Efficient process for preparation of highly purified 5 '-capped oligonucleotides

Abstract

Described herein are high purity, chemically synthesized, stable 5 '-capped oligonucleotides. Additionally, methods for making and using the oligonucleotides are described herein.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 401,544, filed Aug. 26, 2022, U.S. Provisional Application No. 63 / 414,361, filed Oct. 7, 2022, and U.S. Provisional Application No. 63 / 430,987, filed Dec. 7, 2022, the disclosures of all of the U.S. provisional applications being incorporated herein by reference in their entirety. Field of the Invention

[0003] The field of the invention relates to highly purified, chemically synthesized, stable 5′-capped oligonucleotides and methods of preparing and using the 5′-capped oligonucleotides. Background of the Invention

[0004] In vitro transcribed messenger RNA (mRNA) has many in vivo applications, such as vaccination, where mRNA encoding a specific antigen is administered to elicit a protective immune response in a patient; cell therapy, where mRNA is transfected into cells ex vivo to alter cell phenotype or function before delivering these altered cells to the patient; or replacement therapy, where mRNA encoding a therapeutic protein is administered to a patient.

[0005] The major structural element of an mRNA molecule for in vivo applications comprises a cap structure at the 5′ end of the mRNA. Naturally occurring cap structures comprise 7-methylguanosine ( 7m G or m7 G) linked by a 5′-to-5′ triphosphate chain to the 5′ end of the mRNA molecule. The cap must be present for the mRNA to retain its template activity for protein synthesis. The chemical structure of the cap can drive translation efficiency in cells. Thus, an effective cap structure is necessary.

[0006] Traditionally, enzymatic methods have been used to prepare 5′-capped mRNA. Non-enzymatic methods of preparing mRNA may be more cost-effective and easier to scale up. However, there are technical challenges in preparing highly pure, stable synthetic mRNA, particularly 5′-capped mRNA having 40 or more bases.

[0007] Accordingly, there is a need to develop robust non-enzymatic methods for preparing stable 5′-capped mRNA having a high level of purity, which methods are easy to scale up. Summary of the Invention

[0008] The present disclosure describes methods for preparing highly pure, chemically synthesized, stable oligonucleotides that include a cap analog at their 5′-end. Additionally, the present disclosure describes highly pure, chemically synthesized, stable oligonucleotides that include a cap analog at their 5′-end, which can be produced by the disclosed methods.

[0009] In one aspect, the present disclosure provides an efficient method for preparing 5′-capped oligonucleotides, the method comprising reacting a 5′-phosphate oligonucleotide with a modified Im-m 7 GDP, the modified Im-m 7 GDP including a cleavable hydrophobic moiety that can be removed after the reaction. For example, after purifying the product resulting from the reaction of the 5′-phosphate oligonucleotide with the modified Im-m 7 GDP, the hydrophobic group can be removed. Alternatively, the present disclosure provides an efficient method for preparing 5′-capped oligonucleotides, the method comprising reacting a 5′-phosphate oligonucleotide with a modified Im-m 7 GDP, the modified Im-m 7 GDP including a non-cleavable hydrophobic moiety, yet the 5′-capped oligonucleotide permits efficient translation.

[0010] The present disclosure further provides modified Im-m 7 GDP compounds that can react with 5′-phosphate oligonucleotide molecules to produce 5′-capped oligonucleotide molecules. In embodiments, Im-m 7 GDP is modified at the 2′ and / or 3′ and / or N2 and / or N7 positions (in any combination) with removable or non-removable hydrophobic groups. In embodiments, the 2′-position and / or 3′-position of Im-m7GDP is modified with a removable hydrophobic group. In embodiments, the 2′-position and / or 3′-position of Im-m7GDP is modified with a non-removable hydrophobic group. In embodiments, the N7-methylated GDP moiety of Im-m 7 GDP is modified with a removable hydrophobic group. In embodiments, the N7-methylated GDP moiety of Im-m 7 GDP is modified with a non-removable hydrophobic group. In embodiments, both the 2′-position and the N7-methylated GDP moiety of Im-m 7 GDP are modified with removable hydrophobic groups. In embodiments, both the 2′-position and the N7-methylated GDP moiety of Im-m 7 GDP are modified with non-removable hydrophobic groups. In embodiments, Im-m 7Both the 3′-position of GDP and the N7-methylated GDP moiety are modified with a removable hydrophobic group. In an embodiment, Im-m 7 Both the 3′-position of GDP and the N7-methylated GDP moiety are modified with a non-removable hydrophobic group.

[0011] As disclosed herein, after the modified Im-m 7 GDP compound reacts with a 5′-phosphate oligonucleotide molecule, a 5′-capped oligonucleotide having one or more removable or non-removable hydrophobic groups is produced. Then, the 5′-capped oligonucleotide molecule bearing the one or more hydrophobic groups can be easily separated from impurities in the reaction mixture, which contains uncapped oligonucleotide molecules. In an embodiment, the one or more hydrophobic groups can be chemically removed from the purified 5′-capped oligonucleotide to produce a 5′-capped oligonucleotide of high purity and easy to translate. In other embodiments, the one or more hydrophobic groups can remain on the 5′-capped oligonucleotide to produce a 5′-capped oligonucleotide of high purity and easy to translate.

[0012] In one aspect, provided herein is an oligonucleotide comprising 50 - 12,000 nucleotides, the 5′-end of the oligonucleotide comprising a structure of formula (I)

[0013]

[0014] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof;

[0015] Wherein:

[0016] B 1 and B 3 are each independently a natural, modified, or unnatural nucleobase;

[0017] Each B 2 is independently a natural, modified, or unnatural nucleobase;

[0018] Ring A is a substituted or unsubstituted cycloalkylidene, a substituted or unsubstituted heterocycloalkylidene, a substituted or unsubstituted arylidene, or a substituted or unsubstituted heteroarylidene;

[0019] X 1 and X 2 are each independently -O-, -CH 2 -, -CX 2 -, -N(R 101) -, -BH-, or -S;

[0020] Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each independently is O, S, or Se;

[0021] R 1 independently is hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0022] R 2 independently is hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group;

[0023] R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0024] Each R 7 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH2 F, -CH 2 I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0025] Each R 19 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 19A , -NR 19A R 19B, -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0026] Or R 7 And R 19 Together with the carbon atom to which it is attached form a substituted or unsubstituted subcycloalkyl or a substituted or unsubstituted subheterocycloalkyl;

[0027] Each R 11 Independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 11A , -NR 11A R11B ,-COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0028] Or R 11 and R 19 together with the carbon atom to which it is attached form a substituted or unsubstituted subcycloalkyl or a substituted or unsubstituted subheterocycloalkyl;

[0029] Each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A and R 19B is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2, -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 , -OCHX 2 , -OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0030] or R bonded to the same nitrogen atom 7A and R 7B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 11A and R 11B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 19A and R 19B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

[0031] Each R 101 independently is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0032] m is an integer from 0 to 8;

[0033] n is an integer from 0 to 3; and

[0034] Each X is independently -Cl, -Br, -I or -F.

[0035] Herein and throughout the disclosure, indicates the point of attachment of the structure to the remainder of the oligonucleotide (e.g., the body and the 3' end).

[0036] In one aspect, the present disclosure provides an oligonucleotide comprising 50 - 12000 nucleotides, wherein the 5' end of the oligonucleotide comprises a structure of formula (II):

[0037]

[0038] or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0039] Wherein:

[0040] B 1 and B 2 each independently is a natural, modified or unnatural nucleobase;

[0041] Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted hetero cycloalkylene, a substituted or unsubstituted arylene or a substituted or unsubstituted heteroarylene;

[0042] X 1 and X 2 each independently is -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-;

[0043] Y 1 、Y 2 、Y 3 and Y 4 each independently is O, S or Se;

[0044] R 1 independently is hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0045] R 2 independently is hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group;

[0046] R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0047] R 7 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0048] Each R 19 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 19A , -NR 19A R 19B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0049] Or R 7 and R 19Together with the carbon atom to which it is attached, form a substituted or unsubstituted subcycloalkyl or a substituted or unsubstituted subheterocycloalkyl;

[0050] Each R 11 independently is hydrogen, halogen, -CCl 3 -, -CBr 3 -, -CF 3 -, -CI 3 -, -CHCl 2 -, -CHBr 2 -, -CHF 2 -, -CHI 2 -, -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 11A -, -NR 11A R 11B -, -COOH, -CONH 2 -, -NO 2 -, -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 -, -NHNH 2 -, -ONH 2 -, -NHC(O)NHNH 2 -, -NHC(O)NH 2 -, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 -, -OCF 3 -, -OCBr 3 -, -OCI 3 -, -OCHCl 2 -, -OCHBr 2 -, -OCHI 2 -, -OCHF 2 -, -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 -, -SF 5 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0051] Or R 11 and R19 forms, together with the carbon atom to which it is attached, a substituted or unsubstituted sub-cycloalkyl or a substituted or unsubstituted sub-heterocycloalkyl;

[0052] Each R 1A 、R 2A 、R 3A 、R 7A 、R 7B 、R 11A 、R 11B 、R 19A and R 19B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0053] or the R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; the R 11A and R 11B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; the R 19A and R 19B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

[0054] Each R 101 is independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0055] n is an integer from 0 to 3; and

[0056] Each X is independently -Cl, -Br, -I or -F;

[0057] Provided that R 11Not OH.

[0058] The disclosed methods can also be used to prepare translatable 5′-capped mRNA molecules that have site-specific modifications in the 5′-capped mRNA molecules. These site-specific modifications may increase translational activity and reduce immunogenicity. In an embodiment, an oligonucleotide as described herein is provided, wherein the oligonucleotide is prepared by chemical synthesis. In an embodiment, an oligonucleotide as described herein is provided, wherein the oligonucleotide comprises three or more modified nucleosides at its 3′ end and two or more nucleotides linked together by modified internucleotide linkages. In an embodiment, an oligonucleotide as described herein is provided, wherein the oligonucleotide comprises three or more modified nucleosides at its 3′ end. In an embodiment, an oligonucleotide as described herein is provided, wherein the oligonucleotide comprises two or more nucleotides linked together by modified internucleotide linkages at its 3′ end. In an embodiment, an oligonucleotide as described herein is provided, wherein the structure of formula (I) or formula (II) comprises one or more removable hydrophobic groups. In an embodiment, an oligonucleotide as described herein is provided, wherein the structure of formula (I) or formula (II) comprises one or more non-removable hydrophobic groups. In an embodiment, an oligonucleotide as described herein is provided, wherein the pharmaceutically acceptable salt is a sodium salt, a lithium salt or a potassium salt. In an embodiment, an oligonucleotide as described herein is provided, wherein the pharmaceutically acceptable salt is a sodium salt.

[0059] In an embodiment, R 1 , R 2 and R 3 are each independently a removable hydrophobic group. In an embodiment, R 1 is independently a removable hydrophobic group. In an embodiment, R 2 is independently a removable hydrophobic group. In an embodiment, R 3 is independently a removable hydrophobic group.

[0060] In one aspect, an oligonucleotide is provided herein, the 5′ end of which comprises a compound having the following structure:

[0061]

[0062] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0063] On the one hand, the present disclosure provides an oligonucleotide, wherein the 5'-end of the oligonucleotide comprises a compound having the following structure:

[0064]

[0065] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0066] On the one hand, the present disclosure provides an oligonucleotide, wherein the 5'-end of the oligonucleotide comprises a compound having the following structure:

[0067]

[0068] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0069] On the one hand, the present disclosure provides a protected 5'-capped oligonucleotide as described herein, the protected 5'-capped oligonucleotide being prepared by the reaction of the following two: the structure of formula (III):

[0070]

[0071] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof;

[0072] wherein:

[0073] Ring A is a substituted or unsubstituted cycloalkylidene, a substituted or unsubstituted heterocycloalkylidene, a substituted or unsubstituted arylidene, or a substituted or unsubstituted heteroarylidene;

[0074] X 1 is independently -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH-, or -S-;

[0075] Y 1 and Y 2 are each independently O, S, or Se;

[0076] R 1 is independently hydrogen, -C(O)R 1A, -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0077] R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group;

[0078] R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0079] Each R 1A , R 2A and R 3A is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3 、 -OCHX 2 、 -OCH 2 X, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0080] Each R 101 is independently hydrogen, oxo, halogen, -CCl 3 、 -CBr 3 、 -CF 3 、 -CI 3 、 -CHCl 2 、 -CHBr 2 、 -CHF 2 、 -CHI 2 、 -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 、 -COOH, -CONH 2 、 -NO 2 、 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、 -NHNH 2 、 -ONH 2 、 -NHC(O)NHNH 2 、 -NHC(O)NH 2 、 -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、 -OCF 3 、 -OCBr 3 、 -OCI 3 、 -OCHCl 2 、 -OCHBr 2 、 -OCHI 2 、 -OCHF 2 、 -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 、 -SF 5, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and

[0081] Each X is independently -Cl, -Br, -I or -F;

[0082] and a 5'-phosphate oligonucleotide

[0083]

[0084] In an embodiment, provided herein is a protected 5'-capped oligonucleotide prepared by chemical synthesis as described herein. In an embodiment, provided herein is a 5'-capped oligonucleotide prepared by removing the protecting group of the protected 5'-capped oligonucleotide as described herein. In an embodiment, the 5'-capped oligonucleotide as described herein is substantially free of enzymatic by-products.

[0085] In one aspect, provided herein is a composition comprising a chemically synthesized oligonucleotide as described herein, wherein the composition comprises less than 1 wt%, less than 0.5 wt%, less than 0.25 wt%, less than 0.1 wt% or less than 0.05 wt% of oligonucleotides whose 5'-end does not contain the structure of formula (I) or formula (II). In an embodiment, provided herein is a composition comprising a chemically synthesized oligonucleotide as described herein, wherein the composition is substantially free of oligonucleotides whose 5'-end does not contain the structure of formula (I) or formula (II). In an embodiment, provided herein is a composition comprising a chemically synthesized oligonucleotide as described herein, wherein the composition is substantially free of enzymatic by-products.

[0086] In one aspect, provided herein is a composition comprising (a) more than 90% of 5'-capped oligonucleotides without protecting groups; (b) less than 10% of 5'-capped oligonucleotides with protecting groups; and optionally (c) less than 1% of oligonucleotides whose 5'-end does not contain the structure of formula (I) or formula (II). In one aspect, provided herein is a composition comprising (a) more than 95% of 5'-capped oligonucleotides without protecting groups; (b) less than 5% of 5'-capped oligonucleotides with protecting groups; and optionally (c) less than 1% of oligonucleotides whose 5'-end does not contain the structure of formula (I) or formula (II).

[0087] On the one hand, the present disclosure provides a method for preparing an oligonucleotide comprising 50 to 12,000 nucleotides, wherein the 5′-end of the oligonucleotide comprises a structure of formula (I):

[0088] or a structure of formula (II):

[0089]

[0090] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0091] The method comprises (a) reacting: an imidazolide of formula (III)

[0092]

[0093] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0094] wherein:

[0095] Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene or a substituted or unsubstituted heteroarylene;

[0096] X 1 independently is -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-;

[0097] Y 1 and Y 2 each independently is O, S or Se;

[0098] R 1 independently is hydrogen, -C(O)R 1A -, -C(O)OR 1A -, -OR 1A -, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0099] R 2 independently is hydrogen, -C(O)R2A 、 -C(O)OR 2A 、 -OR 2A 、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group;

[0100] R 3 is hydrogen, -C(O)R 3A 、 -C(O)OR 3A 、 -OR 3A 、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0101] Each R 1A 、 R 2A and R 3A is independently hydrogen, -CX 3 、 -CHX 2 、 -CH 2 X, -C(O)OH, -C(O)NH 2 、 -CN, -OH, -NH 2 、 -COOH, -CONH 2 、 -NO 2 、 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、 -NHNH 2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、 -OCHX 2 、 -OCH 2 X, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0102] Each R 101Independently is hydrogen, oxo, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 、-OCHCl 2 、-OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl、-OCH 2 Br、-OCH 2 I、-OCH 2 F、-N 3 、-SF 5 、a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0103] Each X is independently -Cl, -Br, -I or -F;

[0104] and a 5'-phosphorylated oligonucleotide

[0105]

[0106] and (b) optionally removing the removable hydrophobic group.

[0107] On the other hand, the present disclosure provides hybrid mRNAs produced using the enzymatic or chemical ligation methods disclosed herein. In some embodiments, the 5′-capped mRNA produced according to the methods of the present disclosure can be ligated to another RNA molecule to increase the size of the mRNA (i.e., the number of nucleobases). In some embodiments, the 5′-capped mRNA produced according to the methods of the present disclosure can be ligated to another RNA molecule that comprises at least about 500 nucleobases up to no more than 12,000 nucleobases. In some embodiments, the 5′-capped mRNA produced according to the methods of the present disclosure can be ligated to another RNA molecule that comprises at least about 500 nucleobases and no more than 8,000 nucleobases.

[0108] In some embodiments, the 5′-capped mRNA transcript and the second (uncapped) RNA transcript are enzymatically ligated. RNA ligase catalyzes the formation of a 3′→5′ phosphodiester bond between the 3′-OH group on the capped mRNA and the 5′-phosphate group on the second (uncapped) transcript. In some embodiments, the ligation reaction is a template-independent ligation reaction. In some embodiments, the RNA ligase is T4 RNA ligase 1. In some embodiments, the 5′-capped mRNA transcript and the second (uncapped) transcript are chemically ligated. For example, the 5′-capped mRNA transcript and the second (uncapped) can be ligated by a click reaction.

[0109] In some embodiments, the ligation methods disclosed herein (e.g., RNA ligase-mediated ligation or click ligation) can produce hybrid RNA transcripts that have a modified (i.e., non-natural) nucleoside or modified internucleoside bond at the 5′ end of the transcript and an unmodified (i.e., naturally occurring) nucleoside at the 3′ end of the transcript, the nucleoside comprising a phosphodiester bond.

[0110] In some embodiments, the first 50 to 150 nucleobases of the transcript (along with the 5′-cap) are produced using the synthetic methods disclosed herein and then ligated to a longer transcript produced by in vitro transcription. The longer transcript will comprise naturally occurring nucleobases and a phosphodiester backbone. However, the 5′-capped RNA transcript produced according to the present disclosure can comprise at least one modified nucleoside and / or at least one modified internucleoside bond. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] Figure 1A Shows with m7 G 3′OMe pppm6 A 2′OMe IP-RP HPLC chromatogram of Wasabi mRNA capped with pG(A-control) - top trace. Using N7-(4-氯苄基) G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of Wasabi mRNA capped with pG(A-1) - middle trace. Using m7 G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of Wasabi mRNA capped with pG(A-control) and using N7-(4-氯苄基) G 3′ OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of co-injected Wasabi mRNA capped with pG(A-1) - bottom trace.

[0112] Figure 1B Shows using m7 G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of Wasabi mRNA capped with pG(A-control) - top trace. Using m7,N2-丁基 G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of Wasabi mRNA capped with pG(A-2) - middle trace. Using m7 G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of Wasabi mRNA capped with pG(A-control) and using m7,N2-丁基 G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of co-injected Wasabi mRNA capped with pG(A-2) - bottom trace.

[0113] Figure 1C Shows using m7 G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of FLuc mRNA capped with pG(A-control) - top trace. Using m7,N2-丁基 G 3′OMe ppp m6 A 2′OMeIP-RP HPLC chromatogram of pG(A-2)-capped FLuc mRNA - middle trace. Using m7 G 3′OMe ppp m6 A 2′OMe IP-RP HPLC chromatogram of pG(A-control)-capped FLuc mRNA and co-injected with m7,N2-丁基 G 3′OMe ppp m6 A 2′OMe pG(A-2)-capped FLuc mRNA - bottom trace.

[0114] Figure 2 is a bar graph showing the translation of mWasabi-encoding mRNA with different cap analogs 24 hours after transfection. Figure 2A In HEK293T cells. Figure 2B In HeLa cells.

[0115] Figure 3A IP-RP HPLC chromatogram of a 10-mer oligomer (SEQ ID NO:2) capped with compound 9 (oligonucleotide A-5) is shown. Figure 3B LCMS chromatogram of an HPLC fraction containing a capped 10-mer oligomer (where the cap contains a removable hydrophobic group - MMT) is shown.

[0116] Figure 4A IP-RP HPLC chromatogram of a 10-mer oligomer (SEQID NO:2) capped with compound 9 and then deprotected for MMT (oligonucleotide A-6) is shown. Figure 4B LCMS chromatogram of an HPLC fraction containing a capped 10-mer oligomer (where MMT has been removed from the cap) is shown.

[0117] Figure 5A IP-RP HPLC chromatogram of a 100-mer oligomer (SEQ ID NO:1) capped with compound 9 (oligonucleotide A-3) is shown. Figure 5B LCMS chromatogram of an HPLC fraction containing a capped 100-mer oligomer (where the cap contains a removable hydrophobic group - MMT) is shown.

[0118] Figure 6A IP-RP HPLC chromatogram of a modified 80-mer oligomer (SEQ IDNO:7) capped with compound 9 (oligonucleotide A-11) is shown. Figure 6B LCMS chromatogram of an HPLC fraction containing a capped modified 80-mer oligomer (where the cap contains a removable hydrophobic group - MMT) is shown.

[0119] Figure 7A The IP-RP HPLC chromatogram of a modified 90-mer oligomer (SEQ ID NO:5) capped with compound 9 (oligonucleotide A-8) is shown. Figure 7B The LCMS chromatogram of an HPLC fraction containing a capped modified 90-mer oligomer, where the cap contains a removable hydrophobic group - MMT, is shown.

[0120] Figure 8 shows at t = 0 ( Figure 8A ); t = 2 hours ( Figure 8B ); and t = 4 hours ( Figure 8C ) the LCMS chromatogram of a crude unmodified 90-mer oligomer (SEQ ID NO:4) after digestion with RNase.

[0121] Figure 9 shows at t = 0 ( Figure 9A ); t = 2 hours ( Figure 9B ); and t = 4 hours ( Figure 9C ) the LCMS chromatogram of a crude modified 90-mer oligomer (SEQ ID NO:5) after digestion with RNase. DETAILED DESCRIPTION

[0122] The following description lists various examples of the methods of the present invention. Specific examples are not intended to limit the scope of the methods. Instead, these are non-limiting exemplary methods. The description will be read from the perspective of a person of ordinary skill in the art; thus, it may not necessarily include information well known to a person skilled in the art.

[0123] As used in this specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents. For example, reference to "a transcript" or "the transcript" may include multiple transcripts.

[0124] Unless the context clearly indicates otherwise, "or" is used in an inclusive sense, i.e., equivalent to "and / or".

[0125] Unless otherwise stated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to better illustrate the invention and does not limit the scope of the invention.

[0126] Unless the context clearly indicates otherwise, the terms "may", "may be", "can", and "can be", and related terms are intended to express that the subject matter involved is optional (i.e., the subject matter exists in some examples and does not exist in other examples), rather than a reference to the ability or probability of the subject matter.

[0127] Unless otherwise indicated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is for illustrative purposes only to better explain the invention and does not limit the scope of the invention.

[0128] I. Definitions

[0129] As used herein, the term "about" means a range of values including the specified value, which values would be reasonably similar to the specified value by one of ordinary skill in the art. In embodiments, about means within the standard deviation of measurement results generally acceptable in the art. In embodiments, about means extending to a range of + / −10% of the specified value. In embodiments, about includes the specified value.

[0130] The abbreviations used herein have their conventional meanings within the fields of chemistry and biology. The chemical structures and chemical formulas set forth herein are constructed according to the standard rules of chemical valence known in the art of chemistry.

[0131] When a substituent is specified by its conventional chemical formula (written left to right), the substituent equally encompasses the chemically identical substituent that results when the structure is written right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.

[0132] Unless otherwise specified, the term "alkyl", by itself or as part of another substituent, means a straight-chain (i.e., unbranched) or branched carbon chain (or carbon) or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. Alkyl may include a specified number of carbons (e.g., C 1 -C 10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl is an alkyl having one or more double bonds or triple bonds. Examples of unsaturated alkyls include, but are not limited to, vinyl, 2-propenyl, 2-butenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule through an oxygen linkage (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and / or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and / or one or more double bonds in addition to the one or more triple bonds.

[0133] Unless otherwise specified, the term "alkylene", by itself or as part of another substituent, means a divalent group derived from an alkane, such as, but not limited to, -CH 2 CH 2 CH 2 CH 2 -. Generally, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a short-chain alkyl or alkylene typically having eight or fewer carbon atoms. Unless otherwise specified, the term "alkenylene", by itself or as part of another substituent, means a divalent group derived from an alkene.

