GALNAC compositions for improving siRNA bioavailability

Abstract

Provided herein are GALNAC compositions for improving siRNA bioavailability, specifically compositions comprising GalNAc moieties that can be conjugated to oligonucleotides. The oligonucleotides can be small interfering RNAs or antisense oligonucleotides. Also provided herein are methods of treatment comprising administering the compositions to a subject.

Description

[0001] This application is a divisional application of Chinese patent application No. 202380040964.6, entitled "GALNAC Composition for Improving siRNA Bioavailability" (the corresponding PCT application was filed on March 15, 2023, with application number PCT / US2023 / 064384). Cross-references

[0002] This application claims the benefits of U.S. Provisional Application No. 63 / 320,431, filed March 16, 2022; U.S. Provisional Application No. 63 / 354,359, filed June 22, 2022; and U.S. Provisional Application No. 63 / 430,542, filed December 6, 2022, which are incorporated herein by reference. Incorporation of sequence lists

[0003] This application is accompanied by a sequence list submitted electronically. The sequence list is provided as a file named “54462-735601_PCT.xml”, created on March 13, 2023, and is 922,453 bytes in size. The information in the electronic sequence list is incorporated herein by reference in its entirety. Background Technology

[0004] There are many conditions related to the cardiovascular, metabolic, and liver systems, and they can affect a wide range of people. Improved therapies are needed to treat these conditions. Summary of the Invention

[0005] This article discloses a compound represented by formula (I) or (II): (I), or (II); or its salt, wherein J is an oligonucleotide; Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C; If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 The connectors are selected from the following: -O-, -S-, -N(R) 7 -, -C(O)-, -C(O)N(R) 7 )-、-N(R 7 )C(O)-、-N(R 7 )C(O)N(R 7 )-、-OC(O)N(R 7 )-、-N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - )S-、-OP(O)(OR 7 )NR 7-、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2NR 7 -; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7-OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 )2; Each R 6 Selected independently from: hydrogen; Halogen, -CN, -NO2, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ;as well as C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

[0006] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from both 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7)2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 5-6 A carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R... 1 Selected from -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - )S-、-OP(O)(OR 7 )NR 7 -、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2NR 7 In some implementations, R 1 Selected from -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - S- and -OP(OR) 7 In some implementations, R 1 Selected from -OP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(OR 7 In some implementations, R 1 Selected from -OP(O)(OR 7 )O- and -OP(OR 7 In some implementations, R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -OC(O)R 7 -SR 7 -N(R) 7 )2、-C(O)R 7 and -S(O)R 7 In some implementations, R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 )2. In some implementation schemes, R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 and -OC(O)R 7 In some implementations, R 3 Selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7and -S(O)R 7 In some implementations, R 3 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2. In some implementation schemes, R 3 Selected from -OR 7 -and-OC(O)R 7 In some implementations, R 4 Selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 In some implementations, R 4 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2. In some implementation schemes, R 4 Selected from -OR 7 -and-OC(O)R 7 In some implementations, R 5 Selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2 and -N(R 7 )C(O)OR 7 In some implementations, R 5 Selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 In some implementations, each R 7 Independently selected from: hydrogen; and C4 groups optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings or 3- to 10-membered heterocyclic rings. In some embodiments, each R...7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 Alkyl). In some embodiments, each R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted by one or more substituents, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, and C. 1-3 Alkyl; R 1 Selected from -OP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(OR 7 )O-;R 2 It is a C1 alkyl group substituted with -OH or -OC(O)CH3; R 3 It is -OH or -OC(O)CH3; R 4 It is -OH or -OC(O)CH3; and R 5 It is -NH(O)CH3. In some embodiments, the compound comprises:

[0007]

[0008] In some embodiments, the oligonucleotide (J) is attached at the 5' or 3' end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified nucleoside links. In some embodiments, one or more modified nucleoside links comprise alkylphosphonates, thiophosphates, methylphosphonates, dithiophosphates, alkylthiophosphonates, aminophosphates, carbamates, carbonates, triphosphates, acetylimine esters, or carboxymethyl esters, or combinations thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified nucleoside links. In some embodiments, the oligonucleotide comprises one or more modified nucleosides. In some embodiments, one or more modified nucleosides include locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or combinations thereof. In some embodiments, one or more modified nucleosides include 2',4'-restricted ethyl nucleoside, 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'-ON-methylacetamido(2'-O-NMA) nucleoside, 2'-O-dimethylaminoethoxyethyl(2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl(2'-O-AP) nucleoside, 2'-ara-F, 2'-fluoro, or 2'-O-alkyl, or combinations thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or more modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithochyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or combinations thereof. In some embodiments, the oligonucleotide comprises an arginine-glycine-aspartic (RGD) peptide attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid-derived RGD, or combinations thereof. In some embodiments, the oligonucleotide comprises small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleotides in length.In some embodiments, the antisense strand is 12-30 nucleotides in length. In some embodiments, the sense and antisense strands form a double-stranded RNA double helix. In some embodiments, the first base pair of the double-stranded RNA double helix is ​​an AU base pair. In some embodiments, the sense or antisense strand includes a 3' overhang. In some embodiments, the 3' overhang includes one, two, or more nucleotides. In some embodiments, the sense strand includes any one of the modification patterns 1S to 6S or 1S#2 to 6S#2. In some embodiments, the antisense strand includes any one of the modification patterns 1AS to 9AS. In some embodiments, the oligonucleotide includes an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleotides in length. In some embodiments, the ASO includes the modification pattern ASO1. In some embodiments, the compound binds to asialylate glycoprotein receptors. In some embodiments, the compound targets hepatocytes.

[0009] This document discloses a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the pharmaceutical composition is sterile. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes water, a buffer, or physiological saline. In some embodiments, the oligonucleotide targets target mRNA and, when administered to a subject in an effective amount, reduces the target mRNA or target protein by at least 10%.

[0010] This document discloses a method for reducing target mRNA or target protein in a subject of need, the method comprising administering an effective amount of a pharmaceutical composition of any of the compounds described herein. In some embodiments, the effective amount reduces a measurement of the target mRNA or target protein in the subject relative to a baseline measurement. In some embodiments, the effective amount treats a condition in the subject. In some embodiments, the effective amount reduces a measurement of a condition-related symptom or parameter in the subject relative to a baseline measurement. In some embodiments, the measurement of a condition-related symptom or parameter in the subject is reduced for at least 10 days. In some embodiments, the measurement of a condition-related symptom or parameter in the subject is reduced for at least 100 days. In some embodiments, the condition is a metabolic condition. In some embodiments, the condition is a liver condition.

[0011] This article discloses a compound represented by formula (A) or (B): (A), or (B); or its salt, wherein Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C. If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 Selected from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R7 -S(O)R 7 -S(O)2R 7 -OS(O)2R 7 -OP(O)(OR) 7 )2、-OP(S)(OR 7 )2、-SP(O)(OR 7 )2、-OP(O)(SR 7 (OR) 7 ), -OP(O)(OR 7 )N(R 7 )2、-OP(S)(OR 7 )N(R 7 )2、-SP(O)(OR 7 )N(R 7 )2、-OP(O)(SR 7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(S)(N(R 7 )2)2、-SP(O)(N(R 7 )2)2、-OP(OR 7 )2、-SP(OR 7 2. -OP(OR) 7 (SR) 7 -OP(OR) 7 )N(R 7 )2、-OP(SR 7 )N(R 7 )2、-SP(OR 7 )N(R 7 )2、-OP(N(R 7 )2)2 and -SP(N(R 7 )2)2; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 )2; Each R 6 Selected independently from: hydrogen; Halogen, -CN, -NO2, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ;as well as C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

[0012] In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from both 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 5-6 A carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R... 1 Selected from -OP(O)(OR 7 )2、-OP(O)(OR 7 )N(R7 )2、-OP(O)(N(R 7 )2)2、-OP(OR 7 2. -OP(OR) 7 )N(R 7 )2 and -OP((NR 7 )2)2. In some implementations, R 1 Selected from -OP(O)(OR 7 )2 and -OP(OR 7 )N(R 7 )2. In some implementation schemes, R 1 Selected from -OP(O)(OCH2CH3)OH and -OP(OCH2CH2CN)N(CH(CH3)2)2. In some embodiments, R 1 It is -OP(OCH2CH2CN)N(CH(CH3)2)2. In some implementations, R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -OC(O)R 7 -SR 7 -N(R) 7 )2、-C(O)R 7 and -S(O)R 7 In some implementations, R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 )2. In some implementation schemes, R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 and -OC(O)R 7 In some implementations, R 3 Selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 In some implementations, R 3 Selected from -OR 7 -SR 7 -OC(O)R 7and -N(R) 7 )2. In some implementation schemes, R 3 Selected from -OR 7 and -OC(O)R 7 In some implementations, R 4 Selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 In some implementations, R 4 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2. In some implementation schemes, R 4 Selected from -OR 7 and -OC(O)R 7 In some implementations, R 5 Selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2 and -N(R 7 )C(O)OR 7 In some implementations, R 5 Selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 In some implementations, each R 7 Independently selected from: hydrogen; and C4 groups optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings, or 3- to 10-membered heterocyclic rings. In some embodiments, each R... 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 Alkyl). In some embodiments, each R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted by one or more substituents, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, and C. 1-3 Alkyl; R 1 Selected from -OP(O)(OR 7 )2 and -OP(OR 7 )N(R 7 )2;R 2 It is a C1 alkyl group substituted with -OH or -OC(O)CH3; R 3 -OH or -OC(O)CH3; R 4 It is -OH or -OC(O)CH3; and R 5 It is -NH(O)CH3. In some embodiments, the compound comprises: . Detailed Implementation

[0013] N-acetylgalactosamine (GalNAc) is an amino sugar derivative of galactose. GalNAc and its moiety can bind lectins, such as desialyl glycoprotein receptors. These receptors are present on hepatocytes. Therefore, GalNAc can target oligonucleotides to hepatocytes or the liver.

[0014] This article provides information on GalNAc moieties. These GalNAc moieties can be conjugated to oligonucleotides, such as small interfering RNA (siRNA) or antisense oligonucleotides (ASO). Oligonucleotides conjugated to GalNAc moieties can be administered to the subject, targeting the liver or hepatocytes, or used to treat liver-related conditions in the subject.

[0015] I. Composition In some embodiments, this document provides compositions comprising an oligonucleotide and an N-acetylgalactosamine (GalNAc) moiety. In some embodiments, the composition comprises an oligonucleotide. This oligonucleotide may inhibit a target gene or oligonucleotide. This oligonucleotide may bind to a target oligonucleotide. In some embodiments, the composition is used in the methods described herein.

[0016] In some embodiments, this document provides compounds comprising an oligonucleotide and a GalNAc moiety. In some embodiments, the compound comprises an oligonucleotide. The oligonucleotide can bind to a target oligonucleotide. In some embodiments, the compound is used in the methods described herein. In some embodiments, the compound is included in the compositions described herein.

[0017] The oligonucleotides of the compounds or compositions described herein may contain small interfering RNA (siRNA) or antisense oligonucleotides (ASO).

[0018] Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that, when applied to a subject in an effective amount, reduces the level of a target mRNA or protein in the subject's cells, fluid, or tissue. Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that, when applied to a subject in an effective amount, reduces the level of a target mRNA or protein in liver tissue or hepatocytes. In some embodiments, the composition comprises a GalNAc moiety and an oligonucleotide that, when applied to a subject in an effective amount, reduces the level of a target (e.g., mRNA) in cells or tissue. In some embodiments, the cells are hepatocytes. In some embodiments, the tissue is liver tissue. Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that, when applied to a subject in an effective amount, reduces the level of a target mRNA in liver tissue. Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that, when applied to a subject in an effective amount, reduces the level of a target mRNA in hepatocytes.

[0019] In some embodiments, the reduction in target oligonucleotide levels relative to other cell types is specifically targeted at hepatocytes. In some embodiments, the reduction in target RNA levels relative to other cell types is specifically targeted at hepatocytes. In some embodiments, the reduction in target mRNA levels relative to other cell types is specifically targeted at hepatocytes. In some embodiments, the reduction in target protein levels relative to other cell types is specifically targeted at hepatocytes. In some embodiments, the reduction in target oligonucleotide levels relative to other cell types is specifically targeted at liver tissue. In some embodiments, the reduction in target RNA levels relative to other cell types is specifically targeted at the liver. In some embodiments, the reduction in target mRNA levels relative to other cell types is specifically targeted at the liver. In some embodiments, the reduction in target protein levels relative to other cell types is specifically targeted at the liver.

[0020] In some embodiments, the composition comprises a GalNAc moiety and an oligonucleotide that binds to a target oligonucleotide, which, when applied to a subject in an effective amount, reduces the level of the target oligonucleotide in cells or tissues. In some embodiments, the target oligonucleotide level is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before application. In some embodiments, the target oligonucleotide level is reduced by about 10% or more compared to before application. In some embodiments, the target oligonucleotide level is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to before application. In some embodiments, the target oligonucleotide level is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before application. In some embodiments, the target oligonucleotide level is reduced by no more than about 10% compared to before application. In some embodiments, the target oligonucleotide level is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to before administration. In some embodiments, the target oligonucleotide level is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by any two of the percentages defined above.

[0021] In some embodiments, the composition comprises a GalNAc moiety and an oligonucleotide that binds to a target mRNA, which, when applied to a subject in an effective amount, reduces the level of the target mRNA in cells or tissues. In some embodiments, the target mRNA level is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before application. In some embodiments, the target mRNA level is reduced by about 10% or more compared to before application. In some embodiments, the target mRNA level is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to before application. In some embodiments, the target mRNA level is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before application. In some embodiments, the target mRNA level is reduced by no more than about 10% compared to before application. In some implementations, the target mRNA level is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to before administration. In some implementations, the target mRNA level is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by any two of the percentages defined above.

[0022] In some embodiments, the composition comprises a GalNAc moiety and an oligonucleotide binding to an oligonucleotide encoding a target protein, which, when applied to a subject in an effective amount, reduces the level of the target protein in cells or tissues. In some embodiments, the cells are hepatocytes. In some embodiments, the tissue is liver tissue. In some embodiments, the target protein level is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before application. In some embodiments, the target protein level is reduced by about 10% or more compared to before application. In some embodiments, the target protein level is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to before application. In some embodiments, the target protein level is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before application. In some embodiments, the target protein level is reduced by no more than about 10% compared to before application. In some embodiments, the target protein level is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to before administration. In some embodiments, the target protein level is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by any two of the percentages defined above.

[0023] In some embodiments, the composition comprises a GalNAc moiety and an oligonucleotide that binds to a target oligonucleotide (e.g., mRNA), which, when administered to a subject in an effective amount, reduces an undesirable phenotype (e.g., disease symptoms associated with the target oligonucleotide). In some embodiments, the undesirable phenotype is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the undesirable phenotype is reduced by about 10% or more compared to before administration. In some embodiments, the undesirable phenotype is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% compared to before administration. In some embodiments, the undesirable phenotype is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the undesirable phenotype is reduced by no more than about 10% compared to before administration. In some implementations, the adverse phenotype is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to before application. In some implementations, the adverse phenotype is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or the range of reduction is defined by any two of the above percentages.

[0024] In some embodiments, the composition comprises a GalNAc moiety and an oligonucleotide that binds to a target oligonucleotide (e.g., mRNA), which, when applied to a subject in an effective amount, increases a protective phenotype (e.g., protection against a disease). In some embodiments, the protective phenotype increases by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before application. In some embodiments, the protective phenotype increases by about 10% or more compared to before application. In some embodiments, the protective phenotype increases by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more compared to before application. In some embodiments, the protective phenotype increases by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more compared to before application. In some embodiments, the protective phenotype increases by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before application. In some embodiments, the protective phenotype increases by no more than about 10% compared to before application. In some embodiments, the protective phenotype increases by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% compared to before application. In some embodiments, the protective phenotype increases by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000% compared to before application. In some embodiments, the protective phenotype increases by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or the range of increase is defined by any two of the percentages above.

[0025] A. GalNAc components and compounds In some embodiments, compositions comprising the GalNAc moiety are provided herein. In some embodiments, compositions comprising the GalNAc moiety and an oligonucleotide are also provided herein. In some embodiments, the compositions comprising the GalNAc moiety and an oligonucleotide are described by compounds of formula (I) or (II). In some embodiments, the oligonucleotide in formula (I) or (II) is J. In some embodiments, the GalNAc moiety in formula (I) or (II) is a molecular moiety that binds to J. The oligonucleotide may comprise small interfering RNA (siRNA) or antisense oligonucleotide (ASO).

[0026] In some embodiments, compounds represented by formula (I) or (II) are provided herein: (I), or (II); or its salt, wherein J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein If z is 3, then Y is C; if z is 2, then Y is CR. 6 Or, if z is 1, then Y is C(R). 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R1 The connectors are selected from the following: -O-, -S-, -N(R) 7 -, -C(O)-, -C(O)N(R) 7 )-、-N(R 7 )C(O)-、-N(R 7 )C(O)N(R 7 )-、-OC(O)N(R 7 )-、-N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - )S-、-OP(O)(OR 7 )NR 7 -、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2NR 7 -; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 )2; Each R 6 Selected independently from: hydrogen; Halogen, -CN, -NO2, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7)2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ;as well as C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

[0027] In some embodiments, each w is independently selected from any value from 1 to 20. In some embodiments, each w is independently selected from any value from 1 to 15. In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is independently selected from any value from 1 to 4. In some embodiments, each w is independently selected from any value from 1 to 3. In some embodiments, each w is independently selected from any value from 1 to 2. In some embodiments, each w is independently 1. In some embodiments, w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0028] In some embodiments, each v is independently selected from any value from 1 to 20. In some embodiments, each v is independently selected from any value from 1 to 15. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is independently selected from any value from 1 to 4. In some embodiments, each v is independently selected from any value from 1 to 3. In some embodiments, each v is independently selected from any value from 1 to 2. In some embodiments, each v is independently 1. In some embodiments, v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0029] In some embodiments, n is selected from any value from 1 to 20. In some embodiments, n is selected from any value from 1 to 15. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 9. In some embodiments, n is selected from any value from 1 to 8. In some embodiments, n is selected from any value from 1 to 7. In some embodiments, n is selected from any value from 1 to 6. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is selected from any value from 1 to 4. In some embodiments, n is selected from any value from 2 to 4. In some embodiments, n is selected from any value from 1 to 3. In some embodiments, n is 2 or 3. In some embodiments, n is 3. In some embodiments, n is selected from any value from 1 to 2. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0030] In some embodiments, m is selected from any value from 1 to 20. In some embodiments, m is selected from any value from 1 to 15. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 9. In some embodiments, m is selected from any value from 1 to 8. In some embodiments, m is selected from any value from 1 to 7. In some embodiments, m is selected from any value from 3 to 7. In some embodiments, m is selected from any value from 1 to 6. In some embodiments, m is selected from any value from 2 to 6. In some embodiments, m is selected from any value from 3 to 6. In some embodiments, m is selected from any value from 4 to 6. In some embodiments, m is 6. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from any value from 3 to 5. In some embodiments, m is 5. In some embodiments, m is 4 or 5. In some embodiments, m is selected from any value from 1 to 4. In some embodiments, m is 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from any value from 2 to 4. In some embodiments, m is selected from any value from 1 to 3. In some implementations, m is 3. In some implementations, m is selected from any value from 1 to 2. In some implementations, m is 2. In some implementations, m is 1. In some implementations, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0031] In some implementations, z is selected from any value from 1 to 3. In some implementations, z is 3 and Y is C. In some implementations, z is 2 and Y is CR. 6In some implementations, z is 1 and Y is C(R). 6 )2.

[0032] In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents, said substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 3-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6The alkyl group is optionally substituted with one or more substituents, said substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some embodiments, Q is selected from a C6 carbon ring optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some embodiments, Q is selected from a C5 carbon ring optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7)C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 5-6 A carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl, cyclohexyl, cyclopentadiene, and cyclopentyl, each of which is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl. In some embodiments, Q is phenyl. In some embodiments, Q is cyclohexyl.

[0033] In some implementation schemes, R 1 The connectors are selected from the following: -O-, -S-, -N(R) 7 -, -C(O)-, -C(O)N(R) 7 )-、-N(R 7 )C(O)-、-N(R 7 )C(O)N(R 7 )-、-OC(O)N(R 7 )-、-N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(OR 7 )NR 7 -、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7)N(R 7 )-WA-OPN(R 7 )2NR 7 --. Currently under construction, R 1 The following prefixes are: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-,-N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-,-OC(O)N(R 7 )-,-N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-,-OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )-WA-OPN(R 7 )2NR 7 -. Currently under construction, R 1 Select from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O -)O-、-OP(O)(S - )O-、-OP(O)(O - )S-、-OP(O)(OR 7 )NR 7 -、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2NR 7 In some implementations, R 1 Selected from -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - S- and -OP(OR) 7 In some implementations, R 1 Selected from -OP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(OR 7 In some implementations, R 1 Selected from -OP(O)(OR 7 )O- and -OP(OR 7 In some implementations, R 1 It is selected from the following connectors: -OP(O)(OH)O-, -SP(O)(OH)O-, -OP(S)(OH)O-, -OP(O)(SH)O-, -OP(O)(OH)S-, -OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S- )O- and -OP(O)(O - In some implementations, R 1 Selected from -OP(O)(OR 7 )O-、-OP(O)(OR 7 )NR 7 -、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2NR 7 -. In some implementations, R 1 Selected from -S-, -S(O)-, -S(O)2-, -OS(O)2, -SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(O)(O - In some implementations, R 1 Selected from -S-, -S(O)-, -S(O)2-, -OS(O)2, -SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O- and -OP(O)(OR 7 In some implementations, R 1 Selected from -OP(S)(OR) 7 )O-、-OP(O)(SR 7 )O- and -OP(O)(OR 7 In some implementations, R 1 Selected from -OP(S)(OR) 7 )O-、-OP(O)(SR 7 )O-、-OP(S)(O - )O- and -OP(O)(S - In some implementations, R 1 Selected from -OP(S)(OR) 7)O-and-OP(O)(SR 7 In some implementations, R 1 Selected from -OP(O)(OR 7 )O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2O-. In some implementations, R 1 It is -OP(O)(OH)O-, -OP(O)(OCH2CH3)O-, -OP(OCH2CH2CN)N(CH(CH3)2)-, or -OPN(CH(CH3)2)2O-. In some embodiments, R 1 Selected from -OP(O)(OH)O- and OP(O)(O - In some implementations, R 1 Contains -O- or -S-. In some implementations, R 1 Includes -O-. In some implementations, R 1 Includes -S-. In some implementations, R 1 It is a connector selected from -O- or -S-. In some implementations, R 1 Yes -O-. In some implementations, R 1 Yes -S-.

[0034] In some implementations, each R 2 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 2 Independently selected from C14 cells substituted with one or more substituents. 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -OC(O)R7 -SR 7 -N(R) 7 )2、-C(O)R 7 and -S(O)R 7 In some implementations, each R 2 Independently selected from C14 cells substituted with one or more substituents. 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 2. In some implementations, each R 2 Independently selected from C1 alkyl groups substituted with one or more substituents, wherein the one or more substituents are independently selected from -OR 7 and -OC(O)R 7 In some implementations, each R 2 It is independently selected from -CH2OH and -CH2OC(O)CH3.

[0035] In some implementations, each R 3 Independently selected from -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 3 Independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 3 Independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 72. In some implementations, each R 3 Independently selected from -OR 7 and -OC(O)R 7 In some implementations, R 3 It is independently selected from -OH and -OC(O)CH3.

[0036] In some implementations, each R 4 Independently selected from -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 4 Independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 4 Independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 2. In some implementations, each R 4 Independently selected from -OR 7 and -OC(O)R 7 In some implementations, R 4 It is independently selected from -OH and -OC(O)CH3.

[0037] In some implementations, each R 5 Independently selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 2. In some implementations, each R 5 Selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2 and -N(R 7 )C(O)OR 7 In some implementations, each R 5 Independently selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 In some implementations, each R 5 It is independently selected from -N(H)C(O)CH3.

[0038] In some implementations, each R 6 Independently selected from hydrogen, halogen, -CN, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; and C substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R)7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 6 Independently selected from hydrogen, halogen, -CN, -OR 7 -SR 7 -N(R) 7 )2 and C, optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 and -N(R) 7 2. In some implementations, each R 6 It is independently selected from hydrogen, halogen, -CN, -OH, -SH and -NH2.

[0039] In some implementations, each R 7 Independently selected from: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 7Independently selected from: hydrogen; and C4 groups optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings, 3- to 10-membered heterocyclic rings. In some implementations, each R... 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 Alkyl group). In some embodiments, R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH, and -SH. In some embodiments, each R 7 Independently selected from hydrogen. In some implementations, each R... 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 alkyl).

