CB1 ligand conjugate 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 conditions in a subject (e.g., diseases, disorders, and conditions of the central nervous system). Embodiments provided herein relate to compounds (e.g., any of those defined herein) and methods for targeting cells expressing the cannabinoid type 1 receptor (CB1). Certain embodiments provided herein relate to compounds and methods for delivering agents to cells expressing CB1.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 315,472, filed March 1, 2022, and U.S. Provisional Application No. 63 / 327,345, filed April 4, 2022. The disclosures of each of these prior applications are considered part of the disclosure of this application and are incorporated by reference in their entirety into the disclosure of this application. [Background technology]

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

[0003] One type of compound that can be targeted using targeting ligands is an oligomeric compound, such as, for example, proteins, peptides, antibodies, and oligonucleotides. Oligomeric compounds that contain nucleotide sequences (e.g., oligonucleotides) that are at least partially complementary to a target nucleic acid have been shown to change the function and activity of the target both in vitro and in vivo. Oligonucleotides have been shown to regulate the expression or activity of a target nucleic acid when delivered to a cell that contains the target nucleic acid (e.g., mRNA or pre-mRNA). In certain cases, oligonucleotides can reduce gene expression by inhibiting the translation of the nucleic acid target and / or inducing the degradation of the target nucleic acid.

[0004] When the target nucleic acid is an mRNA, one mechanism by which an oligonucleotide can regulate the expression of an 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 the RNA-induced silencing complex (RISC) pathway. Furthermore, an oligonucleotide can regulate the expression of a target nucleic acid, such as a target mRNA, through an RNase recruitment mechanism, a microRNA mechanism, an occupancy-based mechanism, and an editing mechanism. An oligonucleotide can be single-stranded or double-stranded. An oligonucleotide can include DNA, RNA, and RNA-like molecules, and can also include modified nucleosides that include one or more modified sugars, modified nucleobases, and modified internucleoside linkages.

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

[0006] The embodiments provided herein relate to cannabinoid type 1 receptor (CB 1 Certain embodiments provided herein relate to compounds (e.g., any of those defined herein) and methods for targeting cells expressing CB 1The present invention relates to compounds and methods for delivering an agent to a cell expressing CB. In certain embodiments, the cell is in the brain. In certain embodiments, the cell is in the frontal lobe. In certain embodiments, the cell is in the striatum. In certain embodiments, the cell is in the cerebellum. In certain embodiments, the cell is in the brain stem. In certain embodiments, the cell is in the hippocampus. In certain embodiments, the cell is in the spinal cord. In certain embodiments, the agent is a therapeutic compound. In certain embodiments, delivery of the agent is for the treatment of diseases, disorders, and conditions in a subject. In certain embodiments, the agent is a diagnostic compound. In certain embodiments, the compound is a CB 1 The compound comprises a ligand and one or more linker moieties for attachment to a therapeutic, prophylactic, or diagnostic agent. 1 The CB1222 comprises a 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 CB1222 comprises a CB1222. 1 The ligand is CB 1 In certain embodiments, the CB 1 The ligand is CB 1 In certain embodiments, the CB 1 The ligand is a small molecule, an aptamer, a peptide, or an antibody. 1 The ligand is anandamide, or a derivative thereof. In certain embodiments, CB 1 The 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, CB 1 The ligand is any of those defined herein, or a derivative or prodrug thereof.

[0007] In certain embodiments, CB cells, such as brain cells, 1 When a cell expressing CB1 is contacted with a compound provided herein, the agent is delivered to the cell. In certain embodiments, the agent is delivered to a cell expressing CB1, such as a brain cell. 1 Contacting a cell expressing CB with a compound provided herein treats a disease, disorder, or condition in a subject. 1 The ligand-containing compound is CB 1 Compared with cells that do not express CB 1 In certain embodiments, the method selectively or preferentially targets cells expressing CB 1 The ligand-containing compound is CB 1 Compared to the ligand-free compound, CB 1 The present invention selectively or preferentially targets cells expressing

[0008] Certain embodiments provided herein are 1 The present invention relates to compounds and methods for modulating expression of a nucleic acid target in a cell expressing a CB, such as a brain cell. In certain embodiments, the cell is in the brain. In certain embodiments, the cell is in the frontal lobe. In certain embodiments, the cell is in the striatum. In certain embodiments, the cell is in the cerebellum. In certain embodiments, the cell is in the brain stem. In certain embodiments, the cell is in the hippocampus. In certain embodiments, the cell is in the spinal cord. In certain embodiments, the cell is in a CB, such as a brain cell. 1 Contacting a cell expressing CB with a compound provided herein modulates the expression or activity of a nucleic acid target in the cell. In certain embodiments, the compound is 1 It comprises a ligand, one or more linker moieties, and an oligonucleotide.

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

[0010] In one aspect, the disclosure provides a compound comprising the structure of formula (I'), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] Each of these independently binds to the cannabinoid type 1 receptor (CB 1 ) ligand, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; z1 is 0 or 1).

[0011] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] is an oligonucleotide, [ka] L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0012] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, X 1 is NR 10 or CR 11 R 12 and X 2 is NR 13 or CR 14 R 15 and R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19 is 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 19BR 19C , -C(O)R 19D , -C(O)OR 19D , -C(O)NR 19B R 19C , -OR 19A , -NR 19B SO 2 R 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 is 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 SO 2 R 21A , -NR 21B C(O)R 21D , -NR 21B C(O)OR 21D , -NR 21B OR 21D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19A , R 19B , R 19C , R 19D , R 21A , R 21B , R 21C , and R 21D are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 19B and R 19C Substituents and R 21B and R 21C The substituents may optionally be combined 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; v19 and v21 are each independently 1 or 2; L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0013] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-a-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, X 1 , X 2 , L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0014] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-a-2), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, X 1 , X 2 , L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0015] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-b), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0016] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-b-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0017] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-b-2), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0018] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-c), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0019] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-c-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0020] In some embodiments, the disclosure provides compounds comprising the structure of formula (I″-c-2), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0021] In some embodiments, the disclosure provides a compound comprising the structure of formula (XII), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , L 4A , R 1 , and R 17 is as described herein; z2 and z3 are each independently 0, 1, 2, 3, or 4; z4 is 0 or 1, R 25 , R 25A , R 26 , and R 26A are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 27 is 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 SO 2 R 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; R 27A , R 27B , R 27C , and R 27Dare each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 27B and R 27C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 28 is 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 SO 2 R 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; R27A , R 27B , R 27C , R 27D , R 28A , R 28B , R 28C , and R 28D are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 27B and R 27C Substituent;R 28B and R 28C and the substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n27 and n28 are each independently 0, 1, 2, 3, or 4; v27 and v28 are each independently 1 or 2).

[0022] In some embodiments, z4 is 0.

[0023] In some embodiments, the disclosure provides compounds, as well as stereoisomers, tautomers, prodrugs, and salts thereof, wherein CB 1 The ligand comprises the structure of formula (XII-a): [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , R 17 , R 25 , R 26 , R 27 , R 1, and z2 are as described herein.

[0024] In some embodiments, the disclosure provides a compound comprising the structure of formula (XII-a-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , R 17 , R 25 , R 26 , R 27 , R 1 , and z2 are as described herein.

[0025] In some embodiments, the disclosure provides a compound comprising the structure of formula (XII-b), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is as described herein).

[0026] In some embodiments, the disclosure provides a compound comprising the structure of formula (XII-c), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4Ais as described herein).

[0027] In another aspect, the disclosure provides compounds comprising the structure of formula (I), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] The cannabinoid type 1 receptor (CB 1 ) ligand, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

[0028] In some embodiments, CB 1 The ligand is CB 1 In some embodiments, the CB 1 The ligand is CB 1 In some embodiments, the CB 1 The ligand is a selective ligand. In some embodiments, CB 1 The ligand is a non-selective ligand. In certain embodiments, CB 1The ligands were minocycline, dronabinol, epigallocatechin, epicatechin, kavain, yangonin, oleamide, N-arachidonoyldopamine, cannabinol, HU-210, 11-hydroxy-THC, levonantradol, 2-arachidonyl glyceryl ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP 55,940, JWH-018, and WIN. 55,212-2, GAT228, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodamine, 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-CB 1 The antibody is selected from the group consisting of antibodies and derivatives thereof.

[0029] In some embodiments, the disclosure provides compounds, as well as stereoisomers, tautomers, prodrugs, and salts thereof, wherein CB 1 The ligand comprises the structure of formula (II'): [ka] (In the formula, R 17 is 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)NR17B R 17C , -OR 17A , -NR 17B SO 2 R 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 17B and R 17C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n17 is 0, 1, 2, 3, or 4; v17 is either 1 or 2).

[0030] 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 17Care each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl.

[0031] In certain embodiments, CB 1 The ligand has the structure [ka] Includes.

[0032] In some embodiments, the disclosure provides a compound comprising the structure of formula (II), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , R 17 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0033] In some embodiments, the disclosure provides compounds comprising the structure of formula (II-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0034] In certain embodiments, CB 1 The ligand has the structure [ka] or derivatives thereof.

[0035] In some embodiments, the disclosure provides a compound comprising the structure of formula (III), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0036] In some embodiments, the disclosure provides a compound comprising the structure of formula (III-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0037] In some embodiments, the disclosure provides compounds comprising the structure of formula (VIII), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; R 3 , R 4 , R 5 , R 6 , and R 8are each 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 may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; R 7 is 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 SO 2 R 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 , R7B , R 7C , R 7D are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 7B and R 7C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n7 is 0, 1, 2, 3, or 4, v7 is either 1 or 2).

[0038] In some embodiments, R 7 and R 8 are each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl. In some embodiments, R 4 is a halogen, and R 3 , R 5 , and R 6 are each independently hydrogen. 3 , R 4 , R 5 , and R 6 are each independently hydrogen. 6 and R 9 The substituents may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl. In some embodiments, R 9 is hydrogen or optionally substituted alkyl.

[0039] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0040] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-a-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0041] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-a-2), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0042] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-b), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1, L 1 , L 2 , L 3 , and L 4 is as described herein).

[0043] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-b-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0044] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-c), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0045] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-c-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0046] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-c-2), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0047] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-d), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0048] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-d-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0049] In some embodiments, the disclosure provides a compound comprising the structure of formula (VIII-d-2), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0050] In some embodiments, the disclosure provides a compound comprising the structure of formula (IX), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; X 1 is NR 10 or CR 11 R 12 and R 10 , R 11 , and R 12 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19 is 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 R19C , -C(O)R 19D , -C(O)OR 19D , -C(O)NR 19B R 19C , -OR 19A , -NR 19B SO 2 R 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 19B and R 19C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n19 is 0, 1, 2, 3, or 4; v19 is either 1 or 2).

[0051] In some embodiments, the disclosure provides a compound comprising the structure of formula (IX-a-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, X 1 , R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0052] In some embodiments, the disclosure provides a compound comprising the structure of formula (IX-a-2), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, X 1 , R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0053] In some embodiments, X 1 is NR 10 and R 10 is hydrogen or optionally substituted alkyl. In some embodiments, R 10 is hydrogen, -CH 3 , or -CH 2 CH 2 F. In some embodiments, X 1 CR 11 R 12 and R 11 and R 12 are each independently hydrogen or optionally substituted alkyl. In some embodiments, R 11 is hydrogen, -CH 3 , or -CH 2 CH 2 F and R 12 is hydrogen.

[0054] In some embodiments, the disclosure provides a compound comprising the structure of formula (X), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; R 16 is hydrogen, halogen, -CN, -N 3 , -NO 2 , -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 16A , R 16B , R 16C , and R 16D are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 16B and R 16CThe substituents may be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0055] In some embodiments, the disclosure provides a compound comprising the structure of formula (Xa), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0056] In some embodiments, the disclosure provides a compound comprising the structure of formula (Xa-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4 is as described herein).

[0057] In certain embodiments, CB 1 The ligand has the structure: [ka] or derivatives thereof.

[0058] In some embodiments, the compound comprises the following structure: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , and L 4is as described herein).

[0059] In some embodiments, L 1 , L 2 , L 3 , and L 4 each is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester linkage, or a phosphorothioate linkage.

[0060] In certain embodiments, L 1 is a bond. In certain embodiments, L 1 is oxygen. In certain embodiments, L 1 The structure [ka] wherein n7 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0061] In some embodiments, L 2 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, L 2 is an optionally substituted alkyl linker. In certain embodiments, L 2 The structure [ka] Includes.

[0062] In some embodiments, L 4is an optionally substituted heteroalkyl linker or bond. In certain embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In some embodiments, L 4 teeth, [ka] Including, wherein X is O or S. In certain embodiments, L 4 The structure [ka] Including, In the formula, X is O or S.

[0063] In some embodiments, L 3 is an optionally substituted heteroaryl linker. In some embodiments, L 3 and L 4 is an optionally substituted phosphodiester bond or an optionally substituted phosphorothioate bond, and L 3 and L 4 The other of L is a bond. 3 is an optionally substituted partially unsaturated heteroaryl or an optionally substituted partially unsaturated heterocycloalkyl linker. In certain embodiments, L 3 The structure [ka] Includes.

[0064] In some embodiments, L 1 , L 2 , L 3 , and L 4 Taken together, the structure: [ka] wherein 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, or 10; 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.

[0065] In certain embodiments, L 1 , L 2 , L 3 , and L 4 Taken together, the structure: [ka] wherein 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, or 10; 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.

[0066] In some embodiments, X is S. In some embodiments, X is O.

[0067] In another aspect, the disclosure provides a compound comprising the structure of formula (IV') or a salt thereof, as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] Each of them independently activates the cannabinoid type 1 receptor (CB 1 ) ligand, or [ka] One of them is CB1 is a ligand, [ka] the remainder comprising a lipid or ligand, L 1 , L 2 , L 3 , L 4 , L 5 , L 1A , L 2A , L A3 , L A4 , and L A5 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

[0068] In some embodiments, the disclosure provides compounds comprising the structure of formula (IV″), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] is an oligonucleotide, [ka] L 1 , L 2 , L 3 , L 4 , L 5 , L 1A , L 2A , L A3 , L A4 , and L A5 is as described herein).

[0069] In some embodiments, the disclosure provides compounds comprising the structure of formula (IV″-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 17 is 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 SO 2 R 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 is 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 SO 2 R 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 is 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 SO 2 R 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 is 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 SO 2 R 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 is 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 SO 2 R 24A , -NR 24B C(O)R 24D , -NR 24B C(O)OR 24D , -NR 24B OR 24D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 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, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 17B and R 17C The substituents may optionally be combined 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; v17, v18, v22, and v23 are each independently 1 or 2).

[0070] In some embodiments, the disclosure provides compounds comprising the structure of formula (IV″-b), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 5 , L 1A , L 2A , L A3 , L A4 , and L A5 is as described herein).

[0071] In some embodiments, the disclosure provides compounds comprising the structure of formula (IV''-b-1), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 5 , L 1A , L 2A , L A3 , L A4 , and L A5 is as described herein).

[0072] In some embodiments, the disclosure provides a compound comprising the structure of formula (IV) or a salt thereof, as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] Each of them independently activates the cannabinoid type 1 receptor (CB 1 ) ligand, or [ka] One of them is CB 1 is a ligand, [ka] the other comprises a lipid or a ligand, L 1 , L 2 , L 3 , L 4 , and L 5 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

[0073] In some embodiments, [ka] are each independently 1 In some embodiments, CB 1 One or both of the ligands may be CB 1 In some embodiments, the CB 1 One or both of the ligands may be CB 1 In some embodiments, the CB 1 The ligand is a selective ligand. In some embodiments, CB 1 The ligand is a non-selective ligand. In certain embodiments, CB 1The ligands were minocycline, dronabinol, epigallocatechin, epicatechin, kavain, yangonin, oleamide, N-arachidonoyldopamine, cannabinol, HU-210, 11-hydroxy-THC, levonantradol, 2-arachidonyl glyceryl ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP 55,940, JWH-018, and WIN. 55,212-2, GAT228, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodamine, 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-CB 1 In some embodiments, the CB 1 Each of the ligands has the structure [ka] or derivatives thereof.

[0074] In some embodiments, the disclosure provides a compound comprising the structure of formula (V), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 17 is 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 17BR17 C , -NR 17B R 17C , -C(O)R 17D , -C(O)OR 17D , -C(O)NR 17B R 17C , -OR 17A , -NR 17B SO 2 R 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 is 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 SO 2 R 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, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 17B and R 17C The substituents may be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 17B and R 17C Substituent or R 18B and R 18C The substituents may optionally be combined 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; v17 and v18 are each independently 1 or 2).

[0075] In some embodiments, the disclosure provides a compound comprising the structure of Formula (Va), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , L 4 , and L 5 is as described herein).

[0076] In some embodiments, the disclosure provides compounds, as well as stereoisomers, tautomers, prodrugs, and salts thereof, having the structure: [ka] or its derivatives, other CB 1 The ligand has the structure: [ka] or derivatives thereof.

[0077] In some embodiments, the disclosure provides a compound comprising the structure of formula (IX), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , L 4 , and L 5 is as described herein).

[0078] In some embodiments, the disclosure provides a compound comprising the structure of formula (IX-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , L 1 , L 2 , L 3 , L 4 , and L 5 is as described herein).

[0079] In some embodiments, the disclosure provides compounds, as well as stereoisomers, tautomers, prodrugs, and salts thereof, wherein CB 1 Each of the ligands independently comprises the structure: [ka] (In the formula, X 1 is NR 10 or CR 11 R 12 and R 10 , R 11 , and R 12 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19 is 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 SO 2 R 19A , -NR 19B C(O)R 19D , -NR 19B C(O)OR 19D , -NR 19B OR19D , 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 19B and R 19C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n19 is 0, 1, 2, 3, or 4; v19 is either 1 or 2).

[0080] In some embodiments, the disclosure provides a compound comprising the structure of formula (XI), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , and L 5 is as described herein; X 1 is NR 10 or CR 11 R 12 and X 2is NR 13 or CR 14 R 15 and R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each 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, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 21B and R 21C The substituents may optionally be combined 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; v19 and v21 are each independently 1 or 2).

[0081] In some embodiments, the disclosure provides a compound comprising the structure of formula (XI-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, X 1 , X 2 , L 1 , L 2 , L 3 , L 4 , and L 5 is as described herein).

[0082] In some embodiments, X 1 is NR 10 and X 2 is NR 13 and R 10 and R 13 are each independently hydrogen or optionally substituted alkyl. In some embodiments, R 10 and R 13 are each independently hydrogen, -CH 3 , or -CH 2 CH 2 F. In some embodiments, X 1 CR 11 R 12 and X 2 CR 14 R 15 and R 11 , R 12 , R 14 , and R 15 are each independently hydrogen or optionally substituted alkyl. In some embodiments, R 12 and R 15 are each independently hydrogen, -CH 3 , or -CH 2 CH 2 F and R 11 and R 14 are each independently hydrogen.

[0083] In some embodiments, L 1 , L 2 , L 3 , L 4 , and L 5each is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester linkage, or a phosphorothioate linkage.

[0084] In some embodiments, L 1 and L 5 are each optionally substituted PEG linkers. In some embodiments, L 1 and L 5 are optionally substituted PEG linkers of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length, respectively.

[0085] In some embodiments, L 2 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L 2 The structure [ka] Includes.

[0086] In some embodiments, L 3 is an optionally substituted heteroaryl linker. In some embodiments, L 3 is an optionally substituted partially unsaturated heteroaryl linker or an optionally substituted partially unsaturated heterocycloalkyl linker. In certain embodiments, L 3 The structure [ka] Includes.

[0087] In some embodiments, L 4is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In some embodiments, L 4 The structure [ka] Including, wherein X is O or S. In certain embodiments, L 4 The structure [ka] Including, In the formula, X is O or S.

[0088] In some embodiments, X is S. In some embodiments, X is O.

[0089] In some embodiments, L 1 , L 2 , L 3 , L 4 , and L 5 Taken together, the structure: [ka] [ka] [ka] wherein X is O or S.

[0090] In certain embodiments, L 1 , L 2 , L 3 , L 4 , and L 5 Taken together, the structure: [ka] [ka] [ka] wherein X is O or S.

[0091] In some embodiments, the disclosure provides a compound comprising the structure of formula (VI) or a salt thereof, as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, [ka] The cannabinoid type 1 receptor (CB 1 ) ligand, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 is independently a linker, a bond, or absent; R 1 and R 2 each independently comprises one or more of an oligonucleotide, a protecting group, a small molecule, a protein, an antibody, and / or a peptide.

[0092] In some embodiments, CB 1 The ligand is CB 1 In some embodiments, the CB 1 The ligand is CB 1 In certain embodiments, the CB 1The ligands were minocycline, dronabinol, epigallocatechin, epicatechin, kavain, yangonin, oleamide, N-arachidonoyldopamine, cannabinol, HU-210, 11-hydroxy-THC, levonantradol, 2-arachidonyl glyceryl ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP 55,940, JWH-018, and WIN. 55,212-2, GAT228, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodamine, 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-CB 1 In certain embodiments, the CB 1 The ligand has the structure [ka] Includes.

[0093] In some embodiments, the disclosure provides a compound comprising the structure of formula (VII), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 17 is 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 SO 2 R 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 17B and R 17C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n17 is 0, 1, 2, 3, or 4; v17 is either 1 or 2).

