CB1 ligand conjugated compounds and uses thereof

Abstract

Provided herein are CB1 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 / 315,472, filed on March 1, 2022, and U.S. Provisional Application No. 63 / 327,345, filed on April 4, 2022. The disclosure of each of the prior applications 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 compounds (e.g., any of those described herein) and methods for targeting cells expressing cannabinoid receptor type 1 (CB1). Certain embodiments provided herein relate to compounds and methods for delivering agents to cells expressing CB1. 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 used to treat a disease, disorder, or symptom of a subject. In certain embodiments, the agent is a diagnostic compound. In certain embodiments, the compound comprises a CB1 ligand and one or more linker moieties for attaching to a therapeutic, prophylactic, or diagnostic agent. In certain embodiments, the compound comprises a CB1 ligand, one or more linker moieties, and a therapeutic agent. In certain embodiments, the therapeutic agent is selected from a small molecule or an oligomeric compound. In certain embodiments, the oligomeric compound is a protein, a peptide, an antibody, an oligonucleotide, or a combination thereof. In certain embodiments, the CB1 ligand is a CB1 agonist. In certain embodiments, the CB1 ligand is a CB1 antagonist. In certain embodiments, the CB1 ligand is a small molecule, an aptamer, a peptide, or an antibody. In certain embodiments, the CB1 ligand is anandamide or a derivative thereof. In certain embodiments, the CB1 ligand is (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide or a derivative thereof. In certain embodiments, the CB1 ligand is any of those described herein, or a derivative or prodrug thereof.

[0008] In certain embodiments, contacting cells expressing CB1 (such as brain cells) with a compound provided herein delivers the agent to the cell. In certain embodiments, contacting cells expressing CB1 (such as brain cells) with a compound provided herein treats a disease, disorder, or symptom in a subject. In certain embodiments, a compound comprising a CB1 ligand selectively or preferentially targets cells expressing CB1 compared to cells that do not express CB1. In certain embodiments, a compound comprising a CB1 ligand selectively or preferentially targets cells that express CB1 compared to a compound that does not contain a CB1 ligand.

[0009] Certain embodiments provided herein relate to compounds and methods for regulating the expression of a nucleic acid target in a cell expressing CB1. 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, cells expressing CB1 (such as brain cells) are contacted with a compound provided herein to regulate the expression or activity of the nucleic acid target in the cell. In certain embodiments, the compound comprises a CB1 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 independently is a cannabinoid receptor type 1 ( CB1 ) ligand;

[0015] L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A each 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 present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"):

[0019]

[0020] in:

[0021] is an oligonucleotide; and

[0022] L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0023] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-a):

[0024]

[0025] in:

[0026] X 1 NR 10 or CR 11 R 12 ;

[0027] X 2 NR 13 or CR 14 R 15 ;

[0028] R 10 、R 11 、R 12 、R 13 、R 14 and R 15 each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0029] R 19 For hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C 、-C(O)R 19D 、-C(O)OR 19D 、-C(O)NR 19B R 19C 、-OR 19A 、-NR 19B SO2R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0030] R 21 For hydrogen, -SO n21 R 21A 、-SO v21 NR 21B R 21C 、-NHNR 21B R 21C 、-ONR 21B R 21C 、-NHC(O)NHNR 21B R 21C 、-NHC(O)NR 21B R 21C 、-NR 21B R 21C 、-C(O)R 21D 、-C(O)OR 21D 、-C(O)NR 21B R 21C 、-OR 21A 、-NR 21B SO2R 21A 、-NR 21B C(O)R 21D 、-NR 21B C(O)OR 21D 、-NR 21B OR 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0031] R 19A 、R 19B 、R 19C 、R 19D 、R 21A 、R 21B 、R 21C and R 21D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 19B and R 19C and R 21B and R 21C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0032] n19 and n21 are each independently 0, 1, 2, 3 or 4;

[0033] v19 and v21 are each independently 1 or 2; and

[0034] L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0035] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-a-1):

[0036]

[0037] where X 1 、X 2 、L1、L2、L3、L4、L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0038] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-a-2):

[0039]

[0040] where X 1 、X 2 、L1、L2、L3、L4、L 1A 、L2A 、L 3A and L 4A As defined herein.

[0041] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-b):

[0042]

[0043] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0044] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-b-1):

[0045]

[0046] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0047] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-b-2):

[0048]

[0049] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0050] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-c):

[0051]

[0052] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0053] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-c-1):

[0054]

[0055] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0056] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I"-c-2):

[0057]

[0058] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0059] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (XII):

[0060]

[0061] in:

[0062] L1, L2, L3, L4, L 1A 、L 2A 、L 3A 、L 4A 、R 1 and R 17 As defined herein;

[0063] z2 and z3 are each independently 0, 1, 2, 3 or 4;

[0064] z4 is 0 or 1;

[0065] R 25 、R 25A 、R 26 and R 26A each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0066] R 27 For hydrogen, -SO n27 R 27A、-SO v27 NR 27B R 27C 、-NHNR 27B R 27C 、-ONR 27B R 27C 、-NHC(O)NHNR 27B R 27C 、-NHC(O)NR 27B R 27C 、-NR 27B R 27C 、-C(O)R 27D 、-C(O)OR 27D 、-C(O)NR 27B R 27C 、-OR 27A 、-NR 27B SO2R 27A 、-NR 27B C(O)R 27D 、-NR 27B C(O)OR 27D 、-NR 27B OR 27D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0067] R 27A 、R 27B 、R 27C and R 27D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 27B and R 27C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0068] R 28 For hydrogen, -SO n28 R 28A 、-SO v28 NR 28B R 28C 、-NHNR 28B R 28C 、-ONR 28B R 28C 、-NHC(O)NHNR 28B R 28C、-NHC(O)NR 28B R 28C 、-NR 28B R 28C 、-C(O)R 28D 、-C(O)OR 28D 、-C(O)NR 28B R 28C 、-OR 28A 、-NR 28B SO2R 28A 、-NR 28B C(O)R 28D 、-NR 28B C(O)OR 28D 、-NR 28B OR 28D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0069] R 27A 、R 27B 、R 27C 、R 27D 、R 28A 、R 28B 、R 28C and R 28D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 27B and R 27C and R 28B and R 28C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0070] n27 and n28 are each independently 0, 1, 2, 3 or 4; and

[0071] v27 and v28 are each independently 1 or 2.

[0072] In some embodiments, z4 is 0.

[0073] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, wherein the CB1 ligand comprises a structure of Formula (XII-a):

[0074]

[0075] Among them, L1, L2, L3, L4, R 17 、R 25 、R 26 、R 27 、R 1 and z2 are as defined herein.

[0076] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (XII-a-1):

[0077]

[0078] Among them, L1, L2, L3, L4, R 17 、R 25 、R 26 、R 27 、R 1 and z2 are as defined herein.

[0079] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (XII-b):

[0080]

[0081] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0082] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (XII-c):

[0083]

[0084] Among them, L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A As defined herein.

[0085] In another aspect, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (I):

[0086]

[0087] in

[0088] It is a cannabinoid receptor type 1 (CB1) ligand;

[0089] L1, L2, L3 and L4 are each independently a linker, a bond or absent; and

[0090] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0091] In some embodiments, the CB1 ligand is a CB1 agonist. In some embodiments, the CB1 ligand is a CB1 antagonist. In some embodiments, CB1 The ligand is a selective ligand. In some embodiments, CB1 The ligand is a non-selective ligand. In certain embodiments, CB1 The ligand is selected from the group consisting of minocycline, dronabinol, epigallocatechin, epicatechin, kavaccin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonylglycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP55,940, JWH-018, WIN55,212-2, GAT2 28. Cannabidiol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutane-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti- CB1 Antibodies and their derivatives.

[0092] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, wherein the CB1 ligand comprises a structure of Formula (II'):

[0093]

[0094] in:

[0095] R 17 For hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR17B R 17C 、-NR 17B R 17C 、-C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C 、-OR 17A 、-NR 17B SO2R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0096] R 17A 、R 17B 、R 17C and R 17D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0097] n17 is 0, 1, 2, 3 or 4; and

[0098] v17 is 1 or 2.

[0099] In some embodiments, R 17 -NR 17B R 17C 、-C(O)R 17D or-C(O)OR 17D In some embodiments, R 17B and R 17C Each is independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl.

[0100] In certain embodiments, the CB1 ligand comprises the structure

[0101] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (II):

[0102]

[0103] where R 1 、R 17 , L1, L2, L3 and L4 are as defined herein.

[0104] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (II-a):

[0105]

[0106] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0107] In certain embodiments, the CB1 ligand comprises the structure or its derivatives.

[0108] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (III):

[0109]

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

[0111] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (III-a):

[0112]

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

[0114] In some aspects, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII):

[0115]

[0116] in:

[0117] L1, L2, L3 and L4 are each independently a linker, a bond or absent;

[0118] R 1comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides;

[0119] R 3 、R 4 、R 5 、R 6 and R 8 each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0120] R 9 is hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl; or R 6 and R 9 The substituents may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;

[0121] R 7 For hydrogen, -SO n7 R 7A 、-SO v7 NR 7B R 7C 、-NHNR 7B R 7C 、-ONR 7B R 7C 、-NHC(O)NHNR 7B R 7C 、-NHC(O)NR 7B R 7C 、-NR 7B R 7C 、-C(O)R 7D 、-C(O)OR 7D 、-C(O)NR 7B R 7C 、-OR 7A 、-NR 7B SO2R 7A 、-NR 7B C(O)R 7D 、-NR 7B C(O)OR 7D 、-NR 7B OR 7D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0122] R 7A 、R 7B 、R 7C 、R 7Dare each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 7B and R 7C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0123] n7 is 0, 1, 2, 3 or 4; and

[0124] v7 is 1 or 2.

[0125] In some embodiments, R 7 and R 8 Each is independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. 4 is halogen; and R 3 、R 5 and R 6 are each independently hydrogen. In some embodiments, R 3 、R 4 、R 5 and R 6 are each independently hydrogen. In certain embodiments, R 6 and R 9 The substituents are joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl. 9 is hydrogen or optionally substituted alkyl.

[0126] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-a):

[0127]

[0128] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0129] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-a-1):

[0130]

[0131] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0132] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-a-2):

[0133]

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

[0135] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-b):

[0136]

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

[0138] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-b-1):

[0139]

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

[0141] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-c):

[0142]

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

[0144] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-c-1):

[0145]

[0146] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0147] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-c-2):

[0148]

[0149] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0150] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-d):

[0151]

[0152] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0153] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-d-1):

[0154]

[0155] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0156] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VIII-d-2):

[0157]

[0158] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0159] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IX):

[0160]

[0161] in:

[0162] L1, L2, L3 and L4 are each independently a linker, a bond or absent;

[0163] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides;

[0164] X 1 NR 10 or CR 11 R 12 ;

[0165] R 10 、R11 and R 12 each independently is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0166] R 19 For hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C 、-C(O)R 19D 、-C(O)OR 19D 、-C(O)NR 19B R 19C 、-OR 19A 、-NR 19B SO2R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0167] R 19A 、R 19B 、R 19C 、R 19D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 19B and R 19C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0168] n19 is 0, 1, 2, 3, or 4; and

[0169] v19 is 1 or 2.

[0170] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IX-a-1):

[0171]

[0172] where X 1 、R 1 , L1, L2, L3 and L4 are as defined herein.

[0173] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IX-a-2):

[0174]

[0175] where X 1 、R 1 , L1, L2, L3 and L4 are as defined herein.

[0176] In some embodiments, X 1 NR 10 ; and R 10 is hydrogen or optionally substituted alkyl. 10 is hydrogen, -CH3 or -CH2CH2F. In some embodiments, X 1 CR 11 R 12 ; and R 11 and R 12 Each is independently hydrogen or optionally substituted alkyl. 11 is hydrogen, -CH3 or -CH2CH2F; and R 12 For hydrogen.

[0177] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (X):

[0178]

[0179] in:

[0180] L1, L2, L3 and L4 are each independently a linker, a bond or absent;

[0181] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides;

[0182] R16 For hydrogen, halogen, -CN, -N3, -NO2, -NR 16B R 16C 、-C(O)R 16D 、-C(O)OR 16D 、-C(O)NR 16B R 16C 、-OR 16A 、-NR 16B C(O)R 16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0183] R 16A 、R 16B 、R 16C and R 16D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 16B and R 16C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[0184] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (Xa):

[0185]

[0186] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0187] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (Xa-1):

[0188]

[0189] where R 1 , L1, L2, L3 and L4 are as defined herein.

[0190] In certain embodiments, the CB1 ligand comprises the structure:

[0191]

[0192] or its derivatives.

[0193] In some embodiments, the compound comprises the structure:

[0194]

[0195]

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

[0197] In some embodiments, L1, L2, L3, and L4 are each 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, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester bond, or a phosphorothioate bond.

[0198] In certain embodiments, L1 is a bond. In certain embodiments, L1 is oxygen. In certain embodiments, L1 comprises the structure wherein n7 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0199] In some embodiments, L2 is an optionally substituted PEG linker. In some embodiments, the PEG linker is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length. In some embodiments, L2 is an optionally substituted alkyl linker. In certain embodiments, L2 comprises the structure

[0200] In some embodiments, L4 is an optionally substituted heteroalkyl linker or bond. In certain embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In some embodiments, L4 comprises the structure

[0201] wherein X is O or S. In certain embodiments, L4 comprises the structure

[0202]

[0203] Wherein X is O or S.

[0204] In some embodiments, L3 is an optionally substituted heteroaryl linker. In some embodiments, one of L3 and L4 is an optionally substituted phosphodiester bond or an optionally substituted phosphorothioate bond, and the other of L3 and L4 is a bond. In some embodiments, L3 is an optionally substituted partially unsaturated heteroaryl or an optionally substituted partially unsaturated heterocycloalkyl linker. In certain embodiments, L3 comprises the structure

[0205] In some embodiments, L1, L2, L3, and L4 together comprise the following structure:

[0206]

[0207]

[0208] in:

[0209] X is O or S;

[0210] n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0211] n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

[0212] In certain embodiments, L1, L2, L3, and L4 together comprise the following structure:

[0213]

[0214] in:

[0215] X is O or S; and

[0216] n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[0217] n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

[0218] In some embodiments, X is S. In some embodiments, X is O.

[0219] In another aspect, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising a structure of Formula (IV') or a salt thereof:

[0220]

[0221] in:

[0222] each independently a cannabinoid receptor type 1 (CB1) ligand, or One of them is a CB1 ligand, and The other of comprises a lipid or a ligand;

[0223] L1, L2, L3, L4, L5, L 1A 、L 2A 、L A3 、L A4 and L A5 each independently a linker, a bond, or absent; and

[0224] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0225] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IV"):

[0226]

[0227] in:

[0228] is an oligonucleotide, and

[0229] L1, L2, L3, L4, L5, L 1A 、L 2A 、L A3 、L A4 and L A5 As defined herein.

[0230] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IV"-a):

[0231]

[0232] where R 17 For hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R 17C 、-NR 17B R 17C 、-C(O)R 17D 、-C(O)OR 17D、-C(O)NR 17B R 17C 、-OR 17A 、-NR 17B SO2R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0233] R 18 For hydrogen, -SO n18 R 18A 、-SO v18 NR 18B R 18C 、-NHNR 18B R 18C 、-ONR 18B R 18C 、-NHC(O)NHNR 18B R 18C 、-NHC(O)NR 18B R 18C 、-NR 18B R 18C 、-C(O)R 18D 、-C(O)OR 18D 、-C(O)NR 18B R 18C 、-OR 18A 、-NR 18B SO2R 18A 、-NR 18B C(O)R 18D 、-NR 18B C(O)OR 18D 、-NR 18B OR 18D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0234] R 22 For hydrogen, -SO n22 R 22A 、-SO v22 NR 22B R 22C 、-NHNR 22B R 22C 、-ONR 22B R 22C、-NHC(O)NHNR 22B R 22C 、-NHC(O)NR 22B R 22C 、-NR 22B R 22C 、-C(O)R 22D 、-C(O)OR 22D 、-C(O)NR 22B R 22C 、-OR 22A 、-NR 22B SO2R 22A 、-NR 22B C(O)R 22D 、-NR 22B C(O)OR 22D 、-NR 22B OR 22D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0235] R 23 For hydrogen, -SO n23 R 23A 、-SO v23 NR 23B R 23C 、-NHNR 23B R 23C 、-ONR 23B R 23C 、-NHC(O)NHNR 23B R 23C 、-NHC(O)NR 23B R 23C 、-NR 23B R 23C 、-C(O)R 23D 、-C(O)OR 23D 、-C(O)NR 23B R 23C 、-OR 23A 、-NR 23B SO2R 23A 、-NR 23B C(O)R 23D 、-NR 23B C(O)OR 23D 、-NR 23B OR 23D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0236] R24 For hydrogen, -SO n24 R 24A 、-SO v24 NR 24B R 24C 、-NHNR 24B R 24C 、-ONR 24B R 24C 、-NHC(O)NHNR 24B R 24C 、-NHC(O)NR 24B R 24C 、-NR 24B R 24C 、-C(O)R 24D 、-C(O)OR 24D 、-C(O)NR 24B R 24C 、-OR 24A 、-NR 24B SO2R 24A 、-NR 24B C(O)R 24D 、-NR 24B C(O)OR 24D 、-NR 24B OR 24D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0237] R 17A 、R 17B 、R 17C 、R 17D 、R 18A 、R 18B 、R 18C 、R 18D 、R 22A 、R 22B 、R 22C 、R 22D 、R 23A 、R 23B 、R 23C and R 23D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0238] n17, n18, n22 and n23 are each independently 0, 1, 2, 3 or 4; and

[0239] v17, v18, v22 and v23 are each independently 1 or 2.