[0040] In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2 and C. 1-3 Alkyl; R 1 Selected from -OP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(OR7 )O-;R 2 It is a C1 alkyl group substituted with -OH or -OC(O)CH3; R 3 It is -OH or -OC(O)CH3; R 4 It is -OH or -OC(O)CH3; and R 5 It is -NH(O)CH3.

[0041] In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2 and C. 1-3 Alkyl; R 1 Selected from -OP(O)(OH)O-, -OP(S)(OH)O-, -OP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(OH)O-; R 2 It is a C1 alkyl group substituted with -OH or -OC(O)CH3; R 3 It is -OH or -OC(O)CH3; R 4 It is -OH or -OC(O)CH3; and R 5 It is -NH(O)CH3. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2 and C. 1-3 Alkyl; R 1 Selected from -OP(O)(OH)O-, -OP(S)(OH)O- and -OP(OH)O-; R 2 It is a C1 alkyl group substituted with -OH or -OC(O)CH3; R 3 It is -OH or -OC(O)CH3; R 4 It is -OH or -OC(O)CH3; and R 5 It is -NH(O)CH3.

[0042] In some embodiments, the compounds of formula (I) are selected from: .

[0043] In some embodiments, the compounds of formula (II) are selected from: .

[0044] In some embodiments, the compound of formula (I), (II), or (III) binds to lectins. In some embodiments, the compound binds to desialyl glycoprotein receptors. In some embodiments, the compound binds to hepatocyte receptors. In some embodiments, the compound binds to hepatocyte receptors. In some embodiments, the compound targets hepatocytes.

[0045] In the embodiments provided herein, the compositions described herein comprise a GalNAc compound. In some embodiments, the GalNAc compound describes a compound of formula (A) or formula (B): (A), or (B); Or its salt, wherein: each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein If z is 3, then Y is C; if z is 2, then Y is CR. 6 Or, if z is 1, then Y is C(R). 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7)C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 Selected from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 -S(O)2R 7 -OS(O)2R 7 -OP(O)(OR) 7 )2、-OP(S)(OR 7 )2、-SP(O)(OR 7 )2、-OP(O)(SR 7 (OR) 7 ), -OP(O)(OR 7 )N(R 7 )2、-OP(S)(OR 7 )N(R 7 )2、-SP(O)(OR 7 )N(R 7 )2、-OP(O)(SR 7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(S)(N(R 7 )2)2、-SP(O)(N(R 7 )2)2、-OP(OR 7 )2、-SP(OR 7 2. -OP(OR) 7 (SR)7 -OP(OR) 7 )N(R 7 )2、-OP(SR 7 )N(R 7 )2、-SP(OR 7 )N(R 7 )2、-OP(N(R 7 )2)2 and -SP(N(R 7 )2)2; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 )2; Each R 6 Selected independently from: hydrogen; Halogen, -CN, -NO2, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ;as well as C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

[0046] In some embodiments, each w is independently selected from any value from 1 to 20. In some embodiments, each w is independently selected from any value from 1 to 15. In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is independently selected from any value from 1 to 4. In some embodiments, each w is independently selected from any value from 1 to 3. In some embodiments, each w is independently selected from any value from 1 to 2. In some embodiments, w is 1. In some embodiments, w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0047] In some embodiments, each v is independently selected from any value from 1 to 20. In some embodiments, each v is independently selected from any value from 1 to 15. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is independently selected from any value from 1 to 4. In some embodiments, each v is independently selected from any value from 1 to 3. In some embodiments, each v is independently selected from any value from 1 to 2. In some embodiments, each v is 1. In some embodiments, v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0048] In some embodiments, n is selected from any value from 1 to 20. In some embodiments, n is selected from any value from 1 to 15. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 9. In some embodiments, n is selected from any value from 1 to 8. In some embodiments, n is selected from any value from 1 to 7. In some embodiments, n is selected from any value from 1 to 6. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is selected from any value from 1 to 4. In some embodiments, n is selected from any value from 2 to 4. In some embodiments, n is selected from any value from 1 to 3. In some embodiments, n is 2 or 3. In some embodiments, n is 3. In some embodiments, n is selected from any value from 1 to 2. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0049] In some embodiments, m is selected from any value from 1 to 20. In some embodiments, m is selected from any value from 1 to 15. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 9. In some embodiments, m is selected from any value from 1 to 8. In some embodiments, m is selected from any value from 1 to 7. In some embodiments, m is selected from any value from 3 to 7. In some embodiments, m is selected from any value from 1 to 6. In some embodiments, m is selected from any value from 2 to 6. In some embodiments, m is selected from any value from 3 to 6. In some embodiments, m is selected from any value from 4 to 6. In some embodiments, m is 6. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from any value from 3 to 5. In some embodiments, m is 5. In some embodiments, m is 4 or 5. In some embodiments, m is selected from any value from 1 to 4. In some embodiments, m is 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from any value from 2 to 4. In some embodiments, m is selected from any value from 1 to 3. In some implementations, m is 3. In some implementations, m is selected from any value from 1 to 2. In some implementations, m is 2. In some implementations, m is 1. In some implementations, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0050] In some implementations, z is selected from any value from 1 to 3. In some implementations, z is 3 and Y is C. In some implementations, z is 2 and Y is CR. 6 In some implementations, z is 1 and Y is C(R). 6 )2.

[0051] In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7-OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents, said substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 3-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents, said substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7In some embodiments, Q is selected from a C6 carbon ring optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some embodiments, Q is selected from a C5 carbon ring optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some embodiments, Q is selected from C that is optionally substituted with one or more substituents. 5-6A carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl, cyclohexyl, cyclopentadiene, and cyclopentyl, each of which is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, and -NH2. In some embodiments, Q is selected from phenyl and cyclohexyl. In some embodiments, Q is phenyl. In some embodiments, Q is cyclohexyl.

[0052] In some implementation schemes, R 1 Selected from -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 -S(O)2R 7 -OS(O)2R 7 -OP(O)(OR) 7 )2、-OP(S)(OR 7 )2、-SP(O)(OR 7 )2、-OP(O)(SR 7 (OR) 7 ), -OP(O)(OR 7 )N(R 7 )2、-OP(S)(OR 7 )N(R 7 )2、-SP(O)(OR 7 )N(R 7 )2、-OP(O)(SR 7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(S)(N(R 7)2)2, -SP(O)(N(R 7 )2)2, -OP(OR 7 )2, -SP(OR 7 )2, -OP(OR 7 )(SR 7 ), -OP(OR 7 )N(R 7 )2, -OP(SR 7 )N(R 7 )2, -SP(OR 7 )N(R 7 )2, -OP(N(R 7 )2)2 and -SP(N(R 7 )2)2. In some embodiments, R 1 is selected from -OR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -OP(O)(OR 7 )2, -OP(O)(OR 7 )N(R 7 )2, -OP(O)(N(R 7 )2)2, -OP(OR 7 )2, OP(OR 7 )N(R 7 )2 and -OP(N(R 7 )2)2. In some embodiments, R 1 is selected from -SR 7 , -S(O)R 7 , -S(O)2R 7 , -OS(O)2R 7 , -OP(S)(OR 7 )2, -SP(O)(OR 7 )2, -OP(O)(SR 7 S )(OR 7 ), -OP(S)(OR 7 )N(R 7 )2, -SP(O)(OR7 )N(R 7 )2, -OP(O)(SR 7 )N(R 7 )2, -OP(S)(N(R 7 )2)2, -SP(O)(N(R 7 )2)2, -SP(OR 7 )2, -OP(OR 7 )(SR 7 )、-OP(SR 7 )N(R 7 )2, -SP(OR 7 )N(R 7 )2和-SP(N(R 7 )2)2。In some embodiments, R 1 is selected from -OP(O)(OR 7 )2, -OP(S)(OR 7 )2, -SP(O)(OR 7 )2, -OP(O)(SR 7 )(OR 7 )、-OP(O)(OR 7 )N(R 7 )2, -OP(S)(OR 7 )N(R 7 )2, -SP(O)(OR 7 )N(R 7 )2, -OP(O)(SR 7 )N(R 7 )2, -OP(O)(N(R 7 )2)2, -OP(S)(N(R 7 )2)2, -SP(O)(N(R 7 )2)2, -OP(OR 7 )2, -SP(OR 7 )2, -OP(OR 7 )(SR 7 )、-OP(OR 7 )N(R 7 )2, -OP(SR 7 )N(R 7 )2, -SP(OR 7 )N(R 7 )2, -OP(N(R 7 )2)2和-SP(N(R 7 )2)2。In some embodiments, R 1 is selected from -OP(O)(OR 7 )2, -OP(O)(OR7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(OR 7 2. -OP(OR) 7 )N(R 7 )2 and -OP((NR 7 )2)2. In some implementations, R 1 Selected from -OP(O)(OR 7 )2 and -OP(OR 7 )N(R 7 )2. In some implementation schemes, R 1 Selected from -OP(O)(OCH2CH3)OH and -OP(OCH2CH2CN)N(CH(CH3)2)2. In some embodiments, R 1 It is -OP(OCH2CH2CN)N(CH(CH3)2)2.

[0053] In some implementations, each R 2 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 2 Independently selected from C14 cells substituted with one or more substituents. 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -OC(O)R 7 -SR 7 -N(R) 7 )2、-C(O)R 7 and -S(O)R 7 In some implementations, each R 2 Independently selected from C14 cells substituted with one or more substituents.1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 2. In some implementations, each R 2 Independently selected from C1 alkyl groups substituted with one or more substituents, wherein the one or more substituents are independently selected from -OR 7 and -OC(O)R 7 In some implementations, each R 2 It is independently selected from -CH2OH and -CH2OC(O)CH3.

[0054] In some implementations, each R 3 Independently selected from -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 3 Independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 3 Independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 2. In some implementations, each R 3 Independently selected from -OR 7 and -OC(O)R 7 In some implementations, R 3 It is independently selected from -OH and -OC(O)CH3.

[0055] In some implementations, each R 4 Independently selected from -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 4 Independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 In some implementations, each R 4 Independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 2. In some implementations, each R 4 Independently selected from -OR 7 and -OC(O)R 7 In some implementations, R 4 It is independently selected from -OH and -OC(O)CH3.

[0056] In some implementations, each R 5 Independently selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 2. In some implementations, each R 5Selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2 and -N(R 7 )C(O)OR 7 In some implementations, each R 5 Independently selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 In some implementations, each R 5 It is independently selected from -N(H)C(O)CH3.

[0057] In some implementations, each R 6 Independently selected from hydrogen, halogen, -CN, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; and C substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7and -S(O)R 7 In some implementations, each R 6 Independently selected from hydrogen, halogens, -CN, -OR 7 -SR 7 -N(R) 7 )2 and C, optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 and -N(R) 7 2. In some implementations, each R 6 It is independently selected from hydrogen, halogen, -CN, -OH, -SH and -NH2.

[0058] In some implementations, each R 7 Independently selected from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The carbon ring and 3 to 10-membered heterocycles, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups. In some embodiments, each R... 7 Independently selected from: hydrogen; and C4 groups optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings, 3- to 10-membered heterocyclic rings. In some implementations, each R... 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 Alkyl). In some embodiments, each R 7 Independently selected from hydrogen. In some implementations, each R... 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 Alkyl). In some embodiments, each R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH and -SH.

[0059] In some embodiments, the compound of formula (A) is selected from: .

[0060] In some embodiments, this document provides a compound represented by formula (B): .

[0061] In some embodiments, the phosphate is deprotonated to form a salt of formula (I), (II), (A), or (B). In some embodiments, the cation is a metal ion, such as a metal cation. Examples of non-limiting metal cations include Na. + K + Mg 2+ and Ca 2+ In some implementations, the metal cation includes Na.+ In some embodiments, the metal cation includes K. + In some embodiments, the metal cation includes Mg. 2+ In some embodiments, the metal cation includes Ca. 2+ In some embodiments, the cation is a small organic or inorganic molecule. In some embodiments in which the compound is a deprotonated form of formula (I) or (II), the cation is a positively charged nucleic acid present in an oligonucleotide.

[0062] Some implementation schemes include the following, where J is an oligonucleotide: J may include one or more additional phosphate esters or one or more thiophosphate esters linked to an oligonucleotide. J may include one or more additional phosphate esters linked to an oligonucleotide. J may include one or more thiophosphate esters linked to an oligonucleotide.

[0063] Some implementation schemes include the following, where J is an oligonucleotide: J may include one or more additional phosphate esters or one or more thiophosphate esters linked to an oligonucleotide. J may include one or more additional phosphate esters linked to an oligonucleotide. J may include one or more thiophosphate esters linked to an oligonucleotide.

[0064] Some implementation schemes include the following, where J is an oligonucleotide: J may include one or more phosphate esters or thiophosphate esters linked to an oligonucleotide. J may include one or more phosphate esters linked to an oligonucleotide. J may include one or more phosphate esters linked to an oligonucleotide. J may include one or more thiophosphate esters linked to an oligonucleotide.

[0065] Some implementation schemes include the following, where J is an oligonucleotide: The structure attached to the oligonucleotide (J) in this compound is an example of the GalNAc moiety. J may include one or more phosphate esters or thiophosphate esters linked to the oligonucleotide. J may include one or more phosphate esters linked to the oligonucleotide. J may include one or more thiophosphate esters linked to the oligonucleotide. J may include thiophosphate esters linked to the oligonucleotide.

[0066] Some implementation schemes include the following, where J is an oligonucleotide: J may include one or more additional phosphate esters or one or more thiophosphate esters linked to an oligonucleotide. J may include one or more additional phosphate esters linked to an oligonucleotide. J may include one or more thiophosphate esters linked to an oligonucleotide.

[0067] Some implementation schemes include the following, where J is an oligonucleotide: J may include one or more additional phosphate esters or one or more thiophosphate esters linked to an oligonucleotide. J may include one or more additional phosphate esters linked to an oligonucleotide. J may include one or more thiophosphate esters linked to an oligonucleotide.

[0068] Some implementation schemes include the following, where J is an oligonucleotide: J may include one or more phosphate esters or thiophosphate esters linked to an oligonucleotide. J may include one or more phosphate esters linked to an oligonucleotide. J may include one or more phosphate esters linked to an oligonucleotide. J may include one or more thiophosphate esters linked to an oligonucleotide.

[0069] Some implementation schemes include the following, where J is an oligonucleotide: The structure attached to the oligonucleotide (J) in this compound may be referred to as "ETL17," and is an example of the GalNAc moiety. J may include one or more phosphate esters or thiophosphate esters linked to the oligonucleotide.

[0070] Some implementation schemes include the following, where J is an oligonucleotide: The structure attached to the oligonucleotide (J) in this compound is an example of the GalNAc moiety. J may include one or more phosphate esters or thiophosphate esters linked to the oligonucleotide. In any embodiment, J may include additional linkers.

[0071] 1. Analogs Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can be... Z -or EIt exists in the - form (or cis- or trans-). Furthermore, some chemical entities can exist in different tautomeric forms. Unless otherwise stated, the compounds described herein also include all... Z -、 E - and tautomerism.

[0072] A "tautomer" is a molecule or part thereof in which a proton may transfer from one atom of the molecule to another atom within the same molecule. The compounds presented herein exist as tautomers in some embodiments. In cases where tautomerism is possible, a chemical equilibrium of tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include: .

[0073] The compounds and some of the compounds disclosed herein are employed in different enriched isotopic forms in some embodiments, such as those enriched with... 2 H, 3 H, 11 C 13 C and / or 14 C. In one particular embodiment, the compound is deuterated at at least one position. These deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or potency, thereby prolonging the duration of action of the drug.

[0074] Unless otherwise stated, the compounds and portions described herein are intended to include compounds and portions that differ only in the presence of atoms enriched by one or more isotopes. For example, compounds and portions having existing structures but with hydrogen replaced by deuterium or tritium, or carbon replaced by... 13 C or 14 Compounds enriched with carbon and substituted with carbon all fall within the scope of this disclosure.

[0075] The compounds and portions thereof disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting the compound. For example, the compounds may be composed of isotopes such as deuterium (… 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Marking. 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 Isotopic substitutions of I are all considered. All isotopic variants of the compounds and portions thereof of the present invention, whether or not they are radioactive, are included within the scope of the present invention.

[0076] In some embodiments, the disclosed compounds and some or all of them are... 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art and are included by way of non-limiting example only.

[0077] Deuterium-substituted compounds are synthesized using a variety of methods, as described in: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0078] Deuteration starting materials are readily available and can be processed by the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and structural units are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0079] The disclosure herein includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. The compounds disclosed herein, possessing functional groups that are sufficiently acidic, sufficiently basic, or both, can react with a variety of inorganic bases, inorganic acids, and organic acids to form salts. Alternatively, compounds with intrinsic charges, such as those containing quaternary ammonium nitrogen, can form salts with suitable counterions, such as bromides, chlorides, or fluorides, particularly bromides.

[0080] The compounds described herein may exist in some cases as diastereomers, enantiomers, or other stereoisomers. The compounds provided herein include all diastereomers, enantiomers, and epimers, as well as suitable mixtures thereof. Separation of stereoisomers can be performed by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0081] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be present as pharmaceutically acceptable salts. Furthermore, in some embodiments, active metabolites of these compounds having the same activity are also included within the scope of this disclosure. Additionally, the compounds described herein may be present in solvent-free or solvated forms, wherein pharmaceutically acceptable solvents are, for example, water, ethanol, etc. The solvated forms of the compounds described herein are also considered disclosed.

[0082] B. Oligonucleotides In some embodiments, this document provides compositions or compounds comprising oligonucleotides. The oligonucleotides may be conjugated to the GalNAc moiety. The oligonucleotides may be directly linked to a linker attached to the GalNAc moiety. The oligonucleotides may be used in the methods described herein.

[0083] In some embodiments, the oligonucleotide binds to a target oligonucleotide. Examples of target oligonucleotides include target RNA or target DNA. In some embodiments, the oligonucleotide binds to target DNA. In some embodiments, the oligonucleotide binds to target DNA and inhibits the expression of RNA (e.g., mRNA) derived from that target DNA. In some embodiments, the oligonucleotide binds to target RNA. Target RNA may include target mRNA. In some embodiments, the oligonucleotide binds to target mRNA. In some embodiments, the oligonucleotide inhibits target mRNA, for example, by reducing the amount of target mRNA, causing degradation of target mRNA, or reducing or preventing translation of target mRNA. In some embodiments, the oligonucleotide reduces the amount of target protein produced from target mRNA, for example, by inhibiting target mRNA. The oligonucleotide may include small interfering RNA (siRNA). The oligonucleotide may include antisense oligonucleotides (ASO).

[0084] In some embodiments, the composition comprises an oligonucleotide that binds to the target oligonucleotide and inhibits the expression of a target protein encoded by the target oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that binds to the target RNA and inhibits the expression of a target protein encoded by the target RNA. In some embodiments, the composition comprises an oligonucleotide that binds to the target mRNA and inhibits the expression of a target protein encoded by the target mRNA.

[0085] In some embodiments, the composition comprises an oligonucleotide that binds to the target oligonucleotide and inhibits the expression of a second oligonucleotide encoded by the target oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that binds to the target DNA and inhibits the expression of a target RNA encoded by the target DNA. In some embodiments, the composition comprises an oligonucleotide that binds to the target DNA and inhibits the expression of a target mRNA encoded by the target DNA.

[0086] Target oligonucleotides can be identified in a variety of ways. In some cases, target oligonucleotides include mRNA whose expression level is associated with the pathogenesis of a disease (e.g., liver disease). In others, target oligonucleotides include mRNA encoded by genes with specific genotypes associated with the disease. Large-scale human genetic data can improve the success rate of drug discovery and development. Genome-wide association studies (GWAS) can detect associations between genetic variants and traits in a population sample. GWAS can enable a better understanding of the biology of diseases and provide applicable treatments. GWAS can utilize genotyping and / or sequencing data and typically involves the evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is a case-control study, which involves comparing the frequency of variants in cases relative to controls. If a variant has a significantly different frequency in cases relative to controls, this variant is said to be associated with the disease. Association statistics that can be used in GWAS are the p-value as a measure of statistical significance; the odds ratio (OR) as a measure of effect size; or the beta coefficient (β) as a measure of effect size. Researchers typically assume additive genetic models and calculate allele advantage ratios, which are the increased (or decreased) risk of disease conferred by each additional copy of the allele (compared to not carrying a copy of that allele). Another concept in GWAS design and interpretation is linkage disequilibrium, which is a non-random association of alleles. The presence of linkage disequilibrium can confuse which variant is "causal."

[0087] Functional annotation and / or wet laboratory experiments of variants can identify causal genetic variants identified via GWAS and, in many cases, may lead to the identification of disease-causing genes. In particular, understanding the functional effects of causal genetic variants (e.g., loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) can allow the variant to be used as a representative of therapeutic regulation of a target gene, or to gain insights into the potential therapeutic efficacy and safety of therapeutic agents that regulate this target.

[0088] The identification of such gene-disease associations has provided insights into the biology of disease and can be used to identify novel therapeutic targets for the pharmaceutical industry. To translate therapeutic insights derived from human genetics, the disease biology in a patient can be exogenously “programmed” to replicate observations from human genetics. Several potential therapeutic modalities exist for translating therapeutic targets identified via human genetics into novel drugs. These can include well-established modalities such as small molecules and monoclonal antibodies; mature modalities such as oligonucleotides; and emerging modalities such as gene therapy and gene editing. The choice of modality can depend on several factors, including the location of the target (e.g., intracellular, extracellular, or secreted), the relevant tissue (e.g., the liver), and the relevant indication. Such research can be used to identify specific targets associated with liver conditions for inhibition by siRNA or ASO via the components or compounds described herein.

[0089] Some embodiments include methods for preparing oligonucleotides or siRNAs using the methods disclosed herein. For example, any aspect of the synthesis steps included in the examples herein can be used. Some embodiments include preparing a GalNAc moiety, or preparing an oligonucleotide having a GalNAc moiety.

[0090] 1. siRNA In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide (e.g., mRNA), wherein the oligonucleotide comprises small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide (e.g., mRNA), wherein the oligonucleotide comprises siRNA containing a sense strand and an antisense strand. In some embodiments, the sense strand comprises RNA. In some embodiments, the antisense strand comprises RNA.

[0091] In some embodiments, the sense chain is 12 to 30 nucleotides long. In some embodiments, the sense chain is 14 to 30 nucleotides long. In some embodiments, the sense chain is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides long. In some embodiments, the sense chain is at least 12 nucleotides long. In some embodiments, the sense chain is at least 14 nucleotides long. In some embodiments, the sense chain is at least 16 nucleotides long. In some embodiments, the sense chain is at least 18 nucleotides long. In some embodiments, the sense chain is at least 20 nucleotides long. In some embodiments, the sense chain is at least 22 nucleotides long. In some embodiments, the sense chain is at least 24 nucleotides long. In some embodiments, the sense chain is at least 26 nucleotides long. In some embodiments, the sense strand is at least 28 nucleotides long. In some embodiments, the sense strand is at least 30 nucleotides long. In some embodiments, the sense strand is no more than about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides long. In some embodiments, the sense strand is no more than 12 nucleotides long. In some embodiments, the sense strand is no more than 14 nucleotides long. In some embodiments, the sense strand is no more than 16 nucleotides long. In some embodiments, the sense strand is no more than 18 nucleotides long. In some embodiments, the sense strand is no more than 20 nucleotides long. In some embodiments, the sense strand is no more than 22 nucleotides long. In some embodiments, the sense strand is no more than 24 nucleotides long. In some embodiments, the sense strand is no more than 26 nucleotides long. In some embodiments, the sense strand is no more than 28 nucleotides long. In some implementations, the length of the sense strand does not exceed 30 nucleotides.

[0092] In some embodiments, the antisense strand is 12 to 30 nucleotides long. In some embodiments, the antisense strand is 14 to 30 nucleotides long. In some embodiments, the antisense strand is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides long. In some embodiments, the antisense strand is at least 12 nucleotides long. In some embodiments, the antisense strand is at least 14 nucleotides long. In some embodiments, the antisense strand is at least 16 nucleotides long. In some embodiments, the antisense strand is at least 18 nucleotides long. In some embodiments, the antisense strand is at least 20 nucleotides long. In some embodiments, the antisense strand is at least 22 nucleotides long. In some embodiments, the antisense strand is at least 24 nucleotides long. In some embodiments, the antisense strand is at least 26 nucleotides long. In some embodiments, the antisense strand is at least 28 nucleotides long. In some embodiments, the antisense strand is at least 30 nucleotides long. In some embodiments, the antisense strand is no more than about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides long. In some embodiments, the antisense strand is no more than 12 nucleotides long. In some embodiments, the antisense strand is no more than 14 nucleotides long. In some embodiments, the antisense strand is no more than 16 nucleotides long. In some embodiments, the antisense strand is no more than 18 nucleotides long. In some embodiments, the antisense strand is no more than 20 nucleotides long. In some embodiments, the antisense strand is no more than 22 nucleotides long. In some embodiments, the antisense strand is no more than 24 nucleotides long. In some embodiments, the antisense strand is no more than 26 nucleotides long. In some embodiments, the antisense strand is no more than 28 nucleotides long. In some embodiments, the antisense strand is no more than 30 nucleotides long. In some implementations, the antisense chain is the same length as the sense chain.