[0094] In some embodiments, the disclosure provides a compound comprising the structure of formula (VII-a), as well as stereoisomers, tautomers, prodrugs, and salts thereof: [ka] (In the formula, R 1 , R 2 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 is as described herein).

[0095] In some embodiments, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 each is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, an optionally substituted saturated or partially unsaturated heterocycloalkyl linker, oxygen, an optionally substituted nitrogen, an amide, a phosphodiester linkage, or a phosphorothioate linkage.

[0096] In some embodiments, L 1 is an optionally substituted PEG linker. In certain embodiments, L 1 is an optionally substituted PEG linker that is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PEG units in length.

[0097] In some embodiments, L 2 and L 5 are each independently an optionally substituted PEG linker. In some embodiments, L 2 and L 5 are each independently an optionally substituted PEG linker of 3 or 4 PEG units in length. In certain embodiments, L 1 , L2 , and L 5 Together, the structure [ka] Includes.

[0098] In some embodiments, L 3 and L 6 are each independently an optionally substituted heteroaryl linker or an optionally substituted heterocycloalkyl linker. In some embodiments, L 3 and L 6 are each independently an optionally substituted partially unsaturated heteroaryl linker or an optionally substituted partially unsaturated heterocycloalkyl linker. 3 and L 6 are the structures, [ka] Includes.

[0099] In some embodiments, L 4 and L 7 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, L 4 and L 7 are the structures, [ka] Including, wherein X is O or S. In certain embodiments, L 4 and L 7 are the structures, [ka] Including, In the formula, X is O or S.

[0100] In some embodiments, R 1 comprises an oligonucleotide. In certain embodiments, the oligonucleotide is attached at its 5' end. In certain embodiments, the oligonucleotide is attached at its 3' end. In certain embodiments, the oligonucleotide is attached at an internal position of the oligonucleotide. In some embodiments, the internal position is at an internucleoside linkage. In some embodiments, R 1 one or more additional CBs 1 In certain embodiments, the oligonucleotide comprises an oligonucleotide conjugated to a ligand. In certain embodiments, the oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional CB 1 In some embodiments, the additional CB 1 The ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, at one or more internal positions of the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0101] In some embodiments, L 1 , L 2 , L 3 , and L 4 Taken together, the structure: [ka] Including, In the formula, X is O or S.

[0102] In certain embodiments, L 1 , L 2 , L 3 , and L 4 Taken together, the structure: [ka] wherein X is O or S.

[0103] In some embodiments, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 Taken together, the structure: [ka] Including, In the formula, X is O or S.

[0104] In certain embodiments, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 Taken together, the structure: [ka] Including, In the formula, X is O or S.

[0105] In some embodiments, the disclosure provides a compound, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the following structure: [ka] (In the formula, R 1 and R 2 each independently comprises one or more of an oligonucleotide, a protecting group, a small molecule, a protein, an antibody, and / or a peptide; X is O or S).

[0106] In some embodiments, the disclosure provides a compound comprising the following structure: [ka]

[0107] In some embodiments, the disclosure provides a compound, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, R 1 and R 2 each independently comprises one or more of an oligonucleotide, a protecting group, a small molecule, a protein, an antibody, and / or a peptide; X is O or S).

[0108] In certain embodiments, the disclosure provides a compound, and stereoisomers, tautomers, prodrugs, and salts thereof, comprising the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, [ka] is an oligonucleotide, X is O or S).

[0109] In some embodiments, X is S. In some embodiments, X is O.

[0110] In some embodiments, any of the compounds provided herein is provided as a salt, wherein the salt is a potassium salt or a sodium salt.

[0111] In another aspect, the disclosure provides a composition comprising any of the compounds or salts thereof and a pharma- ceutically acceptable excipient.

[0112] In another aspect, the present disclosure provides a method for delivering a therapeutic oligonucleotide to the brain of a subject, comprising administering to the subject any of the compounds provided herein or salts thereof, or any of the compositions provided herein. In some embodiments, the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal lobe, and spinal cord.

[0113] In another aspect, the present disclosure provides a method for treating or ameliorating a disease, disorder, or a symptom thereof in a subject, comprising administering to the subject any of the compounds provided herein or salts thereof, or any of the compositions provided herein.In some embodiments, the disease, disorder, or a symptom thereof is a disease, disorder, or a symptom thereof of the central nervous system (CNS).In certain embodiments, the disease, disorder, or a symptom thereof is Alzheimer's disease, or a symptom thereof.In some embodiments, the administration is intrathecal administration or intracerebroventricular (ICV) administration.

[0114] In another aspect, the disclosure provides a precursor compound of any one of structural formulas (A)-(M), as well as stereoisomers, tautomers, and salts thereof: [ka] [ka] [ka] [ka] (In the formula, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 is independently a linker, a bond, or absent; X 1 is NR 10 or CR 11 R 12 and X 2 is NR 13 or CR 14 R 15 and R 3 , R 4 , R 5 , R 6 , and R 8 are each 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 may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; R 7 is 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 R7C , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D , -C(O)NR 7B R 7C , -OR 7A , -NR 7B SO 2 R 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 7B and R 7C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n7 is 0, 1, 2, 3, or 4, v7 is either 1 or 2, R 10 , R 11 , R 12 , R 13 , R 14 , and R 15are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 16 is hydrogen, halogen, -CN, -N 3 , -NO 2 , -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 is 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 SO 2 R 17A , -NR 17B C(O)R 17D , -NR 17B C(O)OR 17D , -NR 17BOR 17D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 18 is 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 SO 2 R 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 is 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 SO 2 R 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 is 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 SO 2 R 20A , -NR 20B C(O)R 20D , -NR 20B C(O)OR 20D , -NR 20B OR 20D, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 21 are 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 SO 2 R 21A , -NR 21B C(O)R 21D , -NR 21B C(O)OR 21D , -NR 21B OR 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; n19 and n21 are each independently 0, 1, 2, 3, or 4; 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 , R18B , 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 16B and R 16C substituent, R 17B and R 17D substituent, R 18B and R 18D substituent, R 19B and R 19C substituent, R 20B and R 20C Substituents and R 21B and R 21C The substituents may optionally be combined 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; v16, v17, v18, v19, v20, and v21 are each independently 1 or 2).

[0115] In another aspect, the disclosure provides a method for making any of the compounds provided herein, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising reacting any of the precursor compounds provided herein with a compound of structural formula (W) and / or (Q): [ka] or its salt (In the formula, X 7 and X 8 are each independently O or S.

[0116] In another aspect, the disclosure provides methods for making any of the compounds provided herein, including one or more of the compounds and chemical transformations described herein, including Examples 2-24. [Brief description of the drawings]

[0117] [Figure 1] 1H NMR of compound 2 is shown. [Diagram 2] 1H NMR of compound 3 is shown. [Diagram 3] The 31P NMR of compound 3 is shown. [Figure 4] 1H NMR of compound 4 is shown. [Diagram 5] 1H NMR of compound 6 is shown. [Figure 6] 1H NMR of compound 10 is shown. [Figure 7] 1H NMR of compound 11 is shown. [Figure 8] 1H NMR of compound 15 is shown. [Figure 9] The mass spectrum of compound 15 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0118] definition It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the claimed embodiments. As used herein, the use of the singular includes the plural unless expressly stated otherwise. As used herein, the use of "or" means "and / or" unless otherwise indicated. Furthermore, the use of the term "including" and other forms, such as "includes" and "included", is not limiting. The section headings used herein are merely organizational and should not be construed as limiting the subject matter described.

[0119] Unless otherwise indicated, the following terms have the following meanings:

[0120] As used herein, the term "treating" a disorder includes improving, alleviating, and / or managing the disorder and / or conditions that may cause the disorder. The terms "treating" and "treatment" refer to a method of alleviating or reducing a disease and / or its associated symptoms. According to the present disclosure, "treating" includes, for example, blocking, inhibiting, attenuating, protecting against, modulating, reversing, and reducing the occurrence of the deleterious effects of a disorder. As used herein, "inhibiting" includes preventing, alleviating, and halting progression.

[0121] The terms "isolated," "purified," or "biologically pure" refer to a material that is substantially or essentially free from components that normally accompany it when found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography (HPLC). In particular, in certain embodiments, the compounds are at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0122] The term "administration" or "administering" includes routes of introducing a compound(s) into a subject to perform its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0123] The term "effective amount" includes an amount effective at the dosage and duration necessary to achieve the desired result. The effective amount of a compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide optimal therapeutic responses. An effective amount is also an amount in which any intolerable or adverse effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.

[0124] As used herein, the terms "systemic administration," "systemically administered," "peripheral administration," and "administered peripherally" refer to administration of a compound(s), oligonucleotide(s), drug, or other substance such that it enters the patient's circulatory system and undergoes metabolic and other similar processes.

[0125] The term "therapeutically effective amount" refers to that amount of compound administered that is sufficient to prevent the occurrence of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.

[0126] A therapeutically effective amount (i.e., an effective dosage) of a compound may range from about 0.005 μg / kg body weight to about 200 mg / kg body weight, preferably from about 0.01 mg / kg body weight to about 200 mg / kg body weight, more preferably from about 0.015 mg / kg body weight to about 30 mg / kg body weight. In other embodiments, a therapeutically effective amount may range from about 1.0 pM to about 10 μM. One of ordinary skill in the art will recognize that certain factors, including but not limited to the severity of the disease or disorder, previous treatments, the overall health and / or age of the subject, and other diseases present, may affect the dosage required to effectively treat the subject. Furthermore, treatment of a subject with a therapeutically effective amount of a compound may include a single treatment, or preferably, may include a series of treatments. In one example, a subject is treated daily, weekly, monthly, quarterly, or yearly with a compound in the range of about 0.005 μg / kg body weight to about 200 mg / kg body weight. In another example, a subject may be treated daily, weekly, monthly, quarterly, or yearly for several years in the case of a chronic condition or disease. It will also be appreciated that the effective dosage of the compound used for treatment may increase or decrease over a particular course of treatment.

[0127] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, and the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0128] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds, and their enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids, (D)- or (L)-, and individual isomers are encompassed within the scope of the present disclosure. Compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure form. Optically active (R)- and (S)-isomers, or (D)- and (L)-isomers, may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When compounds described herein contain olefinic bonds or other geometrically asymmetric centers, unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0129] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0130] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0131] Unless otherwise indicated, structures depicted herein are also meant to include all stereochemical forms (i.e., the R and S configurations at each asymmetric center). Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0132] As used herein, "chirally enriched population" refers to a number or percentage of molecules in a population of the same molecular formula that contain a specific stereochemical configuration at a specific chiral center that is greater than the number or percentage of molecules that would be expected to contain the same specific stereochemical configuration at the same specific chiral center in the population if that specific chiral center were stereorandom. A chirally enriched population of molecules that has multiple chiral centers in each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecule is a modified oligonucleotide. In certain embodiments, the molecule is a compound that includes a modified oligonucleotide.

[0133] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, a hydrogen has been replaced by deuterium or tritium, or a carbon has been replaced by 13 C or 14 Compounds having this structure except for the replacement by a C-enriched carbon are within the scope of this disclosure.

[0134] As used herein, "stereorandom chiral center" in the context of a population of molecules of the same molecular formula refers to a chiral center that has a random stereochemical configuration. For example, in a population of molecules that includes stereorandom chiral centers, the number of molecules that have stereorandom chiral centers in the (S) configuration may be, but is not necessarily, the same as the number of molecules that have stereorandom chiral centers in the (R) configuration. The stereochemical configuration of a chiral center is considered random if it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, the stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

[0135] The term "diastereomer" refers to a stereoisomer with two or more centers of asymmetricity and whose molecules are not mirror images of one another.

[0136] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or a "racemate."

[0137] The term "isomer" or "stereoisomer" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0138] The term "prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active form of a compound (e.g., a biologically active form of a nucleic acid) or its analog as described herein. Thus, the term "prodrug" refers to a precursor of a pharma- ceutically acceptable biologically active compound (e.g., a nucleic acid) or its analog. A prodrug may be inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer the advantage of solubility, tissue compatibility, or delayed release in mammals (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). 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 fully incorporated herein by reference. The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein can be prepared by modifying functional groups present in the active compound such that the modification is cleaved either by routine manipulation or in vivo to the parent active compound. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group is bonded to any group that is cleaved to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of suitable prodrugs include, but are not limited to, glutathione, acyloxy, thioacyloxy, 2-carbalkoxyethyl, disulfide, thiaminal, and enol ester derivatives of phosphorus atom modified nucleic acids. The term "prooligonucleotide" or "pronucleotide" or "nucleic acid prodrug" refers to an oligonucleotide modified to be a prodrug of an oligonucleotide. Phosphonate and phosphate prodrugs can be found, for example, in Wiener et al., "Prodrugs or phosphonates and phosphates:crossing the membrane" Top.Curr.Chem.2015,360:115-160, which is incorporated herein by reference in its entirety. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In an embodiment, the compounds of the present disclosure are prodrugs of any of the formulas herein.

[0139] The term "prodrug" includes compounds having moieties that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to become active drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compounds, or they can be prepared by separately reacting the purified compounds with a suitable esterifying agent at their free acid form or at a hydroxyl group. Hydroxyl groups can be converted to esters by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or branched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionate esters and acyl esters. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In an embodiment, the compounds of the present disclosure are prodrugs of any of the formulas herein.

[0140] The term "subject" refers to an animal, e.g., a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human.

[0141] The terms "a," "an," and "the" as used in this application, including the claims, refer to "one or more." Thus, for example, a reference to "a sample" includes a plurality of samples unless the context clearly indicates to the contrary (e.g., a plurality of samples), and so forth.

[0142] Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in a non-exclusive sense unless the context requires otherwise.

[0143] As used herein, the term "about" when referring to a value is meant to encompass variations in some embodiments of ±20%, in some embodiments of ±10%, in some embodiments of ±5%, in some embodiments of ±1%, in some embodiments of ±0.5%, and in some embodiments of ±0.1% from the specified amount, where such variations are appropriate for the practice of the disclosed methods or utilization of the disclosed compositions.

[0144] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched carbon chain (or carbon), having the specified number of carbon atoms, or combinations thereof, which may be fully saturated, monounsaturated (e.g., alkenes or alkenyls) or polyunsaturated (e.g., alkynes or alkynyls), and which may include monovalent, divalent and polyvalent radicals. For example, C 1 -C 24 means 1 to 24 carbon atoms. Specific numbers of carbon atoms within this range include, for example, C 1 -C 20 Alkyl (having 1 to 20 carbon atoms), C 1 -C 12 Alkyl (having 1 to 12 carbon atoms) and C 1 -C 4 Alkyl (having 1 to 4 carbon atoms) is included.

[0145] The term "alkenyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups can be optionally substituted with one or more substituents.

[0146] The term "alkynyl" refers to an unsaturated hydrocarbon chain, which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups can be optionally substituted with one or more substituents.

[0147] The term "lower alkyl" means C 1 -C 6 Refers to an alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups can be optionally substituted with one or more substituents.

[0148] The term "haloalkyl" refers to an alkyl group that is substituted by one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0149] The term "arylalkenyl" refers to an unsaturated hydrocarbon chain, which may be linear or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, and wherein the sp 2 One or more of the hybridized carbons is bonded to an aryl moiety. Alkenyl groups can be optionally substituted with one or more substituents.

[0150] 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, in which one or more of the sp2 hybridized carbons of the alkynyl unit are bonded to an aryl moiety. The alkynyl group may be optionally substituted with one or more substituents.

[0151] Alkenyl and alkynyl groups sp 2 The hybridized or sp hybridized carbon may optionally be the point of attachment of an alkenyl or alkynyl group, respectively.

[0152] The term "alkoxy" refers to an --O-alkyl substituent.

[0153] As used herein, the terms "halogen," "hal," or "halo" mean -F, -Cl, -Br, or -I.

[0154] The term "alkylthio" refers to an --S-alkyl substituent.

[0155] The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.

[0156] The term "haloalkoxy" refers to an -O-alkyl substituted by one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.

[0157] The term "haloalkoxyalkyl" refers to alkyl-O-alkyl', where the alkyl' is substituted by one or more halo substituents.

[0158] The term "haloalkylaminocarbonyl" refers to -C(O)-amino-alkyl, where the alkyl is substituted by one or more halo substituents.

[0159] The term "haloalkylthio" refers to an -S-alkyl substituted by one or more halo substituents. Examples of haloalkylthio groups include trifluoromethylthio and 2,2,2-trifluoroethylthio.

[0160] The term "haloalkylcarbonyl" refers to -C(O)-alkyl substituted by one or more halo substituents. An example of a haloalkylcarbonyl group is trifluoroacetyl.

[0161] The term "cycloalkyl" refers to a 3-8 membered monocyclic or 7-14 membered bicyclic hydrocarbon ring system having at least one saturated ring or at least one non-aromatic ring, where the non-aromatic ring may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0162] The term "cycloalkoxy" refers to an --O-cycloalkyl substituent.

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

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

[0165] The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.

[0166] The term "aryl" refers to a hydrocarbon monocyclic, bicyclic, or tricyclic aromatic ring system. An aryl group can be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5, or 6 atoms of each ring of an aryl group can be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

[0167] The term "aryloxy" refers to an --O-aryl substituent.

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

[0169] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.

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

[0171] The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.

[0172] The term "arylalkylsulfonyl" refers to -S(O) 2 -alkyl-aryl substituents.

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

[0174] The term "aryloxyalkyl" refers to an alkyl-O-aryl substituent.

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

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

[0177] The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and / or S), where the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) (e.g., O, N, P, Si, and / or S) may be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclized chain. Examples include -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , -CH=CH-N(CH 3 )-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 Up to two or three heteroatoms include, but are not limited to, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, B, or P). The heteroalkyl moiety may include two heteroatoms (e.g., O, N, S, Si, B, and / or P), which are optionally different. The heteroalkyl moiety may include three heteroatoms (e.g., O, N, S, Si, B, and / or P), which are optionally different. The heteroalkyl moiety may include four heteroatoms (e.g., O, N, S, Si, B, and / or P), which are optionally different. The heteroalkyl moiety may include five heteroatoms (e.g., O, N, S, Si, B, and / or P), which are optionally different. The heteroalkyl moiety may include up to eight or more heteroatoms (e.g., O, N, S, Si, B, and / or P), which are optionally different.

[0178] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, including, but not limited to, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction written in the formula of the linking group. For example, a group of the formula -C(O) 2 R'- is -C(O) 2 R'- and -R'C(O) 2 As noted above, heteroalkyl groups as used herein include, but are not limited to, -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO. 2It will be understood that when "heteroalkyl" is shown followed by a list of specific heteroalkyl groups, such as -NR'R", the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are listed for clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R".

[0179] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, including, but not limited to, —CH 2 CH 2 CH 2 CH 2 Examples include -. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 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.

[0180] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, mean, unless otherwise specified, cyclic forms of "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Furthermore, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0181] The term "heteroaryl" refers to a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic aromatic ring system having 1-4 ring heteroatoms in the monocyclic, 1-6 heteroatoms in the bicyclic, or 1-9 heteroatoms in the tricyclic, the heteroatoms being selected from O, N, or S, with the remaining ring atoms being carbon (with appropriate hydrogen atoms unless otherwise specified). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Heteroaryl groups may be fully unsaturated or partially unsaturated and partially saturated. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolylthiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

[0182] The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.

[0183] The term "heteroaryloxy" refers to an --O-heteroaryl substituent.

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

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

[0186] The term "nitrogen-containing heteroaryl" refers to a heteroaryl group having 1 to 4 ring nitrogen heteroatoms if monocyclic, 1 to 6 ring nitrogen heteroatoms if bicyclic, or 1 to 9 ring nitrogen heteroatoms if tricyclic.

[0187] The term "heterocycloalkyl" refers to a 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic non-aromatic ring system containing 1-3 heteroatoms in the monocyclic, 1-6 heteroatoms in the bicyclic, or 1-9 heteroatoms in the tricyclic, the heteroatoms being selected from O, N, S, B, P, or Si, and the non-aromatic ring system being fully saturated. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thiirenyl, and the like.

[0188] The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.

[0189] The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl or aryl portions of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

[0190] [ka] The symbol indicates the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0191] The term "nucleobase" refers to nitrogen-containing biological compounds that form nucleosides. Nucleobases include purine and pyrimidine bases. The five nucleobases, adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), are referred to as primary or canonical nucleobases. When a nucleobase is listed in a formula definition, it refers to the moiety that is covalently attached to the listed formula.

[0192] The term "modified nucleobase" refers to a derivative of 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 the definition of a formula, it refers to the moiety that is covalently attached to the listed formula.