[0134] Unless otherwise specified, the term "heteroalkyl", by itself or in combination with another term, means a stable straight-chain or branched-chain or combination thereof that includes at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., O, N, S, Si, or P) may be placed at any internal position of the heteroalkyl or at the position where the alkyl is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -S-CH 2 、-S(O)-CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH=CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH=N-OCH 3 、-CH=CH-N(CH 3 )-CH 3 、-O-CH 3 、-O-CH2 -CH 3 and -CN. Up to two or three heteroatoms can be consecutive, e.g., -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 . The heteroalkyl moiety can include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety can include two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety can include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise specified, the term "heteroalkenyl", by itself or in combination with another term, means a heteroalkyl including at least one double bond. In addition to the one or more double bonds, the heteroalkenyl can optionally include more than one double bond and / or one or more triple bonds. Unless otherwise specified, the term "heteroalkynyl", by itself or in combination with another term, means a heteroalkyl including at least one triple bond. In addition to the one or more triple bonds, the heteroalkynyl can optionally include more than one triple bond and / or one or more double bonds.

[0135] Similarly, unless otherwise specified, the term "heteroalkylidene", by itself or as part of another substituent, means a divalent group derived from a heteroalkyl, such as but not limited to -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -. For heteroalkylidene, the heteroatom can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkylamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylidene linking groups, the direction of writing the formula of the linking group does not imply the orientation of the linking group. For example, the formula -C(O) 2 R′- represents -C(O) 2 R′- and -R′C(O) 2-both. As described above, as used herein, heteroalkyl includes those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R′, -C(O)NR′, -NR′R″, -OR′, -SR′, and / or -SO 2 R′. In instances where the term “heteroalkyl” is recited followed by a recitation of a specific heteroalkyl such as -NR′R″, it should be understood that the terms heteroalkyl and -NR′R″ are not redundant or mutually exclusive. Rather, the recitation of the specific heteroalkyl is for purposes of added clarity. Thus, the term “heteroalkyl” should not be construed herein to exclude specific heteroalkyls such as -NR′R″, etc.

[0136] Unless otherwise specified, the terms “cycloalkyl” and “heterocycloalkyl,” alone or in combination with other terms, mean the cyclic forms of “alkyl” and “heteroalkyl,” respectively. Cycloalkyls and heterocycloalkyls are not aromatic. Additionally, for heterocycloalkyls, the heteroatom can occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyls include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. “Cycloalkylene” and “heterocycloalkylene,” alone or as part of another substituent, mean divalent groups derived from cycloalkyls and heterocycloalkyls, respectively.

[0137] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, where such group can be saturated or unsaturated, but not aromatic. In embodiments, the cycloalkyl is fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic or fused bicyclic. In embodiments, a bridged monocyclic contains a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic are connected by an alkylene bridge of between one and three additional carbon atoms (i.e., of the form (CH 2 ) wa bridging group, where w is 1, 2, or 3). Representative examples of bicyclic systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. In embodiments, the bridged or fused bicyclic cycloalkyl is connected to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl is optionally substituted with one or two groups independently selected from oxo or thio. In embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to a benzene ring, 5- or 6-membered monocyclic cycloalkyl, 5- or 6-membered monocyclic cycloalkenyl, 5- or 6-membered monocyclic heterocyclic, or 5- or 6-membered monocyclic heteroaryl group, where the fused bicyclic cycloalkyl is optionally substituted with one or two groups independently selected from oxo or thio. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic; or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic. In embodiments, the polycyclic cycloalkyl is connected to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic; or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic. Examples of polycyclic cycloalkyls include, but are not limited to, tetradecahydrophenanthrenyl, perhydro-1-phenothiazinyl, and perhydro-1-phenoxazinyl.

[0138] In an embodiment, the cycloalkyl group is a cycloalkenyl group. The term "cycloalkenyl" is used in its ordinary and general sense. In an embodiment, the cycloalkenyl group is a monocyclic, bicyclic or polycyclic cycloalkenyl ring system. In an embodiment, the monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, wherein such a group is unsaturated (i.e., contains at least one cyclic carbon-carbon double bond), but is not aromatic. Examples of the monocyclic cycloalkenyl ring system include cyclopentenyl and cyclohexenyl. In an embodiment, the bicyclic cycloalkenyl ring is a bridged monocyclic or fused bicyclic. In an embodiment, the bridged monocyclic contains a monocyclic cycloalkenyl ring, wherein two non-adjacent carbon atoms of the monocyclic are connected by an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form (CH 2 ) w , where w is 1, 2 or 3). Representative examples of the bicyclic cycloalkenyl include, but are not limited to, norbornyl and bicyclo[2.2.2]oct-2-enyl. In an embodiment, the fused bicyclic cycloalkenyl ring system contains a monocyclic cycloalkenyl ring fused to a phenyl group, a monocyclic cycloalkyl group, a monocyclic cycloalkenyl group, a monocyclic heterocyclic group or a monocyclic heteroaryl group. In an embodiment, the bridged or fused bicyclic cycloalkenyl is connected to the parent molecular moiety through any carbon atom contained in the monocyclic cycloalkenyl ring. In an embodiment, the cycloalkenyl group is optionally substituted with one or two groups independently selected from oxo or thio. In an embodiment, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (base ring) fused to: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl and bicyclic heterocyclic; or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl and monocyclic or bicyclic heterocyclic. In an embodiment, the polycyclic cycloalkenyl is connected to the parent molecular moiety through any carbon atom contained in the base ring. In an embodiment, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (base ring) fused to: (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl and bicyclic heterocyclic; or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl and monocyclic heterocyclic.

[0139] In an embodiment, a heterocycloalkyl is a heterocyclic group. As used herein, the term "heterocyclic group" means a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclic group monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, P, and S, wherein the ring is saturated or unsaturated but not aromatic. A 3- or 4-membered ring contains 1 heteroatom selected from the group consisting of O, N, P, and S. A 5-membered ring may contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, P, and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, P, and S. The heterocyclic group monocyclic heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclic group monocyclic heterocycle. Representative examples of the heterocyclic group monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofurfuryl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, tetrahydrothiazolyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. A heterocyclic group bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. The heterocyclic group bicyclic heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of the bicyclic heterocyclic group include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothiophen-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In an embodiment, the heterocyclic group is optionally substituted with one or two groups independently being oxo or thioxo. In certain embodiments, the bicyclic heterocyclic group is a 5- or 6-membered monocyclic heterocyclic group ring fused to a benzene ring, 5- or 6-membered monocyclic cycloalkyl, 5- or 6-membered monocyclic cycloalkenyl, 5- or 6-membered monocyclic heterocyclic group, or 5- or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclic group is optionally substituted with one or two groups independently being oxo or thioxo.A polycyclic heterocyclic ring system is fused to a monocyclic heterocyclic ring (base ring) selected from the group consisting of: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic; or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic. The polycyclic heterocyclic is attached to the parent molecular moiety through any carbon or nitrogen atom contained in the base ring. In an embodiment, the polycyclic heterocyclic ring system is fused to a monocyclic heterocyclic ring (base ring) selected from the group consisting of: (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic; or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic. Examples of the polycyclic heterocyclic include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0140] Unless otherwise specified, the term "halo" or "halogen", alone or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" mean including monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1 -C 4 )alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0141] Unless otherwise specified, the term "acyl" means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0142] Unless otherwise indicated, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be a monocyclic or fused together (i.e., fused polycyclic aryl) or covalently linked multiple rings (preferably, 1 to 3 rings). Fused polycyclic aryl means multiple rings fused together, where at least one of the fused rings is an aryl ring. The term "heteroaryl" means an aryl (or ring) containing at least one heteroatom such as N, O or S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused polycyclic heteroaryl (i.e., multiple rings fused together, where at least one of the fused rings is a heteroaryl ring). 5,6-Fused polycyclic heteroarylene means two rings fused together, where one ring has 5 members and the other ring has 6 members, and where at least one ring is a heteroaryl ring. Similarly, 6,6-fused polycyclic heteroarylene means two rings fused together, where one ring has 6 members and the other ring has 6 members, and where at least one ring is a heteroaryl ring. And 6,5-fused polycyclic heteroarylene means two rings fused together, where one ring has 6 members and the other ring has 5 members, and where at least one ring is a heteroaryl ring. Heteroaryl may be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. Substituents of each of the above-indicated aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene", alone or as part of another substituent, mean divalent groups derived from aryl and heteroaryl, respectively. A heteroaryl substituent may be -O- bonded to the ring heteroatom nitrogen.

[0143] A fused heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. A fused heterocycloalkyl-aryl, a fused heterocycloalkyl-heteroaryl, a fused heterocycloalkyl-cycloalkyl, or a fused heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0144] A spiro ring is two or more rings in which adjacent rings are joined by a single atom. The individual rings within a spiro ring may be the same or different. The individual rings within a spiro ring may be substituted or unsubstituted and may have substituents different from the other individual rings within a set of spiro rings. The possible substituents for an individual ring within a spiro ring are the possible substituents for the same ring when not part of a spiro ring (e.g., substituents for a cycloalkyl ring or a heterocycloalkyl ring). A spiro ring may be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heterocycloalkylene, and the individual rings within a spiro ring group may be any of the rings in the immediately preceding list, including all rings of one type (e.g., all rings of a substituted heterocycloalkylene, where each ring may be the same or different substituted heterocycloalkylene). When referring to a spiro ring system, a heterospiro ring means a spiro ring in which at least one ring is a heterocycle and in which each ring may be a different ring. When referring to a spiro ring system, a substituted spiro ring means that at least one ring is substituted and each substituent may optionally be different.

[0145] The symbol represents the point at which a chemical moiety is attached to the remainder of a molecule or chemical formula.

[0146] As used herein, the term "oxo" means an oxygen double-bonded to a carbon atom.

[0147] As used herein, the term "alkylsulfonyl" means a moiety having the formula -S(O 2 )-R′, where R′ is a substituted or unsubstituted alkyl as defined above. R′ may have a specified number of carbons (e.g., "C 1 -C 4 alkylsulfonyl").

[0148] The term "alkylarylene" is an arylene moiety covalently attached to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene has the formula:

[0149]

[0150] The alkyl aryl moiety may be substituted (e.g., by substituents) at the alkylene moiety or the arylene linker (e.g., at carbon 2, 3, 4, or 6) with: halogen, oxo, -N 3 -, -CF 3 -, -CCl 3 -, -CBr 3 -, -CI 3 -, -CN, -CHO, -OH, -NH 2 -, -COOH, -CONH 2 -, -NO 2 -, -SH, -SO 2 CH 3 -, -SO 3 H, -OSO 3 H, -SO 2 NH 2 -, -NHNH 2 -, -ONH 2 -, -NHC(O)NHNH 2 -, a substituted or unsubstituted C 1 -C 5 alkyl or a substituted or unsubstituted 2- to 5-membered heteroalkyl). In an embodiment, the alkyl aryl is unsubstituted.

[0151] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes both the substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

[0152] Substituents for alkyl and heteroalkyl (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more groups selected from, but not limited to, the following: -OR′, =O, =NR′, =N-OR′, -NR′R”, -SR′, -halogen, -SiR′R”R”′, -OC(O)R′, -C(O)R′, -CO 2 R′, -CONR′R”, -OC(O)NR′R”, -NR”C(O)R′, -NR′-C(O)NR”R”′, -NR”C(O) 2 R′, -NR-C(NR′R”R”′)=NR””, -NR-C(NR′R”)=NR”′, -S(O)R′, -S(O) 2 R′, -S(O) 2 NR′R”, -NRSO 2R′, -NR′NR”R”′, -ONR′R”, -NR′C(O)NR”NR”′R””, -CN, -NO 2 , -NR′SO 2 R”, -NR′C(O)R”, -NR′C(O)-OR”, -NR′OR”, in the range of zero to (2m′ + 1), where m′ is the total number of carbon atoms in such groups. R, R′, R”, R”′, and R”” are each preferably independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 - 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or aralkyl. When the compounds described herein include more than one R group, each R group is independently selected, for example, as each R′ group, R” group, R”′ group, and R”” group is independently selected when there is more than one of these groups. When R′ and R” are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR′R” includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the discussion of substituents above, one of ordinary skill in the art will understand that the term “alkyl” is meant to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , etc.).

[0153] Similar to the substituents described for alkyl, the substituents of aryl and heteroaryl vary and are selected from, for example: -OR′, -NR′R”, -SR′, -halogen, -SiR′R”R”′, -OC(O)R′, -C(O)R′, -CO 2 R′, -CONR′R”, -OC(O)NR′R”, -NR”C(O)R′, -NR′-C(O)NR”R”′, -NR”C(O) 2 R′, -NR-C(NR′R”R”′)=NR””, -NR-C(NR′R”)=NR”′, -S(O)R′, -S(O) 2 R′, -S(O) 2 NR′R”, -NRSO 2R′, -NR′NR”R”′, -ONR′R”, -NR′C(O)NR”NR”′R””, -CN, -NO 2 , -R′, -N 3 , -CH(Ph) 2 , fluoro(C 1 -C 4 )alkoxy and fluoro(C 1 -C 4 )alkyl, -NR′SO 2 R”, -NR′C(O)R”, -NR′C(O)-OR”, -NR′OR”, in a number ranging from zero to the total number of open valences on the aromatic ring system; and wherein R′, R”, R”′ and R”” are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, each R group in the R groups is independently selected, for example, as each R′ group, R” group, R”′ group and R”” group is independently selected when more than one of these groups are present.

[0154] Substituents of a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of the ring (commonly referred to as a floating substituent). In such cases, the substituent may be attached to any of the ring atoms of the ring (subject to valence rules), and in the case of fused or spiro rings, a substituent depicted as associated with one member of the fused or spiro ring (a floating substituent on a monocyclic ring) may be a substituent on any of the fused or spiro rings (a floating substituent on multiple rings). When a substituent is attached to a ring rather than a specific atom (floating substituent) and the subscript of the substituent is an integer greater than one, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, different spiro rings, and each substituent may optionally be different. In cases where the point of attachment of the ring to the remainder of the molecule is not limited to a single atom (floating substituent), the point of attachment may be any atom of the ring, and in the case of fused or spiro rings, may be any atom of any of the fused or spiro rings while following valence rules. In cases where the ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring is shown to have more than one floating substituent (including but not limited to the point of attachment to the remainder of the molecule), the floating substituent may be bonded to the heteroatom. In cases where a ring heteroatom is shown to be bonded to one or more hydrogens in a structure or formula having a floating substituent (e.g., a ring nitrogen having two bonds to ring atoms and a third bond to a hydrogen), when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen while following valence rules.

[0155] Two or more substituents may optionally be joined to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. It has been found that such so-called ring-forming substituents are generally (although not necessarily) attached to the cyclic backbone structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the backbone structure. For example, two ring-forming substituents attached to adjacent members of a cyclic backbone structure result in a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the backbone structure. For example, two ring-forming substituents attached to a single member of a cyclic backbone structure result in a spiro ring structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the backbone structure.

[0156] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a group of the formula -T-C(O)-(CRR′) p-U- ring, where T and U are independently -NR-, -O-, -CRR′-, or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents among the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced by a substituent of the formula -A-(CH 2 ) r -B-, where A and B are independently -CRR′-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR′-, or a single bond, and r is an integer from 1 to 4. One of the single bonds of the newly formed ring can optionally be replaced by a double bond. Alternatively, two substituents among the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced by a substituent of the formula -(CRR′) s -X′-(C”R”R”′) d (-), where s and d are independently integers from 0 to 3, and X′ is -O-, -NR′-, -S-, -S(O)-, -S(O) 2 (-), or -S(O) 2 NR′-. The substituents R, R′, R”, and R”′ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0157] As used herein, the term “heteroatom” or “ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0158] As used herein, “substituent” means a group selected from the following moieties:

[0159] (A) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl); and

[0160] (B) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl) substituted with at least one substituent selected from 3 -C 8 cycloalkyl, C 3 -C6 cycloalkyl or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl):

[0161] (i) oxo, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 、-OCHCl 2 、-OCHBr 2 、-OCHI 2 、-OCHF 2 、-N 3 、unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl); and

[0162] (ii) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), or heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl):

[0163] (a) oxo, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CN、-OH、-NH2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl); and

[0164] (b) alkyl substituted with at least one substituent selected from the following (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl): oxo, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 、-OCHCl 2 、-OCHBr 2 、-OCHI 2 、-OCHF 2 、-N 3 、 unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C6 alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0165] As used herein, "size-limited substituent" or "size-limited substituent group" means a group selected from all of the substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0166] As used herein, "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8An alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, and each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C 3 -C 7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted phenyl group, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 6-membered heteroaryl group.

[0167] In some embodiments, each substituted group described in the compounds of the present invention is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl group, substituted heteroalkyl group, substituted cycloalkyl group, substituted heterocycloalkyl group, substituted aryl group, substituted heteroaryl group, substituted alkylene group, substituted heteroalkylene group, substituted cycloalkylene group, substituted heterocycloalkylene group, substituted arylene group, and / or substituted heteroarylene group described in the compounds of the present invention is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower-level substituent.

[0168] In other embodiments of the compounds of the present invention, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C 1 -C 20 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 20-membered heteroalkyl group, and each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C 3 -C 8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C 6 -C 10 aryl group and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 10-membered heteroaryl group. In some embodiments of the compounds of the present invention, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C 1 -C 20 alkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 2- to 20-membered heteroalkylene group, and each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C 3 -C 8A cycloalkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 3- to 8-membered heteroalkylene group, and each substituted or unsubstituted arylene group is a substituted or unsubstituted C 6 -C 10 arylene group and / or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5- to 10-membered heteroarylene group.

[0169] In some embodiments, each substituted or unsubstituted alkyl group can be a substituted or unsubstituted C 1 -C 8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, and each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C 3 -C 7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C 6 -C 10 aryl group and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C 1 -C 8 alkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 2- to 8-membered heteroalkylene group, and each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C 3 -C 7 cycloalkylene group, each substituted or unsubstituted heterocycloalkylene group is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene group, and each substituted or unsubstituted arylene group is a substituted or unsubstituted C 6 -C 10 arylene group, and / or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5- to 9-membered heteroarylene group. In some embodiments, the compound is a chemical species described in the Examples section, the drawings, or the tables below.

[0170] In an embodiment, a substituted or unsubstituted moiety (e.g., a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, and / or a substituted or unsubstituted heteroarylene) is unsubstituted (e.g., an unsubstituted alkyl, an unsubstituted heteroalkyl, an unsubstituted cycloalkyl, an unsubstituted heterocycloalkyl, an unsubstituted aryl, an unsubstituted heteroaryl, an unsubstituted alkylene, an unsubstituted heteroalkylene, an unsubstituted cycloalkylene, an unsubstituted heterocycloalkylene, an unsubstituted arylene, and / or an unsubstituted heteroarylene, respectively). In an embodiment, a substituted or unsubstituted moiety (e.g., a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, and / or a substituted or unsubstituted heteroarylene) is substituted (e.g., a substituted alkyl, a substituted heteroalkyl, a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, a substituted heteroaryl, a substituted alkylene, a substituted heteroalkylene, a substituted cycloalkylene, a substituted heterocycloalkylene, a substituted arylene, and / or a substituted heteroarylene, respectively).

[0171] In an embodiment, a substituted moiety (e.g., a substituted alkyl, a substituted heteroalkyl, a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, a substituted heteroaryl, a substituted alkylene, a substituted heteroalkylene, a substituted cycloalkylene, a substituted heterocycloalkylene, a substituted arylene, and / or a substituted heteroarylene) is substituted with at least one substituent, where if the substituted moiety is substituted with multiple substituents, each substituent may optionally be different. In an embodiment, if the substituted moiety is substituted with multiple substituents, each substituent is different.

[0172] In an embodiment, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-restricted substituent, wherein if the substituted moiety is substituted with a plurality of size-restricted substituents, each size-restricted substituent may optionally be different. In an embodiment, if the substituted moiety is substituted with a plurality of size-restricted substituents, each size-restricted substituent is different.

[0173] In an embodiment, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower-level substituent, wherein if the substituted moiety is substituted with a plurality of lower-level substituents, each lower-level substituent may optionally be different. In an embodiment, if the substituted moiety is substituted with a plurality of lower-level substituents, each lower-level substituent is different.

[0174] In an embodiment, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, at least one size-restricted substituent, or a lower-level substituent; wherein if the substituted moiety is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower-level substituents; then each substituent, size-restricted substituent, and / or lower-level substituent may optionally be different. In an embodiment, if the substituted moiety is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower-level substituents, then each substituent, size-restricted substituent, and / or lower-level substituent is different.

[0175] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; in terms of absolute stereochemistry, they can be defined as enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisomeric forms in the form of (R)- or (S)- or (D)- or (L)-amino acids and individual isomers, which are encompassed within the scope of the present disclosure. Compounds known in the art to be too unstable to be synthesized and / or isolated are not included in the present disclosure. The present disclosure is intended to include compounds in racemic form and optically pure form. The optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometrically asymmetric centers, and unless otherwise specified, it is contemplated that the compounds include both E and Z geometric isomers. In certain embodiments, "optically active" and "enantiomerically active" refer to a population of molecules having an enantiomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, based on the total weight of the racemate under discussion, the compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer.

[0176] As used herein, the term "isomer" refers to compounds having the same number and kind of atoms and thus the same molecular weight, but differing in the structural arrangement or configuration of the atoms.

[0177] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another.

[0178] It will be apparent to those skilled in the art that certain compounds of the present disclosure can exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0179] Unless otherwise stated, the structures depicted herein are also intended to include all stereochemical forms of the structures; i.e., the R and S configurations at each asymmetric center. Accordingly, single stereoisomers as well as mixtures of enantiomers and mixtures of diastereomers of the compounds of the present invention are within the scope of the present disclosure.

[0180] Unless otherwise indicated, structures depicted herein also mean compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention except for the substitution of hydrogen by deuterium or tritium or the substitution of carbon by 13 C or 14 C-enriched carbon are within the scope of this disclosure.

[0181] Compounds of the present disclosure may also contain unnatural proportions of atomic isotopes on one or more of the atoms that make up such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or non-radioactive, are encompassed within the scope of this disclosure.

[0182] It should be noted that throughout this application, alternative embodiments are written in Markush groups, for example, in each nucleobase position containing more than one possible nucleobase. Each member of the Markush group is specifically considered and thereby includes another embodiment, and the Markush group should not be construed as a single unit.

[0183] Regarding any group containing one or more substituents disclosed herein, it should be understood that such groups do not, of course, contain any substitutions or substitution patterns that are spatially impracticable and / or synthetically infeasible. Additionally, the subject compounds include all stereochemical isomers resulting from the substitution of these compounds.

[0184] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules, such as the compounds provided herein, and one or more solvent molecules present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is crystalline. In another embodiment, the complex or aggregate is amorphous. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0185] As used herein, the term "cap analogue" means a structural derivative of an RNA cap. The term "cap" refers to a trinucleotide, tetranucleotide, or longer structure that, when incorporated at the 5′ end of an mRNA transcript (oligonucleotide), promotes / improves translation and / or prevents degradation of the mRNA transcript (oligonucleotide).

[0186] As used herein, the terms "complement", "complementary", or "complementarity" refer to the specific base pairing between nucleotides or nucleic acids. Complementary nucleotides are generally A and T (or A and U), and G and C. For example, the complementarity between a capping oligonucleotide primer and a single-stranded DNA template or one strand of a dsDNA template can be "complete" or "total", where all nucleobases of the two nucleic acid strands match according to recognized base pairing rules, it can be "partial", where only some of the nucleobases of the starting capping oligonucleotide primer and the DNA template match according to recognized base pairing rules, or it can be "non-complementary", where the nucleobases of the two nucleic acid strands do not match according to recognized base pairing rules. Complementarity can also be "substantial complementarity", where the nucleobases of the two nucleic acids match according to recognized base pairing rules but include one or more mismatches (e.g., 1, 2, 3, 4) from total complementarity.

[0187] As used herein, "deoxyribonuclease (DNase)" is an enzyme that catalyzes the hydrolytic cleavage of phosphodiester bonds in the DNA backbone, thereby degrading DNA.

[0188] As used herein, the term "hybridization" or "specific hybridization" refers to the process by which a starting trinucleotide primer anneals to a DNA template during a transcription reaction under appropriate stringent conditions. Hybridization with a starting capping oligonucleotide primer, in certain embodiments, the primer is 3-10 nucleotides in length and includes a 5′-5′ reverse cap structure. Nucleic acid hybridization techniques are well known in the art (see, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Press, Plainview, N.Y. (1989); Ausubel, F.M. et al., Current Protocols in Molecular Biology, John Wiley & Sons, Secaucus, N.J. (1994)).