[0240] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IV"-b):

[0241]

[0242] Among them, L1, L2, L3, L4, L5, L 1A 、L 2A 、L A3 、L A4 and L A5 As defined herein.

[0243] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IV"-b-1):

[0244]

[0245] Among them, L1, L2, L3, L4, L5, L 1A 、L 2A 、L A3 、L A4 and L A5 As defined herein.

[0246] In some aspects, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising a structure of Formula (IV) or a salt thereof:

[0247]

[0248] in:

[0249] each independently a cannabinoid receptor type 1 (CB1) ligand, or One of them is a CB1 ligand, and The other of comprises a lipid or a ligand;

[0250] L1, L2, L3, L4 and L5 are each independently a linker, a bond or absent; and

[0251] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0252] In some embodiments, wherein Each is independently a CB1 ligand. In some embodiments, one or both of the CB1 ligands is a CB1 agonist. In some embodiments, one or both of the CB1 ligands is a CB1 antagonist. In some embodiments, CB1 The ligand is a selective ligand. In some embodiments, CB1 The ligand is a non-selective ligand. In certain embodiments, CB1 The ligands are each independently selected from the group consisting of minocycline, dronabinol, epigallocatechin, epicatechin, kavaccin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonylglycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP55,940, JWH-018, WIN55,212-2, GA T228, cannabinol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutane-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti- CB1 Antibodies and derivatives thereof. In some embodiments, each CB1 ligand comprises the structure or its derivatives.

[0253] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (V):

[0254]

[0255] in:

[0256] R 17 For hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R17 C 、-NR17B R 17C 、-C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C 、-OR 17A 、-NR 17B SO2R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0257] R 18 For hydrogen, -SO n18 R 18A 、-SO v18 NR 18B R 18C 、-NHNR 18B R 18C 、-ONR 18B R 18C 、-NHC(O)NHNR 18B R 18C 、-NHC(O)NR 18B R 18C 、-NR 18B R 18C 、-C(O)R 18D 、-C(O)OR 18D 、-C(O)NR 18B R 18C 、-OR 18A 、-NR 18B SO2R 18A 、-NR 18B C(O)R 18D 、-NR 18B C(O)OR 18D 、-NR 18B OR 18D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0258] R 17A 、R 17B 、R 17C 、R 17D 、R 18A 、R 18B 、R18C and R 18D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R 17B and R 17C or R 18B and R 18C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0259] n17 and n18 are each independently 0, 1, 2, 3 or 4; and

[0260] v17 and v18 are each independently 1 or 2.

[0261] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (Va):

[0262]

[0263] where R 1 , L1, L2, L3, L4 and L5 are as defined herein.

[0264] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the following structure:

[0265] or a derivative thereof, and the other CB1 ligand comprises the following structure:

[0266] or its derivatives.

[0267] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IX):

[0268]

[0269] where R 1 , L1, L2, L3, L4 and L5 are as defined herein.

[0270] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (IX-a):

[0271]

[0272] where R 1 , L1, L2, L3, L4 and L5 are as defined herein.

[0273] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, wherein the CB1 ligands each independently comprise a structure of the formula:

[0274]

[0275] in:

[0276] X 1 NR 10 or CR 11 R 12 ;

[0277] R 10 、R 11 and R 12 each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0278] R 19 For hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C 、-C(O)R 19D 、-C(O)OR 19D 、-C(O)NR 19B R 19C 、-OR 19A 、-NR 19B SO2R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0279] R 19A 、R 19B 、R 19C and R 19D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 19B and R 19C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0280] n19 is 0, 1, 2, 3, or 4; and

[0281] v19 is 1 or 2.

[0282] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (XI):

[0283]

[0284] in:

[0285] L1, L2, L3, L4 and L5 are as defined herein;

[0286] X 1 NR 10 or CR 11 R 12 ;

[0287] X 2 NR 13 or CR 14 R 15 ;

[0288] R 10 、R 11 、R 12 、R 13 、R 14 and R 15 each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0289] R 19A 、R 19B 、R 19C 、R 19D 、R 21A 、R 21B 、R 21C and R 21D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 21B and R 21C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0290] n19 and n21 are each independently 0, 1, 2, 3 or 4; and

[0291] v19 and v21 are each independently 1 or 2.

[0292] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (XI-a):

[0293]

[0294] where X 1 、X 2 , L1, L2, L3, L4 and L5 are as defined herein.

[0295] In some embodiments, X 1 NR 10 ;X 2 NR 13 ; and R 10 and R 13 Each is independently hydrogen or optionally substituted alkyl. 10 and R 13 Each is independently hydrogen, -CH3 or -CH2CH2F. In some embodiments, X 1 CR 11 R 12 ;X 2 CR 14 R 15 ; and R 11 、R 12 、R 14 and R 15 Each is independently hydrogen or optionally substituted alkyl.12 and R 15 are each independently hydrogen, -CH3 or -CH2CH2F; and R 11 and R 14 are each independently hydrogen.

[0296] In some embodiments, L1, L2, L3, L4 and L5 are each 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, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester bond, or a phosphorothioate bond.

[0297] In some embodiments, L1 and L5 are each an optionally substituted PEG linker. In some embodiments, L1 and L5 are each an optionally substituted PEG linker of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length.

[0298] In some embodiments, L2 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L2 comprises the structure

[0299] In some embodiments, L3 is an optionally substituted heteroaryl linker. In some embodiments, L3 is an optionally substituted partially unsaturated heteroaryl linker or an optionally substituted partially unsaturated heterocycloalkyl linker. In certain embodiments, L3 comprises the structure

[0300] In some embodiments, L4 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In some embodiments, L4 comprises the structure

[0301] wherein X is O or S. In certain embodiments, L4 comprises the structure

[0302] Wherein X is O or S.

[0303] In some embodiments, X is S. In some embodiments, X is O.

[0304] In some embodiments, L1, L2, L3, L4, and L5 together comprise the following structure:

[0305]

[0306]

[0307] wherein X is O or S. In certain embodiments, L1, L2, L3, L4 and L5 together comprise the following structure:

[0308]

[0309]

[0310]

[0311] Wherein X is O or S.

[0312] In some aspects, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VI) or a salt thereof:

[0313]

[0314] in:

[0315] It is a cannabinoid receptor type 1 (CB1) ligand;

[0316] L1, L2, L3, L4, L5, L6 and L7 are each independently a linker, a bond or absent; and

[0317] R 1 and R 2 Each comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0318] In some embodiments, the CB1 ligand is a CB1 agonist. In some embodiments, the CB1 ligand is a CB1 antagonist. In certain embodiments, CB1 The ligand is selected from the group consisting of minocycline, dronabinol, epigallocatechin, epicatechin, kavaccin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonylglycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP55,940, JWH-018, WIN55,212-2, GAT2 28. Cannabidiol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutane-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti- CB1Antibodies and derivatives thereof. In certain embodiments, the CB1 ligand comprises the structure

[0319] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VII):

[0320]

[0321] in:

[0322] R 17 For hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R17 C 、-NR 17B R 17C 、-C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C 、-OR 17A 、-NR 17B SO2R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0323] R 17A 、R 17B 、R 17C and R 17D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17CThe substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0324] n17 is 0, 1, 2, 3 or 4; and

[0325] v17 is 1 or 2.

[0326] In some embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the structure of Formula (VII-a):

[0327]

[0328] where R 1 、R 2 , L1, L2, L3, L4, L5, L6 and L7 are as defined herein.

[0329] In some embodiments, L1, L2, L3, L4, L5, L6 and L7 are each 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.

[0330] In some embodiments, L1 is an optionally substituted PEG linker.In certain embodiments, each L1 is an optionally substituted PEG linker of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length.

[0331] In some embodiments, L2 and L5 are each independently an optionally substituted PEG linker. In some embodiments, L2 and L5 are each independently an optionally substituted PEG linker of three or four PEG units in length. In certain embodiments, L1, L2, and L5 together comprise the structure

[0332] In some embodiments, L3 and L6 are each independently an optionally substituted heteroaryl linker or an optionally substituted heterocycloalkyl linker. In some embodiments, L3 and L6 are each independently an optionally substituted partially unsaturated heteroaryl linker or an optionally substituted partially unsaturated heterocycloalkyl linker. In certain embodiments, L3 and L6 each comprise the structure

[0333] In some embodiments, L4 and L7 are each independently an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In some embodiments, L4 and L7 each comprise the structure

[0334]

[0335] wherein X is O or S. In certain embodiments, L4 and L7 each comprise the structure

[0336]

[0337] Wherein X is O or S.

[0338] 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 an internucleoside linkage. In some embodiments, R 1 Contains an oligonucleotide conjugated to one or more additional CB1 ligands. In certain embodiments, the oligonucleotide is conjugated to two, three, four, five, or more than five additional CB1 ligands. In some embodiments, the additional CB1 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.

[0339] In some embodiments, L1, L2, L3, and L4 together comprise the following structure:

[0340]

[0341]

[0342] Wherein X is O or S.

[0343] In certain embodiments, L1, L2, L3, and L4 together comprise the following structure:

[0344] Wherein X is O or S.

[0345] In some embodiments, L1, L2, L3, L4, L5, L6, and L7 together comprise the following structure:

[0346]

[0347]

[0348] Wherein X is O or S.

[0349] In certain embodiments, L1, L2, L3, L4, L5, L6, and L7 taken together comprise the following structure.

[0350] Wherein X is O or S.

[0351] In some aspects, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the following structure:

[0352]

[0353]

[0354] in:

[0355] R 1 and R 2 each comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; and

[0356] X is O or S.

[0357] In some embodiments, the present disclosure provides compounds comprising the following structure:

[0358]

[0359]

[0360] In some aspects, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the following structure:

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374] in:

[0375] R 1 and R 2 each comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; and

[0376] X is O or S.

[0377] In certain embodiments, the present disclosure provides compounds, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the following structure:

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388] in:

[0389] is an oligonucleotide; and

[0390] X is O or S.

[0391] In some embodiments, X is S. In some embodiments, X is O.

[0392] In some embodiments, any compound provided herein is provided as a salt, and the salt is a potassium salt or a sodium salt.

[0393] In another aspect, the present disclosure provides a composition comprising any of the compounds or salts thereof and a pharmaceutically acceptable excipient.

[0394] In another aspect, the disclosure provides a method for delivering a therapeutic oligonucleotide to a subject's brain, the method comprising administering to the subject any compound or salt thereof provided herein or any composition provided herein. In some embodiments, the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal cortex, and spinal cord.

[0395] In another aspect, the disclosure provides a method for treating or improving a disease, disorder or its symptom of a subject, the method comprising administering to the subject any compound or its salt provided herein or any composition provided herein. In some embodiments, the disease, disorder or its symptom is a central nervous system (CNS) disease, disorder or its symptom. In certain embodiments, the disease, disorder or its symptom is Alzheimer's disease or its symptom. In some embodiments, administration is intrathecal administration or intracerebroventricular (ICV) administration.

[0396] In another aspect, the present disclosure provides a precursor compound of any one of structural formulas (A)-(M), and stereoisomers, tautomers, and salts thereof:

[0397]

[0398]

[0399]

[0400] in:

[0401] L 1 、L 2 、L 3 、L 4 、L 5 、L 6 and L 7 each independently a linker, a bond, or absent;

[0402] X 1 NR 10 or CR 11 R 12 ;

[0403] X 2 NR 13 or CR 14 R 15 ;

[0404] R 3 、R 4 、R 5 、R 6 and R 8each independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0405] R 9 is hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl; or R 6 and R 9 The substituents may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;

[0406] R 7 For hydrogen, -SO n7 R 7A 、-SO v7 NR 7B R 7C 、-NHNR 7B R 7C 、-ONR 7B R 7C 、-NHC(O)NHNR 7B R 7C 、-NHC(O)NR 7B R 7C 、-NR 7B R 7C 、-C(O)R 7D 、-C(O)OR 7D 、-C(O)NR 7B R 7C 、-OR 7A 、-NR 7B SO2R 7A 、-NR 7B C(O)R 7D 、-NR 7B C(O)OR 7D 、-NR 7B OR 7D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0407] R 7A 、R 7B 、R 7C 、R 7D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 7B and R 7CThe substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0408] n7 is 0, 1, 2, 3, or 4;

[0409] v7 is 1 or 2;

[0410] R 10 、R 11 、R 12 、R 13 、R 14 and R 15 each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0411] R 16 For hydrogen, halogen, -CN, -N3, -NO2, -NR 16B R 16C 、-C(O)R 16D 、-C(O)OR 16D 、-C(O)NR 16B R 16C 、-OR 16A 、-NR 16B C(O)R 16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0412] R 17 For hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R 17C 、-NR 17B R 17C 、-C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C 、-OR 17A 、-NR 17B SO2R 17A 、-NR 17B C(O)R17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0413] R 18 For hydrogen, -SO n18 R 18A 、-SO v18 NR 18B R 18C 、-NHNR 18B R 18C 、-ONR 18B R 18C 、-NHC(O)NHNR 18B R 18C 、-NHC(O)NR 18B R 18C 、-NR 18B R 18C 、-C(O)R 18D 、-C(O)OR 18D 、-C(O)NR 18B R 18C 、-OR 18A 、-NR 18B SO2R 18A 、-NR 18B C(O)R 18D 、-NR 18B C(O)OR 18D 、-NR 18B OR 18D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0414] R 19 For hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C、-C(O)R 19D 、-C(O)OR 19D 、-C(O)NR 19B R 19C 、-OR 19A 、-NR 19B SO2R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0415] R 20 For hydrogen, -SO n20 R 20A 、-SO v20 NR 20B R 20C 、-NHNR 20B R 20C 、-ONR 20B R 20C 、-NHC(O)NHNR 20B R 20C 、-NHC(O)NR 20B R 20C 、-NR 20B R 20C 、-C(O)R 20D 、-C(O)OR 20D 、-C(O)NR 20B R 18C 、-OR 20A 、-NR 20B SO2R 20A 、-NR 20B C(O)R 20D 、-NR 20B C(O)OR 20D 、-NR 20B OR 20D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0416] R 21 are independently hydrogen, -SO n21 R 21A 、-SO v21 NR 21B R 21C 、-NHNR 21B R21C 、-ONR 21B R 21C 、-NHC(O)NHNR 21B R 21C 、-NHC(O)NR 21B R 21C 、-NR 21B R 21C 、-C(O)R 21D 、-C(O)OR 21D 、-C(O)NR 21B R 21C 、-OR 21A 、-NR 21B SO2R 21A 、-NR 21B C(O)R 21D 、-NR 21B C(O)OR 21D 、-NR 21B OR 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; n19 and n21 are each independently 0, 1, 2, 3 or 4;

[0417] v19 and v21 are each independently 1 or 2;

[0418] R 16A 、R 16B 、R 16C 、R 16D 、R 17A 、R 17B 、R 17C 、R 17D 、R 18A 、R 18B 、R 18C 、R 18D 、R 19A 、R 19B 、R 19C 、R 19D 、R 20A 、R 20B 、R 20C 、R 20D 、R 21A 、R 21B 、R 21C and R 21Dare each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 16B and R 16C 、R 17B and R 17D 、R 18B and R 18D 、R 19B and R 19C 、R 20B and R 20C , and R 21B and R 21C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

[0419] n16, n17, n18, n19, n20 and n21 are each independently 0, 1, 2, 3 or 4; and

[0420] v16, v17, v18, v19, v20 and v21 are each independently 1 or 2.