[0193] The terms "substituent" and "substituent group" refer to an atom or group that replaces an atom or group of a specified parent compound. For example, a substituent of a modified nucleoside is an atom or group that is different from the atom or group found in a naturally occurring nucleoside (e.g., a modified 2'-substituent is any atom or group other than H or OH at the 2' position of a nucleoside). A substituent may be protected or unprotected. A substituent may also be further substituted with other substituents, attached to the parent compound directly or through a linking group such as an alkyl or hydrocarbyl group. Similarly, as used herein, "substituent" in reference to a chemical functional group refers to an atom or group that is different from the atom or group normally present in the specified functional group. In certain embodiments, substituents on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be at any atom of the group, where any group that can be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, etc.) can be optionally substituted with one or more substituents (which can be the same or different) each replacing a hydrogen atom.Examples of suitable substituents include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, Examples include, but are not limited to, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido, carbamyl, thioureido, thiocyanato, sulfamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N'-aryl, N''-hydroxyamidinyl.In certain embodiments, substituents on any group include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, thiocarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl, or amido. In certain embodiments, the substituents on any group include alkyl, halogen, haloalkyl, cyano, nitro, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, thio, mercapto, mercaptoalkyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkylamino.

[0194] The term "protecting group" or "protecting moiety" refers to a substituent that is commonly utilized to block or protect a particular functionality while reacting other functional groups on a compound, its derivatives, or conjugates, including nitrogen protecting groups when attached to a nitrogen atom and oxygen protecting groups when attached to an oxygen atom. Nitrogen 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 PG M Huts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0195] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups, each R aa , R bb , and R cc are independently alkyl, cycloalkyl, aryl, or heteroaryl, each of which is selected from 1 to 3 independent R dd and each R ddare independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoa The nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 31(1):311-315. The nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 31(1):311-315. The nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 31(1):311-315. The nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 31(1):311-315. rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0196] Amide nitrogen protecting groups (e.g., -C(=O)R aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0197] Carbamate nitrogen protecting groups (e.g., -C(=O)OR aa) include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthy- l)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl ether carbamate (Troc), and 2-trimethylsilyl ether carbamate (Troc). Teocyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bum eoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl Dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrile benzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzoisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chloro Monyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2, 2-Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1 1-methyl-1-cyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.

[0198] Sulfonamide nitrogen protecting groups (e.g., -S(=O) 2 R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- These include, but are not limited to, dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0199] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyl. 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 amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethylamine N-Benzylidineamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobenzylideneamine, N-Salicylideneamine, N-5-Chlorosalicylideneamine, N-(5-Chloro-2-hydroxyphenyl)phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,5-Dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidate benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0200] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2, -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 (In the formula, R aa , R bb , and R cc (wherein is as defined herein). Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0201] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM). , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(isopropylamino)phenylmethyl, 4 ... midazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), Dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxy oxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), t-butyl carbonate (BOC), alkyl methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl aryl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate phenoxyacetate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methylphenylacetate, These include, but are not limited to, ethyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0202] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 (In the formula, R aa , R bb , and R cc Sulfur protecting groups include, but are not limited to, aryl, aryl- ... rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0203] The term "antisense oligonucleotide" or "antisense strand" means an oligonucleotide that contains a region that is complementary to a target nucleic acid.

[0204] The term "composition" or "pharmaceutical composition" refers to a mixture of substances suitable for administration to a subject. For example, a composition can include one or more compounds or salts thereof and a sterile aqueous solution.

[0205] The term "nucleic acid" refers to a molecule composed of linked monomeric nucleotides or nucleosides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0206] The term "nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkages.

[0207] The term "nucleoside" refers to a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moieties are each independently unmodified or modified. A "modified nucleoside" refers to a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase.

[0208] The term "oligomeric compound" refers to a polymer of linked subunits. With respect to a protein, peptide, polypeptide, or antibody, a "subunit" refers to an amino acid or peptide bond. With respect to an oligonucleotide, a "subunit" refers to a nucleotide, nucleoside, nucleobase, or sugar, or a modified nucleotide, nucleoside, nucleobase, or sugar, as provided herein.

[0209] The term "oligonucleotide" refers to a polymer of linked nucleosides (e.g., polynucleotide, nucleic acid, polymer of nucleotides), each of which may be modified or unmodified, independently of the other. Without limitation, an oligonucleotide may be composed of ribonucleic acid (e.g., composed of ribonucleosides), deoxyribonucleic acid (e.g., composed of deoxyribonucleosides), modified nucleic acid (e.g., composed of modified nucleobases, sugars, and / or phosphate groups), or combinations thereof. Examples of oligonucleotide compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), oligonucleotides targeting microRNAs (miRNAs), miRNA mimics, occupancy-based compounds (e.g., compounds that block mRNA processing or translation and splicing compounds), and editing compounds (e.g., ADAR recruiting molecules, ADAR targeting molecules, single-stranded guide nucleic acids, or combinations thereof). RNAi compounds include double-stranded compounds (e.g., small interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics), which act at least in part through the RNA-induced silencing complex (RISC) pathway, resulting in sequence-specific degradation and / or sequestering of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is meant to be equivalent to other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, small interfering RNA, small interfering oligonucleotide, small interfering nucleic acid, small interfering modified oligonucleotide, chemically modified siRNA, and the like. Furthermore, the term "RNAi" is meant to be equivalent to other terms used to describe sequence-specific RNA interference.

[0210] 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.

[0211] The term "therapeutic compound" includes any pharmaceutical agent or compound that provides a therapeutic benefit to a subject. Therapeutic compounds include nucleic acids, oligomeric compounds, oligonucleotides, proteins, peptides, antibodies, small molecules, and other such agents.

[0212] "Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

[0213] By "targeting moiety" is meant a conjugate group that enhances affinity for a selected target, e.g., a molecule, a cell or cell type, a compartment, e.g., a cellular or organ compartment, a tissue, an organ, or a region of the body, e.g., compared to the compound in the absence of the moiety.

[0214] "Terminal group" refers to a chemical group or group of atoms that is covalently attached to the end of an oligonucleotide.

[0215] The term "ligand" refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biological molecule. In some embodiments, a ligand is a small molecule. In some embodiments, a ligand binds to a protein (e.g., a receptor). In certain embodiments, a ligand binds to a CB 1 Binds to receptors.

[0216] “Cannabinoid type 1 receptor” or “CB 1 The term "cannabinoid receptors" refers to G protein-coupled receptors for cannabinoids. In humans, CB 1 is encoded by the CNR1 gene. 1 Also known as cannabinoid receptor 1.

[0217] “Cannabinoid type 2 receptor” or “CB2 The term "cannabinoid receptors" refers to G protein-coupled receptors for cannabinoids. In humans, CB 2 is encoded by the CNR2 gene. 2 Also known as cannabinoid receptor 2.

[0218] “Cannabinoid type 3 receptor” or “CB 3 The term "CB" refers to a G protein-coupled receptor for cannabinoids. 3 Also known as cannabinoid receptor 3, CB is an orphan receptor. 3 Also known as GPR55 (i.e., G protein-coupled receptor 55), is the putative "type 3" cannabinoid receptor.

[0219] In certain embodiments, the compounds provided herein are 1 In certain embodiments, the compounds provided herein modulate CB2. In certain embodiments, the compounds provided herein modulate CB 3 Adjust.

[0220] The terms "sense oligonucleotide" or "sense strand" refer to the strand of a double-stranded compound that includes a region that is substantially complementary to a region of the antisense strand of the double-stranded compound.

[0221] The terms "microRNA" and "miRNA," which may be used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides long) non-coding ribonucleic acid (RNA) that is involved in the post-transcriptional control of gene expression in multicellular organisms by affecting both mRNA stability and translation. miRNAs are transcribed by RNA polymerase II as capped and polyadenylated primary transcripts (pri-miRNAs) that may or may not code for proteins. The primary transcripts are cleaved by the Drosha ribonuclease III enzyme to generate approximately 70 nucleotide long stem-loop precursor miRNAs (pre-miRNAs), which are further processed in the RNAi pathway. As part of this pathway, the pre-miRNAs are cleaved by the cytoplasmic Dicer ribonuclease to generate mature miRNA products and antisense miRNA star (miRNA*) products. Mature miRNAs are incorporated into RNA-induced silencing complexes (RISCs), which recognize target mRNAs through imperfect base pairing (i.e., partial complementarity) with the miRNA, most commonly resulting in translation inhibition or destabilization of the target mRNA. This mechanism most often occurs through the binding of the miRNA on the 3' untranslated region (UTR) of the target mRNA, which can reduce gene expression by either inhibiting translation (e.g., by blocking ribosome access required for translation) or directly causing degradation of the transcript. This term (i.e., miRNA) can be used herein to refer to any form of the miRNA of interest (e.g., precursor miRNA, primary miRNA, and / or mature miRNA).

[0222] The terms "small interfering RNA," "small interfering RNA," and "siRNA," which may be used interchangeably herein, refer to RNA molecules that exist as non-coding double-stranded RNA (dsRNA) molecules of about 20 to about 24 nucleotides in length and are useful for RNA interference (RNAi). siRNAs are often found to have a phosphorylated 5' end and a hydroxylated 3' end, with the 3' end typically having an overhang of 2 nucleotides beyond the 5' end of the antiparallel strand (e.g., the complementary strand of the dsRNA molecule). siRNAs can interfere with the expression of a particular gene by binding to a complementary target sequence (e.g., a target nucleic acid sequence) and inducing (e.g., promoting, inducing, initiating) degradation of the mRNA, thereby inhibiting (e.g., suppressing, silencing, interfering) translation. After incorporation into and segregation from the RISC complex, the siRNA base pairs (e.g., perfect complementarity) with and cleaves its target mRNA, thereby preventing it from being used as a translation template. As described herein above, which is also part of the RNAi pathway, the miRNA-loaded RISC complex scans cytoplasmic mRNAs for potential complementarity (eg, partial complementarity).

[0223] The term "ADAR recruiting molecule" as used herein refers to a nucleic acid that is configured to increase the concentration of adenosine deaminase (ADAR) enzyme acting on ribonucleic acid in a local area around the nucleic acid.In some embodiments, the increase in concentration is compared to the concentration in a given local area where no ADAR recruiting molecule is present.In some embodiments, the ADAR recruiting molecule comprises a double-stranded RNA duplex.

[0224] The term "ADAR targeting molecule" as used herein refers to a nucleic acid configured to guide an ADAR molecule to a desired location (e.g., local). As used herein, the term "guide" refers to increasing the concentration of ADAR at a desired location compared to the concentration in the absence of the ADAR targeting molecule. In some embodiments, the ADAR targeting molecule can be configured to control the desired location by changing the sequence and / or properties of the nucleic acid (e.g., by modification to the nucleobase, sugar, internucleoside linkage, or other components). In some embodiments, the ADAR targeting molecule comprises an ADAR recruiting molecule and a single-stranded guide nucleic acid. In some embodiments, the ADAR targeting molecule comprises a double-stranded RNA duplex and a single-stranded guide nucleic acid.

[0225] The term "single-stranded guide nucleic acid" or "guide RNA" as used herein refers to a single-stranded nucleic acid that comprises a specific sequence that is at least partially complementary to a target sequence.In some embodiments, the target sequence is located in, adjacent to, or close to the desired local area where ADAR concentration is to be regulated.In some embodiments, the degree of complementarity is sufficient to promote the single-stranded guide nucleic acid to bind (e.g., anneal) to the target sequence.

[0226] The compounds of the present disclosure may also contain proportions of atomic isotopes not found in nature at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 Any isotopic variant of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0227] The term "isotopic variant" refers to a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein) that contains a proportion of an isotope not found in nature at one or more of the atoms that constitute the therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains one or more isotopes not found in nature, including hydrogen (H), deuterium ( 2 H), tritium ( 3 H), Carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131In certain embodiments, an "isotopic variant" of a therapeutic agent contains one or more isotopes in proportions not found in nature, including, but not limited to, hydrogen (H), deuterium ( 2 H), tritium ( 3 H), Carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 I) are included, but are not limited to these.

[0228] In a therapeutic agent (e.g., a compound and / or modified oligonucleotide disclosed herein), where feasible according to the judgment of one of skill in the art, for example, any hydrogen may be 2H, for example, any carbon may be 13 C, for example, any nitrogen may be 15 N, for example, any oxygen 18 It will be understood that the isotope may be O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains deuterium (D) in a proportion not found in nature.

[0229] "Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase, or internucleoside linkage has been modified.

[0230] "Nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide, regardless of any sugar or internucleoside linkages.

[0231] The term "oligomeric duplex" refers to a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may also be referred to as a "duplex oligomeric compound." The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides. In some embodiments, the terms "duplex oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligomeric duplex" and "compound" are used interchangeably.

[0232] By "phosphorothioate linkage" is meant a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced with a sulfur atom.

[0233] The terms "RNA interference compound," "RNAi compound," and / or "iRNA agent" refer to compounds that act, at least in part, through the RNA-induced silencing complex (RISC) pathway or Ago2, rather than RNase H, to regulate a target nucleic acid and / or a protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNAs, single-stranded siRNAs, and microRNAs, including microRNA mimics.

[0234] Certain embodiments In certain embodiments, the compound is CB 1 In certain embodiments, the compound comprises a ligand and one or more linker moieties. In certain embodiments, the compound comprises a ligand having a structure as 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), (VI In certain embodiments, one or more linker moieties (L) are selected from any of the following: (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"), (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. 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 etc.) are CB 1The ligand is linked to a therapeutic, prophylactic, or diagnostic agent. In certain embodiments, the compound further comprises one or more therapeutic, prophylactic, or diagnostic agents. In certain embodiments, the therapeutic, prophylactic, or diagnostic agent is a small molecule or an oligomeric compound. In certain embodiments, the oligomeric compound comprises a protein, a peptide, an antibody, an oligonucleotide, or a combination thereof.

[0235] In certain embodiments, the oligomeric compound is any of those described herein. In certain embodiments, the oligomeric compound is about 10-50 subunits in length. In certain embodiments, the oligomeric compound is an oligonucleotide. In certain embodiments, the oligonucleotide is any of those described herein. In certain embodiments, the oligonucleotide is 8-80 linked nucleosides in length, 12-50 linked nucleosides in length, 12-30 linked nucleosides in length, or 15-30 linked nucleosides in length.

[0236] 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.

[0237] 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., composed of ribonucleosides), deoxyribonucleic acid (e.g., composed of deoxyribonucleosides), or a combination thereof.In certain embodiments, the oligonucleotide is small interfering RNA (siRNA), microRNA (miRNA) antagonist, miRNA mimic, ADAR recruiting molecule, ADAR targeting molecule, guide RNA, antisense oligonucleotide, short hairpin RNA (shRNA), or a combination thereof.

[0238] 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 3 or 4 PEG units in length. In certain embodiments, the linker has the structure [ka] In some embodiments, the linker is 2 or 3 PEG units in length.

[0239] In some embodiments, the linker is an optionally substituted heteroaryl linker. In some embodiments, the linker is an optionally substituted partially unsaturated heteroaryl linker. In some embodiments, the linker has the structure [ka] Includes.

[0240] In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the linker is substituted with one or more =O substituents. In certain embodiments, the linker has the structure [ka] wherein X is O or S. In some embodiments, the linker has the structure [ka] wherein X is O or S.

[0241] In some embodiments, the linker is a phosphodiester bond or a phosphorothioate bond. In certain embodiments, the linker has the structure [ka] wherein X is O or S.

[0242] In certain embodiments, the linker has the structure [ka] wherein X is O or S.

[0243] In some embodiments, the linker is an optionally substituted PEG linker. In some embodiments, the linker is an optionally substituted PEG linker of 3 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 has the structure [ka] 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 has the structure [ka] 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 has the structure [ka] wherein X is O or S. In some embodiments, the linker comprises the structure [ka] wherein X is O or S.

[0244] In some embodiments, the linker is an optionally substituted PEG linker. In certain embodiments, the linker is an optionally substituted PEG linker that is 2 or 3 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 that is 3 or 4 PEG units in length. In certain embodiments, the linker has the structure [ka] 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 has the structure [ka] 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 has the structure [ka] wherein X is O or S. In some embodiments, the linker comprises the structure [ka] wherein X is O or S.

[0245] In certain embodiments, the compound has the following structure: [ka] or a salt thereof (wherein X is O or S).

[0246] In some embodiments, X is O. In some embodiments, X is S.

[0247] In some embodiments, R 1 (and R if present) 2 ) comprises an oligonucleotide. In some embodiments, the oligonucleotide is attached at its 5' end. In some embodiments, the oligonucleotide is attached at its 3' end. In some embodiments, the oligonucleotide is attached at an internal position of the oligonucleotide. In some embodiments, the internal position is an internucleoside linkage. In some embodiments, R 1 one or more additional CBs 1 In some embodiments, the oligonucleotide comprises an oligonucleotide conjugated to a ligand. In some embodiments, the oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional CB 1In certain embodiments, the additional CB 1 The ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, at one or more internal positions of the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.

[0248] Certain embodiments provide a composition comprising a compound of any of the embodiments herein and a pharma- ceutically acceptable carrier or excipient.

[0249] Certain embodiments provide a composition comprising a compound of any embodiment anywhere herein for use in therapy.

[0250] In certain embodiments, a method for delivering an agent to a cell comprises contacting the cell with a compound of any of the embodiments herein, thereby delivering the agent to the cell. In certain embodiments, the cell comprises a CB 1 In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a cell of the frontal lobe. In certain embodiments, the cell is a cell of the striatum. In certain embodiments, the cell is a cell of the cerebellum. In certain embodiments, the cell is a cell of the brain stem. In certain embodiments, the cell is a cell of the hippocampus. In certain embodiments, the cell is a cell of the spinal cord. In certain embodiments, the agent is a therapeutic or diagnostic agent. In certain embodiments, the cell is within an animal.

[0251] In certain embodiments, a method of modulating expression of a nucleic acid target in a cell comprises contacting the cell with a compound of any of the embodiments herein, thereby modulating expression of a nucleic acid target in the cell. In certain embodiments, the cell comprises a CB 1In certain embodiments, the cell is a brain cell. In certain embodiments, the cell is a cell of the frontal lobe. In certain embodiments, the cell is a cell of the striatum. In certain embodiments, the cell is a cell of the cerebellum. In certain embodiments, the cell is a cell of the brain stem. In certain embodiments, the cell is a cell of the hippocampus. In certain embodiments, the cell is a cell of the spinal cord. In certain embodiments, the agent is a therapeutic or diagnostic agent. In certain embodiments, contacting the cell with a compound of any embodiment herein inhibits expression of the nucleic acid target. In certain embodiments, the nucleic acid target is a pre-mRNA, an mRNA, a non-coding RNA, or an miRNA. In certain embodiments, the cell is in an animal.

[0252] In certain embodiments, a method for modulating expression of a nucleic acid target in a subject comprises administering to the subject any of the compounds or compositions provided herein, thereby modulating expression of the nucleic acid target in the subject. In certain embodiments, expression of the nucleic acid is modulated by the expression of CB 1 In certain embodiments, expression of the nucleic acid is regulated in brain cells that express CB 1 The cell expressing is a brain cell. In certain embodiments, the brain cell is a cell of the frontal lobe. In certain embodiments, the brain cell is a cell of the striatum. In certain embodiments, the brain cell is a cell of the cerebellum. In certain embodiments, the brain cell is a cell of the brain stem. In certain embodiments, the brain cell is a cell of the hippocampus. In certain embodiments, the brain cell is a cell of the spinal cord. In certain embodiments, the nucleic acid target is a pre-mRNA, an mRNA, a non-coding RNA, or an miRNA. In certain embodiments, the compound is administered intrathecally to the subject.

[0253] In certain embodiments, the method of treating or ameliorating a disease, disorder, or a symptom thereof in a subject comprises administering any of the compounds or compositions provided herein to the subject, thereby treating, preventing, or ameliorating the disease, disorder, or a symptom thereof in the subject. In certain embodiments, the disease, disorder, or a symptom thereof is a disease, disorder, or a symptom thereof of the central nervous system (CNS). In certain embodiments, the disease, disorder, or a symptom thereof is Alzheimer's disease, or a symptom thereof. In certain embodiments, the compound is administered intrathecally to the subject. In certain embodiments, the compound or composition is administered to the subject in a therapeutically effective amount.

[0254] In certain embodiments, CB 1 The ligand-containing compound is CB 1 Compared with cells that do not express CB 1 In certain embodiments, the method selectively or preferentially targets cells expressing CB 1 The ligand-containing compound is CB 1 Compared to the ligand-free compound, CB 1 The present invention selectively or preferentially targets cells expressing

[0255] Also provided is the use of a compound described herein for the manufacture of a medicament in the treatment of a disease or disorder.

[0256] In another aspect, the disclosure provides methods for making any of the compounds provided herein, including one or more of the compounds and chemical transformations described herein, including Examples 2-24.

[0257] Certain compounds containing oligonucleotides In certain embodiments, the compounds described herein include oligonucleotides. In certain embodiments, the oligonucleotides have a nucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., a target nucleic acid expressed in a cell). In some embodiments, the oligonucleotides, when delivered to a cell expressing a target nucleic acid, can modify expression of the underlying gene. In some embodiments, the oligonucleotides, when delivered to a cell expressing a target nucleic acid, can inhibit expression of the underlying gene. Gene expression can be 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 nucleobases, sugars, and / or internucleoside linkages), 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 nucleobases, modified sugars, or modified internucleoside linkages).

