integrin receptors, such as brain cells, with the compounds provided herein modulates the expression or activity of a nucleic acid target in the cell. In certain embodiments, the compound comprises α4β 1 / 7 an integrin receptor ligand, one or more linker moieties, and an oligonucleotide.

[0010] It should be understood that the embodiments provided herein with respect to preferred variable selections may be taken alone or in combination with one or more embodiments, or in combination with other preferred variable selections provided herein, as if each combination were expressly listed herein.

[0011] In one aspect, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I'):

[0012]

[0013] in:

[0014] Each of which is independently α4β 1 / 7 Integrin ligands;

[0015] L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A Each of is independently a linker, a bond, or absent;

[0016] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; and

[0017] z1 is 0 or 1.

[0018] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (I"):

[0019]

[0020] in:

[0021] is an oligonucleotide, and wherein L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0022] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (I):

[0023]

[0024] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0025] In some embodiments, α4β 1 / 7 The integrin ligand is α4β 1 / 7 Integrin agonists. In some embodiments, α4β 1 / 7 The integrin ligand is α4β 1 / 7 Integrin antagonists. In certain embodiments, α4β 1 / 7 The integrin ligand is selected from the group consisting of:

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032] where each instance of R is independently Anti-α4β 1 / 7 Integrin antibodies and their derivatives.

[0033] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (II'):

[0034]

[0035] in

[0036] R 2 and R 2A Each is independently H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl;

[0037] R 3 、R 3A 、R 4 and R 4A are each independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl; and

[0038] R 1 、z1、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0039] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (II"):

[0040]

[0041] Among them, L1, L2, L3, L4, R 1 、R 2 、R 3 and R 4 As defined herein.

[0042] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (II"-a):

[0043]

[0044] Among them, L1, L2, L3, L4, R 1 、R2 、R 3 and R 4 As defined herein.

[0045] In some embodiments, the compound or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (II"-a-1):

[0046]

[0047] Among them, L1, L2, L3, L4, R 1 、R 2 、R 3 and R 4 As defined herein.

[0048] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (II"-a-2):

[0049]

[0050] Among them, L1, L2, L3, L4, R 1 、R 3 and R 4 As defined herein.

[0051] In some embodiments, α4β 1 / 7 Integrin ligands contain structures or its derivatives.

[0052] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (II):

[0053]

[0054] where R 1 , 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 (II-a):

[0056]

[0057] where 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 (III'):

[0059]

[0060] in

[0061] R 2 and R 2A each independently represents H, halogen, polyethylene glycol (PEG), optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl;

[0062] R 3 and R 3A are each independently optionally substituted heteroalkyl or optionally substituted heterocyclyl;

[0063] n and n A Each independently is 1, 2 or 3;

[0064] z1 is 0 or 1; and

[0065] R 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0066] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (III):

[0067]

[0068] Where n, R 1 、R 2 、R 3 , L1, L2, L3 and L4 are as defined herein.

[0069] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (III-a):

[0070]

[0071]

[0072] Where n, R 1 、R 2 、R 3 , L1, L2, L3 and L4 are as defined herein.

[0073] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (III-b):

[0074]

[0075] Where n, R 1 、R 3 , L1, L2, L3 and L4 are as defined herein.

[0076] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (IV'):

[0077]

[0078] in

[0079] R 2 and R 2A Each independently represents H, -OH, -NH2, -NHR 3 、-OR 3 or does not exist;

[0080] R 3 is, in each instance, independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0081] z1.R 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0082] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (IV):

[0083]

[0084] where R 1 、R 2 , L1, L2, L3 and L4 are as defined herein.

[0085] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (IV-a):

[0086]

[0087] where R 1 、R 2 , L1, L2, L3 and L4 are as defined herein.

[0088] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (IV-b):

[0089]

[0090] where R 1 、R 2 , L1, L2, L3 and L4 are as defined herein.

[0091] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (IV-c):

[0092]

[0093] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0094] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (V'):

[0095]

[0096] in

[0097] n and n A are each independently 0, 1, 2 or 3; and

[0098] z 1 、R 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0099] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (V'-a):

[0100]

[0101] where R 1 、n、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0102] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (V):

[0103]

[0104] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0105] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (Va):

[0106]

[0107] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0108] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (Vb):

[0109]

[0110] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0111] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (Vc):

[0112]

[0113] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0114] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (Vd):

[0115]

[0116] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0117] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (Ve):

[0118]

[0119] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0120] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (VI'):

[0121]

[0122] in

[0123] n and n A are each independently 0, 1, 2 or 3; and

[0124] z 1 、R 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0125] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VI'-a):

[0126]

[0127] where R 1 、n、n A 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0128] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VI):

[0129]

[0130] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0131] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VI-a):

[0132]

[0133]

[0134] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0135] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VI-b):

[0136]

[0137] where R 1, n, L1, L2, L3 and L4 are as defined herein.

[0138] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (VI-c):

[0139]

[0140] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0141] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VI-d):

[0142]

[0143] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0144] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII'):

[0145]

[0146] in

[0147] R 2 、R 2A 、R 3 、R 3A 、R 4 、R 4A 、R 5 and R 5A Each is independently H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl or absent;

[0148] R 8 and R 8A each independently represents optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0149] R 6 、R 6A 、R 7 and R 7A are each independently H, halogen, alkyl, optionally substituted alkyl, optionally substituted heteroalkyl, and

[0150] R 1 、z1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0151] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII'-a):

[0152]

[0153] where R 1 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0154] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII'-a-1):

[0155]

[0156] where R 1 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0157] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII'-a-2):

[0158]

[0159] where R 1 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0160] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VII):

[0161]

[0162] where 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.

[0163] In certain embodiments, R 6 is F, CF3 or CH3, and R 7 for In certain embodiments, R 7 is F, CF3 or CH3, and R 6 for

[0164] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-a):

[0165]

[0166] where R 1 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , L1, L2, L3 and L4 are as defined herein.

[0167] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-b):

[0168]

[0169] where R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、R 8 , L1, L2, L3 and L4 are as defined herein.

[0170] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (VII-c):

[0171]

[0172] where R 1 、R 2 、R 3 、R4 、R 5 、R 6 、R 7 , L1, L2, L3 and L4 are as defined herein.

[0173] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-c-1):

[0174]

[0175] where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 8 , L1, L2, L3 and L4 are as defined herein.

[0176] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-c-2):

[0177]

[0178] where R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 , L1, L2, L3 and L4 are as defined herein.

[0179] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d):

[0180]

[0181] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0182] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-1):

[0183]

[0184] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0185] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-2):

[0186]

[0187] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0188] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-3):

[0189]

[0190] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0191] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-4):

[0192]

[0193] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0194] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-5):

[0195]

[0196] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0197] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-6):

[0198]

[0199] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0200] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-7):

[0201]

[0202] where R 1, L1, L2, L3 and L4 are as defined herein.

[0203] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-8):

[0204]

[0205] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0206] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-9):

[0207]

[0208] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0209] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VII-d-10):

[0210]

[0211] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0212] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VIII'):

[0213]

[0214] in

[0215] R 2 and R 2A Each is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or absent;

[0216] R 3 、R 3A 、R 4 and R 4A are each independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl;

[0217] R 5 and R 5A Each is independently -OH or absent;

[0218] Y and YA are each independently -CH2- or -(CH2)2-; and

[0219] R 1 、z1、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0220] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VIII'-a):

[0221]

[0222] where 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 As defined herein.

[0223] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (VIII):

[0224]

[0225] where R 1 、R 2 、R 3 、R 4 、R 5 , Y, L1, L2, L3 and L4 are as defined herein.

[0226] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VIII-a):

[0227]

[0228] where R 1 、R 2 、R 3 、R 4 , Y, L1, L2, L3 and L4 are as defined herein.

[0229] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VIII-a-1):

[0230]

[0231] where R 1 、R 2 、R 3 、R 4 , Y, L1, L2, L3 and L4 are as defined herein.

[0232] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (VIII-a-2):

[0233]

[0234] where R 1 、R 2 、R 3 、R 4 , Y, L1, L2, L3 and L4 are as defined herein.

[0235] In some embodiments, the compound comprises the structure of Formula (VIII-a-3):

[0236]

[0237] where R 1 、R 2 、R 3 、R 4 , Y, L1, L2, L3 and L4 are as defined herein.

[0238] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (IX'):

[0239]

[0240] in

[0241] R 2 and R 2A Each of the above is independently H, -OH, -NH2, -NHR 3 、-OR 3 or -CONHR 3 ;

[0242] R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0243] n and n A Each of is independently 1 or 2; and

[0244] R 1 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0245] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (IX):

[0246]

[0247] where R 1 、R 2 , n, L1, L2, L3 and L4 are as defined herein.

[0248] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (IX-a):

[0249]

[0250] where R 1 、R 2 , n, L1, L2, L3 and L4 are as defined herein.

[0251] In some embodiments, the compound comprises the structure of Formula (IX-b):

[0252]

[0253] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0254] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (X'):

[0255]

[0256] in

[0257] R 2 and R 2A Each independently represents H, -CH2OR 3 、-(CH2)2OR 3 、-CH2NHCOR 3 OR 3 ;and

[0258] R 3 is, in each instance, independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0259] R 1 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0260] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (X):

[0261]

[0262] where R 1 、R 2 , L1, L2, L3 and L4 are as defined herein.

[0263] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (Xa):

[0264]

[0265] where R 1 、R 2 , L1, L2, L3 and L4 are as defined herein.

[0266] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (Xb):

[0267]

[0268] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0269] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XI'):

[0270]

[0271] in

[0272] R 2 and R 2A Each of which is independently H, -CONHR 3 、-CH2OR 3 、-(CH2)2OR3 、-CH2NHCOR 3 OR 3 ;

[0273] R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0274] X and X A Each of is independently H or halogen; and

[0275] R 1 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0276] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XI):

[0277]

[0278] where R 1 、R 2 , X, L1, L2, L3 and L4 are as defined herein.

[0279] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (XI-a):

[0280]

[0281] where R 1 、R 2 , X, L1, L2, L3 and L4 are as defined herein.

[0282] The compound or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XI-b):

[0283]

[0284] where R 1 , X, L1, L2, L3 and L4 are as defined herein.

[0285] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises a structure of Formula (XII'):

[0286]

[0287] in

[0288] R 2 and R 2A Each of which is independently H, -CONHR 4 、-CH2OR 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ;

[0289] R 3 and R 3A Each of is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0290] R 4 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0291] R 5 and R 5A Each of is independently -OH or absent;

[0292] n and n A Each instance of is independently 0, 1, 2, or 3;

[0293] n1 and n1 A Each instance of is independently 1, 2, or 3; and

[0294] R 1 、z 1 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0295] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XII):

[0296]

[0297] where R 1 、R 2 、R 3 、R 4 、R 5 , n, n1, L1, L2, L3 and L4 are as defined herein.

[0298] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XII-a):

[0299]

[0300] where R 1 、R 2 、R 4 , n, L1, L2, L3 and L4 are as defined herein.

[0301] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XII-b):

[0302]

[0303] where R 1 , n, L1, L2, L3 and L4 are as defined herein.

[0304] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises the structure of Formula (XIII'):

[0305]

[0306] in

[0307] R 2 and R 2A Each of which is independently H, -CONHR 4 、-CH2OR 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ;

[0308] R 3 and R 3A Each of is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0309] R 4 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0310] R 5 and R 5A Each of is independently -OH or absent;

[0311] X and X A Each of is independently H, optionally substituted CH2, optionally substituted NH or cycloalkyl; and

[0312] R 1 、z1、L1、L2、L3、L4、L 1A 、L2A 、L 3A and L 4A As defined herein.

[0313] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XIII):

[0314]

[0315] where R 1 、R 2 、R 3 、R 4 、R 5 , X, L1, L2, L3 and L4 are as defined herein.

[0316] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XIII-a):

[0317]

[0318] where R 1 、R 2 、R 3 、R 4 , X, L1, L2, L3 and L4 are as defined herein.

[0319] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XIII-b):

[0320]

[0321] where R 1 、R 2 、R 3 、R 4 , X, L1, L2, L3 and L4 are as defined herein.

[0322] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XIII-c):

[0323]

[0324] where R 1 , X, L1, L2, L3 and L4 are as defined herein.

[0325] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XIV'):

[0326]

[0327] in

[0328] R 2 and R 2A Each of the 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ;

[0329] R 3 and R 3A Each of the above is independently H, -OH, -NH2, -NHR 5 OR 5 ;

[0330] R 4 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0331] R 5 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0332] n and n A Each of is independently 1, 2 or 3;

[0333] R 1 、z1、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0334] In some embodiments, the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprises the structure of Formula (XIV):

[0335]

[0336]

[0337] where R 1 、R 2 、R 3 、R 4 、R 5 , n, L1, L2, L3 and L4 are as defined herein.

[0338] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XIV-a):

[0339]

[0340] where R 1 、R 2 , n, L1, L2, L3 and L4 are as defined herein.

[0341] In some embodiments, the compound or a stereoisomer, tautomer, prodrug, or salt thereof comprises a structure of Formula (XIV-b):

[0342]

[0343] where R 1 、R 3 , n, L1, L2, L3 and L4 are as defined herein.

[0344] In some embodiments, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A Each of the 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 bond, or a phosphorothioate bond.

[0345] In certain embodiments, L1 and / or L 1A is the key.

[0346] In some embodiments, L2 and / or L 2A L is an optionally substituted PEG linker. In some embodiments, the length of the PEG linker is two, three, four, five, six, seven, eight, nine or ten PEG units. In certain embodiments, L2 and / or L 2A Contains structure

[0347] In some embodiments, L3 and / or L 3A is an optionally substituted heteroaryl linker. In some embodiments, L3 and / or L 3A is an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, L3 and / or L 3A Contains structure

[0348] In some embodiments, L4 and / or L 4Ais an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted by one or more =O substituents. In some embodiments, the heteroalkyl linker comprises two substituents linked together to form an optionally substituted carbocyclyl ring. In certain embodiments, L4 and / or L 4A Contains structure wherein X is O or S. In certain embodiments, L4 and / or L 4A Contains structure Wherein X is O or S.

[0349] In certain embodiments, L1, L2, L3, and L4 and / or L 1A 、L 2A 、L 3A and L 4A Together they contain the following structures:

[0350]

[0351]

[0352]

[0353] Wherein X is O or S.

[0354] In certain embodiments, the compound comprises the structure:

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361] Wherein X is O or S.

[0362] In certain embodiments, X is O. In certain embodiments, X is S.

[0363] In some embodiments, R 1 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 1Conjugated to one or more additional α4β 1 / 7 In some embodiments, the oligonucleotide is conjugated to two, three, four, five, or more than five additional α4β 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 on the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0364] In another aspect, the present disclosure provides a composition comprising any compound disclosed herein, or a stereoisomer, tautomer, prodrug, or salt thereof, and a pharmaceutically acceptable excipient.

[0365] In another aspect, the present disclosure provides a method for delivering a therapeutic oligonucleotide to a subject's brain, the method comprising administering to the subject any compound described herein, or a stereoisomer, tautomer, prodrug or salt thereof, or any composition described 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 cortex, and spinal cord.

[0366] On the other hand, the present disclosure provides a method for treating or improving a disease, disorder or its symptoms in a subject, the method comprising administering to the subject any compound disclosed herein or its stereoisomer, tautomer, prodrug or salt or any composition disclosed herein. In some embodiments, the disease, disorder or its symptoms are central nervous system (CNS) diseases, disorders or their symptoms. In certain embodiments, the disease, disorder or its symptoms are Alzheimer's disease or its symptoms. In certain embodiments, the compound or its stereoisomer, tautomer, prodrug or salt is administered intrathecally to the subject.

[0367] In another aspect, the present disclosure provides methods for preparing any compound disclosed herein, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising one or more compounds described herein and chemical transformations, including Examples 1-13. BRIEF DESCRIPTION OF THE DRAWINGS

[0368] Figure 1 Compound 2 from Example 1 is shown 1 H NMR.

[0369] Figure 2 Compound 5 from Example 1 is shown 1 H NMR.

[0370] Figure 3Compound 6 from Example 1 is shown 1 H NMR.

[0371] Figure 4 Compound 7 from Example 1 is shown 1 H NMR.

[0372] Figure 5 Compound 8 from Example 1 is shown 1 H NMR.

[0373] Figure 6 Compound 10 from Example 1 is shown. 1 H NMR.

[0374] 7A to 7C The characterization of compound 11 from Example 1 is shown. 1 H NMR ( Figure 7A )、LC / MS( Figure 7B ) and mass spectrometry data ( Figure 7C ). DETAILED DESCRIPTION

[0375] definition

[0376] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limitations of the claimed embodiments. In this document, unless otherwise specifically stated, the use of the singular includes the plural. As used herein, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms such as "include" and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0377] Unless otherwise indicated, the following terms have the following meanings:

[0378] As used herein, the term "treating" a condition encompasses improving, alleviating, and / or managing a condition and / or symptoms that may cause a condition. The terms "treating" and "treatment" refer to a method of alleviating or alleviating a disease and / or its attendant symptoms. According to the present disclosure, "treating" includes blocking, inhibiting, attenuating, preventing, modulating, reversing the effects of a condition, and reducing the occurrence of, for example, harmful effects of a condition. As used herein, "inhibiting" encompasses preventing, reducing, and stopping progression.

[0379] The terms "isolated," "purified," or "biologically pure" refer to material that is substantially or essentially free from components that normally accompany it as 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). Specifically, in certain embodiments, the compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0380] The term "administration" or "administering" includes a route by which a compound is introduced 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.

[0381] The term "effective amount" includes an amount effective to achieve the desired result within the necessary dosage and time period. The effective amount of a compound may vary depending on factors such as the disease state, age, and weight of the subject, as well as the ability of the compound to elicit the desired response in the subject. The dosing regimen may be adjusted to provide the optimal therapeutic response. An effective amount is also an amount in which any intolerable or deleterious effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.

[0382] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" refer to the administration of a compound, oligonucleotide, drug, or other substance so that it enters the patient's circulatory system and thereby undergoes metabolism and other similar processes.

[0383] The term "therapeutically effective amount" refers to that amount of the compound being administered which is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.

[0384] The therapeutically effective amount (i.e., effective dose) of the compound can be in the range of about 0.005 μg / kg to about 200 mg / kg, preferably about 0.01 mg / kg to about 200 mg / kg and more preferably about 0.015 mg / kg to about 30 mg / kg body weight. In other embodiments, the therapeutically effective amount can be in the range of about 1.0 pM to about 10 μM. It will be understood by those skilled in the art that certain factors may affect the dosage required for the effective treatment of the subject, including but not limited to the severity of the disease or condition, previous treatment, the general health and / or age of the subject, and other diseases present. In addition, treating a subject with a therapeutically effective amount of a compound can include a single treatment, or preferably can include a series of treatments. In one example, a subject is treated with a compound in the range of about 0.005 μg / kg to about 200 mg / kg body weight daily, weekly, monthly, quarterly, or annually. In another example, in the case of a chronic condition or disease, the subject can be treated daily, weekly, monthly, quarterly, or annually for several years. It should also be understood that the effective dose of the compound used for treatment can increase or decrease during a specific treatment.

[0385] The term "chiral" refers to molecules that have the property of non-superimposability on their mirror image partner, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0386] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms (which can be defined as (R)- or (S)- or (D)- or (L)- of an amino acid based on absolute stereochemistry) 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 separate. The present disclosure is intended to include racemic and optically pure forms of the compounds. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are expected to include both E and Z geometric isomers.

[0387] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and that is readily converted from one isomeric form to another.

[0388] It will be apparent to those skilled 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.

[0389] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure (i.e., R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the present disclosure.

[0390] As used herein, "chirally enriched population" means a plurality of molecules having the same molecular formula, wherein if a particular chiral center is stereoatactic, the number or percentage of molecules within the population that contain a particular stereochemical configuration at the particular chiral center is greater than the number or percentage of molecules within the population that would be expected to contain the same particular stereochemical configuration at the same particular chiral center. A population of chirally enriched molecules having multiple chiral centers within each molecule may contain one or more stereoatactic chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

[0391] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by 13 C- or 14 Compounds having the present structures other than C-enriched carbon substitutions are within the scope of this disclosure.

[0392] As used herein, in the context of a population of molecules of the same molecular formula, a "stereorandom chiral center" means a chiral center with a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules with the (S) configuration of the stereorandom chiral center may, but need not, be the same as the number of molecules with the (R) configuration of the stereorandom chiral center. A chiral center is considered random when its stereochemical configuration is the result of a synthetic method. In certain embodiments, the stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

[0393] The term "diastereomer" refers to stereoisomers that have two or more asymmetric centers and whose molecules are not mirror images of one another.

[0394] 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 a "racemate."

[0395] The term "isomers" or "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0396] The term "prodrug" means a compound that can be converted into a biologically active form of a compound as described herein (e.g., a biologically active form of a nucleic acid) or an analog thereof under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable 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 typically provide advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T. et al., "Pro-drugs 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 intended 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 in a manner such that the modifications are cleaved in routine manipulation or in vivo to the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of suitable prodrugs include, but are not limited to, glutathione, acyloxy, thioacyloxy, 2-carbon alkoxyethyl, disulfide, thiamine hydrochloride (thiaminal) and enol ester derivatives of nucleic acids modified with phosphorus atoms. The term "pre-oligonucleotide" or "prenucleotide" or "nucleic acid prodrug" refers to an oligonucleotide that has been modified to become a prodrug of an oligonucleotide. Phosphonate and phosphate prodrugs may be found in, for example, 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. Also included are prodrugs that are converted into active forms by other mechanisms in vivo. In some aspects, the compounds of the present disclosure are prodrugs of any formula herein.

