An efficient method for producing highly purified 5'-capped oligonucleotides

Abstract

Described herein are chemically synthesized, stabilized, and highly pure 5'-capped oligonucleotides. Additionally, described herein are methods for producing and using the oligonucleotides. Described herein are methods for producing chemically synthesized, stabilized, and highly pure oligonucleotides containing a cap analog at the 5'-terminus. Further, described herein are chemically synthesized, stabilized, and highly pure oligonucleotides containing a cap analog at the 5'-terminus that can be produced by the disclosed methods.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 401,544, filed August 26, 2022, U.S. Provisional Application No. 63 / 414,361, filed October 7, 2022, and U.S. Provisional Application No. 63 / 430,987, filed December 7, 2022, the disclosures of all of which are incorporated by reference herein in their entireties.

[0002] Technical Field FIELD OF THE INVENTION The field of the invention relates to chemically synthesized, highly purified, and stabilized 5'-capped oligonucleotides, as well as methods of making and using said 5'-capped oligonucleotides. [Background technology]

[0003] background In vitro transcribed messenger RNA (mRNA) has numerous in vivo applications, including vaccination (administering mRNA encoding a specific antigen(s) to induce protective immunity in a patient), cell therapy (transfecting mRNA into cells ex vivo to alter the phenotype or function of the cells and then delivering these altered cells to a patient), or replacement therapy (administering mRNA encoding a therapeutic protein to a patient).

[0004] The main structural element of mRNA molecules utilized in vivo includes a cap structure at the 5' end of the mRNA. Naturally occurring cap structures consist of 7-methylguanosine ( ) linked via a 5'- to 5'-triphosphate chain at the 5' end of the mRNA molecule. 7m G or m7 The cap must be present in order for mRNA to retain its template activity for protein synthesis. The chemical structure of the cap can increase translation efficiency within the cell. Therefore, an effective cap structure is essential.

[0005] Traditionally, 5'-capped mRNA has been prepared using enzymatic methods. Non-enzymatic methods for producing mRNA are potentially more cost-effective and easier to scale up. However, producing highly pure and stable synthetic mRNA, especially 5'-capped mRNA of 40 or more bases, presents technical challenges.

[0006] Therefore, there is a need to develop a robust, non-enzymatic method that is amenable to scalability for preparing stable 5'-capped mRNA at high purity levels. Summary of the Invention [Means for solving the problem]

[0007] overview Described herein are methods for producing chemically synthesized, stabilized, highly pure oligonucleotides containing a cap analog at the 5' end. Further described herein are chemically synthesized, stabilized, highly pure oligonucleotides containing a cap analog at the 5' end that can be produced by the disclosed methods.

[0008] In one aspect, the present disclosure provides a method for converting a 5'-phosphate-oligonucleotide into a modified Im-m oligonucleotide containing a cleavable hydrophobic moiety that can be removed after the reaction. 7 This provides an efficient method for producing 5'-capped oligonucleotides, including reacting them with GDP. For example, the hydrophobic group can be modified with a 5'-phosphate-oligonucleotide and an Im-m modified oligonucleotide. 7 The product generated from the reaction with GDP can be removed after purification. Alternatively, the present disclosure provides a method for cleaving a 5'-phosphate-oligonucleotide by cleaving a modified Im-m oligonucleotide containing a non-cleavable hydrophobic moiety. 7 It provides an efficient method for generating 5'-capped oligonucleotides, including reaction with GDP, which allows for efficient translation.

[0009] The present disclosure further provides modified Im-m oligonucleotides that can react with 5'-phosphate-oligonucleotide molecules to produce 5'-capped oligonucleotide molecules. 7 In some embodiments, Im-m GDP compounds are provided. 7 The GDP is modified at the 2' and / or 3' and / or N2 and / or N7 positions (in any combination) with either removable or non-removable hydrophobic group(s). 7 The 2' and / or 3' positions of GDP are modified with removable hydrophobic groups. 7 The 2' and / or 3' positions of GDP are modified with non-removable hydrophobic groups. 7 The N7-methylated GDP moiety of the GDP is modified with a removable hydrophobic group. 7 The N7-methylated GDP moiety of the GDP is modified with a non-removable hydrophobic group. 7 Both the 2' position of GDP and the N7-methylated GDP moiety are modified with removable hydrophobic groups. 7 Both the 2' position of the GDP and the N7-methylated GDP moiety are modified with non-removable hydrophobic groups. 7 Both the 3' position of the GDP and the N7-methylated GDP moiety are modified with removable hydrophobic groups. 7 Both the 3' position of GDP and the N7-methylated GDP moiety are modified with non-removable hydrophobic groups.