[0258] In certain embodiments, the oligonucleotide is single-stranded. In some embodiments, the single-stranded oligonucleotide is single-stranded RNA (ssRNA), ssDNA, or ssRNA / DNA hybrid (e.g., a single-stranded oligonucleotide composed of both ribonucleosides (modified or unmodified) and deoxyribonucleosides (modified or unmodified)). In some embodiments, the oligonucleotide is double-stranded (e.g., composed of two single-stranded nucleic acids). Such a double-stranded oligonucleotide comprises a first oligonucleotide having a region complementary to a target nucleic acid and a second oligonucleotide having a region complementary to the first oligonucleotide. The first and second oligonucleotides may be independently modified. In certain embodiments, the first oligonucleotide is modified by one or more CB1 In certain embodiments, the second oligonucleotide is linked to one or more CB 1 It is linked to a ligand.

[0259] In some embodiments, the oligonucleotide comprises at least 2 nucleotides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 12 0, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, or more) in length. In some embodiments, the oligonucleotide is at least 5 nucleotides in length. In some embodiments, the oligonucleotide is at least 10 nucleotides in length. In some embodiments, the oligonucleotide is at least 15 nucleotides in length. In some embodiments, the oligonucleotide is at least 16 nucleotides in length. In some embodiments, the oligonucleotide is at least 17 nucleotides in length. In some embodiments, the oligonucleotide is at least 18 nucleotides in length. In some embodiments, the oligonucleotide is at least 19 nucleotides in length. In some embodiments, the oligonucleotide is at least 20 nucleotides in length. In some embodiments, the oligonucleotide is at least 21 nucleotides in length. In some embodiments, the oligonucleotide is at least 22 nucleotides in length.In some embodiments, the oligonucleotide is at least 23 nucleotides in length. In some embodiments, the oligonucleotide is at least 24 nucleotides in length. In some embodiments, the oligonucleotide is at least 25 nucleotides in length. In some embodiments, the oligonucleotide is at least 26 nucleotides in length. In some embodiments, the oligonucleotide is at least 27 nucleotides in length. In some embodiments, the oligonucleotide is at least 28 nucleotides in length. In some embodiments, the oligonucleotide is at least 29 nucleotides in length. In some embodiments, the oligonucleotide is at least 30 nucleotides in length. In some embodiments, the oligonucleotide is at least 40 nucleotides in length. In some embodiments, the oligonucleotide is at least 50 nucleotides in length. In some embodiments, the oligonucleotide is at least 60 nucleotides in length. In some embodiments, the oligonucleotide is at least 70 nucleotides in length. In some embodiments, the oligonucleotide is at least 80 nucleotides in length. In some embodiments, the oligonucleotide is at least 90 nucleotides in length. In some embodiments, the oligonucleotide is at least 100 nucleotides in length. In some embodiments, the oligonucleotide is at least 150 nucleotides in length.

[0260] In some embodiments, the oligonucleotide is 150 nucleotides or less (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 , 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150) in length. In some embodiments, the oligonucleotide is 150 nucleotides or less in length. In some embodiments, the oligonucleotide is 100 nucleotides or less in length. In some embodiments, the oligonucleotide is 90 nucleotides or less in length. In some embodiments, the oligonucleotide is 80 nucleotides or less in length. In some embodiments, the oligonucleotide is 70 nucleotides or less in length. In some embodiments, the oligonucleotide is 60 nucleotides or less in length. In some embodiments, the oligonucleotide is 50 nucleotides or less in length. In some embodiments, the oligonucleotide is 40 nucleotides or less in length. In some embodiments, the oligonucleotide is 30 nucleotides or less in length. In some embodiments, the oligonucleotide is 29 nucleotides or less in length.In some embodiments, the oligonucleotide is 28 nucleotides or less in length. In some embodiments, the oligonucleotide is 27 nucleotides or less in length. In some embodiments, the oligonucleotide is 26 nucleotides or less in length. In some embodiments, the oligonucleotide is 25 nucleotides or less in length. In some embodiments, the oligonucleotide is 24 nucleotides or less in length. In some embodiments, the oligonucleotide is 23 nucleotides or less in length. In some embodiments, the oligonucleotide is 22 nucleotides or less in length. In some embodiments, the oligonucleotide is 21 nucleotides or less in length. In some embodiments, the oligonucleotide is 20 nucleotides or less in length. In some embodiments, the oligonucleotide is 19 nucleotides or less in length. In some embodiments, the oligonucleotide is 18 nucleotides or less in length. In some embodiments, the oligonucleotide is 17 nucleotides or less in length. In some embodiments, the oligonucleotide is 16 nucleotides or less in length. In some embodiments, the oligonucleotide is 15 nucleotides or less in length. In some embodiments, the oligonucleotide is 10 nucleotides or less in length. In some embodiments, the oligonucleotide is 5 nucleotides or less in length.

[0261] In some embodiments, the oligonucleotide is about 5 to about 150 nucleotides in length. In some embodiments, the oligonucleotide is about 10 to about 100 nucleotides in length. In some embodiments, the oligonucleotide is about 20 to about 90 nucleotides in length. In some embodiments, the oligonucleotide is about 30 to about 80 nucleotides in length. In some embodiments, the oligonucleotide is about 40 to about 70 nucleotides in length. In some embodiments, the oligonucleotide is about 50 to about 60 nucleotides in length.

[0262] In some embodiments, the oligonucleotide is therapeutic oligonucleotide.Therapeutic oligonucleotide can include, but is not limited to, small interfering RNA (siRNA), microRNA (miRNA) antagonist, miRNA mimic, ADAR recruiting molecule, ADAR targeting molecule, guide RNA, antisense oligonucleotide, short hairpin RNA (shRNA) or combinations thereof.

[0263] In certain embodiments, the miRNA is a precursor miRNA, a primary miRNA, and / or a mature miRNA.

[0264] In certain embodiments, the oligonucleotide comprises or consists of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide is complementary to mRNA. In certain embodiments, the antisense oligonucleotide is complementary to pre-mRNA. In certain embodiments, the antisense oligonucleotide blocks translation and promotes 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 mRNA expression regulation, and promotes the degradation of miRNA.

[0265] Certain modifications In certain embodiments, the present disclosure relates to a compound comprising an oligonucleotide. In certain embodiments, the oligonucleotide may be unmodified RNA or DNA, or may be modified. In certain embodiments, the oligonucleotide is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage compared to unmodified RNA or DNA. In certain embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also comprise a terminal modification, for example, a 5' terminal modification and a 3' terminal decoration.

[0266] GlycosylationSugar modifications and motifs In certain embodiments, the modified sugar is a substituted furanosyl sugar or a non-bicyclic modified sugar. In certain embodiments, the modified sugar is a bicyclic or tricyclic modified sugar. In certain embodiments, the modified sugar is a sugar substitute. The sugar substitute may include one or more of the substitutions described herein.

[0267] In certain embodiments, the modified sugar is a substituted furanosyl or non-bicyclic modified sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar includes one or more substituents, including but not limited to, at the 2', 3', 4', and 5' positions.

[0268] In certain embodiments, the substituent at the 2' position includes F and OCH 3 ("OMe", "O-methyl" or "methoxy"). In certain embodiments, suitable 2'-position substituents for non-bicyclic modified sugars include, but are not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF 3 , OCF 3 , F, Cl, Br, SCH 3 , SOCH 3 , S.O. 2 CH 3 , O.N.O. 2 , ΝΟ 2 , N 3 , and NH 2 In certain embodiments, the substituent at the 2' position includes, but is not limited to, O-(C 1 -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, but are not limited thereto, where alkyl, alkenyl, and alkynyl are substituted or unsubstituted C 1 ~C 10 Alkyl or C 2 ~C 10 It can be alkenyl and alkynyl. In certain embodiments, the substituents at the 2' position include, but are not limited to, alkaryl, aralkyl, O-alkaryl, and O-aralkyl. In certain embodiments, these 2' substituents are hydroxyl, alkoxy, carboxy, benzyl, phenyl, nitro (ΝΟ 2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the substituent at the 2' position includes O[(CH 2 ) n O] m CH 3 , O(CH 2 ) n OCH 3 , O(CH 2 ) n CH 3 , O(CH2) n O.N.H. 2 , O(CH 2 ) n NH 2 , O(CH 2 ) n SCH 3 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 )] 2 In certain embodiments, the substituent at the 2' position includes, but is not limited to, OCH 2 CH 2 OCH 3 ("MOE"), O(CH 2 ) 2 ON(CH 3 ) 2 ("DMAOE"), O(CH 2 ) 2 O(CH 2 ) 2 N(CH 3 ) 2 ("DMAEOE"), and OCH 2 C(=O)-N(H)CH 3 ("NMA"), but are not limited to these.

[0269] In certain embodiments, suitable 4'-position substituents for non-bicyclic modified sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, those described in Manoharan et al., WO 2015 / 106128. In certain embodiments, suitable 5'-position substituents for non-bicyclic modified sugars include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, one or more sugars include a 5'-vinyl phosphonate modification. In certain embodiments, the 2', 4', and 5'-position substituents described herein 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 of the 3'-terminal nucleoside or the 5'-position of the 5'-terminal nucleoside. In certain embodiments, a non-bicyclic modified sugar may include two or more non-bridging sugar substituents. In certain such embodiments, substituents of non-bicyclic modified sugars include, but are not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, substituents of modified sugars include those described in Migawa et al., WO 2008 / 101157 and Rajeev et al., US2013 / 0203836. In certain embodiments, suitable substituents at the 5' position for non-bicyclic modified sugars include 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'; 5'-diphosphate ((HO) 2 (O)POP(HO)(O)-O-5'); 5'-triphosphate ((HO) 2(O)PO-(HO)(O)POP(HO)(O)-O-5'); 5'-guanosine cap (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); 5' adenosine cap (Appp), as well as any modified or unmodified nucleotide cap structure (NO-5'(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5'); 5'-monothiophosphate (phosphorothioate; (HO) 2 (S)PO-5'; 5'-monodithiophosphate (phosphorodithioate; (HO)(HS)(S)PO-5'), 5' phosphorothioate ((HO) 2 (O)PS-5'; any further combination of oxygen / sulfur substituted monophosphates, diphosphates and triphosphates (e.g., 5'-alpha-thiotriphosphate, 5'-gamma-thiotriphosphate, etc.), 5'-phosphoramidates ((HO) 2 (O)P-NH-5', (HO)(NH 2 )(O)PO-5'), 5' alkyl phosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-5'-, 5' alkenyl phosphonates (i.e., vinyl, substituted vinyl), (OH) 2 (O)P-5'-CH 2 -), 5' alkyl ether phosphonates (R = alkyl ether methoxymethyl (MeOCH 2 -), 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 end of the oligonucleotide. In certain embodiments, the 5' modification is at the end of the antisense oligonucleotide.

[0270] In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar that includes two rings, the second ring being formed via a bridge connecting two atoms of the first ring, thereby forming a bicyclic structure. In certain embodiments, the bicyclic sugar includes a bridging substituent that bridges two atoms of a furanosyl ring to form a second ring. In certain embodiments, the bicyclic sugar does not include a furanosyl moiety. A "bicyclic nucleoside" ("BNA") is a nucleoside that has a bicyclic sugar. In certain embodiments, the bicyclic sugar includes a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar includes a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, the 4'-2' bridge substituent includes a 4'-CH 2 -2',4'-(CH 2 ) 2 -2',4'-(CH 2 ) 3 -2',4'-CH 2 -O-2' ("LNA"), 4'-CH 2 -S-2',4'-(CH 2 ) 2 -O-2' ("ENA"), 4'-CH(CH 3 )-O-2' ("constrained ethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH 2 -2',4'-CH 2 -N(R)-2',4'-CH(CH 2 OCH 3 )-O-2' ("constrained MOE" or "cMOE") and its analogs (e.g., U.S. Pat. No. 7,399,845), 4'-C(CH 3 )(CH 3 )-O-2' and its analogs (e.g., U.S. Pat. No. 8,278,283), 4'-CH 2 -N(OCH 3 )-2' and its analogs (e.g., U.S. Pat. No. 8,278,425), 4'-CH 2 -ON(CH 3)-2' (e.g., U.S. Patent Application Publication No. 2004 / 0171570), 4'-CH 2 -N(R)-O-2' (wherein R is H, C 1 -C 12 alkyl, or a protecting group) (e.g., U.S. Pat. No. 7,427,672), 4'-CH 2 -C(H)(CH 3 )-2' (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134), as well as 4'-CH 2 -C(=CH 2 )-2' and analogs thereof (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the foregoing are incorporated herein by reference. Additional representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include U.S. Patent Nos. 6,268,490, 6,525,191, 6,670,461, 6,770,748, 6,794,499, 6,998,484, 7,053,207, 7,034,133, 7,084,125, 7,399,845, 7,427,672, 7, Nos. 569,686, 7,741,457, 8,022,193, 8,030,467, 8,278,425, 8,278,426, 8,278,283, US2008 / 0039618, US2009 / 0012281, US2013 / 0190383, and WO2013 / 036868, the entire contents of each of which are incorporated herein by reference. Any of the foregoing bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, e.g., WO99 / 14226). Certain bicyclic nucleosides herein are in the β-D configuration, unless otherwise specified.

[0271] In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the sugar substitute has an oxygen atom replaced with, for example, a sulfur atom, a carbon atom, or a nitrogen atom. In certain such embodiments, the sugar substitute may also include bridging and / or non-bridging substituents as described herein. In certain such embodiments, the sugar substitute includes a ring having atoms other than five atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a tetrahydropyran ("THP") in place of the pentofuranosyl sugar. In certain embodiments, the sugar substitute includes a morpholino in place of the pentofuranosyl sugar. Representative United States patents which teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957, 5,118,800, 5,166,315, 5,185,444, 5,319,080, 5,359,044, 5,393,878, 5,446,137, 5,466,786, 5,514,785, 5,519,134, 5,567,811, 5,576,427, 5,591,722, 5,581,723, 5,581,724, 5,581,725, 5,581,726, 5,581,727, 5,581,728, 5,581,729, 5,591,729, 5,601 ... Nos. 5,597,909, 5,610,300, 5,627,053, 5,639,873, 5,646,265, 5,658,873, 5,670,633, 5,700,920, 7,875,733, 7,939,677, 8,088,904, 8,440,803 and 9,005,906, the entire contents of each of the foregoing are incorporated herein by reference.

[0272] In some embodiments, the surrogate sugar comprises an acyclic moiety. In certain embodiments, the surrogate sugar is an unlocked nucleic acid ("UNA"). A UNA is an acyclic unlocked nucleic acid in which any of the sugar bonds have been removed to form an unlocked "sugar" residue. In one example, a UNA also encompasses a monomer in which the C1'-C4' bond (i.e., the carbon-oxygen-carbon covalent bond between the C1' and C4' carbons) has been removed. In another example, the C2'-C3' bond (i.e., the carbon-carbon covalent bond between the C2' and C3' carbons) of the sugar has been removed. Representative U.S. publications teaching the preparation of UNAs include, but are not limited to, U.S. Patent No. 8,314,227, and U.S. Patent Application Publication Nos. 2013 / 0096289, 2013 / 0011922, and 2011 / 0313020, the entire contents of each of which are incorporated herein by reference. In certain embodiments, sugar surrogates include peptide nucleic acids ("PNAs"), acyclic butyl nucleic acids (see Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and the nucleosides and oligonucleotides described in Manoharan et al., US2013 / 130378, the entire contents of which are incorporated herein by reference. Many other bicyclic and tricyclic sugars and alternative sugar ring systems are known in the art that can be used in modified nucleosides.

[0273] In certain aspects, the present disclosure refers to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotide contain one or more modified and / or unmodified sugars arranged along the oligonucleotide or a region thereof in a defined pattern or "sugar motif." In certain cases, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

[0274] In certain embodiments, the oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two outer "wing" regions and a central or internal "gap" region. The gap region and the wing regions form a contiguous sequence of nucleosides, with the majority of the nucleoside sugars of each of the wings being different from the majority of the nucleoside sugars of the gap. In certain embodiments, the wing regions comprise a majority of modified sugars and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleosides of the gap are deoxynucleosides. Compounds containing gapmer sugar motifs are described, for example, in U.S. Pat. No. 8,790,919, the entire contents of which are incorporated herein by reference.

[0275] In certain embodiments, one or both of the oligonucleotides of the double-stranded compound contain a triplex sugar motif. An oligonucleotide with a triplex sugar motif contains three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplex is at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain two or more triplex sugar motifs. In certain embodiments, the identical sugar modification of the triplex sugar motif is a 2'-F modification. Compounds with triplex sugar motifs are disclosed, for example, in U.S. Pat. No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0276] In certain embodiments, one or both of the oligonucleotides of the double-stranded compound contain a quadruplex sugar motif. An oligonucleotide with a quadruplex sugar motif contains four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is at or near the cleavage site. In certain embodiments, an oligonucleotide of a double-stranded compound may contain two or more quadruplex sugar motifs. In certain embodiments, the identical sugar modification of a quadruplex sugar motif is a 2'-F modification. For double-stranded compounds having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically at about the 10th, 11th, and 12th positions from the 5' end. In certain embodiments, the quadruplex sugar motif is at the 8th, 9th, 10th, 11th position; 9th, 10th, 11th, 12th position; 10th, 11th, 12th position; 11th, 12th, 13th position; 11th, 12th, 13th, 14th position; or 12th, 13th, 14th, 15th position of the sense oligonucleotide, counting from the first nucleoside at the 5' end of the sense oligonucleotide or counting from the first paired nucleotide in the duplex region from the 5' end of the sense oligonucleotide. In certain embodiments, the quadruplex sugar motif is at the 8th, 9th, 10th, 11th position; 9th, 10th, 11th, 12th position; 10th, 11th, 12th position; 11th, 12th, 13th position; 11th, 12th, 13th position; or 12th, 13th, 14th, 15th position of the antisense oligonucleotide, counting from the first nucleoside at the 5' end of the antisense oligonucleotide or counting from the first paired nucleotide in the duplex region from the 5' end of the antisense oligonucleotide. The cleavage site may vary depending on the length of the duplex region of the double-stranded compound, and the position of the quadruplex may vary accordingly.

[0277] In certain embodiments, the oligonucleotide comprises an alternating sugar motif. In certain embodiments, one or both of the oligonucleotides of the double-stranded compound comprise an alternating sugar motif. An oligonucleotide with an alternating sugar motif comprises at least two different sugar modifications, where one or more consecutive nucleosides comprising a first sugar modification alternate with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, the alternating motif can be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC...", where A, B, and C each represent one type of modification on a nucleoside. In certain embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobases along the oligonucleotide. In certain embodiments, the alternating sugar motif is composed of two different sugar modifications. In certain embodiments, the alternating sugar motif comprises a 2'-OMe and a 2'-F sugar modification.

[0278] In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications as provided herein.In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs as provided herein.In certain embodiments, the oligonucleotide that contains a sugar motif is fully modified in that each nucleoside other than the nucleoside that contains the sugar motif contains a sugar modification.

[0279] Nucleobase modifications and motifs In certain embodiments, modified oligonucleotides include one or more nucleosides that include a modified nucleobase. In certain embodiments, modified oligonucleotides include one or more nucleosides that do not include a nucleobase, referred to as abasic nucleosides.

[0280] In certain embodiments, the modified nucleobase is selected from 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines. In certain embodiments, the modified nucleobase is selected from 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-CH 3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-azapurines and other 8-substituted purines, 5-halo, especially 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-methyl-2-propenyl-1-pyrid ... -aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-Ν-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-Ν-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal base, hydrophobic base, promiscuous base, size-expanded base, and fluorinated base. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazin-2-one, 1,3-diazaphenothiazin-2-one, and 9-(2-aminoethoxy)-1,3-diazaphenoxazin-2-one (G-clamp). Modified nucleobases also include those in which the purine or pyrimidine base is replaced by other heterocycles, for example, 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0281] Further nucleobases include those described in U.S. Pat. No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859; Kroschwitz, JL, Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pages 289-302; Antisense Research and Applications, Crooke, ST and Lebleu, B., Eds., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke ST, Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15), each of which is incorporated herein by reference.

[0282] Publications which teach the preparation of some of the above and other modified nucleobases include, but are not limited to, U.S. Publication Nos. 2003 / 0158403 and 2003 / 0175906, U.S. Patents 4,845,205, 5,130,302, 5,134,066, 5,175,273, 5,367,066, 5,432,272, 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, 5,681,941, 5,811,534, 5,750,692, 5,948,903, 5,587,470, 5,457,191, 5,763,588, 5,830,653, 5,808,027, 6,005,096, 6,015,886, 6,147,200, 6,166,197 , 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 incorporated herein by reference.

[0283] In certain embodiments, an oligonucleotide comprises modified and / or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or a region thereof. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methylcytosine.

[0284] In certain embodiments, the modified oligonucleotide comprises a modified nucleobase block. In certain such embodiments, the block is at the 3' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides from the 3' end of the oligonucleotide. In certain embodiments, the block is at the 5' end of the oligonucleotide. In certain embodiments, the block is within 3 nucleosides from the 5' end of the oligonucleotide.