[0093] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target oligonucleotide (e.g., mRNA), wherein the oligonucleotide comprises siRNA containing a sense strand and an antisense strand, wherein the sense strand is 12 to 30 nucleotides in length. In some embodiments, the composition comprises a sense strand of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length, or a range defined by any two of the above numbers. In some embodiments, the composition comprises an antisense strand of 12 to 30 nucleotides in length. In some embodiments, the composition comprises an antisense strand of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleosides, or a range defined by any two of the above numbers.

[0094] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target oligonucleotide (e.g., mRNA), wherein the oligonucleotide comprises siRNA containing a sense strand and an antisense strand, each strand being independently about 14 to 30 nucleotides in length, and at least one of the sense strands and the antisense strand contains a nucleoside sequence of about 12 to 30 consecutive nucleotides containing a full-length human target mRNA sequence. In some embodiments, at least one of the sense strands and the antisense strand contains a nucleoside sequence of at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more consecutive nucleotides containing one of the full-length human target mRNA sequences.

[0095] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises siRNA containing a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

[0096] In some embodiments, the sense strand further includes a 3' overhang. In some embodiments, the 3' overhang contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, or a range of nucleotides defined by any two of the above numbers. In some embodiments, the 3' overhang contains 1, 2, or more nucleotides. In some embodiments, the 3' overhang contains 2 nucleotides. In some embodiments, the sense strand further includes a 5' overhang. In some embodiments, the 5' overhang contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, or a range of nucleotides defined by any two of the above numbers. In some embodiments, the 5' overhang contains 1, 2, or more nucleotides. In some embodiments, the 5' overhang contains 2 nucleotides.

[0097] In some embodiments, the antisense strand further includes a 3' overhang. In some embodiments, the 3' overhang contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, or a range of nucleotides defined by any two of the above numbers. In some embodiments, the 3' overhang contains 1, 2, or more nucleotides. In some embodiments, the 3' overhang contains 2 nucleotides. In some embodiments, the antisense strand further includes a 5' overhang. In some embodiments, the 5' overhang contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, or a range of nucleotides defined by any two of the above numbers. In some embodiments, the 5' overhang contains 1, 2, or more nucleotides. In some embodiments, the 5' overhang contains 2 nucleotides.

[0098] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises siRNA containing sense and antisense strands, wherein the siRNA binds to a 19-mer in human target mRNA encoding the target protein. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer in human target mRNA.

[0099] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises siRNA containing a sense strand and an antisense strand, wherein the siRNA binds to a 17-mer in a non-human primate target mRNA encoding the target protein. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer in the non-human primate target mRNA.

[0100] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds to a 19-mer, or a combination thereof, in human target mRNA encoding the target protein. In some embodiments, the siRNA binds to a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer, or 25-mer in human target mRNA.

[0101] 2. ASO In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target oligonucleotide (e.g., mRNA), wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleotides in length. In some embodiments, the ASO is 14-30 nucleotides in length. In some embodiments, the ASO is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length, or a range defined by any two of the above numbers. In some embodiments, the ASO is 15-25 nucleotides in length. In some embodiments, the ASO is 20 nucleotides in length. In some embodiments, the ASO comprises DNA.

[0102] In some embodiments, the ASO is 12-30 nucleotides in length. In some embodiments, the ASO is 14-30 nucleotides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the ASO is at least 12 nucleotides in length. In some embodiments, the ASO is at least 14 nucleotides in length. In some embodiments, the ASO is at least 16 nucleotides in length. In some embodiments, the ASO is at least 18 nucleotides in length. In some embodiments, the ASO is at least 20 nucleotides in length. In some embodiments, the ASO is at least 22 nucleotides in length. In some embodiments, the ASO is at least 24 nucleotides in length. In some embodiments, the ASO is at least 26 nucleotides in length. In some embodiments, the ASO is at least 28 nucleotides in length. In some embodiments, the ASO is at least 30 nucleotides long. In some embodiments, the ASO is no longer than about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, the ASO is no longer than 12 nucleotides. In some embodiments, the ASO is no longer than 14 nucleotides. In some embodiments, the ASO is no longer than 16 nucleotides. In some embodiments, the ASO is no longer than 18 nucleotides. In some embodiments, the ASO is no longer than 20 nucleotides. In some embodiments, the ASO is no longer than 22 nucleotides. In some embodiments, the ASO is no longer than 24 nucleotides. In some embodiments, the ASO is no longer than 26 nucleotides. In some embodiments, the ASO is no longer than 28 nucleotides. In some embodiments, the ASO is no longer than 30 nucleotides.

[0103] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises an ASO of about 12-30 nucleotides in length and a nucleoside sequence complementary to about 12-30 consecutive nucleotides of the target sequence of the full-length human premRNA encoding the target protein; wherein (i) the oligonucleotide comprises a modification including a modified nucleoside and / or a modified inter-nucleoside bond, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0104] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises an ASO of about 12-30 nucleotides in length and a nucleoside sequence complementary to about 12-30 consecutive nucleotides in the full-length human target mRNA sequence encoding the target protein; wherein (i) the oligonucleotide comprises a modification including a modified nucleoside and / or a modified inter-nucleoside bond, and / or (ii) the composition comprises a pharmaceutically acceptable carrier.

[0105] 1. Oligonucleotide modification patterns In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide comprises a modification including a modified nucleoside and / or a modified inter-nucleoside link, and / or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification including a modified nucleoside and / or a modified inter-nucleoside link. In some embodiments, the oligonucleotide comprises a modified inter-nucleoside link. In some embodiments, the modified inter-nucleoside link comprises alkylphosphonates, thiophosphates, methylphosphonates, dithiophosphates, alkylthiophosphonates, aminophosphates, carbamates, carbonates, triphosphates, acetylimine esters, or carboxymethyl esters, or combinations thereof. In some embodiments, the modified inter-nucleoside link comprises one or more thiophosphate links. The benefits of the modified inter-nucleoside link may include reduced toxicity or improved pharmacokinetics.

[0106] In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide comprises modified internucleotide links, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleotide links, or a range of modified internucleotide links defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleotide links. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleotide links. In some embodiments, the oligonucleotide comprises 2 or more modified nucleoside links, 3 or more modified nucleoside links, 4 or more modified nucleoside links, 5 or more modified nucleoside links, 6 or more modified nucleoside links, 7 or more modified nucleoside links, 8 or more modified nucleoside links, 9 or more modified nucleoside links, 10 or more modified nucleoside links, 11 or more modified nucleoside links, etc. Multiple modified nucleoside links, 12 or more modified nucleoside links, 13 or more modified nucleoside links, 14 or more modified nucleoside links, 15 or more modified nucleoside links, 16 or more modified nucleoside links, 17 or more modified nucleoside links, 18 or more modified nucleoside links, 19 or more modified nucleoside links, or 20 or more modified nucleoside links.

[0107] In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside includes locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or combinations thereof. In some embodiments, the modified nucleoside includes LNA. In some embodiments, the modified nucleoside includes 2',4'-restricted ethyl nucleic acid. In some embodiments, the modified nucleoside includes HLA. In some embodiments, the modified nucleoside includes CeNA. In some embodiments, the modified nucleoside includes 2'-methoxyethyl. In some embodiments, the modified nucleoside includes 2'-O-alkyl. In some embodiments, the modified nucleoside includes 2'-O-allyl. In some embodiments, the modified nucleoside includes 2'-fluoro. In some embodiments, the modified nucleoside includes 2'-deoxy. In some embodiments, the modified nucleoside includes 2'-O-methyl nucleoside, 2'-deoxyfluorinated nucleoside, 2'-ON-methylacetamido(2'-O-NMA) nucleoside, 2'-O-dimethylaminoethoxyethyl(2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl(2'-O-AP) nucleoside, or 2'-ara-F, or combinations thereof. In some embodiments, the modified nucleoside includes 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside includes 2'-deoxyfluorinated nucleoside. In some embodiments, the modified nucleoside includes 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside includes 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside includes 2'-O-aminopropyl(2'-O-AP) nucleoside. In some embodiments, the modified nucleoside includes 2'-ara-F. In some embodiments, the modified nucleoside includes one or more 2'-fluorinated nucleosides. In some embodiments, the modified nucleoside includes 2'O-alkyl-modified nucleosides. The benefits of modified nucleosides may include reduced toxicity or improved pharmacokinetics.

[0108] In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the foregoing numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

[0109] In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid includes cholesterol, myristoyl, palmitoyl, stearoyl, lithochyl, docosanoyl, docosahexaenoic acid yl, myristyl, palmityl, stearyl, or α-tocopherol, or combinations thereof.

[0110] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may comprise an N-acetylgalactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetylglucosamine moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may comprise 1, 2, 3, or more sugar molecules. The sugar moiety may be attached to the 3' or 5' end of the oligonucleotide. The sugar moiety may comprise an N-acetylgalactose moiety. The sugar moiety may comprise an N-acetylglucosamine (GalNAc) moiety. The sugar moiety may comprise an N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may comprise a fucose moiety. The sugar moiety may comprise a mannose moiety. N-acetylglucosamine, GlcNAc, fucose, or mannose can be used to target macrophages because they can target or bind to mannose receptors, such as CD206.

[0111] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc can be used to target hepatocytes. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. The GalNAc moiety may comprise 1, 2, 3 or more GalNAc molecules. The GalNAc moiety may comprise a bivalent or trivalent branching linker. The oligonucleotide may be attached to 1, 2 or 3 GalNAc molecules via a bivalent or trivalent branching linker. The GalNAc moiety may be attached to the 3' or 5' end of the oligonucleotide.

[0112] Oligonucleotides may include purines. Examples of purines include adenine (A) or guanine (G) or their modified forms. Oligonucleotides may also include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U) or their modified forms.

[0113] In some embodiments, the purines of the oligonucleotide include 2'-fluorine-modified purines. In some embodiments, the purines of the oligonucleotide include 2'-O-methyl-modified purines. In some embodiments, the purines of the oligonucleotide include a mixture of 2'-fluorine and 2'-O-methyl-modified purines. In some embodiments, all purines of the oligonucleotide include 2'-fluorine-modified purines. In some embodiments, all purines of the oligonucleotide include 2'-O-methyl-modified purines. In some embodiments, all purines of the oligonucleotide include a mixture of 2'-fluorine and 2'-O-methyl-modified purines. In some embodiments, the 2'-O-methyl group comprises 2'-O-methyl.

[0114] In some embodiments, the pyrimidines of the oligonucleotide include 2'-fluorine-modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide include 2'-O-methyl-modified pyrimidines. In some embodiments, the pyrimidines of the oligonucleotide include a mixture of 2'-fluorine and 2'-O-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide include 2'-fluorine-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide include 2'-O-methyl-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide include a mixture of 2'-fluorine and 2'-O-methyl-modified pyrimidines.

[0115] In some embodiments, the purine of the oligonucleotide comprises a 2'-fluorine-modified purine, and the pyrimidine of the oligonucleotide comprises a mixture of 2'-fluorine and 2'-O-methyl-modified pyrimidines. In some embodiments, the purine of the oligonucleotide comprises a 2'-O-methyl-modified purine, and the pyrimidine of the oligonucleotide comprises a mixture of 2'-fluorine and 2'-O-methyl-modified pyrimidines. In some embodiments, the purine of the oligonucleotide comprises a 2'-fluorine-modified purine, and the pyrimidine of the oligonucleotide comprises a 2'-O-methyl-modified pyrimidine. In some embodiments, the purine of the oligonucleotide comprises a 2'-O-methyl-modified purine, and the pyrimidine of the oligonucleotide comprises a 2'-fluorine-modified pyrimidine. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2'-fluorine-modified pyrimidine, and the purine of the oligonucleotide comprises a mixture of 2'-fluorine and 2'-O-methyl-modified purines. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2'-O-methyl-modified pyrimidine, and the purine of the oligonucleotide comprises a mixture of 2'-fluorine and 2'-O-methyl-modified purines. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2'-fluorine-modified pyrimidine, and the purine of the oligonucleotide comprises a 2'-O-methyl-modified purine. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2'-O-methyl-modified pyrimidine, and the purine of the oligonucleotide comprises a 2'-fluorine-modified purine.

[0116] In some embodiments, all purines of the oligonucleotide comprise 2'-fluorinated purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2'-fluorinated and 2'-O-methylinated pyrimidines. (This text is repeated four times in the original.) In some embodiments, all pyrimidines of the oligonucleotide include 2'-fluorinated pyrimidines, and all purines of the oligonucleotide include 2'-O-methylinated purines.

[0117] 2. siRNA modification pattern In some embodiments, the sense chain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 modified nucleoside interlinks, or modified nucleoside interlinks within the range defined by any two integers above. In some embodiments, the sense chain comprises 1-11 modified nucleoside interlinks. In some embodiments, the sense chain comprises 2-6 modified nucleoside interlinks. In some embodiments, the sense chain comprises 5 modified nucleoside interlinks. In some embodiments, the sense chain comprises 4 modified nucleoside interlinks.

[0118] In some embodiments, the antisense strand comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 modified nucleoside interlinks, or modified nucleoside interlinks within the range defined by any two integers above. In some embodiments, the antisense strand comprises 1-11 modified nucleoside interlinks. In some embodiments, the antisense strand comprises 2-6 modified nucleoside interlinks. In some embodiments, the antisense strand comprises 5 modified nucleoside interlinks. In some embodiments, the antisense strand comprises 4 modified nucleoside interlinks.

[0119] In some embodiments, the sense chain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 modified nucleosides, or modified nucleosides within the range defined by any two integers above. In some embodiments, the sense chain comprises 12-19 modified nucleosides. In some embodiments, the sense chain comprises 12-21 modified nucleosides. In some embodiments, the sense chain comprises 19 modified nucleosides. In some embodiments, the sense chain comprises 21 modified nucleosides.

[0120] In some embodiments, the antisense strand comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 modified nucleosides, or modified nucleosides within the range defined by any two integers above. In some embodiments, the antisense strand comprises 12-19 modified nucleosides. In some embodiments, the antisense strand comprises 12-21 modified nucleosides. In some embodiments, the antisense strand comprises 19 modified nucleosides. In some embodiments, the antisense strand comprises 21 modified nucleosides.

[0121] In some embodiments, the sense strand or antisense strand further comprises at least two additional nucleosides attached to the 3' end of the sense strand or antisense strand. These additional nucleosides, as part of the sense strand, may or may not be complementary to the target mRNA. The additional nucleosides of the antisense strand may include uracil. Both additional nucleosides of the antisense strand may include uracil.

[0122] In some embodiments, the sense chain or sense chain further includes at least two additional nucleosides attached to the 3' end of the sense chain or sense chain. In some embodiments, the sense chain or sense chain includes two additional nucleosides attached to the 3' end of the sense chain or sense chain. The additional nucleosides of the sense chain may include uracil. Both additional nucleosides of the sense chain may include uracil.

[0123] In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide comprises siRNA containing a sense strand and an antisense strand, wherein the sense strand contains a modification pattern. In some embodiments, the sense strand contains the modification pattern 1S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3', wherein "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, and "s" is a phosphate thioester bond. In some embodiments, the sense strand contains the modification pattern 1S#2: 5'-NfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3', wherein "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, and "s" is a phosphate thioester bond. In some embodiments, the sense chain comprises the modification pattern 2S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3', wherein "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the sense chain comprises the modification pattern 2S#2: 5'-nnnnNfnNfNfnnnnnnnnnnnnsnsn-3', wherein "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the sense chain comprises the modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnnnnnsnsn-3', wherein "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the sense chain comprises the modification pattern 3S#2: 5'-nnnnNfnNfnNfnnnnnnnnnnsnsn-3', wherein "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the sense chain comprises the modification pattern 4S: 5'-NfsnsNfnNfnNfNfnNfnNfnNfnNfnNfsnsnN-3', wherein "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, "s" is a thiophosphate bond, and N comprises one or more nucleosides. In some embodiments, the sense chain comprises the modification pattern 4S#2: 5'-NfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsnN-3', wherein "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, "s" is a phosphate thioester bond, and N contains one or more nucleosides.In some embodiments, the sense chain comprises the modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnnnnsnsnN-3', wherein "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, "s" is a thiophosphate linker, and N comprises one or more nucleosides. In some embodiments, the sense chain comprises the modification pattern 5S#2: 5'-nnnnNfnNfNfnnnnnnnnnnnnsnsnN-3', wherein "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, "s" is a thiophosphate linker, and N comprises one or more nucleosides. In some embodiments, the sense chain comprises the modification pattern 6S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3', wherein "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, "s" is a thiophosphate linker, and N comprises one or more nucleosides. In some embodiments, the sense chain comprises the modification pattern 6S#2: 5'-NfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3', wherein "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, "s" is a thiophosphate linker, and N comprises one or more nucleosides. In some embodiments, the sense chain comprises any one of the modification patterns 1S, 2S, 3S, 4S, 5S, or 6S. In some embodiments, the sense chain includes any one of modification patterns 1S#2, 2S#2, 3S#2, 4S#2, 5S#2, or 6S#2. In some embodiments, the sense chain includes any one of modification patterns 1S, 3S, 4S, or 6S. In some embodiments, the sense chain includes any one of modification patterns 1S#2, 3S#2, 4S#2, or 6S#2. Any modification pattern 1S-6S may include a GalNAc ligand attached to the 3' end. Any modification pattern 1S-6S may include a GalNAc ligand attached to the 5' end. Any modification pattern 1S-6S#2 may include a GalNAc ligand attached to the 3' end. Any modification pattern 1S-6S#2 may include a GalNAc ligand attached to the 5' end.

[0124] In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide comprises siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a modification pattern. In some embodiments, the antisense strand comprises the modification pattern 1AS: 5'-nsNfsnNfnNfnNfnnnNfnnNfnNfnsnsn-3', wherein "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, and "s" is a phosphate thioester bond. In some embodiments, the antisense strand comprises the modification pattern 2AS: 5'-nsNfsnnnNfnNfnnnnnNfnnnsnsn-3', wherein "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, and "s" is a phosphate thioester bond. In some embodiments, the antisense chain comprises the modification pattern 3AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the antisense chain comprises the modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the antisense chain comprises the modification pattern 5AS: 5'-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the antisense chain comprises the modification pattern 6AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the antisense chain comprises the modification pattern 7AS: 5'-nsNfsnNfnNfNfNfnnnnNfnNfnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond. In some embodiments, the antisense chain comprises the modification pattern 8AS: 5'-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3', where "Nf" is a 2'-fluoro-modified nucleoside, "n" is a 2'-O-methyl-modified nucleoside, and "s" is a thiophosphate bond.In some embodiments, the antisense chain comprises modification pattern 9AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnsnsn-3', where "Nf" is a 2'-fluoromodified nucleoside, "n" is a 2'-O-methylmodified nucleoside, and "s" is a phosphate thioester bond. Any of modification patterns 1AS-9AS may include a GalNAc ligand attached to the 3' end. Any of modification patterns 1AS-9AS may include a GalNAc ligand attached to the 5' end.

[0125] Modifications in any modification pattern can be optional. For example, one, two, three, or more phosphate thioester bonds in any of the modification patterns 1S-6S, 1S#2-6S#2, or 1AS-9AS can be replaced by unmodified bonds or different modified bonds. In some cases, one, two, three, or more modified nucleosides in any of the modification patterns 1S-6S or 1AS-9AS can be replaced by unmodified nucleosides or different modified nucleosides.

[0126] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S, and the antisense strand comprises modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 2S, and the antisense strand comprises modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 3S, and the antisense strand comprises modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 4S, and the antisense strand comprises modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 5S, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 6S, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 1S#2, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 2S#2, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 3S#2, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 4S#2, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 5S#2, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense chain includes the modification pattern 6S#2, and the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the antisense chain includes the modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS.In some implementations, the sense chain or antisense chain contains the modification pattern ASO1.

[0127] Any combination of meaningful and antisense modification patterns can be used. In some embodiments, the meaningful chain includes modification pattern 1S, and the antisense chain includes modification pattern 1AS. In some embodiments, the meaningful chain includes modification pattern 2S, and the antisense chain includes modification pattern 2AS. In some embodiments, the meaningful chain includes modification pattern 2S, and the antisense chain includes modification pattern 3AS. In some embodiments, the meaningful chain includes modification pattern 3S, and the antisense chain includes modification pattern 1AS. In some embodiments, the meaningful chain includes modification pattern 3S, and the antisense chain includes modification pattern 4AS. In some embodiments, the meaningful chain includes modification pattern 3S, and the antisense chain includes modification pattern 5AS. In some embodiments, the meaningful chain includes modification pattern 3S, and the antisense chain includes modification pattern 6AS. In some embodiments, the meaningful chain includes modification pattern 3S, and the antisense chain includes modification pattern 7AS. In some embodiments, the meaningful chain includes modification pattern 3S, and the antisense chain includes modification pattern 8AS. In some embodiments, the meaningful chain includes modification pattern 6S, and the antisense chain includes modification pattern 1AS. In some embodiments, the sense chain includes modification pattern 6S, and the antisense chain includes modification pattern 4AS. In some embodiments, the sense chain includes modification pattern 6S, and the antisense chain includes modification pattern 5AS. In some embodiments, the sense chain includes modification pattern 6S, and the antisense chain includes modification pattern 6AS. In some embodiments, the sense chain includes modification pattern 6S, and the antisense chain includes modification pattern 7AS. In some embodiments, the sense chain includes modification pattern 6S, and the antisense chain includes modification pattern 8AS. In some embodiments, the sense chain includes modification pattern 1S#2, and the antisense chain includes modification pattern 1AS. In some embodiments, the sense chain includes modification pattern 2S#2, and the antisense chain includes modification pattern 2AS. In some embodiments, the sense chain includes modification pattern 2S#2, and the antisense chain includes modification pattern 3AS. In some embodiments, the sense chain includes modification pattern 3S#2, and the antisense chain includes modification pattern 1AS. In some embodiments, the sense chain includes modification pattern 3S#2, and the antisense chain includes modification pattern 4AS. In some embodiments, the sense chain includes modification pattern 3S#2, and the antisense chain includes modification pattern 5AS. In some embodiments, the sense chain includes modification pattern 3S#2, and the antisense chain includes modification pattern 6AS. In some embodiments, the sense chain includes modification pattern 3S#2, and the antisense chain includes modification pattern 7AS. In some embodiments, the sense chain includes modification pattern 3S#2, and the antisense chain includes modification pattern 8AS. In some embodiments, the sense chain includes modification pattern 6S#2, and the antisense chain includes modification pattern 1AS. In some embodiments, the sense chain includes modification pattern 6S#2, and the antisense chain includes modification pattern 4AS.In some embodiments, the sense chain includes the modification pattern 6S#2, and the antisense chain includes the modification pattern 5AS. In some embodiments, the sense chain includes the modification pattern 6S#2, and the antisense chain includes the modification pattern 6AS. In some embodiments, the sense chain includes the modification pattern 6S#2, and the antisense chain includes the modification pattern 7AS. In some embodiments, the sense chain includes the modification pattern 6S#2, and the antisense chain includes the modification pattern 8AS.

[0128] In some embodiments, the sense purine comprises a 2'-fluorinated purine. In some embodiments, the sense purine comprises a 2'-O-methylinated purine. In some embodiments, the sense purine comprises a mixture of 2'-fluorinated and 2'-O-methylinated purines. In some embodiments, all sense purines comprise a 2'-fluorinated purine. In some embodiments, all sense purines comprise a 2'-O-methylinated purine. In some embodiments, all sense purines comprise a mixture of 2'-fluorinated and 2'-O-methylinated purines.

[0129] In some embodiments, the sense pyrimidine comprises a 2'-fluoro-modified pyrimidine. In some embodiments, the sense pyrimidine comprises a 2'-O-methyl-modified pyrimidine. In some embodiments, the sense pyrimidine comprises a mixture of 2'-fluoro-modified and 2'-O-methyl-modified pyrimidines. In some embodiments, all sense pyrimidines comprise 2'-fluoro-modified pyrimidines. In some embodiments, all sense pyrimidines comprise 2'-O-methyl-modified pyrimidines. In some embodiments, all sense pyrimidines comprise a mixture of 2'-fluoro-modified and 2'-O-methyl-modified pyrimidines.