[0397] The term "prodrug" includes compounds having a moiety that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo to active drugs by esterases or by other mechanisms. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). Prodrugs can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound or hydroxyl group in its free acid form with a suitable esterifying agent alone. Hydroxyl groups can be converted into esters by treatment with carboxylic acids. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), amido lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halogen, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionate and acyl esters. Also included are prodrugs that are converted to active forms in vivo by other mechanisms. In some aspects, the compounds of the present disclosure are prodrugs of any formula herein.

[0398] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0399] When used in this application, including the claims, the terms "a," "an," and "the" mean "one or more." Thus, for example, reference to "a sample" includes a plurality of samples unless the context clearly dictates otherwise (e.g., a plurality of samples), etc.

[0400] Throughout the specification and claims, the word "comprise" is used in its non-exclusive sense, unless the context requires otherwise.

[0401] As used herein, the term "about" when referring to a value is intended to encompass variations of the specified amount, 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%, as such variations are suitable for performing the disclosed methods or employing the disclosed compositions.

[0402] As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight chain (i.e., unbranched) or branched carbon chain (or carbon), 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 groups having the specified number of carbon atoms. For example, C1-C 24 Means 1 to 24 carbon atoms. The specified number of carbon atoms in this range includes, for example, C1-C 20 Alkyl (having 1-20 carbon atoms), C1-C 12 Alkyl groups (having 1 to 12 carbon atoms) and C1-C4 alkyl groups (having 1 to 4 carbon atoms).

[0403] The term "alkenyl" refers to an unsaturated hydrocarbon chain which may be linear or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. An alkenyl group may be optionally substituted with one or more substituents.

[0404] The term "alkynyl" refers to an unsaturated hydrocarbon chain which may be linear or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

[0405] 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. The alkyl group may be optionally substituted with one or more substituents.

[0406] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen 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 linear or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond, wherein one or more sp 2 The hybridized carbon is attached to the aryl portion. The alkenyl group may be optionally substituted with one or more substituents.

[0407] The term "arylalkynyl" refers to an unsaturated hydrocarbon chain, which may be linear or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond, wherein one or more sp hybridized carbons of the alkynyl unit are attached to the aryl portion. The alkynyl group may be optionally substituted with one or more substituents.

[0408] sp of alkenyl and alkynyl groups 2 An sp- or sp-hybridized carbon can optionally be the point of attachment for an alkenyl or alkynyl group, respectively.

[0409] The term "alkoxy" refers to an -O-alkyl substituent.

[0410] As used herein, the term "halogen," "halo," or "halo" means -F, -Cl, -Br, or -I.

[0411] The term "alkylthio" refers to an -S-alkyl substituent.

[0412] The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

[0413] The term "haloalkoxy" refers to an -O-alkyl group substituted with one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0414] The term "haloalkoxyalkyl" refers to -alkyl-O-alkyl' where alkyl' is substituted with one or more halo substituents.

[0415] The term "haloalkylaminocarbonyl" refers to a -C(O)-amino-alkyl group wherein the alkyl group is substituted with one or more halo substituents.

[0416] The term "haloalkylthio" refers to an -S-alkyl group substituted with one or more halogen substituents. Examples of haloalkylthio groups include trifluoromethylthio and 2,2,2-trifluoroethylthio.

[0417] The term "haloalkylcarbonyl" refers to a -C(O)-alkyl group substituted with one or more halogen substituents. Examples of haloalkylcarbonyl groups include trifluoroacetyl.

[0418] The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have a certain degree of unsaturation. The cycloalkyl group may optionally be substituted with one or more substituents. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl etc.

[0419] The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.

[0420] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0421] The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.

[0422] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0423] The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. The aryl group may optionally be substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of the aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, etc.

[0424] The term "aryloxy" refers to an -O-aryl substituent.

[0425] The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.

[0426] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.

[0427] The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.

[0428] The term "aralkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0429] The term "aralkylsulfonyl" refers to a -S(O)2-alkyl-aryl substituent.

[0430] The term "aralkylsulfinyl" refers to a -S(O)-alkyl-aryl substituent.

[0431] The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.

[0432] The term "alkaryl" refers to an -aryl-alkyl substituent.

[0433] The term "aralkyl" refers to an -alkyl-aryl substituent.

[0434] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si and / or S), and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (e.g., O, N, P, Si and / or S) may be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the rest of the molecule. A heteroalkyl group is an uncyclized chain. Examples include, but are not limited to, —CH—CH—O—CH, —CH—CH—NH—CH, —CH—CH—N(CH)—CH, —CH—S—CH—CH, —CH—CH, —S(O)—CH, —CH—CH—S(O)—CH, —CH═CH—O—CH, —Si(CH), —CH—CH═N—OCH, —CH═CH—N(CH)—CH, —O—CH, —O—CH—CH, and —CN. Up to two or three heteroatoms may be consecutive, such as —CH—NH—OCH and —CH—O—Si(CH). A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, B, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P). The heteroalkyl moiety may include up to 8 or more optionally different heteroatoms (e.g., O, N, S, Si, B, and / or P).

[0435] Similarly, unless otherwise indicated, the term "heteroalkylene," by itself or as part of another substituent, means a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy one or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and / or —S02R′. When “heteroalkyl,” followed by a specific heteroalkyl group such as —NR′R″, etc., is recited, it should be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to increase clarity. Thus, the term “heteroalkyl” should not be construed herein to exclude specific heteroalkyl groups, such as —NR′R″, etc.

[0436] Unless otherwise stated, the term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically having eight or fewer carbon atoms. The term "alkenylene" by itself or as part of another substituent means, unless otherwise stated, a divalent radical derived from an alkene group.

[0437] Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl groups are not aromatic. Additionally, for heterocycloalkyl groups, a heteroatom may occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl. "Cycloalkylene" and "heterocycloalkylene" by themselves or as part of another substituent mean divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively. "Cycloalkyl" also means bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0438] The term "heteroaryl" refers to an aromatic 5-8 yuan monocyclic, 8-12 yuan bicyclic or 11-14 yuan tricyclic ring system having 1-4 ring heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic), wherein the heteroatoms are selected from O, N or S, and the remaining ring atoms are carbon (with appropriate hydrogen atoms, unless otherwise specified). The heteroaryl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the heteroaryl group may be substituted with a substituent. The heteroaryl groups may be fully unsaturated, or they may be partially unsaturated and partially saturated. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0439] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0440] The term "heteroaryloxy" refers to an -O-heteroaryl substituent.

[0441] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

[0442] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0443] The term "nitrogen-containing heteroaryl" refers to heteroaryl groups having 1-4 ring nitrogen heteroatoms (if monocyclic), 1-6 ring nitrogen heteroatoms (if bicyclic), or 1-9 ring nitrogen heteroatoms (if tricyclic).

[0444] The term "heterocycloalkyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system containing 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic), wherein the heteroatoms are selected from O, N, S, B, P, or Si, wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of the heterocycloalkyl group may be substituted with substituents. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thienyl, etc.

[0445] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0446] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl groups may be optionally substituted with one or more substituents.

[0447] symbol Indicates the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.

[0448] The term "nucleobase" refers to nitrogenous biological compounds that form nucleosides. These include purine bases and pyrimidine bases. Five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are referred to as the principal or canonical nucleobases. When a nucleobase is listed in a formula definition, it refers to the moiety that is covalently bonded to the formula.

[0449] 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 the moiety that is covalently bonded to the formula.

[0450] The terms "substituent" and "substituent group" mean an atom or group that replaces the atom or group of the named parent compound. For example, the substituent of a modified nucleoside is an atom or group different from the atom or group found in a naturally occurring nucleoside (for example, a modified 2'-substituent is any atom or group other than H or OH at the 2'-position of a nucleoside). A substituent may be protected or unprotected. A substituent may also be further substituted with other substituent groups and may be attached to the parent compound directly or via a linking group such as an alkyl or hydrocarbyl group. Similarly, as used herein, a "substituent" with respect to a chemical functional group means an atom or group of atoms that is different from the atom or group of atoms that is typically present in a specified functional group. In certain embodiments, substituents on any group (such as alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) may be at any atom of the group, wherein any group (such as alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) that can be substituted may be optionally substituted with one or more substituents (which may be the same or different), each substituent replacing a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, urea In some embodiments, substituents on any group include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, thiocarbonyl, thio, thio, thioalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl or amide.In certain embodiments, substituents on any group include alkyl, halo, haloalkyl, cyano, nitro, alkoxy, hydroxy, hydroxyalkyl, carboxyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, thio, mercapto, mercaptoalkyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkylamino.

[0451] The term "protecting group" or "protecting moiety" refers to a substituent typically used to block or protect a particular functional group while reacting other functional groups on a compound, its derivative, or its conjugate, and includes a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom. Nitrogen and oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0452] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R ddgroup substituted, and each R aa 、R bb and R cc R is independently alkyl, cycloalkyl, aryl or heteroaryl, each of which may be optionally replaced by 1-3 independent R dd Replace, and each R dd are independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, Aryl substituted with alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl or arylamino; Arylalkylamino, aralkylaminocarbonyl, amide, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, urea, carbamoyl, thiourea, thiocyanato, sulfonamido, sulfonylalkyl, sulfonylaryl or mercaptoalkoxy. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0453] Amide nitrogen protecting groups (e.g., -C(=O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyamido)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0454] Carbamate nitrogen protecting groups (e.g., -C(=O)OR aa) include but are not limited to methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adp oc), 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-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), ammonia allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-methyl)carbamate phenylsulfonyl) ethyl ester, [2-(1,3-dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphoethyl carbamate (Peoc), 2-triphenylphosphinopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolemethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-Dimethoxy-6-nitrobenzyl ester, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylformamide)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamide)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, amino isobutyl carbamate, isonicotinoyl carbamate, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 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-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0455] Sulfonamide nitrogen protecting groups (e.g., -S(=O)2R aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzenemethylsulfonamide, trifluoromethylsulfonamide, and phenylacylsulfonamide.

[0456] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-toluenesulfonylaminoacyl derivatives, N'-phenylaminosulfonyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilazide adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2 -ketone, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-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-phenylfluorenamine (PhF), N-2 ,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-pyridylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyleneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl) Amines, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitramines, N-nitrosamines, amine N-oxides, diphenylphosphoramide (Dpp), dimethylphosphoramide (Mpt), diphenylphosphoramide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0457] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxy protecting group). Oxygen protecting groups include but are not limited to -R aa 、-N(R bb )2, -C(=O)SRaa 、-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, where R aa 、R bb and R cc As described herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, incorporated herein by reference.

[0458] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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-benzyloxy ethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylhydrogen selenyl)ethyl, tert-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'-dinitrodibenzyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl 1-Hydroxy-1-methyl-2-thiazolyl, 1-(4-(9-phenyl)-1-oxo)-1-thiazolyl)-1,1-bis(4-methoxyphenyl)-1,1-bis(4-methoxyphenyl)-2,1-dimethyl-1-thiazolyl, 1-(4-(9-phenyl)-1-oxo ...S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formates, benzoylformates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxy Acetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid dithioacetal), pivalate, adamantanoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (trimethylbenzoate), tert-butyl carbonate (BOC), methyl alkyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl alkyl carbonate, 2,2,2-trichloroethyl alkyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) Ethyl carbonate (Psec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), isobutyl alkyl carbonate, vinyl alkyl carbonate, allyl alkyl carbonate, p-nitrophenyl alkyl carbonate, benzyl alkyl carbonate, p-methoxybenzyl alkyl carbonate, 3,4-dimethoxybenzyl alkyl carbonate, o-nitrobenzyl alkyl carbonate, p-nitrobenzyl alkyl carbonate, S-benzyl alkyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 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, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphoramide, N-phenylcarbamic acid alkyl ester, borate, dimethylphosphinothioate, 2,4-dinitrophenylsulfenic acid alkyl ester, sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate (Ts).

[0459] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known as a thiol protecting group). Sulfur protecting groups include but are not limited to -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, where R aa 、R bb and R cc As defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Wine and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0460] The term "antisense oligonucleotide" or "antisense strand" means an oligonucleotide that contains a region that is complementary to a target nucleic acid.

[0461] The term "composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to a subject. For example, a composition may include one or more compounds or their salts and a sterile aqueous solution.

[0462] 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 acid, and double-stranded nucleic acid.

[0463] The term "nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

[0464] The term "nucleoside" means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. "Modified nucleoside" means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides that lack a nucleobase.

[0465] The term "oligomeric compound" means a polymer of linked subunits. With respect to proteins, peptides, polypeptides, or antibodies, "subunit" refers to an amino acid or peptide bond. With respect to oligonucleotides, "subunit" refers to a nucleotide, nucleoside, nucleobase, or sugar, or a modified nucleotide, nucleoside, nucleobase, or sugar as provided herein.

[0466] The term "oligonucleotide" means a polymer of connected nucleosides (e.g., polynucleotides, nucleic acids, nucleotide polymers), each of which can be modified or unmodified independently of one another. Without limitation, an oligonucleotide can comprise ribonucleic acids (e.g., comprising ribonucleosides), deoxyribonucleic acids (e.g., comprising deoxyribonucleosides), modified nucleic acids (e.g., comprising modified core bases, sugars and / or phosphate groups), or combinations thereof. Examples of oligonucleotide compounds include single-stranded and double-stranded compounds such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA (miRNA) targeting oligonucleotides, miRNA mimics, placeholder compounds (e.g., mRNA processing or translation blocking compounds 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., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that act at least in part through the RNA-induced silencing complex (RISC) pathway, resulting in sequence-specific degradation and / or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is intended to refer to other terms equivalent to those used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agents, RNAi agents, small interfering RNA, short interfering RNA, short interfering oligonucleotides, short interfering nucleic acids, short interfering modified oligonucleotides, chemically modified siRNA, etc. Additionally, the term "RNAi" is intended to refer to other terms equivalent to those used to describe sequence-specific RNA interference.

[0467] 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.

[0468] The term "therapeutic compound" includes any 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.

[0469] "Target region" means a portion of a target nucleic acid that is targeted by one or more compounds.

[0470] By "targeting moiety" is meant a conjugated group that provides enhanced affinity for a selected target (e.g., a molecule, cell or cell type), compartment (e.g., a cellular or organ compartment), tissue, organ or body region, e.g., compared to a compound in the absence of such moiety.

[0471] "Terminus group" means a chemical group or group of atoms covalently attached to the terminus of an oligonucleotide.

[0472] "Derivative" means a molecule or compound described herein that has been transformed by a chemical reaction.

[0473] The term "ligand" refers to a substance that binds to or interacts with a protein, nucleic acid, or other biological molecule. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand binds to a protein (e.g., a receptor). In certain embodiments, the ligand binds to an α4β 1 / 7 Integrin receptor binding.

[0474] The term "α4β 1 / 7 The term "integrin receptor" refers to a heterodimeric integrin receptor formed by the association of integrin α4 and integrin β1 (i.e., α4β1 integrin receptor) and integrin α4 and integrin β7 (i.e., α4β7 integrin receptor). In certain embodiments, 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 The binding affinity of integrin receptor ligands to α4β7 integrin receptor is higher than that to α4β1 integrin receptor.

[0475] The term "sense oligonucleotide" or "sense strand" means the strand of a double-stranded compound that comprises a region that is substantially complementary to a region of the antisense strand of the double-stranded compound.

[0476] The terms "microRNA" and "miRNA", used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides in length) non-coding ribonucleic acids (RNAs) that participate in post-transcriptional regulation of gene expression in multicellular organisms by affecting the stability and translation of mRNA. miRNAs are transcribed by RNA polymerase II as part of a capped and polyadenylated primary transcript (pri-miRNA), which can be protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce a stem-loop precursor miRNA (pre-miRNA) of about 70 nucleotides in length, which is further processed in the RNAi pathway. As part of this pathway, pre-miRNAs are cleaved by the cytoplasmic Dicer ribonuclease to produce mature miRNAs and antisense miRNA star (miRNA*) products. Mature miRNA is incorporated into the silencing complex (RISC) induced by RNA, which recognizes target mRNA by incomplete base pairing (i.e., partial complementation) with miRNA, and most commonly results in translational inhibition or destabilization of target mRNA. The most common mechanism of this is the combination of miRNA on the 3' untranslated region (UTR) of target mRNA, which can reduce gene expression by inhibiting translation (e.g., by blocking ribosome entry translation) or directly causing the degradation of transcripts. The term (i.e., miRNA) can be used herein to refer to any form (e.g., precursor, primary and / or mature miRNA) of subject miRNA.

[0477] The terms "small interfering RNA," "short interfering RNA," and "siRNA," used interchangeably herein, refer to RNA molecules that exist as non-coding double-stranded RNA (dsRNA) molecules of about 20 to about 24 nucleotides in length and can be used for RNA interference (RNAi). siRNAs are typically found with a phosphorylated 5' end and a hydroxylated 3' end, the 3' end typically having a 2-nucleotide overhang beyond the 5' end of the antiparallel strand (e.g., the complementary strand of the dsRNA molecule). siRNAs can interfere with the expression of specific genes by binding to their complementary target sequence (e.g., target nucleic acid sequence) and promoting (e.g., favoring, triggering, initiating) the degradation of mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. After integration and sequestration into the RISC complex, siRNA forms base pairs (e.g., fully complementary) with its target mRNA and cleaves it, thereby preventing it from serving as a translation template. As described above, and also as part of the RNAi pathway, the miRNA-loaded RISC complex scans cytoplasmic mRNA for potential complementarity (e.g., partial complementarity).

[0478] As used herein, the term "ADAR recruiting molecule" refers to a nucleic acid that is configured to increase the concentration of adenosine deaminases (ADARs) acting on ribonucleic acids in a location surrounding the nucleic acid. In some embodiments, the increased concentration is relative to the concentration in a given location where the ADAR recruiting molecule is not present. In some embodiments, the ADAR recruiting molecule comprises a double-stranded RNA duplex.

[0479] As used herein, the term "ADAR targeting molecule" refers to a nucleic acid that is configured to guide the ADAR molecule to a desired position (e.g., a site). As used herein, the term "directly" refers to increasing the concentration of ADAR at a desired position 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 position by changing the sequence and / or properties of the nucleic acid (e.g., by modification of a core base, sugar, internucleoside linkage or other components). In some embodiments, the ADAR targeting molecule comprises an ADAR recruitment 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.

[0480] As used herein, the term "single-stranded guide nucleic acid" or "guide RNA" refers to a single-stranded nucleic acid comprising a specific sequence that is at least partially complementary to a target sequence. In some embodiments, the target sequence is located at, adjacent to, or near a location where modulation of ADAR concentration is desired. In some embodiments, the level of complementarity is sufficient to promote binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.

[0481] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be treated with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeled. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0482] The term "isotopic variant" refers to a therapeutic agent that contains unnatural ratios of isotopes at one or more atoms comprising the therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural ratios of one or more isotopes, 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 O), 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). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes 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 O), 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).

[0483] It is understood that, where feasible according to the judgment of the skilled artisan, in a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), any hydrogen may be, for example, 2 H, or any carbon can be e.g. 13 C, or any nitrogen may be e.g. 15 N, or any oxygen may be e.g. 18 O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).

[0484] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage is modified.

[0485] "Nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

[0486] The term "oligoduplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligoduplex may be referred to as a "double-stranded oligomeric compound." The oligonucleotides of each oligomeric compound of an oligoduplex may contain non-complementary overhanging nucleosides. In some embodiments, the terms "double-stranded oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.

[0487] "Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

[0488] The terms "RNA interference compound," "RNAi compound," and / or "iRNA agent" mean a compound that acts at least in part through the RNA-induced silencing complex (RISC) pathway or Ago2, but not through RNase H, to modulate 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 microRNA, including microRNA mimics.

[0489] Certain embodiments

[0490] In certain embodiments, the compound comprises α4β 1 / 7 In certain embodiments, the compound is selected from any of the formulas provided herein. In certain embodiments, 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, L31, L40, L19, L21, L32, L41, L5 1A 、L 2A 、L 3A 、L 4A etc.) will α4β 1 / 7 The ligand is connected to a therapeutic agent, a prophylactic agent, or a diagnostic agent. In certain embodiments, the compound further comprises one or more therapeutic agents, prophylactic agents, or diagnostic agents. In certain embodiments, the therapeutic agent, prophylactic agent, or diagnostic agent is a small molecule or oligomeric compound. In certain embodiments, the oligomeric compound comprises a protein, a peptide, an antibody, an oligonucleotide, or a combination thereof.

[0491] In certain embodiments, the oligomeric compound is any of those described herein. In certain embodiments, the length of the oligomeric compound is about 10-50 subunits. In certain embodiments, the oligomeric compound is an oligonucleotide. In certain embodiments, the oligonucleotide is any of those described herein. In certain embodiments, the length of the oligonucleotide is the nucleosides of 8 to 80 connections, the nucleosides of 12-50 connections, the nucleosides of 12-30 connections, or the nucleosides of 15-30 connections.

[0492] 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.

[0493] 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 (e.g., comprising ribonucleosides), deoxyribonucleic acid (e.g., comprising deoxyribonucleosides) or a combination thereof. In certain embodiments, the oligonucleotide is a small interfering RNA (siRNA), a microRNA (miRNA) antagonist, a miRNA mimic, an ADAR recruiting molecule, an ADAR targeting molecule, a guide RNA, an antisense oligonucleotide, a short hairpin RNA (shRNA) or a combination thereof.

[0494] 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 two, three, four, five, six, seven, eight, nine, or ten PEG units in length. In certain embodiments, the linker comprises the structure

[0495] 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 comprises the structure

[0496] In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the linker is substituted with one or more =O substituents. In some embodiments, the linker comprises two substituents linked together to form an optionally substituted carbocyclyl ring. In certain embodiments, the linker comprises the structure wherein X is O or S. In certain embodiments, the linker comprises the structure Wherein X is O or S.

[0497] In some embodiments, the linker comprises the structure

[0498]

[0499]

[0500]

[0501] Wherein X is O or S.