[0285] Internucleoside linkage modifications and motifs The 3'-5' phosphodiester linkage is the natural internucleoside linkage of RNA and DNA. In certain embodiments, oligonucleotides have one or more modified, i.e., non-natural, internucleoside linkages. Certain non-natural internucleoside linkages can provide desirable properties, such as enhanced cellular uptake, increased affinity for target nucleic acids, and improved stability in the presence of nucleases. Exemplary phosphorus-containing modified internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonates), phosphoramidates, and phosphorothioates ("P=S"), and phosphorodithioates ("HS-P=S"). Exemplary non-phosphorus-containing internucleoside linkage groups include methylenemethylimino (-CH 2 -N(CH 3 )-O-CH 2 ), thiodiesters, thionocarbamates (-OC(=O)(NH)-S-); siloxanes (-O-SiH 2 -O-); and N,N'-dimethylhydrazine (-CH 2 -Ν((CΗ 3 )-Ν((CΗ 3 )-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those of skill in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriesters, methylphosphonates, MMI(3'-CH 2 -N(CH 3 )-O-5'), Amide-3 (3'-CH2 -C(=O)-N(H)-5'), amide-4 (3'-CH 2 -N(H)-C(=O)-5'), formacetal (3'-O-CH 2 -O-5'), methoxypropyl, and thioformyl acetal (3'-S-CH 2 -O-5'). Additional neutral internucleoside linkages include nonionic linkages including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates, and amides (see, e.g., Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Additional neutral internucleoside linkages include N, O, S, and CH 2 Non-ionic linkages involving mixtures of moieties are included.

[0286] In certain embodiments, oligonucleotide comprises at least one modified internucleoside linkage.Modified internucleoside linkage can be located in any part of oligonucleotide.In the case of double-stranded compound, modified internucleoside linkage can be located in sense oligonucleotide, antisense oligonucleotide, or both oligonucleotides of double-stranded compound.

[0287] In certain embodiments, the internucleoside linkage modifications may be present at every nucleoside of an oligonucleotide. In certain embodiments, the internucleoside linkage modifications may be present in an alternating pattern along the oligonucleotide. In certain embodiments, essentially all internucleoside linkage groups are phosphate internucleoside linkages (P=O). In certain embodiments, each internucleoside linkage group of a modified oligonucleotide is phosphorothioate (P=S). In certain embodiments, each internucleoside linkage group of a modified oligonucleotide is independently selected from phosphorothioate internucleoside linkages and phosphate internucleoside linkages. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of a double-stranded compound is the same. In certain embodiments, the pattern of internucleoside linkage modifications of each oligonucleotide of a double-stranded compound is different. In certain embodiments, a double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, the 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'-terminus and 3'-terminus. 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'-terminus and 3'-terminus. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages.

[0288] In certain embodiments, the double-stranded compound comprises an overhang region. In certain embodiments, the double-stranded compound comprises phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded compound comprises phosphorothioate internucleoside linkage or alkylphosphonate internucleoside linkage that connects the overhang nucleotide and the paired nucleotide next to the overhang nucleotide. For example, there can be at least two phosphorothioate internucleoside linkages between the terminal three nucleosides, where two of the three nucleosides are overhang nucleosides and the third nucleoside is the paired nucleoside next to the overhang nucleoside. These terminal three nucleosides can be at the 3' end of the antisense oligonucleotide, the 3' end of the sense oligonucleotide, the 5' end of the antisense oligonucleotide, or the 5' end of the antisense oligonucleotide.

[0289] In certain embodiments, the modified oligonucleotides contain one or more internucleoside linkages with a chiral center. Exemplary chiral internucleoside linkages include, but are not limited to, alkyl phosphonates and phosphorothioates. Modified oligonucleotides containing internucleoside linkages with a chiral center can be prepared as a population of modified oligonucleotides containing stereorandom internucleoside linkages or as a population of modified oligonucleotides containing phosphorothioate linkages of a specific stereochemical configuration. In certain embodiments, the population of modified oligonucleotides contains phosphorothioate internucleoside linkages, all of which are stereorandom. Such modified oligonucleotides can be generated using a synthetic method in which the stereochemical configuration of each of the phosphorothioate linkages is randomly selected. As will be appreciated by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereochemical configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides containing one or more specific phosphorothioate internucleoside linkages of a specific stereochemical configuration that are independently selected. In certain embodiments, a particular arrangement of a particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, a particular arrangement of a particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, a particular arrangement of a particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, a particular arrangement of a particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, a particular arrangement of a particular phosphorothioate linkage is present in at least 99% of the molecules in the population.Such enriched populations of modified oligonucleotides can be produced using synthetic methods known in the art, such as those described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO2017 / 015555. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one designated phosphorothioate in the (Sp) configuration. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.

[0290] CB 1 Ligand In some embodiments, the compounds provided herein bind to the cannabinoid type 1 receptor (CB 1 In some embodiments, the CB 1 The ligands are useful for directing therapeutic, prophylactic, or diagnostic agents. In certain embodiments, the therapeutic agent is an oligonucleotide (e.g., a therapeutic oligonucleotide). In some embodiments, the CB 1 The ligand targets the oligonucleotide to a localized location. In some embodiments, the TrkB ligand targets a tissue. In some embodiments, the tissue is brain tissue. In some embodiments, the CB 1 The ligand targets a cellular receptor. In some embodiments, the cellular receptor is a CB 1 In some embodiments, CB 1 The receptor is in the brain. In some embodiments, the TrkB receptor is in the frontal lobe. In some embodiments, the CB 1 The receptor is located in the striatum. In some embodiments, the CB 1 The receptor is located in the cerebellum. In some embodiments, the CB 1 The receptor is located in the brain stem. In some embodiments, the CB1 The receptor is located in the hippocampus. In some embodiments, the CB 1 The receptors are located in the spinal cord.

[0291] Any CB in the compounds provided herein 1 The use of ligands is also contemplated in this disclosure. 1 Ligands are known in the art and one of ordinary skill in the art would be able to identify additional CB ligands for use in the compounds described herein beyond those expressly provided in this disclosure. 1 The present disclosure also relates to any CB ligand provided herein or known in the art. 1 Derivatives and prodrugs of the ligands are also contemplated for use with the compounds described herein, and those of skill in the art would know how to make such derivatives and prodrugs.

[0292] In some embodiments, CB 1 The ligand is CB 1 In some embodiments, the CB 1 The ligand is CB 1 Exemplary CB antagonists for use in the present disclosure 1 The ligands are the following CB 1 Ligands and derivatives thereof, including, but not limited to: [ka] [ka] [ka] [ka] [ka]

[0293] In some embodiments, CB 1 The ligand is RVD-Hpα (fragment of hemoglobin (pepcan-12), alpha 1).

[0294] 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. 1 The ligand is anandamide.

[0295] In some embodiments, CB 1 The ligand is anti-CB 1 In certain embodiments, CB 1 The ligand is anti-CB 1 Antibody fragments, or anti-CB 1 It is an antibody variant. 1 "Antibody" means CB 1 Refers to an immune system protein that recognizes, binds to, or otherwise interacts with a receptor.

[0296] In certain embodiments, CB 1 The ligand is conjugated (e.g., linked, connected, bound, associated) with one or more agent moieties. In certain embodiments, the agent moiety is a therapeutic agent, a preventive agent, a diagnostic agent, or an imaging agent. In certain embodiments, the agent is a small molecule or an oligomeric compound. In certain embodiments, the agent moiety is a protein, a peptide, an antibody, an oligonucleotide, a small molecule, a polymer, or a combination thereof.

[0297] In some embodiments, multiple CB 1 The ligand is conjugated to the agent moiety. In some embodiments, at least two CB 1 Ligand (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more CB 1 Ligand) is conjugated to the agent moiety. In some embodiments, two CB1 The ligand is conjugated to the agent moiety. In some embodiments, three CB 1 The ligand is conjugated to the agent moiety. In some embodiments, four CB 1 The ligand is conjugated to the agent moiety. In some embodiments, five CB 1 The ligand is conjugated to the agent moiety. In some embodiments, more than five CB 1 The ligand is conjugated to the agent moiety. In some embodiments, at least one to about five CB 1 The ligand is conjugated to the agent moiety. In some embodiments, at least one to about four CB 1 The ligand is conjugated to the agent moiety. In some embodiments, at least one to about three CB 1 The ligand is conjugated to the agent moiety. In some embodiments, at least one to about two CB 1 The ligand is conjugated to the agent moiety.

[0298] The agent portion contains multiple CBs. 1 When conjugated to a ligand, CB 1 The ligands may all be conjugated to the same or nearby position on the agent moiety, or the CB 1 The ligand may be conjugated to a number of different positions on the agent moiety.

[0299] In some embodiments, the oligonucleotide is modified with a CB 1 In some embodiments, the oligonucleotide is conjugated (e.g., connected, bound, associated) to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand via the 3' end of the oligonucleotide.1 In some embodiments, the oligonucleotide is conjugated to a ligand via both the 5' and 3' ends of the oligonucleotide. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 It is conjugated to a ligand.

[0300] In some embodiments, the oligonucleotide comprises two or more CB 1 In some embodiments, the oligonucleotide is conjugated to at least two CB 1 Ligand (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more CB 1 In some embodiments, the oligonucleotide is conjugated to two CB 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 In some embodiments, the oligonucleotide is conjugated to a ligand. 1 It is conjugated to a ligand.

[0301] Multiple oligonucleotide CB 1 When conjugated to a ligand, CB 1 The ligands may all be conjugated to the same or nearby position on the oligonucleotide, or CB 1 The ligand may be conjugated to multiple different positions on the oligonucleotide. In some embodiments, multiple CB 1 Ligand (i.e., 2, 3, 4, 5, or more CB 1 Ligand) is conjugated to the 5' end of the oligonucleotide. In some embodiments, multiple CB 1 Ligand (i.e., 2, 3, 4, 5, or more CB 1 Ligand) is conjugated to the 3' end of the oligonucleotide. In some embodiments, multiple CB 1 Ligand (i.e., 2, 3, 4, 5, or more CB 1 Ligand) is conjugated at one or more internal positions of the oligonucleotide. In some embodiments, the oligonucleotide comprises one or more CB ligands at the 5' end of the oligonucleotide. 1 at the ligand and / or at the 3' end of the oligonucleotide 1 one or more CBs at the ligand and / or at an internal position or positions of the oligonucleotide 1 It is conjugated to a ligand.

[0302] Linker In certain embodiments, conjugates of the compound formula described herein are provided. In certain embodiments, the conjugate comprises a CB 1 In certain embodiments, the conjugates provided herein comprise one or more linker moieties. In certain embodiments, the one or more linker moieties are CB 1The ligand is linked to an agent moiety. In certain embodiments, the agent moiety is a protein, peptide, antibody, nucleic acid, small molecule, macromolecule, therapeutic agent, prophylactic agent, diagnostic agent, or imaging agent. In some embodiments, the compound is conjugated to an oligonucleotide. In certain embodiments, the CB 1 The ligand is conjugated to an oligonucleotide. In certain embodiments, the compound comprises one or more CB 1 Ligand, one or more linker moieties, and one or more agent moieties, wherein CB 1 The ligand is conjugated (eg, linked, connected, bound, associated) to one or more agent moieties via one or more linker moieties.

[0303] The conjugates disclosed herein can be prepared using any available method. 1 When associating the ligand and the oligonucleotide, the moieties can be linked directly or indirectly (e.g., via a linker moiety, i.e., the linker is a linker between the oligonucleotide and the CB 1 and in some formulas herein is "-Ln-", where n is a number (e.g., L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 )). For example, oligonucleotides and CB 1 The ligands may be attached to each other directly, for example, by one or more covalent bonds, or through one or more linkers. A "linker" is a linker that connects two components of the compounds provided herein (e.g., CB 1The term "linker" refers to any chemical moiety (e.g., a combination of atoms having appropriate valences according to known chemical principles) used to conjugate two or more compounds (e.g., a ligand and an oligonucleotide) to one another. Each of the two components can be connected to any portion of any of the linkers provided herein. In some embodiments, one component of the compounds provided herein (e.g., a CB 1 A linker (ligand or oligonucleotide) is connected by a bond to one end of the linker, and the other component is connected by a bond to the other end of the linker. In some embodiments, one or both components of the compounds provided herein can be connected by a bond to any internal position of the linker described herein. For example, in the context of an "alkyl linker," CB 1The ligand may be linked by a bond to a carbon at one end of the alkyl linker, and the oligonucleotide may be linked by a bond to a carbon at the other end of the alkyl linker. In some embodiments, the linker is a bond (including, for example, phosphodiester and phosphorothioate bonds). In some embodiments, the linker is an optionally substituted alkyl linker (i.e., two moieties are linked using an alkyl chain, and the two moieties may be conjugated to both ends of the alkyl linker, or one or both moieties may be conjugated to an internal carbon on the alkyl linker). In some embodiments, the linker is an optionally substituted polyethylene glycol (PEG) linker (i.e., two moieties are linked using a PEG chain, and the two moieties may be conjugated to both ends of the PEG linker, or one or both moieties may be conjugated to an internal position on the PEG linker). In some embodiments, the linker is an optionally substituted heteroalkyl linker (i.e., a heteroalkyl chain is used to link two moieties, each of which may be conjugated to both termini of the heteroalkyl linker, or one or both moieties may be conjugated to an internal position of the heteroalkyl linker). In some embodiments, the linker is an optionally substituted heteroaryl linker (i.e., a heteroaryl group is used to link two moieties, each of which may be conjugated at any position on the heteroaryl group).

[0304] In certain embodiments, the compounds provided herein include one or more linking groups. 1 , L 2 , L 3 , and L 4 Each of L includes a linking group. 1 , L 2 , L 3 , L 4 , and L 5Each of L includes a linking group. 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 Each of the groups comprises a linking group. In certain embodiments, the linking group is 1 In certain embodiments, the linking group is covalently attached to the ligand. In certain embodiments, the linking group is covalently attached to the oligonucleotide. In certain embodiments, the linking group is covalently attached to a cleavable moiety. In certain embodiments, the linking group comprises a cleavable bond. In certain embodiments, the linking group does not comprise a cleavable moiety. In certain embodiments, the linking group comprises a covalent bond to a solid support. In certain embodiments, the linking group is a CB 1 It contains multiple sites for the attachment of ligands.

[0305] In certain embodiments, the linking group comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeat units or combinations of such repeat units. In certain embodiments, the linking group comprises 1-50 repeat units, 1-40 repeat units, 1-25 repeat units, 1-20 repeat units, 1-15 repeat units, 1-10 repeat units, or 1-5 repeat units. In certain embodiments, the linking group is 1-50 atoms long, 1-40 atoms long, 1-25 atoms long, 1-20 atoms long, 1-15 atoms long, 1-10 atoms long, or 1-5 atoms long.

[0306] In certain embodiments, the linking group contains a carbon atom. In certain embodiments, the linking group contains a heteroatom (e.g., nitrogen, oxygen, sulfur, etc.). In certain embodiments, the linking group forms an amide linkage, an ester linkage, or a disulfide linkage. In certain embodiments, the linking group forms a hydrazone linkage, an oxime linkage, an imine linkage, a guanidine linkage, a urea linkage, a carbamate linkage, an unsaturated alkyl linkage, a sulfonamide linkage, or a 4-8 membered heterocyclic linkage. In certain embodiments, the linking group comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain embodiments, the linking group comprises at least one phosphorus group. In certain embodiments, the linking group comprises at least one phosphate group. In certain embodiments, the linking group comprises at least one neutral linking group. In certain embodiments, the linking group is substituted with a variety of substituents including, but not limited to, hydrogen atoms, alkyl, alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, hydroxyl, alkoxy, halogen, aryl, heterocycle, aromatic heterocycle, cyano, amido, carbamoyl, carboxylic acid, ester, thioether, alkylthioether, thiol, and ureido groups, each of which may in turn be substituted, as will be appreciated by those skilled in the art.

[0307] 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, with a non-limiting list of preferred substituents including hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the linking group is aliphatic or heteroaliphatic. For example, the linking group can be a polyalkyl linking group. The linking group can be a polyether linking group. The linking group can be a polyethylene linking group, such as PEG.

[0308] In certain embodiments, the linking group is a short peptide chain, hi certain embodiments, the linking group comprises 1 to 40 amino acids, 1 to 25 amino acids, 1 to 20 amino acids, 1 to 15 amino acids, 1 to 10 amino acids, or 1 to 5 amino acids.

[0309] In certain embodiments, the linking group comprises a linker nucleoside. In certain embodiments, the linking group comprises 1-40 linker nucleosides, 1-25 linker nucleosides, 1-20 linker nucleosides, 1-15 linker nucleosides, 1-10 linker nucleosides, or 1-5 linker nucleosides. In certain embodiments, such linker nucleosides can be modified or unmodified nucleosides. Typically, it is desirable for the linker nucleoside to be cleaved from the compound after reaching the target tissue. Thus, the linker nucleosides herein can be linked to each other or to the remainder of the compound via a cleavable bond. As used herein, the linker-nucleoside is not considered to be part of the oligonucleotide payload. Thus, compounds include oligonucleotides containing a particular number or range of linked nucleosides and / or a particular percent complementarity to a reference nucleic acid, and compounds include CB oligonucleotides containing linker-nucleoside-containing linking groups. 1In embodiments that include ligands, those linker-nucleosides are not counted in the length of the oligonucleotide, nor are they used in determining the percent complementarity of the oligonucleotide to a reference nucleic acid.

[0310] In certain embodiments, the linking group comprises a protein-binding group. In certain embodiments, the protein-binding group is a lipid, such as, but not limited to, cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholene. acid, dimethoxytrityl, or phenoxazine), vitamins (e.g., folate, vitamin A, vitamin E, biotin, pyridoxal), peptides, carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides), endosomolytic components, steroids (e.g., uvaol, hesigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, friedelin, epifriedelanol-derivatized lithocholic acid), or cationic lipids. 16 ~C 22 long chain saturated or unsaturated fatty acids, cholesterol, cholic acid, vitamin E, adamantane or 1-pentafluoropropyl.

[0311] In certain embodiments, linking groups include, but are not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHE or AHA).

[0312] It's a nice selection of snowflakes It has a current assets:US5,994,517;US 6,300,319;US6,660,720;US6,906,182;US7,262,177;US7,491 ,805;US8,106,022;US7,723,509;US9,127,276;US2006 / 0148740;US2011 / 0123520;WO2013 / 033230;WO2012 / 037254、Biessen et al.,J.Med.Chem.1995,38,1846-1852;Lee et al.,Bioorganic & Medicinal Chemistry 2011,19,2494-2500;Rensen et al.,J.Biol.Chem.2001,276,37577-37584; al.,J.Med.Chem.2004,47,5798-5808;Sliedregt et al.,J.Med.Chem.1999,42,609-618;Valentijn et al.,Tetrahedron,1997,53,759-770;Lee,Carhohydr Res,1978,67,509-514;Connolly et al,J Biol Chem,1982,257,939-945;Pavia et al,Int J Pep Protein Res,1983,22,539-548;Lee et al,Biochem,1984,23,4255-4261;Lee et al al.,Glycoconjugate J,1987,4,317-328;Toyokuni et al.,Tetrahedron Light,1990,31,2673-2676;Biessen et al.,J Med Chem,1995,38,1538-1546;Valentijn et al al.,Tetrahedron,1997,53,759-770;Kim et al.,Tetrahedron Light,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;Leeorg et al. 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,Bioorg et al. Chem,2011,19,2494-2500;Kornilova et al.,Analyt Biochem,2012,425,43-46;Pujol et al.,Angew Chemie Int Ed Engl,2012,51,7445-7448;Jed Messen et al., 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.,Arterioscler6 Biol-67208; Rossenberg et al.,Gene Ther,2004,11,457-464;Sato et al.,JAm Chem Soc,2004,126,14013-14022;Lee et al.,J Org Chem,2012,77,7564-7571 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,91;20 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;W02008 / 098788;W02004 / 101619;WO2012 / 037254;WO2011 / 120053;WO2011 / 100131;WO2011 / 163121;WO2012 / 177947;W02013 / 033230;W02013 / 075035;WO2012 / 083185;WO2012 / 08 3046;W02009 / 082607;WO2009 / 134487;W02010 / 144740;W02010 / 148013;WO1997 / 020563;W02010 / 088537;W02002 / 043771;W02010 WO2012 / 089352;WO2012 / 089602;WO2013 / 166121;WO20 13 / 165816;US Patents4,751,219;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;8,50 1,930;8,158,601;7,262,177;6,906,182;6,620,916;8,435,491;8,404,862;7,851,615;US Patent Application Publications US2011 / 0097264;US2011 / 0097265;US2013 / 0004427;US2003 / 0119724;US2011 / 0207799;US2012 / 0035115;US2012 / 0230938;US2005 / 0164235;US2006 / 0183886;US2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132, each of which is incorporated herein by reference in its entirety.

[0313] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka] wherein each n is independently 1 to 20, and p is 1 to 6.

[0314] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7) comprise, independently or together, structures selected from the following: [ka] (wherein each n is independently 1 to 20).

[0315] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka] (wherein each n is independently 1 to 20).

[0316] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka] (wherein each n is independently 1 to 20).

[0317] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka] wherein each L is independently a phosphorus linking group and each n is independently 1 to 20.

[0318] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka] [ka]

[0319] In certain embodiments, L 1 , L 2, L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka]

[0320] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka]

[0321] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4, L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka] (In the formula, n is 1 to 20).