[0421] In another aspect, the present disclosure provides a method for preparing any compound provided herein, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising contacting any precursor compound provided herein with a compound of structural formula (W) and / or (Q), or a salt thereof:

[0422] and / or

[0423]

[0424] where X 7 and X 8 are each independently O or S.

[0425] 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 2-24. BRIEF DESCRIPTION OF THE DRAWINGS

[0426] Figure 1 Compound 2 is provided 1 H NMR.

[0427] Figure 2 Compound 3 is provided 1 HNMR.

[0428] Figure 3 Compound 3 is provided 31 P NMR.

[0429] Figure 4 Compound 4 is provided 1 H NMR.

[0430] Figure 5 Compound 6 is provided 1 H NMR.

[0431] Figure 6 Compound 10 is provided 1 H NMR.

[0432] Figure 7 Compound 11 is provided 1 H NMR.

[0433] Figure 8 Compound 15 is provided 1 H NMR.

[0434] Figure 9 The mass spectrum of Compound 15 is provided. DETAILED DESCRIPTION

[0435] definition

[0436] 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.

[0437] Unless otherwise indicated, the following terms have the following meanings:

[0438] 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.

[0439] 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.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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.

[0445] 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.

[0446] 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.

[0447] 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.

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] 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.

[0453] The term "diastereomer" refers to stereoisomers that have two or more asymmetric centers and whose molecules are not mirror images of one another.

[0454] 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."

[0455] 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.

[0456] 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 by phosphorus atoms. The term "pre-oligonucleotide" or "prenucleotide" or "nucleic acid prodrug" refers to an oligonucleotide modified to become a prodrug of an oligonucleotide. Phosphonate and phosphate prodrugs may be present 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.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] Throughout the specification and claims, the word "comprise" is used in its non-exclusive sense, unless the context requires otherwise.

[0461] 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.

[0462] 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).

[0463] 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.

[0464] 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.

[0465] 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.

[0466] 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.

[0467] 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 moiety. The alkenyl group may be optionally substituted with one or more substituents.

[0468] 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.

[0469] 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.

[0470] The term "alkoxy" refers to an -O-alkyl substituent.

[0471] As used herein, the term "halogen," "halo," or "halo" means -F, -Cl, -Br, or -I.

[0472] The term "alkylthio" refers to an -S-alkyl substituent.

[0473] The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

[0474] 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.

[0475] The term "haloalkoxyalkyl" refers to an -alkyl-O-alkyl' group wherein the alkyl' group is substituted with one or more halo substituents.

[0476] The term "haloalkylaminocarbonyl" refers to a -C(O)-amino-alkyl group wherein the alkyl group is substituted with one or more halo substituents.

[0477] 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.

[0478] The term "haloalkylcarbonyl" refers to a -C(O)-alkyl group substituted with one or more halogen substituents. Examples of haloalkylcarbonyl groups include trifluoroacetyl.

[0479] 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.

[0480] The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.

[0481] The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.

[0482] The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.

[0483] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0484] 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.

[0485] The term "aryloxy" refers to an -O-aryl substituent.

[0486] The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.

[0487] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.

[0488] The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.

[0489] The term "aralkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0490] The term "aralkylsulfonyl" refers to a -S(O)2-alkyl-aryl substituent.

[0491] The term "aralkylsulfinyl" refers to a -S(O)-alkyl-aryl substituent.

[0492] The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.

[0493] The term "alkaryl" refers to an -aryl-alkyl substituent.

[0494] The term "aralkyl" refers to an -alkyl-aryl substituent.

[0495] 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).

[0496] 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” is recited, followed by a specific heteroalkyl group such as —NR′R″, etc., it should be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited to increase clarity. Thus, the term “heteroalkyl” should not be construed herein to exclude specific heteroalkyl groups, such as —NR′R″, etc.

[0497] 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.

[0498] 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.

[0499] 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.

[0500] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0501] The term "heteroaryloxy" refers to an -O-heteroaryl substituent.

[0502] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.

[0503] The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.

[0504] 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).

[0505] 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.

[0506] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0507] 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.

[0508] symbol Indicates the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.

[0509] 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.

[0510] 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.

[0511] 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.

[0512] 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.

[0513] 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, Alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl or arylamino substituted aryl; 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 P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0514] 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.

[0515] 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.

[0516] 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.

[0517] 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).

[0518] 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.

[0519] 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-benzyloxyethyl , 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 , bis(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfan-2-yl, benzisothiazolyl S,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 toluenesulfonate (Ts).

[0520] 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 Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, incorporated herein by reference.

[0521] The term "antisense oligonucleotide" or "antisense strand" means an oligonucleotide that contains a region that is complementary to a target nucleic acid.

[0522] 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.

[0523] 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.

[0524] The term "nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

[0525] 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.

[0526] 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.

[0527] 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.

[0528] 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.

[0529] 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.

[0530] "Target region" means a portion of a target nucleic acid that is targeted by one or more compounds.

[0531] 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.

[0532] "Terminus group" means a chemical group or group of atoms covalently attached to the terminus of an oligonucleotide.

[0533] The term "ligand" refers to a substance that binds to or interacts with a protein, nucleic acid, or other biomolecule. 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 the CB1 receptor.

[0534] The term "cannabinoid receptor type 1" or "CB1" refers to the G protein-coupled receptor for cannabinoids. In humans, CB1 is encoded by the CNR1 gene. CB1 is also known as cannabinoid receptor 1.

[0535] The term "cannabinoid receptor type 2" or "CB2" refers to the G protein-coupled receptor for cannabinoids. In humans, CB2 is encoded by the CNR2 gene. CB2 is also known as cannabinoid receptor 2.

[0536] The term "cannabinoid receptor type 3" or "CB3" refers to the G protein-coupled receptor for cannabinoids. CB3 is also known as cannabinoid receptor 3 and is an orphan receptor. In certain embodiments, CB3 is also known as GPR55 (i.e., G protein-coupled receptor 55), which is a putative "type 3" cannabinoid receptor.

[0537] In certain embodiments, the compounds provided herein modulate CB1. In certain embodiments, the compounds provided herein modulate CB2. In certain embodiments, the compounds provided herein modulate CB3.

[0538] 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.

[0539] 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.

[0540] 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).

[0541] 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.

[0542] 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.

[0543] 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.

[0544] 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.

[0545] 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).

[0546] 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).

[0547] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage is modified.

[0548] "Nucleobase sequence" means the order of consecutive nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

[0549] 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.

[0550] "Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

[0551] 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.

[0552] Certain embodiments

[0553] In certain embodiments, the compound comprises a CB1 ligand and one or more linker moieties. In certain embodiments, the compound is selected from any of the formulae provided herein (e.g., Formula (I), (I'), (I"), (I"-a), (I"-a-1), (I"-a-2), (I"-b), (I"-b-1), (I"-b-2), (I"-c), (I"-c-1), (I"-c-2), (II), (II'), (II-a), (III), (III-a), (VIII), (VIII-a), (VIII-a-1), (VIII-a-2), (VIII-b), (VIII-b-1), (VIII-c), (VIII-c-1) , (VIII-c-2), (VIII-d), (VIII-d-1), (VIII-d-2), (IX), (IX-a-1), (IX-a-2), (X), (Xa), (Xa-1), (IV'), (IV"), (IV"-a), (IV"-b), (IV"-b-1), (IV), (V), (Va), (IX), (IX-a), (XI), (XI-a), (VI), (VII), (VII-a), (XII), (XII-a), (XII-a-1), (XII-b), and (XII-c)), or a salt thereof as described herein. In certain embodiments, one or more linker moieties (L1, L2, L3, L4, L5, L6, L7, etc.) connect the CB1 ligand to a therapeutic, prophylactic, or diagnostic agent. In certain embodiments, the compound further comprises one or more therapeutic, prophylactic, or diagnostic agents. In certain embodiments, the therapeutic, prophylactic, or diagnostic agent is a small molecule or oligomeric compound. In certain embodiments, the oligomeric compound comprises a protein, peptide, antibody, oligonucleotide, or a combination thereof.

[0554] 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.

[0555] 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.

[0556] 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.

[0557] 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 three or four PEG units in length. In certain embodiments, the linker comprises the structure In some embodiments, the linker is two or three PEG units in length.

[0558] 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

[0559] In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the linker is substituted with one or more =0 substituents. In certain embodiments, the linker comprises the structure Wherein X is O or S.

[0560] In some embodiments, the linker comprises the structure

[0561] Wherein X is O or S.

[0562] In some embodiments, the linker is a phosphodiester bond or a phosphorothioate bond. In certain embodiments, the linker comprises the structure Wherein X is O or S.

[0563] In certain embodiments, the linker comprises the structure Wherein X is O or S.

[0564] In some embodiments, the linker is an optionally substituted PEG linker. In some embodiments, the linker is an optionally substituted PEG linker of three PEG units in length. In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, the linker comprises the structure 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 certain embodiments, the linker comprises the structure In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments, the linker comprises the structure wherein X is O or S. In some embodiments, the linker comprises the structure Wherein X is O or S.

[0565] In some embodiments, the linker is an optionally substituted PEG linker. In certain embodiments, the linker is an optionally substituted PEG linker of two or three PEG units in length. In some embodiments, the linker is an optionally substituted PEG linker. In some embodiments, the linker is an optionally substituted PEG linker of three or four PEG units in length. In certain embodiments, the linker comprises the structure 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 certain embodiments, the linker comprises the structure In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments, the linker comprises the structure wherein X is O or S. In some embodiments, the linker comprises the structure Wherein X is O or S.

[0566] In certain embodiments, the compound comprises or consists of one of the following structures:

[0567]

[0568]

[0569] or a salt thereof, wherein X is O or S.

[0570] In some embodiments, X is O. In some embodiments, X is S.

[0571] In some embodiments, R 1 (and R 2 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 Comprising an oligonucleotide conjugated to one or more additional CB1 ligands. In some embodiments, the oligonucleotide is conjugated to two, three, four, five, or more than five additional CB1 ligands. In certain embodiments, the additional CB1 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.

[0572] Certain embodiments provide a composition comprising a compound according to any of the embodiments herein and a pharmaceutically acceptable carrier or excipient.

[0573] Certain embodiments provide a composition comprising a compound according to any of the embodiments herein for use in therapy.

[0574] 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 CB1 on the surface of the cell. 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, the cell is in an animal.

[0575] In certain embodiments, a method of regulating the expression of a nucleic acid target in a cell comprises contacting the cell with a compound of any embodiment herein, thereby regulating the expression of the nucleic acid target in the cell. In certain embodiments, the cell expresses CB1 on the surface of the cell. 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 the expression of the nucleic acid target. In certain embodiments, the nucleic acid target is pre-mRNA, mRNA, non-coding RNA or miRNA. In certain embodiments, the cell is in an animal.

[0576] In certain embodiments, a method for regulating the expression of a nucleic acid target in a subject comprises administering any compound or composition provided herein to the subject, thereby regulating the expression of the nucleic acid target in the subject. In certain embodiments, the expression of the nucleic acid is regulated in cells of a subject expressing CB1 on the surface of the cell. In certain embodiments, the expression of the nucleic acid is regulated in brain cells. In certain embodiments, the cells expressing CB1 on their surface are brain cells. In certain embodiments, the brain cells are cells of the frontal cortex. In certain embodiments, the brain cells are cells of the striatum. In certain embodiments, the brain cells are cells of the cerebellum. In certain embodiments, the brain cells are cells of the brainstem. In certain embodiments, the brain cells are cells of the hippocampus. In certain embodiments, the brain cells are cells of the spinal cord. In certain embodiments, the nucleic acid target is pre-mRNA, mRNA, non-coding RNA or miRNA. In certain embodiments, the compound is administered intrathecally to the subject.

[0577] 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.

[0578] In certain embodiments, a compound comprising a CB1 ligand selectively or preferentially targets cells expressing CB1 compared to cells not expressing CB1. In certain embodiments, a compound comprising a CB1 ligand selectively or preferentially targets cells expressing CB1 compared to a compound not comprising a CB1 ligand.

[0579] Also provided herein are uses of the compounds described herein for the preparation of a medicament for treating a disease or condition.

[0580] 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 2-24.

[0581] Certain compounds containing oligonucleotides

[0582] 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).

[0583] In certain embodiments, oligonucleotide is single-stranded. In some embodiments, single-stranded oligonucleotide is single-stranded RNA (ssRNA), ssDNA or ssRNA / DNA hybrid (for example, single-stranded oligonucleotide comprising ribonucleoside (modified or unmodified) and deoxyribonucleoside (modified or unmodified)). In some embodiments, oligonucleotide is double-stranded (for example, comprising two single-stranded nucleic acids). Such double-stranded oligonucleotides include the first oligonucleotide with a region complementary to the target nucleic acid and the second oligonucleotide with 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 CB1 parts. In certain embodiments, the second oligonucleotide is connected to one or more CB1 parts.

[0584] 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.

[0585] 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.

[0586] 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.

[0587] 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.

[0588] In certain embodiments, the miRNA is a precursor, primary and / or mature miRNA.

[0589] 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.

[0590] Certain modifications

[0591] 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.

[0592] Sugar modifications and motifs

[0593] 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.

[0594] 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.

[0595] 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[(C H2) 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 ("MO E"), O(CH2)2ON(CH3)2 ("DMAOE"), O(CH2)2O(CH2)2N(CH3)2 ("DMAEOE"), and OCH2C(=O)-N(H)CH3 ("NMA").

[0596] 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′) ; 5′-monodithioate (phosphorodithioate; (HO)(HS)(S)PO-5′), 5′-phosphorothioate ((HO)2(O)PS-5′); any additional combination of oxygen / sulfur substituted mono-, di-, 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.

[0597] 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

[0598] -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 the like (e.g., U.S. Pat. No. 7,399,845), 4'-C(C H3)(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.

[0599] 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; 5,584,878; No. 591,722; No. 5,597,909; No. 5,610,300; No. 5,627,053; No. 5,639,873; No. 5,646,265; No. 5,658,873; No. 5,670,633; No. 5,700,920; No. 7,875,733; No. 7,939,677; No. 8,088,904; No. 8,440,803; and No. 9,005,906, the entire contents of each of which are hereby incorporated by reference into this document.

[0600] 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 No. 2013 / 0096289; No. 2013 / 0011922; and No. 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 hereby incorporated by reference herein. Many other bicyclic and tricyclic sugars and sugar surrogate ring systems are known in the art and can be used in modified nucleosides.

[0601] In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotide 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.

[0602] 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 No. 8,790,919, the entire content of which is hereby incorporated by reference into this paper.

[0603] In certain embodiments, one or two oligonucleotides of the double-stranded compound include a triplet sugar motif. An oligonucleotide with a triplet sugar motif includes 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 oligonucleotide 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 triplet sugar motifs are disclosed in, for example, U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0604] 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.

[0605] 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 "ABABA BABABAB...", "AABBAABBAABB...", "AABAABAABAAB," "AAABAAABAAAB...", "AAABBBAAABBB..." or "ABCABCABCABC" etc. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobases along the oligonucleotide. In certain embodiments, the alternating sugar motif comprises two different sugar modifications. In certain embodiments, the alternan motif comprises 2'-OMe and 2'-F sugar modifications.

[0606] 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.

[0607] Nucleobase modifications and motifs

[0608] 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.

[0609] 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.

[0610] Other nucleobases include U.S. Pat. No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed., Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, 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 and Applications, pp. 289-302; Antisense Research and Applications, Crooke, ST and Lebleu, B. eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke ST ed., CRC Those disclosed in Pharmacopoeia Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is hereby incorporated by reference.

[0611] 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. Application 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; 5,645,985; ,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; 6,166,197; 6,166,199; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated by reference into this document.

[0612] 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.

[0613] In certain embodiments, the modified oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is at the 3'-end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is at the 5' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides of the 5' end of the oligonucleotide.

[0614] Internucleoside linkage modifications and motifs

[0615] 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.

[0616] 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.

[0617] 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.

[0618] 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.

[0619] 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.