[0502] In certain embodiments, the compound comprises or consists of one of the following structures:

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509] or a salt thereof, wherein X is O or S.

[0510] In some embodiments, X is O. In some embodiments, X is S.

[0511] In some embodiments, R 1 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 Conjugated to one or more additional α4β 1 / 7 In some embodiments, the oligonucleotide is conjugated to two, three, four, five, or more than five additional α4β 1 / 7 Integrin receptor ligands. In certain embodiments, additional α4β 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 on the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0512] Certain embodiments provide a composition comprising a compound according to any of the embodiments herein and a pharmaceutically acceptable carrier or excipient.

[0513] Certain embodiments provide a composition comprising a compound according to any of the embodiments herein for use in therapy.

[0514] In certain embodiments, a method for delivering an agent to a cell comprises contacting the cell with a compound of any embodiment herein, thereby delivering the agent to the cell. In certain embodiments, the cell expresses α4β on the surface of the cell. 1 / 7Integrin receptors. In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a cell of the frontal cortex. 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 pharmaceutical agent is a therapeutic agent or a diagnostic agent. In certain embodiments, the cell is in an animal.

[0515] 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 embodiment herein, thereby modulating expression of the nucleic acid target in the cell. In certain embodiments, the cell expresses α4β on the surface of the cell. 1 / 7 Integrin receptors. In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a cell of the frontal cortex. 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 agent or a diagnostic agent. In certain embodiments, contacting the cell with a compound of any embodiment herein inhibits expression of a nucleic acid target. In certain embodiments, the nucleic acid target is a pre-mRNA, mRNA, non-coding RNA, or miRNA. In certain embodiments, the cell is in an animal.

[0516] In certain embodiments, a method of regulating the expression of a nucleic acid target in a subject comprises administering to the subject any compound or composition provided herein, thereby regulating the expression of the nucleic acid target in the subject. In certain embodiments, α4β is expressed on the surface of a cell. 1 / 7 In some embodiments, the expression of the nucleic acid is regulated in cells of a subject expressing an integrin receptor. In some embodiments, the expression of the nucleic acid is regulated in brain cells. In some embodiments, the expression of the nucleic acid is regulated in cells expressing α4β on their surface. 1 / 7 The cell of the integrin receptor is a brain cell. In certain embodiments, the brain cell is a cell of the frontal cortex. 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 a pre-mRNA, mRNA, non-coding RNA, or miRNA. In certain embodiments, the compound is administered intrathecally to the subject.

[0517] In certain embodiments, a method for treating or improving a disease, illness or its symptom of a subject includes administering any compound or composition provided herein to the subject, so as to treat, prevent or improve the disease, illness or symptom of the subject. In certain embodiments, disease, illness or its symptom is a central nervous system (CNS) disease, illness or its symptom. In certain embodiments, disease, illness or its symptom is Alzheimer's disease or its symptom. In certain embodiments, compound is administered to the subject intrathecally. In certain embodiments, compound or composition is administered to the subject in a therapeutically effective amount.

[0518] In certain embodiments, the 1 / 7 Compared to cells with integrin receptors, cells containing α4β 1 / 7 Compounds that are ligands for integrin receptors selectively or preferentially target α4β 1 / 7 In certain embodiments, cells that do not contain α4β 1 / 7 Compared to compounds containing α4β integrin receptor ligands 1 / 7 Compounds that are ligands for integrin receptors selectively or preferentially target α4β 1 / 7 Integrin receptors on cells.

[0519] Also provided herein are uses of the compounds described herein for the preparation of a medicament for treating a disease or condition.

[0520] In another aspect, the present disclosure provides methods for preparing any of the compounds provided herein, including one or more compounds and chemical transformations described herein, including Examples 1-13.

[0521] Certain compounds containing oligonucleotides

[0522] In certain embodiments, the compounds described herein include oligonucleotides. In certain embodiments, the oligonucleotides have a core base 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 can change the expression of a potential gene after being delivered to a cell expressing the target nucleic acid. In some embodiments, the oligonucleotides can inhibit the expression of a potential gene after being delivered to a cell expressing the target nucleic acid. Gene expression can be modified or inhibited in vitro or in vivo. In certain embodiments, the oligonucleotides include 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 core bases, sugars, and / or internucleoside bonds), or combinations thereof. In some embodiments, the oligonucleotides include ribonucleic acids (RNA). In some embodiments, the oligonucleotides include deoxyribonucleic acids (DNA). In some embodiments, the oligonucleotides include modifications (e.g., modified core bases, modified sugars, or modified internucleoside bonds).

[0523] In certain embodiments, the oligonucleotide is single-stranded. In some embodiments, the single-stranded oligonucleotide is a single-stranded RNA (ssRNA), ssDNA or ssRNA / DNA hybrid (e.g., a single-stranded oligonucleotide comprising a ribonucleoside (modified or unmodified) and a deoxyribonucleoside (modified or unmodified)). In some embodiments, the oligonucleotide is double-stranded (e.g., comprising two single-stranded nucleic acids). Such double-stranded oligonucleotides include a first oligonucleotide having a region complementary to the target nucleic acid and a second oligonucleotide having a region complementary to the first oligonucleotide. The first oligonucleotide and the second oligonucleotide can be modified independently. In certain embodiments, the first oligonucleotide is connected to one or more α4β 1 / 7 Integrin receptor ligands. In certain embodiments, the second oligonucleotide is linked to one or more α4β 1 / 7 Integrin receptor ligand.

[0524] In some embodiments, the length of the oligonucleotide is at least 2 (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 ,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,1 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.

[0525] In some embodiments, the length of the oligonucleotide is less than or equal to 150 (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 ,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,8 2, 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 In some embodiments, the oligonucleotide has a length of less than or equal to 90 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 80 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 70 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 60 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 50 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 40 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 30 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 29 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 28 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 27 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 26 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 25 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 24 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 23 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 22 nucleotides.In some embodiments, the length of the oligonucleotide is less than or equal to 21 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 20 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 19 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 18 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 17 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 16 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 15 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 10 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 5 nucleotides.

[0526] In some embodiments, the length of the oligonucleotide is about 5 nucleotides to about 150 nucleotides. In some embodiments, the length of the oligonucleotide is about 10 nucleotides to about 100 nucleotides. In some embodiments, the length of the oligonucleotide is about 20 nucleotides to about 90 nucleotides. In some embodiments, the length of the oligonucleotide is about 30 nucleotides to about 80 nucleotides. In some embodiments, the length of the oligonucleotide is about 40 nucleotides to about 70 nucleotides. In some embodiments, the length of the oligonucleotide is about 50 nucleotides to about 60 nucleotides.

[0527] In some embodiments, the oligonucleotide is a therapeutic oligonucleotide. Therapeutic oligonucleotides may include, for example, but are not limited to, small interfering RNA (siRNA), microRNA (miRNA) antagonists, miRNA mimics, ADAR recruiting molecules, ADAR targeting molecules, guide RNA, antisense oligonucleotides, short hairpin RNA (shRNA), or a combination thereof.

[0528] In certain embodiments, the miRNA is a precursor, primary and / or mature miRNA.

[0529] In certain embodiments, the oligonucleotide comprises an antisense oligonucleotide 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 the degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide recruits RNase H and promotes the degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide targets miRNA, inhibits miRNA from regulating mRNA expression and promotes the degradation of miRNA.

[0530] Certain modifications

[0531] In certain aspects, the present disclosure relates to compounds comprising oligonucleotides. In certain embodiments, the oligonucleotide can be unmodified RNA or DNA, or can be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, relative to unmodified RNA or DNA, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage. In certain embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also comprise terminal modifications, such as 5' end modifications and 3' end modifications.

[0532] Sugar modifications and motifs

[0533] 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 surrogate. The sugar surrogate may comprise one or more substitutions as described herein.

[0534] 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 comprises one or more substituent groups, including but not limited to substituent groups at the 2′, 3′, 4′, and 5′ positions.

[0535] In certain embodiments, the substituents at the 2′ position include, but are not limited to, F and OCH3 (“OMe”, “O-methyl” or “methoxy”). In certain embodiments, the substituent groups at the 2′ position of sugars suitable for non-bicyclic modifications include, but are not limited to, halogen, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ONO2, NO2, N3 and NH2. In certain embodiments, the substituent groups at the 2′ position include, but are not limited to, O—(C1-C 10 ) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein alkyl, alkenyl and alkynyl can be substituted or unsubstituted C1 to C 10 Alkyl or C2 to C 10In some embodiments, the 2′ substituent groups include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In some embodiments, these 2′ substituent groups may be further substituted with one or more substituent groups independently selected from the group consisting of hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In some embodiments, the 2′ substituent groups include, but are not limited to, O[(CH2) n O] m CH3, O(CH2) n OCH3, O(CH2) n CH3, O(CH2) n ONH2、O(CH2) n NH2, O(CH2) n SCH3 and O(CH2) n ON[(CH2) n CH3)]2, wherein n and m are independently 1 to about 10. In certain embodiments, the substituent groups 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").

[0536] In certain embodiments, the substituent groups at the 4' position of the sugar suitable for non-bicyclic modification include but are not limited to alkoxy (e.g., methoxy), alkyl, and Manoharan et al., those described in WO 2015 / 106128. In certain embodiments, the substituent groups at the 5' position of the sugar suitable for non-bicyclic modification include but are not limited to methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, one or more sugars include 5'-vinylphosphonate modifications. In certain embodiments, the substituents described herein for 2', 4', and 5' positions may be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, the sugar of non-bicyclic modification may include more than one non-bridging sugar substituent. In certain such embodiments, the sugar substituents of non-bicyclic modification include but are not limited to 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, modified sugar substituents include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US 2013 / 0203836. In certain embodiments, substituent groups suitable for the 5′ position of non-bicyclic modified sugars include, but are not limited to, methyl (“Me” or “CH 3 ”) (R or S), vinyl, and methoxy.In certain embodiments, the 5′ modification is a 5′-monophosphate ((HO)2(O)PO-5′); a 5′-diphosphate ((HO)2(O)POP(HO)(O)-O-5′); a 5′-triphosphate ((HO)2(O)PO-(HO)(O)POP(HO)(O)-O-5′); a 5′-guanosine cap (7-methylated or unmethylated) (7m-GO-5′-(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5′); a 5′-adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (NO-5′(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5′); a 5′-monothioate (phosphorothioate; (HO)2(S)PO-5′); a 5′-monodithioate (dithioate); Phosphoroate; (HO)(HS)(S)PO-5′), 5′-thiophosphate ((HO)2(O)PS-5′); any additional combination of oxygen / sulfur substituted monophosphates, diphosphates, and triphosphates (e.g., 5′-α-thiotriphosphate, 5′-γ-thiotriphosphate, etc.), 5′-phosphoramidate ((HO)2(O)P-NH-5′, (HO)(NH2)(O)PO-5′), 5′-alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-5′-, 5′-alkenylphosphonates (i.e., vinyl, substituted vinyl), (OH)2(O)P-5′-CH2-), 5′-alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH2-), ethoxymethyl, etc., e.g., RP(OH)(O)-O-5′-). In certain embodiments, one or more sugars comprise a 5′-vinylphosphonate modification. In certain embodiments, the 5' modification is at the terminus of the oligonucleotide.In certain embodiments, the 5' modification is at the terminus of the antisense oligonucleotide.

[0537] In certain embodiments, modified sugar is a bicyclic sugar. Bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed via a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, bicyclic sugar comprises two atoms of a bridging furanosyl ring to form a bridging substituent of the second ring. In certain embodiments, bicyclic sugar does not comprise a furanosyl moiety. " Bicyclic nucleoside " (" BNA ") is a nucleoside with a bicyclic sugar. In certain embodiments, bicyclic sugar comprises a bridge between 4 ' and 2 ' furanose ring atoms. In certain embodiments, bicyclic sugar comprises a bridge between 5 ' and 3 ' furanose ring atoms. In some such embodiments, the furanose ring is a ribose ring. In certain embodiments, 4' to 2' bridged substituents include, but are not limited to, 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2' ("LNA"), 4'-CH2-S-2', 4'-(CH2)2-O-2' ("ENA"), 4'-CH(CH3)-O-2' ("constrained ethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CH2OCH3)- O-2' ("constrained MOE" or "cMOE") and its analogs (e.g., U.S. Patent No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and its analogs (e.g., U.S. Patent No. 8,278,283), 4'-CH2-N(OCH3)-2' and its analogs (e.g., U.S. Patent No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., U.S. Patent Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2' (wherein R is H, C1-C 12alkyl or protecting group) (e.g., U.S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134) and 4'-CH2-C(=CH2)-2' and the like (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the above are hereby incorporated herein by reference. Other representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include, but are not limited to, the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399 ,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US2008 / 0039618; and US2009 / 0012281, US2013 / 0190383; and WO 2013 / 036868, the entire contents of each of which are hereby incorporated by reference herein. 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, for example, WO 99 / 14226). Unless otherwise indicated, bicyclic nucleosides designated herein are in the β-D configuration.

[0538] In certain embodiments, modified sugar is a sugar substitute. In certain embodiments, the sugar substitute has an oxygen atom, for example, substituted by a sulfur, carbon, or nitrogen atom. In certain embodiments of this type, the sugar substitute may also include a bridging and / or non-bridging substituent as described herein. In certain embodiments, the sugar substitute includes a ring with non-5 atoms. In certain embodiments of this type, the sugar substitute includes a cyclobutyl moiety replacing the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring replacing the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes tetrahydropyran ("THP") replacing the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes morpholine replacing the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, 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; 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 documents are hereby incorporated herein by reference.

[0539] In some embodiments, the sugar surrogate comprises an acyclic portion. In certain embodiments, the sugar surrogate is a non-locked nucleic acid ("UNA"). UNA is a non-locked acyclic nucleic acid in which any bond of the sugar has been removed to form a non-locked "sugar" residue. In one example, UNA also encompasses monomers in which the bond between C1'-C4' has been removed (i.e., a covalent carbon-oxygen-carbon bond between C1' and C4' carbons). In another example, the C2'-C3' bond of the sugar (i.e., a covalent carbon-carbon bond between C2' and C3' carbons) has been removed. Representative U.S. publications teaching the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos. 2013 / 0096289; 2013 / 0011922; and 2011 / 0313020, the entire contents of each of which are hereby incorporated herein by reference. In certain embodiments, sugar surrogates include peptide nucleic acids ("PNAs"), acyclic butyl nucleic acids (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., US 2013 / 130378, the entire contents of which are incorporated herein by reference. Many other bicyclic and tricyclic sugars and sugar surrogate ring systems are known in the art and can be used in modified nucleosides.

[0540] In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotides comprise one or more types of modified sugars and / or unmodified sugars arranged in a defined pattern or "sugar motif" along the oligonucleotide or a region thereof. In some cases, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0541] In certain embodiments, oligonucleotide comprises gap polymer (gapmer) sugar motif. Gap polymer oligonucleotide comprises or is composed of the region with two external " wing " district and center or inner " gap " district. Gap district and wing district form continuous nucleoside sequence, and wherein most of the nucleoside sugar of each wing is different from most of the nucleoside sugar of gap. In certain embodiments, wing district comprises most of modified sugar, and gap comprises most of unmodified sugar. In certain embodiments, the nucleoside of gap is deoxynucleoside. Compound with gap polymer sugar motif is described in, for example, U.S. Patent number 8,790,919, the content of this patent is incorporated herein by reference.

[0542] In certain embodiments, one or two oligonucleotides of the double-stranded compound include a triplet sugar motif. Oligonucleotides with a triplet sugar motif include three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is located at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotides of the double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds with a triplet sugar motif are disclosed in, for example, U.S. Patent No. 10,668,170, the contents of which are incorporated herein by reference.

[0543] In certain embodiments, one or two oligonucleotides of the double-stranded compound include a quadruplex sugar motif. Oligonucleotides with a quadruplex sugar motif include four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may contain more than one quadruplex sugar motif. In certain embodiments, the identical sugar modification of the quadruplex sugar motif is a 2'-F modification. For double-stranded compounds with a duplex region of 19-23 nucleotides in length, the cleavage sites of the antisense oligonucleotide are typically around positions 10, 11, and 12 of the 5' end. In certain embodiments, counting begins with the first nucleoside at the 5' end of the sense oligonucleotide, and the quadruplex sugar motif is located at position 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, or the counting begins with the first paired nucleotide in the duplex region of the 5' end of the sense oligonucleotide. In certain embodiments, counting begins with the first nucleoside at the 5' end of the antisense oligonucleotide, and the quadruplex sugar motif is located at position 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, or the counting begins with the first paired nucleotide in the duplex region of the 5' end of the antisense oligonucleotide. The cleavage site can be varied depending on the length of the duplex region of the double-stranded compound, and the position of the quadruplex can be altered accordingly.

[0544] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or two oligonucleotides of the double-stranded compound comprise an alternating sugar motif. The oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, wherein 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. For example, if A, B, and C each represent a type of modification to a nucleoside, the alternating motif can be "ABAB ABABABAB...", "AABBAABBAABB...", "AABAABAABAAB," "AAA BAAABAAAB...", "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 comprises two different sugar modifications. In certain embodiments, the alternan motif comprises 2'-OMe and 2'-F sugar modifications.

[0545] In certain embodiments, each nucleoside of oligonucleotide is modified independently with one or more sugar modifications provided by this paper. In certain embodiments, each oligonucleotide of double-stranded compound has one or more sugar motifs provided by this paper independently. In certain embodiments, the oligonucleotide comprising sugar motif is modified fully because each nucleoside except the nucleoside comprising sugar motif comprises sugar modification.

[0546] Nucleobase modifications and motifs

[0547] In certain embodiments, a modified oligonucleotide comprises one or more nucleosides comprising a modified nucleobase. In certain embodiments, a modified oligonucleotide comprises one or more nucleosides that do not comprise a nucleobase, termed abasic nucleosides.

[0548] In certain embodiments, the modified nucleobase is selected from the group consisting of a 5-substituted pyrimidine, a 6-azapyrimidine, an alkyl or alkynyl substituted pyrimidine, an alkyl substituted purine, and N-2, N-6, and O-6 substituted purines. In certain embodiments, the modified nucleobase is selected from the group consisting of: 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-azauracil, 6-azacytosine, 6-azathymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogen, 8-amino, 8-thiol, 8-sulfanyl, 8-hydroxy, 8-aza and Other 8-substituted purines, 5-halogens, specifically 5-bromo, 5-trifluoromethyl, 5-halouracil and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, hybrid bases, size-extended bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenthiazine-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0549] Other nucleobases include U.S. Pat. No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed., Wilé-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pp. 858-859; Kroschwitz, J. L. ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, dsRNA Research Hand Applications, pp. 289-302; Antisense Research and Applications, Crooke, S. T. and Lebleu, B. eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S. T. ed., CRC Those disclosed in Pharmacopoeia Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is incorporated herein by reference.

[0550] Publications teaching the preparation of some of the above-mentioned modified nucleobases, as well as 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; 5,432,272; 5,434,257; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,9 85; 5,681,941; 5,811,534; 5,750,692; 5,948,903; 5,587,470; 5,457,191; 5,763,588; 5,830,653; 5,808,027; 6,005,096; 6,015,886; 6,147,200; 6,1 66,197; 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.

[0551] In certain embodiments, the oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or its region. In certain embodiments, each nucleobase is modified. In certain embodiments, no nucleobase 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 the modified oligonucleotide are 5-methylcytosine.

[0552] In certain embodiments, the modified oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is located at the 3' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is located at the 5' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 5' end of the oligonucleotide.

[0553] Internucleoside linkage modifications and motifs

[0554] 3' to 5' phosphodiester linkages are naturally occurring internucleoside linkages of RNA and DNA. In certain embodiments, oligonucleotides have one or more modified (i.e., non-naturally occurring) internucleoside linkages. Certain non-naturally occurring internucleoside linkages can impart desired properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative modified phosphorus-containing 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 linking groups include, but are not limited to, methylenecarbaminyl (-CH2-N(CH3)-O-CH2), thiodiesters, thiocarbamates (-OC(=O)(NH)-S-); siloxanes (-O-SiH2-O-); and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriesters, methylphosphonates, MMI(3 '-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), methylal (3'-O-CH2-O-5'), methoxypropyl and thiomethylal (3'-S-CH2-O-5'). Other neutral internucleoside linkages include nonionic linkages, including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates and amides (see, for example: Carbohydrate Modifications in Antisense Research; YS Sanghvi and P.D. Cook, eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Additional neutral internucleoside linkages include nonionic linkages containing mixed N, O, S and CH2 components.

[0555] In certain embodiments, the oligonucleotide comprises at least one modified internucleoside bond. The modified internucleoside bond may be located at any position of the oligonucleotide. For double-stranded compounds, the modified internucleoside bond may be located within a sense oligonucleotide, an antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

[0556] In certain embodiments, the internucleoside linkage modification may occur on each nucleoside of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may occur in an alternating pattern along the oligonucleotide. In certain embodiments, substantially each internucleoside linking group is a phosphate internucleoside linkage (P=O). In certain embodiments, each internucleoside linking group of the modified oligonucleotide is a phosphorothioate (P=S). In certain embodiments, each internucleoside linking group of the modified oligonucleotide is independently selected from phosphorothioate and phosphate internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modification on each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modification on each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, 6-8 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' and 3' ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either or both of the 5' and 3' ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0557] In certain embodiments, the double-stranded compound includes an overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or alkylphosphonate internucleoside bond modification in the overhang region. In certain embodiments, the double-stranded compound includes a phosphorothioate or alkylphosphonate internucleoside bond connecting the overhang nucleotide to the paired nucleotide next to the overhang nucleotide. For example, at least two phosphorothioate internucleoside bonds may be present between the three terminal nucleosides, wherein two of the three nucleosides are overhang nucleosides, and the third nucleoside is a paired nucleoside next to the overhang nucleoside. These three terminal nucleosides may be located 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.