[0010] As disclosed herein, modified Im-m 7After reaction of the GDP compound with the 5'-phosphate-oligonucleotide molecule, a 5'-capped oligonucleotide bearing one or more removable or non-removable hydrophobic groups is produced. The 5'-capped oligonucleotide molecule bearing one or more hydrophobic groups can then be easily separated from impurities, including uncapped oligonucleotide molecules, in the reaction mixture. In some embodiments, one or more hydrophobic groups can be chemically removed from the purified 5'-capped oligonucleotide to produce a highly pure, readily translatable 5'-capped oligonucleotide. In other embodiments, one or more hydrophobic groups can be left on the 5'-capped oligonucleotide to produce a highly pure, readily translatable 5'-capped oligonucleotide.

[0011] In one aspect, provided herein is an oligonucleotide comprising 50 to 12,000 nucleotides, the 5' end of which comprises a group represented by formula (I): [ka] 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, During the ceremony, B 1 and B 3 are each independently a natural, modified, or unnatural nucleoside base; Each B 2 are independently a natural, modified, or unnatural nucleoside base; Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-; Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se; R 1 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 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 they are attached form a substituted or unsubstituted heteroaryl or 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; Each R 7 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 7A , -NR 7A R 7B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 19A , -NR 19A R 19B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R 11are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 11 and R 19 together with the carbon atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A and R 19Bare independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 bonded to the same nitrogen atom 7A and R 7B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 11A and R 11B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 19A and R 19B The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each R 101are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O) OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; 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. Here, and throughout this disclosure, [ka] indicates the point of attachment of the structure to the remainder of the oligonucleotide (eg, the body and the 3' end).

[0012] In one aspect, provided herein is an oligonucleotide comprising 50 to 12,000 nucleotides, the 5' end of which comprises a group represented by formula (II): [ka] 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, During the ceremony, B 1 and B 2are each independently a natural, modified, or unnatural nucleoside base; Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-; Y 1 , Y 2 , Y 3 , and Y 4 are each independently O, S, or Se; R 1 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 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 they are attached form a substituted or unsubstituted heteroaryl or 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 7 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 19A , -NR 19A R 19B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R 11 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 11 and R 19together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A and R 19B are independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 bonded to the same nitrogen atom 7A and R 7B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 11A and R 11B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 19A and R 19B The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each R 101are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O) OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; However, R 11 is not OH.

[0013] The disclosed methods can also be used to prepare translatable 5'-capped mRNA molecules with site-specific modifications to the 5'-capped mRNA molecule. These site-specific modifications have the potential to enhance translational activity and reduce immunogenicity. In some embodiments, provided herein are oligonucleotides described herein, wherein the oligonucleotides are prepared by chemical synthesis. In some embodiments, provided herein are oligonucleotides described herein, wherein the oligonucleotides comprise three or more modified nucleosides at their 3'-end and two or more nucleotides linked together by modified internucleotide linkages. In some embodiments, provided herein are oligonucleotides described herein, wherein the oligonucleotides comprise three or more modified nucleosides at their 3'-end. In some embodiments, provided herein are oligonucleotides described herein, wherein the oligonucleotides comprise two or more nucleotides linked together by modified internucleotide linkages at their 3'-end. In some embodiments, provided herein are oligonucleotides described herein, wherein the structure of Formula (I) or Formula (II) comprises one or more removable hydrophobic groups. In some embodiments, provided herein are oligonucleotides as described herein, wherein the structure of Formula (I) or Formula (II) comprises one or more non-removable hydrophobic groups. In some embodiments, provided herein are oligonucleotides as described herein, wherein the pharmaceutically acceptable salt is a sodium salt, a lithium salt, or a potassium salt. In some embodiments, provided herein are oligonucleotides as described herein, wherein the pharmaceutically acceptable salt is a sodium salt.

[0014] In some embodiments, R 1 , R 2 , and R 3are each independently a removable hydrophobic group. In some embodiments, R 1 are independently removable hydrophobic groups. In some embodiments, R 2 are independently removable hydrophobic groups. In some embodiments, R 3 is independently a removable hydrophobic group.