[0620] CB1 ligand

[0621] In some embodiments, the compounds provided herein comprise cannabinoid receptor type 1 (CB1, also known as cannabinoid receptor 1) ligands. In some embodiments, CB1 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, the CB1 ligand directs the oligonucleotide to a certain location. In some embodiments, the CB1 ligand targets a tissue. In some embodiments, the tissue is brain tissue. In some embodiments, the CB1 ligand targets a cell receptor. In some embodiments, the cell receptor is CB1. In some embodiments, the CB1 receptor is in the brain. In some embodiments, the CB1 receptor is in the frontal cortex. In some embodiments, the CB1 receptor is in the striatum. In some embodiments, the CB1 receptor is in the cerebellum. In some embodiments, the CB1 receptor is in the brainstem. In some embodiments, the CB1 receptor is in the hippocampus. In some embodiments, the CB1 receptor is in the spinal cord.

[0622] The present disclosure contemplates the use of any CB1 ligand in the compounds provided herein. CB1 ligands are known in the art, and one of ordinary skill in the art will be able to identify additional CB1 ligands for use in the compounds described herein, in addition to those explicitly provided herein. The present disclosure also contemplates the use of derivatives and prodrugs of any CB1 ligand provided herein or known in the art in the compounds described herein, and one of ordinary skill in the art will know how to prepare such derivatives and prodrugs.

[0623] In some embodiments, the CB1 ligand is a CB1 agonist. In some embodiments, the CB1 ligand is a CB1 antagonist. Exemplary CB1 ligands for use in the present disclosure include, but are not limited to, any of the following CB1 ligands and their derivatives:

[0624]

[0625]

[0626]

[0627]

[0628]

[0629] In some embodiments, the CB1 ligand is RVD-Hpα (fragment of hemoglobin (pepcan-12), α1).

[0630] In certain embodiments, the CB1 ligand is (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide. In certain embodiments, the CB1 ligand is anandamide.

[0631] In some embodiments, the CB1 ligand is an anti-CB1 antibody. In certain embodiments, the CB1 ligand is an anti-CB1 antibody fragment or anti-CB1 antibody variant. "Anti-CB1 antibody" refers to an immune system protein that recognizes, binds to, or otherwise interacts with a CB1 receptor.

[0632] In certain embodiments, the CB1 ligand is conjugated (e.g., linked, connected, attached, associated) to one or more pharmaceutical moieties. In certain embodiments, the pharmaceutical moiety is a therapeutic agent, a prophylactic agent, a diagnostic agent, or an imaging agent. In certain embodiments, the pharmaceutical agent is a small molecule or an oligomeric compound. In certain embodiments, the pharmaceutical moiety is a protein, a peptide, an antibody, an oligonucleotide, a small molecule, a macromolecule, or a combination thereof.

[0633] In some embodiments, more than one CB1 ligand is conjugated to the agent moiety. In some embodiments, at least two CB1 ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more CB1 ligands) are conjugated to the agent moiety. In some embodiments, two CB1 ligands are conjugated to the agent moiety. In some embodiments, three CB1 ligands are conjugated to the agent moiety. In some embodiments, four CB1 ligands are conjugated to the agent moiety. In some embodiments, five CB1 ligands are conjugated to the agent moiety. In some embodiments, more than five CB1 ligands are conjugated to the agent moiety. In some embodiments, at least one to about five CB1 ligands are conjugated to the agent moiety. In some embodiments, at least one to about four CB1 ligands are conjugated to the agent moiety. In some embodiments, at least one to about three CB1 ligands are conjugated to the agent moiety. In some embodiments, at least one to about two CB1 ligands are conjugated to the agent moiety.

[0634] When the agent moiety is conjugated to multiple CB1 ligands, all of the CB1 ligands can be conjugated at or near the same position on the agent moiety, or the CB1 ligands can be conjugated to multiple different positions on the agent moiety.

[0635] In some embodiments, the oligonucleotide is conjugated (e.g., connected, attached, associated) to the CB1 ligand 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). In some embodiments, the oligonucleotide is conjugated to the CB1 ligand via the 5' end of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to the CB1 ligand via the 3' end of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to the CB1 ligand via the 5' and 3' ends of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to the CB1 ligand at an internal position within the oligonucleotide (e.g., in an "internally modified oligonucleotide").

[0636] In some embodiments, the oligonucleotide is conjugated to more than one CB1 ligand. In some embodiments, the oligonucleotide is conjugated to at least two CB1 ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more CB1 ligands). In some embodiments, the oligonucleotide is conjugated to two CB1 ligands. In some embodiments, the oligonucleotide is conjugated to three CB1 ligands. In some embodiments, the oligonucleotide is conjugated to four CB1 ligands. In some embodiments, the oligonucleotide is conjugated to five CB1 ligands. In some embodiments, the oligonucleotide is conjugated to more than five CB1 ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about five CB1 ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about four CB1 ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about three CB1 ligands. In some embodiments, the oligonucleotide is conjugated to at least one to about two CB1 ligands.

[0637] When an oligonucleotide is conjugated to multiple CB1 ligands, all CB1 ligands may be conjugated to or near the same position on the oligonucleotide, or the CB1 ligand may be conjugated to multiple different positions on the oligonucleotide. In some embodiments, multiple CB1 ligands (i.e., two, three, four, five or more CB1 ligands) are conjugated to the 5' end of the oligonucleotide. In some embodiments, multiple CB1 ligands (i.e., two, three, four, five or more CB1 ligands) are conjugated to the 3' end of the oligonucleotide. In some embodiments, multiple CB1 ligands (i.e., two, three, four, five or more CB1 ligands) are conjugated to one or more internal positions of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to one or more CB1 ligands at the 5' end of the oligonucleotide and / or one or more CB1 ligands at the 3' end of the oligonucleotide and / or one or more CB1 ligands at one or more internal positions of the oligonucleotide.

[0638] connector

[0639] In certain embodiments, conjugates of the compound formulae described herein are provided. In certain embodiments, the conjugate comprises a CB1 ligand covalently coupled to an agent moiety. In certain embodiments, the conjugates provided herein comprise one or more linker moieties. In certain embodiments, one or more linker moieties connect the CB1 ligand to the agent moiety. In certain embodiments, the agent moiety is a protein, peptide, antibody, nucleic acid, small molecule, macromolecule, therapeutic agent, prophylactic agent, diagnostic agent, or imaging agent. In some embodiments, the compound is conjugated to an oligonucleotide. In certain embodiments, the CB1 ligand is conjugated to an oligonucleotide. In certain embodiments, the compound comprises one or more CB1 ligands, one or more linker moieties, and one or more agent moieties, wherein the CB1 ligand is conjugated (e.g., linked, connected, attached, associated) to one or more agent moieties via one or more linker moieties.

[0640] Conjugates as disclosed herein can be prepared using any available method. When a compound provided herein is associated with an agent moiety (e.g., a CB1 ligand and an oligonucleotide), the moiety can be linked directly or indirectly (e.g., through a linker moiety; i.e., the linker is covalently bound to each of the oligonucleotide and the CB1 ligand; in some formulas herein, "-L n-", where n is a number (e.g., L1, L2, L3, L4, L5, L6, and L7). For example, the oligonucleotide and the CB1 ligand can be directly associated with each other, for example, by one or more covalent bonds, or can be associated through one or more linkers. "Linker" refers to any chemical moiety (e.g., a combination of atoms with appropriate valence according to known chemical principles) used to conjugate two components of the compounds provided herein (e.g., CB1 ligand and oligonucleotide) to each other. Each of the two components can be linked to any part of any linker provided herein. In some embodiments, one component of the compounds provided herein (e.g., CB1 ligand or oligonucleotide) is linked to one end of the linker by a bond, and the other component is linked to the other end of the linker by a bond. In some embodiments, one or both components of the compounds provided herein can be linked to an internal position in any linker described herein by a bond. For example, in the context of an "alkyl linker", the CB1 ligand can be linked to the carbon of one end of the alkyl linker by a bond, and the oligonucleotide can be linked to the carbon of one end of the alkyl linker by a bond, and the oligonucleotide can be linked to the carbon of one end of the alkyl linker by a bond. In some embodiments, the joint is an optionally substituted alkyl joint (i.e., an alkyl chain is used to connect two parts, and it can each be conjugated to the opposite end of the alkyl joint, or one or two parts can be conjugated to the internal carbon on the alkyl joint). In some embodiments, the joint is an optionally substituted polyethylene glycol (PEG) joint (i.e., a PEG chain is used to connect two parts, and it can each be conjugated to the opposite end of the PEG joint, or one or two parts can be conjugated to the internal position on the PEG joint). In some embodiments, the joint is an optionally substituted heteroalkyl joint (i.e., a heteroalkyl chain is used to connect two parts, and it can each be conjugated to the opposite end of the heteroalkyl joint, or one or two parts can be conjugated to the internal position on the heteroalkyl joint). In some embodiments, the joint is an optionally substituted heteroaryl joint (i.e., a heteroaryl is used to connect two parts, and it can each be conjugated to any position on the heteroaryl).

[0641] In certain embodiments, the compounds provided herein comprise one or more linking groups. In certain embodiments, L1, L2, L3, and L4 each comprise a linking group. In certain embodiments, L1, L2, L3, L4, and L5 comprise a linking group. In certain embodiments, L1, L2, L3, L4, L5, L6, and L7 each comprise a linking group. In certain embodiments, the linking group is covalently bound to the CB1 ligand. 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 multiple positions for attaching the CB1 ligand.

[0642] 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.

[0643] 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.

[0644] 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.

[0645] 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.

[0646] 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-nucleosides will be cracked from the compound after reaching the target tissue. Therefore, the joint-nucleosides herein can be connected to each other and to the remainder of the compound by a cleavable bond. In this article, the joint-nucleosides are not considered to be a part of the oligonucleotide payload. Therefore, in embodiments in which 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 a CB1 part containing a linking group comprising a joint-nucleoside, those joint-nucleosides are not counted into the length of the oligonucleotide and are not used to determine the complementary percentage of the oligonucleotide to the reference nucleic acid.

[0647] 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, dimethoxytribenzyl 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, terpenoids, epi-suberin-derived lithocholic acid) or cationic lipids. In certain embodiments, the protein binding group is C 16 to C 22 Long-chain saturated or unsaturated fatty acids, cholesterol, bile acid, vitamin E, adamantane or 1-pentafluoropropyl.

[0648] 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).

[0649] 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; WO2013 / 033230; WO2012 / 037254; Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carhohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem, 1982, 257, 939-945; Pavia et al., Int J Pep Protein Res, 1983, 22, 539-548; Le e et al., Biochem, 1984, 23, 4255-4261; Lee et al., Glycoconjug. 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., Glycohiol, 2001, 11, 821-829; Rensen et al., J Biol. Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362, 38-43;Westerlind et al., Glycoconj J, 2004, 21, 227-241; 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; K ornilova et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., J Am Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998 / 013381; WO2011 / 038356; WO1997 / 046098; WO2008 / 098788;W02004 / 101619; WO2012 / 037254; WO2011 / 120053; W O2011 / 100131;WO2011 / 163121;WO2012 / 177947;W02013 / 033230;W02013 / 075035;WO2012 / 083185;WO2012 / 083046;W02009 / 082607;W O2009 / 134487; W02010 / 144740; W02010 / 148013; WO1997 / 020563; W02010 / 088537; W02002 / 043771; W02010 / 129709; WO2012 / 068187; W WO2009 / 126933; WO2004 / 024757; WO2010 / 054406; WO2012 / 089352; WO2012 / 089602; WO2013 / 166121; WO2013 / 165816; U.S. Patents 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; Published U.S. Patent Applications Publication Nos. US2011 / 0097264; US2011 / 0097265; US 2013 / 0004427; US2003 / 0119724; US2011 / 0207799; US2012 / 0035115; US2012 / 023093 8; US2005 / 0164235; US2006 / 0183886; US2012 / 0136042; US2012 / 0095075; US2013 / 01 09817; US2006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132;Each of these references is incorporated herein by reference in its entirety.

[0650] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0651]

[0652]

[0653] wherein each n is independently 1 to 20; and p is 1 to 6.

[0654] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0655]

[0656]

[0657] wherein each n is independently 1 to 20.

[0658] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0659]

[0660] wherein each n is independently 1 to 20.

[0661] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0662]

[0663] wherein each n is independently 1 to 20.

[0664] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0665]

[0666]

[0667] wherein each L is independently a phosphorus linking group; and each n is independently 1 to 20.

[0668] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0669]

[0670]

[0671]

[0672] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0673]

[0674] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0675]

[0676]

[0677] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0678] Wherein n is 1 to 20.

[0679] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0680]

[0681] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0682]

[0683] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0684]

[0685] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together have the following structure:

[0686]

[0687] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together have the following structure:

[0688]

[0689] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0690]

[0691] In certain embodiments, L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) independently comprise or together comprise a structure selected from the group consisting of:

[0692] wherein each n is independently 0, 1, 2, 3, 4, 5, 6 or 7.

[0693] In some embodiments, any one of L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) can independently be a linker (e.g., an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker). In some embodiments, any one of L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) can independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). In some embodiments, any one of L1, L2, L3, and L4 (or L1, L2, L3, L4, and L5, or L1, L2, L3, L4, L5, L6, and L7) can independently be absent.

[0694] In some embodiments, L1 is a bond.

[0695] In some embodiments, L2 is an optionally substituted PEG linker. In some embodiments, the PEG linker is three or four PEG units in length. In certain embodiments, L2 comprises the structure In some embodiments, the PEG linker is two or three PEG units in length.

[0696] 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

[0697] 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 certain embodiments, L4 comprises the structure Wherein X is O or S.

[0698] In some embodiments, L1, L2, L3, and L4 together comprise the structure Wherein X is O or S.

[0699] In some embodiments, one of L3 and L4 is a phosphodiester bond or a phosphorothioate bond, and the other of L3 and L4 is a bond. In certain embodiments, L1, L2, L3, and L4 together comprise the structure Wherein X is O or S.

[0700] In certain embodiments, L1, L2, L3, and L4 together comprise the structure Wherein X is O or S.

[0701] In some embodiments, any one of L1, L2, L3, L4, and L5 can independently be a linker (e.g., an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker). In some embodiments, any one of L1, L2, L3, L4, and L5 can independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). In some embodiments, any one of L1, L2, L3, L4, and L5 can independently be absent.

[0702] In some embodiments, L1 and L5 are each an optionally substituted PEG linker. In some embodiments, L1 and L5 are each an optionally substituted PEG linker that is three PEG units in length.

[0703] In some embodiments, L2 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L2 comprises the structure

[0704] 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

[0705] 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 certain embodiments, L4 comprises the structure Wherein X is O or S.

[0706] In some embodiments, L1, L2, L3, L4, and L5 together comprise the structure

[0707] Wherein X is O or S.

[0708] In some embodiments, any one of L1, L2, L3, L4, L5, L6, and L7 can independently be a linker (e.g., an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker). In some embodiments, any one of L1, L2, L3, L4, L5, L6, and L7 can independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). In some embodiments, any one of L1, L2, L3, L4, L5, L6, and L7 can independently be absent.

[0709] In some embodiments, L1 is an optionally substituted PEG linker.In certain embodiments, L1 is an optionally substituted PEG linker that is two or three PEG units in length.

[0710] In some embodiments, L2 and L5 are each independently an optionally substituted PEG linker. In some embodiments, L2 and L5 are each independently an optionally substituted PEG linker of three or four PEG units in length. In certain embodiments, L1, L2, and L5 together comprise the structure

[0711] In some embodiments, L3 and L6 are each independently an optionally substituted heteroaryl linker. In some embodiments, L3 and L6 are each independently an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, L3 and L6 each comprise the structure

[0712] In some embodiments, L4 and L7 are each independently an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L4 and L7 each comprise the structure Wherein X is O or S.

[0713] In some embodiments, L1, L2, L3, L4, L5, L6, and L7 together comprise the structure

[0714] Wherein X is O or S.

[0715] Methods for preparing compounds

[0716] In some aspects, the present disclosure relates to methods of making the compounds and compositions comprising a CB1 ligand as disclosed herein.

[0717] 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; EIsevier 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.

[0718] 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.

[0719] 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.

[0720] 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.

[0721] Treatment

[0722] 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.

[0723] 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.

[0724] 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.

[0725] 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.

[0726] 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.

[0727] 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.

[0728] In certain embodiments, the CNS disorder is stroke (eg, ischemic stroke).

[0729] In certain embodiments, the CNS disorder is multiple sclerosis.

[0730] In certain embodiments, the CNS disorder is spinal cord injury.