[0130] In some embodiments, the sensed purine comprises a 2'-fluoro-modified purine, and the sensed pyrimidine comprises a mixture of 2'-fluoro-modified pyrimidine and 2'-O-methyl-modified pyrimidine. In some embodiments, the sensed purine comprises a 2'-O-methyl-modified purine, and the sensed pyrimidine comprises a mixture of 2'-fluoro-modified pyrimidine and 2'-O-methyl-modified pyrimidine. In some embodiments, the sensed purine comprises a 2'-fluoro-modified purine, and the sensed pyrimidine comprises a 2'-O-methyl-modified pyrimidine. In some embodiments, the sensed purine comprises a 2'-O-methyl-modified purine, and the sensed pyrimidine comprises a 2'-fluoro-modified pyrimidine. In some embodiments, the sensed pyrimidine comprises a 2'-fluoro-modified pyrimidine, and the sensed purine comprises a mixture of 2'-fluoro-modified purine and 2'-O-methyl-modified purine. In some embodiments, the sense pyrimidine comprises a 2'-O-methyl-modified pyrimidine, and the sense purine comprises a mixture of a 2'-fluoro-modified purine and a 2'-O-methyl-modified purine. In some embodiments, the sense pyrimidine comprises a 2'-fluoro-modified pyrimidine, and the sense purine comprises a 2'-O-methyl-modified purine. In some embodiments, the sense pyrimidine comprises a 2'-O-methyl-modified pyrimidine, and the sense purine comprises a 2'-fluoro-modified purine.

[0131] In some embodiments, all purines with a sense chain comprise 2'-fluoro-modified purines, and all pyrimidines with a sense chain comprise a mixture of 2'-fluoro-modified pyrimidines and 2'-O-methyl-modified pyrimidines. In some embodiments, all purines with a sense chain comprise 2'-O-methyl-modified purines, and all pyrimidines with a sense chain comprise a mixture of 2'-fluoro-modified pyrimidines and 2'-O-methyl-modified pyrimidines. In some embodiments, all purines with a sense chain comprise 2'-fluoro-modified purines, and all pyrimidines with a sense chain comprise 2'-O-methyl-modified pyrimidines. In some embodiments, all purines with a sense chain comprise 2'-O-methyl-modified purines, and all pyrimidines with a sense chain comprise 2'-fluoro-modified pyrimidines. In some embodiments, all pyrimidines with a sense chain comprise 2'-fluoro-modified pyrimidines, and all purines with a sense chain comprise a mixture of 2'-fluoro-modified purines and 2'-O-methyl-modified purines. In some embodiments, all pyrimidines with a sense chain comprise 2'-O-methyl-modified pyrimidines, and all purines with a sense chain comprise a mixture of 2'-fluoro-modified purines and 2'-O-methyl-modified purines. In some embodiments, all pyrimidines with a sense chain comprise 2'-fluoro-modified pyrimidines, and all purines with a sense chain comprise 2'-O-methyl-modified purines. In some embodiments, all pyrimidines with a sense chain comprise 2'-O-methyl-modified pyrimidines, and all purines with a sense chain comprise 2'-fluoro-modified purines.

[0132] In some embodiments, the purine in the antisense chain comprises a 2'-fluorinated purine. In some embodiments, the purine in the antisense chain comprises a 2'-O-methylated purine. In some embodiments, the purine in the antisense chain comprises a mixture of 2'-fluorinated and 2'-O-methylated purines. In some embodiments, all purines in the antisense chain comprise a 2'-fluorinated purine. In some embodiments, all purines in the antisense chain comprise a 2'-O-methylated purine. In some embodiments, all purines in the antisense chain comprise a mixture of 2'-fluorinated and 2'-O-methylated purines.

[0133] In some embodiments, the antisense pyrimidine comprises a 2'-fluorinated pyrimidine. In some embodiments, the antisense pyrimidine comprises a 2'-O-methylinated pyrimidine. In some embodiments, the antisense pyrimidine comprises a mixture of 2'-fluorinated and 2'-O-methylinated pyrimidines. In some embodiments, all pyrimidines of the antisense chain comprise 2'-fluorinated pyrimidines. In some embodiments, all pyrimidines of the antisense chain comprise 2'-O-methylinated pyrimidines. In some embodiments, all pyrimidines of the antisense chain comprise a mixture of 2'-fluorinated and 2'-O-methylinated pyrimidines.

[0134] In some embodiments, the antisense purine comprises a 2'-fluorinated purine, and the antisense pyrimidine comprises a mixture of 2'-fluorinated and 2'-O-methylinated pyrimidines. In some embodiments, the antisense purine comprises a 2'-O-methylinated purine, and the antisense pyrimidine comprises a mixture of 2'-fluorinated and 2'-O-methylinated pyrimidines. In some embodiments, the antisense purine comprises a 2'-fluorinated purine, and the antisense pyrimidine comprises a 2'-O-methylinated pyrimidine. In some embodiments, the antisense purine comprises a 2'-O-methylinated purine, and the antisense pyrimidine comprises a 2'-fluorinated pyrimidine. In some embodiments, the antisense pyrimidine comprises a 2'-fluorinated pyrimidine, and the antisense purine comprises a mixture of 2'-fluorinated and 2'-O-methylinated purines. In some embodiments, the antisense pyrimidine comprises a 2'-O-methyl-modified pyrimidine, and the antisense purine comprises a mixture of a 2'-fluorine-modified purine and a 2'-O-methyl-modified purine. In some embodiments, the antisense pyrimidine comprises a 2'-fluorine-modified pyrimidine, and the antisense purine comprises a 2'-O-methyl-modified purine. In some embodiments, the antisense pyrimidine comprises a 2'-O-methyl-modified pyrimidine, and the antisense purine comprises a 2'-fluorine-modified purine.

[0135] In some embodiments, all purines in the antisense chain comprise 2'-fluorinated purines, and all pyrimidines in the antisense chain comprise a mixture of 2'-fluorinated pyrimidines and 2'-O-methylinated pyrimidines. In some embodiments, all purines in the antisense chain comprise 2'-O-methylinated purines, and all pyrimidines in the antisense chain comprise a mixture of 2'-fluorinated pyrimidines and 2'-O-methylinated pyrimidines. In some embodiments, all purines in the antisense chain comprise 2'-fluorinated purines, and all pyrimidines in the antisense chain comprise 2'-O-methylinated pyrimidines. In some embodiments, all purines in the antisense chain comprise 2'-O-methylinated purines, and all pyrimidines in the antisense chain comprise 2'-fluorinated pyrimidines. In some embodiments, all pyrimidines in the antisense chain comprise 2'-fluorinated pyrimidines, and all purines in the antisense chain comprise a mixture of 2'-fluorinated pyrimidines and 2'-O-methylinated purines. In some embodiments, all pyrimidines in the antisense chain comprise 2'-O-methyl-modified pyrimidines, and all purines in the antisense chain comprise a mixture of 2'-fluorine-modified pyrimidines and 2'-O-methyl-modified purines. In some embodiments, all pyrimidines in the antisense chain comprise 2'-fluorine-modified pyrimidines, and all purines in the antisense chain comprise 2'-O-methyl-modified purines. In some embodiments, all pyrimidines in the antisense chain comprise 2'-O-methyl-modified pyrimidines, and all purines in the antisense chain comprise 2'-fluorine-modified purines.

[0136] In some cases, oligonucleotides contain specific modification patterns. In some embodiments, position 9, counting from the 5' end of the oligonucleotide chain, may have a 2'F modification. In some embodiments, when position 9 of the oligonucleotide chain is a pyrimidine, all purines in the oligonucleotide chain have a 2'OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense strand, position 9 is the only position in the oligonucleotide chain with a 2'F modification. In some embodiments, when only one other base between positions 9 and 5 and 11 of the oligonucleotide chain is a pyrimidine, these two pyrimidines are the only two positions in the oligonucleotide chain with 2'F modifications. In some embodiments, when only two other bases between positions 9 and 5 and 11 of the oligonucleotide chain are pyrimidines, and these two other pyrimidines are in adjacent positions such that there are no three consecutive 2'F modifications, any combination of 2'F modifications that produces a total of three 2'F modifications can be performed. In some implementations, when there are more than two pyrimidines between positions 5 and 11 of the oligonucleotide chain, all combinations of pyrimidines with 2'F modifications are allowed to have a total of 3 to 5 2'F modifications, provided that the oligonucleotide chain does not have 3 consecutive 2'F modifications. In some cases, the oligonucleotide chain of any siRNA contains a modification pattern that conforms to any or all of these oligonucleotide chain rules.

[0137] In some embodiments, when position 9 of the oligonucleotide chain is a purine, all purines in the oligonucleotide chain have a 2'OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense strand, position 9 is the only position in the oligonucleotide chain with a 2'F modification. In some embodiments, when only one other base between positions 9 and 5 and 11 of the oligonucleotide chain is a purine, these two purines are the only two positions in the oligonucleotide chain with a 2'F modification. In some embodiments, when only two other bases between positions 9 and 5 and 11 of the oligonucleotide chain are purines, and these two other purines are in adjacent positions such that there are no three consecutive 2'F modifications, any combination of 2'F modifications that produces a total of three 2'F modifications is permissible. In some embodiments, when there are more than two purines between positions 5 and 11 of the oligonucleotide chain, all combinations of purines with 2'F modifications are allowed to have a total of three to five 2'F modifications, provided that the oligonucleotide chain does not have three consecutive 2'F modifications. In some cases, the oligonucleotide chain of any siRNA contains a modification pattern that conforms to any or all of these oligonucleotide chain rules.

[0138] In some cases, position 9 of the oligonucleotide chain can be 2' deoxygenated. In these cases, 2'F and 2'OMe modifications can occur at other positions on the oligonucleotide chain. In some cases, the oligonucleotide chain of any siRNA contains modification patterns that conform to these oligonucleotide chain rules.

[0139] In some embodiments, position 9 of the sense strand includes a 2'-fluorinated pyrimidine. In some embodiments, all purines in the sense strand include 2'-O-methylated purines. In some embodiments, the 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 include 2'-fluorinated pyrimidines, provided that there are no three consecutive 2'-fluorinated pyrimidines. In some embodiments, odd-numbered positions of the antisense strand include a 2'-O-methylated nucleotide. In some embodiments, even-numbered positions of the antisense strand include a 2'-fluorinated nucleotide and an unmodified deoxyribonucleotide. In some embodiments, even-numbered positions of the antisense strand include a 2'-fluorinated nucleotide, a 2'-O-methylated nucleotide, and an unmodified deoxyribonucleotide. In some embodiments, position 9 of the sense strand includes a 2'-fluorinated pyrimidine; all purines of the sense strand include 2'-O-methylated purines; the 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 include 2'-fluorinated pyrimidines, provided that there are no three consecutive 2'-fluorinated pyrimidines; the odd-numbered positions of the antisense strand include 2'-O-methylated nucleotides; and the even-numbered positions of the antisense strand include 2'-fluorinated nucleotides and unmodified deoxyribonucleotides.

[0140] In some embodiments, position 9 of the sense strand includes a 2'-fluorinated purine. In some embodiments, all pyrimidines of the sense strand include 2'-O-methylinated purines. In some embodiments, the 1, 2, 3, 4, or 5 purines between positions 5 and 11 include 2'-fluorinated purines, provided that there are no three consecutive 2'-fluorinated purines. In some embodiments, odd-numbered positions of the antisense strand include a 2'-O-methylinated nucleotide. In some embodiments, even-numbered positions of the antisense strand include a 2'-fluorinated nucleotide and an unmodified deoxyribonucleotide. In some embodiments, even-numbered positions of the antisense strand include a 2'-fluorinated nucleotide, a 2'-O-methylinated nucleotide, and an unmodified deoxyribonucleotide. In some embodiments, position 9 of the sense strand includes a 2'-fluorinated purine; all pyrimidines of the sense strand include 2'-O-methylated pyrimidines; the 1, 2, 3, 4, or 5 purines between positions 5 and 11 include 2'-fluorinated purines, provided that there are no three consecutive 2'-fluorinated purines; the odd-numbered positions of the antisense strand include a 2'-O-methylated nucleotide; and the even-numbered positions of the antisense strand include a 2'-fluorinated nucleotide and an unmodified deoxyribonucleotide. In some embodiments, there are no three consecutive 2'-fluorinated purines. In some embodiments, there are no three consecutive 2'-fluorinated pyrimidines.

[0141] In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2'-fluorine-modified nucleotides. In some embodiments, all pyrimidines at positions 10 to 21 of the sense strand comprise 2'-O-methyl-modified pyrimidines, and all purines at positions 10 to 21 of the sense strand comprise either 2'-O-methyl-modified purines or 2'-fluorine-modified purines. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluorine-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluorine-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2'-fluorine-modified nucleotides; all pyrimidines at positions 10 to 21 of the sense strand comprise 2'-O-methyl-modified pyrimidines, and all purines at positions 10 to 21 comprise either 2'-O-methyl-modified purines or 2'-fluorine-modified purines; odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides; and even-numbered positions of the antisense strand comprise 2'-fluorine-modified nucleotides and unmodified deoxyribonucleotides.

[0142] In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2'-fluorine-modified nucleotides. In some embodiments, all purines at positions 10 to 21 of the sense strand comprise 2'-O-methyl-modified purines, and all pyrimidines at positions 10 to 21 of the sense strand comprise either 2'-O-methyl-modified pyrimidines or 2'-fluorine-modified pyrimidines. In some embodiments, odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluorine-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand comprise 2'-fluorine-modified nucleotides, 2'-O-methyl-modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position 9 of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2'-fluorine-modified nucleotides; all purines at positions 10 to 21 of the sense strand comprise 2'-O-methyl-modified purines, and all pyrimidines at positions 10 to 21 comprise 2'-O-methyl-modified pyrimidines or 2'-fluorine-modified pyrimidines; odd-numbered positions of the antisense strand comprise 2'-O-methyl-modified nucleotides; and even-numbered positions of the antisense strand comprise 2'-fluorine-modified nucleotides and unmodified deoxyribonucleotides.

[0143] 3. ASO (App Store Optimization) Mode In some embodiments, the composition comprises an oligonucleotide that binds to the target oligonucleotide, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises the modified pattern ASO1: 5'-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3', where "dN" is any deoxynucleotide, "n" is a 2'O-methyl or 2'O-methoxyethyl modified nucleoside, and "s" is a phosphate thioester linker. In some embodiments, the ASO comprises the modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS.

[0144] In some embodiments, the ASO is partially concatenated with the GalNAc portion. The GalNAc portion may be concatenated to the ASO at either the 5' or 3' end. In some embodiments, the GalNAc portion is concatenated to the 5' end of the ASO. In some embodiments, the GalNAc portion is concatenated to the 3' end of the ASO.

[0145] C. Preparations In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. The formulation may include compounds such as the GalNAc moiety, as well as oligonucleotides conjugated to the GalNAc moiety described herein.

[0146] In some embodiments, the pharmaceutically acceptable carrier includes water. In some embodiments, the pharmaceutically acceptable carrier includes a buffer. In some embodiments, the pharmaceutically acceptable carrier includes an aqueous saline solution. In some embodiments, the pharmaceutically acceptable carrier includes water, a buffer, or an aqueous saline solution. In some embodiments, the composition comprises liposomes. In some embodiments, the pharmaceutically acceptable carrier includes liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogels, or combinations thereof.

[0147] II. Methods and Applications In some embodiments, methods of applying the compositions described herein to a subject are disclosed herein. Some embodiments involve using the compositions described herein, such as applying the compositions to a subject.

[0148] Some embodiments relate to a method of treating a condition in a subject. Some embodiments relate to the use of the compositions described herein in a treatment method. Some embodiments include applying the compositions described herein to a subject suffering from a condition. In some embodiments, the composition is applied to treat the condition of the subject. In some embodiments, the composition treats the condition of the subject.

[0149] In some embodiments, treatment includes preventing, inhibiting, or reversing a condition in a subject. Some embodiments relate to the use of the compositions described herein in methods of preventing, inhibiting, or reversing a condition. Some embodiments relate to a method of preventing, inhibiting, or reversing a condition in a subject with a need. Some embodiments include applying the compositions described herein to a subject suffering from a condition. In some embodiments, application prevents, inhibits, or reverses a subject's condition. In some embodiments, the composition prevents, inhibits, or reverses a subject's condition.

[0150] Some embodiments relate to a method of preventing a disease in a subject of need. Some embodiments relate to the use of the compositions described herein in a method of preventing a disease. Some embodiments include applying the compositions described herein to a subject suffering from a disease. In some embodiments, the composition is used to prevent the subject from contracting a disease. In some embodiments, the composition prevents the subject from contracting a disease.

[0151] Some embodiments relate to a method of suppressing a symptom in a subject. Some embodiments relate to the use of the compositions described herein in a method of suppressing a symptom. Some embodiments include applying the compositions described herein to a subject suffering from a symptom. In some embodiments, the application suppresses the symptom in the subject. In some embodiments, the composition suppresses the symptom in the subject.

[0152] Some embodiments relate to a method for reversing a symptom in a subject. Some embodiments relate to the use of the compositions described herein in a method for reversing a symptom. Some embodiments include applying the compositions described herein to a subject suffering from a symptom. In some embodiments, the application reverses the subject's symptom. In some embodiments, the composition reverses the subject's symptom.

[0153] A. Symptoms Some embodiments of the methods described herein include treating a condition in a subject of need. In some embodiments, the condition is a liver condition. Non-limiting examples of liver conditions include hepatitis, liver cancer, liver fibrosis, cholestasis, gallbladder disease, biliary tract disease, alcoholic liver disease, non-alcoholic steatohepatitis, liver infection, or hereditary liver conditions. In some embodiments, the liver condition includes hepatitis. In some embodiments, the liver condition includes liver cancer. In some embodiments, the liver condition includes liver fibrosis. In some embodiments, the liver condition includes cholestasis. In some embodiments, the liver condition includes gallbladder disease. In some embodiments, the liver condition includes biliary tract disease. In some embodiments, the liver condition includes alcoholic liver disease. In some embodiments, the liver condition includes non-alcoholic steatohepatitis.

[0154] In some embodiments, liver disease includes liver infection. In some embodiments, liver infection includes hepatitis A. In some embodiments, liver infection includes hepatitis B. In some embodiments, liver infection includes hepatitis C.

[0155] In some embodiments, the liver condition includes hereditary liver conditions. In some embodiments, the hereditary liver condition includes hemochromatosis. In some embodiments, the hereditary liver condition includes Wilson's disease.

[0156] B. Object Some embodiments of the methods described herein include treatment of the object. Non-limiting examples of the object include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the object is a vertebrate. In some embodiments, the object is an animal. In some embodiments, the object is a mammal. In some embodiments, the object is a dog. In some embodiments, the object is a cat. In some embodiments, the object is a cow. In some embodiments, the object is a mouse. In some embodiments, the object is a rat. In some embodiments, the object is a primate. In some embodiments, the object is a monkey. In some embodiments, the object is an animal, mammal, dog, cat, cattle, rodent, mouse, rat, primate, or monkey. In some embodiments, the object is a human.

[0157] In some implementations, the subject is male. In some implementations, the subject is female.

[0158] In some implementations, the subject's body mass index (BMI) is 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 or higher, or a range defined by any two of the above integers. In some implementations, the subject is overweight. In some implementations, the subject's BMI is 25 or higher. In some implementations, the subject's BMI is 25-29. In some implementations, the subject is obese. In some implementations, the subject's BMI is 30 or higher. In some implementations, the subject's BMI is 30-39. In some implementations, the subject's BMI is 40-50. In some implementations, the subject's BMI is 25-50.

[0159] In some implementations, the participants are ≥90 years old. In some implementations, the participants are ≥85 years old. In some implementations, the participants are ≥80 years old. In some implementations, the participants are ≥70 years old. In some implementations, the participants are ≥60 years old. In some implementations, the participants are ≥50 years old. In some implementations, the participants are ≥40 years old. In some implementations, the participants are ≥30 years old. In some implementations, the participants are ≥20 years old. In some implementations, the participants are ≥10 years old. In some implementations, the participants are ≥1 year old. In some implementations, the participants are ≥0 years old.

[0160] In some implementations, the subject is ≤100 years old. In some implementations, the subject is ≤90 years old. In some implementations, the subject is ≤85 years old. In some implementations, the subject is ≤80 years old. In some implementations, the subject is ≤70 years old. In some implementations, the subject is ≤60 years old. In some implementations, the subject is ≤50 years old. In some implementations, the subject is ≤40 years old. In some implementations, the subject is ≤30 years old. In some implementations, the subject is ≤20 years old. In some implementations, the subject is ≤10 years old. In some implementations, the subject is ≤1 year old.

[0161] In some embodiments, the subject's age is between 0 and 100 years old. In some embodiments, the subject's age is between 20 and 90 years old. In some embodiments, the subject's age is between 30 and 80 years old. In some embodiments, the subject's age is between 40 and 75 years old. In some embodiments, the subject's age is between 50 and 70 years old. In some embodiments, the subject's age is between 40 and 85 years old.

[0162] C. Baseline measurements Some embodiments of the methods described herein include obtaining baseline measurements from the subject. For example, in some embodiments, baseline measurements are obtained from the subject prior to treatment. Non-limiting examples of baseline measurements include measurements of baseline symptoms (e.g., symptoms of liver disease), baseline protective phenotypes, baseline target oligonucleotides (e.g., mRNA), or baseline target proteins.

[0163] In some embodiments, baseline measurements are obtained directly from the subject. In some embodiments, baseline measurements are obtained by observation, such as by observing the subject or its tissue. In some embodiments, baseline measurements are obtained non-invasively using an imaging device. In some embodiments, baseline measurements are obtained from a sample from the subject. In some embodiments, baseline measurements are obtained from one or more histological tissue sections. In some embodiments, baseline measurements are obtained by assays such as immunoassays, colorimetric assays, or fluorescence assays on a sample obtained from the subject. In some embodiments, baseline measurements are obtained by immunoassays, colorimetric assays, or fluorescence assays. In some embodiments, baseline measurements are obtained by PCR.

[0164] In some implementations, the baseline measurement is a baseline symptom measurement. This symptom can be a symptom of a condition associated with the target oligonucleotide. This condition could be a liver condition.

[0165] In some implementations, the baseline measurement is the baseline protective phenotype measurement. The protective phenotype protects the subject from developing diseases associated with the target oligonucleotide. This protective phenotype may be negatively correlated with the incidence of the disease.

[0166] In some embodiments, the baseline measurement is a baseline target protein measurement. In some embodiments, the baseline target protein measurement includes the baseline target protein level. In some embodiments, the baseline target protein level is expressed as the mass or percentage of target protein per sample weight. In some embodiments, the baseline target protein level is expressed as the mass or percentage of target protein per sample volume. In some embodiments, the baseline target protein level is expressed as the mass or percentage of target protein per total protein in the sample. In some embodiments, the baseline target protein measurement is a baseline liver or hepatocyte target protein measurement. In some embodiments, the baseline target protein measurement is a baseline circulating target protein measurement. In some embodiments, the baseline target protein measurement is obtained by assays such as immunoassays, colorimetric assays, or fluorescence assays.

[0167] In some embodiments, the baseline measurement is a baseline target mRNA measurement. In some embodiments, the baseline target mRNA measurement includes the baseline target mRNA level. In some embodiments, the baseline target mRNA level is expressed as the mass or percentage of target mRNA per sample weight. In some embodiments, the baseline target mRNA level is expressed as the mass or percentage of target mRNA per sample volume. In some embodiments, the baseline target mRNA level is expressed as the mass or percentage of target mRNA per total mRNA in the sample. In some embodiments, the baseline target mRNA level is expressed as the mass or percentage of target mRNA per total nucleic acid in the sample. In some embodiments, the baseline target mRNA level is expressed relative to another mRNA level in the sample (such as the mRNA level of a housekeeping gene). In some embodiments, the baseline target mRNA measurement is a baseline liver or hepatocyte target mRNA measurement. In some embodiments, the baseline target mRNA measurement is obtained by an assay such as polymerase chain reaction (PCR). In some embodiments, the PCR includes quantitative PCR (qPCR). In some embodiments, the PCR includes reverse transcription of the target mRNA.

[0168] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, baseline measurements are obtained from a sample obtained from the subject. In some embodiments, a sample is obtained from the subject prior to administration of the composition described herein or treatment of the subject with the composition described herein. In some embodiments, baseline measurements are obtained from a sample obtained from the subject prior to administration of the composition to the subject. In some embodiments, the sample is obtained from a subject in a fasting state. In some embodiments, the sample is obtained from the subject after overnight fasting. In some embodiments, the sample is obtained from a subject in a feeding state.