[0015] In one embodiment, the 5' end comprises: [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0016] In one embodiment, the 5' end comprises: [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Provided herein is an oligonucleotide comprising:

[0017] In one embodiment, the 5' end comprises: [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0018] In one aspect, provided herein is a protected 5' capped oligonucleotide as described herein, which has the formula (III): [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [In the formula, Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X 1 -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-; Y 1 and Y 2 are each independently O, S, or Se; R 1 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 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 2together with the nitrogen atom to which they are attached form a substituted or unsubstituted heteroaryl or 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; Each R 1A , R 2A , and R 3A are independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 101are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)O H, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 each X is independently -Cl, -Br, -I, or -F. 5'-phosphate-oligonucleotide [ka] It is prepared by reaction with

[0019] In some embodiments, provided herein are protected 5'-capped oligonucleotides described herein prepared by chemical synthesis. In some embodiments, provided herein are 5'-capped oligonucleotides prepared by removing the protecting group(s) of a protected 5'-capped oligonucleotide described herein. In some embodiments, the 5'-capped oligonucleotides described herein are substantially free of enzymatic by-products.

[0020] In one aspect, provided herein are compositions comprising chemically synthesized oligonucleotides described herein, wherein the compositions comprise less than 1%, less than 0.5%, less than 0.25%, less than 0.1%, or less than 0.05% by weight of oligonucleotides whose 5'-terminus does not comprise a structure of Formula (I) or Formula (II). In some embodiments, provided herein are compositions comprising chemically synthesized oligonucleotides described herein, wherein the compositions are substantially free of oligonucleotides whose 5'-terminus does not comprise a structure of Formula (I) or Formula (II). In some embodiments, provided herein are compositions comprising chemically synthesized oligonucleotides described herein, wherein the compositions are substantially free of enzyme by-products.

[0021] In one aspect, provided herein is a composition comprising: (a) greater than 90% 5'-capped oligonucleotides that are free of protecting groups, (b) less than 10% 5'-capped oligonucleotides that have protecting group(s), and optionally (c) less than 1% of oligonucleotides whose 5'-terminus does not contain a structure of Formula (I) or Formula (II). In one aspect, provided herein is a composition comprising: (a) greater than 95% 5'-capped oligonucleotides that are free of protecting groups, (b) less than 5% 5'-capped oligonucleotides that have protecting group(s), and optionally (c) less than 1% of oligonucleotides whose 5'-terminus does not contain a structure of Formula (I) or Formula (II).

[0022] In one aspect, provided herein is a process for preparing an oligonucleotide comprising 50 to 12,000 nucleotides, the 5' end of which comprises a group represented by formula (I): [ka] or formula (II) [ka]

[0023] or the structure of 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;

[0024] (a) Formula (III) [ka] 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 [In the formula, Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X 1 -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-; Y 1 and Y 2 are each independently O, S, or Se; R 1 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 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 they are attached form a substituted or unsubstituted heteroaryl or 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; Each R 1A , R 2A , and R 3A are independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 101are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O) OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 X is independently -Cl, -Br, -I, or -F. , 5'-phosphate-oligonucleotide [ka] [ka] and reacting with (b) removing any removable hydrophobic groups as needed Includes.

[0025] In another aspect, 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 (i.e., number of nucleotide bases) of the mRNA. In some embodiments, the 5'-capped mRNA produced according to the methods of the present disclosure can be ligated to another RNA molecule containing at least about 500 nucleotide bases and up to 12,000 nucleotide bases. In some embodiments, the 5'-capped mRNA produced according to the methods of the present disclosure can be ligated to another RNA molecule containing at least about 500 nucleotide bases and up to 8,000 nucleotide bases.

[0026] In some embodiments, the 5'-capped mRNA transcript and the second (uncapped) RNA transcript are enzymatically ligated. An RNA ligase catalyzes the formation of a 3'→5' phosphodiester bond between the 3'-OH group of the capped mRNA and the 5'-phosphate group of 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) transcript can be ligated by a Click reaction.

[0027] In some embodiments, the ligation methods disclosed herein (e.g., RNA ligase-mediated ligation or click ligation) can generate hybrid RNA transcripts that have modified (i.e., non-natural) nucleosides or modified internucleoside linkages at the 5' end of the transcript and unmodified (i.e., naturally occurring) nucleosides containing phosphodiester linkages at the 3' end of the transcript.