[0731] In certain embodiments, the CNS disorder is epilepsy.

[0732] In certain embodiments, the CNS disorder is a psychiatric disorder, such as depression, anxiety or an anxiety-related disorder, a learning disability, a somatic symptom disorder, schizophrenia, or schizoaffective disorder.

[0733] 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.

[0734] 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).

[0735] In certain embodiments, the CNS disorder is a learning disorder (eg, attention deficit disorder (ADD)).

[0736] In certain embodiments, the CNS disorder is schizophrenia or schizoaffective disorder.

[0737] 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).

[0738] 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.

[0739] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0740] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0741] In certain embodiments, the CNS disorder is nausea and / or vomiting.

[0742] In certain embodiments, the CNS disorder is drug addiction (eg, addiction to opioids, nicotine, cocaine, psychostimulants, or alcohol).

[0743] 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 disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; 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 essential blepharospasm; benign lesions; amyotrophic lateral sclerosis; benign intracranial hypertension; Binswanger disease; blepharospasm; Bloch-Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumor (including glioblastoma multiforme); spinal tumors; Brown-Ségar 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 (CIDP); 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's syndrome; syncope; familial spastic paraplegia; febrile seizures; Fisher's 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 yndrome); HIV-associated dementia and neuropathy (see also Neurological Manifestations of AIDS); holoprosencephaly; Huntington disease and other polyglutamine repeat disorders; hydrocephalus; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; 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 brain Leukodystrophies; 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 disease;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.

[0744] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0745] In another embodiment, provided is a method as described above, wherein the effective amount of a compound provided herein is as described above.

[0746] 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.

[0747] 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.

[0748] 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.

[0749] Pharmaceutical composition

[0750] In one aspect, provided is a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

[0751] 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.

[0752] 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.

[0753] 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.

[0754] 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.

[0755] 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.

[0756] 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.

[0757] 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.

[0758] 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.

[0759] 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.

[0760] 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.

[0761] 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.

[0762] 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.

[0763] 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.

[0764] 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.

[0765] 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).

[0766] 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.

[0767] 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.

[0768] 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.

[0769] 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.

[0770] 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.

[0771] 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.

[0772] 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.

[0773] 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.

[0774] 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.

[0775] 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.

[0776] 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.

[0777] 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.

[0778] 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.

[0779] 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.

[0780] Other implementation plans

[0781] Certain embodiments include the following Embodiments P1 through P114.

[0782] Embodiment P1. A compound comprising a structure of formula (I) or a salt thereof:

[0783]

[0784] in

[0785] It is a cannabinoid receptor type 1 (CB1) ligand;

[0786] L1, L2, L3 and L4 are each independently a linker, a bond or absent; and

[0787] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0788] Embodiment P2. The compound or salt thereof according to Embodiment P1, wherein the CB1 ligand is a CB1 agonist.

[0789] Embodiment P3. The compound or salt thereof according to Embodiment P1, wherein the CB1 ligand is a CB1 antagonist.

[0790] Embodiment P4. A compound or salt thereof according to embodiment P1, wherein CB1The ligand is selected from the group consisting of minocycline, dronabinol, epigallocatechin, epicatechin, kavaccin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonylglycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP55,940, JWH-018, WIN55,212-2, GAT228, cannabinoids. Phenol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti-CB1 antibodies and their derivatives.

[0791] Embodiment P5. A compound or salt thereof according to embodiment P1, wherein the CB1 ligand comprises the structure or its derivatives.

[0792] Embodiment P6. A compound or salt thereof according to Embodiment P1, wherein the compound comprises a structure of Formula (II):

[0793]

[0794] or a salt thereof.

[0795] Embodiment P7. A compound or salt thereof according to Embodiment P6, wherein the compound comprises a structure of Formula (II-a):

[0796]

[0797] or its salts

[0798] Embodiment P8. A compound or salt thereof as described in any one of Embodiments P1 to P7, wherein L1, L2, L3 and L4 are each 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.

[0799] Embodiment P9. A compound or salt thereof according to Embodiment P8, wherein L1 is a bond.

[0800] Embodiment P10. A compound or salt thereof as described in Embodiment P8 or P9, wherein L2 is an optionally substituted PEG linker.

[0801] Embodiment P11. A compound or salt thereof according to Embodiment P10, wherein the PEG linker is three or four PEG units in length.

[0802] Embodiment P12. A compound or salt thereof as described in any one of Embodiments P8 to P11, wherein L2 comprises the structure

[0803] Embodiment P13. A compound or salt thereof as described in any one of Embodiments P8 to P12, wherein L3 is an optionally substituted heteroaryl linker.

[0804] Embodiment P14. A compound or salt thereof according to Embodiment P13, wherein L3 is an optionally substituted partially unsaturated heteroaryl linker.

[0805] Embodiment P15. A compound or salt thereof as described in Embodiment P13 or P14, wherein L3 comprises the structure

[0806] Embodiment P16. A compound or salt thereof as described in any one of Embodiments P8 to P15, wherein L4 is an optionally substituted heteroalkyl linker.

[0807] Embodiment P17. A compound or salt thereof according to Embodiment P16, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

[0808] Embodiment P18. A compound or salt thereof as described in Embodiment P16 or P17, wherein L4 comprises the structure

[0809] Wherein X is O or S.

[0810] 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

[0811]

[0812] Wherein X is O or S.

[0813] Embodiment P20. A compound or salt thereof according to any one of Embodiments P1 to P19, wherein the compound comprises the following structure:

[0814]

[0815] or a salt thereof, wherein X is O or S.

[0816] Embodiment P21. A compound or salt thereof as described in any one of Embodiments P18 to P20, wherein X is O.

[0817] Embodiment P22. A compound or salt thereof as described in any one of Embodiments P18 to P20, wherein X is S.

[0818] Embodiment P23. A compound or salt thereof according to Embodiment P1, wherein the CB1 ligand comprises the structure or its derivatives.

[0819] Embodiment P24. A compound or salt thereof according to Embodiment P23, wherein the compound comprises a structure of Formula (III):

[0820]

[0821] or a salt thereof.

[0822] Embodiment P25. A compound or salt thereof according to Embodiment P24, wherein the compound comprises a structure of Formula (III-a):

[0823]

[0824] or a salt thereof.

[0825] Embodiment P26. A compound or salt thereof as described in any of Embodiments P23 to P25, wherein L1, L2, L3 and L4 are each 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.

[0826] Embodiment P27. A compound or salt thereof according to Embodiment P26, wherein L1 is a bond.

[0827] Embodiment P28. A compound or salt thereof as described in Embodiment P26 or P27, wherein L2 is an optionally substituted PEG linker.

[0828] Embodiment P29. A compound or salt thereof according to Embodiment P28, wherein the PEG linker is two or three PEG units in length.

[0829] Embodiment P30. A compound or salt thereof as described in any one of Embodiments P26 to P29, wherein one of L3 and L4 is a phosphodiester bond or a phosphorothioate bond, and the other of L3 and L4 is a bond.

[0830] Embodiment P31. A compound or salt thereof as described in any one of Embodiments P26 to P30, wherein L1, L2, L3 and L4 together comprise the structure Wherein X is O or S.

[0831] Embodiment P32. A compound or salt thereof as described in any one of Embodiments P26 to P29, wherein L3 is an optionally substituted heteroaryl linker.

[0832] Embodiment P33. A compound or salt thereof according to Embodiment P32, wherein L3 is an optionally substituted partially unsaturated heteroaryl linker.

[0833] Embodiment P34. A compound or salt thereof as described in Embodiment P32 or P33, wherein L3 comprises the structure

[0834] Embodiment P35. A compound or salt thereof as described in any one of Embodiments P26 to P29 or P32 to P34, wherein L4 is an optionally substituted heteroalkyl linker.

[0835] Embodiment P36. A compound or salt thereof according to Embodiment P35, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

[0836] Embodiment P37. A compound or salt thereof as described in Embodiment P35 or P36, wherein L4 comprises the structure Wherein X is O or S.

[0837] Embodiment P38. A compound or salt thereof as described in any one of Embodiments P26 to P29 or P32 to P37, wherein L1, L2, L3 and L4 together comprise the structure Wherein X is O or S.

[0838] Embodiment P39. A compound or salt thereof according to any one of Embodiments P23 to P38, wherein the compound comprises the following structure:

[0839]

[0840] or a salt thereof, wherein X is O or S.

[0841] Embodiment P40. A compound or salt thereof as described in any one of Embodiments P23 to P39, wherein X is O.

[0842] Embodiment P41. A compound or salt thereof as described in any one of Embodiments P23 to P39, wherein X is S.

[0843] Embodiment P42. A compound comprising a structure of formula (IV) or a salt thereof:

[0844]

[0845] in

[0846] each independently a cannabinoid receptor type 1 (CB1) ligand, or One of them is a CB1 ligand, and The other of comprises a lipid or a ligand;

[0847] L1, L2, L3, L4 and L5 are each independently a linker, a bond or absent; and

[0848] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0849] Embodiment P43. A compound or salt thereof according to embodiment P42, wherein

[0850] Each is independently a CB1 ligand.

[0851] Embodiment P44. A compound or salt thereof according to Embodiment P43, wherein one or both of the CB1 ligands is a CB1 agonist.

[0852] Embodiment P45. A compound or salt thereof according to Embodiment P43, wherein one or both of the CB1 ligands is a CB1 antagonist.

[0853] Embodiment P46. A compound or salt thereof according to embodiment P43, wherein said CB1 The ligands are each independently selected from the group consisting of minocycline, dronabinol, epigallocatechin, epicatechin, kavaccin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonyl glycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoyl glycerol, AM-2201, CP55,940, JWH-018, WIN55,212-2, GAT228, Cannabigerol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti-CB1 antibodies and their derivatives.

[0854] Embodiment P47. A compound or salt thereof according to embodiment P43, wherein the CB1 ligands each comprise the structure or its derivatives.

[0855] Embodiment P48. A compound or salt thereof according to Embodiment P43, wherein the compound comprises a structure of Formula (V):

[0856]

[0857] or a salt thereof.

[0858] Embodiment P49. A compound or salt thereof according to Embodiment P48, wherein the compound comprises a structure of Formula (Va):

[0859]

[0860] or a salt thereof.

[0861] Embodiment P50. A compound or salt thereof as described in any of Embodiments P42 to P49, wherein L1, L2, L3, L4 and L5 are each 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.

[0862] Embodiment P51. A compound or salt thereof as described in Embodiment P50, wherein L1 and L5 are each an optionally substituted PEG linker.

[0863] Embodiment P52. A compound or salt thereof as described in Embodiment P51, wherein L1 and L5 are each an optionally substituted PEG linker of three PEG units in length.

[0864] Embodiment P53. A compound or salt thereof as described in any one of Embodiments P50 to P52, wherein L2 is an optionally substituted heteroalkyl linker.

[0865] Embodiment P54. A compound or salt thereof according to Embodiment P53, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

[0866] Embodiment P55. A compound or salt thereof as described in any one of Embodiments P50 to P54, wherein L2 comprises the structure

[0867] Embodiment P56. A compound or salt thereof as described in any one of Embodiments P50 to P55, wherein L3 is an optionally substituted heteroaryl linker.

[0868] Embodiment P57. A compound or salt thereof according to Embodiment P56, wherein L3 is an optionally substituted partially unsaturated heteroaryl linker.

[0869] Embodiment P58. A compound or salt thereof as described in embodiment P56 or P57, wherein L3 comprises the structure

[0870] Embodiment P59. A compound or salt thereof as described in any one of Embodiments P50 to P58, wherein L4 is an optionally substituted heteroalkyl linker.

[0871] Embodiment P60. A compound or salt thereof according to Embodiment P59, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

[0872] Embodiment P61. A compound or salt thereof as described in Embodiment P59 or P60, wherein L4 comprises the structure

[0873] Wherein X is O or S.

[0874] Embodiment P62. A compound or salt thereof as described in any one of Embodiments P50 to P61, wherein L1, L2, L3, L4 and L5 together comprise the structure

[0875]

[0876] Wherein X is O or S.

[0877] Embodiment P63. A compound or salt thereof according to any one of Embodiments P42 to P62, wherein the compound comprises the following structure:

[0878]

[0879] or a salt thereof, wherein X is O or S.

[0880] Embodiment P64. A compound or salt thereof as described in any one of Embodiments P42 to P63, wherein X is O.

[0881] Embodiment P65. A compound or salt thereof as described in any one of Embodiments P42 to P63, wherein X is S.

[0882] Embodiment P66. A compound or salt thereof as described in any one of Embodiments P1 to P65, wherein R 1 Contains oligonucleotides.

[0883] Embodiment P67. A compound or salt thereof according to embodiment P66, wherein the oligonucleotide is attached at its 5' end.

[0884] Embodiment P68. A compound or salt thereof according to embodiment P66, wherein the oligonucleotide is attached at its 3' end.

[0885] Embodiment P69. A compound or salt thereof according to embodiment P66, wherein the oligonucleotide is attached at an internal position on the oligonucleotide.

[0886] Embodiment P70. A compound or salt thereof according to Embodiment P69, wherein the internal position is an internucleoside linkage.

[0887] Embodiment P71. A compound or salt thereof as described in any one of Embodiments P1 to P70, wherein R 1 comprising an oligonucleotide conjugated to one or more additional CB1 ligands.

[0888] Embodiment P72. A compound or salt thereof according to embodiment P71, wherein the oligonucleotide is conjugated to two, three, four, five or more than five additional CB1 ligands.

[0889] Embodiment P73. A compound or salt thereof according to embodiment P71 or P72, wherein the additional CB1 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.

[0890] Embodiment P74. The compound of any one of Embodiments P66 to P73, wherein the oligonucleotide is a modified oligonucleotide.

[0891] Embodiment P75. A compound comprising the structure of formula (VI) or a salt thereof:

[0892]

[0893] in

[0894] It is a cannabinoid receptor type 1 (CB1) ligand;

[0895] L1, L2, L3, L4, L5, L6 and L7 are each independently a linker, a bond or absent; and

[0896] R 1 and R 2 Each comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0897] Embodiment P76. A compound or salt thereof according to Embodiment P75, wherein the CB1 ligand is a CB1 agonist.

[0898] Embodiment P77. A compound or salt thereof according to Embodiment P75, wherein the CB1 ligand is a CB1 antagonist.

[0899] Embodiment P78. A compound or salt thereof as described in Embodiment P75, wherein CB1 The ligand is selected from the group consisting of minocycline, dronabinol, epigallocatechin, epicatechin, kavaccin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonylglycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP55,940, JWH-018, WIN55,212-2, GAT228, cannabinoids. Phenol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti-CB1 antibodies and their derivatives.

[0900] Embodiment P79. A compound or salt thereof according to embodiment P75, wherein the CB1 ligand comprises the structure or its derivatives.

[0901] Embodiment P80. A compound or salt thereof according to Embodiment P75, wherein the compound comprises a structure of Formula (VII):

[0902]

[0903] or a salt thereof.

[0904] Embodiment P81. A compound or salt thereof according to Embodiment P80, wherein the compound comprises a structure of Formula (VII-a):

[0905]

[0906] or a salt thereof.

[0907] Embodiment P82. A compound or salt thereof as described in any of Embodiments P75 to P81, wherein L1, L2, L3, L4, L5, L6 and L7 are each 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.

[0908] Embodiment P83. A compound or salt thereof as described in Embodiment P82, wherein L1 is an optionally substituted PEG linker.

[0909] Embodiment P84. A compound or salt thereof as described in Embodiment P83, wherein L1 is an optionally substituted PEG linker of two or three PEG units in length.

[0910] Embodiment P85. A compound or salt thereof as described in any one of Embodiments P82 to P84, wherein L2 and L5 are each independently an optionally substituted PEG linker.

[0911] Embodiment P86. A compound or salt thereof as described in Embodiment P85, wherein L2 and L5 are each independently an optionally substituted PEG linker of three or four PEG units in length.

[0912] Embodiment P87. A compound or salt thereof as described in any one of Embodiments P82 to P86, wherein L1, L2 and L5 together comprise the structure

[0913]

[0914] Embodiment P88. A compound or salt thereof as described in any one of Embodiments P82 to P86, wherein L3 and L6 are each independently an optionally substituted heteroaryl linker.

[0915] Embodiment P89. A compound or salt thereof according to Embodiment P88, wherein L3 and L6 are each independently an optionally substituted partially unsaturated heteroaryl linker.