[0169] In some embodiments, the sample comprises a liquid. In some embodiments, the sample is a liquid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample contains blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample contains plasma. In some embodiments, the sample is a plasma sample. In some embodiments, the sample contains serum. In some embodiments, the sample is a serum sample.

[0170] In some embodiments, the sample includes tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the sample includes liver tissue. In some embodiments, the sample is a liver sample. In some embodiments, the sample includes hepatocytes. In some embodiments, the sample consists of hepatocytes. For example, baseline target mRNA measurements or baseline target protein measurements can be obtained from a liver or hepatocyte sample from a patient. In some embodiments, the sample includes adipose tissue. In some embodiments, the sample is adipose tissue. Adipose tissue may include white adipose tissue or be composed of white adipose tissue. Adipose tissue may include brown adipose tissue or be composed of brown adipose tissue. In some embodiments, the sample includes kidney tissue. In some embodiments, the sample is a kidney sample. In some embodiments, the sample includes cardiac tissue, such as ventricular or atrial tissue. In some embodiments, the sample is a heart sample. In some embodiments, the sample includes intestinal tissue, such as small intestinal tissue. In some embodiments, the sample is a small intestinal sample. In some embodiments, the sample includes lymph node tissue, such as mesenteric lymph node tissue. In some embodiments, the sample is a mesenteric lymph node sample. In some embodiments, the sample includes muscle tissue. In some embodiments, the sample is a muscle sample. In some embodiments, the tissue sample includes liver, fat, kidney, or heart tissue. In some embodiments, the tissue sample includes brown adipose tissue, white adipose tissue, kidney tissue, intestinal tissue, mesenteric lymph nodes, or muscle tissue.

[0171] D. Therapeutic effect In some embodiments, relative to baseline measurements, the composition or application of the composition affects measurements such as symptom (e.g., symptoms of liver disease), protective phenotype, target oligonucleotide (e.g., mRNA) or target protein (e.g., liver tissue target protein levels).

[0172] Some embodiments of the methods described herein include obtaining measurements from a subject. For example, measurements may be obtained from the subject after treatment. In some embodiments, measurements are obtained from a second sample (such as a fluid or tissue sample as described herein) obtained from the subject after the composition has been applied to it. In some embodiments, the measurements are an indication that the condition has been treated.

[0173] In some embodiments, the measurements are obtained directly from the subject. In some embodiments, the measurements are obtained non-invasively using an imaging device. In some embodiments, the measurements are obtained in a second sample from the subject. In some embodiments, the measurements are obtained in one or more histological tissue sections. In some embodiments, the measurements are obtained by assaying a second sample obtained from the subject. In some embodiments, the measurements are obtained by assays (such as those described herein). In some embodiments, the assay is an immunoassay, colorimetric assay, fluorescence assay, or PCR assay. In some embodiments, the measurements are obtained by assays such as immunoassays, colorimetric assays, or fluorescence assays. In some embodiments, the measurements are obtained by PCR. In some embodiments, the measurements are obtained histologically. In some embodiments, the measurements are obtained by observation. In some embodiments, additional measurements are performed, such as in a third, fourth, or fifth sample.

[0174] In some embodiments, the measurements are obtained within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after application of the composition. In some embodiments, the measurements are obtained within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after application of the composition. In some embodiments, the measurements are obtained within 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after application of the composition. In some embodiments, the measurements are obtained 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after application of the composition. In some embodiments, the measurements are obtained 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after application of the composition. In some embodiments, the measurements are obtained 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after the application of the composition.

[0175] In some implementations, measurements of the subject's symptoms or condition-related parameters decrease or are affected over a longer period of time compared to baseline measurements. In some implementations, the decrease or effect of measurements occurs at least approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, or approximately 2... The application period is 6 days, approximately 27 days, approximately 28 days, approximately 29 days, approximately 30 days, approximately 35 days, approximately 40 days, approximately 45 days, approximately 50 days, approximately 55 days, approximately 60 days, approximately 65 days, approximately 70 days, approximately 75 days, approximately 80 days, approximately 85 days, approximately 90 days, approximately 95 days, approximately 100 days, approximately 105 days, approximately 110 days, approximately 115 days, or approximately 120 days, or a period of time after application that continues to include the range defined by any two of the above number of days. In some implementations, the reduction or impact of measured values ​​is observed for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, up to Less than 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, at least 60 days, at least 65 days, at least 70 days, at least 75 days, at least 80 days, at least 85 days, at least 90 days, at least 95 days, at least 100 days, at least 105 days, at least 110 days, at least 115 days, or at least 120 days.In some implementation schemes, the duration of continued application after a reduction or impact on measured values ​​is limited to no more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or more. The duration of the measured value reduction or impact is limited to 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 35 days, 40 days, 45 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 105 days, 110 days, 115 days, or 120 days. In some implementations, the reduction or impact lasts for at least approximately 5 days. In some implementations, the reduction or impact lasts for at least approximately 10 days. In some implementations, the reduction or impact lasts for at least approximately 15 days. In some implementations, the reduction or impact lasts for at least approximately 20 days. In some implementations, the reduction or impact lasts for at least approximately 25 days. In some implementations, the reduction or impact lasts for at least approximately 30 days. In some implementations, the reduction or impact lasts for at least approximately 40 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 50 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 60 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 70 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 80 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 90 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 100 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 110 days. In some embodiments, the reduction or impact of the measurement lasts for at least about 120 days. Examples of measurements of symptoms or parameters related to a condition may include target mRNA measurements, target protein measurements, biomarker measurements, or physiological measurements. The measurement may be in tissues (e.g., liver) or biological fluids (e.g., blood, serum, or plasma).

[0176] In some embodiments, the composition reduces symptom measurements relative to baseline symptom measurements. In some embodiments, the reduction is measured in a second tissue sample obtained from the subject after application of the composition to the subject. In some embodiments, the reduction is measured directly in the subject after application of the composition to the subject. In some embodiments, the symptom measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to baseline symptom measurements. In some embodiments, the symptom measurement is reduced by about 10% or more relative to baseline symptom measurements. In some embodiments, the symptom measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more relative to baseline symptom measurements. In some embodiments, the symptom measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to baseline symptom measurements. In some embodiments, the symptom measurement is reduced by no more than about 10% relative to baseline symptom measurements. In some implementations, the symptom measurement value is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline symptom measurement value. In some implementations, the symptom measurement value is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by any two of the above percentages.

[0177] In some embodiments, the composition increases the protective phenotypic measurement relative to a baseline protective phenotypic measurement. In some embodiments, the increase is measured in a second tissue sample obtained from the subject after the composition has been applied to the subject. In some embodiments, the increase is measured directly from the subject after the composition has been applied to the subject. In some embodiments, the protective phenotypic measurement increases by about 2.5% or more, about 5% or more, or about 7.5% or more relative to a baseline protective phenotypic measurement. In some embodiments, the protective phenotypic measurement increases by about 10% or more relative to a baseline protective phenotypic measurement. In some embodiments, the protective phenotypic measurement increases by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more relative to a baseline protective phenotypic measurement. In some embodiments, the protective phenotypic measurement increases by about 100% or more, about 250% or more, about 500% or more, about 750% or more, or about 1000% or more relative to a baseline protective phenotypic measurement. In some embodiments, the protection phenotypic measurement value increases by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline protection phenotypic measurement value. In some embodiments, the protection phenotypic measurement value increases by no more than about 10% relative to the baseline protection phenotypic measurement value. In some embodiments, the protection phenotypic measurement value increases by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline protection phenotypic measurement value. In some embodiments, the protection phenotypic measurement value increases by no more than about 100%, no more than about 250%, no more than about 500%, no more than about 750%, or no more than about 1000% relative to the baseline protection phenotypic measurement value. In some implementations, the protective phenotypic measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by any two of the above percentages.

[0178] In some embodiments, the measurement is a target protein measurement. In some embodiments, the target protein measurement includes the target protein level. In some embodiments, the target protein level is expressed as the mass or percentage of target protein per sample weight. In some embodiments, the target protein level is expressed as the mass or percentage of target protein per sample volume. In some embodiments, the target protein level is expressed as the mass or percentage of target protein per total protein in the sample. In some embodiments, the target protein measurement is a cellular (e.g., hepatocyte) target protein measurement. In some embodiments, the target protein measurement is a tissue (e.g., liver tissue) target protein measurement. In some embodiments, the target protein measurement is a circulating target protein measurement. In some embodiments, the baseline target protein measurement is obtained by assays such as immunoassays, colorimetric assays, or fluorescence assays.

[0179] In some embodiments, the composition reduces the target protein measurement relative to a baseline target protein measurement. In some embodiments, the composition reduces the tissue target protein level (such as, but not limited to, liver tissue target protein levels) relative to a baseline target protein measurement. In some embodiments, the composition reduces the cellular target protein level (such as, but not limited to, hepatocyte target protein levels) relative to a baseline target protein measurement. In some embodiments, the composition reduces the circulating target protein level relative to a baseline target protein measurement. In some embodiments, the reduced target protein level is measured in a second sample obtained from the subject after the composition has been applied to the subject.

[0180] In some embodiments, the target protein measurement value is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline target protein measurement value. In some embodiments, the target protein measurement value is reduced by about 10% or more relative to the baseline target protein measurement value. In some embodiments, the target protein measurement value is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% relative to the baseline target protein measurement value. In some embodiments, the target protein measurement value is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline target protein measurement value. In some embodiments, the target protein measurement value is reduced by no more than about 10% relative to the baseline target protein measurement value. In some embodiments, the target protein measurement value is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or about 100% relative to the baseline target protein measurement value. In some embodiments, the target protein measurement decreases by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by any two of the above percentages. The target protein measurement may decrease over a longer period of time. In some embodiments, the target protein measurement decreases for 7 days, 14 days, 28 days, 42 days, 56 days, 70 days, 77 days, 84 days, 91 days, 98 days, or 105 days, or a range thereof. In some embodiments, the target protein measurement decreases for approximately 7 days, approximately 14 days, approximately 28 days, approximately 42 days, approximately 56 days, approximately 70 days, approximately 77 days, approximately 84 days, approximately 91 days, approximately 98 days, or approximately 105 days, or a range thereof.

[0181] In some embodiments, the measurement is a target mRNA measurement. In some embodiments, the target mRNA measurement includes the target mRNA level. In some embodiments, the target mRNA level is expressed as the target mRNA mass or percentage per sample weight. In some embodiments, the target mRNA level is expressed as the target mRNA mass or percentage per sample volume. In some embodiments, the target mRNA level is expressed as the target mRNA mass or percentage per total mRNA in the sample. In some embodiments, the target mRNA level is expressed as the target mRNA mass or percentage per total nucleic acid in the sample. In some embodiments, the target mRNA level is expressed relative to the level of another mRNA in the sample (such as the mRNA level of a housekeeping gene). In some embodiments, the target mRNA measurement is obtained by assays such as PCR. In some embodiments, PCR includes qPCR. In some embodiments, PCR includes reverse transcription of the target mRNA.

[0182] In some embodiments, the composition reduces the target mRNA measurement relative to a baseline target mRNA measurement. In some embodiments, the target mRNA measurement is obtained from a second sample obtained from the subject after administration of the composition. In some embodiments, the composition reduces the target mRNA level relative to a baseline target mRNA level. In some embodiments, the reduced target mRNA level is measured in a second sample obtained from the subject after administration of the composition. In some embodiments, the second sample is a second liver sample. In some embodiments, the second sample is a second hepatocyte sample.

[0183] In some embodiments, the target mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline target mRNA measurement. In some embodiments, the target mRNA measurement is reduced by about 10% or more relative to the baseline target mRNA measurement. In some embodiments, the target mRNA measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% relative to the baseline target mRNA measurement. In some embodiments, the target mRNA measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline target mRNA measurement. In some embodiments, the target mRNA measurement is reduced by no more than about 10% relative to the baseline target mRNA measurement. In some embodiments, the target mRNA measurement value decreases relative to the baseline target mRNA measurement value by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the target mRNA measurement value decreases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range defined by any two of the above percentages. The target mRNA measurement value may decrease over a longer period of time. In some embodiments, the target mRNA measurement value decreases for 7 days, 14 days, 28 days, 42 days, 56 days, 70 days, 77 days, 84 days, 91 days, 98 days, 105 days, or a range thereof. In some implementations, target protein measurements are reduced for approximately 7 days, approximately 14 days, approximately 28 days, approximately 42 days, approximately 56 days, approximately 70 days, approximately 77 days, approximately 84 days, approximately 91 days, approximately 98 days, approximately 105 days, or a range thereof. Some implementations include reducing RNA measurements other than mRNA measurements.

[0184] III. Definition Unless otherwise defined, all technical terms, symbols, and other technical, scientific, or professional terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or convenience of reference, and such definitions contained herein should not necessarily be construed as indicating a material difference from the meaning commonly understood in the art.

[0185] Throughout this application, various embodiments may be presented in scope form. It should be understood that the scope form is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of this disclosure. Therefore, a scope description should be considered to have all possible sub-scopes of the exact disclosure, as well as individual numerical values ​​within that scope. For example, a scope such as 1 to 6 should be considered to have exactly disclosed sub-scopes, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within that scope, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the scope.

[0186] Unless the context clearly indicates otherwise, as used in the specification and claims, the singular forms “a” and “the” include a plural of indicators. For example, the term “sample” includes multiple samples, including mixtures thereof.

[0187] Some instances involve sequences. If the sequence list conflicts with the disclosure in the specification, the specification shall prevail.

[0188] The terms “determine,” “measure,” “evaluate,” “assess,” “determine,” and “analyze” are generally used interchangeably herein to refer to a form of measurement. This term includes determining the presence of an element (e.g., detecting). These terms can include quantitative, qualitative, or a combination of quantitative and qualitative determination. Assessments can be relative or absolute. In addition to determining whether something is present or absent in context, “detecting the presence of…” can also include determining the quantity of something present.

[0189] The terms “subject” and “patient” are used interchangeably in this document. A “subject” can be a biological entity containing expressed genetic material. A biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject can be a mammal. A mammal can be a human. A subject may be diagnosed or suspected of being at high risk of disease. In some cases, a subject may not necessarily be diagnosed or suspected of being at high risk of disease.

[0190] As used herein, the term “about” for a number means the number plus or minus 10% of the number. The term “about” for a range means the range minus 10% of its lowest value and plus 10% of its highest value.

[0191] As used herein, the term "treatment" refers to a drug or other intervention intended to achieve a beneficial or desired outcome in a recipient. Beneficial or desired outcomes include, but are not limited to, therapeutic and / or preventative benefits. A therapeutic benefit may refer to the eradication or improvement of an underlying condition or its symptoms that is being treated. Additionally, a therapeutic benefit may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition to the point that improvement is observed in the subject, although the subject may still be troubled by the underlying condition. Preventative effects include delaying, preventing, or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, terminating, or reversing the progression of a disease or condition, or any combination thereof. For preventative benefits, treatment may be given to subjects at risk of developing a specific disease or to subjects who report one or more physiological symptoms of a disease (even if a diagnosis of the disease may not yet have been made).

[0192] "Treatment" or "treatment" can include actions taken to obtain a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventative benefits) for a disease, condition, or medical condition. Therapeutic benefits can include, for example, the eradication or improvement of an underlying condition that is being treated. Furthermore, therapeutic benefits can also include, for example, the eradication or improvement of one or more physiological symptoms associated with an underlying condition, such that improvement is observed in the subject, even if the subject may still have the underlying condition. In some embodiments, for preventative benefits, the composition is administered to a subject at risk of developing a specific disease or to a subject reporting one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed. Treatment by administering the compounds described herein does not necessarily require the involvement of a medical professional.

[0193] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the topics described.

[0194] When the term "C" x-y "or "C x -C y When used with a chemical part (such as alkyl, alkenyl, or alkynyl), it refers to a chain group containing x to y carbons. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups containing 1 to 6 carbons. The term "C"... x-y "or "C x -C y "It does not limit the number of carbon atoms that can be attached to a chemical part when the chemical part is replaced by a second chemical group. For example, the term "C 1-6 "Alkyl" or "C1 to C6 alkyl" refers to a saturated, substituted or unsubstituted hydrocarbon group, including straight-chain alkyl groups (e.g., linear alkyl groups) and branched alkyl groups containing 1, 2, 3, 4, 5 or 6 carbon atoms, as well as C1 to C6 alkyl groups.1-6 How many carbon atoms can be present in any substituent of an alkyl group? For example, if C... 1-6 The alkyl group is optionally replaced with a second chemical group containing two carbon atoms, which can be understood as the C 1-6 Alkyl groups can contain 1 to 8 carbon atoms.

[0195] Term "C" x-y "Alkenyl" and "C" x-y "Alkyne" refers to an unsaturated aliphatic group, whether substituted or unsubstituted, with length and possible substitutions similar to the alkyl groups described above, but containing at least one double or triple bond.

[0196] "Amino" refers to the –NH2 part.

[0197] “Cyano” refers to the -CN part.

[0198] "Nitro" refers to the -NO2 group.

[0199] “O-” refers to the -O- part.

[0200] “Oxygenation” refers to the O portion.

[0201] "Thiolated" refers to the S-part.

[0202] "Imine" refers to the NH part.

[0203] "Oxime group" refers to the N-OH group.

[0204] "Hydrazine" refers to the N-NH2 group.

[0205] "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon moiety consisting only of carbon and hydrogen atoms. In some embodiments, "alkyl" contains one to fifteen carbon atoms (e.g., C1-C1). 15 Alkyl group). In some embodiments, the alkyl group contains one to thirteen carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In some embodiments, the alkyl group comprises one to six carbon atoms (e.g., C1-C6 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl, such as methyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C6 alkyl).15 Alkyl group. In other embodiments, the alkyl group comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from: methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (2-propyl, isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond.

[0206] "Aminoalkyl" refers to a portion bonded by a nitrogen atom, in the form of –N(H)(alkyl) or N(alkyl)(alkyl), wherein when the portion is N(alkyl)(alkyl), the two alkyl groups bonded to the nitrogen atom can be the same alkyl group or different alkyl groups.

[0207] "Alkoxy" refers to the –O-alkyl portion bonded by an oxygen atom, where the alkyl is an alkyl chain as defined above.

[0208] "Alkenyl" refers to a straight-chain or branched hydrocarbon group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond. In some embodiments, the alkenyl group contains two to twelve carbon atoms. In some embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to four carbon atoms. The alkenyl group is attached to other parts of the molecule by a single bond, such as vinyl (i.e., ethylene), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0209] "Alynyl" refers to a straight-chain or branched hydrocarbon group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having two to twelve carbon atoms, and optionally also containing at least one carbon-carbon double bond. In some embodiments, the alkynyl group contains two to eight carbon atoms. In other embodiments, the alkynyl group contains two to six carbon atoms. In still other embodiments, the alkynyl group contains two to four carbon atoms. The alkynyl group is attached to other parts of the molecule by single bonds, such as ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc.

[0210] "alkylene" or "alkylene chain" refers to a linear (e.g., straight-chain) or branched divalent hydrocarbon group. An "alkylene" or "alkylene chain" can connect one part of a molecule to a second part. An "alkylene" or "alkylene chain" consists only of carbon and hydrogen atoms (the alkylene may be specified to be substituted with one or more substituents containing atoms other than hydrogen, such as nitrogen, oxygen, and sulfur). An "alkylene" or "alkylene chain" may be unsaturated (although the alkylene has attachment points to other parts of the molecule). In some embodiments, an "alkylene" or "alkylene chain" contains one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butyl, etc. An alkylene chain can be attached to one part of the molecule by a single bond and to a second part by a single bond. The attachment points of the alkylene chain to the rest of the molecule and the second part can be through one carbon in the alkylene chain or through any two carbons within the alkylene. In some embodiments, an alkylene contains one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene group comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene group comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene).

[0211] "Idenoyl" or "idenoyl chain" refers to a linear (e.g., straight-chain) or branched divalent hydrocarbon portion. An "idenoyl" or "idenoyl chain" can connect a portion of a molecule to a second portion. An "idenoyl" or "idenoyl chain" consists only of carbon and hydrogen atoms (the idenoyl may be substituted by one or more substituents containing atoms other than hydrogen, such as nitrogen, oxygen, and sulfur). An "idenoyl" or "idenoyl chain" contains at least one carbon-carbon double bond. In some embodiments, an "idenoyl" or "idenoyl chain" contains two to twelve carbon atoms. The idenoyl chain can be attached to a portion of the molecule by a single bond and to a second portion by a single bond. The attachment point of the idenoyl chain to other portions of the molecule and the second portion can be through one carbon atom in the idenoyl chain or any two carbon atoms in the idenoyl chain. In some embodiments, the idenoyl contains two to eight carbon atoms (e.g., C2-C8 idenoyl). In other embodiments, the idenoyl contains two to five carbon atoms (e.g., C2-C5 idenoyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (e.g., C2-C4 alkenyl). In other embodiments, the alkenyl group comprises two to three carbon atoms (e.g., C2-C3 alkenyl). In other embodiments, the alkenyl group comprises five to eight carbon atoms (e.g., C5-C8 alkenyl). In other embodiments, the alkenyl group comprises two to five carbon atoms (e.g., C2-C5 alkenyl). In other embodiments, the alkenyl group comprises three to five carbon atoms (e.g., C3-C5 alkenyl).

[0212] "Inyynyl" or "Inyynyl chain" refers to a linear (e.g., straight-chain) or branched divalent hydrocarbon moiety. "Inyynyl" or "Inyynyl chain" can connect a portion of a molecule to a second portion. "Inyynyl" or "Inyynyl chain" consists only of carbon and hydrogen (the ynylyl group may be substituted by one or more substituents containing atoms other than hydrogen, such as nitrogen, oxygen, and sulfur). "Inyynyl" or "Inyynyl chain" contains at least one carbon-carbon triple bond. In some embodiments, "Inyynyl" or "Inyynyl chain" contains two to twelve carbon atoms. The ynylyl chain can be attached to a portion of the molecule by a single bond and to a second portion by a single bond. The attachment point of the ynylyl chain to the remainder of the molecule and the second portion can be through one carbon atom in the ynylyl chain or through any two carbon atoms in the ynylyl chain. In some embodiments, the ynylyl group contains two to eight carbon atoms (e.g., C2-C8 ynylyl). In other embodiments, the ynylyl group contains two to five carbon atoms (e.g., C2-C5 ynylyl). In other embodiments, the ynylene group comprises two to four carbon atoms (e.g., C2-C4 ynylene). In other embodiments, the ynylene group comprises two to three carbon atoms (e.g., C2-C3 ynylene). In other embodiments, the ynylene group comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, the ynylene group comprises five to eight carbon atoms (e.g., C5-C8 ynylene). In other embodiments, the ynylene group comprises three to five carbon atoms (e.g., C3-C5 ynylene).

[0213] As used herein, the term "carbocyclic ring" refers to a saturated ring, an unsaturated ring, or an aromatic ring, wherein each atom of the ring is carbon. Carbocyclic rings include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as a phenyl ring, may be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence state permits, bicyclic carbocyclic rings include any combination of saturated bicyclic rings, unsaturated bicyclic rings, and aromatic bicyclic rings. Bicyclic carbocyclic rings also include spirobicyclic rings, such as spiropentane. Bicyclic carbocyclic rings include any combination of ring sizes, such as 3-3 spirocyclic systems, 4-4 spirocyclic systems, 4-5 fused-ring systems, 5-5 fused-ring systems, 5-6 fused-ring systems, 6-6 fused-ring systems, 5-7 fused-ring systems, 6-7 fused-ring systems, 5-8 fused-ring systems, and 6-8 fused-ring systems. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indene, naphthyl, and bicyclic [1.1.1]pentyl. "Carbocyclic ring" may include "aryl" and "cycloalkyl".

[0214] The term "aryl" refers to an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon and contains 5 to 18 carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2) π-electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene. In some embodiments, the aryl substituent carries a positive or negative charge. In some embodiments, the aryl substituent is neutral. In some embodiments, the aryl substituent is zwitterionic; alternatively or additionally, in some embodiments, the aryl substituent is uncharged. In some embodiments, the aryl substituent is uncharged. In some embodiments, the aryl substituent has no net charge. In some embodiments, the aryl substituent has no net charge and is not zwitterionic.

[0215] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is a carbon atom. Cycloalkyl groups can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms. In other embodiments, the cycloalkyl group contains 5 to 7 carbon atoms. The cycloalkyl group can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, spiropentane, borneol (i.e., bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl, etc.