[0558] In certain embodiments, the modified oligonucleotide comprises one or more internucleoside bonds with a chiral center. Representative chiral internucleoside bonds include but are not limited to alkyl phosphonates and thiophosphates. The modified oligonucleotide comprising internucleoside bonds with a chiral center can be prepared as a modified oligonucleotide population comprising a stereo-random internucleoside bond, or as a modified oligonucleotide population comprising a thiophosphate bond comprising a stereochemical configuration. In certain embodiments, the modified oligonucleotide population comprises a thiophosphate internucleoside bond, wherein all thiophosphate internucleoside bonds are stereo-random. Such modified oligonucleotides can be generated using a synthetic method that results in the random selection of the stereochemical configuration of each thiophosphate bond. As is well known to those skilled in the art, each individual thiophosphate of each individual oligonucleotide molecule has a limited stereochemical configuration. In certain embodiments, the modified oligonucleotide population is rich in modified oligonucleotides comprising one or more specific thiophosphate internucleoside bonds, wherein the thiophosphate internucleoside bonds are specific, independently selected stereochemical configurations. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 65% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 70% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 80% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 90% of the molecules in the population. In certain embodiments, the specific configuration of a specific phosphorothioate bond is present in at least 99% of the molecules in the population. Such enriched modified oligonucleotide populations can be generated using synthetic methods known in the art, such as Oka et al., JACS 125, 8307 (2003); Wan et al., Nuc. Acid. Res. 42, 13456 (2014) and the methods described in WO 2017 / 015555. In certain embodiments, the modified oligonucleotide population is rich in modified oligonucleotides having at least one phosphorothioate represented by the (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched in modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0559] α 4 β 1 / 7 Integrin receptor ligands

[0560] In some embodiments, the compounds provided herein comprise α4β 1 / 7 Integrin receptor ligands. In some embodiments, α4β 1 / 7 Integrin receptor ligands can be used to direct therapeutic, prophylactic, or diagnostic agents. In certain embodiments, the therapeutic agent is an oligonucleotide (e.g., a therapeutic oligonucleotide). In some embodiments, α4β1 / 7 Integrin receptor ligands direct the oligonucleotide to a location. In some embodiments, α4β 1 / 7 Integrin receptor ligands target tissue. In some embodiments, the tissue is brain tissue. In some embodiments, α4β 1 / 7 Integrin receptor ligands target cell receptors. In some embodiments, the cell receptor is α4β 1 / 7 Integrin receptors. In some embodiments, α4β 1 / 7 Integrin receptors are in the brain. In some embodiments, α4β 1 / 7 Integrin receptors are in the frontal cortex. In some embodiments, α4β 1 / 7 Integrin receptors are in the striatum. In some embodiments, α4β 1 / 7 Integrin receptors are in the cerebellum. In some embodiments, α4β 1 / 7 Integrin receptors are in the brainstem. In some embodiments, α4β 1 / 7 Integrin receptors are in the hippocampus. In some embodiments, α4β 1 / 7 Integrin receptors are in the spinal cord.

[0561] The present disclosure contemplates any α4β 1 / 7 Use of integrin receptor ligands in the compounds provided herein. 1 / 7 Integrin receptor ligands are known in the art, and one of ordinary skill in the art will be able to identify additional α4β-integrins for use in the compounds described herein in addition to those explicitly provided in this disclosure. 1 / 7 Integrin receptor ligands. The present disclosure also contemplates any α4β 1 / 7 Derivatives and prodrugs of integrin receptor ligands are useful in the compounds described herein, and one of ordinary skill in the art will know how to prepare such derivatives and prodrugs.

[0562] In some embodiments, α4β 1 / 7 The integrin receptor ligand is α4β 1 / 7 Integrin receptor agonists. In some embodiments, α4β 1 / 7 The integrin receptor ligand is α4β 1 / 7 Integrin receptor antagonists. In some embodiments, α4β 1 / 7 The integrin receptor ligand is any of those disclosed in International Patent Application Publication No. WO 2019 / 246455, which is incorporated herein by reference. In some embodiments, α4β 1 / 7The integrin receptor ligand is any of those disclosed in Baiula, M. et al., Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives. Front. Chem. 2019, 7, 489, which is incorporated herein by reference. 1 / 7 Integrin receptor ligands include but are not limited to any of the following α4β 1 / 7 Integrin receptor ligands and their derivatives:

[0563]

[0564]

[0565]

[0566]

[0567]

[0568] where each instance of R is

[0569] In certain embodiments, α4β 1 / 7 Integrin receptor ligands are or its derivatives.

[0570] In some embodiments, α4β 1 / 7 Integrin receptor ligand is anti-α4β 1 / 7 Integrin receptor antibodies. In certain embodiments, α4β 1 / 7 Integrin receptor ligand is anti-α4β 1 / 7 Integrin receptor antibody fragment or anti-α4β 1 / 7 Integrin receptor antibody variants. "Anti-α4β 1 / 7 Integrin receptor antibodies are antibodies that recognize and bind to α4β 1 / 7 Integrin receptors or immune system proteins that otherwise interact with them.

[0571] In certain embodiments, α4β 1 / 7 Integrin receptor ligands are conjugated (e.g., linked, connected, attached, 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, a peptide, an antibody, an oligonucleotide, a small molecule, a macromolecule, or a combination thereof.

[0572] In some embodiments, more than one α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, at least two α4β 1 / 7 Integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more α4β 1 / 7 Integrin receptor ligand) is conjugated to the agent moiety. In some embodiments, two α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, three α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, four α4β 1 / 7 Integrin receptor ligands are conjugated to the pharmaceutical moiety. In some embodiments, five α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, more than five α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, at least one to about five α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, at least one to about four α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, at least one to about three α4β 1 / 7 Integrin receptor ligands are conjugated to the agent moiety. In some embodiments, at least one to about two α4β 1 / 7 The integrin receptor ligand is conjugated to the pharmaceutical moiety.

[0573] When the drug moiety is conjugated to multiple α4β 1 / 7 When integrin receptor ligands are present, all α4β 1 / 7 Integrin receptor ligands can be conjugated to the same position or nearby on the agent moiety, or to α4β 1 / 7 Integrin receptor ligands can be conjugated to a variety of different positions on the pharmaceutical moiety.

[0574] In some embodiments, the oligonucleotide is conjugated (e.g., linked, attached, associated) to the α4β4 oligonucleotide via the 5′ and / or 3′ end of the oligonucleotide or at an internal position of the oligonucleotide (e.g., at a nucleotide other than the 5′ or 3′ nucleotide on the oligonucleotide). 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to the α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to the α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to the α4β 1 / 7Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to an α4β-integrin at an internal position within the oligonucleotide (e.g., in an "internally modified oligonucleotide"). 1 / 7 Integrin receptor ligand.

[0575] In some embodiments, the oligonucleotide is conjugated to more than one α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to at least two α4β 1 / 7 Integrin receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more α4β 1 / 7 Integrin receptor ligands). In some embodiments, the oligonucleotide is conjugated to two α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to three α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to four α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to five α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to more than five α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about five α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about four α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about three α4β 1 / 7 Integrin receptor ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about two α4β 1 / 7 Integrin receptor ligand.

[0576] When oligonucleotides are conjugated to multiple α4β 1 / 7 When integrin receptor ligands are present, all α4β 1 / 7 Integrin receptor ligands can be conjugated to the same position or nearby on the oligonucleotide, or to α4β 1 / 7 Integrin receptor ligands can be conjugated to multiple different positions on the oligonucleotide. In some embodiments, multiple α4β 1 / 7 Integrin receptor ligands (i.e., two, three, four, five or more α4β 1 / 7 Integrin receptor ligands) are conjugated to the 5' end of the oligonucleotide. In some embodiments, multiple α4β 1 / 7 Integrin receptor ligands (i.e., two, three, four, five or more α4β 1 / 7 Integrin receptor ligand) is conjugated to the 3' end of the oligonucleotide. In some embodiments, multiple α4β 1 / 7Integrin receptor ligands (i.e., two, three, four, five or more α4β 1 / 7 Integrin receptor ligands) are conjugated to one or more internal positions of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to one or more α4β 1 / 7 Integrin receptor ligands and / or one or more α4β at the 3′ end of the oligonucleotide 1 / 7 One or more α4β integrin receptor ligands and / or one or more internal positions of the oligonucleotide 1 / 7 Integrin receptor ligand.

[0577] connector

[0578] In certain embodiments, conjugates of the compounds of the formula described herein are provided. In certain embodiments, the conjugate comprises an α4β-antigen covalently coupled to a pharmaceutical moiety. 1 / 7 Integrin receptor ligands. In certain embodiments, the conjugates provided herein comprise one or more linker moieties. In certain embodiments, one or more linker moieties bind α4β 1 / 7 Integrin receptor ligands are 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, α4β 1 / 7 Integrin receptor ligands are conjugated to oligonucleotides. In certain embodiments, the compound comprises one or more α4β 1 / 7 Integrin receptor ligand, one or more linker moieties and one or more drug moieties, wherein α4β 1 / 7 The integrin receptor ligand is conjugated (eg, linked, connected, attached, associated) to one or more agent moieties via one or more linker moieties.

[0579] Conjugates as disclosed herein can be prepared using any available method. 1 / 7 When an integrin receptor ligand is associated with an oligonucleotide, the moiety can be linked directly or indirectly (e.g., via a linker moiety; i.e., a linker covalently bound to the oligonucleotide and the α4β 1 / 7 Each of the integrin receptor ligands; in some formulas herein, "-L n -", 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 / 7Integrin receptor ligands can be directly associated with each other, for example, through one or more covalent bonds, or can be associated through one or more linkers. "Linker" refers to a compound provided herein that is used to connect two components (e.g., α4β 1 / 7 In some embodiments, one component of the compounds provided herein (e.g., an α4β4 oligonucleotide) can be conjugated to any chemical moiety (e.g., a combination of atoms with appropriate valence according to known chemical principles). Each of the two components can be linked to any portion of any linker provided herein. In some embodiments, one component of the compounds provided herein (e.g., an α4β4 oligonucleotide) can be conjugated to any chemical moiety (e.g., a combination of atoms with appropriate valence according to known chemical principles). 1 / 7 Integrin receptor ligand or oligonucleotide) is connected to one end of the linker by a bond, and the other component is connected to the other end of the linker by a bond. In some embodiments, one or both components of the compounds provided herein can be connected to an internal position in any linker described herein by a bond. For example, in the context of an "alkyl linker", α4β 1 / 7 Integrin receptor ligands can be connected to the carbon at one end of an alkyl linker by a bond, and oligonucleotides can be connected to the carbon at the other end of an alkyl linker by a bond. In some embodiments, the linker is a bond (including, for example, a phosphodiester bond and a phosphorothioate bond). In some embodiments, the linker is an optionally substituted alkyl linker (i.e., an alkyl chain is used to connect two parts, which can each be conjugated to the opposite end of an alkyl linker, or one or two parts can be conjugated to the internal carbon on the alkyl linker). In some embodiments, the linker is an optionally substituted polyethylene glycol (PEG) linker (i.e., a PEG chain is used to connect two parts, which can each be conjugated to the opposite end of a PEG linker, or one or two parts can be conjugated to the internal position on a PEG linker). In some embodiments, the linker is an optionally substituted heteroalkyl linker (i.e., a heteroalkyl chain is used to connect two parts, which can each be conjugated to the opposite end of a heteroalkyl linker, or one or two parts can be conjugated to the internal position on a heteroalkyl linker). In some embodiments, the linker is an optionally substituted heteroaryl linker (i.e., a heteroaryl group is used to connect two parts, which can each be conjugated to any position on a heteroaryl group).

[0580] 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, each of L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A Each of the comprises a linking group. In certain embodiments, the linking group is covalently bound to α4β 1 / 7Integrin receptor ligands. In certain embodiments, the linking group is covalently bound to an oligonucleotide. In certain embodiments, the linking group is covalently bound 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 attachment to a solid support. In certain embodiments, the linking group comprises a 1 / 7 Multiple locations of integrin receptor ligands.

[0581] In certain embodiments, the linking group comprises a chain structure, such as a hydrocarbon chain, or an oligomer of a repeating unit or a combination 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 long, 1 to 40 atoms long, 1 to 25 atoms long, 1 to 20 atoms long, 1 to 15 atoms long, 1 to 10 atoms long, or 1 to 5 atoms long.

[0582] In certain embodiments, the linking group contains carbon atoms. In certain embodiments, the linking group contains heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.). In certain embodiments, the linking group forms amide bonds, ester bonds or disulfide bonds. In certain embodiments, the linking group forms hydrazone bonds, oxime bonds, imine bonds, guanidine bonds, urea bonds, carbamate bonds, unsaturated alkyl bonds, sulfonamide bonds or 4-8 membered heterocycle bonds. In certain embodiments, the linking group comprises one or more groups selected from alkyl, amino, oxo, amides, disulfide, polyethylene glycol, ether, thioether and hydroxyamino groups. 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 includes at least one neutral linking group. In certain embodiments, the linking group is substituted with various substituents including, but not limited to, hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, amino groups, alkylamino groups, dialkylamino groups, trialkylamino groups, hydroxyl groups, alkoxy groups, halogen groups, aryl groups, heterocycles, aromatic heterocycles, cyano groups, amides, carbamoyl groups, carboxylic acids, esters, thioethers, alkylthioethers, thiols, and ureido groups. As will be appreciated by those skilled in the art, each of these groups may in turn be substituted.

[0583] In certain embodiments, the linking group includes but is not limited to substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl or substituted or unsubstituted C2-C10 alkynyl, wherein the non-limiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxyl, 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.

[0584] In certain embodiments, the linking group is a short peptide chain.In 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.

[0585] In certain embodiments, the linking group comprises a joint-nucleoside. In certain embodiments, the linking group comprises 1 to 40 joint-nucleosides, 1 to 25 joint-nucleosides, 1 to 20 joint-nucleosides, 1 to 15 joint-nucleosides, 1 to 10 joint-nucleosides or 1 to 5 joint-nucleosides. In certain embodiments, such joint-nucleosides can be modified or unmodified nucleosides. It is generally expected that the joint-nucleoside will be cracked out from the compound after reaching the target tissue. Therefore, the joint-nucleoside herein can be connected to each other and connected to the rest of the compound by a cleavable bond. In this article, the joint-nucleoside is not considered to be a part of the oligonucleotide payload. Therefore, the compound comprises an oligonucleotide consisting of a specified number or range of connected nucleosides and / or having a specified complementary percentage with a reference nucleic acid and the compound also comprises an α4β-linked nucleoside containing a linking group comprising a joint-nucleoside. 1 / 7 In embodiments of the integrin receptor ligand, those linker-nucleosides are not counted in the length count of the oligonucleotide and are not used to determine the percent complementarity of the oligonucleotide to a reference nucleic acid.

[0586] In certain embodiments, the linking group includes a protein binding group. In certain embodiments, the protein binding group is a lipid, such as including but not limited to cholesterol, cholic acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O (hexadecyl) glycerol, geranyloxyhexyl group, hexadecyl glycerol, borneol, menthol, 1,3-propylene glycol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) cholenic acid, dimethoxytrityl or phenoxazine), vitamins (e.g., folic acid, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosomal dissolution components, steroids (e.g., agave sapogenin, diosgenin), terpenes (e.g., triterpenes, such as smilagenin, terpenoid, epi-suberin-derived lithocholic acid) or cationic lipids. In certain embodiments, the protein binding group is a C16 to C22 long chain saturated or unsaturated fatty acid, cholesterol, bile acid, vitamin E, adamantane, or 1-pentafluoropropyl.

[0587] In certain embodiments, the linking group includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA).

[0588] In certain embodiments, the linking groups include, but are not limited to, those described in the following references: US5,994,517; US6,300,319; US6,660,720; US6,906,182; US7,262,177; US7,491,805; US8,106,022; US7,723,509; US9,127,276; US2006 / 0148740; US2011 / 0123520; WO 2013 / 033230; WO 2012 / 037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Te trahedron, 1997, 53, 759-770; Lee, Carbohydr. Res. 1978, 67, 509-514; Connolly et al., J. Biol. Chem. 1982, 257, 939-945; Pavia et al., Int. J. Pep. Protein Res. 1983, 22, 539-548; Lee et al., Biochem. 1984, 23, 4255-4261; Lee et al., Glycoconjugate J. 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett. 1990, 31, 2673-2676; Biessen et al., J. Med. Chem. 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett. 1997, 38, 3487-3490; Lee et al., Bioconjug. Chem. 1997, 8, 762-765; Kato et al., Glycobiol. 2001, 11, 821-829; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Lee et al., Methods Enzymol.2003, 362, 38-43; Westerlind et al., Glycoconj. J. 2004, 21, 227-241; Lee et al., Bioorg. Med. Chem. Lett. 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg. Med. Chem. 2007, 15, 7661-7676; Khorev et al., Bioorg. Med. Chem. 2008, 16, 5216-5231; Lee et al., Bioorg. Med. Chem. 2011, 19, 2494-2500; Kornilova et al., Analyt. Biochem. 2012, 425, 43-46; Pujol et al., Angew. Chemie Int. Ed. Engl. 2012, 51, 7445-7448; Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Rensen et al., Arterioscler. Thromh. Vase. Biol. 2006, 26, 169-175; van Rossenberg et al., Gene Ther. 2004, 11, 457-464; Sato et al., J. Am. Chem. Soc. 2004, 126, 14013-14022; Lee et al., J. Org. Chem. 2012, 77, 7564-7571; Biessen et al., FASEB J. 2000, 14, 1784-1792; Rajur et al., Bioconjug. Chem. 1997, 8, 935-940; Duff et al., Methods Enzymol. 2000, 313, 297-321; Maier et al., Bioconju g. Chem. 2003, 14, 18-29; Jayaprakash et al., Org. Lett. 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev. 2002, 12, 103-128; Merwin et al., Bioconjug. Chem. 1994, 5, 612-620; Tomiya et al., Bioorg. Med. Chem., 2013, 21, 5275 - 5281; International Applications WO 1998 / 013381; WO 2011 / 038356; WO 1997 / 046098; WO 2008 / 098788; WO 2004 / 101619; WO 2012 / 037254; WO 2011 / 120053; WO 2011 / 100131; WO 2011 / 163121; WO 2012 / 177947; WO 2013 / 033230; WO 2013 / 075035; WO 2012 / 083185; WO 2012 / 083046; WO 2009 / 082607; WO 2009 / 134487; WO 2010 / 144740; WO 2010 / 148013; WO 1997 / 020563; WO 2010 / 088537; WO 2002 / 043771; WO 2010 / 129709; WO 2012 / 068187; WO 2009 / 126933; WO 2004 / 024757; WO 2010 / 054406; WO 2012 / 089352; WO 2012 / 089602; WO 2013 / 166121; WO 2013 / 165816; U.S. Patent Nos. 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; U.S. Patent Application Publication Nos. U.S. 2011 / 0097264; U.S. 2011 / 0097265; U.S. 2013 / 0004427; U.S. 2003 / 0119724; U.S. 2011 / 0207799; U.S. 2012 / 0035115; U.S. 2012 / 0230938; U.S. 2005 / 0164235; U.S. 2006 / 0183886; U.S. 2012 / 0136042; U.S. 2012 / 0095075; U.S. 2013 / 0109817; U.S. 2006 / 0148740; U.S.2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132; each of which is incorporated herein by reference.

[0589] 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 contain structures selected from the following:

[0590]

[0591]

[0592] wherein each n is independently 1 to 20; and p is 1 to 6.

[0593] 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 contain structures selected from the following:

[0594]

[0595] wherein each n is independently 1 to 20.

[0596] 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 contain structures selected from the following:

[0597]

[0598] wherein each n is independently 1 to 20.

[0599] 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 contain structures selected from the following:

[0600]

[0601] wherein each n is independently 1 to 20.

[0602] 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 contain structures selected from the following:

[0603]

[0604]

[0605] wherein each L is independently a phosphorus linking group; and each n is independently 1 to 20.

[0606] 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 contain structures selected from the following:

[0607]

[0608]

[0609]

[0610] 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 contain structures selected from the following:

[0611]

[0612] 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 contain structures selected from the following:

[0613]

[0614] In certain embodiments, L1, L2, L3, and L4 independently or together comprise a structure selected from the group consisting of:

[0615] Wherein n is 1 to 20.

[0616] 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 contain structures selected from the following:

[0617]

[0618] 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 contain structures selected from the following:

[0619]

[0620] 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 contain structures selected from the following:

[0621]

[0622] 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 contain the following structures:

[0623]

[0624] 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 contain the following structures:

[0625]

[0626] 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 contain structures selected from the following:

[0627]

[0628] 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 contain structures selected from the following:

[0629] wherein each n is independently 0, 1, 2, 3, 4, 5, 6 or 7.

[0630] 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, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A ) can be independently a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). In some embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A ) may independently be absent.

[0631] In some embodiments, L1 is a bond.

[0632] In some embodiments, L2 is an optionally substituted PEG linker. In some embodiments, the PEG linker is two, three, four, five, six, seven, eight, nine, or ten PEG units in length. In certain embodiments, L2 comprises the structure

[0633] 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 comprises the structure

[0634] In some embodiments, L4 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In some embodiments, the heteroalkyl linker comprises two substituents linked together to form an optionally substituted carbocyclyl ring. In certain embodiments, L4 comprises the structure wherein X is O or S. In certain embodiments, L4 comprises the structure Wherein X is O or S.

[0635] In some embodiments, L1, L2, L3 and L4 and / or L 1A 、L 2A 、L 3A and L 4A Together they form a structure

[0636]

[0637]

[0638]

[0639] Wherein X is O or S.

[0640] Methods for preparing compounds

[0641] In some aspects, the present disclosure relates to the preparation of a molecule comprising an α4β 1 / 7 Integrin receptor ligand compounds and methods of compositions.