[0189] As used herein, "locked nucleic acid" (LNA) refers to a ribonucleotide having a bridge between the 2′O and 4′C methylene bicyclic nucleotide monomer. The LNA moiety can have the following structure:

[0190]

[0191] As used herein, the use of the terms "including", "comprising", or "having" and variations thereof are meant to cover the recited elements and their equivalents as well as additional elements. Embodiments recited as "including", "comprising", or "having" a particular element are also contemplated to be "consisting essentially of those particular elements" and "consisting of those particular elements". As used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the absence of combinations when interpreted in the alternative ("or").

[0192] In this disclosure, ranges can be expressed as from one specific value and / or to another specific value. When expressing such a range, unless the context clearly dictates otherwise, it is also specifically contemplated and considered to disclose the range from one particular value and / or to another particular value. Finally, it should be understood that, unless the context clearly dictates otherwise, all individual values and sub-ranges contained within the explicitly disclosed range are also specifically contemplated and should be considered to be disclosed. Further, it should be understood that all ranges refer to the recited range as a range and to a set of individual numbers from the first endpoint (and including the first endpoint) to the second endpoint (and including the second endpoint). In the latter case, it should be understood that any single number within the individual numbers can be selected as a form of the quantity, value, or feature to which the range refers. In this way, the range describes a set of numbers or values from the first endpoint (and including the first endpoint) to the second endpoint (and including the second endpoint), from which individual members (i.e., single numbers) of the set can be selected as the quantity, value, or feature to which the range refers.

[0193] As used herein, "messenger RNA transcript" or "mRNA transcript" is a transcript transcribed from a DNA template encoding a desired polypeptide. The mRNA transcript can contain a coding region and a non-coding region. For example, the DNA template can include an RNA polymerase promoter sequence, a 5′UTR sequence, an open reading frame, and a 3′UTR sequence. In some instances, the DNA template further includes a nucleic acid sequence encoding a poly(A) tail.

[0194] As used herein, the terms "5'-capped oligonucleotide" and "5'-capped mRNA" are used interchangeably and refer to a chemically synthesized capped oligonucleotide or a hybrid-capped oligonucleotide consisting of two or more chemically synthesized oligonucleotides linked together. Alternatively, the hybrid-capped oligonucleotide can consist of two or more oligonucleotides, where at least one oligonucleotide is chemically synthesized and the other oligonucleotide can be produced by an in vitro transcription process and then the two oligonucleotides are linked. In embodiments, the chemically synthesized oligonucleotide can be modified to improve its stability. For example, the chemically synthesized oligonucleotide can have modified internucleotide linkages, modified sugars, or modified nucleobases as described in the specification. Various alternative schemes for linkage are described in the specification.

[0195] As used herein, the term "nucleoside" refers to a nitrogenous base linked to a 5-pentose (e.g., ribose or deoxyribose). The term includes all nucleosides that encompass all forms of nucleobases and furanosides. The base ring includes purine rings and pyrimidine rings. Purine rings include, for example, adenine, guanine, and N6-methyladenine. Pyrimidine rings include, for example, cytosine, thymine, 5-methylcytosine, and pseudouridine.

[0196] As used herein, the terms "nucleoside triphosphate", "nucleoside 5'-triphosphate", or "NTP" refer to a nucleoside linked to three phosphate groups. The term encompasses natural NTPs (e.g., adenosine triphosphate (ATP), uridine triphosphate (UTP), guanosine triphosphate (GTP), and cytidine triphosphate (CTP)) as well as modified NTPs (e.g., pseudouridine and N 1 -methyl-pseudouridine triphosphate).

[0197] "Inorganic pyrophosphatase" refers to an enzyme that catalyzes the conversion of a pyrophosphate ion into two phosphate ions, thereby inhibiting aggregation and, in some cases, preventing the interaction of pyrophosphate with magnesium ions during the T7 transcription reaction.

[0198] As used herein, the term "internucleotide linkage" refers to the bond that links two nucleosides of an oligonucleotide or nucleic acid and can be a natural phosphodiester bond or a modified bond.

[0199] As used herein, the term "substantially free of" refers to a state in which little or no impurities (e.g., prematurely terminated RNA sequences, uncapped RNA, DNA, and / or double-stranded RNA) are present in a sample. "Substantially free of impurities" means that the impurities are present in the sample at a level of less than about 5%, 4%, 3%, 2%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less (w / w). For example, "substantially free of double-stranded RNA" means that double-stranded RNA is present in the sample at a level of less than about 5%, 4%, 3%, 2%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less (w / w). In embodiments, "substantially free of impurities" means that the impurities are present at a level of less than about 5%, the impurities are present at a level of less than about 4%, the impurities are present at a level of less than about 3%, the impurities are present at a level of less than about 2%, the impurities are present at a level of less than about 1%, the impurities are present at a level of less than about 0.9%, the impurities are present at a level of less than about 0.8%, the impurities are present at a level of less than about 0.7%, the impurities are present at a level of less than about 0.6%, the impurities are present at a level of less than about 0.5%, the impurities are present at a level of less than about 0.4%, the impurities are present at a level of less than about 0.3%, the impurities are present at a level of less than about 0.2%, the impurities are present at a level of less than about 0.1%.

[0200] As used herein, the term "impurity" refers to a substance (e.g., an mRNA transcript) that has a chemical composition different from that of the target material. Impurities are also referred to as contaminants.

[0201] As used herein, the term "enzymatic by-product" refers to an undesired product from an IVT reaction, such as uncapped RNA, truncated RNA (RNA that is not fully synthesized or lacks a tail), dsRNA. Enzymatic by-products can be considered impurities.

[0202] As used herein, "tangential flow filtration (TFF)" is a type of filtration in which the material to be filtered passes tangentially across the filter rather than through it. In TFF, the undesired permeate passes through the filter while the desired retentate passes along the filter and is collected downstream. In TFF, the desired material is typically contained in the retentate, which is the opposite of what is encountered when performing conventional membrane filtration or dead-end filtration.

[0203] As used herein, the term "in vitro" refers to a process that occurs outside of a living organism (e.g., a multicellular organism such as a human or non-human animal), such as in a test tube, a culture dish, or elsewhere outside of a living organism.

[0204] As used herein, the term "in vivo" refers to an event that occurs within a living organism.

[0205] As used herein, the term "transcription" refers to the enzymatic preparation or synthesis of RNA complementary to a DNA template, thereby generating a substantial number of RNA complementary sequences of the DNA sequence. The RNA molecule synthesized in a transcription reaction is an "RNA transcript", a "primary transcript", or a "transcript". Transcription reactions involving the compositions and methods provided herein use the initiation capping oligonucleotide primers described herein. Transcription of a DNA template can be exponential, non-linear, or linear. The DNA template can be double-stranded linear DNA, partially double-stranded linear DNA, circular double-stranded DNA, a DNA plasmid, a PCR amplification product, or a modified nucleic acid template compatible with RNA polymerase.

[0206] As used herein, the term "modified oligonucleotide" includes, for example, oligonucleotides containing modified nucleosides, modified internucleotide linkages, or any combination having modified nucleosides and internucleotide linkages. Examples of internucleotide linkage modifications include phosphorothioates, phosphotriesters, and methylphosphonate derivatives (Stec, W. J. et al., Chem. Int. Ed. Engl. 33:709-722 (1994); Lebedev, A. V. et al., Perspect. Drug Discov. Des., 4:17-40 (1996); and Zon et al., U.S. Patent Application No. 20070281308). Other examples of internucleotide linkage modifications can be found in Waldner et al., Bioorg. Med. Chem. Lett. 6:2363-2366 (1996).

[0207] As used herein, "oligo dT purification" is an affinity chromatography used to purify mRNA comprising or containing a poly-A tail.

[0208] As used herein, a "phosphorothioate bond" refers to a bond between nucleosides in which a phosphodiester bond is modified by replacing one oxygen atom attached to the phosphorus atom with a sulfur atom.

[0209] As used herein, the term "prematurely terminated RNA transcript" refers to an incomplete product of an in vitro transcription reaction. A prematurely terminated RNA sequence can be any length less than the expected length of the desired transcription product.

[0210] As used herein, the term "promoter" refers to a nucleotide sequence in a DNA template that directs and controls the initiation of transcription of a specific DNA sequence. A promoter is typically adjacent to (or partially overlapping with) the DNA sequence to be transcribed. The promoter sequence is usually located directly upstream or at the 5' end of the transcription start site. Nucleotide positions in the promoter are designated relative to the transcription start site at which DNA transcription begins (position +1).

[0211] As used herein, the term "nucleoside" refers to a nitrogenous base linked to a 5-carbon sugar (e.g., ribose or deoxyribose). The term includes all nucleosides that contain all forms of nucleobases and furanosides. The base ring includes purine rings and pyrimidine rings. Purine rings include, for example, adenine, guanine, and N6-methyladenine. Pyrimidine rings include, for example, cytosine, thymine, 5-methylcytosine, and pseudouridine. Other nucleosides include, but are not limited to, ribose, 2′-O-methyl, or 2′-deoxyribose derivatives of adenosine, guanosine, cytidine, thymidine, uridine, inosine, 7-methylguanosine, or pseudouridine. The term "natural nucleoside" refers to adenosine, guanosine, cytidine, uridine, and thymidine. According to Aduri et al. (Aduri, R. et al., AMBER force field parameters for the naturally occurring modified nucleotides in RNA. Journal of Chemical Theory and Computation. 2006. 3(4):1464-75), there are 107 naturally occurring nucleosides, including 1-methyladenosine, 2-methylthio-N6-hydroxy-norvalylcarbamoyladenosine, 2-methyladenosine, 2-O-ribosylphosphoadenosine, N6-methyl-N6-threonylcarbamoyladenosine, N6-acetyladenosine, N6-glycylcarbamoyladenosine, N6-isopentenyladenosine, N6-methyladenosine, N6-threonylcarbamoyladenosine, N6,N6-dimethyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, N6-hydroxy-norvalylcarbamoyladenosine, 1,2-O-dimethyladenosine, N6,2-O-dimethyladenosine, 2-O-methyladenosine, N6,N6,O-2-trimethyladenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-methyladenosine, 2-methylthio-N6-isopentenyladenosine, 2-methylthio-N6-threonylcarbamoyladenosine, 2-thiocytidine, 3-methylcytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-methylcytidine, 5-hydroxymethylcytidine, lysidine, N4-acetyl-2-O-methylcytidine, 5-formyl-2-O-methylcytidine, 5,2-O-dimethylcytidine, 2-O-methylcytidine, N4,2-O-dimethylcytidine, N4,N4,2-O-trimethylcytidine, 1-methylguanosine, N2,7-dimethylguanosine, N2-methylguanosine, 2-O-ribosylphosphoguanosine, 7-methylguanosine, under-modified hydroxywybutosine, 7-aminomethyl-7-deazaguanosine, 7-cyano-7-deazaguanosine, N2,N2-dimethylguanosine, 4-demethylwyeoside, epoxywyosine, hydroxywybutosine, isowyoside, N2,7,2-O-trimethylguanosine, N2,2-O-dimethylguanosine, 1,2-O-dimethylguanosine, 2-O-methylguanosine, N2,N2,2-O-trimethylguanosine, N2,N2,7-trimethylguanosine, peroxwybutosine, galactosyl-wyosine, mannosyl-wyosine, wyosine, queuosine, wybutosine, methylwyeoside, wyeoside, 2-thiouridine, 3-(3-amino-3-carboxypropyl)uridine, 3-methyluridine, 4-thiouridine, 5-methyl-2-thiouridine, 5-methylaminomethyluridine, 5-carboxymethyluridine, 5-carboxymethylaminomethyluridine, 5-hydroxyuridine, 5-methyluridine, 5-taurylmethyluridine, 5-carbamoylmethyluridine, methyl 5-(carboxyhydroxymethyl)uridine, dihydrouridine, 5-methyldihydrouridine, 5-methylaminomethyl-2-thiouridine, 5-(carboxyhydroxymethyl)uridine, 5-(isopentenylaminomethyl)uridine, 5-(isopentenylaminomethyl)-2-thiouridine, 3,2-O-dimethyluridine, 5-carboxymethylaminomethyl-2-O-methyluridine, 5-carbamoylmethyl-2-O-methyluridine, 5-methoxycarbonylmethyl-2-O-methyluridine, 5-(isopentenylaminomethyl)-2-O-methyluridine, 5,2-O-dimethyluridine, 2-O-methyluridine, 2-thio-2-O-methyluridine, 5-oxyacetic acid uridine, 5-methoxycarbonylmethyluridine, methyl 5-oxyacetic acid uridine, 5-methoxyuridine, 5-aminomethyl-2-thiouridine, 5-carboxymethylaminomethyl-2-thiouridine, 5-methylaminomethyl-2-selenouridine, 5-methoxycarbonylmethyl-2-thiouridine, 5-taurine methyl-2-thiouridine, pseudouridine, 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine, 1-methylpseudouridine, 3-methylpseudouridine, 2-O-methylpseudouridine, inosine, 1-methylinosine, 1,2-O-dimethylinosine, and 2-O-methylinosine. Each of these or its modified nucleobases can be a component of the nucleic acids of the present invention.,

[0212] All other nucleosides (excluding the natural nucleosides or modified natural nucleosides described above) are non-natural nucleosides.,

[0213] As used herein, the terms "nucleoside analog", "modified nucleoside", or "nucleoside derivative" include synthetic nucleosides as described herein. Nucleoside derivatives also include nucleosides having modified bases and / or sugar moieties, with or without protecting groups, and include, for example, 2'-deoxy-2'-fluorouridine, 5-fluorouridine, and the like. The compounds and methods provided herein include such base rings and their synthetic analogs, as well as unnatural heterocyclic-substituted base sugars and acyclic-substituted base sugars. Other nucleoside derivatives that can be used in conjunction with the present disclosure include, for example, LNA nucleosides, halogen-substituted purines (e.g., 6-fluoropurine), halogen-substituted pyrimidines, N 6 -ethyladenine, N 4 -(alkyl)-cytosine, 5-ethylcytosine, and the like (U.S. Patent No. 6,762,298).

[0214] As used herein, the term "nucleoside base" or "nucleobase" refers to the base portion (nitrogenous base) of a nucleotide or nucleoside; nucleobases include natural, modified, and unnatural nucleobases. "Natural nucleoside bases" include purine rings and pyrimidine rings. Purine rings include, for example, adenine and guanine. Pyrimidine rings include, for example, cytosine, thymine, and uracil.

[0215] As used herein, the term "modified nucleoside base" or "modified nucleobase" describes naturally modified nucleoside bases, including but not limited to, for example, pseudouracil, 5-methylcytosine, N6-methyladenine, hypoxanthine, 5-hydroxymethylcytosine, 5-carboxycytosine, N4-acetylcytosine, N4-methylcytosine, N1-methyladenine, N2,N2-dimethylguanine, and the like. Additionally, see naturally occurring modified nucleosides above.

[0216] As used herein, the term "unnatural nucleoside base" or "unnatural nucleobase" refers to all unnatural nucleoside bases (whether or not modified; see naturally occurring modified nucleosides above), including but not limited to, for example, N1-methylpseudouridine, 7-deazaadenine, 2-aminoadenine, 5-methylisocytosine, 5-fluorouracil, 5-bromouracil, 5-iodouracil, 2-methylthioadenine, 2-thio-5-methyluracil, 2-amino-6-methylthiopurine, and the like. Natural nucleosides are as described above.

[0217] As used herein, the term "RNA polymerase" refers to an enzyme that synthesizes RNA using a DNA template. For in vitro transcription methods, a single-subunit phage RNA polymerase derived from T7, T3, SP6, K1-5, K1E, K1F, or K11 phage or variants thereof is typically used. This family of polymerases has a simple minimum promoter sequence of approximately 17 nucleotides, does not require accessory proteins, and has minimal restrictions on the starting nucleotide sequence.

[0218] As used herein, the term "purified" or "purification" refers to the separation of a substance from at least some of the components with which it is initially associated (e.g., impurities or contaminants). For example, an RNA transcript is purified by removing contaminating proteins or other undesired nucleic acid species (e.g., double-stranded RNA, DNA, and / or incomplete or aborted RNA transcripts). A purified substance (e.g., a capped mRNA transcript) can be separated from 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% of the other components with which it was initially associated.

[0219] Salts of one or more of the compounds described herein can be used in the disclosed methods. As used herein, the term "salt" refers to a derivative of a compound described herein prepared by reacting an acidic or basic moiety of the compound with an inorganic acid or inorganic base or an organic acid or organic base. Optionally, the salt can be a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds described herein or their derivatives, as well as the zwitterionic forms (if possible) of the compounds described herein, which are suitable, within the scope of sound medical judgment, for contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., having a reasonable benefit / risk ratio, and being effective for their intended use. These salts can be prepared in situ during the isolation and purification of the compounds, or by separately reacting the purified compound in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, methanesulfonate, and laurylsulfonate, among others. Salts can contain cations based on alkali metals or alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc.; as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. (See S.M. Barge et al., Journal of Pharmaceutical Sciences (J. Pharm. Sci.) (1977) 66, 1; and Remington: The Science and Practice of Pharmacy, 23rd Edition, edited by Adejare et al., Academic Press (2020); the disclosures of which are incorporated herein by reference in their entirety.)

[0220] References in the specification and concluding claims to the weight portions of specific elements or components in a composition represent the weight relationship between the element or component in the composition or article and any other element or component, and this is expressed as weight portions. Thus, in a compound containing 2 weight portions of component X and 5 weight portions of component Y, X and Y are present in a weight ratio of 2:5, and this ratio exists regardless of whether there are other components in the compound.

[0221] Unless specifically stated to the contrary, the weight percentage (wt.%) of a component is based on the total weight of the formulation or composition containing the component.

[0222] As used herein, the term "or" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the situation where the event or situation occurs and the situation where the event or situation does not occur.

[0223] As used herein, the terms "subject" or "patient" can be a vertebrate, such as a mammal, fish, bird, reptile or amphibian. Thus, the subjects of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not indicate a specific age or gender. Thus, it is intended to cover adult subjects and neonatal subjects as well as fetuses, whether male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes human and livestock subjects.

[0224] The terms "immunization" or "vaccination" describe the process of treating a subject for therapeutic or prophylactic reasons.

[0225] As used herein, the term "treatment" refers to the medical management of a patient, aiming to cure, improve, stabilize or prevent a disease, pathological condition or disorder. This term includes symptomatic treatment, i.e., treatment specifically for the improvement of a disease, pathological condition or disorder, and also includes etiological treatment, i.e., treatment for the removal of the cause of the relevant disease, pathological condition or disorder. Additionally, this term includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure a disease, pathological condition or disorder. In various aspects, the term covers any treatment of a subject including a mammal (e.g., a human), and includes: (i) preventing a disease from occurring in a subject who may be predisposed to having the disease but has not been diagnosed as having the disease; (ii) inhibiting a disease, i.e., preventing its development; or (iii) alleviating a disease, i.e., causing the disease to subside. In one aspect, the subject is a mammal, such as a primate, and in a further aspect, the subject is a human.

[0226] As used herein, the terms "prevent" or "preventing" mean to impede, keep from happening, avoid, preclude, stop, or hinder something from occurring, especially by advance action. It should be understood that where reduction, inhibition, or prevention is used herein, the use of the other two terms is also expressly disclosed, unless otherwise expressly indicated.

[0227] As used herein, the term "diagnosed" means having undergone a physical examination by a person skilled in the art, such as a physician, and having been found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0228] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical formulation to a subject. Such methods are well known to those of skill in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ocular administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, the formulation can be administered therapeutically; i.e., the formulation is administered to treat an existing disease or condition. In additional various aspects, the formulation can be administered prophylactically; i.e., the formulation is administered to prevent a disease or condition.

[0229] As used herein, the terms "effective amount" and "amount effective" refer to an amount sufficient to achieve a desired result or to have an effect on an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to have an effect on an undesired symptom but generally not sufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, the route of administration, the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed and like factors well known in the medical arts. For example, it is entirely within the skill of the art to start the administration of the compounds at a dose level lower than those levels required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, for purposes of administration, the effective daily dose may be divided into multiple doses. Thus, a single dosage composition may contain such an amount or an approximate multiple thereof to constitute the daily dose. In the event of any contraindications, the dosage may be adjusted by the individual physician. The dosage may vary and may be administered in one or more doses per day for one or several days. Guidance regarding appropriate dosages for a given class of pharmaceutical products can be found in the literature. In further individual aspects, the formulations may be administered in a "prophylactically effective amount"; i.e., an amount effective to prevent a disease or condition.

[0230] As used herein, "dosage form" means a pharmacologically active material in a medium, carrier, vehicle or device suitable for administration to a subject. The dosage form may comprise a compound disclosed herein, a product of the disclosed preparation method, or a combination of a salt, solvate or polymorph thereof with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline or phosphate buffered saline. The dosage form can be prepared using conventional pharmaceutical manufacturing and compounding techniques. The dosage form may include inorganic or organic buffers (e.g., sodium or potassium salts of phosphoric, carbonic, acetic or citric acid) and pH regulators (e.g., hydrochloric acid, sodium hydroxide or potassium hydroxide, citrate or acetate, amino acids and their salts), antioxidants (e.g., ascorbic acid, α-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonylphenol, sodium deoxycholate), solution and / or freeze / dry stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic regulators (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsiloxane), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers and viscosity regulators (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethyl cellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use may suspend the disclosed compound, the product of the disclosed preparation method, or a salt, solvate or polymorph thereof together with a preservative in a sterile saline solution for injection.

[0231] As used herein, the terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" refer to sterile aqueous solutions or dispersions, suspensions or emulsions, and sterile powders for the reconstitution of sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. Appropriate fluidity may be maintained, for example, by using coating materials such as lecithin, in the case of dispersions by maintaining the desired particle size, and by using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The action of microorganisms may be prevented by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable depot forms are prepared by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). The rate of drug release may be controlled according to the ratio of the drug to the polymer and the nature of the particular polymer employed. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions compatible with body tissues. Injectable formulations may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media immediately prior to use. Suitable inert carriers may include sugars such as lactose. Desirably, at least 95% by weight of the active ingredient particles have an effective particle size in the range of 0.01 to 10 microns.

[0232] As used herein, the term "therapeutic agent" encompasses any synthetic or naturally-occurring bioactive compound or composition of substances which, when administered to an organism (human or non-human animal), induces a desired pharmacological, immunogenic, and / or physiological effect by local and / or systemic action. The term thus covers those compounds or chemicals that are traditionally regarded as including drugs, vaccines, and biopharmaceuticals containing molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc. Examples of therapeutic agents are described in well-known references such as the Merck Index (14th Edition), the Physicians' Desk Reference (64th Edition), and The Pharmacological Basis of Therapeutics (12th Edition), and the therapeutic agents include, but are not limited to, drugs; vitamins; mineral supplements; substances for the treatment, prevention, diagnosis, cure, or alleviation of diseases or disorders; substances that affect the structure or function of the body, or prodrugs which become bioactive or more active when placed in a physiological environment. For example, the term "therapeutic agent" encompasses compounds or compositions for all major therapeutic areas, including but not limited to adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorectics, anti-inflammatory agents, antiepileptic drugs, local and general anesthetics, hypnotics, sedatives, antipsychotics, neuroleptics, antidepressants, anxiolytics, antagonists, neuronal blockers, anticholinergics and cholinergics, antimuscarinics and muscarinics, adrenergic blockers, antiarrhythmics, antihypertensives, hormones and nutrients, anti-arthritics, anti-asthmatics, anticonvulsants, antihistamines, antiemetics, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, β-blockers, β-agonists, and antiarrhythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostic agents; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressants; muscle relaxants; stimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized, or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides (ribonucleotides (RNA) or deoxyribonucleotides (DNA)), including double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, etc.), small molecules (e.g., doxorubicin), and other bioactive macromolecules such as proteins and enzymes. The agents can be bioactive substances for medical (including veterinary) applications and agriculture (such as plants) and other fields.The term "therapeutic agent" also includes, but is not limited to, drugs; vitamins; mineral supplements; substances for the treatment, prevention, diagnosis, cure or alleviation of a disease or disorder; or substances that affect the structure or function of the body; or prodrugs, which become biologically active or more active when placed in a predetermined physiological environment.

[0233] As used herein, the term "derivative" refers to a compound whose structure is derived from the structure of a parent compound (e.g., a compound disclosed herein), and whose structure is sufficiently similar to the structure disclosed herein such that, based on this similarity, one of ordinary skill in the art would expect the compound to exhibit the same or similar activities and utilities as the claimed compound, or to induce the same or similar activities and utilities as the claimed compound as a precursor. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0234] "Analog" or "analogue" is used in its ordinary general sense within chemistry and biology, and refers to a chemical compound that is structurally similar but compositionally different from another compound (i.e., the so-called "reference" compound), for example, in the substitution of an atom with an atom of a different element, or in the presence of a particular functional group, or in the substitution of one functional group with another functional group, or in the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to the reference compound in function and appearance, but not in structure or origin.