[0216] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is a carbon atom, and there is at least one double bond between two ring carbons. Cycloalkenyl groups can include monocyclic and polycyclic groups, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, the cycloalkenyl group comprises 5 to 7 carbon atoms. The cycloalkenyl group can be attached to the remainder of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0217] The term "halogen" or alternatively "halogen" or "halide" refers to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

[0218] The term "haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl, 2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl group may optionally be further substituted as described herein.

[0219] As used herein, the term "heterocycle" refers to a saturated ring, unsaturated ring, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. Where valence state permits, bicyclic heterocycles include any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings. In one exemplary embodiment, the aromatic ring, such as a pyridyl group, may be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles also include spirobicycles, such as 5- to 12-membered spirobicycles, such as 2-oxa-6-azaspiro[3.3]heptane. “Heterocycle” can include “heteroaryl” and “heterocyclic alkyl”.

[0220] The term "heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group, comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, wherein at least one ring in the ring system is aromatic, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2) π-electron system. Heteroaryls include fused-ring or bridged-ring systems. One or more heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl group is attached to the remainder of the molecule via any atom of the ring.Examples of heteroaryl groups include, but are not limited to, azaheptatrienyl, acridinel, benzimidazolyl, benzoindolyl, 1,3-benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptenyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxacyclohexyl, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexadienyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl, benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a] Pyridyl, carbazolyl, cyclopentadieno[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentadieno[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]pyrimidinyl, 6,7-dihydro-5H-benzo[6,7]cyclopentadieno[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienoyl, furanyl, furanoneyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridazinyl Tetraeno[d]pyridinyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, inazinyl, isoxazolyl, 5,8-bridged methylene-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphridinoneyl, oxadiazolyl, 2-oxoazapyridine-heptadienyl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl1Hpyrroleyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purineyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyridolo[3,2-d] Pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, quinazolinyl, quinoxolinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8 tetrahydroquinazolinyl, 5,6,7,8 tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9 tetrahydro5Hcyclopentadien[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8 tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thienoyl.

[0221] If one or more nitrogen atoms are present, they can be selectively quaternized. In some embodiments, the heterocyclic substituent is positively or negatively charged. In some embodiments, the heterocyclic substituent is neutral. In some embodiments, the heterocyclic substituent is zwitterionic; alternatively or additionally, in some embodiments, the heterocyclic substituent is uncharged. In some embodiments, the heterocyclic substituent is uncharged. In some embodiments, the heterocyclic substituent has no net charge. In some embodiments, the heterocyclic substituent has no net charge and is not zwitterionic.

[0222] The term "heterocyclic alkyl" refers to a saturated ring having a carbon atom and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic alkyl groups can include monocyclic and polycyclic forms, such as 3- to 10-membered monocyclic, 6- to 12-membered bicyclic, 5- to 12-membered spirobicyclic, and 5- to 12-membered bridged rings. The heteroatom in the heterocyclic alkyl group is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Where valence permits, the heterocyclic alkyl group is attached to the remainder of the molecule by any atom of the heterocyclic alkyl group, such as any carbon or nitrogen atom of the heterocyclic alkyl group. Examples of heterocyclic alkyl groups include, but are not limited to, dioxacyclopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, 2-oxa-6-azaspiro[3,3]heptane, and 1,1-dioxothiomorpholinyl. In some embodiments, the heterocyclic alkyl group comprises a heteroatom. In some embodiments, the heterocyclic alkyl group comprises a heteroatom selected from N, O, and S. In some embodiments, the heterocyclic alkyl group comprises multiple heteroatoms. In some embodiments, the heterocyclic alkyl group comprises multiple heteroatoms selected from N, O, and S.

[0223] The term "heterocyclic alkenyl" refers to an unsaturated ring having a carbon atom and at least one heteroatom, with at least one double bond between the two ring carbons. Heterocyclic alkenyls do not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic alkenyls can include monocyclic and polycyclic compounds, such as 3- to 10-membered monocyclics, 6- to 12-membered bicyclics, and 5- to 12-membered bridged rings. In other embodiments, the heterocyclic alkenyl comprises 5 to 7 ring atoms. The heterocyclic alkenyl can be attached to the remainder of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrrolidone (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazolium), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazolium), isothiazolinium (dihydroisothiazolium), oxadiazolinium (dihydrooxadiazole), thiadiazolinium (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridine, tetrahydropyrimidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, thiaran, dihydrothiaran, dioxazolidinene, dihydrodioxazolidinene, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0224] The term "substituted" refers to a portion having a substituent that replaces one or more hydrogen atoms or substituted heteroatoms (e.g., NH or NH2 in a compound). It should be understood that "substituted" or "replaced by" includes the implicit precondition that such substitution conforms to the permissible valence states of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. In some embodiments, "substituted" refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon atom with an oxo group, imino group, or thio group. As used herein, the term "substituted" is envisioned to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents can be one or more and can be the same or different.

[0225] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(Ra )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, arylenyl, aryynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each of which may optionally be replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazyl (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b-C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) replace; where each R a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein, where the valence state permits, each R a It can be optionally divided by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(Ra )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) replace; and where each R b Independently selected from direct-chain or straight-chain or branched alkylene, alkenyl, or ynylene chains, and each R c It is a straight-chain or branched alkylene, alkenyl, or ynylene chain.

[0226] Double bonds with oxygen atoms, such as oxo groups, are represented in this document as both "=O" and "(O)". Double bonds with nitrogen atoms are represented as both "=NR" and "(NR)". Double bonds with sulfur atoms are represented as both "=S" and "(S)".

[0227] As used herein, the phrases “parenteral administration” and “administered via a parenteral route” refer to administration methods that are normally administered by injection, other than enteral and topical administration, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0228] As used in this article, "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that, to a reasonable extent of medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a proportionate and reasonable benefit / risk ratio.

[0229] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be acceptable in the sense of compatibility with other components of the formulation and must not be harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil and cottonseed oil. (10) Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Atherless water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic and compatible substances used in pharmaceutical preparations.

[0230] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and particularly isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0231] This invention provides, but is not limited to, the following embodiments: 1. The compound represented by formula (I) or (II): (I), or (II); or its salt, wherein J is an oligonucleotide; Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C; If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 The connectors are selected from the following: -O-, -S-, -N(R) 7 -, -C(O)-, -C(O)N(R) 7 )-、-N(R 7 )C(O)-、-N(R 7 )C(O)N(R 7 )-、-OC(O)N(R 7 )-、-N(R 7)C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - )S-、-OP(O)(OR 7 )NR 7 -、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2NR 7 -; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 -SR7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 )2; Each R 6 Selected independently from: hydrogen; Halogen, -CN, -NO2, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ;as well as C can be optionally substituted with one or more substituents 1-6Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

[0232] 2. The compound or salt as described in Embodiment 1, wherein each w is independently selected from any value from 1 to 10.

[0233] 3. A compound or salt as described in Embodiment 1, wherein each w is independently selected from any value from 1 to 5.

[0234] 4. The compound or salt as described in Embodiment 1, wherein each w is 1.

[0235] 5. A compound or salt as described in Embodiment 1, wherein each v is independently selected from any value from 1 to 10.

[0236] 6. A compound or salt as described in Embodiment 1, wherein each v is independently selected from any value from 1 to 5.

[0237] 7. A compound or salt as described in Embodiment 1, wherein each v is 1.

[0238] 8. A compound or salt as described in Embodiment 1, wherein n is selected from any value from 1 to 10.

[0239] 9. A compound or salt as described in Embodiment 1, wherein n is selected from any value from 1 to 5.

[0240] 10. The compound or salt as described in Embodiment 1, wherein n is 2.

[0241] 11. The compound or salt as described in Embodiment 1, wherein m is selected from any value from 1 to 10.

[0242] 12. A compound or salt as described in Embodiment 1, wherein m is selected from any value from 1 to 5.

[0243] 13. The compound or salt as described in Embodiment 1, wherein m is selected from 1 and 2.

[0244] 14. The compound or salt as described in Embodiment 1, wherein z is 3 and Y is C.

[0245] 15. A compound or salt as described in Embodiment 1, wherein Q is selected from C that is optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR7 -OC(O)R 7 and -S(O)R 7 .

[0246] 16. A compound or salt as described in Embodiment 1, wherein Q is selected from C that is optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2.

[0247] 17. A compound or salt as described in Embodiment 1, wherein Q is selected from phenyl and cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2.

[0248] 18. The compound or salt as described in Embodiment 1, wherein Q is selected from phenyl.

[0249] 19. The compound or salt as described in Embodiment 1, wherein Q is selected from cyclohexyl.

[0250] 20. A compound or salt as described in Embodiment 1, wherein R 1 Selected from -OP(O)(OR 7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - )S-、-OP(O)(OR 7 )NR 7 -、-OP(O)(N(R 7 )2)NR 7 -、-OP(OR 7 )O-、-OP(N(R 7 )2)O-、-OP(OR 7 )N(R 7 - and -OPN(R) 7 )2NR 7 .

[0251] 21. A compound or salt as described in Embodiment 1, wherein R 1 Selected from -OP(O)(OR7 )O-、-SP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(SR 7 )O-、-OP(O)(OR 7 )S-、-OP(O)(O - )O-、-SP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O-、-OP(O)(O - S- and -OP(OR) 7 )O-.

[0252] 22. A compound or salt as described in Embodiment 1, wherein R 1 Selected from -OP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(OR 7 )O-.

[0253] 23. A compound or salt as described in Embodiment 1, wherein R 1 Selected from -OP(O)(OR 7 )O- and -OP(OR 7 )O-.

[0254] 24. A compound or salt as described in Embodiment 1, wherein R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -OC(O)R 7 -SR 7 -N(R) 7 )2、-C(O)R 7 and -S(O)R 7 .

[0255] 25. A compound or salt as described in Embodiment 1, wherein R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 )2.

[0256] 26. A compound or salt as described in Embodiment 1, wherein R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 and -OC(O)R 7 .

[0257] 27. A compound or salt as described in Embodiment 1, wherein R 3 Selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 .

[0258] 28. A compound or salt as described in Embodiment 1, wherein R 3 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2.

[0259] 29. A compound or salt as described in Embodiment 1, wherein R 3 Selected from -OR 7 -and-OC(O)R 7 .

[0260] 30. A compound or salt as described in Embodiment 1, wherein R 4 Selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 .

[0261] 31. A compound or salt as described in Embodiment 1, wherein R 4 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2.

[0262] 32. The compound or salt as described in Embodiment 1, wherein R 4 Selected from -OR 7 -and-OC(O)R 7 .

[0263] 33. A compound or salt as described in Embodiment 1, wherein R 5 Selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2 and -N(R 7 )C(O)OR 7 .

[0264] 34. A compound or salt as described in Embodiment 1, wherein R 5 Selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 .

[0265] 35. A compound or salt as described in Embodiment 1, wherein each R 7 Selected independently from: Hydrogen; and C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings or heterocyclic rings ranging from 3 to 10 members.

[0266] 36. A compound or salt as described in any one of embodiments 1 to 30, wherein each R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 alkyl).

[0267] 37. A compound or salt as described in any one of embodiments 1 to 34, wherein each R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH and -SH.

[0268] 38. The compound or salt as described in Embodiment 1, wherein w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, and C. 1-3 alkyl; R 1 Selected from -OP(O)(OR 7 )O-、-OP(S)(OR 7 )O-、-OP(O)(O - )O-、-OP(S)(O - )O-、-OP(O)(S - )O- and -OP(OR 7 )O-; R 2 It is a C1 alkyl group substituted with -OH or -OC(O)CH3; R 3 It is -OH or -OC(O)CH3; R 4 It is -OH or -OC(O)CH3; and R 5 It is -NH(O)CH3.

[0269] 39. A compound or salt as described in Embodiment 1, wherein the compound comprises: .

[0270] 40. The compound of embodiment 1, wherein the oligonucleotide (J) is attached at the 5' end or 3' end of the oligonucleotide.

[0271] 41. The compound as described in Embodiment 1, wherein the oligonucleotide comprises DNA.

[0272] 42. The compound as described in Embodiment 1, wherein the oligonucleotide comprises RNA.

[0273] 43. The compound of embodiment 1, wherein the oligonucleotide comprises one or more modified nucleoside links.

[0274] 44. The compound of embodiment 43, wherein the one or more modified nucleoside links comprise alkyl phosphonates, thiophosphates, methyl phosphonates, dithiophosphates, alkyl thiophosphonates, aminophosphates, carbamates, carbonates, triphosphates, acetylimine esters, or carboxymethyl esters, or combinations thereof.

[0275] 45. The compound of embodiment 1, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 modified nucleoside linkages.

[0276] 46. ​​The compound of embodiment 1, wherein the oligonucleotide comprises one or more modified nucleosides.

[0277] 47. The compound of embodiment 46, wherein the one or more modified nucleosides comprise locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro or 2'-deoxy, or combinations thereof.

[0278] 48. The compound of embodiment 46, wherein the one or more modified nucleosides comprise 2',4'-restricted ethyl nucleoside, 2'-O-methyl nucleoside, 2'-deoxyfluorinated nucleoside, 2'-ON-methylacetamido(2'-O-NMA) nucleoside, 2'-O-dimethylaminoethoxyethyl(2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl(2'-O-AP) nucleoside, 2'-ara-F, 2'-fluoro or 2'-O-alkyl, or combinations thereof.

[0279] 49. The compound of embodiment 1, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or more modified nucleosides.

[0280] 50. The compound of embodiment 1, wherein the oligonucleotide comprises a lipid attached at the 3' or 5' end of the oligonucleotide.

[0281] 51. The compound of embodiment 50, wherein the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithochyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl or α-tocopherol, or combinations thereof.

[0282] 52. The compound of embodiment 1, wherein the oligonucleotide comprises an arginine-glycine-aspartic acid (RGD) peptide attached to the 3' or 5' end of the oligonucleotide.

[0283] 53. The compound of embodiment 52, wherein the RGD peptide comprises cyclic (-Arg-Gly-Asp-D-Phe-Cys), cyclic (-Arg-Gly-Asp-D-Phe-Lys), cyclic (-Arg-Gly-Asp-D-Phe-azido), aminobenzoic acid-derived RGD, or combinations thereof.

[0284] 54. The compound of embodiment 1, wherein the oligonucleotide comprises a small interfering RNA (siRNA) containing a sense strand and an antisense strand.

[0285] 55. The compound as described in embodiment 54, wherein the length of the sense chain is 12-30 nucleosides.

[0286] 56. The compound of embodiment 54, wherein the antisense chain is 12-30 nucleotides in length.

[0287] 57. The compound of embodiment 54, wherein the sense strand and the antisense strand form a double-stranded RNA double helix.

[0288] 58. The compound of embodiment 57, wherein the first base pair of the double-stranded RNA double helix is ​​an AU base pair.

[0289] 59. The compound of embodiment 54, wherein the sense chain or the antisense chain comprises a 3' protrusion.

[0290] 60. The compound of embodiment 59, wherein the 3' protrusion comprises 1, 2 or more nucleosides.

[0291] 61. The compound as described in Embodiment 1, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).

[0292] 62. The compound of embodiment 61, wherein the length of the ASO is 12-30 nucleosides.

[0293] 63. The compound as described in Embodiment 1, wherein the compound binds to the desialyl glycoprotein receptor.

[0294] 64. The compound as described in Embodiment 1, wherein the compound targets hepatocytes.

[0295] 65. A pharmaceutical composition comprising the compound of embodiment 1 and a pharmaceutically acceptable carrier, excipient or diluent.

[0296] 66. The pharmaceutical composition of embodiment 65, wherein the pharmaceutical composition is sterile.

[0297] 67. The pharmaceutical composition of embodiment 65, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

[0298] 68. The pharmaceutical composition of embodiment 67, wherein the pharmaceutically acceptable carrier includes water, a buffer, or physiological saline.

[0299] 69. The pharmaceutical composition of embodiment 65, wherein the oligonucleotide targets a target mRNA and, when administered to a subject in an effective amount, reduces the target mRNA or target protein by at least 10%.

[0300] 70. A method for reducing target mRNA or target protein of a desired object, comprising administering an effective amount of the pharmaceutical composition of embodiment 65 to said object.

[0301] 71. The method of embodiment 70, wherein the effective amount reduces the measurement of the target mRNA or target protein of the object relative to the baseline measurement of the target mRNA or target protein.

[0302] 72. The method as described in embodiment 70, wherein the effective amount treats the condition of the subject.

[0303] 73. The method of embodiment 72, wherein the effective amount reduces the measurement of the symptoms or parameters of the subject related to the condition relative to the baseline measurement of the symptoms or parameters.

[0304] 74. The method of embodiment 72, wherein the measured value of the symptom or parameter related to the condition of the subject is reduced for at least 10 days.

[0305] 75. The method as described in embodiment 72, wherein the condition includes metabolic disorders.

[0306] 76. The method as described in embodiment 72, wherein the condition includes liver disease.

[0307] 77. The compound represented by formula (A) or (B): (A), or (B); or its salt, wherein Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C. If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 Selected from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 -S(O)2R 7 -OS(O)2R 7 -OP(O)(OR) 7 )2、-OP(S)(OR 7 )2、-SP(O)(OR 7 )2、-OP(O)(SR 7 (OR) 7 ), -OP(O)(OR 7 )N(R 7 )2、-OP(S)(OR 7 )N(R 7 )2、-SP(O)(OR 7 )N(R 7 )2、-OP(O)(SR 7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(S)(N(R 7 )2)2、-SP(O)(N(R 7 )2)2、-OP(OR 7 )2、-SP(OR 7 2. -OP(OR) 7 (SR) 7 -OP(OR) 7 )N(R 7 )2、-OP(SR 7 )N(R 7 )2、-SP(OR 7 )N(R 7 )2、-OP(N(R 7 )2)2 and -SP(N(R 7 )2)2; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)R 7 -C(O)OR 7 and -C(O)N(R) 7 )2; Each R 6 Selected independently from: hydrogen; Halogen, -CN, -NO2, -OR 7 -SR 7 -N(R)7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ;as well as C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

[0308] 78. A compound or salt as described in embodiment 77, wherein each w is independently selected from any value from 1 to 10.

[0309] 79. A compound or salt as described in embodiment 77, wherein each w is independently selected from any value from 1 to 5.

[0310] 80. A compound or salt as described in embodiment 77, wherein each w is 1.

[0311] 81. A compound or salt as described in embodiment 77, wherein each v is independently selected from any value from 1 to 10.

[0312] 82. A compound or salt as described in embodiment 77, wherein each v is independently selected from any value from 1 to 5.

[0313] 83. A compound or salt as described in embodiment 77, wherein each v is 1.

[0314] 84. A compound or salt as described in embodiment 77, wherein n is selected from any value from 1 to 10.

[0315] 85. A compound or salt as described in embodiment 77, wherein n is selected from any value from 1 to 5.

[0316] 86. The compound or salt as described in embodiment 77, wherein n is 2.

[0317] 87. A compound or salt as described in embodiment 77, wherein m is selected from any value from 1 to 10.

[0318] 88. A compound or salt as described in embodiment 77, wherein m is selected from any value from 1 to 5.

[0319] 89. A compound or salt as described in embodiment 77, wherein m is selected from 1 and 2.

[0320] 90. A compound or salt as described in embodiment 77, wherein z is 3 and Y is C.

[0321] 91. A compound or salt as described in embodiment 77, wherein Q is selected from C that is optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 .

[0322] 92. A compound or salt as described in embodiment 77, wherein Q is selected from C that is optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2.

[0323] 93. A compound or salt as described in Embodiment 77, wherein Q is selected from phenyl and cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2.

[0324] 94. The compound or salt as described in Embodiment 77, wherein Q is selected from phenyl.

[0325] 95. The compound or salt of embodiment 77, wherein Q is selected from cyclohexyl.

[0326] 96. A compound or salt as described in embodiment 77, wherein R 1 Selected from -OP(O)(OR 7 )2、-OP(O)(OR 7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(OR 7 2. -OP(OR) 7 )N(R 7)2 and -OP((NR 7 )2)2.

[0327] 97. A compound or salt as described in embodiment 77, wherein R 1 Selected from -OP(O)(OR 7 )2 and -OP(OR 7 )N(R 7 )2.

[0328] 98. A compound or salt as described in embodiment 77, wherein R 1 Selected from -OP(O)(OCH2CH3)OH and -OP(OCH2CH2CN)N(CH(CH3)2)2.

[0329] 99. A compound or salt as described in embodiment 77, wherein R 1 It is -OP(OCH2CH2CN)N(CH(CH3)2)2.

[0330] 100. A compound or salt as described in embodiment 77, wherein R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -OC(O)R 7 -SR 7 -N(R) 7 )2、-C(O)R 7 and -S(O)R 7 .

[0331] 101. A compound or salt as described in embodiment 77, wherein R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 )2.

[0332] 102. A compound or salt as described in embodiment 77, wherein R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 and -OC(O)R 7 .

[0333] 103. A compound or salt as described in embodiment 77, wherein R 3 Selected from halogens, -OR 7 -SR7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 .

[0334] 104. A compound or salt as described in embodiment 77, wherein R 3 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2.

[0335] 105. A compound or salt as described in embodiment 77, wherein R 3 Selected from -OR 7 and -OC(O)R 7 .

[0336] 106. A compound or salt as described in embodiment 77, wherein R 4 Selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -OC(O)R 7 and -S(O)R 7 .

[0337] 107. A compound or salt as described in embodiment 77, wherein R 4 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2.

[0338] 108. A compound or salt as described in embodiment 77, wherein R 4 Selected from -OR 7 and -OC(O)R 7 .

[0339] 109. A compound or salt as described in embodiment 77, wherein R 5 Selected from -OC(O)R 7 -OC(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2 and -N(R 7 )C(O)OR 7 .

[0340] 110. A compound or salt as described in embodiment 77, wherein R 5 Selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 .

[0341] 111. A compound or salt as described in embodiment 77, wherein each R 7 Selected independently from: Hydrogen; and C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings, or 3 to 10-membered heterocyclic rings.

[0342] 112. A compound or salt as described in embodiment 77, wherein each R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 alkyl).

[0343] 113. A compound or salt as described in embodiment 77, wherein each R 7 Independently selected from C14 groups that are optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -OH and -SH.

[0344] 114. The compound or salt as described in embodiment 113, wherein w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, and C. 1-3 alkyl; R 1 Selected from -OP(O)(OR 7 )2 and -OP(OR 7 )N(R 7 )2; R 2 It is a C1 alkyl group substituted with -OH or -OC(O)CH3; R 3 It is -OH or -OC(O)CH3; R 4 It is -OH or -OC(O)CH3; and R 5 It is -NH(O)CH3.

[0345] 115. A compound or salt as described in embodiment 77, wherein the compound comprises: .

[0346] 116. A compound comprising: , wherein J includes an oligonucleotide, or includes a link to said oligonucleotide.

[0347] 117. The compound of embodiment 116, wherein J further comprises one or more phosphate groups that link the structure to the oligonucleotide.

[0348] 118. The compound of embodiment 116, wherein J further comprises one or more thiophosphate groups that link the structure to the oligonucleotide.

[0349] 119. The compound of embodiment 116, wherein the oligonucleotide includes a 5' end, and J includes a link to the 5' end of the oligonucleotide.

[0350] 120. The compound as described in embodiment 116, wherein the oligonucleotide comprises siRNA.

[0351] VI. Examples Example 1: Identification of variants of target oligonucleotides associated with increased or decreased disease risk We will analyze approximately 30,000,000 putative variants from approximately 375,000 individuals in the biobank cohort to investigate their association with liver conditions such as non-alcoholic steatohepatitis.

[0352] Protective or maladaptive associations have been observed between specific allelic variants of many target genes and liver diseases. These associations suggest that, in some cases, therapeutic inhibition or regulation of target proteins encoded by any target gene may be an effective genetically guided approach for treating any liver disease.

[0353] Example 2: Bioinformatics-based sequence selection to identify therapeutic siRNAs that downregulate the expression of target mRNAs The screening set will be defined based on bioinformatics analysis. Therapeutic siRNAs are designed to bind to human target mRNAs and target mRNA sequences from at least one toxicologically relevant species (e.g., non-human primate (NHP) species, such as rhesus monkeys or cynomolgus monkeys). The driving factors for the screening set design are the predicted specificity of the siRNAs to the transcriptomes of relevant species and cross-reactivity between species. The predicted specificity of sense (S) and antisense (AS) strands in humans, rhesus monkeys, cynomolgus monkeys, mice, and rats was determined. These were assigned a “specificity score” that takes into account the probability of unintended downregulation of any other transcript through complete or partial complementarity of the siRNA strand (up to 4 mismatches within positions 2–18) and the number and location of mismatches. Therefore, off-target effects of the antisense and sense strands for each siRNA were identified. Furthermore, the number of possible off-target effects was used as an additional specificity factor in the specificity score. As identified, siRNAs with high specificity and a small number of predicted off-target effects provide the benefit of increased targeting specificity.