[0916] Embodiment P90. A compound or salt thereof as described in Embodiment P88 or P89, wherein L3 and L6 each comprise the structure

[0917] Embodiment P91. A compound or salt thereof as described in any one of Embodiments P82 to P90, wherein L4 and L7 are each independently an optionally substituted heteroalkyl linker.

[0918] Embodiment P92. A compound or salt thereof according to Embodiment P91, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

[0919] Embodiment P93. A compound or salt thereof as described in Embodiment P91 or P92, wherein L4 and L7 each comprise the structure

[0920] Wherein X is O or S.

[0921] Embodiment P94. A compound or salt thereof as described in any one of Embodiments P82 to P93, wherein L1, L2, L3, L4, L5, L6 and L7 together comprise the structure

[0922]

[0923] Wherein X is O or S.

[0924] Embodiment P95. A compound or salt thereof according to any one of Embodiments P75 to P94, wherein the compound comprises the following structure:

[0925]

[0926] or a salt thereof, wherein X is O or S.

[0927] Embodiment P96. A compound or salt thereof as described in any one of Embodiments P75 to P95, wherein X is O.

[0928] Embodiment P97. A compound or salt thereof as described in any one of Embodiments P75 to P95, wherein X is S.

[0929] Embodiment P98. A compound or salt thereof as described in any one of Embodiments P75 to P97, wherein R 1 and R 2 Each comprises an oligonucleotide.

[0930] Embodiment P99. A compound or salt thereof according to embodiment P98, wherein one or both of the oligonucleotides are attached at their 5' end.

[0931] Embodiment P100. The compound of embodiment P98, or a salt thereof, wherein one or both of the oligonucleotides are attached at their 3' end.

[0932] Embodiment P101. A compound or salt thereof according to embodiment P98, wherein one or both of the oligonucleotides are attached at an internal position on the oligonucleotide.

[0933] Embodiment P102. A compound or salt thereof according to Embodiment P101, wherein the internal position is an internucleoside linkage.

[0934] Embodiment P103. A compound or salt thereof as described in any one of Embodiments P98 to P102, wherein R 1 and R 2 Each comprises an oligonucleotide conjugated to one or more additional CB1 ligands.

[0935] Embodiment P104. A compound or salt thereof according to embodiment P103, wherein the oligonucleotide is conjugated to two, three, four, five or more than five additional CB1 ligands.

[0936] Embodiment P105. A compound or salt thereof as described in Embodiment P103 or P104, wherein the additional CB1 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.

[0937] Embodiment P106. The compound of any one of Embodiments P98 to P105, wherein the oligonucleotide is a modified oligonucleotide.

[0938] Embodiment P107. A composition comprising a compound or salt thereof according to any one of Embodiments P1 to P106 and a pharmaceutically acceptable excipient.

[0939] Embodiment P108. 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 P1 to P106 or a composition according to Embodiment P107.

[0940] Embodiment P109. The method of embodiment P108, 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.

[0941] Embodiment P110. 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 P1 to P106 or a composition according to Embodiment P107.

[0942] Embodiment P111. The method of embodiment P110, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.

[0943] Embodiment P112. The method of embodiment P110 or P111, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

[0944] Embodiment P113. The method of any one of Embodiments P108 to P112, wherein the compound or salt thereof is administered intrathecally to the subject.

[0945] Embodiment P114. A process for preparing a compound or salt thereof as described in any one of Embodiments P1 to P106, comprising one or more compounds described herein and a chemical transformation, including Example 1.

[0946] Other embodiments include the following Embodiment 1 to Embodiment 166.

[0947] Embodiment 1. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising a structure of Formula (I'):

[0948]

[0949] in:

[0950] Each independently is a cannabinoid receptor type 1 ( CB1 ) ligand;

[0951] L1, L2, L3, L4, L 1A 、L 2A 、L 3A and L 4A each independently a linker, a bond, or absent;

[0952] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; and

[0953] z1 is 0 or 1.

[0954] Embodiment 2. The compound of embodiment 1 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (I"):

[0955]

[0956] in:

[0957] For oligonucleotides.

[0958] Embodiment 3. The compound of Embodiment 2, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-a):

[0959]

[0960] in:

[0961] X 1 NR 10 or CR 11 R 12 ;

[0962] X 2 NR 13 or CR 14 R 15 ;

[0963] R 10 、R 11 、R12 、R 13 、R 14 and R 15 each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0964] R 19 For hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C 、-C(O)R 19D 、-C(O)OR 19D 、-C(O)NR 19B R 19C 、-OR 19A 、-NR 19B SO2R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0965] R 21 For hydrogen, -SO n21 R 21A 、-SO v21 NR 21B R 21C 、-NHNR 21B R 21C 、-ONR 21B R 21C 、-NHC(O)NHNR 21B R 21C 、-NHC(O)NR 21B R 21C 、-NR 21B R 21C 、-C(O)R 21D、-C(O)OR 21D 、-C(O)NR 21B R 21C 、-OR 21A 、-NR 21B SO2R 21A 、-NR 21B C(O)R 21D 、-NR 21B C(O)OR 21D 、-NR 21B OR 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0966] R 19A 、R 19B 、R 19C 、R 19D 、R 21A 、R 21B 、R 21C and R 21D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 19B and R 19C and R 21B and R 21C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[0967] n19 and n21 are each independently 0, 1, 2, 3 or 4; and

[0968] v19 and v21 are each independently 1 or 2.

[0969] Embodiment 4. The compound of Embodiment 3 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-a-1):

[0970]

[0971] Embodiment 5. The compound of Embodiment 3 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-a-2):

[0972]

[0973] Embodiment 6. The compound of Embodiment 2, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-b):

[0974]

[0975] Embodiment 7. The compound of Embodiment 6 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-b-1):

[0976]

[0977] Embodiment 8. The compound of Embodiment 6 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-b-2):

[0978]

[0979] Embodiment 9. The compound of Embodiment 2, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (I"-c):

[0980]

[0981] Embodiment 10. The compound of Embodiment 9 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-c-1):

[0982]

[0983]

[0984] Embodiment 11. The compound of Embodiment 9 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (I"-c-2):

[0985]

[0986] Embodiment 12. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising the structure of Formula (I):

[0987]

[0988] in

[0989] It is a cannabinoid receptor type 1 (CB1) ligand;

[0990] L1, L2, L3 and L4 are each independently a linker, a bond or absent; and

[0991] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[0992] Embodiment 13. The compound of embodiment 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a CB1 agonist.

[0993] Embodiment 14. The compound of embodiment 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a CB1 antagonist.

[0994] Embodiment 15. The compound of embodiment 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a selective ligand.

[0995] Embodiment 16. The compound of embodiment 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a non-selective ligand.

[0996] Embodiment 17. A compound as described in any one of Embodiments 12 to 16, or a stereoisomer, tautomer, prodrug or salt thereof, wherein CB1 The ligand is selected from the group consisting of minocycline, dronabinol, epigallocatechin, epicatechin, kavaccin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonylglycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP55,940, JWH-018, WIN55,212-2, GAT228, cannabinoids. Phenol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti-CB1 antibodies and their derivatives.

[0997] Embodiment 18. The compound of Embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the CB1 ligand comprises a structure of Formula (II'):

[0998]

[0999] in:

[1000] R17 For hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R 17C 、-NR 17B R 17C 、-C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C 、-OR 17A 、-NR 17B SO2R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1001] R 17A 、R 17B 、R 17C and R 17D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[1002] n17 is 0, 1, 2, 3 or 4; and

[1003] v17 is 1 or 2.

[1004] Embodiment 19. The compound of embodiment 18, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 17 -NR 17B R17C 、-C(O)R 17D or-C(O)OR 17D .

[1005] Embodiment 20. The compound of embodiment 19, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 17B and R 17C Each is independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl.

[1006] Embodiment 21. The compound of embodiment 20, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand comprises the structure

[1007] Embodiment 22. The compound of Embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (II):

[1008]

[1009] Embodiment 23. The compound of Embodiment 22, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (II-a):

[1010]

[1011] Embodiment 24. The compound of embodiment 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand comprises the structure or its derivatives.

[1012] Embodiment 25. The compound of Embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (III):

[1013]

[1015] Embodiment 26. The compound of Embodiment 25, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (III-a):

[1016]

[1017] Embodiment 27. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising the structure of Formula (VIII):

[1018]

[1019] in:

[1020] L1, L2, L3 and L4 are each independently a linker, a bond or absent;

[1021] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides;

[1022] R 3 、R 4 、R 5 、R 6 and R 8 each independently is hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[1023] R 9 is hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl; or R 6 and R 9 The substituents may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl;

[1024] R 7 For hydrogen, -SO n7 R 7A 、-SO v7 NR 7B R 7C 、-NHNR 7B R 7C 、-ONR 7B R 7C 、-NHC(O)NHNR 7B R 7C 、-NHC(O)NR 7B R 7C 、-NR 7B R 7C 、-C(O)R 7D 、-C(O)OR 7D 、-C(O)NR 7B R 7C 、-OR 7A 、-NR 7B SO2R 7A 、-NR 7B C(O)R 7D 、-NR 7B C(O)OR 7D 、-NR 7B OR 7D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1025] R 7A 、R 7B 、R 7C 、R 7D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 7B and R 7C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[1026] n7 is 0, 1, 2, 3 or 4; and

[1027] v7 is 1 or 2.

[1028] Embodiment 28. The compound of embodiment 27, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 7 and R 8 Each is independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl.

[1029] Embodiment 29. The compound of Embodiment 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein:

[1030] R 4 is a halogen; and

[1031] R 3 、R 5 and R 6 are each independently hydrogen.

[1032] Embodiment 30. The compound of embodiment 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 3 、R 4 、R 5 and R 6 are each independently hydrogen.

[1033] Embodiment 31. The compound of embodiment 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 6 and R 9 The substituents are joined together to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

[1034] Embodiment 32. The compound of embodiment 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R9 is hydrogen or optionally substituted alkyl.

[1035] Embodiment 33. The compound of Embodiment 27, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-a):

[1036]

[1037] Embodiment 34. The compound of Embodiment 33, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-a-1):

[1038]

[1039] Embodiment 35. The compound of Embodiment 27, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-a-2):

[1040]

[1041] Embodiment 36. The compound of Embodiment 27, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-b):

[1042]

[1043] Embodiment 37. The compound of Embodiment 27 or 36, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-b-1):

[1044]

[1045] Embodiment 38. The compound of Embodiment 27, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-c):

[1046]

[1047] Embodiment 39. The compound of Embodiment 27 or 38, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-c-1):

[1048]

[1049] Embodiment 40. The compound of Embodiment 27, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-c-2):

[1050]

[1051] Embodiment 41. The compound of Embodiment 27, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-d):

[1052]

[1053] Embodiment 42. The compound of Embodiment 27 or 41, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (VIII-d-1):

[1054]

[1055] Embodiment 43. The compound of Embodiment 27, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (VIII-d-2):

[1056]

[1057] Embodiment 44. The compound of Embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (IX):

[1058]

[1059] in:

[1060] L1, L2, L3 and L4 are each independently a linker, a bond or absent;

[1061] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides;

[1062] X 1 NR 10 or CR 11 R 12 ;

[1063] R 10 、R 11 and R 12 each independently is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[1064] R 19 For hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C 、-C(O)R 19D 、-C(O)OR 19D 、-C(O)NR 19B R 19C 、-OR 19A 、-NR 19B SO2R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1065] R 19A 、R 19B 、R 19C 、R 19D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 19B and R 19C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl;

[1066] n19 is 0, 1, 2, 3, or 4; and

[1067] v19 is 1 or 2.

[1068] Embodiment 45. The compound of Embodiment 12 or 44, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (IX-a-1):

[1069]

[1070] Embodiment 46. The compound of Embodiment 12 or 44, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure of Formula (IX-a-2):

[1071]

[1072] Embodiment 47. The compound of any one of Embodiments 44 to 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein:

[1073] X 1 NR 10 ;and

[1074] R 10 is hydrogen or optionally substituted alkyl.

[1075] Embodiment 48. The compound of Embodiment 47, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein:

[1076] R 10 It is hydrogen, -CH3 or -CH2CH2F.

[1077] Embodiment 49. The compound of any one of Embodiments 44 to 46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein:

[1078] X 1 CR 11 R 12 ;and

[1079] R 11 and R 12 Each is independently hydrogen or optionally substituted alkyl.

[1080] Embodiment 50. The compound of Embodiment 49, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein:

[1081] R 11 is hydrogen, -CH3 or -CH2CH2F; and

[1082] R 12 For hydrogen.

[1083] Embodiment 51. The compound of Embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising a structure of Formula (X):

[1084]

[1085] in:

[1086] L1, L2, L3 and L4 are each independently a linker, a bond or absent;

[1087] R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides;

[1088] R 16 For hydrogen, halogen, -CN, -N3, -NO2, -NR 16B R 16C 、-C(O)R 16D 、-C(O)OR 16D 、-C(O)NR 16B R 16C 、-OR 16A 、-NR 16B C(O)R 16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[1089] R 16A 、R 16B 、R 16C and R 16D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 16B and R 16C The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[1090] Embodiment 52. The compound of Embodiment 51 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (Xa):

[1091]

[1092] Embodiment 53. The compound of Embodiment 12 or 52, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises a structure of Formula (Xa-1):

[1093]

[1094] Embodiment 54. The compound of Embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the CB1 ligand comprises the structure:

[1095]

[1096] or its derivatives.

[1097] Embodiment 55. The compound of Embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the compound comprises the structure:

[1098]

[1099]

[1100] Embodiment 56. A compound as described in any one of Embodiments 1 to 55, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3 and L4 are each 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, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester bond, or a phosphorothioate bond.

[1101] Embodiment 57. The compound of any one of Embodiments 1 to 56, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 is a bond.

[1102] Embodiment 58. A compound as described in any one of Embodiments 1 to 56, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 is oxygen.

[1103] Embodiment 59. A compound as described in any one of Embodiments 1 to 56, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 comprises the structure wherein n7 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[1104] Embodiment 60. The compound of any one of Embodiments 1 to 59, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 is an optionally substituted PEG linker.

[1105] Embodiment 61. A compound as described in Embodiment 60, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the PEG linker is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units in length.

[1106] Embodiment 62. The compound of any one of Embodiments 1 to 59, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 is an optionally substituted alkyl linker.

[1107] Embodiment 63. The compound of embodiment 62, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 comprises the structure

[1108] Embodiment 64. A compound as described in any one of Embodiments 1 to 63, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 is an optionally substituted heteroalkyl linker or bond.

[1109] Embodiment 65. The compound of Embodiment 64, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

[1110] Embodiment 66. A compound according to embodiment 64 or 65, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 comprises the structure

[1111]

[1112] Wherein X is O or S.

[1113] Embodiment 67. The compound of embodiment 66, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 comprises the structure

[1114]

[1115] Wherein X is O or S.

[1116] Embodiment 68. The compound of any one of Embodiments 1 to 67, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 is an optionally substituted heteroaryl linker.

[1117] Embodiment 69. The compound of any one of Embodiments 1 to 63, or a stereoisomer, tautomer, prodrug or salt thereof, wherein one of L3 and L4 is an optionally substituted phosphodiester bond or an optionally substituted phosphorothioate bond and the other of L3 and L4 is a bond.

[1118] Embodiment 70. The compound of any one of Embodiments 1 to 67, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 is an optionally substituted partially unsaturated heteroaryl or an optionally substituted partially unsaturated heterocycloalkyl linker.

[1119] Embodiment 71. The compound of embodiment 70, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 comprises the structure

[1120] Embodiment 72. The compound of any one of Embodiments 1 to 71, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein L1, L2, L3, and L4 together comprise the following structure:

[1121]

[1122]

[1123] in:

[1124] X is O or S; and

[1125] n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[1126] n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

[1127] Embodiment 73. The compound of embodiment 72, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3 and L4 together comprise the following structure:

[1128]

[1129] Wherein: X is O or S;

[1130] n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[1131] n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

[1132] Embodiment 74. The compound of embodiment 66, 67, 72 or 73, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is S.

[1133] Embodiment 75. The compound of embodiment 66, 67, 72 or 73, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is O.