[0235] As used herein, the terms "hydrophobic moiety" or "hydrophobic group" are used interchangeably and refer to a hydrophobic substituent or a combination of carbon-rich hydrophobic substituents. The hydrophobicity of a substituent can be determined, measured, or calculated by the value of its partition coefficient (log P). The partition coefficient (log P) of a substance defines the ratio of its solubility in two immiscible solvents, typically octanol:water. When this value is calculated rather than measured, it is called cLog P. In embodiments, the cLog P of the hydrophobic group is at least 2, or the aggregate value of the cLog P of a combination of two, three, or four "partially hydrophobic groups" is at least 2. The nucleobases cytosine, thymine, uracil, adenine, and guanine with a cLog P less than 2 are not considered "hydrophobic groups" as defined herein. Non-limiting examples of hydrophobic groups include C 6 -C 24 alkyl, C 4 -C 24 alkenyl, C 4 -C 24 alkynyl, C 3 -C 8 cycloalkyl, C6 -C 10 Aryl, trityl, silyl, lipid, and steroid. Fluoro substituents or fluoro-substituted groups can be used to increase the hydrophobicity of the hydrophobic group.

[0236] As used herein, the terms "cleavable hydrophobic moiety", "cleavable hydrophobic group", "removable hydrophobic moiety", or "removable hydrophobic group" are used interchangeably and refer to a hydrophobic group such as C 3 -C 20 or a longer saturated alkyl, cycloalkyl ring, aryl ring, silyl, etc., which can be removed chemically or by heating from the 5'-capped oligonucleotide using mild conditions. In an embodiment, such groups can be removed under weakly acidic conditions with a pH of not less than about 5 (for 1 hour at room temperature). In an embodiment, such groups can be removed under weakly basic conditions with a pH of not more than about 9 (for 1 hour at room temperature). In an embodiment, such groups can be removed by mild heating at not more than about 65 °C for 1 hour. In an embodiment, such groups can be removed by reductive amination. In an embodiment, such groups can be removed by desilylation. In an embodiment, such groups can be removed by oxidation. In an embodiment, such groups can be removed by photolysis. In an embodiment, these terms do not include photocleavable (photolabile) groups. In the present application, a hydrophobic group is considered "cleavable" or "removable" if it can be removed from the 5'-capped RNA under conditions that do not alter its integrity. In an embodiment, once these groups are removed, a 5'-capped oligonucleotide of high purity and easy to translate is produced.

[0237] As used herein, the terms "non-cleavable hydrophobic moiety" or "non-cleavable hydrophobic group" are used interchangeably and refer to a hydrophobic group such as C 3 -C 20 or a longer saturated alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10An aryl group or the like that is not easily removed from the 5'-capped oligonucleotide. In an embodiment, the hydrophobic group cannot be removed using the mild conditions described above for cleavable hydrophobic groups. In an embodiment, the non-cleavable hydrophobic group cannot be removed at a pH of about 5 to about 9 (for 1 hour at room temperature). In an embodiment, the non-cleavable hydrophobic group cannot be removed by heating at below about 65 °C for 1 hour. In an embodiment, the non-cleavable hydrophobic group does not interfere with the translation of the 5'-capped oligonucleotide. In an embodiment, at most 5% of the non-cleavable hydrophobic groups are cleaved from the protected 5'-capped oligonucleotide. In an embodiment, at most 10% of the non-cleavable hydrophobic groups are cleaved from the protected 5'-capped oligonucleotide. In an embodiment, at most 15% of the non-cleavable hydrophobic groups are cleaved from the protected 5'-capped oligonucleotide. In an embodiment, at most 20% of the non-cleavable hydrophobic groups are cleaved from the protected 5'-capped oligonucleotide.

[0238] As used herein, the term "translation-permissive hydrophobic group" refers to any hydrophobic group that does not inhibit (or interfere with) the translation of 5'-capped RNA. Generally, most non-removable hydrophobic groups are translation-permissive. In an embodiment, a removable hydrophobic group can be translation-permissive. In such cases, even though these groups may be "removable", it may not be permitted for the groups to remain.

[0239] As used herein, the terms "photocleavable group" or "photo-labile group" are used interchangeably and refer to groups such as nitrobenzyl, nitrobenzyl derivatives, benzoyl, benzyl, etc., which can be removed by irradiation with light of a specific frequency.

[0240] As used herein, the term "purification handle" refers to a hydrophobic group covalently linked to a 5'-capped oligonucleotide, and such groups can be removable or non-removable. The purification handle allows for HPLC separation of the 5'-capped oligonucleotide including the covalently linked purification handle from uncapped oligonucleotides and other truncated oligonucleotides. In an embodiment, the purification handle can be a protecting group. In an embodiment, the purification handle includes, for example but not limited to, C 6 -C 24 alkyl, C 4 -C 24 alkenyl, C 4 -C 24 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, silyl compounds, trityl compounds, vinyl ether compounds, modified and unmodified Fmoc compounds, etc. Generally, the hydrophobic group is a purification handle.

[0241] The term "protecting group" is used according to its ordinary meaning in organic chemistry and refers to a moiety that is covalently attached to a heteroatom, heterocycloalkyl, or heteroaryl to prevent the reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions prior to removal of the protecting group. Generally, the protecting group is attached to a heteroatom (e.g., O or N) during a portion of a multi-step synthesis where reaction of the heteroatom with a reagent (e.g., chemical reduction) is not desired. After protection, the protecting group can be removed (e.g., by adjusting the pH or temperature). In an embodiment, the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acyl, acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), tert-butyldimethylsilyl (TBDMS), and silyl ethers (e.g., trimethylsilyl (TMS)). In an embodiment, the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include trityl, monomethoxytrityl (MMT), dimethoxytrityl (DMT), or other modified trityls, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), acyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), tert-butyldiphenylsilyl (TBDPS), and tosyl (Ts).

[0242] II. 5′ - Capped Oligonucleotide

[0243] In one aspect, provided herein is an oligonucleotide comprising 50 to 12,000 nucleotides, wherein the 5′ end of the oligonucleotide comprises a structure of formula (I)

[0244]

[0245] or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof;

[0246] wherein:

[0247] B 1 and B 3 are each independently a natural, modified, or unnatural nucleobase;

[0248] each B 2 is independently a natural, modified, or unnatural nucleobase;

[0249] Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene;

[0250] X 1 and X 2 are each independently -O-, -CH 2 -, -CX 2 -, -N(R 101 ), -BH-, or -S-;

[0251] Y 1 、Y 2 、Y 3 、Y 4 and Y 5 are each independently O, S, or Se;

[0252] R 1 is independently hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0253] R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group;

[0254] R 3 is hydrogen, -C(O)R 3A , -C(O)OR 3A , -OR 3A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0255] Each R 7 is independently hydrogen, halogen, -CCl3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0256] Each R 19 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 19A , -NR 19A R 19B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0257] Or R 7 And R 19 Together with the carbon atom to which it is attached form a substituted or unsubstituted subcycloalkyl group or a substituted or unsubstituted subheterocycloalkyl group;

[0258] Each R 11 Independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl2 、 -CHBr 2 、 -CHF 2 、 -CHI 2 、 -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 11A 、 -NR 11A R 11B 、 -COOH, -CONH 2 、 -NO 2 、 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、 -NHNH 2 、 -ONH 2 、 -NHC(O)NHNH 2 、 -NHC(O)NH 2 、 -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、 -OCF 3 、 -OCBr 3 、 -OCI 3 、 -OCHCl 2 、 -OCHBr 2 、 -OCHI 2 、 -OCHF 2 、 -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 、 -SF 5 、 A substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0259] Or R 11 And R 19 Together with the carbon atom to which it is attached form a substituted or unsubstituted subcycloalkyl group or a substituted or unsubstituted subheterocycloalkyl group;

[0260] Each R 1A 、 R 2A 、 R 3A 、 R 7A 、 R 7B 、 R 11A, R 11B , R 19A and R 19B independently is hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 , -OCHX 2 , -OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0261] Or R 7A and R 7B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl group or a substituted or unsubstituted heteroaryl group; R 11A and R 11B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl group or a substituted or unsubstituted heteroaryl group; R 19A and R 19B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl group or a substituted or unsubstituted heteroaryl group;

[0262] Each R 101 independently is hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0263] m is an integer from 0 to 8;

[0264] n is an integer from 0 to 3; and

[0265] each X is independently -Cl, -Br, -I or -F.

[0266] Here and throughout the disclosure, indicates the point of attachment of the structure to the remainder of the oligonucleotide (e.g., the body and the 3′ end).

[0267] In an embodiment, R 1 is independently hydrogen, substituted (e.g., substituted by at least one substituent, a size - limited substituent or a lower - level substituent) or unsubstituted alkyl (e.g., C1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0268] In an embodiment, substituted R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is independently substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if substituted R 1 is independently substituted by a plurality of groups selected from substituents, size - restricted substituents and lower substituents; then each substituent, size - restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 1 is independently substituted, then it is substituted by at least one substituent. In an embodiment, when R 1 is independently substituted, then it is substituted by at least one size - restricted substituent. In an embodiment, when R 1 is independently substituted, then it is substituted by at least one lower substituent.

[0269] In an embodiment, R 1Independently is hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. In an embodiment, R 1 Independently is hydrogen, a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group) or a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) or unsubstituted aryl group (e.g., C 6 -C 10 aryl group, C 10 aryl group, or phenyl). In an embodiment, R 1 Independently is hydrogen. In an embodiment, R 1 Independently is an unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group). In an embodiment, R 1 Independently is a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group). In an embodiment, R 1 Independently is an unsubstituted aryl group (e.g., C 6 -C 10 aryl group, C 10 aryl group, or phenyl). In an embodiment, R 1 Independently is a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) aryl group (e.g., C 6 -C 10 aryl group, C 10 aryl group, or phenyl).

[0270] In an embodiment, R 1 Independently is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or a modified trityl group.

[0271] R 1Independently is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or a modified triphenylmethyl.

[0272] In an embodiment, R 1 independently is hydrogen or methyl. In an embodiment, R 1 independently is hydrogen or (MMT).

[0273] In an embodiment, R 1 independently is hydrogen. In an embodiment, R 1 independently is methyl. In an embodiment, R 1 independently is ethyl. In an embodiment, R 1 independently is propyl. In an embodiment, R 1 independently is isopropyl. In an embodiment, R 1 independently is butyl. In an embodiment, R 1 independently is isobutyl. In an embodiment, R 1 independently is tert-butyl. In an embodiment, R 1 independently is pentyl. In an embodiment, R 1 independently is isopentyl. In an embodiment, R 1 independently is hexyl. In an embodiment, R 1 independently is phenyl. In an embodiment, R 1 independently is benzyl. In an embodiment, R 1 independently is In an embodiment, R 1 independently is In an embodiment, R 1 independently is In an embodiment, R 1 independently is a modified triphenylmethyl.

[0274] In an embodiment, R 2 independently is hydrogen, substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4(alkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0275] In an embodiment, substituted R 2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is independently substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if substituted R 2 is independently substituted by a plurality of groups selected from substituents, size - restricted substituents and lower substituents; then each substituent, size - restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 2 is independently substituted, then it is substituted by at least one substituent. In an embodiment, when R 2 is independently substituted, then it is substituted by at least one size - restricted substituent. In an embodiment, when R 2 is independently substituted, then it is substituted by at least one lower substituent.

[0276] In an embodiment, R 2 is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In an embodiment, R 2 is independently hydrogen, substituted (e.g., substituted by a substituent, size - restricted substituent or lower substituent) or unsubstituted alkyl (e.g., C1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), or substituted (e.g., substituted by a substituent, a size - restricted substituent, or a lower - level substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl). In an embodiment, R 2 is independently hydrogen. In an embodiment, R 2 is independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 2 is independently substituted (e.g., substituted by a substituent, a size - restricted substituent, or a lower - level substituent) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 2 is independently unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl). In an embodiment, R 2 is independently substituted (e.g., substituted by a substituent, a size - restricted substituent, or a lower - level substituent) aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl).

[0277] In an embodiment, R 2 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or a modified trityl group.

[0278] R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl, phenyl, benzyl,

[0279] or a modified trityl group.

[0280] In an embodiment, R 2 is independently hydrogen or methyl. In an embodiment, R 2 is independently hydrogen or (MMT).

[0281] In an embodiment, R 2 is independently hydrogen. In an embodiment, R 2 is independently methyl. In an embodiment, R 2 is independently ethyl. In an embodiment, R 2 is independently propyl. In an embodiment, R 2 is independently isopropyl. In an embodiment, R 2 is independently butyl. In an embodiment, R 2 is independently isobutyl. In an embodiment, R 2 is independently tert-butyl. In an embodiment, R 2 is independently pentyl. In an embodiment, R 2 is independently isopentyl. In an embodiment, R 2 is independently hexyl. In an embodiment, R 2 is independently phenyl. In an embodiment, R 2 is independently benzyl. In an embodiment, R 2 is independently In an embodiment, R 2 is independently In an embodiment, R 2

[0282] is independently In an embodiment, R 2 is independently a modified trityl group.

[0283] In an embodiment, R 3 is hydrogen, a substituted (e.g., substituted by at least one substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), a substituted (e.g., substituted by at least one substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl group (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl), a substituted (e.g., substituted by at least one substituent, a size-limited substituent, or a lower substituent) or unsubstituted cycloalkyl group (e.g., C 3 -C 8Cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0284] In an embodiment, the substituted R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if the substituted R 3 is substituted by multiple groups selected from substituents, size - restricted substituents and lower substituents; then each substituent, size - restricted substituent and / or lower substituent can optionally be different. In an embodiment, when R 3 is substituted, then it is substituted by at least one substituent. In an embodiment, when R 3 is substituted, then it is substituted by at least one size - restricted substituent. In an embodiment, when R 3 is substituted, then it is substituted by at least one lower substituent.

[0285] In an embodiment, R 3 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In an embodiment, R 3 is hydrogen, substituted (e.g., substituted by a substituent, size - restricted substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl) or substituted (e.g., substituted by a substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10(aryl or phenyl). In an embodiment, R 3 is hydrogen. In an embodiment, R 3 is an unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 3 is a substituted (e.g., substituted by a substituent, a size-limited substituent or a lower-level substituent) alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 3 is an unsubstituted aryl group (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl). In an embodiment, R 3 is a substituted (e.g., substituted by a substituent, a size-limited substituent or a lower-level substituent) aryl group (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl).

[0286] In an embodiment, R 3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl or 4-chlorobenzyl. In an embodiment, R 3 is methyl or 4-chlorobenzyl.

[0287] In an embodiment, R 3 is hydrogen. In an embodiment, R 3 is methyl. In an embodiment, R 3 is ethyl. In an embodiment, R 3 is propyl. In an embodiment, R 3 is isopropyl. In an embodiment, R 3 is butyl. In an embodiment, R 3 is isobutyl. In an embodiment, R 3 is tert-butyl. In an embodiment, R 3 is pentyl. In an embodiment, R 3 is isopentyl. In an embodiment, R 3 is hexyl. In an embodiment, R 3 is phenyl. In an embodiment, R 3is benzyl. In an embodiment, R 3 is 4-chlorobenzyl.

[0288] In an embodiment, R 7 is independently hydrogen, halogen, -CCl 3 -CBr 3 -CF 3 -CI 3 -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 -CHBr 2 -CHF 2 -CHI 2 -CN, -OR 7A -NR 7A R 7B -NO 2 -SH, substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0289] In an embodiment, the substituted R 7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted by at least one substituent, at least one size-limited substituent, or a lower-level substituent; wherein if the substituted R 7 is substituted by multiple groups selected from substituents, size-limited substituents, and lower-level substituents; then each substituent, size-limited substituent, and / or lower-level substituent may optionally be different. In an embodiment, when R 7 is substituted, then it is substituted by at least one substituent. In an embodiment, when R 7 is substituted, then it is substituted by at least one size-limited substituent. In an embodiment, when R 7 is substituted, then it is substituted by at least one lower-level substituent.

[0290] In an embodiment, R 7 is independently hydrogen, a halogen, or -OR 7A . In an embodiment, R 7 is independently hydrogen. In an embodiment, R 7 is independently a halogen. In an embodiment, R 7 is independently -OR 7A . In an embodiment, R 7 is independently chlorine. In an embodiment, R 7 is independently bromine. In an embodiment, R 7 is independently iodine. In an embodiment, R 7 is independently fluorine.

[0291] In an embodiment, R 7 is independently a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, or a tert-butoxy group. In an embodiment, R 7 is independently a hydroxyl group. In an embodiment, R 7 is independently a methoxy group. In an embodiment, R 7 is independently an ethoxy group. In an embodiment, R 7 is independently a propoxy group. In an embodiment, R 7 is independently a butoxy group. In an embodiment, R 7 is independently a tert-butoxy group.

[0292] In an embodiment, R 7A is hydrogen or a substituted or unsubstituted alkyl. In an embodiment, R 7A is hydrogen. In an embodiment, R 7A is a substituted alkyl. In an embodiment, R7A is an unsubstituted alkyl group.

[0293] In an embodiment, R 7A is hydrogen, a substituted (e.g., substituted by at least one substituent, size - limited substituent, or lower - level substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group).

[0294] In an embodiment, the substituted R 7A (e.g., substituted alkyl group, substituted heteroalkyl group, substituted cycloalkyl group, substituted heterocycloalkyl group, substituted aryl group, and / or substituted heteroaryl group) is substituted by at least one substituent, at least one size - limited substituent, or lower - level substituent; wherein if the substituted R 7A is substituted by a plurality of groups selected from substituents, size - limited substituents, and lower - level substituents; then each substituent, size - limited substituent, and / or lower - level substituent can optionally be different. In an embodiment, when R 7A is substituted, then it is substituted by at least one substituent. In an embodiment, when R 7A is substituted, then it is substituted by at least one size - limited substituent. In an embodiment, when R 7A is substituted, then it is substituted by at least one lower - level substituent.

[0295] In an embodiment, R 7A is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 7A is hydrogen or a substituted (e.g., substituted by a substituent, size - limited substituent, or lower - level substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group). In an embodiment, R 7A is hydrogen. In an embodiment, R 7A is an unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group). In an embodiment, R 7Ais a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0296] In an embodiment, R 7A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl. In an embodiment, R 7A is hydrogen. In an embodiment, R 7A is methyl. In an embodiment, R 7A is ethyl. In an embodiment, R 7A is propyl. In an embodiment, R 7A is isopropyl. In an embodiment, R 7A is butyl. In an embodiment, R 7A is isobutyl. In an embodiment, R 7A is tert - butyl. In an embodiment, R 7A is pentyl. In an embodiment, R 7A is hexyl.

[0297] In an embodiment, R 11 is independently hydrogen, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CN、-OR 7A 、-NR 7A R 7B 、-NO 2 、-SH, a substituted (e.g., substituted by at least one substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4(alkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0298] In an embodiment, substituted R 11 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - limited substituent or lower substituent; wherein if substituted R 11 is substituted by multiple groups selected from substituents, size - limited substituents and lower substituents; then each substituent, size - limited substituent and / or lower substituent can optionally be different. In an embodiment, when R 11 is substituted, then it is substituted by at least one substituent. In an embodiment, when R 11 is substituted, then it is substituted by at least one size - limited substituent. In an embodiment, when R 11 is substituted, then it is substituted by at least one lower substituent.

[0299] In an embodiment, R 11 is independently hydrogen, halogen or - OR 11A . In an embodiment, R 11 is independently hydrogen. In an embodiment, R 11 is independently halogen. In an embodiment, R 11 is independently - OR 11A。In an embodiment, R 11 is independently chlorine. In an embodiment, R 11 is independently bromine. In an embodiment, R 11 is independently iodine. In an embodiment, R 11 is independently fluorine.

[0300] In an embodiment, R 11 is independently hydroxyl, methoxy, ethoxy, propoxy, butoxy or tert-butoxy. In an embodiment, R 11 is independently hydroxyl. In an embodiment, R 11 is independently methoxy. In an embodiment, R 11 is independently ethoxy. In an embodiment, R 11 is independently propoxy. In an embodiment, R 11 is independently butoxy. In an embodiment, R 11 is independently tert-butoxy.

[0301] In an embodiment, R 11A is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 11A is hydrogen. In an embodiment, R 11A is a substituted alkyl group. In an embodiment, R 1A is an unsubstituted alkyl group.

[0302] In an embodiment, R 11A is hydrogen, a substituted (e.g., substituted by at least one substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0303] In an embodiment, the substituted R 11A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size-limited substituent or a lower substituent; wherein if the substituted R 11A is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent may optionally be different. In an embodiment, when R 11A is substituted, then it is substituted by at least one substituent. In an embodiment, when R 11AWhen it is substituted, it is substituted by at least one substituent with a limited size. In an embodiment, when R 11A is substituted, it is substituted by at least one lower-level substituent.

[0304] In an embodiment, R 11A is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 11A is hydrogen or a substituted (e.g., substituted by a substituent, a substituent with a limited size, or a lower-level substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 11A is hydrogen. In an embodiment, R 11A is an unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 11A is a substituted (e.g., substituted by a substituent, a substituent with a limited size, or a lower-level substituent) alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).

[0305] In an embodiment, R 11A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl. In an embodiment, R 11A is hydrogen. In an embodiment, R 11A is methyl. In an embodiment, R 11A is ethyl. In an embodiment, R 11A is propyl. In an embodiment, R 11A is isopropyl. In an embodiment, R 11A is butyl. In an embodiment, R 11A is isobutyl. In an embodiment, R 11A is tert-butyl. In an embodiment, R 11A is pentyl. In an embodiment, R 11A is hexyl.

[0306] In an embodiment, R 19 is hydrogen, halogen, -CCl3 、 -CBr 3 、 -CF 3 、 -CI 3 、 -CH 2 Cl、 -CH 2 Br、 -CH 2 F、 -CH 2 I、 -CHCl 2 、 -CHBr 2 、 -CHF 2 、 -CHI 2 、 -CN、 -OR 19A 、 -NR 19A R 19B 、 -CONH 2 、 -COOH、 -NHC(O)OH、 -NO 2 、 -SH, substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower - level substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower - level substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower - level substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0307] In an embodiment, substituted R 19(e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, at least one size-restricted substituent, or a lower-level substituent; wherein if the substituted R 19 is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower-level substituents; then each substituent, size-restricted substituent, and / or lower-level substituent may optionally be different. In an embodiment, when R 19 is substituted, then it is substituted with at least one substituent. In an embodiment, when R 19 is substituted, then it is substituted with at least one size-restricted substituent. In an embodiment, when R 19 is substituted, then it is substituted with at least one lower-level substituent.

[0308] In an embodiment, R 19 is hydrogen.

[0309] In an embodiment, R 7 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene. In an embodiment, R 7 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylidene. In an embodiment, R 7 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted heterocycloalkylidene.

[0310] In an embodiment, R 7 and R 19 together with the carbon atom to which they are attached form a substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower-level substituent) or unsubstituted heterocycloalkylidene (e.g., a 3- to 8-membered heterocycloalkylidene, a 3- to 6-membered heterocycloalkylidene, or a 5- to 6-membered heterocycloalkylidene). In an embodiment, R 7 and R 19 together with the carbon atom to which they are attached form a substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower-level substituent) or unsubstituted cycloalkylidene (e.g., a C 3 -C 8 cycloalkylidene, a C 3 -C 6 cycloalkylidene, or a C 5 -C 6 cycloalkylidene).

[0311] In an embodiment, through R 7 and R19 The substituted heterocycloalkyl formed by linking with the carbon atom to which it is attached is substituted by at least one substituent, size-limited substituent or lower substituent; wherein if the substituted heterocycloalkyl is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent can optionally be different. In an embodiment, when through R 7 and R 19 the heterocycloalkyl formed by linking with the carbon atom to which it is attached is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when through R 7 and R 19 the heterocycloalkyl formed by linking with the carbon atom to which it is attached is substituted, then the heterocycloalkyl is substituted by at least one size-limited substituent. In an embodiment, when through R 7 and R 19 the heterocycloalkyl formed by linking with the carbon atom to which it is attached is substituted, then the heterocycloalkyl is substituted by at least one lower substituent.