[0642] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. If necessary, methods for optimizing reaction conditions and minimizing competing by-products are known in the art. Reaction optimization and scale-up can advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g., Design and Optimization in Organic Synthesis, 2nd edition, Carlson R ed., 2005; Elsevier Science Ltd.; K et al., Angew. Chem. Int. Ed. Engl. 2004 43:406; and references therein). Additional reaction schemes and protocols can be obtained by one skilled in the art using commercially available structure-searchable database software, for example, (CAS division of the American Chemical Society) and (Elsevier), or by using an Internet search engine such as or keyword databases such as the U.S. Patent and Trademark Office text database.

[0643] As will be appreciated by those skilled in the art, methods for synthesizing compounds of the formula herein will be readily apparent to those of ordinary skill in the art and are included in the schemes and examples herein. Additionally, the various synthesis steps may be performed in alternate sequences or orders to yield the desired compounds. Furthermore, the solvents, temperatures, reaction durations, etc. described herein are for illustrative purposes only, and those of ordinary skill in the art will recognize that variations in reaction conditions may yield desired compounds of the present disclosure.

[0644] The compounds herein may also contain bonds (e.g., carbon-carbon bonds) where bond rotation is restricted around that particular bond, such as restrictions caused by the presence of a ring or double bond. Thus, 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; in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form can be 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 expressly included in the present disclosure. Also included are extracts and fractions containing the compounds of the present disclosure. The term "isomer" is intended to include diastereomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. For compounds containing one or more stereocenters, such as chiral compounds, the methods of the present disclosure can be performed with enantiomerically enriched compounds, racemates, or diastereomeric mixtures. All isomers of the compounds described herein are expressly included in the present disclosure.

[0645] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more. More preferably, the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, 99% or more. In preferred embodiments, only one enantiomer or diastereomer of a chiral compound of the present disclosure is administered to a cell or subject.

[0646] Treatment

[0647] In one aspect, provided are methods of treating a subject suffering from or susceptible to a condition or disease, the methods comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

[0648] In other aspects, methods are provided for treating a subject suffering from or susceptible to a condition or disease, wherein the subject has been identified as requiring modulation of protein function, the method comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition described herein, thereby treating the condition in the subject.

[0649] In one aspect, a method of delivering a therapeutic oligonucleotide to a subject's brain is provided, the method comprising contacting the subject with a compound or pharmaceutical composition as 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 cortex, and spinal cord.

[0650] In certain embodiments, methods of 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.

[0651] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep disorders, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and drug addiction.

[0652] In certain embodiments, the CNS disorder is neurotoxic and / or neurotrauma, e.g., as a result of 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 neuroprotection, e.g., against acute neuronal injury or chronic neurodegenerative disorders.

[0653] In certain embodiments, the CNS disorder is stroke (eg, ischemic stroke).

[0654] In certain embodiments, the CNS disorder is multiple sclerosis.

[0655] In certain embodiments, the CNS disorder is spinal cord injury.

[0656] In certain embodiments, the CNS disorder is epilepsy.

[0657] In certain embodiments, the CNS disorder is a psychiatric disorder, such as depression, anxiety or an anxiety-related disorder, a learning disorder, a somatic system disorder, schizophrenia, or schizoaffective disorder.

[0658] In certain embodiments, CNS disorders are depression. "Depression" includes but is not limited to depressive disorders or conditions, such as major depressive disorder (e.g., unipolar depression), refractory depression, dysthymic disorder (e.g., chronic, mild depression), bipolar disorder (e.g., manic depression), seasonal affective disorder and / or the depression associated with substance abuse or substance abuse disorder (e.g., withdrawal). Depression can be clinical or subclinical depression. Depression can be associated with premenstrual syndrome and / or premenstrual dysphoric disorder.

[0659] In certain embodiments, CNS disorders are anxiety." anxiety " includes but is not limited to anxiety and the illness related to anxiety, 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, the adaptive disorder with anxiety features, the anxiety disorder related to depression, the anxiety disorder caused by general medical conditions and the anxiety disorder induced by substances, the anxiety related to substance abuse or substance use disorder (for example, withdrawal, dependence, recovery) and the anxiety related to nausea and / or vomiting.The treatment can also induce or promote the sleep of subject (for example, subject suffering from anxiety).

[0660] In certain embodiments, the CNS disorder is a learning disorder (eg, attention deficit disorder (ADD)).

[0661] In certain embodiments, the CNS disorder is schizophrenia or schizoaffective disorder.

[0662] In certain embodiments, the CNS disorder is a sleep disorder. "Sleep disorders" include, but are not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), obstructive sleep apnea, rapid eye movement sleep behavior disorder (RBD), shift work sleep disorder (SWSD), and sleep problems (e.g., parasomnias) such as nightmares, night terrors, sleep talking, head banging, snoring, and trismus and / or teeth grinding (bruxism).

[0663] In certain embodiments, the CNS disorder is a movement disorder, e.g., a basal ganglia disorder, such as Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Tourette syndrome, tardive dyskinesia, and dystonia.

[0664] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0665] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0666] In certain embodiments, the CNS disorder is nausea and / or vomiting.

[0667] In certain embodiments, the CNS disorder is drug addiction (eg, addiction to opioids, nicotine, cocaine, psychostimulants, or alcohol).

[0668] 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 (parts of which are located in both the central nervous system and the peripheral nervous system). Neurodegenerative disease refers to a class of neurological diseases marked by loss of nerve cells, including but not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), and Huntington's disease. Examples of neurological diseases include but are not limited to headaches, stupor and coma, dementia, epileptic seizures, sleep disorders, trauma, infection, vegetation, neuro-ophthalmologic diseases, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscles, and neuromuscular junctions. Substance abuse or substance use disorder (SUD) and mental illness, including but not limited to bipolar disorder, schizophrenia, and schizoaffective disorder, are also included in the definition of neurological disease. Other examples of neurological disorders include acquired epileptic aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiparesis; Alzheimer's disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; meningitis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia-telangiectasia; attention deficit hyperactivity disorder; autism; dysautonomia; back pain; Batten disease; Behçet disease; Bell's palsy; benign primary Blepharospasm; benign lesions; amyotrophy; benign intracranial hypertension; Binswanger disease; blepharospasm; Bloch-Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumors; Brown-Séquard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; head conditions; cerebral aneurysm; cerebral arteriosclerosis; brain atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CID) P); chronic pain; chronic regional pain syndrome; Coffin-Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder; Cushing's syndrome; cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; familial dysautonomia; dysgraphia; dyslexia; dystonia; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephalocele; cerebral trigeminal angiomatosis; epilepsy; Erb palsy; essential tremor; Fabry disease; Fahr syndrome; syncope; familial spastic paraplegia; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher disease; Gerstmann syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; hereditary movement disorder, polyneuritis; herpes zoster oticus; herpes zoster; Hirayama syndrome syndrome); HIV-associated dementia and neuropathy (see also Neurological Manifestations of AIDS); holoprosencephaly; Huntington disease and other polyglutamine repeat disorders; hydrocephalus; hydrocortisonephritis; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; in children; phytanic acid storage disease; Refsum's disease in children; infantile spasms; inflammatory myopathy; intracranial cysts; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome syndrome; Klippel-Feil syndrome; Krabbe disease; Kugelberg-Weiland disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Klevner syndrome; dorsolateral medullary (Wallenberg) syndrome; learning disabilities; Leigh disease; Lennox-Gastaut syndrome; Lesch-Nyhan 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 disc disease; Lyme disease - neurologic sequelae; Machado-Joseph disease; megalencephaly; megalencephaly; Meikson-Rosenthal syndrome; Meniere's disease; meningitis; Menkes disease; metachromatic leukodystrophy microcephaly; migraine; Miller-Fisher syndrome; mini-stroke; mitochondrial myopathy; Möbius syndrome; monomelic muscular dystrophy; motor neuron disease; moyamoya disease; mucopolysaccharidosis; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with orthostatic hypotension; muscular dystrophy; myasthenia gravis; diffuse myelinolytic sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia congenita; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurologic manifestations of AIDS; neurologic sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migratory disorder; Niemann-Pick disease;O'Sullivan-McLeod syndrome; occipital neuralgia; cryptic neural tube dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus-myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesias; Parkinson's disease; paramyotonia congenita; paraneoplastic disorders; paroxysmal seizures; Parkinson-Rötten syndrome; Pelvic-Merzheimer disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorder; photosensitivity sneeze reflex; phytanic acid storage disease; Pick's disease; nerve compression; pituitary tumor; polymyositis; cerebral puncture malformation; post-polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; orthostatic hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion disease; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing gray matter dystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive movement disorder; repetitive stress injury; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome syndrome; Reye's syndrome; St. Vitus' chorea; Sandhoff's disease; Scheldt's disease; schizencephaly; septooptic dysplasia; shaken baby syndrome; herpes zoster (shingles); Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Sotos syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumor; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; Sydenham's chorea; syncope; syringomyelia; tardive dyskinesia; Tay- Saunders disease; temporal arteritis; tethered cord syndrome; Thomson disease; thoracic outlet syndrome; cramps; Todd's palsy; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis complex; vascular dementia (multi-infarct dementia); vasculitis, including temporal arteritis; Von Hippel-Lindau disease (VHL); Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; whiplash; Williams syndrome; Wilson disease; and Zellweger syndrome.

[0669] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0670] In another embodiment, provided is a method as described above, wherein the effective amount of a compound provided herein is as described above.

[0671] In another embodiment, a method as described above 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.

[0672] In other embodiments, methods as described above are provided, wherein a compound of any of the formulae provided herein is administered alone or in combination with one or more additional therapeutic agents. In another embodiment, the additional therapeutic agent is a central nervous system (CNS) disease agent.

[0673] Another object of the present disclosure is the use of a compound as described herein for the preparation of a medicament for the treatment of a disorder or disease.Another object of the present disclosure is the use of a compound as described herein for the treatment of a disorder or disease.

[0674] Pharmaceutical composition

[0675] In one aspect, provided is a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

[0676] Compound or composition as described herein can be applied in combination with one or more other therapeutic agents (for example, treatment and / or prevention active agent).The compound or composition can be applied in combination with other therapeutic agents, and the other therapeutic agents improve their activity (for example, in the treatment of the disease of the subject in need thereof, in the prevention of the disease of the subject in need thereof and / or in the reduction of the risk of the subject in need thereof developing a disease (for example, effect and / or efficacy)), improve bioavailability, improve safety, reduce drug resistance, reduce and / or change metabolism, suppress excretion and / or change the distribution in the subject or cell. It should also be understood that the therapy adopted can achieve the desired effect for the same disease, and / or it can achieve different effects. In certain embodiments, the pharmaceutical composition described herein comprising compound as described herein and other therapeutic agent shows a synergistic effect, which is not present in the pharmaceutical composition comprising one of compound as described herein or other therapeutic agent but not both.

[0677] The compound or composition can be used simultaneously with one or more other therapeutic agents, before or after it, and these therapeutic agents can be used as, for example, combination therapy.Therapeutic agent includes therapeutically active agents.Therapeutic agent also includes preventive active agents.Therapeutic agent comprises organic small molecules, such as pharmaceutical compounds (for example, compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Federal Regulations (CFR), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules connected to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. In certain embodiments, other therapeutic agents are therapeutic agents that can be used for treating and / or preventing diseases (for example, CNS disorders). Each other therapeutic agent can be used under the dosage and / or timetable determined for the therapeutic agent. Other therapeutic agents can also be used together with each other and / or with compound or composition as herein described with single dose or separately with different doses. The specific combination employed in a regimen will take into account the compatibility of the compounds described herein with the additional therapeutic agent and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is contemplated that the additional therapeutic agents of the combination will be used at levels no greater than those used individually. In some embodiments, the levels used in combination will be lower than those used individually.

[0678] In one aspect, kits are provided comprising an effective amount of a compound provided herein in unit dosage form and instructions for administering the compound to a subject suffering from or susceptible to a disease or condition.

[0679] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is meant to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents present on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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 the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (either neat or in a suitable inert solvent). The example of pharmaceutically acceptable acid addition salt includes those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (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, which allow the compound to be converted into base or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are applicable to the present disclosure.

[0680] 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 for the purposes of this disclosure, the salts are otherwise equivalent to the parent form of the compound.

[0681] In addition to salt forms, the present disclosure provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present disclosure. Additionally, prodrugs can be converted to compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted to a compound of the present disclosure.

[0682] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the purposes contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0683] The present disclosure also provides a pharmaceutical composition comprising an effective amount of a compound as described herein and a pharmaceutically acceptable excipient. In one embodiment, a compound of any formula provided herein is administered to a subject using a pharmaceutically acceptable formulation, for example, a pharmaceutically acceptable formulation that provides sustained delivery of the compound to the subject for at least 12 hours, 24 hours, 36 hours, 48 ​​hours, one week, two weeks, three weeks, or four weeks after administration of the pharmaceutically acceptable formulation to the subject.

[0684] Actual dosage levels and time courses 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 acceptably tolerated by the subject.

[0685] In use, at least one compound according to the present disclosure is administered to a subject in need thereof in a pharmaceutical carrier in a pharmaceutically effective amount by intravenous, intrathecal, intramuscular, subcutaneous or intracerebroventricular injection or by oral administration or topical administration. According to the present disclosure, the compounds of the present disclosure can be administered alone or in combination with a second different therapeutic agent. The so-called "combination" means together, substantially simultaneously or sequentially. In one embodiment, the compounds of the present disclosure are administered acutely. Therefore, the compounds of the present disclosure can be administered within a short course of treatment, such as from about 1 day to about 1 week. In another embodiment, the compounds of the present disclosure can be administered over a longer period of time to improve chronic conditions, such as from about one week to several months, depending on the condition to be treated.

[0686] As used herein, the so-called "pharmaceutically effective amount" means that within the scope of reasonable medical judgment, the amount of the compound of the present disclosure is high enough to significantly and actively change the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio). The pharmaceutically effective amount of the compound of the present disclosure will vary with the specific goals to be achieved, the age and physical condition of the patient to be treated, the severity of the underlying disease, the duration of treatment, the nature of the concurrent therapy, and the specific compound used. For example, the therapeutically effective amount of the compound of the present disclosure administered to a child or a newborn will be proportionally reduced according to reasonable medical judgment. Therefore, the effective amount of the compound of the present disclosure will be the minimum amount that will provide the desired effect.

[0687] A definite practical advantage of the present disclosure is that the compounds can be administered in a convenient manner, such as by intrathecal, intravenous, intramuscular, subcutaneous, oral or intraventricular injection routes or by topical application, such as in a cream or gel. Depending on the route of administration, it may be necessary to coat the active ingredient comprising the compounds of the present disclosure in a material to protect the compounds from enzymes, acids, and other natural conditions that may inactivate the compounds. In order to administer the compounds of the present disclosure by non-parenteral administration, the compounds may be coated with or administered with a material that prevents inactivation.

[0688] 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.

[0689] Some examples of substances that can be used as pharmaceutical excipients or pharmaceutical carriers (the 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 butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffered saline; skim milk powder; and other nontoxic, compatible substances used in pharmaceutical formulations, such as vitamin C, estrogen, and echinacea. Wetting agents and lubricants such as sodium lauryl sulfate may also be present, as well as colorants, flavorings, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives. Solubilizing agents including, for example, cremaphore and beta-cyclodextrin may also be used in the pharmaceutical compositions herein.

[0690] The pharmaceutical composition comprising the active compound of the present disclosure (or its derivative or prodrug) can be prepared by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing methods. Compositions can be prepared in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants, which contribute to the processing of active compounds into pharmaceutically usable preparations. Compositions herein can be prepared (for example, for pharmaceutical, agricultural or veterinary use) by combining a compound as described herein with one or more suitable carriers, diluents, excipients or adjuvants (including those described herein) (for example, contacting, mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing).

[0691] The pharmaceutical compositions of the present disclosure can take a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ocular, oral, buccal, systemic, nasal, parenteral, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.

[0692] Systemic formulations include those designed for administration by injection (eg, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0693] Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compound in aqueous or oily vehicles. The composition also contains a preparaton, such as a suspending agent, a stabilizer and / or a dispersant. The formulation for injection can be in unit dosage form (e.g., in an ampoule or in a multidose container) and may contain an added preservative.

[0694] Alternatively, the injectable formulation may be provided in powder form for reconstitution 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 may be dried by any technique known in the art, such as lyophilization, and reconstituted before use.

[0695] In order to prolong delivery, the active compound or prodrug can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, such as a sparingly soluble salt.

[0696] Alternatively, other drug delivery systems can be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compounds, oligonucleotides or prodrugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), can also be used.

[0697] If desired, the pharmaceutical composition may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound. 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.

[0698] The active compounds or prodrugs of the present invention or their compositions will generally be used in an amount that is effective to achieve the desired result, for example, in an amount that is effective to treat or prevent the specific disease being treated. The compounds and oligonucleotides can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a preventive benefit. The so-called therapeutic benefit means eradication or improvement of the underlying condition being treated and / or eradication or improvement of one or more symptoms associated with the underlying condition, such that the patient reports an improvement in feeling or condition, although the patient may still be suffering from the underlying condition. Therapeutic benefit also includes stopping or slowing the progression of the disease, regardless of whether improvement is achieved.

[0699] For prophylactic administration, the compound can be administered to a patient at risk of developing one of the aforementioned diseases. A patient at risk of developing a disease can be a patient with characteristics that place the patient in a designated group of risk patients, as defined by appropriate medical professionals or groups. A patient at risk can also be a patient who is typically or routinely exposed to conditions that may lead to the development of the underlying disease. In other words, an at-risk patient is a patient who is typically or routinely exposed to conditions that cause the disease or condition, or who may be acutely exposed for a limited period of time. Alternatively, prophylactic administration can be used to prevent the onset of symptoms in a patient diagnosed with an underlying condition.

[0700] 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. The determination of an effective dosage is well within the capability of those skilled in the art.

[0701] Effective doses can be estimated initially from in vitro assays. For example, an initial dose for use in animals can be formulated to achieve circulating blood or serum concentrations of the active compound that are equal to or higher than the IC of the specific compound measured in in vitro assays such as in vitro fungal MIC or MFC and other in vitro assays. 50 Calculating dosages to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular compound, is 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, pages 1-112, 13th ed., McGraw-Hill, and references cited therein, which are incorporated herein by reference.

[0702] Initial dosages can also be estimated from in vivo data such as animal models.Animal models useful for testing the efficacy of compounds in treating or preventing the various diseases mentioned above are well known in the art.

[0703] Dosages will generally be in the range of about 0.0001 or 0.001 or 0.01 mg / kg / day to about 100 mg / kg / day, but may be higher or lower, depending on the activity of the compound, its bioavailability, mode of administration, and the various factors mentioned above. Dosage and interval can be adjusted individually to provide plasma levels of the compound sufficient to maintain a therapeutic or prophylactic effect. In the case of local administration or selective uptake such as topical administration, the effective local concentration of the active compound cannot be related to the plasma concentration. A skilled person will be able to optimize the effective local dose without undue experimentation.

[0704] Preferably, the compound will provide therapeutic or preventive benefit and will have acceptable tolerability. The tolerability of compounds and oligonucleotides can be determined using standard pharmaceutical methods. The dose ratio between intolerable and therapeutic (or preventive) effects is the therapeutic index. Compounds that exhibit a high therapeutic index are preferred.

[0705] The recitation of a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment of 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.

[0706] Other implementation plans

[0707] Certain embodiments include the following embodiments P1 to P30:

[0708] Embodiment P1. A compound comprising a structure of formula (I) or a salt thereof:

[0709]

[0710]

[0711] in

[0712] It is α4β 1 / 7 Integrin ligands;

[0713] L1, L2, L3 and L4 are each independently a linker, a bond or absent; and

[0714] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies or peptides.

[0715] Embodiment P2. A compound or salt thereof according to embodiment 1, wherein the α4β 1 / 7 The integrin ligand is α4β 1 / 7Integrin agonists.

[0716] Embodiment P3. A compound or salt thereof according to embodiment 1, wherein the α4β 1 / 7 The integrin ligand is α4β 1 / 7 Integrin antagonists.

[0717] Embodiment P4. A compound or salt thereof according to embodiment 1, wherein the α4β 1 / 7 The integrin ligand is selected from the group consisting of:

[0718]

[0719]

[0720]

[0721]

[0722] where each instance of R is Anti-α4β 1 / 7 Integrin antibodies and their derivatives;

[0723] Embodiment P5. A compound or salt thereof according to embodiment 1, wherein the α4β 1 / 7 Integrin ligands contain structures or its derivatives.

[0724] Embodiment P6. A compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of Formula (II):

[0725]

[0726] or a salt thereof.

[0727] Embodiment P7. A compound or salt thereof according to Embodiment 6, wherein the compound comprises a structure of Formula (II-a):

[0728]

[0729] or a salt thereof.

[0730] Embodiment P8. A compound or salt thereof as described in any one of Embodiments 1 to 7, 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 bond, or a phosphorothioate bond.

[0731] Embodiment P9. A compound or salt thereof according to Embodiment 8, wherein L1 is a bond.

[0732] Embodiment P10. A compound or salt thereof as described in Embodiment 8 or 9, wherein L2 is an optionally substituted PEG linker.

[0733] Embodiment P11. A compound or salt thereof according to Embodiment 10, wherein the PEG linker is five PEG units in length.

[0734] Embodiment P12. A compound or salt thereof as described in any one of Embodiments 8 to 11, wherein L2 comprises the structure

[0735] Embodiment P13. A compound or salt thereof as described in any one of Embodiments 8 to 12, wherein L3 is an optionally substituted heteroaryl linker.

[0736] Embodiment P14. A compound or salt thereof according to Embodiment 13, wherein L3 is an optionally substituted partially unsaturated heteroaryl linker.