[0322] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka]

[0323] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka]

[0324] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka]

[0325] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently contain or together have the following structures: [ka]

[0326] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) independently contain or together have the following structures: [ka]

[0327] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka]

[0328] In certain embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) comprise, independently or together, structures selected from the following: [ka] wherein each n is independently 0, 1, 2, 3, 4, 5, 6, or 7.

[0329] In some embodiments, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) 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, L 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L 5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) may independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). 1 , L 2 , L 3 , and L 4 (or L 1 , L 2 , L 3 , L 4 , and L5 , or L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 ) may independently be absent.

[0330] In some embodiments, L 1 is a bond.

[0331] In some embodiments, L 2 is an optionally substituted PEG linker. In some embodiments, the PEG linker is 3 or 4 PEG units in length. In certain embodiments, L 2 The structure [ka] In some embodiments, the PEG linker is 2 or 3 PEG units in length.

[0332] In some embodiments, L 3 is an optionally substituted heteroaryl linker. In some embodiments, L 3 is an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, L 3 The structure [ka] Includes.

[0333] In some embodiments, L 4 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L 4 The structure [ka] wherein X is O or S.

[0334] In some embodiments, L 1 , L 2 , L 3 , and L 4 Together, the structure [ka] wherein X is O or S.

[0335] In some embodiments, L 3 and L 4 One of the bonds is a phosphodiester or phosphorothioate bond, and the other is a 3 and L 4 The other of L is a bond. 1 , L 2 , L 3 , and L 4 Together, the structure [ka] wherein X is O or S.

[0336] In certain embodiments, L 1 , L 2 , L 3 , and L 4 Together, the structure [ka] wherein X is O or S.

[0337] In some embodiments, L 1 , L 2 , L 3 , L 4 , and L 5Any of L may 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, L 1 , L 2 , L 3 , L 4 , and L 5 Any of L may independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). 1 , L 2 , L 3 , L 4 , and L 5 Any of the may be independently absent.

[0338] In some embodiments, L 1 and L 5 are each optionally substituted PEG linkers. In some embodiments, L 1 and L 5 are each optionally substituted PEG linkers 3 PEG units in length.

[0339] In some embodiments, L 2 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L 2 The structure [ka] Includes.

[0340] In some embodiments, L 3 is an optionally substituted heteroaryl linker. In some embodiments, L 3is an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, L 3 The structure [ka] Includes.

[0341] In some embodiments, L 4 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =O substituents. In certain embodiments, L 4 The structure [ka] wherein X is O or S.

[0342] In some embodiments, L 1 , L 2 , L 3 , L 4 , and L 5 Together, the structure [ka] wherein X is O or S.

[0343] In some embodiments, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 Any of L may 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, L 1 , L 2 , L 3 , L 4 , L 5, L 6 , and L 7 Any of L may independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 Any of the may be independently absent.

[0344] In some embodiments, L 1 is an optionally substituted PEG linker. In certain embodiments, L 1 is an optionally substituted PEG linker of 2 or 3 PEG units in length.

[0345] In some embodiments, L 2 and L 5 are each independently an optionally substituted PEG linker. In some embodiments, L 2 and L 5 are each independently an optionally substituted PEG linker of 3 or 4 PEG units in length. In certain embodiments, L 1 , L 2 , and L 5 Together, the structure [ka] Includes.

[0346] In some embodiments, L 3 and L 6 are each independently an optionally substituted heteroaryl linker. In some embodiments, L 3 and L 6 are each independently an optionally substituted partially unsaturated heteroaryl linker. In certain embodiments, L 3 and L 6are the structures, [ka] Includes.

[0347] In some embodiments, L 4 and L 7 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, L 4 and L 7 are the structures, [ka] wherein X is O or S.

[0348] In some embodiments, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 Together, the structure [ka] wherein X is O or S.

[0349] How to make the compound In some embodiments, the present disclosure provides a method for the preparation of a CB 1 The present invention relates to methods of making compounds and compositions that include the ligands.

[0350] The compounds of the present disclosure can be made by means known in the art of organic synthesis. Methods for optimizing reaction conditions and, if necessary, minimizing competing by-products are known in the art. High-speed parallel synthesizers and computer-controlled microreactors can be advantageously utilized for reaction optimization and scale-up (see, for example, Design and Optimization in Organic Synthesis, 2001). nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jaehnisch, K et al., Angew. Chem. Int. Ed. Engl. 2004 43:406; and references therein. Additional reaction schemes and protocols can be determined by one of skill in the art by use of publicly available structure search database software, such as SciFinder® (CAS division of the American Chemical Society) and Reaxys® (Elsevier), or by appropriate keyword searches using Internet search engines such as Google® or keyword databases such as the U.S. Patent and Trademark Office text database.

[0351] As can be appreciated by those skilled in the art, methods for synthesizing compounds of the formulae herein, including the schemes and examples herein, will be apparent to those skilled in the art. Furthermore, various synthetic steps may be performed in an alternative order or sequence to obtain the desired compounds. In addition, solvents, temperatures, reaction times, etc. defined herein are for illustrative purposes only, and those skilled in the art will recognize that reaction conditions can be varied to obtain the desired compounds of the present disclosure.

[0352] The compounds herein may also contain linkages (e.g., carbon-carbon bonds), and bond rotation is limited to that particular linkage, e.g., restrictions due to 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, and in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even if only a single tautomeric form is represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. All crystal forms and polymorphs of the compounds described herein are also expressly included in the present disclosure. Extracts and fractions containing the compounds of the present disclosure are also included in the embodiments. The term "isomer" is intended to include diastereoisomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. In the case of compounds containing one or more stereocenters, e.g., chiral compounds, the methods of the disclosure may be practiced with enantiomerically enriched compounds, racemates, or mixtures of diastereomers. All isomers of the compounds defined herein are expressly included in the disclosure.

[0353] Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or greater. More preferably, the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, 99% or greater. In a preferred embodiment, only one enantiomer or diastereomer of the chiral compounds of the present disclosure is administered to a cell or subject.

[0354] Treatment method In one aspect, a method of treating a subject suffering from or susceptible to a disorder or disease is provided, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.

[0355] In another aspect, there is provided a method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of modulation of protein function, comprising administering to said subject in need thereof an effective amount of a compound or pharmaceutical composition described herein, such that said disorder in said subject is treated.

[0356] In one aspect, a method for delivering therapeutic oligonucleotide to the brain of a subject is provided, comprising contacting the subject with the compound or pharmaceutical composition described herein in an amount and under conditions sufficient to target the brain.In some embodiments, the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal lobe, and spinal cord.

[0357] In certain embodiments, a method for treating a disease, disorder, or a symptom thereof is provided, wherein the disease is a central nervous system (CNS) disease, disorder, or a symptom thereof. In some embodiments, the disease is a neurodegenerative disease, disorder, or a symptom thereof. In some embodiments, the disease is Alzheimer's disease, or a symptom thereof.

[0358] Exemplary CNS disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep conditions, movement disorders, nausea and / or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and drug addiction.

[0359] In certain embodiments, the CNS disorder is the result of, for example, neurotoxicity and / or neurotrauma, such as acute neuronal injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or chronic neurodegenerative disorders (e.g., multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease). In certain embodiments, the compounds of the present disclosure provide a neuroprotective effect, for example, against acute neuronal injury or chronic neurodegenerative disorders.

[0360] In certain embodiments, the CNS disorder is stroke (eg, ischemic stroke).

[0361] In certain embodiments, the CNS disorder is multiple sclerosis.

[0362] In certain embodiments, the CNS disorder is a spinal cord injury.

[0363] In certain embodiments, the CNS disorder is epilepsy.

[0364] In certain embodiments, the CNS disorder is, for example, a psychiatric disorder, such as depression, anxiety or an anxiety-related condition, a learning disability, a somatic symptom disorder, schizophrenia, or schizoaffective disorder.

[0365] In certain embodiments, the CNS disorder is depression. "Depression" includes, but is not limited to, depressive disorders or conditions, such as major depressive disorder (e.g., unipolar depression), treatment-resistant depression, dysthymic disorder (e.g., chronic mild depression), bipolar disorder (e.g., manic depression), seasonal affective disorder, and / or depression associated with substance abuse or substance abuse disorder (e.g., withdrawal). Depression can be clinical depression or subclinical depression. Depression can be associated with premenstrual syndrome and / or premenstrual dysphoric disorder.

[0366] In certain embodiments, the CNS disorder is anxiety. "Anxiety" includes, but is not limited to, anxiety and anxiety-related conditions, such as clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder (GAD), specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorder with anxiety features, anxiety disorder associated with depression, anxiety disorder associated with general medical conditions, and substance-induced anxiety disorder, anxiety associated with substance abuse or substance use disorder (e.g., withdrawal, dependence, relapse) and anxiety associated with nausea and / or vomiting.The treatment may be to induce or promote sleep in a subject (e.g., an anxious subject).

[0367] In certain embodiments, the CNS disorder is a learning disorder (eg, Attention Deficit Disorder (ADD)).

[0368] In certain embodiments, the CNS disorder is schizophrenia or schizoaffective disorder.

[0369] In certain embodiments, the CNS disorder is sleep condition. "Sleep condition" includes, but is not limited to, insomnia, narcolepsy, sleep apnea, restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eye movement disorder (RBD), shift work sleep disorder (SWSD), and sleep problems (e.g., parasomnia), such as nightmares, night terrors, sleep talking, head-knocking, snoring, and jaw clenching and / or teeth grinding (bruxism).

[0370] In certain embodiments, the CNS disorder is a movement disorder, such as a basal ganglia disorder, such as Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de la Tourette syndrome, tardive dyskinesia, and dystonia.

[0371] In certain embodiments, the CNS disorder is Alzheimer's disease.

[0372] In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).

[0373] In certain embodiments, the CNS disorder is nausea and / or vomiting.

[0374] In certain embodiments, the CNS disorder is a drug addiction (eg, an addiction to opiates, nicotine, cocaine, psychostimulants, or alcohol).

[0375] The term "nervous system disease" (including, for example, "neurodegenerative disease") refers to any disease of the nervous system, including diseases involving the central nervous system (brain, brain stem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (portions located in both the central and peripheral nervous systems). Neurodegenerative disease refers to a class of nervous system diseases characterized by loss of nerve cells, including, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington's disease. Examples of nervous system diseases include, but are not limited to, headaches, impaired consciousness and coma, dementia, seizures, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of the peripheral nerves, muscles, and neuromuscular junctions. Substance abuse or substance use disorders (SUDs) and psychiatric disorders, including, but not limited to, bipolar disorder, schizophrenia, and schizoaffective disorder, are also included in the definition of nervous system diseases. Further examples of neurological disorders include acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, hemangiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformations, Asperger's syndrome, ataxia-telangiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Batten disease, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal, muscular atrophy, benign intracranial hypertension, Binswanger's disease, blepharospasm, Bloch-Saltuber syndrome. ger syndrome;brachial plexus injury;brain abscess;brain injury;brain tumor (including glioblastoma multiforme);spinal tumor;Brown-Séquard syndrome;Cavan disease;carpal tunnel syndrome (CTS);causalgia;central pain syndrome;central pontine myelinolysis;head injury;cerebral aneurysm;cerebral arteriosclerosis;cerebral atrophy;cerebral gigantism;cerebral palsy;Charcot-Marie-Tooth disease;chemotherapy-induced neuropathy and neuropathic pain;Chiari malformation;chorea;chronic inflammatory demyelinating polyneuropathy (CIDP);chronic pain;chronic regional pain syndrome;Coffin-Lowry syndrome;coma including persistent vegetative state;congenital bilateral facial palsy;corticobasal degeneration;cranial arteritis;craniosynostosis;Creutzfeldt-Jakob disease;accumulated trauma disorder;Cushing's syndrome;Cytomegalic inclusion disease (CIBD);Cytomegalovirus infection;Dancing eyes-dancing feet syndrome;Dandy-Walker syndrome;Dawson's disease;De Morcher syndrome;Degelin-Klumpke palsy;Dementia;Dermatomyositis;Diabetic neuropathy;Diffuse sclerosis;Autonomic neuropathy;Dysgraphia;Dyslexia;Dystonia;Early infantile epileptic encephalopathy;Empty cavity sella syndrome;Encephalitis;Encephalocele;Cerebral trigeminal angiomatosis;Epilepsy;Erb palsy;Essential tremor;Fabry disease;Fahr's syndrome;Syncope;Familial spastic paralysis;Febrile convulsions;Fisher syndrome; Friedreich's ataxia;Frontotemporal dementia and other "tauopathies";Gaucher's disease;Gerstmann's syndrome;Giant cell arteritis;Giant cell inclusion disease;Globoid cell leukodystrophy;Guillain-Barré syndrome;HTLV-1-associated myelopathy;Hallervorden-Spatz disease;Head trauma;Hemifacial spasms;Hereditary spastic paraplegia;Hereditary polyneuropathic ataxia;Herpes zoster oticus;Hirayama syndrome;HIV-associated dementia and neuropathy (see also Neurological symptoms of AIDS);Holoprosencephaly;Huntington's disease and other polyglutamine repeat disorders;Hydrocephalic anencephaly;Hydrocephalus;Hypertrophic neuropathy Cortisolism;Hypoxia;Immune-mediated encephalomyelitis;Inclusion body myositis;Incontinentia pigmenti;Infant;Phytanic acid storage disease;Infantile Refsum disease;Infantile spasms;Inflammatory myopathy;Intracranial cyst;Intracranial hypertension;Joubert syndrome;Kerns-Sayre syndrome;Kennedy disease;Kinsborn syndrome;Klippel-Feil syndrome;Krabbe disease;Kugelberg-Welander disease;Kuru;Lafora disease;Lambert-Eaton myasthenic syndrome;Landau-Kleffner syndrome;Lateral medullary (Wallenberg) syndrome;Learning disabilities;Leigh disease;Lennox-Gastaut syndrome;Lesch-Nyhan syndrome syndrome;leukodystrophy;dementia with Lewy bodies;lissencephaly;locked-in syndrome;Lou Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis);lumbar discopathy;Lyme disease - neurological sequelae;Machado-Joseph disease;megalencephaly;megalencephaly;Melkersson-Rosenthal syndrome;Ménière's disease;meningitis;Menkes disease;metachromatic leukodystrophy;microcephaly;migraine;Miller-Fisher syndrome;ministroke;mitochondrial myopathy;Moebius syndrome;unilateral muscular atrophy;motor neuron disease;moyamoya disease;mucopolysaccharidosis;multi-infarct dementia;Multifocal motor neuropathy;Multiple sclerosis and other demyelinating disorders;Multiple system atrophy with postural hypotension;Muscular dystrophies;Myasthenia gravis;Diffuse myelinating sclerosis;Infantile myoclonic encephalopathy;Myoclonus;Myopathy;Myotonia congenita;Narcolepsy;Neurofibromatosis;Neuroleptic malignant syndrome;Neurological manifestations of AIDS;Neurological sequelae of lupus;Neuromyotonia;Intraneuronal ceroid lipofuscinosis;Neuronal migration disorder;Niemann-Pick disease;O'Sullivan-McLeod syndrome;Occipital neuralgia;Secondary to subclinical spinal dysraphism;Ohtahara syndrome;Olivopontine small infarction Brain atrophy;Opsoclonus-myoclonus;Optic neuritis;Orthostatic hypotension;Overuse syndrome;Paresthesia;Parkinson's disease;Congenital paramyotonia;Paraneoplastic disorders;Ictal seizures;Parry-Romberg syndrome;Pelizaeus-Merzbacher disease;Periodic paralysis;Peripheral neuropathy;Painful neuropathy and neuropathic pain;Persistent vegetative state;Pervasive developmental disorder;Photic sneeze reflex;Phytanic acid storage disease;Pick's disease;Radiculopathy;Pituitary tumors;Polymyositis;Porencephaly;Post-polio syndrome;Postherpetic neuralgia (PHN);Postinfectious encephalomyelitis;Postorthostatic hypotension;Prader-Willi syndrome; Primary lateral sclerosis;Prion disease;Progressive;Hemifacial atrophy;Progressive multifocal leukoencephalopathy;Progressive sclerosing poliodystrophy;Progressive supranuclear palsy;Pseudotumor cerebri;Ramsay Hunt syndrome (types I and II);Rasmussen encephalitis;Reflex sympathetic dystrophy syndrome;Refsum disease;Repetitive movement disorder;Repetitive stress injury;Restless legs syndrome;Retroviral-associated myelopathy;Rett syndrome;Reye syndrome;St. Vitus' dance;Sandhoff disease;Schilder's disease;Schisencephaly;Septo-optic dysplasia;Shaken baby syndrome;Herpes zoster;Shy-Drager syndrome;She -Glenn syndrome;sleep apnea;Sotos syndrome;spasticity;spina bifida;spinal cord injury;spinal tumor;spinal muscular atrophy;stiff-person syndrome;stroke;Sturge-Weber syndrome;subacute sclerosing panencephalitis;subarachnoid hemorrhage;subcortical arteriosclerotic encephalopathy;Sydenham chorea;syncope;syringomyelia;tardive dyskinesia;Tay-Sachs disease;temporal arteritis;tethered spinal cord syndrome;Thomsen's disease;thoracic outlet syndrome;painful tics;Todd's palsy;Tourette's syndrome;transient ischemic attack;transmitting spongiform encephalopathy;transverse myelitis;traumatic brain injury;tremor;trigeminal neuralgia;tropical spastic paraplegia;tuberous sclerosis;Vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; von Hippel-Lindau disease (VHL); Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; whiplash injury; Williams syndrome; Wilson's disease; and Zellweger syndrome.

[0376] In certain embodiments, the subject is a mammal, preferably a primate or a human.

[0377] In another embodiment, the aforementioned method is provided, wherein the effective amount of the compound provided herein is as described above.

[0378] In another embodiment, the above method is provided, wherein the compound provided herein is administered intrathecally, intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally, or topically. In certain embodiments, the compound is administered intrathecally.

[0379] In other embodiments, the above methods are provided, wherein a compound of any of the formulae provided herein is administered alone or in combination with one or more other therapeutic agents. In further embodiments, the additional therapeutic agent is a central nervous system (CNS) disease agent.

[0380] Another object of the present disclosure is the use of the compounds described herein in the manufacture of a medicament for use in treating a disorder or disease.Another object of the present disclosure is the use of the compounds described herein for use in treating a disorder or disease.

[0381] Pharmaceutical Compositions In one aspect, a pharmaceutical composition is provided that includes any of the compounds described herein and a pharma- ceutically acceptable carrier or a pharma- ceutically acceptable excipient.

[0382] The compounds or compositions described herein can be administered in combination with one or more additional therapeutic agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional therapeutic agents that improve their activity (e.g., activity (e.g., efficacy and / or effectiveness) in treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, and / or reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell. It will also be understood that the therapeutic approaches employed may achieve desired effects on the same disorder and / or may achieve different effects. In certain embodiments, the pharmaceutical compositions described herein that include the compounds described herein and additional therapeutic agents exhibit synergistic effects that are not present in pharmaceutical compositions that include either the compounds described herein or the additional therapeutic agents but not both.

[0383] The compound or composition may be administered simultaneously with, prior to, or after one or more additional therapeutic agents that may be useful, for example, as a combination therapy. Therapeutic agents include therapeutically active agents. Therapeutic agents also include prophylactically active agents. Therapeutic agents include drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration under the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules such as cells. In certain embodiments, the additional therapeutic agent is a therapeutic agent useful for treating and / or preventing a disease (e.g., a CNS disorder). Each additional therapeutic agent may be administered at a dose and / or time schedule determined for that therapeutic agent. The additional therapeutic agents may also be administered in a single dose or separately in different doses, together with each other and / or with the compounds or compositions described herein. The particular combination employed in the regimen will take into consideration the compatibility of the compounds described herein with the additional therapeutic agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional therapeutic agent(s) of the combination will be utilized at levels that do not exceed the levels utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0384] In one aspect, a kit is provided that includes an effective amount of a compound provided herein in a unit dosage form together with instructions for administering the compound to a subject suffering from or susceptible to a disease or disorder.

[0385] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is meant to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents present in the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired acid, either neat or in a suitable inert solvent. Examples of pharma-ceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid or galactunolonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functional groups, which allows the compounds to be converted into either base or acid addition salts. Other pharma- ceutically acceptable carriers known to those of ordinary skill in the art are also suitable for the present disclosure.

[0386] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for the purposes of this disclosure.

[0387] In addition to salt forms, the present disclosure provides compounds that are in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0388] Certain compounds of the present disclosure may exist not only in unsolvated form but also in solvated form, including hydrated form.In general, solvated form is equivalent to unsolvated form and is intended to be included within the scope of the present disclosure.Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0389] The present disclosure also provides pharmaceutical compositions comprising an effective amount of the compound described herein and pharmaceutical acceptable excipient.In one embodiment, the compound of any of the formulas provided herein is administered to subject using a pharmaceutical acceptable formulation, for example, a pharmaceutical acceptable formulation that provides sustained delivery of compound to subject for at least 12 hours, 24 hours, 36 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks or 4 weeks after the pharmaceutical acceptable formulation is administered to subject.

[0390] Actual dosage levels and times of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, while being acceptably tolerated by the subject.