[0312] In an embodiment, the substituted cycloalkyl formed by linking with the carbon atom to which it is attached through R 7 and R 19 is substituted by at least one substituent, size-limited substituent or lower substituent; wherein if the substituted cycloalkyl is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent can optionally be different. In an embodiment, when through R 7 and R 19 the cycloalkyl formed by linking with the carbon atom to which it is attached is substituted, then the cycloalkyl is substituted by at least one substituent. In an embodiment, when through R 7 and R 19 the cycloalkyl formed by linking with the carbon atom to which it is attached is substituted, then the cycloalkyl is substituted by at least one size-limited substituent. In an embodiment, when through R 7 and R 19 the cycloalkyl formed by linking with the carbon atom to which it is attached is substituted, then the cycloalkyl is substituted by at least one lower substituent.

[0313] In an embodiment, R 7 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 7 and R 19Together with the carbon atom to which it is attached, form a substituted or unsubstituted 4-membered heteroalkylidene ring.

[0314] In an embodiment, R 7 and R 19 Together with the carbon atom to which it is attached, form a substituted 4-membered heteroalkylidene ring. In an embodiment, R 7 and R 19 Together with the carbon atom to which it is attached, form an unsubstituted 4-membered heteroalkylidene ring.

[0315] In an embodiment, R 7 and R 19 Together with the carbon atom to which it is attached, form a locked nucleic acid (LNA).

[0316] In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heteroalkylidene. In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form a substituted or unsubstituted cycloalkylidene. In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form a substituted or unsubstituted heteroalkylidene.

[0317] In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form a substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkylidene (e.g., 3- to 8-membered heteroalkylidene, 3- to 6-membered heteroalkylidene or 5- to 6-membered heteroalkylidene). In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form a substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted cycloalkylidene (e.g., C 3 -C 8 cycloalkylidene, C 3 -C 6 cycloalkylidene or C 5 -C 6 cycloalkylidene).

[0318] In an embodiment, through R 11 and R 19The substituted heterocycloalkyl formed by linking with the carbon atom to which it is attached is substituted by at least one substituent, size-limited substituent or lower substituent; wherein if the substituted heterocycloalkyl is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent can optionally be different. In an embodiment, when the heterocycloalkyl formed by linking with the carbon atom to which it is attached through R 11 and R 19 is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by linking with the carbon atom to which it is attached through R 11 and R 19 is substituted, then the heterocycloalkyl is substituted by at least one size-limited substituent. In an embodiment, when the heterocycloalkyl formed by linking with the carbon atom to which it is attached through R 11 and R 19 is substituted, then the heterocycloalkyl is substituted by at least one lower substituent.

[0319] In an embodiment, the substituted cycloalkyl formed by linking with the carbon atom to which it is attached through R 11 and R 19 is substituted by at least one substituent, size-limited substituent or lower substituent; wherein if the substituted cycloalkyl is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent can optionally be different. In an embodiment, when the cycloalkyl formed by linking with the carbon atom to which it is attached through R 11 and R 19 is substituted, then the cycloalkyl is substituted by at least one substituent. In an embodiment, when the cycloalkyl formed by linking with the carbon atom to which it is attached through R 11 and R 19 is substituted, then the cycloalkyl is substituted by at least one size-limited substituent. In an embodiment, when the cycloalkyl formed by linking with the carbon atom to which it is attached through R 11 and R 19 is substituted, then the cycloalkyl is substituted by at least one lower substituent.

[0320] In an embodiment, R 11 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 11 and R 19Together with the carbon atom to which it is attached, form a substituted or unsubstituted 4-membered heteroalkylidene ring.

[0321] In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form a substituted 4-membered heteroalkylidene ring. In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form an unsubstituted 4-membered heteroalkylidene ring.

[0322] In an embodiment, R 11 and R 19 Together with the carbon atom to which it is attached, form a locked nucleic acid (LNA).

[0323] In an embodiment, each R 1A 、R 2A 、R 3A 、R 7A 、R 11A 、R 11B 、R 19A and R 19B independently is hydrogen, -CX 3 、-CHX 2 、-CH 2 X、-C(O)OH、-C(O)NH 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H、-NHC=(O)H、-NHC(O)OH、-NHOH、-OCX 3 、-OCHX 2 、-OCH 2 X, a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4alkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0324] In an embodiment, each R 1A , R 2A , R 3A , R 7A , R 11A , R 11B , R 19A and R 19B In an embodiment, each R 1A , R 2A , R 3A , R 7A , R 11A , R 11B , R 19A and R 19B is independently substituted with one or more substituents of limited size. 1A , R 2A , R 3A , R 7A , R 11A , R 11B , R 19A and R 19B are independently substituted with one or more lower substituents.

[0325] In an embodiment, R bonded to the same nitrogen atom 7A and R 7BThe substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl). In an embodiment, via R bonded to the same nitrogen atom 7A and R 7B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, a size - restricted substituent or a lower - level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size - restricted substituents and lower - level substituents; then each substituent, size - restricted substituent and / or lower - level substituent may optionally be different. In an embodiment, when the heterocycloalkyl formed by the linkage of R 7A and R 7B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 7A and R 7B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size - restricted substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 7A and R 7B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower - level substituent. In an embodiment, when the heteroaryl formed by the linkage of R 7A and R 7B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 7A and R 7B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one size - restricted substituent. In an embodiment, when the heteroaryl formed by the linkage of R 7A and R 7B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one lower - level substituent.

[0326] In an embodiment, R 11A and R 11BThe substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl). In an embodiment, via R bonded to the same nitrogen atom 11A and R 11B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, a size - limited substituent or a lower - level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size - limited substituents and lower - level substituents; then each substituent, size - limited substituent and / or lower - level substituent may optionally be different. In an embodiment, when the heterocycloalkyl formed by the linkage of R 11A and R 11B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 11A and R 11B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size - limited substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 11A and R 11B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower - level substituent. In an embodiment, when the heteroaryl formed by the linkage of R 11A and R 11B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 11A and R 11B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one size - limited substituent. In an embodiment, when the heteroaryl formed by the linkage of R 11A and R 11B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one lower - level substituent.

[0327] In an embodiment, R 19A and R 19BThe substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size-limited substituent or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size-limited substituent or a lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl). In an embodiment, via R bonded to the same nitrogen atom 19A and R 19B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, a size-limited substituent or a lower substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent may optionally be different. In an embodiment, when the heterocycloalkyl formed by the linkage of R 19A and R 19B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 19A and R 19B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size-limited substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 19A and R 19B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower substituent. In an embodiment, when the heteroaryl formed by the linkage of R 19A and R 19B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 19A and R 19B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one size-limited substituent. In an embodiment, when the heteroaryl formed by the linkage of R 19A and R 19B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one lower substituent.

[0328] In an embodiment, B 1 and B 3 are each independently a natural, modified or unnatural nucleobase. In an embodiment, B 1 and B 3Each is independently a natural nucleobase. In an embodiment, B 1 and B 3 are each independently a modified nucleobase. In an embodiment, B 1 and B 3 are each independently a non-natural nucleobase.

[0329] In an embodiment, B 1 and B 3 are each independently adenine, guanine, cytosine, uracil, or thymine. In an embodiment, B 1 is adenine. In an embodiment, B 1 is guanine. In an embodiment, B 1 is cytosine. In an embodiment, B 1 is uracil. In an embodiment, B 1 is thymine. In an embodiment, B 3 is adenine. In an embodiment, B 3 is guanine. In an embodiment, B 3 is cytosine. In an embodiment, B 3 is uracil. In an embodiment, B 3 is thymine.

[0330] In an embodiment, B 1 is independently 5-methylcytosine, pseudouracil, hypoxanthine, N1-methylpseudouracil, N6-methyladenine, N6-ethyladenine, 7-deazaadenine, N-(alkyl)-cytosine, or 5-ethylcytosine, etc. (U.S. Patent No. 6,762,298).

[0331] In an embodiment, B 1including but not limited to pyrazolo[3,4-d]pyrimidine, 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyluracil and 5-propynylcytosine, 6-azauracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8-amino, 8-mercapto, 8-thioalkyl, 8-hydroxy and other 8-substituted adenines and guanines, 5-halo specifically 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azadenine, deazaguanine, 7-deazaguanine, 3-deazaguanine, deazaadenine, 7-deazaadenine, 3-deazaadenine, pyrazolo[3,4-d]pyrimidine, imidazo[1,5-a]1,3,5-triazinone, 9-deazapurine, imidazo[4,5-d]pyrazine, thiazolo[4,5-d]pyrimidine, pyrazin-2-one, 1,2,4-triazine, pyridazine; and 1,3,5-triazine.

[0332] In an embodiment, B 3 including but not limited to adenine, guanine, cytosine, uracil, pseudouracil, 5-methylcytosine, N6-methyladenine, hypoxanthine, 5-hydroxymethylcytosine, 5-carboxycytosine, N4-acetylcytosine, N4-methylcytosine, N1-methyladenine, N2,N2-dimethylguanine, etc.

[0333] In an embodiment, each B 2 is independently a natural, modified or unnatural nucleobase. In an embodiment, each B 2 is independently a natural nucleobase. In an embodiment, each B 2 is independently a modified nucleobase. In an embodiment, each B 2 is independently an unnatural nucleobase.

[0334] In an embodiment, each B 2 is independently adenine, guanine, cytosine, uracil or thymine. In an embodiment, B 2 is adenine. In an embodiment, B 2 is guanine. In an embodiment, B 2 is cytosine. In an embodiment, B 2 is uracil. In an embodiment, B 2 is thymine.

[0335] In an embodiment, each B 2 is independently 5-methylcytosine, pseudouracil, hypoxanthine, N1-methylpseudouracil, N6-methyladenine, N6-ethyladenine, 7-deazaadenine, N-(alkyl)-cytosine, 5-ethylcytosine, etc. (U.S. Patent No. 6,762,298).

[0336] In an embodiment, each B 2 includes but is not limited to pyrazolo[3,4-d]pyrimidine, 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine, and 2-thiocytosine, 5-propynyluracil and 5-propynylcytosine, 6-azauracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8-amino, 8-mercapto, 8-thioalkyl, 8-hydroxy and other 8-substituted adenines and guanines, 5-halo specifically 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azadenine, deazaguanine, 7-deazaguanine, 3-deazaguanine, deazadenine, 7-deazadenine, 3-deazadenine, pyrazolo[3,4-d]pyrimidine, imidazo[1,5-a]1,3,5-triazinone, 9-deazapurine, imidazo[4,5-d]pyrazine, thiazolo[4,5-d]pyrimidine, pyrazin-2-one, 1,2,4-triazine, pyridazine; and 1,3,5-triazine.

[0337] Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene.

[0338] In an embodiment, ring A is a substituted or unsubstituted heteroalkylene. In an embodiment, ring A is a substituted heteroalkylene. In an embodiment, ring A is an unsubstituted heteroalkylene.

[0339] In an embodiment, ring A is a substituted or unsubstituted heteroarylene. In an embodiment, ring A is a substituted heteroarylene. In an embodiment, ring A is an unsubstituted heteroarylene.

[0340] In an embodiment, ring A is a 3- to 10-membered substituted heterocycloalkyl. In an embodiment, ring A is a 3-membered substituted heterocycloalkyl. In an embodiment, ring A is a 4-membered substituted heterocycloalkyl. In an embodiment, ring A is a 5-membered substituted heterocycloalkyl. In an embodiment, ring A is a 6-membered substituted heterocycloalkyl. In an embodiment, ring A is a 7-membered substituted heterocycloalkyl. In an embodiment, ring A is an 8-membered substituted heterocycloalkyl. In an embodiment, ring A is a 9-membered substituted heterocycloalkyl. In an embodiment, ring A is a 10-membered substituted heterocycloalkyl.

[0341] In an embodiment, ring A is a 3- to 10-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is a 3-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is a 4-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is a 5-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is a 6-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is a 7-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is an 8-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is a 9-membered unsubstituted heterocycloalkyl. In an embodiment, ring A is a 10-membered unsubstituted heterocycloalkyl.

[0342] In an embodiment, ring A is a substituted or unsubstituted tetrahydrofuranylene. In an embodiment, ring A is a substituted tetrahydrofuranylene. In an embodiment, ring A is an unsubstituted tetrahydrofuranylene. In an embodiment, ring A is a substituted or unsubstituted morpholino. In an embodiment, ring A is a substituted morpholino. In an embodiment, ring A is an unsubstituted morpholino.

[0343] In an embodiment, ring A is In an embodiment,

[0344] Ring A is In an embodiment, ring A is

[0345] In an embodiment, X 1 and X 2 are each independently -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-.

[0346] In an embodiment, X 1 is -O-, -CH 2 - or -CX 2 -. In an embodiment, X 1 is -O-, -CH2 - or -CF 2 -. In an embodiment, X 1 is -O-. In an embodiment, X 1 is -CH 2 -. In an embodiment, X 1 is -CX 2 -. In an embodiment, X 1 is -CF 2 -. In an embodiment, X 1 is -N(R 101 )-. In an embodiment, X 1 is -NH-. In an embodiment, X 1 is -BH-. In an embodiment, X 1 is -S-.

[0347] In an embodiment, X 2 is -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-. In an embodiment, X 2 is -O-, -CH 2 -, -CF 2 -, -NH-, -BH- or -S-. In an embodiment, X 2 is -O-, -CH 2 - or -NH-. In an embodiment, X 2 is -CH 2 - or -NH-.

[0348] In an embodiment, X 2 is -O-. In an embodiment, X 2 is -CH 2 -. In an embodiment, X 2 is -CX 2 -. In an embodiment, X 2 is -CF 2 -. In an embodiment, X 2 is -N(R 101 )-. In an embodiment, X 2 is -NH-. In an embodiment, X 2 is -BH-. In an embodiment, X 2 is -S-.

[0349] In an embodiment, Y 1 , Y 2 , Y 3 , Y 4 and Y 5Each independently is O, S, or Se. In an embodiment, Y 1 , Y 2 , Y 3 and Y 4 each independently is O, S, or Se. In an embodiment, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each independently is O or S. In an embodiment, Y 1 , Y 2 , Y 3 and Y 4 each independently is O or S. In an embodiment, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each independently is O. In an embodiment, Y 1 , Y 2 , Y 3 and Y 4 each independently is O. In an embodiment, Y 1 is O. In an embodiment, Y 1 is S. In an embodiment, Y 1 is Se. In an embodiment, Y 2 is O. In an embodiment, Y 2 is S. In an embodiment, Y 2 is Se. In an embodiment, Y 3 is O. In an embodiment, Y 3 is S. In an embodiment, Y 3 is Se. In an embodiment, Y 4 is O. In an embodiment, Y 4 is S. In an embodiment, Y 4 is Se. In an embodiment, Y 5 is O or S. In an embodiment, Y 5 is O. In an embodiment, Y 5 is S. In an embodiment, Y 5 is Se.

[0350] In an embodiment, R 101 is independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2, -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by a substituent, size - restricted substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6cycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl). In an embodiment, R 101 is substituted by one or more substituents. In an embodiment, R 101 is substituted by one or more size - restricted substituents. In an embodiment, R 101 is substituted by one or more lower substituents.

[0351] In an embodiment, each X is independently -Cl, -Br, -I or -F. In an embodiment, X is independently -Cl. In an embodiment, X is independently -Br. In an embodiment, X is independently -I. In an embodiment, X is independently -F.

[0352] In an embodiment, n is an integer from 0 to 3. In an embodiment, n is 1 or 2. In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3.

[0353] In an embodiment, m is an integer from 0 to 8. In an embodiment, m is 0 or 1. In an embodiment, m is 1. In an embodiment, m is 2. In an embodiment, m is 3. In an embodiment, m is 4. In an embodiment, m is 5. In an embodiment, m is 6. In an embodiment, m is 7. In an embodiment, m is 8.

[0354] In an embodiment, provided herein is a structure of formula (IA)

[0355]

[0356] or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein:

[0357] B 3 is a natural nucleobase;

[0358] R4 is independently hydrogen, -C(O)R 4A , -C(O)OR 4A , -OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0359] R 5 is independently hydrogen, -C(O)R 5A , -C(O)OR 5A , -OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group;

[0360] R 6 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF3 、 -OCBr 3 、 -OCI 3 、 -OCHCl 2 、 -OCHBr 2 、 -OCHI 2 、 -OCHF 2 、 -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 、 -SF 5 、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0361] R 14 is hydrogen, halogen, -CCl 3 、 -CBr 3 、 -CF 3 、 -CI 3 、 -CHCl 2 、 -CHBr 2 、 -CHF 2 、 -CHI 2 、 -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 14A 、 -NR 14A R 14B 、 -COOH, -CONH 2 、 -NO 2 、 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、 -NHNH 2 、 -ONH 2 、 -NHC(O)NHNH 2 、 -NHC(O)NH 2 、 -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、 -OCF 3 、 -OCBr 3 、 -OCI 3 、 -OCHCl 2 、 -OCHBr 2 、 -OCHI2 、 -OCHF 2 、 -OCH 2 Cl、 -OCH 2 Br、 -OCH 2 I、 -OCH 2 F、 -N 3 、 -SF 5 、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0362] Each R 4A 、 R 5A 、 R 6A 、 R 6B 、 R 14A and R 14B independently is hydrogen, -CX 3 、 -CHX 2 、 -CH 2 X、 -C(O)OH、 -C(O)NH 2 、 -CN、 -OH、 -NH 2 、 -COOH、 -CONH 2 、 -NO 2 、 -SH、 -SO 3 H、 -SO 4 H、 -SO 2 NH 2 、 -NHNH 2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H、 -NHC=(O)H、 -NHC(O)OH、 -NHOH、 -OCX 3 、 -OCHX 2 、 -OCH 2 X、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0363] The R 6A and R 6B substituents bonded to the same nitrogen atom may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and the R 14A and R 14BThe substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0364] R 1 、R 2 、R 3 、R 7 、R 11 、R 19 、X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、n, m, and ring A are each as defined in the embodiments herein including.

[0365] In an embodiment, R 4 is independently hydrogen, -C(O)R 4A 、–C(O)OR 4A 、-OR 4A 、a substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl), a substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), a substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl), or a substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), a substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0366] In an embodiment, substituted R 4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is independently substituted by at least one substituent, at least one size - restricted substituent or lower - level substituent; wherein if substituted R 4 is independently substituted by multiple groups selected from substituents, size - restricted substituents and lower - level substituents; then each substituent, size - restricted substituent and / or lower - level substituent can optionally be different. In an embodiment, when R 4 is independently substituted, then it is substituted by at least one substituent. In an embodiment, when R 4 is independently substituted, then it is substituted by at least one size - restricted substituent. In an embodiment, when R 4 is independently substituted, then it is substituted by at least one lower - level substituent.

[0367] In an embodiment, R 4 is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. In an embodiment, R 4 is independently hydrogen, substituted (e.g., substituted by a substituent, size - restricted substituent or lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl) or substituted (e.g., substituted by a substituent, size - restricted substituent or lower - level substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl). In an embodiment, R 4 is independently hydrogen. In an embodiment, R 4 is independently unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 4Independently is a substituted (e.g., substituted by a substituent, a size - limited substituent, or a lower - level substituent) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 4 independently is an unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 4 independently is a substituted (e.g., substituted by a substituent, a size - limited substituent, or a lower - level substituent) aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).

[0368] In an embodiment, R 4 independently is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4 - chlorobenzyl.

[0369] In an embodiment, R 4 independently is hydrogen. In an embodiment, R 4 independently is methyl. In an embodiment, R 4 independently is ethyl. In an embodiment, R 4 independently is propyl. In an embodiment, R 4 independently is isopropyl. In an embodiment, R 4 independently is butyl. In an embodiment, R 4 independently is isobutyl. In an embodiment, R 4 independently is tert - butyl. In an embodiment, R 4 independently is pentyl. In an embodiment, R 4 independently is isopentyl. In an embodiment, R 4 independently is hexyl. In an embodiment, R 4 independently is phenyl. In an embodiment, R 4 independently is benzyl. In an embodiment, R 4 independently is 4 - chlorobenzyl.

[0370] In an embodiment, R 5 independently is hydrogen, -C(O)R 5A , –C(O)OR 5A , -OR 5A, substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0371] In an embodiment, the substituted R 5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is independently substituted by at least one substituent, at least one size - limited substituent or lower substituent; wherein if the substituted R 5 is independently substituted by a plurality of groups selected from substituents, size - limited substituents and lower substituents; then each substituent, size - limited substituent and / or lower substituent may optionally be different. In an embodiment, when R 5 is independently substituted, then it is substituted by at least one substituent. In an embodiment, when R 5 is independently substituted, then it is substituted by at least one size - limited substituent. In an embodiment, when R 5 is independently substituted, then it is substituted by at least one lower substituent.

[0372] In an embodiment, R 5 is independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. In an embodiment, R 5 is independently hydrogen, a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl) or a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) or unsubstituted aryl group (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 5 is independently hydrogen. In an embodiment, R 5 is independently an unsubstituted alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 5 is independently a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) alkyl group (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 5 is independently an unsubstituted aryl group (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl). In an embodiment, R 5 is independently a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) aryl group (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl).

[0373] In an embodiment, R 5 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4-chlorobenzyl.

[0374] In an embodiment, R 5Independently is hydrogen. In an embodiment, R 5 Independently is methyl. In an embodiment, R 5 Independently is ethyl. In an embodiment, R 5 Independently is propyl. In an embodiment, R 5 Independently is isopropyl. In an embodiment, R 5 Independently is butyl. In an embodiment, R 5 Independently is isobutyl. In an embodiment, R 5 Independently is tert-butyl. In an embodiment, R 5 Independently is pentyl. In an embodiment, R 5 Independently is isopentyl. In an embodiment, R 5 Independently is hexyl. In an embodiment, R 5 Independently is phenyl. In an embodiment, R 5 Independently is benzyl. In an embodiment, R 5 Independently is 4-chlorobenzyl.

[0375] In an embodiment, R 6 is hydrogen, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CN、-OR 6A 、-NR 6A R 6B 、-NO 2 、-SH, substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl or 2- to 4-membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3-C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0376] In an embodiment, the substituted R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if the substituted R 6 is substituted by multiple groups selected from substituents, size - restricted substituents and lower substituents; then each substituent, size - restricted substituent and / or lower substituent can optionally be different. In an embodiment, when R 6 is substituted, then it is substituted by at least one substituent. In an embodiment, when R 6 is substituted, then it is substituted by at least one size - restricted substituent. In an embodiment, when R 6 is substituted, then it is substituted by at least one lower substituent.

[0377] In an embodiment, R 6 is hydrogen, halogen or -NR 6A R 6B . In an embodiment, R 6 is hydrogen. In an embodiment, R 6 is halogen. In an embodiment, R 6 is -NR 6A R 6B . In an embodiment, R 6 is -Cl. In an embodiment, R 6 is -Br. In an embodiment, R 6 is -I. In an embodiment, R 6 is -F. In an embodiment, R 6is -NHMe. In an embodiment, R 6 is -NH 2 。In an embodiment, R 6 is -NMe 2 。

[0378] In an embodiment, R 6 is hydrogen, -F, -NHMe, -NH 2 or -NMe 2 。In an embodiment, R 6 is hydrogen or -NHMe. In an embodiment, R 6 is hydrogen.

[0379] In an embodiment, R 6A is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 6A is hydrogen. In an embodiment, R 6A is a substituted alkyl group. In an embodiment, R 6A is an unsubstituted alkyl group. In an embodiment, R 6B is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 6B is hydrogen. In an embodiment, R 6B is a substituted alkyl group. In an embodiment, R 6B is an unsubstituted alkyl group.

[0380] In an embodiment, R 6A is hydrogen, substituted (e.g., substituted by at least one substituent, size - limited substituent or lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 6B is hydrogen or substituted (e.g., substituted by a substituent, size - limited substituent or lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0381] In an embodiment, the substituted R 6A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - limited substituent or lower - level substituent; wherein if the substituted R6A substituted with multiple groups selected from substituents, size - restricted substituents, and lower - level substituents; each substituent, size - restricted substituent, and / or lower - level substituent may optionally be different. In an embodiment, when R 6A is substituted, it is substituted with at least one substituent. In an embodiment, when R 6A is substituted, it is substituted with at least one size - restricted substituent. In an embodiment, when R 6A is substituted, it is substituted with at least one lower - level substituent. In an embodiment, substituted R 6B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, at least one size - restricted substituent, or a lower - level substituent; wherein if substituted R 6B is substituted with multiple groups selected from substituents, size - restricted substituents, and lower - level substituents; each substituent, size - restricted substituent, and / or lower - level substituent may optionally be different. In an embodiment, when R 6B is substituted, it is substituted with at least one substituent. In an embodiment, when R 6B is substituted, it is substituted with at least one size - restricted substituent. In an embodiment, when R 6B is substituted, it is substituted with at least one lower - level substituent.