[0737] Embodiment P15. A compound or salt thereof as described in Embodiment 13 or 14, wherein L3 comprises the structure

[0738] Embodiment P16. A compound or salt thereof as described in any one of Embodiments 8 to 15, wherein L4 is an optionally substituted heteroalkyl linker.

[0739] Embodiment P17. A compound or salt thereof according to Embodiment 16, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

[0740] Embodiment P18. A compound or salt thereof as described in Embodiment 16 or 17, wherein L4 comprises the structure

[0741] Wherein X is O or S.

[0742] Embodiment P19. A compound or salt thereof as described in any one of Embodiments P8 to P18, wherein L1, L2, L3 and L4 together comprise the structure

[0743]

[0744] Wherein X is O or S.

[0745] Embodiment P20. A compound or salt thereof according to any one of Embodiments 1 to 19, wherein the compound comprises the following structure:

[0746]

[0747] or a salt thereof, wherein X is O or S.

[0748] Embodiment P21. A compound or salt thereof as described in any one of Embodiments 18 to 20, wherein X is O.

[0749] Embodiment P22. A compound or salt thereof as described in any one of Embodiments 18 to 20, wherein X is S.

[0750] Embodiment P23. A compound or salt thereof as described in any one of Embodiments 1 to 22, wherein R 1 Contains oligonucleotides.

[0751] Embodiment P24. The compound or salt thereof according to Embodiment 23, wherein the oligonucleotide is attached at its 5' end.

[0752] Embodiment P25. The compound or salt thereof according to Embodiment 23, wherein the oligonucleotide is attached at its 3' end.

[0753] Embodiment P26. A compound or salt thereof according to Embodiment 23, wherein the oligonucleotide is attached at an internal position on the oligonucleotide.

[0754] Embodiment P27. A compound or salt thereof according to Embodiment 26, wherein the internal position is an internucleoside linkage.

[0755] Embodiment P28. A compound or salt thereof as described in any one of Embodiments 1 to 27, wherein R 1 Conjugated to one or more additional α4β 1 / 7 Ligand oligonucleotide.

[0756] Embodiment P29. A compound or salt thereof according to embodiment 28, wherein the oligonucleotide is conjugated to two, three, four, five or more than five additional α4β 1 / 7 ligand.

[0757] Embodiment P30. A compound or salt thereof according to embodiment 28 or 29, wherein 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 on the oligonucleotide, or any combination thereof.

[0758] Embodiment P31. A compound or salt thereof as described in any one of Embodiments 23 to 30, wherein the oligonucleotide is a modified oligonucleotide.

[0759] Embodiment P32. A composition comprising a compound or salt thereof according to any one of Embodiments 1 to 31 and a pharmaceutically acceptable excipient.

[0760] Embodiment P33. A method for delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject a compound or salt thereof according to any one of embodiments 1 to 31 or a composition according to embodiment 32.

[0761] Embodiment P34. The method of embodiment 33, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal cortex, and spinal cord.

[0762] Embodiment P35. A method for treating or ameliorating a disease, disorder or symptom thereof in a subject, the method comprising administering to the subject a compound or salt thereof according to any one of embodiments 1 to 31 or a composition according to embodiment 32.

[0763] Embodiment P36. The method of embodiment 35, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.

[0764] Embodiment P37. The method of embodiment 35 or 36, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

[0765] Embodiment P38. The method of any one of Embodiments 33 to 37, wherein the compound or salt thereof is administered intrathecally to the subject.

[0766] Embodiment P39. A method for preparing a compound or salt thereof as described in any one of Embodiments 1 to 31, comprising one or more compounds described herein and a chemical transformation, including Example 1.

[0767] Other embodiments include the following embodiments 1 to 127:

[0768] Embodiment 1. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising a structure of Formula (I'):

[0769]

[0770] in:

[0771] Each of which is independently α4β 1 / 7 Integrin ligands;

[0772] L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A Each of is independently a linker, a bond, or absent;

[0773] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; and

[0774] z1 is 0 or 1.

[0775] Embodiment 2. The compound of embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (I"):

[0776]

[0777]

[0778] in:

[0779] For oligonucleotides.

[0780] Embodiment 3. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (I):

[0781]

[0782] Embodiment 4. A compound as described in any one of Embodiments 1 to 3, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the α4β 1 / 7 The integrin ligand is α4β 1 / 7 Integrin agonists.

[0783] Embodiment 5. A compound as described in any one of Embodiments 1 to 3, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the α4β 1 / 7 The integrin ligand is α4β 1 / 7 Integrin antagonists.

[0784] Embodiment 6. A compound as described in any one of Embodiments 1 to 3, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the α4β 1 / 7 The integrin ligand is selected from the group consisting of:

[0785]

[0786]

[0787]

[0788]

[0789]

[0790] where each instance of R is Anti-α4β 1 / 7 Integrin antibodies and their derivatives.

[0791] Embodiment 7. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (II′):

[0792]

[0793] in

[0794] R 2 and R 2A are each independently H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl; and

[0795] R 3 、R 3A 、R 4 and R 4A Each is independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl.

[0796] Embodiment 8. The compound of embodiment 7 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (II″):

[0797]

[0798] Embodiment 9. The compound of embodiment 8 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of formula (II"-a):

[0799]

[0800] Embodiment 10. The compound of embodiment 9 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of formula (II"-a-1):

[0801]

[0802] Embodiment 11. The compound of Embodiment 9 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (II"-a-2):

[0803]

[0804] Embodiment 12. A compound as described in any one of Embodiments 1 to 11, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the α4β 1 / 7 Integrin ligands contain structures or its derivatives.

[0805] Embodiment 13. The compound of Embodiment 8, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (II):

[0806]

[0807] Embodiment 14. The compound of Embodiment 13 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (II-a):

[0808]

[0809] Embodiment 15. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (III′):

[0810]

[0811] in

[0812] R 2 and R 2A each independently represents H, halogen, polyethylene glycol (PEG), optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted -O-alkyl, or optionally substituted cycloalkyl;

[0813] R 3 and R 3A are each independently optionally substituted heteroalkyl or optionally substituted heterocyclyl; and

[0814] n and n A Each independently is 1, 2 or 3.

[0815] Embodiment 16. The compound of Embodiment 15, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (III):

[0816]

[0817] Embodiment 17. The compound of Embodiment 16 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (III-a):

[0818]

[0819] Embodiment 18. The compound of Embodiment 16, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (III-b):

[0820]

[0821] Embodiment 19. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (IV′):

[0822]

[0823] in

[0824] R 2 and R 2A Each independently represents H, -OH, -NH2, -NHR 3 、-OR 3 or does not exist; and

[0825] R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0826] Embodiment 20. The compound of Embodiment 19, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (IV):

[0827]

[0828]

[0829] Embodiment 21. The compound of Embodiment 20, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (IV-a):

[0830]

[0831] Embodiment 22. The compound of Embodiment 20, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (IV-b):

[0832]

[0833] Embodiment 23. The compound of Embodiment 20, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (IV-c):

[0834]

[0835] Embodiment 24. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (V′):

[0836]

[0837] in

[0838] n and n A Each independently is 0, 1, 2 or 3.

[0839] Embodiment 25. The compound of Embodiment 24, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (V′-a):

[0840]

[0841] Embodiment 26. The compound of Embodiment 24, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (V):

[0842]

[0843]

[0844] Embodiment 27. The compound of Embodiment 26, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Va):

[0845]

[0846] Embodiment 28. The compound of Embodiment 26, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Vb):

[0847]

[0848] Embodiment 29. The compound of Embodiment 26, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Vc):

[0849]

[0850] Embodiment 30. The compound of Embodiment 26, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Vd):

[0851]

[0852] Embodiment 31. The compound of Embodiment 26, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Ve):

[0853]

[0854] Embodiment 32. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (VI′):

[0855]

[0856] in

[0857] n and n A Each independently is 0, 1, 2 or 3.

[0858] Embodiment 33. The compound of Embodiment 32, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VI′-a):

[0859]

[0860] Embodiment 34. The compound of Embodiment 32, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VI):

[0861]

[0862]

[0863] Embodiment 35. The compound of Embodiment 34, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VI-a):

[0864]

[0865] Embodiment 36. The compound of Embodiment 34, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VI-b):

[0866]

[0867] Embodiment 37. The compound of Embodiment 34, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VI-c):

[0868]

[0869] Embodiment 38. The compound of Embodiment 34, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VI-d):

[0870]

[0871] Embodiment 39. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (VII'):

[0872]

[0873] in

[0874] R 2 、R 2A 、R 3 、R 3A 、R 4 、R 4A 、R 5 and R 5A Each is independently H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl or absent;

[0875] R 8 and R 8A each independently represents optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkylene-(C3-C6)-cycloalkyl or optionally substituted (C1-C4)-alkylene-(C1-C4)-alkoxy;

[0876] R 6 、 R6A 、R 7 and R 7A are each independently H, halogen, alkyl or optionally substituted alkyl, optionally substituted heteroalkyl,

[0877] Embodiment 40. The compound of Embodiment 39 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (VII'-a):

[0878]

[0879] Embodiment 41. The compound of Embodiment 40, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII′-a-1):

[0880]

[0881] Embodiment 42. The compound of Embodiment 40, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII′-a-2):

[0882]

[0883] Embodiment 43. The compound of Embodiment 39, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII):

[0884]

[0885] Embodiment 44. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-a):

[0886]

[0887] Embodiment 45. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-b):

[0888]

[0889] Embodiment 46. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-c):

[0890]

[0891] Embodiment 47. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-c-1):

[0892]

[0893] Embodiment 48. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-c-2):

[0894]

[0895] Embodiment 49. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d):

[0896]

[0897] Embodiment 50. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-1):

[0898]

[0899] Embodiment 51. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-2):

[0900]

[0901] Embodiment 52. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-3):

[0902]

[0903] Embodiment 53. The compound of Embodiment 43, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-4):

[0904]

[0905]

[0906] Embodiment 54. The compound of Embodiment 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-5):

[0907]

[0908] Embodiment 55. The compound of Embodiment 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-6):

[0909]

[0910] Embodiment 56. The compound of Embodiment 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-7):

[0911]

[0912] Embodiment 57. The compound of Embodiment 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-8):

[0913]

[0914] Embodiment 58. The compound of Embodiment 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-9):

[0915]

[0916] Embodiment 59. The compound of Embodiment 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VII-d-10):

[0917]

[0918] Embodiment 60. The compound of embodiment 39, wherein R 6 is F, CF3 or CH3, and R 7 for

[0919] Embodiment 61. The compound of embodiment 39, wherein R 7 is F, CF3 or CH3, and R 6 for

[0920] Embodiment 62. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (VIII′):

[0921]

[0922] in

[0923] R 2 and R 2A Each is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or absent;

[0924] R 3 、R 3A 、R 4 and R 4Aare each independently H, halogen, optionally substituted alkyl, or optionally substituted -O-alkyl;

[0925] R 5 and R 5A Each is independently -OH or absent;

[0926] Y and Y A Each is independently -CH2- or -(CH2)2-.

[0927] Embodiment 63. The compound of Embodiment 62, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII′-a):

[0928]

[0929] Embodiment 64. The compound of Embodiment 62, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII):

[0930]

[0931] Embodiment 65. The compound of Embodiment 64, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-a):

[0932]

[0933] Embodiment 66. The compound of Embodiment 65, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-a-1):

[0934]

[0935] Embodiment 67. The compound of Embodiment 65, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-a-2):

[0936]

[0937] Embodiment 68. The compound of Embodiment 65, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-a-3):

[0938]

[0939] Embodiment 69. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (IX′):

[0940]

[0941] in

[0942] R 2 and R 2A Each of the above is independently H, -OH, -NH2, -NHR 3 、-OR 3 or -CONHR 3 ;

[0943] R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0944] n and n A Each of is independently 1 or 2.

[0945] Embodiment 70. The compound of Embodiment 69, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (IX):

[0946]

[0947] Embodiment 71. The compound of Embodiment 70, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (IX-a):

[0948]

[0949] Embodiment 72. The compound of Embodiment 70, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (IX-b):

[0950]

[0951] Embodiment 73. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (X′):

[0952]

[0953] in

[0954] R 2 and R 2A Each independently represents H, -CH2OR 3、-(CH2)2OR 3 、-CH2NHCOR 3 OR 3 ;and

[0955] R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

[0956] Embodiment 74. The compound of Embodiment 73, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (X):

[0957]

[0958] Embodiment 75. The compound of Embodiment 74, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Xa):

[0959]

[0960] Embodiment 76. The compound of Embodiment 74, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Xb):

[0961]

[0962] Embodiment 77. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XI′):

[0963]

[0964] in

[0965] R 2 and R 2A Each of which is independently H, -CONHR 3 、-CH2OR 3 、-(CH2)2OR 3 、-CH2NHCOR 3 OR 3 ;

[0966] R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[0967] X and X A Each of is independently H or halogen.

[0968] Embodiment 78. The compound of Embodiment 77, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (XI):

[0969]

[0970] Embodiment 79. The compound of Embodiment 78, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XI-a):

[0971]

[0972] Embodiment 80. The compound of Embodiment 78, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XI-b):

[0973]

[0974] Embodiment 81. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XII′):

[0975]

[0976] in

[0977] R 2 and R 2A Each of which is independently H, -CONHR 4 、-CH2OR 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ;

[0978] R 3 and R 3A Each of is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0979] R 4 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0980] R 5 and R 5A Each of is independently -OH or absent;

[0981] n and n A Each instance of is independently 0, 1, 2, or 3; and

[0982] n1 and n1 A Each instance of is independently 1, 2, or 3.

[0983] Embodiment 82. The compound of Embodiment 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (XII):

[0984]

[0985] Embodiment 83. The compound of Embodiment 82, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XII-a):

[0986]

[0987] Embodiment 84. The compound of Embodiment 82, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XII-b):

[0988]

[0989] Embodiment 85. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (XIII′):

[0990]

[0991] in

[0992] R 2 and R 2A Each of which is independently H, -CONHR 4 、-CH2OR 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ;

[0993] R 3 and R 3A Each of is independently H, optionally substituted alkyl, or optionally substituted cycloalkyl;

[0994] R 4 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[0995] R 5 and R 5A Each of is independently -OH or absent; and

[0996] X and X A Each is independently H, optionally substituted CH2, optionally substituted NH or cycloalkyl.

[0997] Embodiment 86. The compound of Embodiment 85, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (XIII):

[0998]

[0999] Embodiment 87. The compound of Embodiment 86, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XIII-a):

[1000]

[1001] Embodiment 88. The compound of Embodiment 86, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XIII-b):

[1002]

[1003]

[1004] Embodiment 89. The compound of Embodiment 86, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XIII-c):

[1005]

[1006] Embodiment 90. The compound of Embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (XIV′):

[1007]

[1008] in

[1009] R 2 and R 2A Each of the 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ;

[1010] R 3 and R 3A Each of the above is independently H, -OH, -NH2, -NHR 5OR 5 ;

[1011] R 4 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;

[1012] R 5 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and

[1013] n and n A Each of is independently 1, 2 or 3.

[1014] Embodiment 91. The compound of Embodiment 90, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (XIV):

[1015]

[1016] Embodiment 92. The compound of Embodiment 91 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (XIV-a):

[1017]

[1018] Embodiment 93. The compound of Embodiment 91 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (XIV-b):

[1019]

[1020]

[1021] Embodiment 94. A compound as described in any one of Embodiments 1 to 93, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A Each of the 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 bond, or a phosphorothioate bond.

[1022] Embodiment 95. The compound of embodiment 94, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 and / or L1A is the key.

[1023] Embodiment 96. The compound of embodiment 94 or 95, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 and / or L 2A is an optionally substituted PEG linker.

[1024] Embodiment 97. A compound as described in Embodiment 96, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the PEG linker is two, three, four, five, six, seven, eight, nine or ten PEG units in length.

[1025] Embodiment 98. A compound as described in any one of Embodiments 94 to 97, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 and / or L 2A Contains structure

[1026] Embodiment 99. A compound as described in any one of Embodiments 94 to 98, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 and / or L 3A is an optionally substituted heteroaryl linker.

[1027] Embodiment 100. The compound of embodiment 99, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 and / or L 3A is an optionally substituted partially unsaturated heteroaryl linker.

[1028] Embodiment 101. A compound according to embodiment 99 or 100, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 and / or L 3A Contains structure

[1029] Embodiment 102. A compound as described in any one of Embodiments 94 to 101, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 and / or L 4A is an optionally substituted heteroalkyl linker.

[1030] 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 =0 substituents.

[1031] Embodiment 104. The compound of Embodiment 102 or 103, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the heteroalkyl linker comprises two substituents linked together to form an optionally substituted carbocyclyl ring.

[1032] Embodiment 105. The compound of embodiment 102 or 103, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 and / or L 4A Contains structure

[1033] Wherein X is O or S.

[1034] Embodiment 106. A compound as described in any one of Embodiments 102 to 104, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 and / or L 4A Contains structure

[1035] Wherein X is O or S.

[1036] Embodiment 107. A compound as described in any one of Embodiments 94 to 106, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3 and L4 and / or L 1A 、L 2A 、L 3A and L 4A Together they contain the following structures:

[1037]

[1038]

[1039] Wherein X is O or S.

[1040] Embodiment 108. The compound of any one of Embodiments 1 to 107, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure:

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047] Wherein X is O or S.

[1048] Embodiment 109. The compound of any one of Embodiments 105 to 108, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is O.

[1049] Embodiment 110. The compound of any one of Embodiments 105 to 108, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is S.

[1050] Embodiment 111. A compound as described in any one of Embodiments 1 to 110, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 1 Contains oligonucleotides.

[1051] Embodiment 112. The compound of embodiment 111, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at its 5' end.

[1052] Embodiment 113. The compound of embodiment 111, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at its 3' end.

[1053] Embodiment 114. The compound of embodiment 111, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the oligonucleotide is attached at an internal position on the oligonucleotide.

[1054] Embodiment 115. The compound of Embodiment 114, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the internal position is an internucleoside linkage.

[1055] Embodiment 116. A compound as described in any one of Embodiments 1 to 115, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 1 Conjugated to one or more additional α4β 1 / 7 Ligand oligonucleotide.

[1056] Embodiment 117. A compound according to embodiment 116, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is conjugated to two, three, four, five or more than five additional α4β 1 / 7 ligand.

[1057] Embodiment 118. A compound according to embodiment 116 or 117, or a stereoisomer, tautomer, prodrug or salt thereof, wherein 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 on the oligonucleotide, or any combination thereof.

[1058] 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.

[1059] 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.

[1060] Embodiment 121. A method for delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject a compound of any one of Embodiments 1 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, or a composition of Embodiment 120.

[1061] 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 cortex, and spinal cord.

[1062] Embodiment 123. A method for treating or ameliorating a disease, disorder, or symptom thereof in a subject, the method comprising administering to the subject a compound as described in any one of Embodiments 1 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, or a composition as described in Embodiment 120.

[1063] Embodiment 124. The method of embodiment 123, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.

[1064] Embodiment 125. The method of embodiment 123 or 124, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

[1065] Embodiment 126. The method of any one of Embodiments 123 to 125, wherein the compound, or a stereoisomer, tautomer, prodrug, or salt thereof, is administered intrathecally to the subject.

[1066] Embodiment 127. A method for preparing a compound as described in any one of Embodiments 1 to 119, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising one or more compounds described herein and chemical transformations, including Examples 1-13.

[1067] Example

[1068] In order that the embodiments described herein may be more completely 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 in any way as limiting the scope thereof.

[1069] General experimental steps

[1070] The definitions of the variables in the structures in the schemes herein are comparable to those at corresponding positions in the formulae described herein.

[1071] Common abbreviations:

[1072] ACN acetonitrile

[1073] br broad peak

[1074] CDI Carbonyldiimidazole

[1075] d Twin Peaks

[1076] DCM dichloromethane

[1077] dd doublet

[1078] dba dibenzylideneacetone

[1079] DBCO Azadibenzocyclooctyne

[1080] DFAA difluoroacetic anhydride

[1081] DIPEA or DIEA diisopropylethylamine

[1082] DMF dimethylformamide

[1083] DMSO dimethyl sulfoxide

[1084] dppf 1,1'-ferrocenediyl-bis(diphenylphosphine)

[1085] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1086] EtOAc

[1087] h hour

[1088] HBTU Benzotriazole tetramethyl urea hexafluorophosphate

[1089] HRMS High Resolution Mass Spectrometry

[1090] HPLC high-performance liquid chromatography

[1091] LCMS liquid chromatography-mass spectrometry

[1092] MS

[1093] MW microwave

[1094] m multiplet

[1095] MeOH methanol

[1096] min

[1097] mL milliliters

[1098] MWCO molecular weight cut-off

[1099] m / z mass-to-charge ratio

[1100] NMP N-Methyl-2-pyrrolidone

[1101] NMR Nuclear Magnetic Resonance

[1102] ppm parts per million

[1103] rt or RT room temperature

[1104] s single peak

[1105] t Triplet

[1106] TFA trifluoroacetic acid

[1107] TFAA trifluoroacetic anhydride

[1108] TLC thin layer chromatography

[1109] Examples 1A-1B: α4β 1 / 7 Synthesis of integrin ligand-conjugated oligonucleotides

[1110] Exemplary compounds falling within the scope of the present disclosure can be synthesized according to the following procedure:

[1111] Example 1A:

[1112] General Procedure I: 5'-Conjugated Sense Strand

[1113] Step 1 To an aqueous solution of the 5'-amine functionalized sense strand (I) was added 10% v / v 1M sodium phosphate buffer (pH = 7) and 20%-50% v / v CH3CN. 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. The dried N-DBCO modified sense strand (III) was reconstituted in RNase-free water for step 2.

[1114]

[1115] Step 2: To a solution of 5'-DBCO modified sense chain (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. After completion, the reaction was analyzed by reverse phase HPLC or with The 5'-conjugated sense strand (IV) was purified using an Ultra-15 Centrifugal filter (3K, 5 times) with a molecular weight cutoff.