[0391] In use, at least one compound according to the present disclosure is administered in a pharmaceutical carrier in a pharma- ceutical effective amount by intravenous, intrathecal, intramuscular, subcutaneous, or intracerebroventricular injection, or by oral administration or topical application to a subject in need thereof. According to the present disclosure, the compounds of the present disclosure may be administered alone or in combination with a second, different therapeutic agent. By "in combination" is meant together, substantially simultaneously, or sequentially. In one embodiment, the compounds of the present disclosure are administered acutely. Thus, the compounds of the present disclosure may be administered for a short treatment period, such as from about one day to about one week. In another embodiment, the compounds of the present disclosure may be administered for a long period of time, such as from about one week to several months, to improve chronic disorders.

[0392] "Pharmaceutically effective amount" as used herein means an amount of the compound of the present disclosure that is high enough to significantly positively modify the condition being treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio), within the scope of sound medical judgment. The pharmaceutically effective amount of the compound of the present disclosure may vary depending on the specific goal to be achieved, the age and physical condition of the patient being treated, the severity of the underlying disease, the duration of treatment, the nature of concurrent treatment, and the specific compound employed. For example, the therapeutically effective amount of the compound of the present disclosure administered to a child or a newborn will be proportionally reduced, in accordance with sound medical judgment. Thus, the effective amount of the compound of the present disclosure will be the minimum amount that provides the desired effect.

[0393] The crucial practical advantage of the present disclosure is that the compound can be administered in a simple manner, for example, by intrathecal, intravenous, intramuscular, subcutaneous, oral, or intracerebroventricular injection route, or by local application, such as cream or gel.Depending on the administration route, the active ingredient contained in the compound of the present disclosure may need to be coated with a material to protect the compound from the action of enzymes, acids, and other natural conditions that may inactivate the compound.In order to administer the compound of the present disclosure in other ways than parenteral administration, the compound may be coated with or administered using a material to prevent inactivation.

[0394] The compounds may be administered parenterally or intraperitoneally.Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.

[0395] Some examples of substances that can function as pharmaceutical excipients or pharmaceutical carriers (these terms are used interchangeably herein) are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and phosphate buffer; nonfat powdered milk; as well as other non-toxic compatible substances used in pharmaceutical formulations, such as vitamin C, estrogen, and echinacea. Wetting agents and lubricants such as sodium lauryl sulfate may also be present, as well as colorants, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives. Solubilizing agents including, for example, cremaphor and beta-cyclodextrin may also be used in the pharmaceutical compositions herein.

[0396] The pharmaceutical composition comprising the active compound (or its derivative or prodrug) of the present disclosure can be prepared by conventional mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing processes. The composition can be formulated in a convenient manner using one or more physiologically acceptable carriers, diluents, excipients, or auxiliary agents that facilitate the processing of the active compound into a preparation that can be used pharmaceutically. The composition herein can be prepared by mixing (e.g., contacting, mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing) the compound defined herein with one or more suitable carriers, diluents, excipients, or auxiliary agents, including those described herein (e.g., for pharmaceutical, agricultural, or veterinary use).

[0397] The pharmaceutical compositions of the present disclosure may be in a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ophthalmic, oral, buccal, systemic, nasal, injectable, transdermal, rectal, vaginal, and the like, or in a form suitable for administration by inhalation or insufflation.

[0398] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0399] Useful injection preparations include sterile suspensions, solutions, or emulsions of active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. Injection preparations may be provided in unit dosage form (e.g., in ampoules or multi-dose containers) and may contain added preservatives.

[0400] Alternatively, the injectable formulations can be provided in powder form to be reconstituted before use with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc. To this end, the active compound(s) can be dried by any known technique, such as lyophilization, and reconstituted prior to use.

[0401] For long-term delivery, the active compound(s) or prodrug(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0402] Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver active compound(s), oligonucleotide(s), or prodrug(s). Certain organic solvents, such as dimethylsulfoxide (DMSO), can also be utilized.

[0403] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0404] The active compound(s) or prodrug(s) of the present disclosure, or compositions thereof, are generally used in an amount effective to achieve the intended result, for example, an amount effective for treating or preventing the particular disease being treated. The compound(s) and oligonucleotide(s) can be administered therapeutically to achieve a therapeutic benefit, or prophylactically to achieve a prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying disorder being treated and / or eradication or amelioration of one or more of the symptoms associated with the underlying disorder, such that the patient reports an improvement in mood or condition, even if the patient is still suffering from the underlying disorder. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether the improvement is realized.

[0405] In the case of prophylactic administration, the compound can be administered to a patient at risk of developing any 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 risk patient group defined by an appropriate medical professional or organization. A risk patient can also be a patient who is usually or regularly in an environment where the development of an underlying disease may occur. In other words, a risk patient is one who is usually or regularly exposed to a disease or disease-causing condition or who may have been acutely exposed for a limited time. Alternatively, prophylactic administration can be performed to avoid the development of symptoms in a patient diagnosed with an underlying disorder.

[0406] 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 capabilities of one of ordinary skill in the art.

[0407] Effective doses can be estimated initially from in vitro assays. For example, initial doses for use in animals may be greater than or equal to the IC50 of a particular compound as measured by in vitro assays such as the in vitro fungal MIC or MFC, and other in vitro assays. 50 The active compound can be formulated to achieve a circulating or serum concentration of at least 100 mg / kg of active compound. Calculation of the dosage to achieve such a circulating or serum concentration, taking into account the bioavailability of a particular compound, is well within the capabilities of a person skilled in the art. For guidance, see "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp.1-112, 13th ed., McGraw-Hill and references therein, which are incorporated herein by reference.

[0408] Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds for treating or preventing the various diseases mentioned above are well known in the art.

[0409] Dosages can typically range from about 0.0001 mg or 0.001 mg or 0.01 mg / kg / day to about 100 mg / kg / day, but can be increased or decreased depending on, among other factors, the activity of the compound, its bioavailability, the mode of administration, and the various factors mentioned above. Dosages and administration intervals can be individually adjusted to provide plasma levels of the compound(s) sufficient to maintain therapeutic or prophylactic effects. In the case of local administration or selective uptake, e.g., local topical administration, the effective local concentration of the active compound(s) may not be related to the plasma concentration. Those skilled in the art will be able to optimize the effective local dosage without undue experimentation.

[0410] Preferably, the compound(s) provide therapeutic or prophylactic benefit and have acceptable tolerability. The tolerability of the compound(s) and oligonucleotide(s) can be determined using standard pharmaceutical procedures. The dose ratio between intolerable effects and therapeutic effect (or prophylactic effect) is the therapeutic index. Compound(s) that exhibit a high therapeutic index are preferred.

[0411] Additional Embodiments Certain specific embodiments include the following embodiments P1 to P114.

[0412] Embodiment P1. A compound comprising the structure of Formula (I), or a salt thereof: [ka] (In the formula, [ka] The cannabinoid type 1 receptor (CB 1 ) ligand, L1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

[0413] Embodiment P2. The CB 1 The ligand is CB 1 The compound according to embodiment P1, or a salt thereof, which is an agonist.

[0414] Embodiment P3. The CB 1 The ligand is CB 1 The compound according to embodiment P1, or a salt thereof, which is an antagonist.

[0415] Embodiment P4. The CB 1 The ligands were minocycline, dronabinol, epigallocatechin, epicatechin, kavain, yangonin, oleamide, N-arachidonoyldopamine, cannabinol, HU-210, 11-hydroxy-THC, levonantradol, 2-arachidonyl glyceryl ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP 55,940, JWH-018, and WIN. 55,212-2, GAT228, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodamine, 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-CB 1 The compound according to embodiment P1, which is selected from the group consisting of antibodies, and derivatives thereof, or a salt thereof.

[0416] Embodiment P5. The CB 1The ligand has the structure [ka] or a derivative thereof, or a salt thereof.

[0417] Embodiment P6. The compound has the structure of Formula (II): [ka] or a salt thereof. A compound according to embodiment P1, comprising:

[0418] Embodiment P7. The compound has the structure of Formula (II-a): [ka] or a salt thereof. A compound according to embodiment P6, comprising:

[0419] Embodiment P8.L 1 , L 2 , L 3 , and L 4 The compound of any one of embodiments P1-P7, wherein each of is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, a phosphodiester linkage, or a phosphorothioate linkage, or a salt thereof.

[0420] Embodiment P9.L 1 The compound according to embodiment P8, wherein is a bond, or a salt thereof.

[0421] Embodiment P10.L 2 The compound according to embodiment P8 or P9, wherein is an optionally substituted PEG linker, or a salt thereof.

[0422] Embodiment P11. The compound according to embodiment P10, or a salt thereof, wherein said PEG linker is 3 or 4 PEG units in length.

[0423] Embodiment P12.L 2 But the structure [ka] The compound according to any one of embodiments P8 to P11, or a salt thereof, comprising:

[0424] Embodiment P13.L 3 A compound according to any one of embodiments P8 to P12, wherein is an optionally substituted heteroaryl linker, or a salt thereof.

[0425] Embodiment P14.L 3 A compound according to embodiment P13, wherein is an optionally substituted partially unsaturated heteroaryl linker, or a salt thereof.

[0426] Embodiment P15.L 3 But the structure [ka] The compound according to embodiment P13 or P14, comprising:

[0427] Embodiment P16.L 4 A compound according to any one of embodiments P8 to P15, wherein is an optionally substituted heteroalkyl linker, or a salt thereof.

[0428] Embodiment P17. A compound according to embodiment P16, or a salt thereof, wherein said heteroalkyl linker is substituted with one or more =O substituents.

[0429] Embodiment P18.L 4 But the structure [ka] Including, A compound according to embodiment P16 or P17, wherein X is O or S, or a salt thereof.

[0430] Embodiment P19.L 1 , L 2 , L 3 , and L 4 But together, the structure [ka] Including, A compound according to any one of embodiments P8 to P18, wherein X is O or S, or a salt thereof.

[0431] Embodiment P20. The compound has the structure: [ka] or a salt thereof, wherein X is O or S. The compound according to any one of embodiments P1 to P19,

[0432] Embodiment P21. A compound according to any one of embodiments P18 to P20, wherein X is O, or a salt thereof.

[0433] Embodiment P22. A compound according to any one of embodiments P18 to P20, wherein X is S, or a salt thereof.

[0434] Embodiment P23. The CB 1 The ligand has the structure [ka] or a derivative thereof, or a salt thereof.

[0435] Embodiment P24. The compound has the structure of Formula (III): [ka] A compound according to embodiment P23, comprising:

[0436] Embodiment P25. The compound has the structure of Formula (III-a): [ka] A compound according to embodiment P24, comprising:

[0437] Embodiment P26.L 1 , L 2 , L 3 , and L 4 The compound of any one of embodiments P23-P25, wherein each of is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, a phosphodiester linkage, or a phosphorothioate linkage, or a salt thereof.

[0438] Embodiment P27.L 1 The compound according to embodiment P26, wherein is a bond, or a salt thereof.

[0439] Embodiment P28.L 2 The compound according to embodiment P26 or P27, wherein is an optionally substituted PEG linker, or a salt thereof.

[0440] Embodiment P29. The compound according to embodiment P28, or a salt thereof, wherein said PEG linker is 2 or 3 PEG units in length.

[0441] Embodiment P30.L 3 and L 4 One of the bonds is a phosphodiester or phosphorothioate bond, and L 3 and L 4 The compound according to any one of embodiments P26 to P29, or a salt thereof, wherein the other of is a bond.

[0442] Embodiment P31.L 1, L 2 , L 3 , and L 4 But together, the structure [ka] wherein X is O or S; or a salt thereof.

[0443] Embodiment P32.L 3 A compound according to any one of embodiments P26 to P29, wherein is an optionally substituted heteroaryl linker, or a salt thereof.

[0444] Embodiment P33.L 3 The compound according to embodiment P32, wherein is an optionally substituted partially unsaturated heteroaryl linker, or a salt thereof.

[0445] Embodiment P34.L 3 But the structure [ka] The compound according to embodiment P32 or P33, comprising:

[0446] Embodiment P35.L 4 A compound according to any one of embodiments P26-P29 or P32-P34, wherein is an optionally substituted heteroalkyl linker, or a salt thereof.

[0447] Embodiment P36. A compound according to embodiment P35, or a salt thereof, wherein said heteroalkyl linker is substituted with one or more =O substituents.

[0448] Embodiment P37.L 4 But the structure [ka] wherein X is O or S; or a salt thereof.

[0449] Embodiment P38.L 1 , L 2 , L 3 , and L 4 But together, the structure [ka] wherein X is O or S; or a salt thereof.

[0450] Embodiment P39. The compound has the structure: [ka] or a salt thereof, wherein X is O or S. The compound according to any one of embodiments P23 to P38,

[0451] Embodiment P40. A compound according to any one of embodiments P23 to P39, wherein X is O, or a salt thereof.

[0452] Embodiment P41. A compound according to any one of embodiments P23 to P39, wherein X is S, or a salt thereof.

[0453] Embodiment P42. A compound comprising the structure of formula (IV), or a salt thereof: [ka] (In the formula, [ka] Each of them independently activates the cannabinoid type 1 receptor (CB 1 ) ligand, or [ka] One of them is CB 1 is a ligand, [ka] the other comprises a lipid or a ligand, L 1 , L 2 , L 3 , L 4 , and L 5 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

[0454] Embodiment P43. [ka] However, independently, CB 1 The compound according to embodiment P42, or a salt thereof, which is a ligand.

[0455] Embodiment P44. The CB 1 One or both of the ligands are CB 1 A compound according to embodiment P43, or a salt thereof, which is an agonist.

[0456] Embodiment P45. The CB 1 One or both of the ligands are CB 1 The compound according to embodiment P43, or a salt thereof, which is an antagonist.

[0457] Embodiment P46. The CB 1Each of the ligands was found to be effective in treating rheumatoid arthritis, including minocycline, dronabinol, epigallocatechin, epicatechin, kavain, yangonin, oleamide, N-arachidonoyldopamine, cannabinol, HU-210, 11-hydroxy-THC, levonantradol, 2-arachidonyl glyceryl ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP 55,940, JWH-018, and WIN. 55,212-2, GAT228, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodamine, 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-CB 1 The compound according to embodiment P43, or a salt thereof, independently selected from the group consisting of antibodies, and derivatives thereof.

[0458] Embodiment P47. The CB 1 Each of the ligands has the structure [ka] or a derivative thereof, or a salt thereof.

[0459] Embodiment P48. The compound has the structure of Formula (V): [ka] A compound according to embodiment P43, comprising:

[0460] Embodiment P49. The compound has the structure of Formula (Va): [ka] A compound according to embodiment P48, comprising:

[0461] Embodiment P50.L 1 , L 2 , L 3 , L 4 , and L 5 The compound of any one of embodiments P42 to P49, wherein each of is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, a phosphodiester linkage, or a phosphorothioate linkage, or a salt thereof.

[0462] Embodiment P51.L 1 and L 5 The compound according to embodiment P50, wherein each is an optionally substituted PEG linker, or a salt thereof.

[0463] Embodiment P52.L 1 and L 5 The compound according to embodiment P51, wherein each is an optionally substituted PEG linker of 3 PEG units in length, or a salt thereof.

[0464] Embodiment P53.L 2 The compound according to any one of embodiments P50 to P52, wherein is an optionally substituted heteroalkyl linker, or a salt thereof.

[0465] Embodiment P54. A compound according to embodiment P53, or a salt thereof, wherein said heteroalkyl linker is substituted with one or more =O substituents.

[0466] Embodiment P55.L 2 But the structure [ka] The compound according to any one of embodiments P50 to P54, or a salt thereof, comprising:

[0467] Embodiment P56.L 3 A compound according to any one of embodiments P50 to P55, wherein is an optionally substituted heteroaryl linker, or a salt thereof.

[0468] Embodiment P57.L 3 The compound according to embodiment P56, wherein is an optionally substituted partially unsaturated heteroaryl linker, or a salt thereof.

[0469] Embodiment P58.L 3 But the structure [ka] The compound according to embodiment P56 or P57, or a salt thereof, comprising:

[0470] Embodiment P59.L 4 A compound according to any one of embodiments P50 to P58, wherein is an optionally substituted heteroalkyl linker, or a salt thereof.

[0471] Embodiment P60. A compound according to embodiment P59, or a salt thereof, wherein said heteroalkyl linker is substituted with one or more =O substituents.

[0472] Embodiment P61.L 4 But the structure [ka] Including, A compound according to embodiment P59 or P60, wherein X is O or S, or a salt thereof.

[0473] Embodiment P62.L 1 , L 2 , L 3 , L 4 , and L 5 But together, the structure [ka] Including, A compound according to any one of embodiments P50 to P61, wherein X is O or S, or a salt thereof.

[0474] Embodiment P63. The compound has the structure: [ka] or a salt thereof, wherein X is O or S. The compound according to any one of embodiments P42 to P62,

[0475] Embodiment P64. A compound according to any one of embodiments P42 to P63, wherein X is O, or a salt thereof.

[0476] Embodiment P65. A compound according to any one of embodiments P42 to P63, wherein X is S, or a salt thereof.

[0477] Embodiment P66.R 1 The compound according to any one of embodiments P1 to P65, or a salt thereof, wherein comprises an oligonucleotide.

[0478] Embodiment P67. The compound according to embodiment P66, or a salt thereof, wherein said oligonucleotide is linked at its 5' end.

[0479] Embodiment P68. The compound according to embodiment P66, or a salt thereof, wherein said oligonucleotide is linked at its 3' end.

[0480] Embodiment P69. The compound according to embodiment P66, or a salt thereof, wherein said oligonucleotide is linked at an internal position of said oligonucleotide.

[0481] Embodiment P70. The compound of embodiment P69, or a salt thereof, wherein said internal position is an internucleoside linkage.

[0482] Embodiment P71.R 1 but one or more additional CBs 1The compound according to any one of embodiments P1 to P70, or a salt thereof, comprising an oligonucleotide conjugated to a ligand.

[0483] Embodiment P72. The oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional CBs. 1 The compound according to embodiment P71, or a salt thereof, which is conjugated to a ligand.

[0484] Embodiment P73. The additional CB 1 The compound according to embodiment P71 or P72, or a salt thereof, wherein the ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, at one or more internal positions of the oligonucleotide, or any combination thereof.

[0485] Embodiment P74. The compound according to any one of embodiments P66 to P73, wherein said oligonucleotide is a modified oligonucleotide.

[0486] Embodiment P75. A compound comprising the structure of formula (VI), or a salt thereof: [ka] (In the formula, [ka] The cannabinoid type 1 receptor (CB 1 ) ligand, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 is independently a linker, a bond, or absent; R 1 and R 2 each independently comprises one or more of an oligonucleotide, a protecting group, a small molecule, a protein, an antibody, and / or a peptide.

[0487] Embodiment P76. The CB 1 The ligand is CB 1 The compound according to embodiment P75, or a salt thereof, which is an agonist.

[0488] Embodiment P77. The CB 1 The ligand is CB 1 The compound according to embodiment P75, or a salt thereof, which is an antagonist.

[0489] Embodiment P78. The CB 1 The ligands were minocycline, dronabinol, epigallocatechin, epicatechin, kavain, yangonin, oleamide, N-arachidonoyldopamine, cannabinol, HU-210, 11-hydroxy-THC, levonantradol, 2-arachidonyl glyceryl ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP 55,940, JWH-018, and WIN. 55,212-2, GAT228, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodamine, 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-CB 1 The compound according to embodiment P75, which is selected from the group consisting of antibodies, and derivatives thereof, or a salt thereof.

[0490] Embodiment P79. The CB 1 The ligand has the structure [ka] or a derivative thereof, or a salt thereof.

[0491] Embodiment P80. The compound has the structure of Formula (VII): [ka] A compound according to embodiment P75, comprising:

[0492] Embodiment P81. The compound has the structure of Formula (VII-a): [ka] A compound according to embodiment P80, comprising:

[0493] Embodiment P82.L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 The compound of any one of embodiments P75 to P81, wherein each of is independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, a phosphodiester linkage, or a phosphorothioate linkage, or a salt thereof.

[0494] Embodiment P83.L 1 The compound according to embodiment P82, wherein is an optionally substituted PEG linker, or a salt thereof.

[0495] Embodiment P84.L 1 The compound according to embodiment P83, wherein is an optionally substituted PEG linker of 2 or 3 PEG units in length, or a salt thereof.

[0496] Embodiment P85.L 2 and L 5 The compound according to any one of embodiments P82 to P84, wherein each is independently an optionally substituted PEG linker, or a salt thereof.

[0497] Embodiment P86. The above L 2 and L 5 The compound according to embodiment P85, wherein each is independently an optionally substituted PEG linker of 3 or 4 PEG units in length, or a salt thereof.

[0498] Embodiment P87.L 1 , L 2 , and L 5 But together, the structure [ka] The compound according to any one of embodiments P82 to P86, or a salt thereof, comprising:

[0499] Embodiment P88.L 3 and L 6 A compound according to any one of embodiments P82 to P86, wherein each is independently an optionally substituted heteroaryl linker, or a salt thereof.

[0500] Embodiment P89.L 3 and L 6 A compound according to embodiment P88, wherein each is independently an optionally substituted partially unsaturated heteroaryl linker, or a salt thereof.