[0382] In an embodiment, R 6A is hydrogen or substituted or unsubstituted alkyl. In an embodiment, R 6A is hydrogen or substituted (e.g., substituted with a substituent, size - restricted substituent, or lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 6A is hydrogen. In an embodiment, R 6A is unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 6A is substituted (e.g., substituted with a substituent, size - restricted substituent, or lower - level substituent) alkyl (e.g., C 1 -C 8alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 6B is hydrogen or a substituted or unsubstituted alkyl. In an embodiment, R 6B is hydrogen or a substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 6B is hydrogen. In an embodiment, R 6B is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 6B is a substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0383] In an embodiment, R 6A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl. In an embodiment, R 6A is hydrogen. In an embodiment, R 6A is methyl. In an embodiment, R 6A is ethyl. In an embodiment, R 6A is propyl. In an embodiment, R 6A is isopropyl. In an embodiment, R 6A is butyl. In an embodiment, R 6A is isobutyl. In an embodiment, R 6A is tert - butyl. In an embodiment, R 6A is pentyl. In an embodiment, R 6A is hexyl. In an embodiment, R 6B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl. In an embodiment, R 6Bis hydrogen. In an embodiment, R 6B is methyl. In an embodiment, R 6B is ethyl. In an embodiment, R 6B is propyl. In an embodiment, R 6B is isopropyl. In an embodiment, R 6B is butyl. In an embodiment, R 6B is isobutyl. In an embodiment, R 6B is tert-butyl. In an embodiment, R 6B is pentyl. In an embodiment, R 6B is hexyl.

[0384] In an embodiment, R 14 is hydrogen, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CN、-OR 14A 、-NR 14A R 14B 、-NO 2 、-SH, substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl or 2- to 4-membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6cycloalkyl) or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0385] In an embodiment, the substituted R 14 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if the substituted R 14 is substituted by a plurality of groups selected from substituents, size - restricted substituents and lower substituents; then each substituent, size - restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 14 is substituted, then it is substituted by at least one substituent. In an embodiment, when R 14 is substituted, then it is substituted by at least one size - restricted substituent. In an embodiment, when R 14 is substituted, then it is substituted by at least one lower substituent.

[0386] In an embodiment, R 14 is hydrogen, halogen or -NR 14A R 14B . In an embodiment, R 14 is hydrogen. In an embodiment, R 14 is halogen. In an embodiment, R 14 is -NR 14A R 14B . In an embodiment, R 14 is -Cl. In an embodiment, R 14 is -Br. In an embodiment, R 14 is -I. In an embodiment, R 14 is -F. In an embodiment, R 14 is -NHMe. In an embodiment, R 14 is -NH 2 . In an embodiment, R 14 is -NMe2 。

[0387] In an embodiment, R 14 is hydrogen, -F, -NHMe, -NH 2 or -NMe 2 。In an embodiment, R 14 is hydrogen or -NH 2 。In an embodiment, R 14 is hydrogen.

[0388] In an embodiment, R 14A is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 14A is hydrogen. In an embodiment, R 14A is a substituted alkyl group. In an embodiment, R 14A is an unsubstituted alkyl group. In an embodiment, R 14B is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 14B is hydrogen. In an embodiment, R 14B is a substituted alkyl group. In an embodiment, R 6B is an unsubstituted alkyl group.

[0389] In an embodiment, R 14A is hydrogen, substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 14B is hydrogen or substituted (e.g., substituted by a substituent, size - restricted substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0390] In an embodiment, the substituted R 14A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if the substituted R 14ASubstituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; each substituent, size-limited substituent, and / or lower substituent can optionally be different. In an embodiment, when R 14A is substituted, it is substituted with at least one substituent. In an embodiment, when R 14A is substituted, it is substituted with at least one size-limited substituent. In an embodiment, when R 14A is substituted, it is substituted with at least one lower substituent. In an embodiment, the substituted R 14B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, at least one size-limited substituent, or a lower substituent; wherein if the substituted R 14B is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; each substituent, size-limited substituent, and / or lower substituent can optionally be different. In an embodiment, when R 14B is substituted, it is substituted with at least one substituent. In an embodiment, when R 14B is substituted, it is substituted with at least one size-limited substituent. In an embodiment, when R 14B is substituted, it is substituted with at least one lower substituent.

[0391] In an embodiment, R 14A is hydrogen or substituted or unsubstituted alkyl. In an embodiment, R 14A is hydrogen or substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 14A is hydrogen. In an embodiment, R 14A is unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 14A is substituted (e.g., substituted with a substituent, size-limited substituent, or lower substituent) alkyl (e.g., C 1 -C 8 alkyl, C1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 14B is hydrogen or a substituted or unsubstituted alkyl. In an embodiment, R 14B is hydrogen or a substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 14B is hydrogen. In an embodiment, R 14B is an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 14B is a substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0392] In an embodiment, R 14A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl. In an embodiment, R 14A is hydrogen. In an embodiment, R 14A is methyl. In an embodiment, R 14A is ethyl. In an embodiment, R 14A is propyl. In an embodiment, R 14A is isopropyl. In an embodiment, R 14A is butyl. In an embodiment, R 14A is isobutyl. In an embodiment, R 14A is tert - butyl. In an embodiment, R 14A is pentyl. In an embodiment, R14 6A is hexyl. In an embodiment, R 14B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, pentyl, isopentyl, hexyl. In an embodiment, R 14B is hydrogen. In an embodiment, R14B is methyl. In an embodiment, R 14B is ethyl. In an embodiment, R 14B is propyl. In an embodiment, R 14B is isopropyl. In an embodiment, R 14B is butyl. In an embodiment, R 14B is isobutyl. In an embodiment, R 14B is tert-butyl. In an embodiment, R 14B is pentyl. In an embodiment, R 14B is hexyl.

[0393] In an embodiment, each R 4A 、R 5A 、R 6A 、R 6B 、R 14A and R 14B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X、-C(O)OH、-C(O)NH 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H、-NHC=(O)H、-NHC(O)OH、-NHOH、-OCX 3 、-OCHX 2 、-OCH 2 X、a substituted (e.g., substituted by a substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4alkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0394] In an embodiment, each R 4A , R 5A , R 6A , R 6B , R 14A and R 14B In an embodiment, each R 4A , R 5A , R 6A , R 6B , R 14A and R 14B is independently substituted with one or more substituents of limited size. 4A , R 5A , R 6A , R 6B , R 14A and R 14B are independently substituted with one or more lower substituents.

[0395] In an embodiment, R bonded to the same nitrogen atom 6A and R 6BThe substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size-limited substituent or a lower-level substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size-limited substituent or a lower-level substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl). In an embodiment, R bonded to the same nitrogen atom 6A and R 6B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, a size-limited substituent or a lower-level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size-limited substituents and lower-level substituents; then each substituent, size-limited substituent and / or lower-level substituent may optionally be different. In an embodiment, when the heterocycloalkyl formed by the linkage of R 6A and R 6B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 6A and R 6B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size-limited substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 6A and R 6B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower-level substituent. In an embodiment, when the heteroaryl formed by the linkage of R 6A and R 6B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 6A and R 6B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one size-limited substituent. In an embodiment, when the heteroaryl formed by the linkage of R 6A and R 6B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one lower-level substituent.

[0396] In an embodiment, R 14A and R 14BThe substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl). In an embodiment, via R bonded to the same nitrogen atom 14A and R 14B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, size - restricted substituent or lower - level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size - restricted substituents and lower - level substituents; then each substituent, size - restricted substituent and / or lower - level substituent may optionally be different. In an embodiment, when the heterocycloalkyl formed by the linkage of R 14A and R 14B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 14A and R 14B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size - restricted substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 14A and R 14B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower - level substituent. In an embodiment, when the heteroaryl formed by the linkage of R 14A and R 14B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 14A and R 14B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one size - restricted substituent. In an embodiment, when the heteroaryl formed by the linkage of R 14A and R 14B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one lower - level substituent.

[0397] In an embodiment, each X is independently - Cl, - Br, - I or - F. In an embodiment, X is independently - Cl. In an embodiment, X is independently - Br. In an embodiment, X is independently - I. In an embodiment, X is independently - F.

[0398] In an embodiment, provided herein is a structure of formula (IB)

[0399]

[0400] or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein:

[0401] R 8 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N3 ,-SF 5 ,a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0402] R 8′ is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8′A , -NR 8′A R 8′B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8′A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0403] Each R 9 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0404] or R 8 and R 9 or R 8′ and R 9 together with the carbon atom to which it is attached forms a substituted or unsubstituted heterocycloalkylidene;

[0405] R 10 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N3 、 -SF 5 、 a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0406] or R 8 and R 10 or R 8′ and R 10 together with the carbon atom to which it is attached form a substituted or unsubstituted subcycloalkyl or a substituted or unsubstituted subheterocycloalkyl;

[0407] Each R 8A 、 R 8B 、 R 8′A 、 R 8′B 、 R 9A 、 R 9B 、 R 10A and R 10B is independently hydrogen, -CX 3 、 -CHX 2 、 -CH 2 X, -C(O)OH, -C(O)NH 2 、 -CN, -OH, -NH 2 、 -COOH, -CONH 2 、 -NO 2 、 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、 -NHNH 2 、 -ONH 2 、 -NHC=(O)NHNH 2 、 -NHC=(O)NH 2 、 -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、 -OCHX 2 、 -OCH 2 X, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0408] R 8A and R 8BThe substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8′A and R 8′B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 9A and R 9B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R bonded to the same nitrogen atom 10A and R 10B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0409] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 11 、R 14 、R 19 、X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、B 3 and n are each as defined in the embodiments herein.

[0410] In an embodiment, R 8 is independently hydrogen, halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CN、-OR 8A 、-NR 8A R 8B 、-CONH 2 、-COOH、-NHC(O)R 8A 、-NO 2, -SH, substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0411] In an embodiment, the substituted R 8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if the substituted R 8 is substituted by multiple groups selected from substituents, size - restricted substituents and lower substituents; then each substituent, size - restricted substituent and / or lower substituent can optionally be different. In an embodiment, when R 8 is substituted, then it is substituted by at least one substituent. In an embodiment, when R 8 is substituted, then it is substituted by at least one size - restricted substituent. In an embodiment, when R 8 is substituted, then it is substituted by at least one lower substituent.

[0412] In an embodiment, R 8 is independently hydrogen, a halogen, -OR 8A or -NHC(O)R 8A . In an embodiment, R 8 is independently hydrogen. In an embodiment, R 8 is independently a halogen. In an embodiment, R 8 is independently -OR 8A . In an embodiment, R 8 is independently -NHC(O)R 8A . In an embodiment, R 8 is independently chlorine. In an embodiment, R 8 is independently bromine. In an embodiment, R 8 is independently iodine. In an embodiment, R 8 is independently fluorine.

[0413] In an embodiment, R 8 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy or tert-butoxy. In an embodiment, R 8 is independently hydrogen or hydroxy.

[0414] In an embodiment, R 8 is independently hydroxy. In an embodiment, R 8 is independently methoxy. In an embodiment, R 8 is independently ethoxy. In an embodiment, R 8 is independently propoxy. In an embodiment, R 8 is independently butoxy. In an embodiment, R 8 is independently tert-butoxy.

[0415] In an embodiment, R 8A is independently hydrogen or a substituted or unsubstituted alkyl. In an embodiment, R 8A is hydrogen. In an embodiment, R 8A is a substituted alkyl. In an embodiment, R 8A is an unsubstituted alkyl.

[0416] In an embodiment, R 8A is hydrogen, substituted (e.g., substituted by at least one substituent, a size-limited substituent or a lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0417] In an embodiment, the substituted R 8A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, at least one size-restricted substituent, or a lower-level substituent; wherein if the substituted R 8A is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower-level substituents; then each substituent, size-restricted substituent, and / or lower-level substituent can optionally be different. In an embodiment, when R 8A is substituted, then it is substituted with at least one substituent. In an embodiment, when R 8A is substituted, then it is substituted with at least one size-restricted substituent. In an embodiment, when R 8A is substituted, then it is substituted with at least one lower-level substituent.

[0418] In an embodiment, R 8A is hydrogen or substituted or unsubstituted alkyl. In an embodiment, R 8A is hydrogen or substituted (e.g., substituted with a substituent, size-restricted substituent, or lower-level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 8A is hydrogen. In an embodiment, R 8A is unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 8A is substituted (e.g., substituted with a substituent, size-restricted substituent, or lower-level substituent) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).

[0419] In an embodiment, R 8A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl. In an embodiment, R 8A is hydrogen. In an embodiment, R 8A is methyl. In an embodiment, R8A is ethyl. In an embodiment, R 8A is propyl. In an embodiment, R 8A is isopropyl. In an embodiment, R 8A is butyl. In an embodiment, R 8A is isobutyl. In an embodiment, R 8A is tert-butyl. In an embodiment, R 8A is pentyl. In an embodiment, R 8A is hexyl.

[0420] In an embodiment, R 8′ is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OR 8′A , -NR 8′A R 8′B , -CONH 2 , -COOH, -NHC(O)R 8 ′A , -NO 2 , -SH, substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl or 2- to 4-membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6cycloalkyl), or substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0421] In an embodiment, the substituted R 8′ (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - restricted substituent or lower substituent; wherein if the substituted R 8′ is substituted by a plurality of groups selected from substituents, size - restricted substituents and lower substituents; then each substituent, size - restricted substituent and / or lower substituent can optionally be different. In an embodiment, when R 8′ is substituted, it is substituted by at least one substituent. In an embodiment, when R 8′ is substituted, it is substituted by at least one size - restricted substituent. In an embodiment, when R 8′ is substituted, it is substituted by at least one lower substituent.

[0422] In an embodiment, R 8′ is independently hydrogen, halogen, -OR 8′A or -NHC(O)R 8′A . In an embodiment, R 8′ is independently hydrogen. In an embodiment, R 8′ is independently halogen. In an embodiment, R 8′ is independently -OR 8′A . In an embodiment, R 8′ is independently -NHC(O)R 8′A . In an embodiment, R 8′ is independently chlorine. In an embodiment, R 8′ is independently bromine. In an embodiment, R 8′ is independently iodine. In an embodiment, R 8′ is independently fluorine.

[0423] In an embodiment, R 8′Independently is hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy or tert-butoxy. In an embodiment, R 8′ Independently is hydrogen or hydroxy.

[0424] In an embodiment, R 8′ Independently is hydroxy. In an embodiment, R 8′ Independently is methoxy. In an embodiment, R 8′ Independently is ethoxy. In an embodiment, R 8′ Independently is propoxy. In an embodiment, R 8′ Independently is butoxy. In an embodiment, R 8′ Independently is tert-butoxy.

[0425] In an embodiment, R 8′A Independently is hydrogen or a substituted or unsubstituted alkyl. In an embodiment, R 8′A is hydrogen. In an embodiment, R 8′A is a substituted alkyl. In an embodiment, R 8′A is an unsubstituted alkyl.

[0426] In an embodiment, R 8′A is hydrogen, substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0427] In an embodiment, the substituted R 8′A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size-limited substituent or lower substituent; wherein if the substituted R 8′A is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent can optionally be different. In an embodiment, when R 8′A is substituted, it is substituted by at least one substituent. In an embodiment, when R 8′A is substituted, it is substituted by at least one size-limited substituent. In an embodiment, when R 8 ′A is substituted, it is substituted by at least one lower substituent.

[0428] In an embodiment, R8′A is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 8′A is hydrogen or a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group). In an embodiment, R 8′A is hydrogen. In an embodiment, R 8′A is an unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group). In an embodiment, R 8′A is a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group).

[0429] In an embodiment, R 8′A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl. In an embodiment, R 8′A is hydrogen. In an embodiment, R 8′A is methyl. In an embodiment, R 8′A is ethyl. In an embodiment, R 8′A is propyl. In an embodiment, R 8′A is isopropyl. In an embodiment, R 8′A is butyl. In an embodiment, R 8′A is isobutyl. In an embodiment, R 8′A is tert-butyl. In an embodiment, R 8′A is pentyl. In an embodiment, R 8′A is hexyl.

[0430] In an embodiment, R 9 is independently hydrogen, halogen, -CCl 3 -CBr 3 -CF 3 -CI 3 -CH 2 Cl, -CH 2Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OR 9A , -NR 9A R 9B , -CONH 2 , -COOH, -NHC(O)R 9A , -NO 2 , -SH, substituted (e.g., substituted by at least one substituent, size - limited substituent or lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower - level substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower - level substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower - level substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or substituted (e.g., substituted by at least one substituent, size - limited substituent or lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0431] In an embodiment, the substituted R 9 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted by at least one substituent, at least one size - limited substituent or lower - level substituent; wherein if the substituted R9 is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; each substituent, size-limited substituent, and / or lower substituent can optionally be different. In an embodiment, when R 9 is substituted, it is substituted with at least one substituent. In an embodiment, when R 9 is substituted, it is substituted with at least one size-limited substituent. In an embodiment, when R 9 is substituted, it is substituted with at least one lower substituent.

[0432] In an embodiment, R 9 is independently hydrogen, halogen, -OR 9A or -NHC(O)R 9A . In an embodiment, R 9 is independently hydrogen. In an embodiment, R 9 is independently halogen. In an embodiment, R 9 is independently -OR 9A . In an embodiment, R 9 is independently -NHC(O)R 9A . In an embodiment, R 9 is independently chlorine. In an embodiment, R 9 is independently bromine. In an embodiment, R 9 is independently iodine. In an embodiment, R 9 is independently fluorine.

[0433] In an embodiment, R 9 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or tert-butoxy.

[0434] In an embodiment, R 9 is independently hydrogen. In an embodiment, R 9 is independently hydroxy. In an embodiment, R 9 is independently methoxy. In an embodiment, R 9 is independently ethoxy. In an embodiment, R 9 is independently propoxy. In an embodiment, R 9 is independently butoxy. In an embodiment, R 9 is independently tert-butoxy.

[0435] In an embodiment, R 9A is independently hydrogen or substituted or unsubstituted alkyl. In an embodiment, R 9A is hydrogen. In an embodiment, R 9A is substituted alkyl. In an embodiment, R 9Ais an unsubstituted alkyl group.

[0436] In an embodiment, R 9A is hydrogen, a substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group or C 1 -C 4 alkyl group).

[0437] In an embodiment, the substituted R 9A (e.g., substituted alkyl group, substituted heteroalkyl group, substituted cycloalkyl group, substituted heterocycloalkyl group, substituted aryl group and / or substituted heteroaryl group) is substituted by at least one substituent, at least one size - limited substituent or lower substituent; wherein if the substituted R 9A is substituted by a plurality of groups selected from substituents, size - limited substituents and lower substituents; then each substituent, size - limited substituent and / or lower substituent can optionally be different. In an embodiment, when R 9A is substituted, then it is substituted by at least one substituent. In an embodiment, when R 9A is substituted, then it is substituted by at least one size - limited substituent. In an embodiment, when R 9A is substituted, then it is substituted by at least one lower substituent.

[0438] In an embodiment, R 9A is hydrogen or a substituted or unsubstituted alkyl group. In an embodiment, R 9A is hydrogen or a substituted (e.g., substituted by a substituent, size - limited substituent or lower substituent) or unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group or C 1 -C 4 alkyl group). In an embodiment, R 9A is hydrogen. In an embodiment, R 9A is an unsubstituted alkyl group (e.g., C 1 -C 8 alkyl group, C 1 -C 6 alkyl group or C 1 -C 4 alkyl group). In an embodiment, R 9A is a substituted (e.g., substituted by a substituent, size - limited substituent or lower substituent) alkyl group (e.g., C1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0439] In an embodiment, R 9A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl. In an embodiment, R 9A is hydrogen. In an embodiment, R 9A is methyl. In an embodiment, R 9A is ethyl. In an embodiment, R 9A is propyl. In an embodiment, R 9A is isopropyl. In an embodiment, R 9A is butyl. In an embodiment, R 9A is isobutyl. In an embodiment, R 9A is tert-butyl. In an embodiment, R 9A is pentyl. In an embodiment, R 9A is isopentyl. In an embodiment, R 9A is hexyl.

[0440] In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom to which they are attached form a substituted or unsubstituted heterocycloalkylidene. In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom to which they are attached form a substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkylidene (e.g., 3- to 8-membered heterocycloalkylidene, 3- to 6-membered heterocycloalkylidene or 5- to 6-membered heterocycloalkylidene).

[0441] In an embodiment, the substituted heterocycloalkylidene formed by connecting (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom to which they are attached is substituted by at least one substituent, size-limited substituent or lower substituent; wherein if the substituted heterocycloalkylidene is substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent may optionally be different. In an embodiment, when through (R 8 and R9 ) or (R 8′ and R 9 ) When the heteroalkyl group formed by connecting with the carbon atom it is attached to is substituted, then the heteroalkyl group is substituted by at least one substituent. In an embodiment, when through (R 8 and R 9 ) or (R 8′ and R 9 ) When the heteroalkyl group formed by connecting with the carbon atom it is attached to is substituted, then the heteroalkyl group is substituted by at least one substituent with a limited size. In an embodiment, when through (R 8 and R 9 ) or (R 8′ and R 9 ) When the heteroalkyl group formed by connecting with the carbon atom it is attached to is substituted, then the heteroalkyl group is substituted by at least one lower substituent.

[0442] In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom it is attached to form a substituted or unsubstituted 5- to 6-membered heteroalkyl group. In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom it is attached to form a substituted or unsubstituted 5-membered heteroalkyl group. In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom it is attached to form a substituted or unsubstituted 6-membered heteroalkyl group.

[0443] In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom it is attached to form a substituted 5-membered heteroalkyl group. In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom it is attached to form an unsubstituted 5-membered heteroalkyl group. In an embodiment, (R 8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom it is attached to form a substituted 6-membered heteroalkyl group. In an embodiment, (R8 and R 9 ) or (R 8′ and R 9 ) together with the carbon atom to which it is attached form an unsubstituted 6 - membered heteroalkyl ring.

[0444] In an embodiment, R 10 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OR 10A , -NR 10A R 10B , -CONH 2 , -COOH, -NHC(O)OH, -NO 2 , -SH, substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 3 - to 8 - membered heteroalkyl, 3 - to 6 - membered heteroalkyl or 5 - to 6 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - restricted substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10an aryl or phenyl group, or a substituted (e.g., substituted by at least one substituent, size-limited substituent, or lower-level substituent) or unsubstituted heteroaryl group (e.g., a 5- to 10-membered heteroaryl group, a 5- to 9-membered heteroaryl group, or a 5- to 6-membered heteroaryl group).

[0445] In an embodiment, the substituted R 10 (e.g., a substituted alkyl group, a substituted heteroalkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group, and / or a substituted heteroaryl group) is substituted by at least one substituent, at least one size-limited substituent, or a lower-level substituent; wherein if the substituted R 10 is substituted by a plurality of groups selected from substituents, size-limited substituents, and lower-level substituents; then each substituent, size-limited substituent, and / or lower-level substituent may optionally be different. In an embodiment, when R 10 is substituted, then it is substituted by at least one substituent. In an embodiment, when R 10 is substituted, then it is substituted by at least one size-limited substituent. In an embodiment, when R 10 is substituted, then it is substituted by at least one lower-level substituent.

[0446] In an embodiment, R 10 is hydrogen.

[0447] In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which they are attached form a substituted or unsubstituted sub-cycloalkyl group or a substituted or unsubstituted sub-heterocycloalkyl group. In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which they are attached form a substituted or unsubstituted sub-cycloalkyl group. In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which they are attached form a substituted or unsubstituted sub-heterocycloalkyl group.

[0448] In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10)Together with the carbon atom to which it is attached, it forms a substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl). In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached forms a substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl).

[0449] In an embodiment, the substituted heterocycloalkyl formed by connecting (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached is substituted by at least one substituent, size - limited substituent or lower substituent; wherein if the substituted heterocycloalkyl is substituted by multiple groups selected from substituents, size - limited substituents and lower substituents; then each substituent, size - limited substituent and / or lower substituent can optionally be different. In an embodiment, when the heterocycloalkyl formed by connecting (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by connecting (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached is substituted, then the heterocycloalkyl is substituted by at least one size - limited substituent. In an embodiment, when the heterocycloalkyl formed by connecting (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached is substituted, then the heterocycloalkyl is substituted by at least one lower substituent.