[0028] In some embodiments, the first 50-150 nucleotide bases of a transcript (including a 5' cap) are generated using the synthetic methods disclosed herein and then ligated to a longer transcript generated by in vitro transcription. The longer transcript will contain naturally occurring nucleotide bases and a phosphodiester backbone. However, 5'-capped RNA transcripts generated according to this disclosure may contain at least one modified nucleoside and / or at least one modified internucleoside linkage. [Brief explanation of the drawings]

[0029] [Figure 1A] Figure 1A shows the IP-RP HPLC chromatogram of Wasabi mRNA capped with m7G3'OMepppm6A2'OMepG (A-control) (top trace), the IP-RP HPLC chromatogram of Wasabi mRNA capped with N7-(4-chlorobenzyl)G3'OMepppm6A2'OMepG (A-1) (middle trace), and the IP-RP HPLC chromatogram of the co-injection of Wasabi mRNA capped with m7G3'OMepppm6A2'OMepG (A-control) and N7-(4-chlorobenzyl)G3'OMepppm6A2'OMepG (A-1) (bottom trace).

[0030] [Figure 1B]Figure 1B shows the IP-RP HPLC chromatogram of Wasabi mRNA capped with m7G3'OMepppm6A2'OMepG (A-control) (top trace), the IP-RP HPLC chromatogram of Wasabi mRNA capped with m7,N2-butylG3'OMepppm6A2'OMepG (A-2) (middle trace), and the IP-RP HPLC chromatogram of the co-injection of Wasabi mRNA capped with m7G3'OMepppm6A2'OMepG (A-control) and m7,N2-butylG3'OMepppm6A2'OMepG (A-2) (bottom trace).

[0031] [Figure 1C] Figure 1C shows the IP-RP HPLC chromatogram of FLuc mRNA capped with m7G3'OMepppm6A2'OMepG (A-control) (top trace), the IP-RP HPLC chromatogram of FLuc mRNA capped with m7,N2-butylG3'OMepppm6A2'OMepG (A-2) (middle trace), and the IP-RP HPLC chromatogram of the co-injection of FLuc mRNA capped with m7G3'OMepppm6A2'OMepG (A-control) and m7,N2-butylG3'OMepppm6A2'OMepG (A-2) (bottom trace).

[0032] [Figure 2] Figure 2 is a bar graph showing the translation of mRNA encoding mWasabi with different cap analogs 24 hours after transfection (Figure 2A: HEK293T cells; Figure 2B: HeLa cells).

[0033] [Figure 3-1]Figure 3A shows an IP-RP HPLC chromatogram of a 10-mer oligo (SEQ ID NO: 2) capped with compound 9 (oligonucleotide A-5). Figure 3B shows an LCMS chromatogram of an HPLC fraction containing the capped 10-mer oligo (the cap contains the removable hydrophobic group MMT). [Figure 3-2] Same as above.

[0034] [Figure 4-1] Figure 4A shows an IP-RP HPLC chromatogram of the 10-mer oligo (SEQ ID NO: 2) (oligonucleotide A-6) after capping with compound 9 and removal of MMT. Figure 4B shows an LCMS chromatogram of the HPLC fraction containing the capped 10-mer oligo (with MMT removed from the cap). [Figure 4-2] Same as above.

[0035] [Figure 5-1] Figure 5A shows an IP-RP HPLC chromatogram of a 100-mer oligo (SEQ ID NO: 1) capped with compound 9 (oligonucleotide A-3). Figure 5B shows an LCMS chromatogram of an HPLC fraction containing the capped 100-mer oligo (the cap contains the removable hydrophobic group MMT).

[0036] [Figure 5-2] Same as above. [Figure 6-1] Figure 6A shows an IP-RP HPLC chromatogram of a modified 80-mer oligo (SEQ ID NO: 7) (oligonucleotide A-11) capped with compound 9. Figure 6B shows an LCMS chromatogram of an HPLC fraction containing the capped modified 80-mer oligo (the cap contains the removable hydrophobic group MMT). [Figure 6-2] Same as above.

[0037] [Figure 7-1]Figure 7A shows an IP-RP HPLC chromatogram of a modified 90-mer oligo (SEQ ID NO: 5) capped with compound 9 (oligonucleotide A-8). Figure 7B shows an LCMS chromatogram of an HPLC fraction containing the capped modified 90-mer oligo (the cap contains the removable hydrophobic group MMT). [Figure 7-2] Same as above.

[0038] [Figure 8-1] Figure 8 shows LCMS chromatograms of the unmodified crude 90mer oligo (SEQ ID NO: 4) after digestion with RNAse at t = 0 (Figure 8A), t = 2 hours (Figure 8B), and t = 4 hours (Figure 8C). [Figure 8-2] Same as above. [Figure 8-3] Same as above.