[0501] Embodiment P90.L 3 and L 6 However, the structure [ka] The compound according to embodiment P88 or P89, or a salt thereof, comprising:

[0502] Embodiment P91.L 4 and L 7 A compound according to any one of embodiments P82 to P90, wherein each is independently an optionally substituted heteroalkyl linker, or a salt thereof.

[0503] Embodiment P92. A compound according to embodiment P91, or a salt thereof, wherein said heteroalkyl linker is substituted with one or more =O substituents.

[0504] Embodiment P93.L 4 and L 7 However, the structure [ka] Including, A compound according to embodiment P91 or P92, wherein X is O or S, or a salt thereof.

[0505] Embodiment P94.L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 7 But together, the structure [ka] Including, A compound according to any one of embodiments P82 to P93, wherein X is O or S, or a salt thereof.

[0506] Embodiment P95. The compound has the structure: [ka] or a salt thereof, wherein X is O or S. The compound according to any one of embodiments P75 to P94,

[0507] Embodiment P96. A compound according to any one of embodiments P75 to P95, wherein X is O, or a salt thereof.

[0508] Embodiment P97. A compound according to any one of embodiments P75 to P95, wherein X is S, or a salt thereof.

[0509] Embodiment P98.R 1 and R2 Each of the compounds according to any one of embodiments P75 to P97, or a salt thereof, comprises an oligonucleotide.

[0510] Embodiment P99. The compound according to embodiment P98, or a salt thereof, wherein one or both of said oligonucleotides are linked at their 5' ends.

[0511] Embodiment P100. The compound according to embodiment P98, or a salt thereof, wherein one or both of said oligonucleotides are linked at their 3' termini.

[0512] Embodiment P101. The compound according to embodiment P98, or a salt thereof, wherein one or both of said oligonucleotides are linked at an internal position of said oligonucleotide.

[0513] Embodiment P102. A compound according to embodiment P101, or a salt thereof, wherein said internal position is an internucleoside linkage.

[0514] Embodiment P103.R 1 and R 2 Each of them has one or more additional CBs. 1 The compound according to any one of embodiments P98 to P102, or a salt thereof, comprising an oligonucleotide conjugated to a ligand.

[0515] Embodiment P104. The oligonucleotide comprises 2, 3, 4, 5, or more than 5 additional CB 1 The compound according to embodiment P103, or a salt thereof, which is conjugated to a ligand.

[0516] Embodiment P105. The additional CB 1 The compound according to embodiment P103 or P104, or a salt thereof, wherein the ligand is conjugated to the oligonucleotide at the 5' end of the oligonucleotide, at the 3' end of the oligonucleotide, at one or more internal positions of the oligonucleotide, or any combination thereof.

[0517] Embodiment P106. The compound according to any one of embodiments P98 to P105, wherein said oligonucleotide is a modified oligonucleotide.

[0518] Embodiment P107. A composition comprising a compound according to any one of embodiments P1 to P106, or a salt thereof, and a pharma- ceutically acceptable excipient.

[0519] Embodiment P108. A method for delivering a therapeutic oligonucleotide to the brain of a subject, comprising administering to the subject a compound described in any one of embodiments P1 to P106, or a salt thereof, or a composition described in embodiment P107.

[0520] Embodiment P109. The method of embodiment P108, wherein said therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of the striatum, cerebellum, brainstem, hippocampus, frontal lobe, and spinal cord.

[0521] Embodiment P110. A method for treating or ameliorating a disease, disorder, or a symptom thereof in a subject, comprising administering to the subject a compound described in any one of embodiments P1 to P106, or a salt thereof, or a composition described in embodiment P107.

[0522] Embodiment P111. The method of embodiment P110, wherein said disease, disorder, or symptom thereof is a disease, disorder, or symptom thereof of the central nervous system (CNS).

[0523] Embodiment P112. The method of embodiment P110 or P111, wherein said disease, disorder, or symptom thereof is Alzheimer's disease, or a symptom thereof.

[0524] Embodiment P113. The method of any one of embodiments P108 to P112, wherein said compound, or salt thereof, is administered intrathecally to said subject.

[0525] Embodiment P114. A method for making a compound according to any one of embodiments P1 to P106, or a salt thereof, comprising one or more compounds and chemical transformations described herein, including Example 1.

[0526] Additional embodiments include the following embodiments 1 to 166.

[0527] Embodiment 1. A compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of Formula (I'): [ka] (In the formula, [ka] Each of these independently binds to the cannabinoid type 1 receptor (CB 1 ) ligand, L 1 , L 2 , L 3 , L 4 , L 1A , L 2A , L 3A , and L 4A is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; z1 is 0 or 1).

[0528] Embodiment 2. The compound of embodiment 1, wherein the compound comprises the structure of formula (I″), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, [ka] is an oligonucleotide).

[0529] Embodiment 3. The compound of embodiment 2, wherein the compound comprises the structure of formula (I″-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, X 1 is NR 10 or CR 11 R 12 and X 2 is NR 13 or CR 14 R 15 and R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19 is 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 SO 2 R 19A , -NR 19B C(O)R19D , -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 is 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 SO 2 R 21A , -NR 21B C(O)R 21D , -NR 21B C(O)OR 21D , -NR 21B OR 21D , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19A , R 19B , R 19C , R 19D , R 21A , R 21B , R 21C , and R 21Dare each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 19B and R 19C Substituents and R 21B and R 21C The substituents may optionally be combined 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; v19 and v21 are each independently 1 or 2).

[0530] Embodiment 4. The compound of embodiment 3, wherein the compound comprises the structure of formula (I″-a-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0531] Embodiment 5. The compound of embodiment 3, wherein the compound comprises the structure of formula (I″-a-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0532] Embodiment 6. The compound of embodiment 2, wherein the compound comprises the structure of formula (I″-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0533] Embodiment 7. The compound of embodiment 6, wherein the compound comprises the structure of formula (I″-b-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0534] Embodiment 8. The compound of embodiment 6, wherein the compound comprises the structure of formula (I″-b-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0535] Embodiment 9. The compound of embodiment 2, wherein the compound comprises the structure of formula (I″-c), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0536] Embodiment 10. The compound of embodiment 9, wherein the compound comprises the structure of formula (I″-c-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0537] Embodiment 11. The compound of embodiment 9, wherein the compound comprises the structure of formula (I″-c-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0538] Embodiment 12. A compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (I): [ka] (In the formula, [ka] The cannabinoid type 1 receptor (CB 1 ) ligand, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

[0539] Embodiment 13. The CB 1 The ligand is CB 1 The compound of embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, which is an agonist.

[0540] Embodiment 14. The CB 1 The ligand is CB 1 The compound of embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, which is an antagonist.

[0541] Embodiment 15. The CB 1 The compound of embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the ligand is a selective ligand.

[0542] Embodiment 16. The CB 1 The compound of embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the ligand is a non-selective ligand.

[0543] Embodiment 17. The CB 1The ligands were minocycline, dronabinol, epigallocatechin, epicatechin, kavain, yangonin, oleamide, N-arachidonoyldopamine, cannabinol, HU-210, 11-hydroxy-THC, levonantradol, 2-arachidonyl glyceryl ether, JWH-073, tetrahydrocannabinol, 2-arachidonoylglycerol, AM-2201, CP 55,940, JWH-018, and WIN. 55,212-2, GAT228, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodamine, 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-CB 1 17. The compound according to any one of embodiments 12 to 16, or a stereoisomer, tautomer, prodrug, or salt thereof, selected from the group consisting of antibodies and derivatives thereof.

[0544] Embodiment 18. The CB 1 The compound of embodiment 12, wherein the ligand comprises the structure of formula (II'), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 17 is 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)R17D , -C(O)OR 17D , -C(O)NR 17B R 17C , -OR 17A , -NR 17B SO 2 R 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 17B and R 17C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n17 is 0, 1, 2, 3, or 4; v17 is either 1 or 2).

[0545] Embodiment 19.R 17 But -NR 17B R 17C , -C(O)R 17D , or -C(O)OR 17D19. The compound of embodiment 18, wherein:

[0546] Embodiment 20.R 17B and R 17C is each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0547] Embodiment 21. The CB 1 The ligand has the structure [ka] 21. The compound of embodiment 20, comprising:

[0548] Embodiment 22. The compound of embodiment 12, wherein the compound comprises the structure of formula (II), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0549] Embodiment 23. The compound of embodiment 22, wherein the compound comprises the structure of formula (II-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0550] Embodiment 24. The CB 1 The ligand has the structure [ka] or a derivative thereof, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0551] Embodiment 25. The compound of embodiment 12, wherein the compound comprises the structure of formula (III), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0552] Embodiment 26. The compound of embodiment 25, wherein the compound comprises the structure of formula (III-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0553] Embodiment 27. A compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (VIII): [ka] (In the formula, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; R 3 , R 4 , R 5 , R 6 , and R 8 are each 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 9the substituents may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; R 7 is 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 SO 2 R 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 7B and R 7C The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n7 is 0, 1, 2, 3, or 4, v7 is either 1 or 2).

[0554] Embodiment 28.R 7 and R 8 is each independently hydrogen, optionally substituted alkyl, or optionally substituted heteroalkyl, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0555] 29. R 4 is a halogen, R 3 , R 5 , and R 6 is each independently hydrogen, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0556] Embodiment 30.R 3 , R 4 , R 5 , and R 6 is each independently hydrogen, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0557] Embodiment 31.R 6 and R 929. The compound of embodiment 27 or 28, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the substituents are joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl.

[0558] Embodiment 32.R 9 The compound of embodiment 27 or 28, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is hydrogen or optionally substituted alkyl.

[0559] Embodiment 33. The compound of embodiment 27, wherein the compound comprises the structure of formula (VIII-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0560] Embodiment 34. The compound of embodiment 33, wherein the compound comprises the structure of formula (VIII-a-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0561] Embodiment 35. The compound of embodiment 27, wherein the compound comprises the structure of formula (VIII-a-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0562] Embodiment 36. The compound of embodiment 27, wherein the compound comprises the structure of formula (VIII-b), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0563] Embodiment 37. The compound of embodiment 27 or 36, wherein the compound comprises the structure of formula (VIII-b-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0564] Embodiment 38. The compound of embodiment 27, wherein the compound comprises the structure of formula (VIII-c), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0565] Embodiment 39. The compound of embodiment 27 or 38, wherein the compound comprises the structure of formula (VIII-c-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0566] Embodiment 40. The compound of embodiment 27, wherein the compound comprises the structure of formula (VIII-c-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0567] Embodiment 41. The compound of embodiment 27, wherein the compound comprises the structure of formula (VIII-d), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0568] Embodiment 42. The compound of embodiment 27 or 41, wherein the compound comprises the structure of formula (VIII-d-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0569] Embodiment 43. The compound of embodiment 27, wherein the compound comprises the structure of formula (VIII-d-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0570] Embodiment 44. A compound according to embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (IX): [ka] (In the formula, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; X 1 is NR 10 or CR 11 R 12 and R 10 , R 11 , and R 12 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 19 is hydrogen, -SOn19 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 SO 2 R 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 are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 19B and R 19CThe substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n19 is 0, 1, 2, 3, or 4; v19 is either 1 or 2).

[0571] Embodiment 45. The compound of embodiment 12 or 44, wherein the compound comprises the structure of formula (IX-a-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0572] Embodiment 46. The compound of embodiment 12 or 44, wherein the compound comprises the structure of formula (IX-a-2), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0573] Embodiment 47.X 1 But NR 10 and R 10 The compound of any one of embodiments 44-46, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is hydrogen or optionally substituted alkyl.

[0574] Embodiment 48.R 10 is hydrogen, -CH 3 , or -CH 2 CH 2 The compound of embodiment 47, wherein R is H, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0575] Embodiment 49.X 1 But, CR 11 R 12 and R 11 and R 12is each independently hydrogen or optionally substituted alkyl, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0576] Embodiment 50.R 11 is hydrogen, -CH 3 , or -CH 2 CH 2 F, R 12 is hydrogen, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0577] Embodiment 51. A compound according to embodiment 12, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (X): [ka] (In the formula, L 1 , L 2 , L 3 , and L 4 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; R 16 is hydrogen, halogen, -CN, -N 3 , -NO 2 , -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 16A , R 16B , R 16C , and R 16D are each independently hydrogen, halogen, or -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 16B and R 16C The substituents may be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0578] Embodiment 52. The compound of embodiment 51, wherein the compound comprises the structure of formula (Xa), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0579] Embodiment 53. The compound of embodiment 12 or 52, wherein the compound comprises the structure of formula (Xa-1), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka]

[0580] Embodiment 54. The CB 1 The ligand has the structure: [ka] or a derivative thereof, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0581] Embodiment 55. The compound has the structure: [ka] or a stereoisomer, tautomer, prodrug, or salt thereof.

[0582] Embodiment 56.L 1 , L 2 , L 3 , and L 4 or a stereoisomer, tautomer, prodrug, or salt thereof.

[0583] Embodiment 57.L 1 The compound of any one of embodiments 1-56, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is a bond.

[0584] Embodiment 58.L 1 The compound of any one of embodiments 1-56, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is oxygen.

[0585] Embodiment 59.L 1 But the structure [ka] wherein n7 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a stereoisomer, tautomer, prodrug, or salt thereof.

[0586] Embodiment 60.L 2The compound of any one of embodiments 1-59, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted PEG linker.

[0587] Embodiment 61. The compound of 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.

[0588] Embodiment 62.L 2 The compound of any one of embodiments 1-59, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted alkyl linker.

[0589] Embodiment 63.L 2 But the structure [ka] or a stereoisomer, tautomer, prodrug, or salt thereof.

[0590] Embodiment 64.L 4 The compound of any one of embodiments 1-63, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted heteroalkyl linker or bond.

[0591] 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 =O substituents.

[0592] Embodiment 66.L 4 But the structure [ka] Including, 66. The compound according to embodiment 64 or 65, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is O or S.

[0593] Embodiment 67.L 4 But the structure [ka] Including, 67. The compound of embodiment 66, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is O or S.

[0594] Embodiment 68.L 3 The compound of any one of embodiments 1-67, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted heteroaryl linker.

[0595] Embodiment 69.L 3 and L 4 is an optionally substituted phosphodiester linkage or an optionally substituted phosphorothioate linkage, and L 3 and L 4 The compound of any one of embodiments 1-63, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the other of is a bond.

[0596] Embodiment 70.L 3 The compound of any one of embodiments 1-67, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein is an optionally substituted partially unsaturated heteroaryl or an optionally substituted partially unsaturated heterocycloalkyl linker.

[0597] Embodiment 71.L 3 But the structure [ka] or a stereoisomer, tautomer, prodrug, or salt thereof.

[0598] Embodiment 72.L 1 , L 2 , L 3 , and L 4 taken together, the compound of any one of embodiments 1-71 comprises the structure: [ka] (In the formula, 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, or 10; (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).

[0599] Embodiment 73.L 1 , L 2 , L 3 , and L 4 taken together, comprises the structure: or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, 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, or 10; (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).

[0600] Embodiment 74. A compound according to embodiment 66, 67, 72, or 73, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is S.

[0601] Embodiment 75. A compound according to embodiment 66, 67, 72, or 73, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein X is O.

[0602] Embodiment 76. A compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (IV'), or a salt thereof: [ka] (In the formula, [ka] Each of them independently activates the cannabinoid type 1 receptor (CB 1 ) ligand, or [ka] One of them is CB 1 is a ligand, [ka] the remainder comprising a lipid or ligand, L 1 , L 2 , L 3 , L 4 , L 5 , L 1A , L 2A , L A3 , L A4 , and L A5 is independently a linker, a bond, or absent; R 1 comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

[0603] Embodiment 77. The compound of embodiment 76, wherein the compound comprises the structure of formula (IV″), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, [ka] is an oligonucleotide).

[0604] Embodiment 78. The compound of embodiment 77, wherein the compound comprises the structure of formula (IV″-a), or a stereoisomer, tautomer, prodrug, or salt thereof: [ka] (In the formula, R 17 is 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 SO 2 R 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 is hydrogen, -SO n18 R 18A , -SOv18 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 SO 2 R 18A , -NR 18B C(O)R 18D , -NR 18B C(O)OR 18D , -NR 18B OR 18D , o...

Claims

1. A compound comprising the structure of formula (I'), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 401】 (In the formula, 【Chemical 402】 Each of the cannabinoids independently binds to the cannabinoid type 1 receptor (CB １ ) ligand, L １ , L ２ , L ３ , L ４ , L １Ａ , L ２Ａ , L ３Ａ , and L ４Ａ is independently a linker, a bond, or absent; R １ comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides; z1 is 0 or 1).

2. 10. The compound of claim 1, wherein the compound comprises the structure of formula (I"), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 403】 (In the formula, 【Chemical 404】 is an oligonucleotide).

3. 3. The compound of claim 2, wherein the compound comprises the structure of formula (I″-a), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 405】 (In the formula, X １ is NR １０ or CR １１ R １２ and X ２ is NR １３ or CR １４ R １５ and R １０ , R １１ , R １２ , R １３ , R １４ , and R １５ are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R １９ is 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 SO ２ R 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 is 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 SO ２ R ２１Ａ , -NR ２１Ｂ C(O)R ２１Ｄ , -NR ２１Ｂ C(O)OR ２１Ｄ , -NR ２１Ｂ OR ２１Ｄ , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R １９Ａ , R １９Ｂ , R １９Ｃ , R １９Ｄ , R ２１Ａ , R ２１Ｂ , R ２１Ｃ , and R ２１Ｄ are each independently hydrogen, halogen, or —CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R １９Ｂ and R １９Ｃ Substituents and R ２１Ｂ and R ２１Ｃ the substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n19 and n21 each independently represent 0, 1, 2, 3, or 4; v19 and v21 are each independently 1 or 2.

4. 3. The compound of claim 2, wherein the compound comprises the structure of formula (I″-b), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 408】

5. 3. The compound of claim 2, wherein the compound comprises the structure of formula (I″-c), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 411】

6. 3. The compound of claim 2, or a stereoisomer, tautomer, prodrug, or salt thereof, wherein the CB1 ligand is conjugated to the oligonucleotide at an internucleoside linkage.

7. The compound of claim 1, wherein z1 is 0 and the compound comprises the structure of formula (I), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 414】 。

8. 8. The compound of claim 7, wherein the compound comprises the structure of formula (II-a), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 419】

9. 8. The compound of claim 7, wherein the compound comprises the structure of formula (III-a), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemistry 422】 10. The compound of claim 7, wherein the compound comprises the structure of formula (IX), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemical 435】 (In the formula, X １ is NR １０ or CR １１ R １２ and R １０ , R １１ , and R １２ are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R １９ is 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 SO ２ R 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 are each independently hydrogen, halogen, or —CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R １９Ｂ and R １９Ｃ the substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n19 is 0, 1, 2, 3, or 4; v19 is 1 or 2).

11. 8. The compound of claim 7, comprising the structure of formula (X), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemistry 438】 (In the formula, R １６ is hydrogen, halogen, -CN, -N ３ , -NO ２ , -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 １６Ａ , R １６Ｂ , R １６Ｃ , and R １６Ｄ are each independently hydrogen, halogen, or —CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R １６Ｂ and R １６Ｃ The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

12. The compound of claim 7, wherein the compound comprises the structure of formula (VIII), or a stereoisomer, tautomer, prodrug, or salt thereof: 【Chemistry 423】 (In the formula, R ３ , R ４ , R ５ , R ６ , and R ８ are each 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 may be joined together to form an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; R ７ is 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 SO ２ R 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 , and R ７Ｄ are each independently hydrogen, halogen, or —CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R ７Ｂ and R ７Ｃ the substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; n7 is 0, 1, 2, 3, or 4; v7 is 1 or 2).

13. A compound, or a stereoisomer, tautomer, prodrug, or salt thereof, comprising the structure of formula (IV'), or a salt thereof: [Chemical 450] (In the formula, 【Chemistry 451】 are independently activated by the cannabinoid type 1 receptor (CB １ ) ligand, or 【Chemistry 452】 One of them is CB １ is a ligand, 【Chemistry 453】 the remainder comprising a lipid or a ligand, L １ , L ２ , L ３ , L ４ , L ５ , L １Ａ , L ２Ａ , L Ａ３ , L Ａ４ , and L Ａ５ are each independently a linker, a bond, or absent; R １ comprises one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, and / or peptides).

14. A composition comprising a compound of any one of claims 1 to 13, or a stereoisomer, tautomer, prodrug, or salt thereof, and a pharmaceutically acceptable excipient.

15. 14. A composition comprising a compound of any one of claims 1 to 13 or a stereoisomer, tautomer, prodrug, or salt thereof, or a composition comprising a compound of any one of claims 1 to 13 or a stereoisomer, tautomer, prodrug, or salt thereof and a pharmaceutically acceptable excipient, for use in treating or ameliorating a disease, disorder, or symptom thereof of the central nervous system (CNS) in a subject.

16. A composition comprising a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, prodrug, or salt thereof, or a composition comprising a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, prodrug, or salt thereof, and a pharmaceutically acceptable excipient, for use in treating or ameliorating a CNS disease, disorder, or symptom thereof in a subject, The composition, wherein the CNS disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.

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