[0450] In an embodiment, by (R 8 and R 10 ) or (R8′ and R 10 ) The substituted subcycloalkyl group formed by connecting with the carbon atom to which it is attached is substituted by at least one substituent, size-limited substituent or lower substituent; wherein if the substituted subcycloalkyl group is substituted by multiple groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent can optionally be different. In an embodiment, when through (R 8 and R 10 ) or (R 8′ and R 10 ) The subcycloalkyl group formed by connecting with the carbon atom to which it is attached is substituted, then the subcycloalkyl group is substituted by at least one substituent. In an embodiment, when through (R 8 and R 10 ) or (R 8′ and R 10 ) The subcycloalkyl group formed by connecting with the carbon atom to which it is attached is substituted, then the subcycloalkyl group is substituted by at least one size-limited substituent. In an embodiment, when through (R 8 and R 10 ) or (R 8′ and R 10 ) The subcycloalkyl group formed by connecting with the carbon atom to which it is attached is substituted, then the subcycloalkyl group is substituted by at least one lower substituent.

[0451] In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached form a substituted or unsubstituted 3- to 6-membered subheterocycloalkyl group. In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached form a substituted or unsubstituted 4-membered subheterocycloalkyl group.

[0452] In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached form a substituted 4-membered subheterocycloalkyl group. In an embodiment, (R 8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached form an unsubstituted 4-membered subheterocycloalkyl group.

[0453] In an embodiment, (R8 and R 10 ) or (R 8′ and R 10 ) together with the carbon atom to which it is attached form locked nucleic acid (LNA).

[0454] In an embodiment, each R 8A , R 8B , R 8′A , R 8′B , R 9A , R 9B , R 10A and R 10B is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 , -OCHX 2 , -OCH 2 X, substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6cycloalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl or phenyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0455] In an embodiment, each R 8A , R 8B , R 8′A , R 8′B , R 9A , R 9B , R 10A and R 10B In an embodiment, each R 8A , R 8B , R 8′A , R 8′B , R 9A , R 9B , R 10A and R 10B is independently substituted with one or more substituents of limited size. 8A , R 8B , R 8′A , R 8′B , R 9A , R 9B , R 10A and R 10B are independently substituted with one or more lower substituents.

[0456] In an embodiment, R bonded to the same nitrogen atom 8A and R 8B Substituents may be optionally linked to form a substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl) or a substituted (e.g., substituted with a substituent, a substituent of limited size, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0457] In an embodiment, R bonded to the same nitrogen atom 8′A and R8′B The substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0458] In an embodiment, R bonded to the same nitrogen atom 8A and R 8B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, a size - restricted substituent or a lower - level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size - restricted substituents and lower - level substituents; then each substituent, size - restricted substituent and / or lower - level substituent may optionally be different.

[0459] In an embodiment, R bonded to the same nitrogen atom 8′A and R 8′B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, a size - restricted substituent or a lower - level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size - restricted substituents and lower - level substituents; then each substituent, size - restricted substituent and / or lower - level substituent may optionally be different.

[0460] In an embodiment, when the heterocycloalkyl formed by the linkage of R 8A and R 8B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 8A and R 8B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size - restricted substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 8A and R 8B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower - level substituent.

[0461] In an embodiment, when R 8′A and R 8′BWhen the heterocycloalkyl formed by the linkage of substituents is substituted, the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when R 8′A and R 8′B substituents linked to the same nitrogen atom form a substituted heterocycloalkyl, the heterocycloalkyl is substituted by at least one size-limited substituent. In an embodiment, when R 8′A and R 8′B substituents linked to the same nitrogen atom form a substituted heterocycloalkyl, the heterocycloalkyl is substituted by at least one lower-level substituent.

[0462] In an embodiment, when the heteroaryl formed by the linkage of R 8A and R 8B substituents linked to the same nitrogen atom is substituted, the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 8A and R 8B substituents linked to the same nitrogen atom is substituted, the heteroaryl is substituted by at least one size-limited substituent. In an embodiment, when the heteroaryl formed by the linkage of R 8A and R 8B substituents linked to the same nitrogen atom is substituted, the heteroaryl is substituted by at least one lower-level substituent.

[0463] In an embodiment, when the heteroaryl formed by the linkage of R 8′A and R 8′B substituents linked to the same nitrogen atom is substituted, the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 8′A and R 8′B substituents linked to the same nitrogen atom is substituted, the heteroaryl is substituted by at least one size-limited substituent. In an embodiment, when the heteroaryl formed by the linkage of R 8′A and R 8′B substituents linked to the same nitrogen atom is substituted, the heteroaryl is substituted by at least one lower-level substituent.

[0464] In an embodiment, R 9A and R 9BThe substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size-restricted substituent or a lower-level substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size-restricted substituent or a lower-level substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl).

[0465] In an embodiment, the substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted by at least one substituent, a size-restricted substituent or a lower-level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower-level substituents; then each substituent, size-restricted substituent and / or lower-level substituent may optionally be different.

[0466] In an embodiment, when the heterocycloalkyl formed by the linkage of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size-restricted substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower-level substituent.

[0467] In an embodiment, when the heteroaryl formed by the linkage of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one size-restricted substituent. In an embodiment, when the heteroaryl formed by the linkage of R 9A and R 9B substituents bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one lower-level substituent.

[0468] In an embodiment, R 10A and R10B The substituents may optionally be linked to form a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl) or a substituted (e.g., substituted by a substituent, a size - restricted substituent or a lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0469] In an embodiment, R bonded to the same nitrogen atom 10A and R 10B The substituted heterocycloalkyl or substituted heteroaryl formed by the linkage of the substituents is substituted by at least one substituent, size - restricted substituent or lower - level substituent; wherein if the substituted heterocycloalkyl or substituted heteroaryl is substituted by a plurality of groups selected from substituents, size - restricted substituents and lower - level substituents; then each substituent, size - restricted substituent and / or lower - level substituent may optionally be different.

[0470] In an embodiment, when the heterocycloalkyl formed by the linkage of R 10A and R 10B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 10A and R 10B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one size - restricted substituent. In an embodiment, when the heterocycloalkyl formed by the linkage of R 10A and R 10B bonded to the same nitrogen atom is substituted, then the heterocycloalkyl is substituted by at least one lower - level substituent.

[0471] In an embodiment, when the heteroaryl formed by the linkage of R 10A and R 10B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one substituent. In an embodiment, when the heteroaryl formed by the linkage of R 10A and R 10B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one size - restricted substituent. In an embodiment, when the heteroaryl formed by the linkage of R 10A and R 10B bonded to the same nitrogen atom is substituted, then the heteroaryl is substituted by at least one lower - level substituent.

[0472] In an embodiment, each X is independently -Cl, -Br, -I, or -F. In an embodiment, X is independently -Cl. In an embodiment, X is independently -Br. In an embodiment, X is independently -I. In an embodiment, X is independently -F.

[0473] In an embodiment, provided herein is a structure of formula (IC):

[0474]

[0475] or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 8′ 、R 9 、R 10 、R 11 、R 14 、R 19 、X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、B 3 and n are each as defined in the embodiments herein including.

[0476] In an embodiment, provided herein is a structure of formula (ID):

[0477]

[0478] or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof;

[0479] wherein:

[0480] R 12 is independently hydrogen, -C(O)R 12A 、-C(O)OR 12A 、-OR 12A, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0481] R 13 is independently hydrogen, -C(O)R 13A , -C(O)OR 13A , -OR 13A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group;

[0482] Each R 12A and R 13A is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 , -OCHX 2 , -OCH 2 X, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

[0483] R 1 、R 2 、R 3 、R 4 、R 5 、R6 , R 7 , R 11 , R 14 , R 19 , X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , B 3 , Ring A and n are each as defined in the embodiments included herein.

[0484] In an embodiment, R 12 is independently hydrogen, -C(O)R 12A , -C(O)OR 12A , -OR 12A , substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl or 2- to 4-membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl or 5- to 6-membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl), substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl).

[0485] In an embodiment, substituted R 12(e.g., a substituted alkyl, a substituted heteroalkyl, a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, and / or a substituted heteroaryl) is independently substituted by at least one substituent, at least one size-limited substituent, or a lower-level substituent; wherein if the substituted R 12 is independently substituted by a plurality of groups selected from a substituent, a size-limited substituent, and a lower-level substituent; then each substituent, size-limited substituent, and / or lower-level substituent may optionally be different. In an embodiment, when R 12 is independently substituted, then it is substituted by at least one substituent. In an embodiment, when R 12 is independently substituted, then it is substituted by at least one size-limited substituent. In an embodiment, when R 12 is independently substituted, then it is substituted by at least one lower-level substituent.

[0486] In an embodiment, R 12 is independently hydrogen or a substituted or unsubstituted alkyl. In an embodiment, R 12 is independently hydrogen or a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 12 is independently hydrogen. In an embodiment, R 12 is independently an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl). In an embodiment, R 12 is independently a substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl).

[0487] In an embodiment, R 12 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl.

[0488] In an embodiment, R 12Independently is hydrogen or methyl.

[0489] In an embodiment, R 12 Independently is hydrogen. In an embodiment, R 12 Independently is methyl. In an embodiment, R 12 Independently is ethyl. In an embodiment, R 12 Independently is propyl. In an embodiment, R 12 Independently is isopropyl. In an embodiment, R 12 Independently is butyl. In an embodiment, R 12 Independently is isobutyl. In an embodiment, R 12 Independently is tert - butyl. In an embodiment, R 12 Independently is pentyl. In an embodiment, R 12 Independently is isopentyl. In an embodiment, R 12 Independently is hexyl.

[0490] In an embodiment, R 13 Independently is hydrogen, -C(O)R 13A , -C(O)OR 13A , -OR 13A , substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl) or substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size - limited substituent or lower substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10an aryl or phenyl), a substituted (e.g., substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl or 5- to 6-membered heteroaryl).

[0491] In an embodiment, the substituted R 13 (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is independently substituted by at least one substituent, at least one size-limited substituent or a lower substituent; wherein if the substituted R 13 is independently substituted by a plurality of groups selected from substituents, size-limited substituents and lower substituents; then each substituent, size-limited substituent and / or lower substituent may optionally be different. In an embodiment, when R 13 is independently substituted, then it is substituted by at least one substituent. In an embodiment, when R 13 is independently substituted, then it is substituted by at least one size-limited substituent. In an embodiment, when R 13 is independently substituted, then it is substituted by at least one lower substituent.

[0492] In an embodiment, R 13 is independently hydrogen or a substituted or unsubstituted alkyl. In an embodiment, R 13 is independently hydrogen or a substituted (e.g., substituted by a substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 13 is independently hydrogen. In an embodiment, R 13 is independently an unsubstituted alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl). In an embodiment, R 13 is independently a substituted (e.g., substituted by a substituent, size-limited substituent or lower substituent) alkyl (e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl).

[0493] In an embodiment, R 13 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl.

[0494] In an embodiment, R 13 is independently hydrogen or methyl.

[0495] In an embodiment, R 13 is independently hydrogen. In an embodiment, R 13 is independently methyl. In an embodiment, R 13 is independently ethyl. In an embodiment, R 13 is independently propyl. In an embodiment, R 13 is independently isopropyl. In an embodiment, R 13 is independently butyl. In an embodiment, R 13 is independently isobutyl. In an embodiment, R 13 is independently tert-butyl. In an embodiment, R 13 is independently pentyl. In an embodiment, R 13 is independently isopentyl. In an embodiment, R 13 is independently hexyl.

[0496] In an embodiment, each R 12A and R 13A is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 , -OCHX 2 , -OCH 2 X, substituted (e.g., substituted by a substituent, a size-limited substituent, or a lower-level substituent) or unsubstituted alkyl (e.g., C1 -C 8 alkyl, C 1 -C 6 alkyl or C 1 -C 4 alkyl), substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted heteroalkyl (e.g., 2 - to 8 - membered heteroalkyl, 2 - to 6 - membered heteroalkyl or 2 - to 4 - membered heteroalkyl), substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkyl), substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted heterocycloalkyl (e.g., 3 - to 8 - membered heterocycloalkyl, 3 - to 6 - membered heterocycloalkyl or 5 - to 6 - membered heterocycloalkyl), substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted aryl (e.g., C 6 -C 10 aryl, C 10 aryl or phenyl) or substituted (e.g., substituted by a substituent, a size - limited substituent or a lower - level substituent) or unsubstituted heteroaryl (e.g., 5 - to 10 - membered heteroaryl, 5 - to 9 - membered heteroaryl or 5 - to 6 - membered heteroaryl).

[0497] In an embodiment, each R 12A and R 13A is independently substituted by one or more substituents. In an embodiment, each R 12A and R 13A is independently substituted by one or more size - limited substituents. In an embodiment, each R 12A and R 13A is independently substituted by one or more lower - level substituents.

[0498] In an embodiment, each X is independently - Cl, - Br, - I or - F. In an embodiment, X is independently - Cl. In an embodiment, X is independently - Br. In an embodiment, X is independently - I. In an embodiment, X is independently - F.

[0499] In an embodiment, provided herein is a structure of formula (IE):

[0500]

[0501] or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 8′ 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 19 、X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、B 3 and n are each as defined in the embodiments included herein.

[0502] In an embodiment, provided herein is a structure of formula (IF):

[0503]

[0504] or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 8′ 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 19 、X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、Y5 , B 3 and n are each as defined in the embodiments herein included.

[0505] In an embodiment, provided herein is a structure of formula (IG):

[0506]

[0507] or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof;

[0508] wherein

[0509] R 15 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 15A , -NR 15A R 15B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0510] R 16 is independently hydrogen, -C(O)R 16A , -C(O)OR 16A , -OR 16A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

[0511] Each R 15A , R 15B and R 16A is independently hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 , -OCHX 2 , -OCH 2 X, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and

[0512] R 15A and R 15BThe substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0513] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 11 、R 19 、X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、B 3 、Ring A and n are each as defined in the embodiments included herein.

[0514] In an embodiment, R 15 is hydrogen, halogen, ...

Claims

1. An oligonucleotide comprising 50 - 12,000 nucleotides, wherein the 5'-end of the oligonucleotide comprises a structure of formula (I) or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： B 1 and B 3 each independently is a natural, modified or unnatural nucleobase; Each B 2 is independently a natural, modified or unnatural nucleobase; ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted hetero cycloalkylene, a substituted or unsubstituted arylene or a substituted or unsubstituted heteroarylene; X 1 and X 2 each independently is -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-; Y 1 、Y 2 、Y 3 、Y 4 and Y 5 each independently is O, S or Se; R 1 is independently hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 3 is hydrogen, -C(O)R 3A -C(O)OR 3A -OR 3A a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 7 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 19 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 19A , -NR 19A R 19B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 7 and R 19 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 11 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 11 and R 19 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 1A 、R 2A 、R 3A 、R 7A 、R 7B 、R 11A 、R 11B 、R 19A and R 19B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R bonded to the same nitrogen atom 7A and R 7B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 11A and R 11B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 19A and R 19B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each R 101 is independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; m is an integer from 0 to 8; n is an integer from 0 to 3; and each X is independently -Cl, -Br, -I or -F.

2. An oligonucleotide comprising 50 - 12,000 nucleotides, wherein the 5'-end of the oligonucleotide comprises a structure of formula (II): or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： B 1 and B 2 each independently is a natural, modified or unnatural nucleobase; ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted hetero cycloalkylene, a substituted or unsubstituted arylene or a substituted or unsubstituted heteroarylene; X 1 and X 2 each independently is -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-; Y 1 , Y 2 , Y 3 and Y 4 each independently is O, S or Se; R 1 is independently hydrogen, -C(O)R 1A -C(O)OR 1A -OR 1A a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 3 is hydrogen, -C(O)R 3A -C(O)OR 3A -OR 3A a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 7 independently is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 19 is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 19A , -NR 19A R 19B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 7 and R 19 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 11 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 11 and R 19 together with the carbon atom to which it is attached forms a substituted or unsubstituted subcycloalkyl or a substituted or unsubstituted subheterocycloalkyl; Each R 1A 、R 2A 、R 3A 、R 7A 、R 7B 、R 11A 、R 11B 、R 19A and R 19B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R bonded to the same nitrogen atom 7A and R 7B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 11A and R 11B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 19A and R 19B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each R 101 is independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; and each X is independently -Cl, -Br, -I or -F; The condition is R 11 not OH.

3. The oligonucleotide according to claim 1 or 2, wherein the oligonucleotide is prepared by chemical synthesis.

4. The oligonucleotide according to any one of claims 1 to 3, wherein the oligonucleotide comprises 3 or more modified nucleosides at its 3'-end and 2 or more nucleotides linked together by modified internucleotide linkages.

5. The oligonucleotide according to claim 4, wherein the oligonucleotide comprises 3 or more modified nucleosides at its 3'-end.

6. The oligonucleotide according to claim 4, wherein the oligonucleotide comprises 2 or more nucleotides linked together by modified internucleotide linkages at its 3'-end.

7. The oligonucleotide according to any one of claims 1 to 6, wherein the structure of formula (I) or formula (II) comprises one or more removable hydrophobic groups.

8. The oligonucleotide according to any one of claims 1 to 6, wherein the structure of formula (I) or formula (II) comprises one or more non-removable hydrophobic groups.

9. The oligonucleotide according to claim 1, wherein its 5'-end comprises a structure of formula (IA): or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： B 3 is a natural nucleobase; R 4 is independently hydrogen, -C(O)R 4A , -C(O)OR 4A , -OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 5 is independently hydrogen, -C(O)R 5A , -C(O)OR 5A , -OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 6 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 14 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 14A , -NR 14A R 14B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 4A 、R 5A 、R 6A 、R 6B 、R 14B and R 14B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R groups bonded to the same nitrogen atom 6A and R 6B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 14A and R 14B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

10. The oligonucleotide according to claim 1 or 9, wherein its 5'-end comprises a structure of formula (IB): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 forms, together with the carbon atom to which it is attached, a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 which, together with the carbon atom to which it is attached, forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

11. The oligonucleotide according to claim 1 or 9, wherein the 5'-end thereof comprises a structure of formula (IC): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9 is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 which together with the carbon atom to which it is attached forms a substituted or unsubstituted heteroalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R groups bonded to the same nitrogen atom 8A and R 8B substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

12. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (ID): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 4 is independently hydrogen, -C(O)R 4A , -C(O)OR 4A , -OR 4A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 5 is independently hydrogen, -C(O)R 5A , -C(O)OR 5A , -OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 12 and R 13 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 6 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R 12 is independently hydrogen, -C(O)R 12A , -C(O)OR 12A , -OR 12A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 13 is independently hydrogen, -C(O)R 13A , -C(O)OR 13A , -OR 13A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 14 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 14A , -NR 14A R 14B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 4A 、R 5A 、R 6A 、R 6B 、R 12A 、R 13A 、R 14A and R 14B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R bonded to the same nitrogen atom 6A and R 6B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 14A and R 14B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

13. The oligonucleotide according to claim 1 or 12, wherein the 5'-end thereof comprises a structure of formula (IE): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 together with the carbon atom to which it is attached forms a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X、-C(O)OH、-C(O)NH 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H、-NHC=(O)H、-NHC(O)OH、-NHOH、-OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

14. The oligonucleotide according to claim 1 or 12, wherein the 5'-end thereof comprises a structure of formula (IF): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; Each R 9 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 together with the carbon atom to which it is attached forms a substituted or unsubstituted heteroalkylidene; R 10 is hydrogen, a halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 、-OCHCl 2 、-OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 、-SF 5 、a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted subcycloalkyl or a substituted or unsubstituted subheterocycloalkyl; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R groups bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

15. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IG): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 4 is independently hydrogen, -C(O)R 4A , -C(O)OR 4A , -OR 4A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 5 independently is hydrogen, -C(O)R 5A , -C(O)OR 5A , -OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 6 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R 15 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 15A , -NR 15A R 15B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 16 is independently hydrogen, -C(O)R 16A , -C(O)OR 16A , -OR 16A , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 4A 、R 5A 、R 6A 、R 6B 、R 15A 、R 15B and R 16A is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R bonded to the same nitrogen atom 6A and R 6B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 15A and R 15B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

16. The oligonucleotide according to claim 1 or 15, wherein the 5'-end thereof comprises a structure of formula (IH): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 9 or R 8' and R 9 which, together with the carbon atom to which it is attached, forms a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 forms, together with the carbon atom to which it is attached, a substituted or unsubstituted subcycloalkyl or a substituted or unsubstituted subheterocycloalkyl; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R groups bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

17. The oligonucleotide according to claim 1 or 15, wherein the 5'-end thereof comprises a structure of formula (IJ): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 independently is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9 is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 together with the carbon atom to which it is attached forms a substituted or unsubstituted heteroalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

18. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IK): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 6 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A 、-NR 6A R 6B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 14 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 14A 、-NR 14A R 14B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 6A , R 6B , R 14A and R 14B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 6A and R 6B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 14A and R 14B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

19. The oligonucleotide according to claim 1 or 18, wherein the 5'-end thereof comprises a structure of formula (IL): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

20. The oligonucleotide according to claim 1 or 18, wherein the 5'-end thereof comprises a structure of formula (IM) or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 8 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9 is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 which, together with the carbon atom to which it is attached, forms a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

21. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IN): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 6 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A 、-NR 6A R 6B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 15A 、-NR 15A R 15B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 16 are independently hydrogen, -C(O)R 16A 、-C(O)OR 16A 、-OR 16A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 6A , R 6B , R 15A , R 15B and R 16A are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 6A and R 6B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 15A and R 15B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

22. The oligonucleotide according to claim 1 or 21, wherein the 5'-end thereof comprises a structure of formula (IO) or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

23. The oligonucleotide according to claim 1 or 21, wherein the 5'-end thereof comprises a structure of formula (IP): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

24. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IQ): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 4 are independently hydrogen, -C(O)R 4A 、-C(O)OR 4A 、-OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 are independently hydrogen, -C(O)R 5A 、-C(O)OR 5A 、-OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R 6 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A 、-NR 6A R 6B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 12 are independently hydrogen, -C(O)R 12A 、-C(O)OR 12A 、-OR 12A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 13 are independently hydrogen, -C(O)R 13A 、-C(O)OR 13A 、-OR 13A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R 15 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 15A 、-NR 15A R 15B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 4A , R 5A , R 6A , R 6B , R 12A , R 13A , R 15A and R 15B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 6A and R 6B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 15A and R 15B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

25. The oligonucleotide according to claim 1 or 24, wherein the 5'-end thereof comprises a structure of formula (IR): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

26. The oligonucleotide according to claim 1 or 24, wherein the 5'-end thereof comprises a structure of formula (IS): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

27. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IT): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 15 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 15A 、-NR 15A R 15B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 16 are independently hydrogen, -C(O)R 16A 、-C(O)OR 16A 、-OR 16A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 17 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 17A 、-NR 17A R 17B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 are independently hydrogen, -C(O)R 18A 、-C(O)OR 18A 、-OR 18A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 15A , R 15B , R 16A , R 17A , R 17B and R 18A are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 15A and R 15B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 17A and R 17B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

28. The oligonucleotide according to claim 1 or 27, wherein the 5'-end thereof comprises a structure of formula (IU): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

29. The oligonucleotide according to claim 1 or 27, wherein the 5'-end thereof comprises a structure of formula (IV): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

30. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IW): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 14 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 14A 、-NR 14A R 14B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 17 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 17A 、-NR 17A R 17B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 18 are independently hydrogen, -C(O)R 18A 、-C(O)OR 18A 、-OR 18A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 14A , R 14B , R 17A , R 17B and R 18A are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 14A and R 14B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 17A and R 17B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

31. The oligonucleotide according to claim 1 or 30, wherein the 5'-end thereof comprises a structure of formula (IX): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

32. The oligonucleotide according to claim 1 or 30, wherein the 5'-end thereof comprises a structure of formula (IY): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

33. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IZ): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 4 are independently hydrogen, -C(O)R 4A 、-C(O)OR 4A 、-OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 are independently hydrogen, -C(O)R 5A 、-C(O)OR 5A 、-OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R 14 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 , CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 14A 、-NR 14A R 14B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 17 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 17A 、-NR 17A R 17B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 4A , R 5A , R 14A , R 14B , R 17A and R 17B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R bonded to the same nitrogen atom 14A and R 14B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 17A and R 17B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

34. The oligonucleotide according to claim 1 or 33, wherein the 5'-end thereof comprises a structure of formula (IAA): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

35. The oligonucleotide according to claim 1 or 33, wherein the 5'-end thereof comprises a structure of formula (IBB): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

36. The oligonucleotide according to claim 2, wherein the 5'-end thereof comprises a structure of formula (IIA): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 4 are independently hydrogen, -C(O)R 4A 、-C(O)OR 4A 、-OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 are independently hydrogen, -C(O)R 5A 、-C(O)OR 5A 、-OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R 6 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A 、-NR 6A R 6B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 14 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 14A 、-NR 14A R 14B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 4A , R 5A , R 6A , R 6B , R 14B and R 14B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 6A and R 6B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 14A and R 14B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

37. The oligonucleotide according to claim 2 or 36, wherein the 5'-end thereof comprises a structure of formula (IIB): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

38. The oligonucleotide according to claim 2 or 36, wherein the 5'-end thereof comprises a structure of formula (IIC) or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

39. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (ICC): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein: Ring A is a substituted or unsubstituted cycloalkylidene, a substituted or unsubstituted heterocycloalkylidene, a substituted or unsubstituted arylidene or a substituted or unsubstituted heteroarylidene; X 1 and X 2 are independently -O-, -CH 2 -、-CX 2 -、-N(R 101 )-, -BH- or -S-; Y 1 , Y 2 , Y 3 and Y 5 each independently is O, S or Se; R 1 are independently hydrogen, -C(O)R 1A 、-C(O)OR 1A 、-OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 are independently hydrogen, -C(O)R 2A 、-C(O)OR 2A 、-OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R 3 is hydrogen, -C(O)R 3A 、-C(O)OR 3A 、-OR 3A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 4 are independently hydrogen, -C(O)R 4A 、-C(O)OR 4A 、-OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 are independently hydrogen, -C(O)R 5A 、-C(O)OR 5A 、-OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclyl; R 6 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A 、-NR 6A R 6B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 7A 、-NR 7A R 7B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 19 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 19A 、-NR 19A R 19B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 19 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 6B , R 7A , R 7B , R 19A and R 19B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 6A and R 6B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 7A and R 7B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 19A and R 19B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each R 101 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 3; and Each X is independently -Cl, -Br, -I or -F.