[0354] In addition to selecting siRNA sequences with high sequence specificity to the target mRNA, the similarity between the siRNA sequence within the seed region and the seed regions of known miRNAs was analyzed. siRNAs can function in a miRNA-like manner by base pairing with complementary sequences within the 3'-UTR of the mRNA molecule. Complementarity typically covers the 5' bases at positions 2-7 (seed region) of the miRNA. To avoid siRNAs acting via functional miRNA binding sites, siRNA strands containing native miRNA seed regions were avoided. Seed regions identified in miRNAs from humans, mice, rats, rhesus monkeys, dogs, rabbits, and pigs were designated "conserved." Combining the "specificity score" with the miRNA seed analysis produced "specificity categories." These were divided into categories 1-4, where 1 has the highest specificity and 4 has the lowest. Each strand of siRNA was assigned to a specificity category.

[0355] Cross-reactivity was assessed in humans, cynomolgus monkeys, rhesus monkeys, mice, and rats. The analysis was based on classic siRNA designs using 19 and 17 bases (ignoring positions 1 and 19) for cross-reactivity. Both perfect match and single mismatch analyses were included.

[0356] A human single nucleotide polymorphism (SNP) database (NCBI-DB-SNP) analysis was also performed to identify siRNA target regions with known SNPs, in order to identify siRNAs that may not be functional in individuals containing SNPs. This analysis yielded information about the location of SNPs within the target sequence and minor allele frequencies (MAFs) in the case data.

[0357] The methods described above can be used to identify therapeutic siRNAs that downregulate the expression of target mRNAs. Bioinformatics methods can also be used to identify ASOs that bind to and downregulate the expression of target mRNAs.

[0358] Example 3: Chemically modified siRNA siRNAs that bind to target mRNAs can be chemically modified, with modifications such as modification pattern 1S on the sense strand and modification pattern 1AS on the antisense strand. Furthermore, adenosine can be located at position 19 on the sense strand, while uridine can be located at position 1 on the antisense strand.

[0359] siRNAs that bind to target mRNAs can also be chemically modified, with the sense strand exhibiting a 2S modification pattern and the antisense strand exhibiting a 3AS modification pattern. Furthermore, adenosine can be located at position 19 of the sense strand, while uridine is located at position 1 of the antisense strand.

[0360] siRNAs that bind to target mRNAs can also be chemically modified, with the sense strand exhibiting a 2S modification pattern and the antisense strand exhibiting a 9AS modification pattern. Furthermore, adenosine can be located at position 19 of the sense strand, while uridine is located at position 1 of the antisense strand.

[0361] siRNA targeting of target mRNA can also synthesize chemically modified molecules, with the sense strand having a 3S modification pattern and the antisense strand having a 3AS modification pattern. Furthermore, adenosine can be located at position 19 of the sense strand, while uridine is located at position 1 of the antisense strand.

[0362] siRNA targeting of target mRNA can also be chemically modified, wherein the sense strand has any of the following: all purines containing 2'-fluorine modified purines, and all pyrimidines containing a mixture of 2'-fluorine modified pyrimidines and 2'-O-methyl modified pyrimidines; all purines containing 2'-O-methyl modified purines, and all pyrimidines containing a mixture of 2'-fluorine modified pyrimidines and 2'-O-methyl modified pyrimidines; all purines containing 2'-fluorine modified purines, and all pyrimidines containing 2'-O-methyl modified pyrimidines; all pyrimidines containing 2'-fluorine modified pyrimidines, and all purines containing a mixture of 2'-fluorine modified purines and 2'-O-methyl modified pyrimidines; all pyrimidines containing 2'-O-methyl modified pyrimidines, and all purines containing a mixture of 2'-fluorine modified purines and 2'-O-methyl modified purines; or all pyrimidines containing 2'-fluorine modified pyrimidines, and all purines containing 2'-O-methyl modified pyrimidines. All purines containing modified purines; and further wherein the antisense chain has any one of the following: all purines containing 2'-fluorine modified purines, and all pyrimidines containing a mixture of 2'-fluorine modified pyrimidines and 2'-O-methyl modified pyrimidines; all purines containing 2'-O-methyl modified purines, and all pyrimidines containing a mixture of 2'-fluorine modified pyrimidines and 2'-O-methyl modified pyrimidines; all purines containing 2'-O-methyl modified purines, and all pyrimidines containing 2'-fluorine modified pyrimidines; all pyrimidines containing 2'-fluorine modified pyrimidines, and all purines containing a mixture of 2'-fluorine modified purines and 2'-O-methyl modified purines; all pyrimidines containing 2'-O-methyl modified pyrimidines, and all purines containing a mixture of 2'-fluorine modified purines and 2'-O-methyl modified purines; or all pyrimidines containing 2'-O-methyl modified pyrimidines, and all purines containing 2'-fluorine modified purines.

[0363] Example 4: Screening the activity of siRNA in cultured cells The knockdown activity of the target mRNA in cultured cells was determined using chemically modified siRNAs derived from the sequences in the previous examples. Cell lines expressing the target mRNA were seeded at a density of 10,000 cells / well in 96-well tissue culture plates supplemented with 10% fetal bovine serum (FBS) and incubated overnight in a water-jacketed humidified incubator at 37°C under an atmosphere of air and 5% carbon dioxide. Using 0.3 µL Lipofectamine RNAiMax (Fisher) / well, the siRNA was transfected individually into cells in duplicate wells at a final concentration of 10 nM. Silencer Select negative control #1 (ThermoFisher, catalog number 4390843) and positive control siRNA transfected at a final concentration of 10 nM served as controls. After incubation at 37°C for 48 hours, total RNA was harvested from each well, and cDNA was prepared using the TaqMan® FastAdvanced Cells-to-CT™ Kit (ThermoFisher, catalog number A35374) according to the manufacturer's instructions. The level of target mRNA in each well was measured in triplicate by real-time qPCR on an Applied Biosystems 7500 Rapid Real-Time PCR instrument using the TaqMan gene expression assay for human target mRNA. Measurements were performed using the TaqMan gene expression assay (ThermoFisher). PPIA The data were used to determine the relative target mRNA level in each well using the Δ-ΔCt method. The data were then normalized for the relative target mRNA level in untreated cells.

[0364] The siRNA that exhibits the highest target mRNA knockdown at 10 nM will be tested in a second activity screening at a concentration of 1 nM using the transfection procedure described above. A similar experiment can be performed using ASO. Therefore, the most effective siRNAs and ASOs for downregulating target mRNA expression can be identified.

[0365] Example 5: GalNAc ligand for hepatocyte targeting of oligonucleotides This disclosure is not limited to these individual methods; at least two general methods are used for attaching polyvalent N-acetylgalactosamine (GalNAc) ligands to oligonucleotides: solid-phase or solution-phase conjugation. GalNAc ligands can be attached to a solid-phase resin for 3' conjugation, or attached to the 5' end using a GalNAc phosphorusamide reagent. GalNAc phosphorusamide can be coupled to the solid phase at any position in the sequence, just like other nucleosides in the oligonucleotide sequence. Table 1 shows non-limiting examples of phosphorusamide reagents for conjugating GalNAc to 5'-terminal oligonucleotides.

[0366] Table 1. GalNAc conjugation reagents

[0367] Example 6: Synthesis of GalNAc ligands Preparation scheme of NAcegal-connector-TMSOTf

[0368] General procedure for preparing compound 2A

[0369] At 0°C, a solution of compound 1A (500 g, 4.76 mol, 476 mL) in 2-methyl-THF (2.00 L) was added dropwise to CbzCl (406 g, 2.38 mol, 338 mL) in 2-methyl-THF (750 mL). The mixture was stirred at 25°C for 2 hours under a N2 atmosphere. TLC (DCM:MeOH = 20:1, PMA) showed that CbzCl was completely consumed and a new spot (R) was formed. f =0.43). HCl / EtOAc (1 N, 180 mL) was added to the reaction mixture and stirred for 30 minutes. The white solid was removed by filtration through diatomaceous earth. The filtrate was concentrated under vacuum to give compound 2A (540 g, 2.26 mol, 47.5% yield), a pale yellow oil, which was used directly in the next reaction without further purification. 1 H NMR: δ 7.28 - 7.41 (m, 5 H), 5.55 (br s, 1 H), 5.01 - 5.22 (m, 2 H), 3.63 - 3.80 (m, 2 H), 3.46 - 3.59 (m, 4 H), 3.29 - 3.44 (m, 2 H), 2.83 - 3.02 (m, 1H).

[0370] General procedure for preparing compound 4A

[0371] Under a nitrogen atmosphere, ethyl acetate (4.73 kg, 46.4 mol, 4.34 L) was added dropwise to a solution of compound 3A (1.00 kg, 4.64 mol, HCl) in pyridine (5.00 L) at 0°C. The mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. TLC (DCM:MeOH = 20:1, PMA) indicated that compound 3A had been completely consumed and two new spots (R) were formed. f=0.35). The reaction mixture was added to cold water (30.0 L) and stirred at 0°C for 0.5 h to form a white solid. The solid was filtered and dried to give compound 4A (1.55 kg, 3.98 mol, 85.8% yield) as a white solid, which was used directly in the next step of the reaction without further purification. 1 H NMR: δ 7.90 (d, J = 9.29 Hz, 1 H), 5.64 (d, J = 8.78 Hz, 1 H), 5.26 (d, J = 3.01 Hz, 1 H), 5.06 (dd, J = 11.29, 3.26 Hz, 1 H), 4.22 (t, J = 6.15 Hz, 1 H), 3.95 - 4.16 (m, 3 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3H), 1.90 (s, 3 H), 1.78 (s, 3 H).

[0372] General procedure for preparing compound 5A

[0373] TMSOTf (257 g, 1.16 mol, 209 mL) was added to a solution of compound 4A (300 g, 771 mmol) in DCE (1.50 L), and the mixture was stirred at 60°C for 2 h, followed by stirring at 25°C for 1 h. Compound 2A (203 g, 848 mmol) was dissolved in DCE (1.50 L), and 4 Å powdered molecular sieve (150 g) was added under N2 atmosphere, followed by stirring for 30 min. The DCE solution of compound 4A was then added dropwise to the mixture at 0°C. The mixture was stirred at 25°C for 16 h under N2 atmosphere. TLC (DCM:MeOH = 25:1, PMA) indicated that compound 4A had been completely consumed and new spots had formed (Rf = 0.24). The reaction mixture was filtered and washed with saturated NaHCO3 (2.00 L), water (2.00 L), and saturated brine (2.00 L). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was ground with 2-Me-THE / heptane (5 / 3, v / v, 1.80 L) for 2 hours, filtered, and dried to give compound 5A (225 g, 389 mmol, 50.3% yield, 98.4% purity) as a white solid. 1 ¹H NMR: δ 7.81 (d, J =9.29 Hz, 1 H), 7.20 - 7.42 (m, 6 H), 5.21 (d, J = 3.26 Hz, 1 H), 4.92 - 5.05 (m, 3 H), 4.55 (d, J = 8.28 Hz, 1 H),3.98 - 4.07 (m, 3 H), 3.82 - 3.93 (m, 1 H),3.71 - 3.81 (m, 1 H), 3.55 - 3.62(m, 1 H), 3.43 - 3.53 (m, 2 H), 3.37 - 3.43 (m, 2 H), 3.14 (q, J = 5.77 Hz, 2H), 2.10 (s, 3H), 1.99 (s, 3H), 1.89 (s, 3H), 1.77 (s, 3H).

[0374] General procedure for preparing NAcegal-linked toluenesulfonate

[0375] Under a nitrogen atmosphere, a solution of compound 5A (200 g, 352 mmol) in THF (1.0 L) was supplemented with dried Pd / C (15.0 g, 10% purity) and TsOH (60.6 g, 352 mmol). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25°C for 3 hours under a H2 (45 psi) atmosphere. TLC (DCM:MeOH = 10:1, PMA) indicated that compound 5A had been completely consumed and a new spot (R) had formed. f =0.04). The reaction mixture was filtered and concentrated under reduced pressure (≤40°C) to give a residue. The residue was diluted and concentrated with anhydrous DCM (500 mL, dried overnight with 4 Å molecular sieve (dried at 300°C for 12 h)) and then checked for water content by Karl Fischer (KF) method. The dilution and concentration were repeated 3 times with anhydrous DCM (500 mL) to give NAcegal-connector-TMSOTf (205 g, 95.8% yield, TsOH salt) as a foamy white solid. 1 H NMR: δ7.91 (d, J = 9.03 Hz, 1 H), 7.53 - 7.86 (m, 2 H), 7.49 (d, J = 8.03 Hz, 2 H), 7.13 (d, J = 8.03 Hz, 2 H), 5.22 (d, J =3.26 Hz, 1 H), 4.98 (dd, J = 11.29, 3.26 Hz, 1 H), 4.57 (d, J = 8.53 Hz, 1 H), 3.99 - 4.05 (m, 3 H), 3.87 - 3.94 (m, 1 H), 3.79 - 3.85 (m, 1 H), 3.51 - 3.62 (m, 5 H), 2.96 (br t, J = 5.14Hz, 2H), 2.29 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.89 (s, 3H), 1.78(s, 3H).

[0376] Preparation scheme of TRIS-PEG2-CBZ

[0377] General procedure for preparing compound 5B

[0378] Compound 4B2 (1.07 kg, 8.36 mol, 1.20 L, 5.00 eq) was added to a solution of compound 4B (400 g, 1.67 mol, 1.00 eq) and NaOH (10 M, 16.7 mL, 0.10 eq) in THF (2.00 L). The mixture was stirred at 30°C for 2 hours. LC-MS showed the desired MS. Five batches of the solution were combined into one batch, and the mixture was diluted with water (6.00 L), extracted with ethyl acetate (3.00 L x 3), washed with brine (3.00 L), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1-10:1, R... f =0.5), yielding compound 5B (2.36 kg, 6.43 mol, 76.9% yield), a pale yellow oil. ¹H NMR: δ 7.31–7.36 (m, 5H), 5.38 (s, 1H), 5.11–5.16 (m, 2H), 3.75 (t, J = 6.4 Hz), 3.54–3.62 (m, 6H), 3.39 (d, δ ≤ 0.5), yielding compound 5B (2.36 kg, 6.43 mol, 76.9% yield), as a pale yellow oil. J =5.2 Hz), 2.61 (t, J =6.0 Hz).

[0379] Preparation of 3-oxo-1-phenyl-2,7,10-trioxa-4-azatridecane-13-acid (hereinafter referred to as compound 2B) General procedures

[0380] TFA (1.43 kg, 12.5 mol, 928 mL, 6.22 eq) was added to a solution of compound 5B (741 g, 2.02 mol, 1.00 eq) in DCM (2.80 L), and the mixture was stirred at 25°C for 3 hours. LC-MS showed the desired MS result. The mixture was diluted with DCM (5.00 L), washed with water (3.00 L x 3) and brine (2.00 L), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give compound 2B (1800 g, crude product) as a pale yellow oil. HNMR: δ 9.46(s, 5 H), 7.27-7.34 (m, 5 H), 6.50-6.65 (m, 1 H), 5.71 (s, 1 H), 5.10-5.15(m, 2 H), 3.68-3.70 (m, 14 H), 3.58-3.61 (m, 6H), 3.39 (s, 2H), 2.55 (s, 6H), 2.44 (s, 2H).

[0381] General procedure for preparing compound 3B

[0382] HATU (570 g, 1.50 mol, 1.50 eq) and DIEA (258 g, 2.00 mol, 348 mL, 2.00 eq) were added to a solution of compound 2B (375 g, 999 mmol, 83.0% purity, 1.00 eq) in DCM (1.80 L) at 0°C. The mixture was stirred at 0°C for 30 min, then compound 1B (606 g, 1.20 mol, 1.20 eq) was added, and the mixture was stirred at 25°C for 1 h. LC-MS yielded the desired MS result. The mixtures were combined into one batch, then diluted with DCM (5.00 L), washed with 1N HCl aqueous solution (2.00 L*2), and the organic layer was washed with saturated Na2CO3 aqueous solution (2.00 L*2) and brine (2.00 L). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum to obtain compound 3B (3.88 kg, crude product), which was a yellow oily substance.

[0383] General procedure for preparing TRIS-PEG2-CBZ

[0384] A solution of compound 3B (775 g, 487 mmol, purity 50.3%, 1.00 eq) in HCl / dioxane (4 M, 2.91 L, 23.8 eq) was stirred at 25°C for 2 h. LC-MS yielded the desired MS. The mixture was concentrated under vacuum to obtain the residue. The combined residue was then diluted with DCM (5.00 L), adjusted to pH 8 with 2.5 M NaOH aqueous solution, and separated. The aqueous phase was extracted again with DCM (3.00 L), then the aqueous solution was adjusted to pH 3 with 1 N HCl aqueous solution, and then extracted with DCM (5.00 L * 2). The combined organic layers were washed with brine (3.00 L), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 0:1-12:1, 0.1% HOAc, R f =0.4). The residue was diluted with DCM (5.00 L), adjusted to pH 8 with 2.5M NaOH aqueous solution, separated, and the aqueous solution was extracted again with DCM (3.00 L). The aqueous solution was then adjusted to pH 3 with 6 N HCl aqueous solution, and extracted with DCM:MeOH = 10:1 (5.00 L * 2). The combined organic layers were washed with brine (2.00 L), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was then diluted with MeCN (5.00 L), concentrated under vacuum, and this procedure was repeated twice to remove water, yielding TRIS-PEG2-CBZ (1.25 kg, 1.91 mol, 78.1% yield, 95.8% purity), a pale yellow oil. 1 HNMR: 400 MHz, MeOD, δ 7.30-7.35 (5 H), 5.07 (s, 2 H), 3.65-3.70 (m, 16 H), 3.59 (s, 4 H), 3.45 (t, J =5.6 Hz), 2.51 (t, J =6.0 Hz), 2.43(t, 6.4 Hz).

[0385] Preparation scheme of TriNGal-TRIS-Peg2-Phosph 8c

[0386] TriGNa1-TRIS-Peg2-Phosph 8c General procedure for preparing compound 3C

[0387] TBTU (260 g, 811 mmol, 3.30 eq), DIEA (209 g, 1.62 mol, 282 mL, 6.60 eq), and compound 2C (492 g, 811 mmol, 3.30 eq, TsOH) were added to a solution of compound 1C (155 g, 245 mmol, 1.00 eq) in ACN (1500 mL) at 0°C. The mixture was stirred at 15°C for 16 h. LC-MS showed the desired MS. The mixture was concentrated under vacuum to give the residue, then diluted with DCM (2000 mL), washed with 1N HCl aqueous solution (700 mL x 2), washed with saturated NaHCO3 aqueous solution (700 mL x 2), and concentrated under vacuum. The crude product was purified by column chromatography to provide compound 3C (304 g, 155 mmol, 63.1% yield, 96.0% purity) as a yellow solid.

[0388] General procedure for preparing compound 4C

[0389] Pd / C (6.60 g, 19.1 mmol, 10.0% purity) and TFA (3.34 g, 29.2 mmol, 2.17 mL, 1.00 eq) were added to two batches of compound 3C (55.0 g, 29.2 mmol, 1.00 eq) in MeOH (1600 mL). The mixture was degassed under vacuum and purged with H2. The mixture was stirred at 15°C for 2 h under H2 (15 psi). LC-MS showed the desired MS. The mixture was filtered and the filtrate was concentrated under vacuum to give compound 4C (106 g, 54.8 mmol, 93.7% yield, 96.2% purity, TFA) as a white solid.

[0390] General procedure for preparing compound 5C

[0391] Two batches were performed in parallel. Compound 4a (25.0 g, 150 mmol, 1.00 eq) was added dropwise to a solution of EDCI (28.8 g, 150 mmol, 1.00 eq) in DCM (125 mL) at 0°C, followed by the addition of compound 4 (25.0 g, 150 mmol, 1.00 eq) to DCM (125 mL) at 0°C, and the mixture was stirred at 25°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.45) showed that the reactants had been consumed and a new spot had formed. The reaction mixture was diluted with DCM (100 mL), washed with aqueous NaHCO3 solution (250 mL*1) and brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 3:1), TLC (SiO2, petroleum ether:ethyl acetate = 3:1), Rf = 0.45, and then concentrated under reduced pressure to obtain the residue. Compound 5C (57.0 g, 176 mmol, 58.4% yield, 96.9% purity) was given as a colorless oil. 1 HNMR confirmed: EW33072-2-P1A, 400 MHz, DMSO δ 9.21 (s, 1 H), 7.07-7.09 (m, 2 H), 6.67-6.70 (m, 2 H), 3.02-3.04 (m, 2 H), 2.86-2.90 (m, 2 H).

[0392] General procedure for preparing compound 6

[0393] TEA (16.6 g, 164 mmol, 22.8 mL, 4.00 eq) was added dropwise to a mixture of compound 3 (79.0 g, 41.0 mmol, 96.4% purity, 1.00 eq) and compound 6C (14.2 g, 43.8 mmol, 96.9% purity, 1.07 eq) in DCM (800 mL) at 0°C, and the mixture was stirred at 15°C for 16 hours. LCMS (EW33072-12-P1B, Rt = 0.844 min) showed that the desired mass was detected. The reaction mixture was diluted with DCM (400 mL) and washed with NaHCO3 aqueous solution (400 mL x 1) and brine (400 mL x 1). The mixture was then diluted with DCM (2.00 L) and washed with 0.7 M Na2CO3 (1000 mL x 3) and brine (800 mL x 3). After drying with Na2SO4, the mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was used directly in the next step without further purification. Compound 6 (80.0 g, crude product) was given as a white solid and... 1 HNMR confirmed: EW33072-12-P1A, 400 MHz, MeOD δ 7.02 - 7.04 (m, 2 H), 6.68 - 6.70 (m, 2H), 5.34 - 5.35 (s, 3 H), 5.07 - 5.08 (d, J = 4.00 Hz, 3 H), 4.62 - 4.64 (d, J = 8.00 Hz, 3 H), 3.71 - 4.16 (m, 16 H), 3.31 - 3.70 (m, 44 H), 2.80 - 2.83(m, 2 H), 2.68 (m, 2 H), 2.46 - 2.47 (m, 10 H), 2.14 (s, 9 H), 2.03 (s, 9 H),1.94 - 1.95 (d, J = 4.00 Hz, 18 H).

[0394] General procedure for preparing TriGNal-TRIS-Peg2-Phosph 8c

[0395] Two batches were synthesized in parallel. A solution of compound 6C (40.0 g, 21.1 mmol, 1.00 eq) in DCM (600 mL) was added dropwise with diisopropylammonium tetrazolium (3.62 g, 21.1 mmol, 1.00 eq) and compound 7c (6.37 g, 21.1 mmol, 6.71 mL, 1.00 eq) in DCM (8.00 mL). The mixture was stirred at 30°C for 1 hour. Then, compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) was added dropwise to DCM (8.00 mL). The mixture was stirred at 30°C for 30 minutes. Finally, compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) was added dropwise to DCM (8.00 mL). The mixture was stirred at 30°C for 1.5 hours. LCMS (EW33072-17-P1C1, Rt=0.921 min) showed the desired MS+1 was detected. LCMS (EW33072-17-P1C2, Rt=0.919 min) showed the desired MS+1 was detected. The two batches were combined for post-processing. The mixture was diluted with DCM (1.20 L), and then with saturated NaHCO3 aqueous solution (1.60 L*2), 3% DMF aqueous solution (1.60 L*2), H2O (1.60 L*3), and brine (1.60 L*3). The residue was washed with L, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH:TEA = 100:3:2) TLC (SiO2, DCM:MeOH = 10:1, Rf = 0.45), and then concentrated under reduced pressure to obtain the residue. Compound 8C was given as a white solid (76.0 g, 34.8 mmol, 82.5% yield, 96.0% purity) and purified by... 1 HNMR confirmed: EW33072-19-P1C, 400 MHz, MeOD δ 7.13-7.15 (d, J = 8.50 Hz, 2 H), 6.95-6.97 (dd, J =8.38, 1.13 Hz, 2H), 5.34 (d, J =2.88 Hz, 3 H), .09 (dd, J =11.26, 3.38 Hz, 3 H), 4.64 (d, J =8.50 Hz, 3 H), 3.99 - 4.20 (m, 12 H), 3.88 - 3.98 (m, 5 H), 3.66 - 3.83 (m, 20 H), 3.51 - 3.65 (m, 17 H), 3.33 - 3.50 (m, 9 H), 2.87 (t, J =7.63 Hz, 2H), 2.76 (t, J =5.94 Hz, 2 H), 2.42 - 2.50 (m, 10 H), 2.14 (s, 9 H), 2.03 (s,9 H), 1.94 - 1.95 (d, J =6.13 Hz, 18 H), 1.24-1.26 (d, J =6.75 Hz, 6 H),1.18-1.20 (d, J =6.75 Hz, 6 H).