[1116] General Procedure II Type A: Double-conjugated sense strand

[1117] Step 1: To an aqueous solution of the 5'-amine functionalized sense strand (I) was added 10% v / v 1M sodium phosphate buffer (pH = 7) and 20%-50% v / v CH3CN. 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. The 5'-DBCO modified sense strand (III) was reconstituted in RNase-free water for step 2.

[1118] Step 2: To an aqueous solution of the 5'-DBCO-modified 3'-(C6-SS-C6)-mC functionalized sense chain (III) was added 10% V / V 1M sodium phosphate buffer (pH=7). Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 equivalents) was dissolved in H2O, and the pH of the solution was adjusted to 7 using 10M NaOH. The TCEP aqueous solution was added to the solution of the sense chain (III). The reaction was monitored by HPLC and LCMS. After completion, excess TCEP was removed by MWCO using 100mM sodium phosphate buffer (pH=7) (3x). A solution of DBCO-MAL (V) (3 equivalents) in DMSO was added to the disulfide-reduced sense chain solution. The reaction was monitored by LCMS and HPLC. After completion, the solid was removed by centrifugation, and the solution was purified by reverse phase HPLC and dried by lyophilization. The dried double-DBCO modified sense chain (VI) was reconstituted in RNase-free water for step 3.

[1119] Step 3 : To a solution of 5'-, 3'-DBCO functionalized sense chain (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. After completion, the reaction was analyzed by reverse phase HPLC or with The 5'-, 3'-di-conjugated sense strand (VII) was purified using an Ultra-15 Centrifugal filter (3K, 5 times) with a molecular weight cutoff. The product was confirmed by HPLC and LCMS.

[1120]

[1121] General Procedure II Type B: 3',5'-Conjugated Sense Strand

[1122] Step 1 To an aqueous solution of the 5'-amine, 3'-(C6-SS-C6)-mC functionalized sense strand (I) was added 10% V / V 1M sodium phosphate buffer (pH=7) and 20%-50% V / V CH3CN. 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 combined product fractions were collected and dried by lyophilization. The 5'-DBCO modified sense strand (III) was reconstituted in RNase-free water for step 2.

[1123] Step 2: To an aqueous solution of 5'-DBCO modified sense chain (III) (1 equivalent) was added a solution of ligand-A-N3 (2 equivalents) in DMSO. The reaction was monitored by HPLC and LCMS. After completion, the reaction was analyzed by reverse phase HPLC or with The 5'-conjugated sense strand (IV) was purified using an Ultra-15 Centrifugal filter (3K, 5 times) with a molecular weight cutoff.

[1124] Step 3: To a solution of 5'-conjugated 3'-(C6-SS-C6)-mC functionalized sense chain (IV) (1 equivalent) in H2O was added 10% V / V 1M sodium phosphate buffer (pH=7). TCEP (V) (20 equivalents) was dissolved in H2O and the pH of the solution was adjusted to 7 using 10M NaOH. An aqueous solution of TCEP was added to the solution of sense chain (IV). The reaction was monitored by HPLC and LCMS. After completion, excess TCEP was removed using 100mM sodium phosphate buffer (pH=7) using MWCO (3x). A DMSO solution of DBCO-MAL (VI) (3 equivalents) was added to the disulfide-reduced sense chain solution. The reaction was monitored by HPLC and LCMS. After completion, the aqueous solution was purified by reverse phase HPLC. The product fractions were collected and dried by lyophilization. The 5'-conjugated 3'-DBCO modified sense chain (VII) was reconstituted in 100mM sodium phosphate buffer for the next step.

[1125] Step 4: To an aqueous solution of 5'-conjugated 3'-DBCO functionalized sense chain (VII) (1 eq) was added a solution of Ligand-B-N3 (2 eq) in DMSO. The reaction was monitored by HPLC and LCMS. After completion, the reaction was analyzed by reverse phase HPLC or with The 5'- and 3'-conjugated sense strand (VIII) was purified using an Ultra-15 Centrifugal filter (3K, 5 times) with a molecular weight cutoff.

[1126]

[1127] General Procedure III: 3'-Conjugated Sense Strand

[1128] Step 1: To an aqueous solution of the 3'-(C6-SS-C6)-mC functionalized sense chain (I) was added 10% V / V 1M sodium phosphate buffer (pH=7). TCEP (II) (20 equivalents) was dissolved in H2O and the pH of the solution was adjusted to 7 using 10M NaOH. The TCEP aqueous solution was added to the solution of the sense chain (I). The reaction was monitored by HPLC and LCMS. After completion, excess TCEP was removed by MWCO using 100mM sodium phosphate buffer (pH=7) (3x). A solution of DBCO-MAL (III) (3 equivalents) in DMSO was added to the disulfide-reduced sense chain solution. The reaction was monitored by LCMS and HPLC. After 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. The dried 3'-DBCO modified sense chain (IV) was reconstituted in 100mM sodium phosphate buffer for step 3.

[1129] Step 3: To an aqueous solution of 3'-DBCO functionalized sense chain (IV) (1 eq) was added a solution of ligand-A-N3 (3 eq) in DMSO. The reaction was monitored by HPLC and LCMS. After completion, the reaction was analyzed by reverse phase HPLC or with The 3'-conjugated sense strand (V) was purified using an Ultra-15 Centrifugal filter (3K, 5x) with a molecular weight cutoff. The product was confirmed by HPLC and LCMS.

[1130]

[1131] Example 1B: α4β 1 / 7 Synthesis of integrin ligand-conjugated oligonucleotides

[1132] General scheme:

[1133]

[1134] Synthesis procedure:

[1135]

[1136] To a mixture of pyridazinone (2 g, 11.173 mmol, 1 eq), finely ground K2CO3 (6.177 g, 44.693 mmol, 4 eq) and tetrabutylammonium bromide (0.36 g, 1.117 mmol, 0.1 eq) in anhydrous acetonitrile (11 ml) was added BnO-(PEG)4-OH (4.766 g, 16.76 mmol, 4.332 ml, 1.5 eq) at room temperature over 10 minutes. The mixture was stirred at room temperature overnight, 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]+.

[1137]

[1138] To a solution of 3,5-dichloroisonicotinic acid (7 g, 36.458 mmol, 1 eq) in DMF (102 ml) was added HBTU (15.209 g, 40.104 mmol, 1.1 eq) and HOBt (1.159 g, 7.292 mmol, 0.2 eq) dropwise at 0°C, followed by DIEA (14.137 g, 109.375 mmol, 19.104 ml, 3 eq). The solution was stirred for 20 minutes, then tert-butyltyrosine (8.219 g, 34.635 mmol, 0.95 eq) was added, and the reaction was stirred at room temperature for 3 hours. The reactants were dissolved in EtOAc and washed with water, then with 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 afford the desired product in 38% yield (5.72 g).MS ESI+ m / z = 411.4 [MH]+.

[1139]

[1140] To a solution of phenol (5.42 g, 13.178 mmol, 1 eq) in DCM (14.5 mL) was added Tf2NPh (6.12 g, 17.132 mmol, 1.3 eq) at 0 ° C., followed by DIEA (5.1 g, 39.535 mmol, 6.892 ml, 3 eq). The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient of 0-20% ethyl acetate / hexane to give the desired product in 87% yield (6.2 g). MS ESI+ m / z = 543.3 [MH]+.

[1141]

[1142] A solution of trifluoromethanesulfonate (3.3 g, 6.07 mmol, 1 equivalent), pinacol diboron (2.31 g, 9.11 mmol, 1.5 equivalents) and KOAc (2.08 g, 21.25 mmol, 3.5 equivalents) in anhydrous DMF (33 ml) was degassed by sparging argon for 10 minutes under stirring. Pd (Dppf) Cl2 (889 mg, 1.21 mmol, 0.2 equivalents) was added under argon and the mixture was degassed for another 5 minutes. The bottle was sealed and stirred at 90 ° C for 10 hours. The mixture was cooled and the catalyst was filtered out using diatomaceous earth. The filtrate was concentrated and the resulting residue was distributed between EtOAc and salt water. The organic phase was dried, filtered, concentrated, and then purified by silica gel column chromatography using 0-30% EtOAc / hexane to obtain the desired product in 84% yield (2.67 g). MS ESI+ m / z = 521.5 [MH]+.

[1143]

[1144] A mixture consisting of a boronate ester (2.2 g, 4.221 mmol, 1 eq), an aryl chloride (1.802 g, 4.221 mmol, 1 eq) and 1 M Na2CO3 (1.118 g, 10.552 mmol, 2.5 eq) in acetonitrile (10.5 ml) was degassed with stirring by sparging with argon for 10 minutes. Pd(PPh3)2Cl2 (0.593 g, 0.844 mmol, 0.2 eq) was added and the mixture was degassed for another 5 minutes. The vial was sealed and stirred at 150°C for 4 minutes before cooling to room temperature. The catalyst was filtered off 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 [MH]+.

[1145]

[1146] A solution of benzyl ether (308 mg, 0.39 mmol) in methanol (6.5 ml) was stirred under 1 atm of H2(g) in the presence of Pd / C (42 mg, 0.39 mmol, 1 equivalent) for 6.5 h. The catalyst was filtered off 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]+.

[1147]

[1148] At 0 ° C, a solution of MsCl (0.145 g, 1.266 mmol, 0.098 ml, 1.5 equivalents) in DCM (8.5 ml) was added dropwise to a solution of alcohol (0.587 g, 0.844 mmol, 1 equivalent) in pyridine (8.5 ml). The reaction mixture was stirred at room temperature for 16 h, then quenched by adding water and extracted with DCM. The organic layer was washed with a saturated solution of NaHCO3 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] +.

[1149]

[1150] To a solution of mesylate (0.5 g, 0.646 mmol, 1 equivalent) in DMF (10 ml) was added NaN (0.092 g, 1.422 mmol, 2.2 equivalents), and the mixture was stirred at 80 ° C overnight, then cooled to room temperature and distributed between EtOAc and water. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layer was 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 / hexane to give the desired product in 67% yield (313 mg). MS ESI+ m / z = 720.5 [MH] +.

[1151]

[1152] At 0 ℃, TFA (0.96 ml) is added dropwise to a DCM (1.9 ml) solution of tert-butyl ester (0.17 g, 0.236 mmol, 1 equivalent). Remove the cooling bath, and stir the mixture at room temperature overnight, then concentrate under reduced pressure. The resulting residue is purified by C18 reverse phase column chromatography using a gradient of 0-100% acetonitrile / water (+0.1% formic acid). The resulting residue is repurified by silica gel column chromatography using a gradient of 0-20% methanol / EtOAc to give the desired product in 44% yield (69 mg). MSESI+ m / z = 664.1 [MH]+.

[1153]

[1154] To the aqueous solution of the AC6 functionalized sense strand was added a solution of DCBO-NHS (12) (3 equivalents) in CH3CN. The reaction was monitored by LCMS and HPLC. Once the reaction was complete, the solid was filtered off and the solution was purified by HPLC and dried by lyophilization. The dried DCBO-modified sense strand was reconstituted in RNase-free water and a solution of ligand 11 (2 equivalents) in THF was added. After the reaction was complete, the conjugate was purified by MWCO (5X).

[1155] General procedure for annealing:

[1156] The concentrations of both the sense and antisense strands were determined by Nanodrop. Double-stranded siRNA was prepared by mixing equimolar amounts of the sense and antisense strands. Annealing was monitored by native RP-HPLC. After annealing, the antisense strand content in the duplex mixture did not exceed 5%. Duplex concentration was determined by measuring the absorbance of the solution on a Nanodrop.

[1157] Example 2: BA-128 conjugate

[1158]

[1159] Wherein X is O or S.

[1160] BA-128: (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoic acid

[1161]

[1162] Step 1: (S)-2-(3,5-dichloroisonicotinamido)-3-(4-(5-(2-(2-(2-hydroxyethoxy)ethoxy) tert-Butyl)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate

[1163] 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 of H2(g) in the presence of Pd / C (0.11 g, 1.02 mmol) for 2 hours. 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] + .

[1164] Step 2: (S)-2-(3,5-dichloroisonicotinamido)-3-(4-(2-methyl-5-(2-(2-(2-(2- ((Methylsulfonyl tert-Butyl)propanoate ester

[1165] At 0 ° C, a solution of methanesulfonyl chloride (17ul, 0.216mmol) in DCM (1.4ml) was added dropwise to a solution of (S)-tert-butyl 2-(3,5-dichloroisonicotinamido)-3-(4-(5-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propanoate (0.10g, 0.144mmol) in pyridine (1.4ml). The reaction mixture was stirred at room temperature for 16h, then quenched by adding water (10ml) and extracted with DCM (3x10ml). The organic layer was washed with a saturated solution of NaHCO3 (10ml) and brine (10ml). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (0.11g, quantitative) as a brown oil. MS (ESI) m / z 773.5 [M+H] + .

[1166] Step 3: (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-methyl tert-Butyl-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoate

[1167] 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)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 1 drop of water. The mixture was stirred at 80° C. for 6 hours, 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 (85 mg, 82%) as a clear oil. MS (ESI) m / z 721.6 [M+H] + .

[1168] Step 4: (S)-3-(4-(5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-2-methyl (3-oxo-2,3-dihydropyridazin-4-yl)phenyl)-2-(3,5-dichloroisonicotinamido)propanoic acid

[1169] At 0 ° C, 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). 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 (500MHz, DMSO-d6) δ12.95(s,1H),9.31(d,J=10Hz,1H),8.63(s,2H),8.20(s,1H),7.42(d,J=10Hz,2H),7.29(d,J=10Hz,2H),4.78-4.72(m, 1H), 4.36-4.32 (m, 2H), 3.66 (s, 5H), 3.57 (t, J = 5Hz, 2H), 3.36 (t, J = 5Hz, 2H), 3.53-3.47 (m, 8H), 3.20 (dd, J = 10, 5Hz, 1H), 2.93 (q, J = 10Hz, 1H).

[1170] BA-128 will be conjugated to the oligonucleotide sense strand according to the general procedure Type I. The product was prepared with 98% purity (MW: 8336.82 g / mol) and confirmed by HPLC and LCMS (m / z: 8335.56).

[1171] BA-128 was double conjugated to the oligonucleotide sense strand according to the general procedure Type IIB. The product was prepared with 96% purity (MW: 9483.37 g / mol) and confirmed by HPLC and LCMS (m / z: 9482.44).

[1172] Example 3: BA-148 conjugate

[1173]

[1174] Wherein X is O or S.

[1175] BA-148: (S)-2-((S)-1-((4-(4-(2-(2-(azidooxy)ethoxy)ethoxy)butoxy)phenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(4-((pyrrolidine-1-carbonyl)oxy)phenyl)propanoic acid

[1176]

[1177] Step 1: 4-((S)-2-((S)-1-((4-hydroxyphenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-methoxy (3-(2 ...2-1-1 methyl-3-oxopropyl)phenylpyrrolidine-1-carboxylate)

[1178] To a pyridine (3 ml) solution of 4-((S)-3-methoxy-3-oxo-2-((S)-pyrrolidine-2-formamido)propyl)phenylpyrrolidine-1-carboxylate hydrochloride (0.43 g, 1 mmol) 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 in vacuo. 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 (0.16 g, 29%) as a yellow oil. MS (ESI) m / z 546.2[M+H] + .

[1179] Step 2: 4-((S)-2-((S)-1-((4-(4-(2-(2-(azidooxy)ethoxy)ethoxy)butoxy) (phenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-methoxy-3-oxopropyl)phenylpyrrolidine-1-carboxylate

[1180] 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) and 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 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 0-40% MeOH / EtOAc to give the title compound as a colorless oil (52 mg, 24%). MS (ESI) m / z 769.5 [M+Na] + .

[1181] Step 3: (S)-2-((S)-1-((4-(4-(2-(2-(azidooxy)ethoxy)ethoxy)butoxy)benzene (4-((pyrrolidine-1-carbonyl)oxy)phenyl)propanoic acid)

[1182] 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 H O (0.5 ml) was added LiOH (11 mg, 0.27 mmol) 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 (43 mg, 88%) as a white solid. MS (ESI) m / z 755.9 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ7.81–7.75(m,2H),7.56(m,1H),7.19–7.05(m,4H),6.89(dd,J=8.5,3.5Hz,2H),4.22–4.16(m,2H ),4.13–3.91(m,3H),3.76(dq,J=4.8,2.4Hz,2H),3.63–3.25(m,22H),3.16–2.87(m,3H),1.91–1.79(m,4H),1.38(m,2H).

[1183] BA-148 will be conjugated to the oligonucleotide sense strand according to the general procedure Type I. The product was prepared with 98% purity (MW: 8032.88 g / mol) and confirmed by HPLC and LCMS (m / z: 8031.37).

[1184] Example 4: BA-149 conjugate

[1185]

[1186] Wherein X is O or S.

[1187] BA-149: (S)-2-(4-(4-(2-(2-(azidooxy)ethoxy)ethoxy)butoxy)-2,6-dichlorobenzamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoic acid

[1188]

[1189] Step 1: (S)-2-(2,6-dichloro-4-hydroxybenzamido)-3-(2',6'-dimethoxy-[1,1'- phenyl]-4-yl)propionic acid methyl ester

[1190] To a solution of (S)-2-amino-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)methyl 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 for 17 hours under an inert atmosphere. The reaction mixture was diluted with water (200 ml) to form 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] + .

[1191] Step 2: (S)-2-(4-(4-(2-(2-(azidooxy)ethoxy)ethoxy)butoxy)-2,6-dichlorobenzene Methyl formamido)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate

[1192] 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 (3×25 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] + .

[1193] Step 3: (S)-2-(4-(4-(2-(2-(azidooxy)ethoxy)ethoxy)butoxy)-2,6-dichlorobenzene Formylamino)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoic acid

[1194] To a solution of (S)-methyl 2-(4-(4-(2-(2-(azidooxy)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 H2O (0.5 ml) was added LiOH (41 mg, 1 mmol) 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 (96 mg, 56%) as a clear, colorless oil. MS (ESI) m / z 692.6 [M+H] + 1H NMR data (500MHz, DMSO-d6) δ12.77 (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=5.5,4.3Hz,2H), 3.16(dd,J=14.1,4.4Hz,1H), 2.92(dd,J=14.1,10.5Hz,1H).

[1195] BA-149 will be conjugated to the oligonucleotide sense strand according to the general procedure Type I. The product was prepared with 87% purity (MW: 7991.63 g / mol) and confirmed by HPLC and LCMS (m / z: 7990.46).

[1196] Example 5: BA-154 conjugate

[1197]

[1198] Wherein X is O or S.

[1199] 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)pentanoylamino)-4-oxobutanoic acid

[1200]

[1201] Step 1: (S)-4-(((S)-1-((S)-2-((4-(2-(2-(azidooxy)ethoxy)ethoxy)butyl) (amino)-3-((S)-4-methyl-2-(2-(4-(3- Methyl (o-tolyl)ureido)phenyl)acetylamino)pentanoylamino)-4-oxobutanoate

[1202] To a solution of ((S)-4-methoxy-2-((S)-4-methyl-2-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)pentanoylamino)-4-oxobutanoyl)-L-valyl-L-proline (0.30 g, 0.415 mmol) in anhydrous DMA (5 ml) was added 4-(2-(2-(azidooxy)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) to form an off-white precipitate. The solid was collected by filtration, washed with water, and air-dried. The crude material 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] + .

[1203] Step 2: (S)-4-(((S)-1-((S)-2-((4-(2-(2-(azidooxy)ethoxy)ethoxy)butyl) (amino)-3-((S)-4-methyl-2-(2-(4-(3- (o-Tolyl)ureido)phenyl)acetylamino)pentanoylamino)-4-oxobutanoic acid

[1204] To a solution of (S)-methyl 4-(((S)-1-((S)-2-((4-(2-(2-(azidooxy)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)pentanoylamino)-4-oxobutanoate (0.18 g, 0.195 mmol) in a mixture of THF (8 ml), MeOH (15 ml) and HO (2 ml) was added LiOH (12 mg, 0.49 mmol) 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 (0.17 g, 98%) as an off-white glassy solid. MS (ESI) m / z 932.1 [M+Na] +. 1H NMR (500MHz, DMSO-d6) δ12.34(s,1H),9.09(d,J=2.9Hz,1H),8.36(d,J=7.9Hz,1H),8.15(ddd,J=20.1,15.8,8.4Hz,2H),7.98(s ,1H),7.82(dd,J=10.4,6.9Hz,2H),7.52(d,J=8.6Hz,0H),7.40–7.29(m,2H),7.15(q,J=6.3,5.6Hz,4H),6.93(t,J=7.4Hz,1H), 4.51(dq,J=30.1,6.9Hz,1H),4.38–4.19(m,3H),3.75–3.35(m,19H),3.24(dt,J=12.3,6.3Hz,1H),3.18–3.06(m,1H),2.74–2.5 6(m,1H),2.24(s,3H),2.08–1.68(m,3H),1.56(tt,J=13.2,6.7Hz,1H),1.44(ddt,J=14.2,10.3,6.5Hz,2H),0.92–0.73(m,12H).

[1205] BA-154 will be conjugated to the oligonucleotide sense strand according to the general procedure Type I. The product was prepared with 99% purity (MW: 8209.13 g / mol) and confirmed by HPLC and LCMS (m / z: 8207.66).

[1206] Example 6: BA-161 conjugate

[1207]

[1208] Wherein X is O or S.

[1209] 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)hexanoylamino)-3,6,9-trioxa-12,15-diazaeicosane-20-oic acid

[1210]

[1211] Step 1: N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-((E)-3-(pyridin-3-yl)acryloyl)-L- Lysyl-L-glutamic acid 1-(tert-butyl) 5-methyl ester

[1212] 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 (2S)-1-tert-butyl 5-methyl 2-aminopentanedioate hydrochloride (1.47 g, 5.805 mmol) in DMF (29 ml) was treated with HATU (3.31 g, 8.707 mmol), and then DIPEA (2.25 g, 17.415 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. 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-enoylamino]hexanoylamino]pentanedioate (3.9 g, 96%) as a white solid. MS (ESI) m / z 699.9 [M+H] + .