40. The oligonucleotide according to claim 1 or 39, wherein the 5'-end thereof comprises a structure of formula (IDD): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

41. The oligonucleotide according to claim 1 or 39, wherein the 5'-end thereof comprises a structure of formula (IEE): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A 、-NR 8A R 8B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8' are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A 、-NR 8'A R 8'B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 8'A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A 、-NR 9A R 9B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)R 9A 、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted heterocycloalkylene group; R 10 It is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cycloalkylene group or a substituted or unsubstituted heterocycloalkylene group; Each R 8A , R 8B , R 8'A , R 8'B , R 9A , R 9B , R 10A and R 10B are independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

42. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IFF): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 4 is independently hydrogen, -C(O)R 4A , -C(O)OR 4A , -OR 4A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 5 is independently hydrogen, -C(O)R 5A , -C(O)OR 5A , -OR 5A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 4 and R 5 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 6 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; Each R 4A 、R 5A 、R 6A and R 6B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; and R groups attached to the same nitrogen atom 6A and R 6B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

43. The oligonucleotide according to claim 1 or 42, wherein the 5'-end thereof comprises a structure of formula (IGG): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 9 is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 which together with the carbon atom to which it is attached forms a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

44. The oligonucleotide according to claim 1 or 42, wherein the 5'-end thereof comprises a structure of formula (IHH): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R 8' is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 9 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 forms, together with the carbon atom to which it is attached, a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 -CBr 3 -CF 3 -CI 3 -CHCl 2 -CHBr 2 -CHF 2 -CHI 2 -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A -NR 10A R 10B -COOH, -CONH 2 -NO 2 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 -NHNH 2 -ONH 2 -NHC(O)NHNH 2 -NHC(O)NH 2 -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 -OCF 3 -OCBr 3 -OCI 3 -OCHCl 2 -OCHBr 2 -OCHI 2 -OCHF 2 -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 -SF 5 a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 forms, together with the carbon atom to which it is attached, a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X、-C(O)OH、-C(O)NH 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H、-NHC=(O)H、-NHC(O)OH、-NHOH、-OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R groups bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

45. The oligonucleotide according to claim 1, wherein the 5'-end thereof comprises a structure of formula (IJJ): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 6 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 6A , -NR 6A R 6B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; and Each R 6A and R 6B independently is hydrogen, -CX 3 , -CHX 2 , -CH 2 X, -C(O)OH, -C(O)NH 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 , -OCHX 2 , -OCH 2 X, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 6A and R 6B substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

46. The oligonucleotide according to claim 1 or 45, wherein the 5'-end thereof comprises a structure of formula (IKK): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; wherein ： R 8 independently is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 9 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 together with the carbon atom to which it is attached forms a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

47. The oligonucleotide according to claim 1 or 45, wherein the 5'-end thereof comprises a structure of formula (ILL): or its enantiomers, mixtures of enantiomers, mixtures of two or more diastereoisomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates or hydrates thereof; R 8 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R 9 independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 together with the carbon atom to which it is attached forms a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X、-C(O)OH、-C(O)NH 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H、-NHC=(O)H、-NHC(O)OH、-NHOH、-OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R groups bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

48. The oligonucleotide according to any one of claims 1 to 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42 or 45, wherein ring A is a substituted or unsubstituted heteroalkylidene.

49. The oligonucleotide according to any one of claims 1 to 48, wherein R 1 is independently hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl.

50. The oligonucleotide according to claim 49, wherein R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or a modified triphenylmethyl.

51. The oligonucleotide according to claim 50, wherein R 1 is independently hydrogen, butyl or 52. The oligonucleotide according to claim 50, wherein R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or a modified trityl group.

53. The oligonucleotide according to any one of claims 1 to 52, wherein R 2 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

54. The oligonucleotide according to claim 53, wherein R 2 is independently hydrogen, methyl, or ethyl.

55. propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or a modified trityl group.

56. The oligonucleotide according to claim 54, wherein R 2 is independently hydrogen, butyl or 57. The oligonucleotide according to claim 54, wherein R 2 is independently hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or a modified trityl group.

58. The oligonucleotide according to any one of claims 1 to 56, wherein R 3 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

59. The oligonucleotide according to claim 57, wherein R 3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl or 4-chlorobenzyl.

60. The oligonucleotide according to claim 58, wherein R 3 is methyl or 4-chlorobenzyl.

61. The oligonucleotide according to any one of claims 9 to 17, 24 to 26, 33 to 44 or 48 to 59, wherein R 4 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

62. The oligonucleotide according to claim 60, wherein R 4 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl or 4-chlorobenzyl.

63. The oligonucleotide according to claim 61, wherein R 4 is independently hydrogen.

64. The oligonucleotide according to any one of claims 9 to 17, 24 to 26, 33 to 44 or 48 to 62, wherein R 5 is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl.

65. The oligonucleotide according to claim 63, wherein R 5 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl or 4-chlorobenzyl.

66. The oligonucleotide according to claim 64, wherein R 5 is independently hydrogen.

67. The oligonucleotide according to any one of claims 9 to 26 or 36 to 65, wherein R 6 is hydrogen, halogen or -NR 6A R 6B .

68. The oligonucleotide according to claim 66, wherein R 6 is hydrogen, -F, -NHMe, -NH 2 or -NMe 2 .

69. The oligonucleotide according to claim 67, wherein R 6 is hydrogen or -NHMe.

70. The oligonucleotide according to claim 68, wherein R 6 is hydrogen.

71. The oligonucleotide according to any one of claims 1 to 69, wherein R 7 is independently hydrogen, halogen or -OR 7A .

72. The oligonucleotide according to claim 70, wherein R 7 is independently a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a butoxy group or a tert-butoxy group.

73. The oligonucleotide according to claim 71, wherein R 7 is independently methoxy.

74. An oligonucleotide according to any one of claims 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47 or 49 to 72, wherein R 8 is independently hydrogen, halogen, -OR 8A or -NHC(O)R 8A .

75. The oligonucleotide according to claim 73, wherein R 8A is independently hydrogen or a substituted or unsubstituted alkyl group.

76. The oligonucleotide according to claim 73 or 74, wherein R 8 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy or tert-butoxy.

77. The oligonucleotide according to claim 75, wherein R 8 is independently hydrogen or a hydroxyl group.

78. An oligonucleotide according to any one of claims 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47 or 49 to 76, wherein R 8 is independently hydrogen, halogen, -OR 8 'A or -NHC(O)R 8'A .

79. The oligonucleotide according to claim 77, wherein R 8'A is independently hydrogen or a substituted or unsubstituted alkyl group.

80. The oligonucleotide according to claim 77 or 78, wherein R 8' is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy or tert-butoxy.

81. The oligonucleotide according to claim 79, wherein R 8' is independently hydrogen or a hydroxyl group.

82. The oligonucleotide according to any one of claims 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47 or 49 to 80, wherein R 9 is independently hydrogen, halogen, -OR 9A or -NHC(O)R 9A .

83. The oligonucleotide according to claim 81, wherein R 9A is independently hydrogen or a substituted or unsubstituted alkyl group.

84. The oligonucleotide according to claim 81 or 82, wherein R 9 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy or tert-butoxy.

85. The oligonucleotide according to claim 83, wherein R 9 is independently methoxy.

86. An oligonucleotide according to any one of claims 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47 or 49 to 84, wherein R 10 is hydrogen. The oligonucleotide according to any one of claims 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47 or 49 to 84, wherein R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached form a substituted or unsubstituted heterocycloalkylidene.

88. The oligonucleotide according to claim 86, wherein R 8 and R 10 or R 8 ' and R 10 together with the carbon atom to which it is attached form a locked nucleic acid (LNA).

89. The oligonucleotide according to any one of claims 1 to 87, wherein R 19 is independently hydrogen.

90. The oligonucleotide according to claim 88, wherein R 7 and R 19 together with the carbon atom to which they are attached form a locked nucleic acid (LNA).

91. The oligonucleotide according to any one of claims 1 to 38 or 48 to 89, wherein R 11 is independently hydrogen, halogen or -OR 7A .

92. The oligonucleotide according to claim 90, wherein R 11 is independently methoxy, ethoxy, propoxy, butoxy or tert-butoxy.

93. The oligonucleotide according to claim 91, wherein R 11 is independently methoxy.

94. The oligonucleotide according to any one of claims 12 to 14, 24 to 26 or 48 to 92, wherein R 12 is independently hydrogen or a substituted or unsubstituted alkyl group.

95. The oligonucleotide according to claim 93, wherein R 12 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl.

96. The oligonucleotide according to claim 94, wherein R 12 is independently hydrogen or methyl.

97. The oligonucleotide according to any one of claims 12 to 14, 24 to 26 or 48 to 95, wherein R 13 is independently hydrogen or a substituted or unsubstituted alkyl group.

98. The oligonucleotide according to claim 96, wherein R 13 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl.

99. The oligonucleotide according to claim 97, wherein R 13 is independently hydrogen or methyl.

100. The oligonucleotide according to any one of claims 9 to 14, 18 to 20, 30 to 38 or 48 to 98, wherein R 14 is hydrogen, a halogen or -NR 14A R 14B .

101. The oligonucleotide according to claim 99, wherein R 14 is hydrogen, -F, -NHMe, -NH 2 or -NMe 2 .

102. The oligonucleotide according to claim 100, wherein R 14 is hydrogen or -NH 2 .

103. The oligonucleotide according to any one of claims 15 to 17, 21 to 29 or 48 to 101, wherein R 15 is hydrogen, a halogen or -NR 15A R 15B .

104. The oligonucleotide according to claim 102, wherein R 15 is hydrogen, -F, -NHMe, -NH 2 or -NMe 2 .

105. The oligonucleotide according to claim 103, wherein R 15 is hydrogen, -NHMe or -NH 2 .

106. The oligonucleotide according to claim 104, wherein R 15 is hydrogen.

107. An oligonucleotide according to any one of claims 15 to 17, 21 to 23, 27 to 29 or 48 to 105, wherein R 16 is hydrogen or a substituted or unsubstituted alkyl group.

108. The oligonucleotide according to claim 106, wherein R 16 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl.

109. The oligonucleotide according to claim 107, wherein R 16 is hydrogen.

110. The oligonucleotide according to any one of claims 27 to 35 or 48 to 108, wherein R 17 is hydrogen, halogen or -NR 17A R 17B .

111. The oligonucleotide according to claim 109, wherein R 17 is hydrogen, -F, -NHMe, -NH 2 or -NMe 2 .

112. The oligonucleotide according to claim 110, wherein R 17 is hydrogen, methyl, -NHMe or -NH 2 .

113. The oligonucleotide according to claim 111, wherein R 17 is hydrogen.

114. The oligonucleotide according to any one of claims 27 to 32 or 48 to 112, wherein R 18 is hydrogen or a substituted or unsubstituted alkyl group.

115. The oligonucleotide according to claim 113, wherein R 18 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl.

116. The oligonucleotide according to claim 114, wherein R 18 is hydrogen.

117. The oligonucleotide according to any one of claims 1 to 115, wherein X 1 is -O-, -CH 2 - or -CX 2 -.

118. The oligonucleotide according to claim 116, wherein X 1 is -O-, -CH 2 -, or -CF 2 -.

119. The oligonucleotide according to claim 117, wherein X 1 is -O-.

120. The oligonucleotide according to any one of claims 1 to 118, wherein X 2 is -O-, -CH 2 -, -CX 2 -, -N(R 101 ), or -BH-.

121. The oligonucleotide according to claim 119, wherein X 2 is -O-, -CH 2 -, -CF 2 -, -NH- or -BH-.

122. The oligonucleotide according to claim 120, wherein X 2 is -O-. An oligonucleotide according to any one of claims 1 to 38 or 48 to 121, wherein Y 1 , Y 2 , Y 3 and Y 4 are each independently O or S.

124. The oligonucleotide according to claim 122, wherein Y 1 , Y 2 , Y 3 and Y 4 are each independently O.

125. The oligonucleotide according to any one of claims 1, 3 to 35 or 48 to 123, wherein Y 5 is O or S.

126. The oligonucleotide according to claim 124, wherein Y 5 is O.

127. The oligonucleotide according to any one of claims 1 to 125, wherein n is 1 or 2.

128. The oligonucleotide according to claim 126, wherein n is 1.

129. The oligonucleotide according to claim 1, wherein m is 0 or 1.

130. The oligonucleotide according to any one of claims 1, 3 to 35 or 48 to 128, wherein B 3 is a natural nucleobase.

131. An oligonucleotide having a compound with the following structure at its 5'-end: or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

132. An oligonucleotide having a compound with the following structure at its 5'-end: or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

133. An oligonucleotide having a compound with the following structure at its 5'-end: or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof.

134. The oligonucleotide according to any one of claims 1 to 132, wherein the pharmaceutically acceptable salt is a sodium salt, a lithium salt or a potassium salt.

135. The oligonucleotide according to claim 133, wherein the pharmaceutically acceptable salt is a sodium salt.

136. The oligonucleotide according to claim 7, wherein the one or more removable hydrophobic groups are linked to the G nucleobase of the structure of formula (I) or formula (II) and / or ring A and / or nucleobase B 1 linked 137. The oligonucleotide according to claim 135, wherein the one or more removable hydrophobic groups are linked to the G nucleobase of the structure of formula (I) or formula (II). linked 138. The oligonucleotide according to claim 135, wherein the one or more removable hydrophobic groups are linked to ring A of the structure of formula (I) or formula (II).

139. The oligonucleotide according to claim 137, wherein the one or more removable hydrophobic groups are linked to ring A, and wherein ring A is a ribose ring.

140. The oligonucleotide according to claim 137, wherein the one or more removable hydrophobic groups are linked to ring A, and wherein ring A is a morpholine ring.

141. The oligonucleotide according to claim 7 or any one of claims 135 to 139, wherein each removable hydrophobic group is not a photocleavable hydrophobic group.

142. The oligonucleotide according to claim 140, wherein each removable hydrophobic group is a removable purification handle.

143. The oligonucleotide according to claim 7, wherein each removable hydrophobic group is independently a silyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group.

144. The oligonucleotide according to claim 142, wherein each removable hydrophobic group is independently a silyl group, trityl, a substituted ether, fluorenylmethoxycarbonyl (Fmoc), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), dimethoxytrityl (DMT), monomethoxytrityl (MMT) or a modified trityl.

145. The oligonucleotide according to claim 143, wherein each removable hydrophobic group is independently MMT.

146. The oligonucleotide according to claim 8, wherein the one or more non-removable hydrophobic groups are linked to the G nucleobase of the structure of formula (I) or formula (II) and / or ring A.

147. The oligonucleotide according to claim 145, wherein the one or more non-removable hydrophobic groups are linked to the G nucleobase of the structure of formula (I) or formula (II). linked 148. The oligonucleotide according to claim 145, wherein the one or more non-removable hydrophobic groups are linked to ring A of the structure of formula (I) or formula (II).

149. The oligonucleotide according to claim 147, wherein the one or more non-removable hydrophobic groups are linked to ring A, and wherein ring A is a ribose ring.

150. The oligonucleotide according to claim 147, wherein the one or more non-removable hydrophobic groups are linked to ring A, and wherein ring A is a morpholine ring.

151. The oligonucleotide according to claim 8 or any one of claims 145 to 149, wherein each non-removable hydrophobic group is a non-removable purification handle.

152. The oligonucleotide according to claim 8, wherein each non-removable hydrophobic group is independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group.

153. The oligonucleotide according to claim 151, wherein each non-removable hydrophobic group is independently ethyl, propyl, butyl, 4-chlorobenzyl, benzyl, isopropyl or acetyl.

154. The oligonucleotide according to claim 8, wherein the one or more non-removable hydrophobic groups are linked to the nucleobase B of the structure of formula (I) or formula (II). 1 linked 155. The oligonucleotide according to claim 153, wherein each non-removable hydrophobic group is independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group.

156. The oligonucleotide according to claim 154, wherein each non-removable hydrophobic group is independently a substituted or unsubstituted alkyl group.

157. The oligonucleotide according to claim 155, wherein each non-removable hydrophobic group is independently ethyl, propyl, butyl, isopropyl or acetyl.

158. The protected 5'-capped oligonucleotide according to claim 1, which is prepared by the reaction of a compound of formula (III): or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: ring A is a substituted or unsubstituted subcycloalkyl group, a substituted or unsubstituted subheterocycloalkyl group, a substituted or unsubstituted subaryl group or a substituted or unsubstituted subheteroaryl group; X 1 independently is -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-; Y 1 and Y 2 each independently is O, S or Se; R 1 is independently hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 3 is hydrogen, -C(O)R 3A -C(O)OR 3A -OR 3A a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 1A 、R 2A and R 3A is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; Each R 101 is independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and each X is independently -Cl, -Br, -I or -F; and a 5'-phosphate oligonucleotide 159. The protected 5'-capped oligonucleotide according to claim 10, which is prepared by the reaction of a compound of formula (IIIA): or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereoisomers, a tautomer, a mixture of two or more tautomers or an isotopic variant; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein ： R 8 independently is hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; R 8' independently is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 8'A , -NR 8'A R 8'B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 8'A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9 is independently hydrogen, a halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or R 8 and R 9 or R 8' and R 9 which together with the carbon atom to which it is attached forms a substituted or unsubstituted heterocycloalkylidene; R 10 is hydrogen, a halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 10A 、-NR 10A R 10B 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 、-OCHCl 2 、-OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 、-SF 5 、a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; or R 8 and R 10 or R 8' and R 10 together with the carbon atom to which it is attached forms a substituted or unsubstituted cycloalkylidene or a substituted or unsubstituted heterocycloalkylidene; Each R 8A 、R 8B 、R 8'A 、R 8'B 、R 9A 、R 9B 、R 10A and R 10B is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X、-C(O)OH、-C(O)NH 2 、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H、-NHC=(O)H、-NHC(O)OH、-NHOH、-OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; R bonded to the same nitrogen atom 8A and R 8B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 8'A and R 8'B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 9A and R 9B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and R 10A and R 10B substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; and a 5'-phosphate oligonucleotide 160. The protected 5'-capped oligonucleotide according to claim 11, which is prepared by the reaction of a compound of formula (IIIB): or its enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a 5'-phosphate oligonucleotide 161. The protected 5'-capped oligonucleotide according to any one of claims 157 to 159, wherein the 5'-phosphate oligonucleotide is prepared by chemical synthesis.

162. A 5'-capped oligonucleotide, which is prepared by removing the protecting group of the protected 5'-capped oligonucleotide according to claim 7 or any one of claims 157 to 159.

163. The oligonucleotide according to claim 161, which is substantially free of enzymatic by-products.

164. A composition, which comprises the chemically synthesized oligonucleotide according to claim 160, wherein the composition comprises less than 1% by weight of oligonucleotides whose 5'-ends do not contain the structure of formula (I) or formula (II).

165. A composition, which comprises the chemically synthesized oligonucleotide according to claim 160, wherein the composition comprises less than 0.5% by weight of oligonucleotides whose 5'-ends do not contain the structure of formula (I) or formula (II).

166. A composition, which comprises the chemically synthesized oligonucleotide according to claim 160, wherein the composition comprises less than 0.25% by weight of oligonucleotides whose 5'-ends do not contain the structure of formula (I) or formula (II).

167. A composition, which comprises the chemically synthesized oligonucleotide according to claim 160, wherein the composition comprises less than 0.1% by weight of oligonucleotides whose 5'-ends do not contain the structure of formula (I) or formula (II).

168. A composition, which comprises the chemically synthesized oligonucleotide according to claim 160, wherein the composition comprises less than 0.05% by weight of oligonucleotides whose 5'-ends do not contain the structure of formula (I) or formula (II).

169. A composition, which comprises the chemically synthesized oligonucleotide according to claim 160, wherein the composition is substantially free of oligonucleotides whose 5'-ends do not contain the structure of formula (I) or formula (II).

170. A composition, which comprises the chemically synthesized oligonucleotide according to claim 160, wherein the composition is substantially free of enzymatic by-products.

171. A composition, which comprises (a) more than 90% of the 5'-capped oligonucleotide according to claim 161; (b) less than 10% of the 5'-capped oligonucleotide according to claim 7 or any one of claims 157 to 160; and optionally (c) less than 1% of oligonucleotides whose 5'-ends do not contain the structure of formula (I) or formula (II).

172. A composition comprising (a) more than 95% of the 5'-capped oligonucleotide according to claim 161; (b) less than 5% of the 5'-capped oligonucleotide according to any one of claims 7 or 157 to 160; and optionally (c) less than 1% of an oligonucleotide whose 5'-end does not comprise the structure of formula (I) or formula (II).

173. A method for preparing an oligonucleotide comprising 50 - 12000 nucleotides, the 5'-end of the oligonucleotide comprising the structure of formula (I): or the structure of formula (II): or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; The method comprising (a) reacting: an imidazolide of formula (III) or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein: Ring A is a substituted or unsubstituted cycloalkylidene, a substituted or unsubstituted heterocycloalkylidene, a substituted or unsubstituted arylidene or a substituted or unsubstituted heteroarylidene; X 1 independently is -O-, -CH 2 -, -CX 2 -, -N(R 101 )-, -BH- or -S-; Y 1 and Y 2 each independently is O, S or Se; R 1 independently is hydrogen, -C(O)R 1A , -C(O)OR 1A , -OR 1A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 2 is independently hydrogen, -C(O)R 2A , -C(O)OR 2A , -OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 1 and R 2 together with the nitrogen atom to which it is attached form a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heterocyclic group; R 3 is hydrogen, -C(O)R 3A -C(O)OR 3A -OR 3A a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 1A 、R 2A and R 3A is independently hydrogen, -CX 3 、-CHX 2 、-CH 2 X, -C(O)OH, -C(O)NH 2 、-CN, -OH, -NH 2 、-COOH, -CONH 2 、-NO 2 、-SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC=(O)NHNH 2 、-NHC=(O)NH 2 、-NHSO 2 H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX 3 、-OCHX 2 、-OCH 2 X, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group; Each R 101 is independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -N 3 , -SF 5 , a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each X is independently -Cl, -Br, -I or -F; and a 5'-phosphate oligonucleotide and (b) optionally removing the removable hydrophobic group.

174. The method according to claim 172, wherein the 5'-capped oligonucleotide is prepared by chemical synthesis.

175. The oligonucleotide according to any one of claims 1 to 162, wherein the oligonucleotide comprises less than 200 nucleotides.

176. The oligonucleotide according to any one of claims 1 to 162, wherein the oligonucleotide comprises less than 150 nucleotides.

177. The oligonucleotide according to any one of claims 1 to 162, wherein the oligonucleotide comprises less than 100 nucleotides.

178. The oligonucleotide according to any one of claims 1 to 162, wherein the oligonucleotide comprises less than 75 nucleotides.

179. The oligonucleotide according to any one of claims 1 to 162, wherein the oligonucleotide comprises about 50 to about 100 nucleotides.

180. An oligonucleotide according to any one of claims 1 to 162 or 174 to 178, wherein R 1 , R 2 and R 3 are each independently a removable hydrophobic group.

181. The oligonucleotide according to claim 179, wherein R 1 is independently a removable hydrophobic group.

182. The oligonucleotide according to claim 179, wherein R 2 is independently a removable hydrophobic group.

183. The oligonucleotide according to claim 179, wherein R 3 is a removable hydrophobic group.

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