[0396] Example 7: In vitro hepatocyte targeting using GalNAc-conjugated siRNA and ASO In this experiment, hepatocyte lines expressing desialyl glycoprotein receptor and GFP were treated with anti-GFP siRNA or ASO conjugated to the GalNAc moiety. In contrast, hepatocyte lines were treated with unconjugated anti-GFP siRNA or ASO in the control experiment. GFP mRNA and protein expression were measured, and the expression levels of GFP mRNA or protein in cells treated with GalNAc-conjugated siRNA or ASO were normalized and compared to those in cells treated with unconjugated GalNAc siRNA or ASO. This helps determine the hepatocyte targeting ability of the GalNAc moiety. Multiple GalNAc moieties can be conjugated to siRNA or ASO and compared to determine which GalNAc moiety is optimal for hepatocyte targeting. The GalNAc moiety tested in these experiments may be the GalNAc moiety described herein.

[0397] Similar experiments can be performed in primary hepatocytes treated with conjugated or unconjugated GalNAc siRNA or ASO, and target mRNAs or proteins other than GFP can be evaluated in primary hepatocytes.

[0398] Example 8: In vivo hepatocyte targeting using GalNAc-conjugated siRNA and ASO In this experiment, siRNA or ASO targeting the target mRNA was conjugated to a GalNAc moiety and administered to mice (n=5 / group). In contrast, mice in the control group were administered unconjugated GalNAc siRNA or ASO. Two days later, the mice were sacrificed, and their livers were frozen, homogenized, and the expression of the target mRNA and protein was tested. The expression levels of the target mRNA or protein in the livers of mice treated with GalNAc-conjugated siRNA or ASO were normalized and compared to the expression levels of GFP mRNA or protein in the livers of mice treated with unconjugated GalNAc siRNA or ASO. This helps determine the liver-targeting ability of the GalNAc moiety. Multiple GalNAc moieties can be conjugated to siRNA or ASO and compared to determine which GalNAc moiety is optimal for liver targeting. The GalNAc moieties included in this experiment may be those that exhibit the strongest hepatocyte targeting. The GalNAc moieties tested in these experiments may be those described herein.

[0399] Example 9: Inhibition of target mRNA in a mouse liver disease model using GalNAc-conjugated siRNA and ASO In this experiment, a mouse liver disease model (fatty liver disease in this case) will be used to evaluate the effects of siRNA or ASO on the inhibition of target mRNAs. Target mRNAs can encode any target protein that is overexpressed or excessively activated in liver disease and has a pathological role. In the mouse model, fatty liver disease was induced by feeding mice a Western diet (WD) for 12 weeks, containing 21.1% fat, 41% sucrose, and 1.25% cholesterol by weight (Teklad diet, TD.120528) and a high-glucose solution (23.1 g / L d-fructose (Sigma-Aldrich, G8270) and 18.9 g / L d-glucose (Sigma-Aldrich, F0127)). Four-week-old C57BL / 6J mice were fed a Western diet instead of a conventional diet for 12 weeks. The GalNAc portion used in this experiment may be the GalNAc portion described herein.

[0400] In summary, mice were divided into five groups: Group 1: fatty liver disease group, treated with non-targeted control siRNA; Group 2: fatty liver disease group, treated with non-targeted control ASO; Group 3: fatty liver disease group, treated with siRNA targeting the target mRNA; Group 4: fatty liver disease group, treated with ASO targeting the target mRNA; Group 5: control mice fed a normal diet. Each group contained 8 mice (4 males and 4 females). Both the siRNA and ASO in groups 1-4 contained a GalNAc portion attached to either the siRNA or the ASO.

[0401] Blood samples should be collected from each group at week 12 of Western diet feeding, prior to the first treatment.

[0402] siRNA or ASO was administered subcutaneously by injection of 200 µL of naked siRNA or ASO resuspended in PBS at a concentration of 10 µM. On day 0 of the study, mice in group 1 received a subcutaneous injection of the non-targeted control siRNA, mice in group 2 received a subcutaneous injection of the non-targeted control ASO, mice in group 3 received a subcutaneous injection of siRNA1 targeting mouse target mRNA, mice in group 4 received a subcutaneous injection of ASO1 targeting mouse target mRNA, and mice in group 5 received a subcutaneous injection of the carrier. Starting from day 14, mice from each group were administered the drug every other week as on day 0, for a total of 5 injections.

[0403] Blood will be collected weekly, and serum and plasma will be separated. Serum ALT, AST, total cholesterol, and triglyceride levels will be measured using the VITROS 5,1 FS (Ortho Clinical Diagnostics). Non-fasting plasma insulin will be measured using a high-sensitivity mouse insulin ELISA kit (Crystal Chem, 90080) according to the manufacturer's instructions. Non-fasting blood glucose will be measured using One Touch Ultra (Life Scan). HOMA-IR and QUICKI will be calculated.

[0404] At the end of 12 weeks of Western diet and siRNA / ASO treatment, mice were euthanized by cervical dislocation and then injected intraperitoneally with 0.3 ml pentobarbital (5 mg / ml). Terminal serum samples were collected via cardiac puncture, and final serum ALT, AST, total cholesterol, and triglyceride levels, as well as non-fasting plasma insulin and blood glucose, were measured. The liver was removed and divided into three parts: one part was placed in an RNAlater for mRNA isolation, one part was rapidly frozen for protein isolation, and the other part was fixed in formalin and subsequently embedded in paraffin.

[0405] mRNA was isolated from tissues placed in RNAlater solution using the PureLink kit (ThermoFisher, lot number 12183020) according to the manufacturer's protocol. Reverse transcriptase reactions were performed according to the manufacturer's protocol. Samples were stored at -80°C until triplet real-time qPCR was performed using the TaqMan gene expression assay (Applied Biosystems FAM probe, BioRad iCycler). Target mRNA expression was decreased in the liver tissues of mice treated with siRNA and ASO compared to levels in the liver tissues of mice treated with nonspecific control siRNA and ASO. It was expected that the amount of SDF-1 in the liver tissues of mice receiving siRNA and ASO would be lower than that in mice receiving nonspecific control siRNA or ASO. These results indicate that siRNA and ASO cause knockdown of target mRNAs and proteins in liver tissues, and that the reduction in target mRNA and protein expression is associated with a reduction in SDF-1 production.

[0406] Formalin-fixed and paraffin-embedded liver sections were stained with hematoxylin and eosin (H&E) to assess liver histology, with Sirius red (Sigma, 365548-5G) / fast green (Sigma, F258) to assess fibrosis, and with periodic acid-Schiff (PAS) to assess glycogen accumulation. NAFLD activity score (NAS) and fibrosis stage were assessed by a pathologist according to the NAFLD CRN scoring system13. Histological scoring was performed blinded, and the pathologist was unaware of the treatment received. These results indicate that siRNA and ASO cause knockdown of target mRNAs and proteins in liver tissue, and that decreased expression of target mRNAs and proteins is associated with decreased NAS and NASH CRN levels.

[0407] Example 10: Suppressing a mouse model of liver disease In this experiment, a mouse liver disease model (hypertriglyceridemia in this case) will be used to evaluate the effects of siRNA or ASO on inhibiting target proteins expressed in the liver, and these effects will be compared with anti-mouse target protein antibodies. C57Bl / 6Apoetm1Unc mice will be maintained on a high-fat Western diet (Research Diets, D12492; 60% of calories from fat). Target proteins can be any proteins that are overexpressed or excessively activated in liver disease and play a pathological role. The GalNAc moiety used in this experiment can be any GalNAc moiety described herein.

[0408] This study will use four groups of mice (n=16 per group). During the study, animals will maintain a high-fat diet. On day 4 prior to the first injection, food will be removed and the animals will be fasted overnight. On day 3 prior to the first injection, all animals will be anesthetized, and 300 µL of blood will be collected via the mandibular vein into a serum separator to assess baseline triglycerides, serum glucose, insulin sensitivity, total cholesterol levels, HDL cholesterol levels, liver function, and serum levels of target proteins. On day 0 of the experiment, group 1 mice will be intraperitoneally injected with 600 µL of saline; group 2 mice will be intraperitoneally injected with 600 µg of anti-mouse target protein antibody (600 µL); group 3 mice will be subcutaneously injected with 150 µg of GalNAc-siRNA targeting the target protein mRNA in 200 µL of saline; and group 4 mice will be subcutaneously injected with 150 µg of GalNAc-ASO targeting the target protein mRNA in 200 µL of saline. On the afternoon of day 3, all groups will be fasted overnight. On day 4, all animals will be anesthetized, and 150 µL of blood will be collected via the mandibular vein into a serum separator to assess serum triglyceride, glucose, total cholesterol, HDL cholesterol, and target protein levels. Subsequently, all animals will undergo oral glucose tolerance and insulin tolerance tests to assess insulin sensitivity. After blood collection and insulin sensitivity testing, food will be reintroduced as usual. From day 7 onwards, animals in group 2 will receive the same medication as on day 0, for a total of 15 injections per week. From day 14 onwards, animals in groups 3 and 4 will receive the same medication as on day 0, for a total of 8 injections per week. From day 10 onwards, mice in all groups will be fasted (overnight), and blood (150 µL, into a serum separator) will be collected every week to assess serum triglyceride, glucose, total cholesterol, HDL cholesterol, and target protein levels, and to perform insulin sensitivity testing. On day 3 after the last injection, all groups will be fasted overnight. On the fourth day after the last injection, all animals in all groups were anesthetized and euthanized, and 500 µL of blood was collected via cardiac puncture into serum separation tubes to assess triglyceride, serum glucose, insulin sensitivity, total cholesterol levels, HDL cholesterol levels, liver function, and serum levels of target proteins. Liver, small intestine, and mesenteric lymph node tissues were collected from all animals and immersed in 10% neutral buffered formalin for histopathological analysis. Liver samples were also collected from all animals and stored in RNAlater. Target mRNA levels of mouse target proteins and the mouse housekeeping gene PPIA were assessed using RT-qPCR via TaqMan assays.

[0409] Compared to mice in group 1 (saline), mice treated with antibodies (group 2), mice treated with GalNAc-siRNA (group 3), and mice treated with GalNAc-ASO (group 4) are expected to have lower levels of triglycerides, serum total cholesterol, serum glucose, and serum target protein, while HDL cholesterol and insulin sensitivity are expected to increase. Target mRNA levels in liver samples from animals in groups 2 and 3 are also expected to be lower.

[0410] Example 11: Inhibition of target mRNAs in non-human primates using GalNAc-siRNA and GalNAc-ASO In this study, a hypertriglyceridemia-induced NHP model was used to evaluate the effects of siRNA or ASO on the inhibition of target mRNAs expressed in the liver. Target proteins can be any target protein that is overexpressed or overactivated in liver disease and plays a pathological role. Three groups of cynomolgus monkeys (n=5 / group) were used, placed on a high-fat diet (Western primate diet, 5S2T) before the start of the study. Alternatively, three groups of rhesus monkeys (n=5 / group) were used, placed on a high-fructose diet before the start of the study. Animals were given seven subcutaneous injections every two weeks of saline (Group 1), GalNAc-siRNA (Group 2), or GalNAc-ASO (Group 3). Modified GalNAc-siRNA sequences can include any modification pattern described herein. The GalNAc moiety used in this study can be any GalNAc moiety described herein. Blood samples were collected at baseline and at weeks 4, 8, and 14 for lipid and blood glucose measurements, and lipid content, serum glucose, insulin sensitivity, and target proteins were analyzed. All animals in each group underwent necropsy two weeks after the last blood collection. Tissue samples from the liver, small intestine, and mesenteric lymph nodes were collected from all animals and immersed in 10% neutral buffered formalin for histopathological analysis. Liver samples were also collected from all animals and placed in RNAlater. Target mRNA levels against cynomolgus monkey or rhesus monkey target proteins and the cynomolgus monkey or rhesus monkey housekeeping gene PPIA were assessed by RT-qPCR using TaqMan assays.

[0411] Compared to Group 1 (saline) animals, animals treated with GalNAc-siRNA (Group 2) and those treated with GalNAc-ASO (Group 3) are expected to exhibit decreased triglycerides, serum total cholesterol, and serum glucose, as well as decreased serum target protein levels, and increased HDL cholesterol and insulin sensitivity. Animals in Groups 1 and 3 are also expected to show decreased target mRNA levels in liver samples.

[0412] Example 12: Inhibition of target mRNA using GalNAc-siRNA and GalNAc-ASO in clinical trials In this study, human subjects with hypertriglyceridemia were used to evaluate the effects of siRNA or ASO on inhibiting target mRNAs expressed in the liver. Target proteins can be any target protein that is overexpressed or excessively activated in liver disease and plays a pathological role. Inclusion criteria were age 40–90 years, BMI ≥ 30, and serum triglycerides ≥ 250 mg / dL. The study included three groups (n = 15 / group). Subjects were given five weekly subcutaneous injections of saline (Group 1), GalNAc-siRNA (Group 2), or GalNAc-ASO (Group 3). The GalNAc portion used in these experiments may include the GalNAc portion described herein.

[0413] The siRNA or ASO sequence should be derived from a selection set that has demonstrated high activity in cultured cells or in the experiments described in other examples. Blood samples will be collected at baseline and at weeks 3, 6, and 12 for lipid and blood glucose measurements, and lipid content, serum glucose, insulin sensitivity, target proteins, and liver and kidney function will be analyzed.

[0414] Compared to the subjects in Group 1 (saline), subjects treated with GalNAc-siRNA (Group 2) and subjects treated with GalNAc-ASO (Group 3) are expected to have lower levels of triglycerides, serum total cholesterol, and serum glucose, lower levels of serum target proteins, and increased HDL cholesterol and insulin sensitivity.

[0415] Example 13: Oligonucleotide Synthesis RNAi reagents (e.g., siRNA) were synthesized using a solid-phase phosphoramide technique employed in oligonucleotide synthesis. A K&A oligonucleotide synthesizer was used. Synthesis was performed on a solid support made of controlled-pore glass (CPG, 500 Å or 600 Å, obtained from AMC Chemicals, Oceanside, CA, USA). All 2'-OMe and 2'-F phosphoramides were purchased from Hongene Biotech (Union City, CA, USA). All phosphoramides were dissolved in anhydrous acetonitrile (100 mM) with the addition of molecular sieves (3 Å). 5-Benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile) or 5-ethylthio-1H-tetrazole (ETT, 250 mM in acetonitrile) was used as the activator solution. Coupling times were 9–18 min (EmpGalNAc) and 6 min (2'OMe and 2'F). To introduce thiophosphate linkages, a solution of 100 mM 3-phenyl-1,2,4-dithiazolin-5-one (POS, obtained from PolyOrg, Inc., Leominster, Mass., USA) in anhydrous acetonitrile was used.

[0416] Following solid-phase synthesis, the dried solid support was treated at 30°C for 2 hours with a 1:1 volume ratio of 40 wt.% methylamine aqueous solution and 28% ammonium hydroxide solution (Aldrich). The solution was evaporated, and the solid residue was reconstituted in water and purified by anion-exchange HPLC using a TKSgel SuperQ-5PW 13u column. Buffer A consisted of 20 mM Tris, 5 mM EDTA, pH 9.0, and 20% acetonitrile; buffer B was the same as buffer A but with the addition of 1 M sodium chloride. UV spectra were recorded at 260 nm. Appropriate fractions were combined and then desalted using Sephadex G-25 media.

[0417] Equimolar amounts of the sense and antisense strands were combined to prepare the bistrands. A bistrand solution was prepared in 0.1×PBS (phosphate-buffered saline, 1×, Gibco). The bistrand solution was annealed at 95°C for 5 min and then slowly cooled to room temperature. The bistrand concentration was determined by measuring the absorbance of the solution at 260 nm using a UV-Vis spectrometer in 0.1×PBS. For some experiments, the conversion factor was calculated from the experimentally determined extinction coefficient.

[0418] Example 14: In vivo hepatocyte targeting using GalNAc-conjugated siRNA and ASO In this experiment, siRNA or ASO targeting the target mRNA was conjugated to a GalNAc moiety and administered to mice (n=5 / group). In contrast, mice...

Claims

1. The compound represented by formula (I) or (II): (I), or (II); or its salt, wherein J is an oligonucleotide; Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C; If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 The connectors are selected from the following: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )- and -OPN(R 7 )2NR 7 -; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 、 -OC(O)N(R 7 )2、 -N(R 7 )C(O)R 7 、 -N(R 7 )C(O)N(R 7 )2、 -N(R 7 )C(O)OR 7 、 -C(O)R 7 、 -C(O)OR 7 和 -C(O)N(R 7 )2; Each R 6 Selected independently from: hydrogen; halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

2. The compound or salt of claim 1, wherein each w, v, n and m is independently selected from any value from 1 to 5.

3. The compound or salt of claim 1, wherein Q is selected from C that is optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2.

4. The compound or salt of claim 1, wherein... (a) R 1 selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S- and -OP(OR 7 )O-; (b) R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 )2; (c) R 3 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2; (d) R 4 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2; (e) R 5 Selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 ;and (f) Each R 7 C10 molecules independently selected from hydrogen and optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings or heterocyclic rings ranging from 3 to 10 members.

5. The compound or salt of claim 1, wherein the compound comprises: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or 。 6. The compound or a salt thereof as claimed in claim 1, wherein... (a) The oligonucleotide (J) is attached to R at the 5' end of the oligonucleotide. 1 ; (b) The 5' end of the oligonucleotide contains a phosphate ester or a thiophosphate ester; (c) The oligonucleotide comprises a phosphate thioester bond; (d) The oligonucleotide comprises a 2'O-methyl or 2'-fluorine modified nucleoside; and (e) The oligonucleotide contains small interfering RNA (siRNA).

7. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

8. A compound comprising: , where J contains oligonucleotides.

9. A composition for reducing target mRNA or target protein in a subject with a disease, comprising a compound of formula (I) or (II): (I), or (II); or its salt, wherein J is an oligonucleotide; Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C; If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 The connectors are selected from the following: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)2-, -OS(O)2-, -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 )2)NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 )2)O-, -OP(OR 7 )N(R 7 )- and -OPN(R 7 )2NR 7 -; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 、 -OC(O)N(R 7 )2、 -N(R 7 )C(O)R 7 、 -N(R 7 )C(O)N(R 7 )2、 -N(R 7 )C(O)OR 7 、 -C(O)R 7 、 -C(O)OR 7 和 -C(O)N(R 7 )2; Each R 6 Selected independently from: hydrogen; halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

10. The composition of claim 9, wherein each w, v, n, and m is independently selected from any value from 1 to 5 and Q is selected from C optionally substituted with one or more substituents. 5-6 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2.

11. The composition of claim 9, wherein (a) R 1 selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S- and -OP(OR 7 )O-; (b) R 2 Selected from C that has been substituted with one or more substituents 1-3 Alkyl group, wherein the one or more substituents are independently selected from -OR 7 -OC(O)R 7 -SR 7 and -N(R) 7 )2; (c) R 3 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2; (d) R 4 Selected from -OR 7 -SR 7 -OC(O)R 7 and -N(R) 7 )2; (e) R 5 Selected from -OC(O)R 7 and -N(R) 7 )C(O)R 7 ;and (f) Each R 7 C10 molecules independently selected from hydrogen and optionally substituted with one or more substituents. 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings or heterocyclic rings ranging from 3 to 10 members.

12. The composition of claim 9, wherein the compound comprises: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or 。 13. The composition of claim 9, wherein (a) The oligonucleotide (J) is attached to R at the 5' end of the oligonucleotide. 1 ; (b) The 5' end of the oligonucleotide contains a phosphate ester or a thiophosphate ester; (c) The oligonucleotide comprises a phosphate thioester bond; (d) The oligonucleotide comprises a 2'O-methyl or 2'-fluorine modified nucleoside; and (e) The oligonucleotide contains small interfering RNA (siRNA).

14. The composition of claim 9, wherein the condition includes metabolic disorders.

15. The compound represented by formula (A) or (B): (A), or (B)； or its salt, wherein Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C; If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 Selected from: -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 、-OS(O)2R 7 、-OP(O)(OR 7 )2、-OP(S)(OR 7 )2、-SP(O)(OR 7 )2、-OP(O)(SR 7 )(OR 7 )、-OP(O)(OR 7 )N(R 7 )2、-OP(S)(OR 7 )N(R 7 )2、-SP(O)(OR 7 )N(R 7 )2、-OP(O)(SR 7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(S)(N(R 7 )2)2、-SP(O)(N(R 7 )2)2、-OP(OR 7 )2、-SP(OR 7 )2、-OP(OR 7 )(SR 7 )、-OP(OR 7 )N(R 7 )2、-OP(SR 7 )N(R 7 )2、-SP(OR 7 )N(R 7 )2、-OP(N(R 7 )2)2 and -SP(N(R 7 )2)2; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 ,-OC(O)N(R 7 )2,-N(R 7 )C(O)R 7 ,-N(R 7 )C(O)N(R 7 )2,-N(R 7 )C(O)OR 7 ,-C(O)R 7 ,-C(O)OR 7 and -C(O)N(R 7 )2; Each R 6 Selected independently from: hydrogen; halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups.

16. A method for synthesizing a compound of formula (I) or (II) or a salt thereof: (I), or (II); in Each w is independently selected from any value between 1 and 20; Each v is independently selected from any value between 1 and 20; n can be any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where If z is 3, then Y is C; If z is 2, then Y is CR. 6 ,or If z is 1, then Y is C(R) 6 )2; Q is selected from: C can be optionally substituted with one or more substituents 3-10 The carbocyclic ring, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 -S(O)R 7 and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2 and -NH2; R 1 Selected from: -OR 7 、-SR 7 、-N(R 7 )2、-C(O)R 7 、-C(O)N(R 7 )2、-N(R 7 )C(O)R 7 、-N(R 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 、-C(O)OR 7 、-OC(O)R 7 、-S(O)R 7 、-S(O)2R 7 、-OS(O)2R 7 、-OP(O)(OR 7 )2、-OP(S)(OR 7 )2、-SP(O)(OR 7 )2、-OP(O)(SR 7 )(OR 7 )、-OP(O)(OR 7 )N(R 7 )2、-OP(S)(OR 7 )N(R 7 )2、-SP(O)(OR 7 )N(R 7 )2、-OP(O)(SR 7 )N(R 7 )2、-OP(O)(N(R 7 )2)2、-OP(S)(N(R 7 )2)2、-SP(O)(N(R 7 )2)2、-OP(OR 7 )2、-SP(OR 7 )2、-OP(OR 7 )(SR 7 )、-OP(OR 7 )N(R 7 )2、-OP(SR 7 )N(R 7 )2、-SP(OR 7 )N(R 7 )2、-OP(N(R 7 )2)2 and -SP(N(R 7 )2)2; Each R 2 Selected independently from: C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -OR 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 Each is selected independently from: -OR 7 、 -SR 7 、 -N(R 7 )2、 -C(O)R 7 、 -C(O)N(R 7 )2、 -N(R 7 )C(O)R 7 、 -N(R 7 )C(O)N(R 7 )2、 -OC(O)N(R 7 )2、 -N(R 7 )C(O)OR 7 、 -C(O)OR 7 、 -OC(O)R 7 and -S(O)R 7 ; Each R 5 Selected independently from: -OC(O)R 7 ,-OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 and -C(O)N(R 7 )2; Each R 6 Selected independently from: hydrogen; halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and C can be optionally substituted with one or more substituents 1-6 Alkyl group, wherein the one or more substituents are independently selected from halogens, -CN, -NO2, -OR. 7 -SR 7 -N(R) 7 )2、-C(O)R 7 -C(O)N(R) 7 )2、-N(R 7 )C(O)R 7 -N(R) 7 )C(O)N(R 7 )2、-OC(O)N(R 7 )2、-N(R 7 )C(O)OR 7 -C(O)OR 7 -OC(O)R 7 and -S(O)R 7 ; Each R 7 Selected independently from: hydrogen; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, each of which is optionally substituted by one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Carbon rings and 3- to 10-membered heterocycles; and C 3-10 The ring consists of a carbocyclic ring and 3- to 10-membered heterocycles, each optionally substituted with one or more substituents, said one or more substituents being independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles and C 1-6 Halogenated alkyl groups; The method includes reacting a compound of formula (A) or formula (B) as described in claim 15 with an oligonucleotide.

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