[1213] Step 2: (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((E)-3-(pyridine-3- (acryloylamino)hexanoylamino)-5-methoxy-5-oxopentanoic acid

[1214] 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-enoylamino]hexanoylamino]pentanedioate (300 mg, 0.429 mmol) in DCM (1 ml) was treated with a solution of hydrogen chloride (3 mL) in dioxane for 3 hours. 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] + .

[1215] 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-triazadodecane- 12-tert-Butyl Acetate

[1216] A solution of (2S)-2-[(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-6-[(2E)-3-(pyridin-3-yl)prop-2-enoylamino]hexanoylamino]-5-methoxy-5-oxopentanoic acid (3 g, 4.67 mmol) and (2S)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride (2.41 g, 9.34 mmol) in DMF (30 ml) was treated with HATU (3.55 g, 9.34 mmol) at room temperature under a nitrogen atmosphere, followed by the dropwise addition of DIPEA (6.03 g, 46.65 mmol) at room temperature. 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 NaSO. 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] + .

[1217] Step 4: (S)-4-((S)-2-amino-6-((E)-3-(pyridin-3-yl)acrylamido)hexanoylamino)-5- Methyl (((S)-1-(tert-Butoxy)-1-oxo-3-phenylpropan-2-yl)amino)-5-oxopentanoate

[1218] A solution of (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-enoylamino]hexanoylamino]butanoic acid methyl ester (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 phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water, 10% to 90% gradient over 35 minutes; detector, UV 254 nm. The resulting product was extracted with DCM (2 x 150 ml). The combined organic layers were washed with brine (2 x 30 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave methyl (4S)-4-[(2S)-2-amino-6-[(2E)-3-(pyridin-3-yl)prop-2-enoylamino]hexanoylamino]-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] + .

[1219] 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) Methyl hexanoylaminovalerate

[1220] To a solution of (S)-4-((S)-2-amino-6-((E)-3-(pyridin-3-yl)acrylamido)hexanoylamino)-5-(((S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl)amino)-5-oxopentanoic acid methyl ester (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 (0.32 g, 76%) as an off-white solid. MS (ESI) m / z 891.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.94(s,1H),8.78(d,J=2.2Hz,1H),8.58(dd,J=4.8,1.6Hz,1H),8.25(d,J=7.3Hz,1H),8.19–8.10(m,2H),8.05(d,J= 8.1Hz,1H),8.00(d,J=8.1Hz,1H),7.88(s,1H),7.83(dd,J=8.2,1.3Hz,1H),7.56–7.43(m,2H),7.43–7.30(m,2H),7.30–7.08(m,9H),6.93(td ,J=7.4,1.3Hz,1H),6.74(d,J=15.9Hz,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=1 2.7,6.2,3.1Hz,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, 4.9Hz, 1H), 1.43 (s, 2H), 1.29 (s, 11H).

[1221] 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)hexanoylamino)pentanoyl)-L-phenylalanine

[1222] To a solution of (S)-methyl 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)hexanoamido)pentanoate (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 give the title compound quantitatively as a yellow oil. MS (ESI) m / z 834.7 [M+H] + ,856.7[M+Na] + .

[1223] Step 7: (14S,17S)-1-azido-14-benzyl-13,16-dioxo-17-((S)-6-((E)-3-(pyridine- 3-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanoylamino)-3,6,9-trioxadiazole Methyl 12,15-diazaeicosanoate

[1224] 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)hexanoylamido)pentanoyl)-L-phenylalanine (0.28 g, 0.34 mmol) in anhydrous DMA (3 ml) was added 4-(2-(2-(azidooxy)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 Na2SO4 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] + .

[1225] Step 8: (14S,17S)-1-azido-14-benzyl-13,16-dioxo-17-((S)-6-((E)-3-(pyridine- 3-(2-(4-(3-(o-tolyl)ureido)phenyl)acetamido)hexanoylamino)-3,6,9-trioxadiazole Hetero-12,15-diazaeicosanoic acid

[1226] To (14S, 17S) -1- azido -14- benzyl -13, 16- dioxo -17- ((S) -6- ((E) -3- (pyridin-3-yl) acrylamido) -2- (2- (4- (3- (o-tolyl) urea) phenyl) acetamido) hexanoyl amino) -3, 6, 9- trioxa -12, 15- diazaeicosane -20- acid methyl ester (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 (0.13 g, 55%) as a white spongy solid. MS (ESI) m / z 1021.2 [M+H] + ,1043.1[M+Na] + . 1 H NMR(500MHz, DMSO-d6)δ9.15(s,1H),8.74(d,J=2.2Hz,1H),8.53(dd,J=4.7,1.6Hz,1H),8.26(s,4H),8.23–8.14(m,2H),8.14–7.92(m,1H),7 .89(d,J=8.2Hz,1H),7.81(d,J=8.2Hz,1H),7.50–7.32(m,4H),7.27–7.08(m,8H),6.93(td,J=7.5,1.4Hz,1H),6.73(d,J=15.9Hz,1H),4.45( td,J=8.3,5.3Hz,1H),4.19(dq,J=13.1,7.8Hz,2H),3.63–3.29(m,18H),3.21(dt,J=11.7,6.3Hz,2H),3.17–3.07(m,2H),3.02–2.90(m,1H), 2.23(s,3H),2.14(tt,J=16.6,8.5Hz,2H),1.83(dt,J=15.7,6.9Hz,1H),1.67(ddd,J=31.5,16.3,8.3Hz,2H),1.43(s,2H),1.36–1.13(m,2H).

[1227] BA-161 will be conjugated to the oligonucleotide sense strand according to the general procedure Type I. The product was prepared with 98% purity (MW: 8367.17 g / mol) and confirmed by HPLC and LCMS (m / z: 8365.37).

[1228] Example 7: BA-171 conjugate

[1229]

[1230]

[1231] Wherein X is O or S.

[1232] BA-171: (3S)-3-(2-(4-(14-azido-3-methyl-6,9,12-trioxa-3-azatetradecyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanoylamino)-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid

[1233]

[1234] Step 1: Ethyl (E)-2-(4-(2-ethoxyvinyl)-2-oxopyridin-1(2H)-yl)-5-methylhexanoate

[1235] 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-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.76 g, 29.081 mmol) in dioxane (50 ml) and H2O (5 ml) was added K2CO3 (4.02 g, 29.10 mmol) and Pd(PPh3)4 (1.68 g, 1.45 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 70 ° C. under a nitrogen atmosphere overnight. The mixture was cooled to room temperature. The reaction was quenched by adding water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. 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 using the following conditions: column, C18 silica gel; mobile phase, MeCN / water, 10%-100% gradient in 25 minutes; detector, UV 254 nm. This gave ethyl 2-(4-[(E)-2-ethoxyvinyl]-2-oxopyridin-1-yl-5-methylhexanoate (4 g, 86%) as a brown oil. MS (ESI) m / z 322.1 [M+H] + . 1H NMR (300MHz, CDCl3) δ7.16 (m, J=19.4, 10.1Hz, 2H), 6.37 (s, 1H), 6.19 (d, J=7.4Hz, 1H), 5 .60(d,J=13.0Hz,1H),5.54(m,J=10.2,5.6Hz,1H),4.19(q,J=7.2Hz,2H),3.94(q,J=7.1 Hz,2H),2.29–2.03(m,1H),1.86(d,J=12.3Hz,1H),1.57(m,J=13.3,6.8Hz,1H),1.35(t, J=7.0Hz, 3H), 1.24 (m, J=8.5, 7.8Hz, 4H), 1.14–1.04 (m, 1H), 0.87 (m, J= 6.8, 3.0Hz, 6H).

[1236] Step 2: Ethyl 5-methyl-2-(2-oxo-4-(2-oxoethyl)pyridin-1(2H)-yl)hexanoate

[1237] To a 250 mL round-bottom flask was added ethyl 2-(4-[(E)-2-ethoxyvinyl]-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. 1 H 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. 0,0.8Hz,2H),2.19(m,J=14.0,11.1,5.5Hz,1H),1.88(m,J=18.8,10.4,4.8Hz,1H),1.59 (m,J=13.3,6.7Hz,1H),1.34–1.16(m,4H),1.16–0.98(m,1H),0.88(q,J=6.6,3.1Hz,6H).

[1238] Step 3: 5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza- 3-(2H)-1(3-silaoctadec-18-yl)pyridin-1(2H)-yl)hexanoic acid ethyl ester

[1239] At room temperature, 15,15,16,16-tetramethyl-5,8,11,14-tetraoxa-2-aza-15-silanheptadecane (1.97g, 6.127mmol), STAB (2.60g, 12.268mmol) are added to a stirred solution of 5-methyl-2-[2-oxo-4-(2-oxoethyl)pyridin-1-yl]ethyl hexanoate (1.8g, 6.136mmol) in DCM (27ml). The resulting mixture is stirred at room temperature for 2 hours. The reaction is quenched at room temperature by adding water (100ml). The resulting mixture is extracted with DCM (3x120ml). The combined organic layer is washed with salt water (2x 50ml) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give ethyl 5-methyl-2-[2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silaoctadec-18-yl)pyridin-1-yl]hexanoate (1.6 g, 44%) as a brown oil. MS (ESI) m / z 599.3 [M+H] + . 1 HNMR (300 MHz, acetonitrile-d3) δ7.25 (d, J = 7.1 Hz, 1H), 6.20 (s, 1H), 6.11 (m, J = 7.1, 2.0 Hz, 1H), 5.08 (m, J = 10.2, 5.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.66 (m, J = 5.7, 4.4 Hz, 2H), 3.57–3.47 (m, 11H), 3.47–3.3 7(m,3H),2.68–2.48(m,4H),2.24(s,3H),2.15–1.99(m,1H),1.90(m,1H),1.48(m,J=13.4,6.8Hz ,1H),1.25–1.11(m,5H),1.07-0.88(m,1H),0.83(s,9H),0.79(m,J=6.6,3.0Hz,6H),0.02(s,6H).

[1240] Step 4: 5-methyl-2-(2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza- 3-Silahiooctadec-18-yl)pyridin-1(2H)-yl)hexanoic acid

[1241] To a stirred solution of 5-methyl-2-[2-oxo-4-(2,2,3,3,16-pentamethyl-4,7,10,13-tetraoxa-16-aza-3-silanoctadecane-18-yl)pyridin-1-yl]ethyl hexanoate (1.4 g, 2.338 mmol) in THF (14 ml) and H2O (2.8 ml) was added LiOH (223.95 mg, 9.352 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 ...

Claims

1. A compound or a stereoisomer, tautomer, prodrug or salt thereof, comprising a structure of formula (I'): in: Each of which is independently α4β 1 / 7 Integrin ligands; L1, L2, L3, L4, L 1A , L 2A , L 3A and L 4A Each of is independently a linker, a bond, or absent; R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; and z1 is 0 or 1.

2. The compound according to claim 1 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises a structure of formula (I"): in: For oligonucleotides.

3. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (I):

4. The compound or stereoisomer, tautomer, prodrug or salt thereof according to any one of claims 1 to 3, wherein the α4β 1 / 7 Integrin ligand is α4β 1 / 7 Integrin agonists.

5. The compound or stereoisomer, tautomer, prodrug or salt thereof according to any one of claims 1 to 3, wherein the α4β 1 / 7 Integrin ligand is α4β 1 / 7 Integrin antagonists.

6. The compound or stereoisomer, tautomer, prodrug or salt thereof according to any one of claims 1 to 3, wherein the α4β 1 / 7 The integrin ligand is selected from the group consisting of: where each instance of R is Anti-α4β 1 / 7 Integrin antibodies and their derivatives.

7. The compound according to claim 1 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises a structure of formula (II′): in R 2 and R 2A each is independently H, polyethylene glycol (PEG), optionally substituted heteroalkyl, or optionally substituted heteroaryl; and R 3 , R 3A , R 4 and R 4A Each is independently H, halogen, optionally substituted alkyl or optionally substituted -O-alkyl.

8. The compound of claim 7 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (II″):

9. The compound according to claim 8 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (II"-a):

10. The compound according to claim 9 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (II"-a-1):

11. The compound according to claim 9 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (II"-a-2):

12. The compound or stereoisomer, tautomer, prodrug or salt thereof according to any one of claims 1 to 11, wherein the α4β 1 / 7 Integrin ligands contain structures or its derivatives.

13. The compound of claim 8 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (II):

14. The compound of claim 13 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (II-a):

15. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (III'): in R 2 and R 2A each 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 optionally substituted heteroalkyl or optionally substituted heterocyclyl; and n and n A Each independently is 1, 2 or 3.

16. The compound of claim 15 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (III):

17. The compound of claim 16 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (III-a):

18. The compound of claim 16 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (III-b):

19. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV′): in R 2 and R 2A Each independently represents H, -OH, -NH2, -NHR 3 、-OR 3 or does not exist; and R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

20. The compound of claim 19 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV):

21. The compound of claim 20 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV-a):

22. The compound of claim 20 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV-b):

23. The compound of claim 20 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV-c):

24. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (V'): in n and n A Each independently is 0, 1, 2 or 3.

25. The compound of claim 24 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (V'-a):

26. The compound of claim 24 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (V):

27. The compound of claim 26 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Va):

28. The compound of claim 26 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Vb):

29. The compound of claim 26 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Vc):

30. The compound of claim 26 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Vd):

31. The compound of claim 26 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Ve):

32. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VI'): in n and n A Each independently is 0, 1, 2 or 3.

33. The compound of claim 32 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VI'-a):

34. The compound of claim 32 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VI):

35. The compound of claim 34 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VI-a):

36. The compound of claim 34 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VI-b):

37. The compound of claim 34 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VI-c):

38. The compound of claim 34 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VI-d):

39. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII'): in R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 5 and R 5A each independently is H, halogen, optionally substituted alkyl, optionally substituted -O-alkyl, cycloalkyl or absent; R 8 and R 8A each independently represents 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 7A are each independently H, halogen, alkyl or optionally substituted alkyl, optionally substituted heteroalkyl, 40. The compound of claim 39 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII'-a):

41. The compound of claim 40 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII'-a-1):

42. The compound of claim 40 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII'-a-2):

43. The compound of claim 39 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (VII):

44. The compound of claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-a):

45. The compound of claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-b):

46. ​​The compound of claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-c):

47. A compound as described in claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-c-1):

48. A compound as described in claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-c-2):

49. The compound of claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d):

50. The compound of claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-1):

51. A compound as described in claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-2):

52. A compound as described in claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-3):

53. The compound of claim 43 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-4):

54. The compound of claim 46 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-5):

55. The compound of claim 46 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-6):

56. The compound of claim 46 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-7):

57. The compound of claim 46 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-8):

58. The compound of claim 46 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-9):

59. The compound of claim 46 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VII-d-10):

60. The compound of claim 39, wherein R 6 is F, CF3 or CH3, and R 7 for 61. The compound of claim 39, wherein R 7 is F, CF3 or CH3, and R 6 for 62. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII′): in R 2 and R 2A each 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 are each independently H, halogen, optionally substituted alkyl or optionally substituted -O-alkyl; R 5 and R 5A Each is independently -OH or absent; Y and Y A Each is independently -CH2- or -(CH2)2-.

63. The compound of claim 62 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII'-a):

64. The compound of claim 62, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (VIII):

65. The compound of claim 64 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-a):

66. The compound of claim 65 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-a-1):

67. The compound of claim 65 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-a-2):

68. The compound of claim 65 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-a-3):

69. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (IX'): in R 2 and R 2A Each of which is independently H, -OH, -NH2, -NHR 3 、-OR 3 or -CONHR 3 ; R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n and n A Each of is independently 1 or 2.

70. The compound of claim 69 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (IX):

71. The compound of claim 70 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (IX-a):

72. The compound of claim 70 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (IX-b):

73. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (X'): in R 2 and R 2A Each independently is H, -CH2OR 3 、-(CH2)2OR 3 、-CH2NHCOR 3 OR 3 ;and R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl.

74. The compound of claim 73 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (X):

75. The compound of claim 74 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (Xa):

76. The compound of claim 74 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Xb):

77. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XI′): in R 2 and R 2A Each of which is independently H, -CONHR 3 、-CH2OR 3 、-(CH2)2OR 3 、-CH2NHCOR 3 OR 3 ; R 3 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and X and X A Each of is independently H or halogen.

78. The compound of claim 77 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XI):

79. The compound of claim 78 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XI-a):

80. The compound of claim 78 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XI-b):

81. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XII′): in R 2 and R 2A Each of which is independently H, -CONHR 4 、-CH2OR 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ; R 3 and R 3A Each of is independently H, optionally substituted alkyl or optionally substituted cycloalkyl; R 4 Each instance of 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 Each instance of is independently 0, 1, 2, or 3; and n1 and n1 A Each instance of is independently 1, 2, or 3.

82. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XII):

83. The compound of claim 82 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XII-a):

84. The compound of claim 82 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XII-b):

85. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XIII′): in R 2 and R 2A Each of which is independently H, -CONHR 4 、-CH2OR 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ; R 3 and R 3A Each of is independently H, optionally substituted alkyl or optionally substituted cycloalkyl; R 4 Each instance of 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; and X and X A Each is independently H, optionally substituted CH2, optionally substituted NH or cycloalkyl.

86. The compound of claim 85 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XIII):

87. The compound of claim 86 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XIII-a):

88. The compound of claim 86 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XIII-b):

89. The compound of claim 86 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (XIII-c):

90. The compound of claim 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XIV'): in R 2 and R 2A Each of the 4 、-(CH2)2OR 4 、-CH2NHCOR 4 OR 4 ; R 3 and R 3A Each of which is independently H, -OH, -NH2, -NHR 5 OR 5 ; R 4 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; R 5 Each instance of is independently H, polyethylene glycol, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, or optionally substituted heteroaryl; and n and n A Each of is independently 1, 2 or 3.

91. The compound of claim 90 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XIV):

92. The compound of claim 91 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XIV-a):

93. The compound of claim 91 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XIV-b):

94. A compound as described in any one of claims 1 to 93, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3, L4, L 1A , L 2A , L 3A and L 4A Each of the 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 bond, or a phosphorothioate bond.

95. The compound of claim 94 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 and / or L 1A is the key.

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

97. The compound of claim 96, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the PEG linker is two, three, four, five, six, seven, eight, nine or ten PEG units in length.

98. A compound or a stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 94 to 97, wherein L2 and / or L 2A Contains structure 99. A compound or a stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 94 to 98, wherein L3 and / or L 3A is an optionally substituted heteroaryl linker.

100. The compound of claim 99 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 and / or L 3A is an optionally substituted partially unsaturated heteroaryl linker.

101. The compound of claim 99 or 100, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 and / or L 3A Contains structure 102. A compound or a stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 94 to 101, wherein L4 and / or L 4A is an optionally substituted heteroalkyl linker.

103. The compound of claim 102, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

104. A compound as described in claim 102 or 103, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the heteroalkyl linker comprises two substituents linked together to form an optionally substituted carbocyclyl ring.

105. The compound of claim 102 or 103 or its stereoisomer, tautomer, prodrug or salt, wherein L4 and / or L 4A Contains structure Wherein X is O or S.

106. A compound as described in any one of claims 102 to 104, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 and / or L 4A Contains structure Wherein X is O or S.

107. A compound or a stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 94 to 106, wherein L1, L2, L3 and L4 and / or L 1A , L 2A , L 3A and L 4A Together they contain the following structures: Wherein X is O or S.

108. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 1 to 107, wherein the compound comprises the following structure: Wherein X is O or S.

109. The compound or stereoisomer, tautomer, prodrug or salt thereof of any one of claims 105 to 108, wherein X is O.

110. The compound or stereoisomer, tautomer, prodrug or salt thereof of any one of claims 105 to 108, wherein X is S.

111. A compound as described in any one of claims 1 to 110, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 1 Contains oligonucleotides.

112. The compound of claim 111 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at its 5' end.

113. The compound of claim 111 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at its 3' end.

114. The compound of claim 111 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at an internal position on the oligonucleotide.

115. The compound of claim 114, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the internal position is an internucleoside linkage.

116. A compound as described in any one of claims 1 to 115, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 1 Conjugated to one or more additional α4β 1 / 7 Ligand oligonucleotides.

117. The compound of claim 116, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is conjugated to two, three, four, five or more than five additional α4β 1 / 7 Ligand.

118. The compound of claim 116 or 117, or a stereoisomer, tautomer, prodrug or salt thereof, wherein 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 on the oligonucleotide, or any combination thereof.

119. The compound of any one of claims 111 to 119, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is a modified oligonucleotide.

120. A composition comprising a compound as described in any one of claims 1 to 119 or a stereoisomer, tautomer, prodrug or salt thereof and a pharmaceutically acceptable excipient.

121. A method for delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject a compound as described in any one of claims 1 to 119, or a stereoisomer, tautomer, prodrug or salt thereof, or a composition as described in claim 120.

122. The method of claim 121, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of striatum, cerebellum, brainstem, hippocampus, frontal cortex, and spinal cord.

123. A method for treating or ameliorating a disease, disorder or symptom thereof in a subject, the method comprising administering to the subject a compound or a stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 1 to 119 or a composition as described in claim 120.

124. The method of claim 123, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.

125. The method of claim 123 or 124, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

126. The method of any one of claims 123 to 125, wherein the compound, or a stereoisomer, tautomer, prodrug or salt thereof, is administered intrathecally to the subject.

127. A method for preparing a compound as described in any one of claims 1 to 119, or a stereoisomer, tautomer, prodrug or salt thereof, comprising one or more compounds described herein and a chemical transformation, including Examples 1-13.

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