[1134] Embodiment 76. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising a structure of Formula (IV') or a salt thereof:

[1135]

[1136] in:

[1137] each independently a cannabinoid receptor type 1 (CB1) ligand, or One of them is a CB1 ligand, and The other of comprises a lipid or a ligand;

[1138] L1, L2, L3, L4, L5, L 1A 、L 2A 、L A3 、L A4 and L A5 each independently a linker, a bond, or absent; and

[1139] R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

[1140] Embodiment 77. The compound of Embodiment 76, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (IV"):

[1141]

[1142] in:

[1143] For oligonucleotides.

[1144] Embodiment 78. The compound of Embodiment 77 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (IV"-a):

[1145]

[1146] in:

[1147] R 17 For hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R 17C 、-NR 17B R 17C 、-C(O)R 17D 、-C(O)OR17D 、-C(O)NR 17B R 17C 、-OR 17A 、-NR 17B SO2R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1148] R 18 For hydrogen, -SO n18 R 18A 、-SO v18 NR 18B R 18C 、-NHNR 18B R 18C 、-ONR 18B R 18C 、-NHC(O)NHNR 18B R 18C 、-NHC(O)NR 18B R 18C 、-NR 18B R 18C 、-C(O)R 18D 、-C(O)OR 18D 、-C(O)NR 18B R 18C 、-OR 18A 、-NR 18B SO2R 18A 、-NR 18B C(O)R 18D 、-NR 18B C(O)OR 18D 、-NR 18B OR 18D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1149] R 22 For hydrogen, -SO n22 R 22A 、-SO v22 NR 22B R 22C 、-NHNR 22B R 22C 、-ONR 22B R22C 、-NHC(O)NHNR 22B R 22C 、-NHC(O)NR 22B R 22C 、-NR 22B R 22C 、-C(O)R 22D 、-C(O)OR 22D 、-C(O)NR 22B R 22C 、-OR 22A 、-NR 22B SO2R 22A 、-NR 22B C(O)R 22D 、-NR 22B C(O)OR 22D 、-NR 22B OR 22D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1150] R 23 For hydrogen, -SO n23 R 23A 、-SO v23 NR 23B R 23C 、-NHNR 23B R 23C 、-ONR 23B R 23C 、-NHC(O)NHNR 23B R 23C 、-NHC(O)NR 23B R 23C 、-NR 23B R 23C 、-C(O)R 23D 、-C(O)OR 23D 、-C(O)NR 23B R 23C 、-OR 23A 、-NR 23B SO2R 23A 、-NR 23B C(O)R 23D 、-NR 23B C(O)OR 23D 、-NR 23B OR 23D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1151] R 24 For hydrogen, -SO n24 R 24A 、-SO v24 NR 24B R 24C 、-NHNR 24B R 24C 、-ONR 24B R 24C 、-NHC(O)NHNR 24B R 24C 、-NHC(O)NR 24B R 24C 、-NR 24B R 24C 、-C(O)R 24D 、-C(O)OR 24D 、-C(O)NR 24B R 24C 、-OR 24A 、-NR 24B SO2R 24A 、-NR 24B C(O)R 24D 、-NR 24B C(O)OR 24D 、-NR 24B OR 24D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[1152] R 17A 、R 17B 、R 17C 、R 17D 、R 18A 、R 18B 、R 18C 、R 18D 、R 22A 、R 22B 、R 22C 、R 22D 、R 23A 、R 23B 、R 23C and R 23D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17CThe substituents may be optionally linked to form a substituted or unsubst...

Claims

1. A compound or a stereoisomer, tautomer, prodrug or salt thereof, comprising a structure of formula (I'): in: Each is independently a cannabinoid receptor type 1 (CB1) ligand; L1, L2, L3, L4, L 1A , L 2A , L 3A and L 4A each independently is 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: ——are oligonucleotides.

3. The compound according to claim 2 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (I"-a): in: X 1 NR 10 or CR 11 R 12 ; X 2 NR 13 or CR 14 R 15 ; R 10 , R 11 , R 12 , R 13 , R 14 and R 15 each is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 19 For hydrogen, –SO n19 R 19A ,–SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C ,–NR 19B R 19C , –C(O)R 19D , –C(O)OR 19D , –C(O)NR 19B R 19C ,–OR 19A 、-NR 19B S02R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D ,–NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 21 For hydrogen, –SO n21 R 21A 、-SO v21 NR 21B R 21C 、-NHNR 21B R 21C 、-ONR 21B R 21C 、-NHC(O)NHNR 21B R 21C 、-NHC(O)NR 21B R 21C ,–NR 21B R 21C , –C(O)R 21D , –C(O)OR 21D 、-C(O)NR 21B R 21C ,–OR 21A 、-NR 21B S02R 21A 、-NR 21B C(O)R 21D ,–NR 21B C(O)OR 21D ,–NR 21B OR 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19A , R 19B , R 19C , R 19D , R 21A , R 21B , R 21C and R 21D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 19B and R 19C and R 21B and R 21C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n19 and n21 are each independently 0, 1, 2, 3 or 4; and v19 and v21 are each independently 1 or 2.

4. The compound according to claim 3 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (I"-a-1):

5. The compound according to claim 3 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (I"-a-2):

6. The compound of claim 2 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises a structure of formula (I"-b):

7. The compound according to claim 6 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (I"-b-1):

8. The compound of claim 6 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (I"-b-2):

9. The compound of claim 2 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises a structure of formula (I"-c):

10. The compound according to claim 9 or its stereoisomer, tautomer, prodrug or salt, wherein the compound comprises the structure of formula (I"-c-1):

11. The compound of claim 9 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (I"-c-2):

12. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising the structure of formula (I): in It is a cannabinoid receptor type 1 (CB1) ligand; L1, L2, L3 and L4 are each independently a linker, a bond or absent; and R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

13. The compound of claim 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a CB1 agonist.

14. The compound of claim 12, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a CB1 antagonist.

15. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a selective ligand.

16. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a non-selective ligand.

17. A compound according to any one of claims 12 to 16, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1The ligand is selected from the group consisting of: minocycline, dronabinol, epigallocatechin, epicatechin, cavaceine, yangonine, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonyl glycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoyl glycerol, AM-2201, CP 55,940, JWH-018, WIN 55,212-2, GAT228, cannabidiol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutane-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti- CB1 Antibodies and their derivatives.

18. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand comprises a structure of formula (II'): in: R 17 For hydrogen, –SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R 17C 、-NR 17B R 17C , –C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C ,–OR 17A 、-NR 17B S02R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D ,–NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 17A , R 17B , R 17C and R 17D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 17B and R 17C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n17 is 0, 1, 2, 3 or 4; and v17 is 1 or 2.

19. The compound of claim 18 or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 17 For-NR 17B R 17C , –C(O)R 17D or-C(O)OR 17D .

20. The compound of claim 19 or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 17B and R 17C Each is independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl.

21. The compound of claim 20 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand comprises the structure 22. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (II):

23. The compound of claim 22 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (II-a):

24. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand comprises the structure or its derivatives.

25. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (III):

26. The compound of claim 25 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (III-a):

27. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising the structure of formula (VIII): in: L1, L2, L3 and L4 are each independently a linker, a bond or absent; R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; R 3 , R 4 , R 5 , R 6 and R 8 each is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 9 is hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl; or R 6 and R 9 The substituents can be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; and R 7 Hydrogen, -SO n7 R 7A ,–SO v7 NR 7B R 7C 、-NHNR 7B R 7C 、-ONR 7B R 7C 、-NHC(O)NHNR 7B R 7C 、-NHC(O)NR 7B R 7C ,–NR 7B R 7C , –C(O)R 7D , –C(O)OR 7D 、-C(O)NR 7B R 7C ,–OR 7A ,–NR 7B S02R 7A ,–NR 7B C(O)R 7D ,–NR 7B C(O)OR 7D 、-NR 7B OR 7D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7A , R 7B , R 7C , R 7D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 7B and R 7C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n7 is 0, 1, 2, 3 or 4; and v7 is 1 or 2.

28. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 7 and R 8 Each is independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl.

29. The compound of claim 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: R 4 is a halogen; and R 3 , R 5 and R 6 are each independently hydrogen.

30. The compound of claim 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 3 , R 4 , R 5 and R 6 are each independently hydrogen.

31. The compound of claim 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 6 and R 9 The substituents are joined together to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

32. The compound of claim 27 or 28, or a stereoisomer, tautomer, prodrug or salt thereof, wherein R 9 is hydrogen or optionally substituted alkyl.

33. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-a):

34. The compound of claim 33 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-a-1):

35. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-a-2):

36. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-b):

37. The compound of claim 27 or 36, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-b-1):

38. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-c):

39. The compound of claim 27 or 38, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-c-1):

40. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-c-2):

41. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-d):

42. The compound of claim 27 or 41, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-d-1):

43. The compound of claim 27 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (VIII-d-2):

44. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof comprising the structure of formula (IX): in: L1, L2, L3 and L4 are each independently a linker, a bond or absent; R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; X 1 NR 10 or CR 11 R 12 ; R 10 , R 11 and R 12 each is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 19 Hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C ,–NR 19B R 19C 、-C(O)R 19D , –C(O)OR 19D , –C(O)NR 19B R 19C ,–OR 19A 、-NR 19B S02R 19A ,–NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19A , R 19B , R 19C , R 19D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 19B and R 19C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n19 is 0, 1, 2, 3 or 4; and v19 is 1 or 2.

45. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in claim 12 or 44, wherein the compound comprises the structure of formula (IX-a-1):

46. ​​A compound as described in claim 12 or 44, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of formula (IX-a-2):

47. A compound as claimed in any one of claims 44 to 46, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: X 1 NR 10 ;and R 10 is hydrogen or optionally substituted alkyl.

48. The compound of claim 47, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: R 10 It is hydrogen, -CH3 or -CH2CH2F.

49. A compound as described in any one of claims 44 to 46, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: X 1 CR 11 R 12 ;and R 11 and R 12 Each is independently hydrogen or optionally substituted alkyl.

50. The compound of claim 49 or a stereoisomer, tautomer, prodrug or salt thereof, wherein: R 11 is hydrogen, -CH3 or -CH2CH2F; and R 12 For hydrogen.

51. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof comprising a structure of formula (X): in: L1, L2, L3 and L4 are each independently a linker, a bond or absent; R 1 comprising one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; R 16 For hydrogen, halogen, –CN, -N3, -NO2, -NR 16B R 16C 、-C(O)R 16D 、-C(O)OR 16D 、-C(O)NR 16B R 16C 、-OR 16A 、-NR 16B C(O)R 16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R 16A , R 16B , R 16C and R 16D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 16B and R 16C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

52. The compound of claim 51 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Xa):

53. The compound of claim 12 or 52, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (Xa-1):

54. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand comprises the structure: Its derivatives.

55. The compound of claim 12 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure:

56. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 1 to 55, wherein L1, L2, L3 and L4 are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted assorted alkyl linker, an optionally substituted heteroaryl linker, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester bond or a thiophosphate bond.

57. A compound as described in any one of claims 1 to 56, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 is a bond.

58. A compound as described in any one of claims 1 to 56, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 is oxygen.

59. A compound as described in any one of claims 1 to 56, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 comprises the structure wherein n7 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

60. The compound of any one of claims 1 to 59, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 is an optionally substituted PEG linker.

61. The compound of claim 60, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the PEG linker is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units in length.

62. A compound as described in any one of claims 1 to 59, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 is an optionally substituted alkyl linker.

63. The compound of claim 62 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 comprises the structure 64. A compound as described in any one of claims 1 to 63, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 is an optionally substituted heteroalkyl linker or bond.

65. The compound of claim 64, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

66. A compound as described in claim 64 or 65, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 comprises the structure Wherein X is O or S.

67. The compound of claim 66 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 comprises the structure Wherein X is O or S.

68. A compound as described in any one of claims 1 to 67, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 is an optionally substituted heteroaryl linker.

69. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 1 to 63, wherein one of L3 and L4 is an optionally substituted phosphodiester bond or an optionally substituted phosphorothioate bond, and the other of L3 and L4 is a bond.

70. A compound as described in any one of claims 1 to 67, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 is an optionally substituted partially unsaturated heteroaryl or an optionally substituted partially unsaturated heterocycloalkyl linker.

71. The compound of claim 70 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 comprises the structure 72. A compound as described in any one of claims 1 to 71, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3 and L4 together comprise the following structure: in: X is O or S; and n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

73. A compound as claimed in claim 72 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3 and L4 together comprise the following structure: in: X is O or S; n1, n2, n4, n5, n6, n7 and n8 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; and n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

74. The compound of claim 66, 67, 72 or 73, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is S.

75. The compound of claim 66, 67, 72 or 73, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is O.

76. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising a structure of formula (IV') or a salt thereof: in: each independently a cannabinoid receptor type 1 (CB1) ligand, or One of them is a CB1 ligand, and The other of the two comprises a lipid or a ligand; L1, L2, L3, L4, L5, L 1A , L 2A , L A3 , L A4 and L A5 each independently is a linker, a bond, or absent; and R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

77. The compound of claim 76 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV"): in: ——are oligonucleotides.

78. The compound of claim 77 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV"-a): in: R 17 Hydrogen, -SO n17 R 17A ,–SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R 17C ,–NR 17B R 17C , –C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C ,–OR 17A 、-NR 17B S02R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 18 For hydrogen, –SO n18 R 18A 、-SO v18 NR 18B R 18C 、-NHNR 18B R 18C 、-ONR 18B R 18C 、-NHC(O)NHNR 18B R 18C 、-NHC(O)NR 18B R 18C ,–NR 18B R 18C 、-C(O)R 18D , –C(O)OR 18D 、-C(O)NR 18B R 18C ,–OR 18A 、-NR 18B S02R 18A 、-NR 18B C(O)R 18D 、-NR 18B C(O)OR 18D ,–NR 18B OR 18D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 22 Hydrogen, -SO n22 R 22A ,–SO v22 NR 22B R 22C 、-NHNR 22B R 22C 、-ONR 22B R 22C 、-NHC(O)NHNR 22B R 22C 、-NHC(O)NR 22B R 22C 、-NR 22B R 22C 、-C(O)R 22D 、-C(O)OR 22D 、-C(O)NR 22B R 22C ,–OR 22A 、-NR 22B S02R 22A 、-NR 22B C(O)R 22D 、-NR 22B C(O)OR 22D ,–NR 22B OR 22D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 23 For hydrogen, –SO n23 R 23A 、-SO v23 NR 23B R 23C 、-NHNR 23B R 23C 、-ONR 23B R 23C 、-NHC(O)NHNR 23B R 23C 、-NHC(O)NR 23B R 23C 、-NR 23B R 23C 、-C(O)R 23D 、-C(O)OR 23D 、-C(O)NR 23B R 23C ,–OR 23A 、-NR 23B S02R 23A 、-NR 23B C(O)R 23D 、-NR 23B C(O)OR 23D 、-NR 23B OR 23D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 24 For hydrogen, –SO n24 R 24A 、-SO v24 NR 24B R 24C 、-NHNR 24B R 24C 、-ONR 24B R 24C 、-NHC(O)NHNR 24B R 24C 、-NHC(O)NR 24B R 24C 、-NR 24B R 24C , –C(O)R 24D , –C(O)OR 24D , –C(O)NR 24B R 24C ,–OR 24A 、-NR 24B S02R 24A 、-NR 24B C(O)R 24D 、-NR 24B C(O)OR 24D ,–NR 24B OR 24D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 17A , R 17B , R 17C , R 17D , R 18A , R 18B , R 18C , R 18D , R 22A , R 22B , R 22C , R 22D , R 23A , R 23B , R 23C and R 23D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n17, n18, n22 and n23 are each independently 0, 1, 2, 3 or 4; and v17, v18, v22 and v23 are each independently 1 or 2.

79. The compound of claim 78 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV"-b):

80. The compound of claim 78 or 79, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of formula (IV"-b-1):

81. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising a structure of formula (IV) or a salt thereof: in: each independently a cannabinoid receptor type 1 (CB1) ligand, or One of them is a CB1 ligand, and The other of the two comprises a lipid or a ligand; L1, L2, L3, L4 and L5 are each independently a linker, a bond or absent; and R 1 Contains one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

82. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein Each is independently a CB1 ligand.

83. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein one or both of the CB1 ligands are CB1 agonists.

84. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein one or both of the CB1 ligands are CB1 antagonists.

85. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a selective ligand.

86. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a non-selective ligand.

87. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 The ligands are each independently selected from the group consisting of: minocycline, dronabinol, epigallocatechin, epicatechin, cavacin, yangonin, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonyl glycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoyl glycerol, AM-2201, CP 55,940, JWH-018, WIN 55,212-2, GAT228, cannabidiol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutane-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti-CB1 antibodies and their derivatives.

88. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein each of the CB1 ligands comprises the structure or its derivatives.

89. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (V): in: R 17 For hydrogen, –SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R17 C ,–NR 17B R 17C , –C(O)R 17D , –C(O)OR 17D , –C(O)NR 17B R 17C ,–OR 17A 、-NR 17B S02R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 18 Hydrogen, -SO n18 R 18A 、-SO v18 NR 18B R 18C 、-NHNR 18B R 18C 、-ONR 18B R 18C 、-NHC(O)NHNR 18B R 18C 、-NHC(O)NR 18B R 18C 、-NR 18B R 18C 、-C(O)R 18D 、-C(O)OR 18D 、-C(O)NR 18B R 18C ,–OR 18A 、-NR 18B S02R 18A 、-NR 18B C(O)R 18D 、-NR 18B C(O)OR 18D ,–NR 18B OR 18D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 17A , R 17B , R 17C , R 17D , R 18A , R 18B , R 18C and R 18D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 17B and R 17C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 17B and R 17C or R 18B and R 18C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n17 and n18 are each independently 0, 1, 2, 3 or 4; and v17 and v18 are each independently 1 or 2.

90. The compound of claim 89 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (Va):

91. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein one of the CB1 ligands comprises the structure: or a derivative thereof, and the other CB1 ligand comprises the following structure: or its derivatives.

92. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (IX):

93. The compound of claim 92 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises the structure of Formula (IX-a):

94. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein each of the CB1 ligands independently comprises the following structure: in: X 1 NR 10 or CR 11 R 12 ; R 10 , R 11 and R 12 each is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 19 Hydrogen, -SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C 、-C(O)R 19D , –C(O)OR 19D , –C(O)NR 19B R 19C ,–OR 19A 、-NR 19B S02R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D 、-NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19A , R 19B , R 19C and R 19D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 19B and R 19C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n19 is 0, 1, 2, 3 or 4; and v19 is 1 or 2.

95. The compound of claim 81 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XI): X 1 Independently for NR 10 or CR 11 R 12 ; X 2 NR 13 or CR 14 R 15 ; R 10 , R 11 , R 12 , R 13 , R 14 and R 15each is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 19A , R 19B , R 19C , R 19D , R 21A , R 21B , R 21C and R 21D are each independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R bonded to the same nitrogen atom 21B and R 21C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n19 and n21 are each independently 0, 1, 2, 3 or 4; and v19 and v21 are each independently 1 or 2.

96. The compound of claim 95 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (XI-a):

97. The compound of claim 95 or 96, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: X1 for NR10 ; X 2 NR 13 ; R 10 and R 13 Each is independently hydrogen or optionally substituted alkyl.

98. The compound of claim 97, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: R 10 and R 13 Each is independently hydrogen, -CH3 or -CH2CH2F.

99. The compound of claim 95 or 96, or a stereoisomer, tautomer, prodrug or salt thereof, wherein: X 1 CR 11 R 12 ; X 2 CR 14 R 15 ;and R 11 , R 12 , R 14 and R 15 Each is independently hydrogen or optionally substituted alkyl.

100. The compound of claim 99 or a stereoisomer, tautomer, prodrug or salt thereof, wherein: R 12 and R 15 are each independently hydrogen, -CH3 or -CH2CH2F; and R 11 and R 14 are each independently hydrogen.

101. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 81 to 100, wherein L1, L2, L3, L4 and L5 are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted assorted alkyl linker, an optionally substituted heteroaryl linker, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester bond or a thiophosphate bond.

102. The compound of claim 101 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 and L5 are each an optionally substituted PEG linker.

103. The compound of claim 102, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 and L5 are each an optionally substituted PEG linker of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units in length.

104. A compound as described in any one of claims 81 to 103, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L2 is an optionally substituted heteroalkyl linker.

105. The compound of claim 104, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

106. A compound or a stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 81 to 105, wherein L2 comprises the structure 107. A compound as described in any one of claims 81 to 106, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 is an optionally substituted heteroaryl linker.

108. A compound as described in any one of claims 81 to 106, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 is an optionally substituted partially unsaturated heteroaryl linker or an optionally substituted partially unsaturated heterocycloalkyl linker.

109. The compound of claim 108 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 comprises the structure 110. The compound or stereoisomer, tautomer, prodrug or salt thereof of any one of claims 81 to 109, wherein L4 is an optionally substituted heteroalkyl linker.

111. The compound of claim 110, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

112. The compound of claim 110 or 111, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 comprises the structure Wherein X is O or S.

113. The compound of claim 112 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 comprises the structure Wherein X is O or S.

114. The compound of claim 112 or 113, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is S.

115. The compound of claim 112 or 113, or a stereoisomer, tautomer, prodrug or salt thereof, wherein X is O.

116. compounds as described in any one of claims 81 to 115, wherein L1, L2, L3, L4 and L5 together comprise the structure Wherein X is O or S.

117. The compound of claim 116, wherein L1, L2, L3, L4 and L5 together comprise the structure or Where X 118. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising a structure of formula (VI) or a salt thereof: in: It is a cannabinoid receptor type 1 (CB1) ligand; L1, L2, L3, L4, L5, L6 and L7 are each independently a linker, a bond or absent; and R 1 and R 2 Each comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides.

119. The compound of claim 118, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a CB1 agonist.

120. The compound of claim 118, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand is a CB1 antagonist.

121. The compound of claim 118 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 The ligand is selected from the group consisting of: minocycline, dronabinol, epigallocatechin, epicatechin, cavaceine, yangonine, oleamide, N-arachidonoyl dopamine, cannabinol, HU-210, 11-hydroxy-THC, levothranol, 2-arachidonyl glycerol ether, JWH-073, tetrahydrocannabinol, 2-arachidonoyl glycerol, AM-2201, CP 55,940, JWH-018, WIN 55,212-2, GAT228, cannabidiol, ibipinabant, octenabant, tetrahydrocannabinol, vilodamine, rimonabant, taranabant, lipoxin A4, ZCZ-011, pregnenolone, cannabidiol, fenofibrate, GAT100, PSNCBAM-1, RVD-Hpα, (S)-N-(1-amino-3,3-dimethyl-1-oxobutane-2-yl)-1-(pent-4-en-1-yl)-1H-indazole-3-carboxamide, anandamide, anti-CB1 antibodies and their derivatives.

122. The compound of claim 118 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the CB1 ligand comprises the structure 123. The compound of claim 118 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (VII): in: R 17 For hydrogen, –SO n17 R 17A ,–SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R17 C 、-NR 17B R 17C 、-C(O)R 17D 、-C(O)OR 17D , –C(O)NR 17B R 17C ,–OR 17A 、-NR 17B S02R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D 、-NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 17A , R 17B , R 17C and R 17D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 17B and R 17C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl. n17 is 0, 1, 2, 3 or 4; and v17 is 1 or 2.

124. The compound of claim 123 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the compound comprises a structure of Formula (VII-a):

125. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 118 to 124, wherein L1, L2, L3, L4, L5, L6 and L7 are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted assorted alkyl 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 thiophosphate bond.

126. The compound of claim 125, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 is an optionally substituted PEG linker.

127. The compound of claim 126, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1 is an optionally substituted PEG linker of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG units in length.

128. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 125 to 127, wherein L2 and L5 are each independently an optionally substituted PEG linker.

129. The compound of claim 128, or a stereoisomer, tautomer, prodrug or salt thereof, wherein said L2 and L5 are each independently an optionally substituted PEG linker of three or four PEG units in length.

130. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 125 to 129, wherein L1, L2 and L5 together comprise the structure 131. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 125 to 129, wherein L3 and L6 are each independently an optionally substituted heteroaryl linker or an optionally substituted heterocycloalkyl linker.

132. A compound as claimed in claim 131 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 and L6 are each independently an optionally substituted partially unsaturated heteroaryl linker or an optionally substituted partially unsaturated heterocycloalkyl linker.

133. A compound as described in claim 131 or 132, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L3 and L6 each comprise the structure 134. A compound as described in any one of claims 125 to 133, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 and L7 are each independently an optionally substituted heteroalkyl linker.

135. The compound of claim 134, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the heteroalkyl linker is substituted with one or more =0 substituents.

136. A compound as described in claim 134 or 135, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 and L7 each comprise the structure Wherein X is O or S.

137. The compound of claim 136 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L4 and L7 each comprise the structure Wherein X is O or S.

138. A compound or salt thereof as described in any one of claims 1 to 137, wherein R 1 Contains oligonucleotides.

139. The compound of claim 138, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at its 5' end.

140. The compound of claim 138, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at its 3' end.

141. The compound of claim 138, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is attached at an internal position on the oligonucleotide.

142. The compound of claim 141 or a stereoisomer, tautomer, prodrug or salt thereof, wherein the internal position is an internucleoside linkage.

143. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 1 to 142, wherein R 1 comprising an oligonucleotide conjugated to one or more additional CB1 ligands.

144. The compound of claim 143, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is conjugated to two, three, four, five or more than five additional CB1 ligands.

145. The compound of claim 143 or 144, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the additional CB1 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.

146. The compound of any one of claims 1 to 145, or a stereoisomer, tautomer, prodrug or salt thereof, wherein the oligonucleotide is a modified oligonucleotide.

147. A compound or salt thereof as described in any one of claims 1 to 146, wherein L1, L2, L3 and L4 together comprise the following structure: Wherein X is O or S.

148. The compound of claim 147 or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3 and L4 together comprise the structure: Wherein X is O or S.

149. A compound or salt thereof as described in any one of claims 118 to 146, wherein L1, L2, L3, L4, L5, L6 and L7 together comprise the following structure: Wherein X is O or S.

150. A compound as described in claim 149, or a stereoisomer, tautomer, prodrug or salt thereof, wherein L1, L2, L3, L4, L5, L6 and L7 together comprise the following structure: Wherein X is O or S.

151. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising the structure: in: R 1 and R 2 Each comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; and X is O or S.

152. The compound of claim 151, wherein the compound comprises the structure:

153. A compound or a stereoisomer, tautomer, prodrug or salt thereof comprising the structure: in R 1 and R 2Each comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and / or peptides; and X is O or S.

154. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 1 to 149, wherein the compound comprises the structure: in: is an oligonucleotide; and X is O or S.

155. The compound or stereoisomer, tautomer, prodrug or salt thereof of any one of claims 112 to 154, wherein X is S.

156. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 112 to 154, wherein X is O.

157. A compound or stereoisomer, tautomer, prodrug or salt thereof as described in any one of claims 1 to 156, wherein the salt is a potassium salt or a sodium salt.

158. A composition comprising a compound or salt thereof as described in any one of claims 1 to 157 and a pharmaceutically acceptable excipient.

159. 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 as described in any one of claims 1 to 157 or a composition as described in claim 158.

160. The method of claim 159, 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.

161. 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 as described in any one of claims 1 to 157 or a composition as described in claim 158.

162. The method of claim 161, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.

163. The method of claim 161 or 162, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

164. The method of any one of claims 159 to 163, wherein the administration is intrathecal administration or intracerebroventricular (ICV) administration.

165. A precursor compound having any one of the structural formulas (A)-(M) or a stereoisomer, tautomer or salt thereof: in: L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 each independently is a linker, a bond or absent; X 1 NR 10 or CR 11 R 12 ; X 2 NR 13 or CR 14 R 15 ; R 3 , R 4 , R 5 , R 6 and R 8 each is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 9 is hydrogen, optionally substituted alkyl or optionally substituted heteroalkyl; or R 6 and R 9 The substituents can be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; R 7 Hydrogen, -SO n7 R 7A 、-SO v7 NR 7B R 7C 、-NHNR 7B R 7C 、-ONR 7B R 7C 、-NHC(O)NHNR 7B R 7C 、-NHC(O)NR 7B R 7C 、-NR 7B R 7C 、-C(O)R 7D , –C(O)OR 7D 、-C(O)NR 7B R 7C ,–OR 7A 、-NR 7B S02R 7A 、-NR 7B C(O)R 7D 、-NR 7B C(O)OR 7D 、-NR 7B OR 7D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 7A , R 7B , R 7C , R 7D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 7B and R 7C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; n7 is 0, 1, 2, 3 or 4; and v7 is 1 or 2; R 10 , R 11 , R 12 , R 13 , R 14 and R 15 each is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; R 16 For hydrogen, halogen, –CN, –N3, –NO2, -NR 16B R 16C 、-C(O)R 16D , –C(O)OR 16D , –C(O)NR 16B R 16C ,–OR 16A 、-NR 16B C(O)R 16D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 17 Hydrogen, -SO n17 R 17A 、-SO v17 NR 17B R 17C 、-NHNR 17B R 17C 、-ONR 17B R 17C 、-NHC(O)NHNR 17B R 17C 、-NHC(O)NR 17B R 17C 、-NR 17B R 17C , –C(O)R 17D 、-C(O)OR 17D 、-C(O)NR 17B R 17C ,–OR 17A 、-NR 17B S02R 17A 、-NR 17B C(O)R 17D 、-NR 17B C(O)OR 17D ,–NR 17B OR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 18 For hydrogen, –SO n18 R 18A 、-SO v18 NR 18B R 18C 、-NHNR 18B R 18C 、-ONR 18B R 18C 、-NHC(O)NHNR 18B R 18C 、-NHC(O)NR 18B R 18C 、-NR 18B R 18C 、-C(O)R 18D 、-C(O)OR 18D , –C(O)NR 18B R 18C 、-OR 18A 、-NR 18B S02R 18A 、-NR 18B C(O)R 18D 、-NR 18B C(O)OR 18D ,–NR 18B OR 18D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19 For hydrogen, –SO n19 R 19A 、-SO v19 NR 19B R 19C 、-NHNR 19B R 19C 、-ONR 19B R 19C 、-NHC(O)NHNR 19B R 19C 、-NHC(O)NR 19B R 19C 、-NR 19B R 19C , –C(O)R 19D , –C(O)OR 19D , –C(O)NR 19B R 19C 、-OR 19A 、-NR 19B S02R 19A 、-NR 19B C(O)R 19D 、-NR 19B C(O)OR 19D ,–NR 19B OR 19D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 20 Hydrogen, -SO n20 R 20A ,–SO v20 NR 20B R 20C 、-NHNR 20B R 20C 、-ONR 20B R 20C 、-NHC(O)NHNR 20B R 20C 、-NHC(O)NR 20B R 20C 、-NR 20B R 20C 、-C(O)R 20D 、-C(O)OR 20D 、-C(O)NR 20B R 18C ,–OR 20A 、-NR 20B S02R 20A 、-NR 20B C(O)R 20D 、-NR 20B C(O)OR 20D ,–NR 20B OR 20D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 21 independently hydrogen, –SO n21 R 21A ,–SO v21 NR 21B R 21C 、-NHNR 21B R 21C 、-ONR 21B R 21C 、-NHC(O)NHNR 21B R 21C 、-NHC(O)NR 21B R 21C ,–NR 21B R 21C , –C(O)R 21D 、-C(O)OR 21D 、-C(O)NR 21B R 21C 、-OR 21A 、-NR 21B S02R 21A 、-NR 21B C(O)R 21D 、-NR 21B C(O)OR 21D 、-NR 21B OR 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; n19 and n21 are each independently 0, 1, 2, 3 or 4; and v19 and v21 are each independently 1 or 2; R 16A , R 16B , R 16C , R 16D , R 17A , R 17B , R 17C , R 17D , R 18A , R 18B , R 18C , R 18D , R 19A , R 19B , R 19C , R 19D , R 20A , R 20B , R 20C , R 20D , R 21A , R 21B , R 21C and R 21D Each of the R atoms bonded to the same nitrogen atom is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R atoms bonded to the same nitrogen atom are ... 16B and R 16C , R 17B and R 17D , R 18B and R 18D , R 19B and R 19C , R 20B and R 20C , and R 21B and R 21C The substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n16, n17, n18, n19, n20 and n21 are each independently 0, 1, 2, 3 or 4; and v16, v17, v18, v19, v20 and v21 are each independently 1 or 2.

166. A method for preparing a compound as described in any one of claims 1 to 157 or a stereoisomer, tautomer, prodrug or salt thereof, the method comprising contacting a precursor compound as described in claim 165 with a compound of formula (W) and / or (Q) or a salt thereof: Where X 7 and X 8 are each independently O or S.

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