[0039] [Figure 9-1] Figure 9 shows LCMS chromatograms of the modified crude 90mer oligo (SEQ ID NO: 5) after digestion with RNAse at t=0 (Figure 9A), t=2 hours (Figure 9B), and t=4 hours (Figure 9C). [Figure 9-2] Same as above. [Figure 9-3] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0040] Detailed Description The following description provides various examples of the method of the present invention. The specific examples are not intended to define the scope of the method. Rather, they are non-limiting exemplary methods. This description should be read from the perspective of a person skilled in the art, and therefore does not necessarily include information that is known to a person skilled in the art.

[0041] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, a reference to "a transcript" or "the transcript" may include a plurality of transcripts.

[0042] "Or" is used in its inclusive sense, ie, equivalent to "and / or," unless the context clearly dictates otherwise.

[0043] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better illustrate the invention and does not limit the scope of the invention unless otherwise specified.

[0044] The terms "may," "might," "could," and "could be," and related terms, unless otherwise clearly indicated by context, are intended to convey that the subject matter involved is of necessity (i.e., the subject matter is present in some instances and absent in other instances), rather than to refer to the ability or probability of the subject matter.

[0045] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better describe the invention and does not limit the scope of the invention unless otherwise specified. I. Definition

[0046] As used herein, the term "about" refers to a range of values ​​that includes the specified value that one of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, about refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range that extends + / - 10% of the specified value. In some embodiments, about includes the specified value.

[0047] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to standard chemical valency rules known in the chemical arts.

[0048] Where substituents are specified by their conventional chemical formula written from left to right, they also encompass the chemically identical substituents that would occur if the structure were written from right to left; for example, -CHO- is equivalent to -OCH-.

[0049] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which may include monovalent, divalent, and polyvalent radicals. An alkyl may contain the specified number of carbons (e.g., C1-C 10means 1 to 10 carbons). An alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are those with one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. The alkenyl may contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. The alkynyl may contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds.

[0050] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified but not limited to, by -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkene.

[0051] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), or a combination thereof, wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. A heteroalkyl is a non-cyclized chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one double bond.Heteroalkenyl may optionally contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. The term "heteroalkynyl", alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one triple bond. Heteroalkynyl may optionally contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds.

[0052] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, and is exemplified, but not limited to, by -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As stated above, heteroalkyl groups, as used herein, include groups that are attached to the remainder of the molecule via a heteroatom, e.g., —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and / or —SOR′. When “heteroalkyl” is recited followed by a specific heteroalkyl group, such as —NR′R″, it is understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be construed herein as excluding specific heteroalkyl groups, such as —NR′R″.

[0053] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyls and heterocycloalkyls are not aromatic. Additionally, for heterocycloalkyls, a heteroatom can occupy the position at which 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, and the like. 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, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0054] In some embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In some embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In some embodiments, a cycloalkyl group 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 ring or a fused bicyclic ring. In some embodiments, a bridged monocyclic ring is a ring in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge (i.e., a group of formula (CH)) of between 1 and 3 additional carbon atoms. wwhere w is 1, 2, or 3. Representative examples of bicyclic ring 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 some embodiments, a fused bicyclic cycloalkyl ring system comprises a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In some embodiments, a bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In some embodiments, a cycloalkyl group is optionally substituted with one or two groups, independently oxo or thia. In some embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted with one or two groups, each independently oxo or thia. In some embodiments, the polycyclic cycloalkyl ring system is (i) a ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) a monocyclic cycloalkyl ring (base ring) fused to either of 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 heterocyclyl. In some embodiments, polycyclic cycloalkyls are attached to the parent molecular moiety through any carbon atom contained within the base ring.In some embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl.

[0055] In some embodiments, a cycloalkyl is a cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In some embodiments, a cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In some embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, and such group is unsaturated (i.e., contains at least one ring carbon-carbon double bond), but is not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In some embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In some embodiments, a bridged monocyclic ring is a ring in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge (i.e., a group of formula (CH)) of between 1 and 3 additional carbon atoms. wwhere w is 1, 2, or 3. Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In some embodiments, the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In some embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In some embodiments, the cycloalkenyl group is optionally substituted with one or two groups, independently oxo or thia. In some embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, 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 heterocyclyl. In some embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In some embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0056] In some embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl 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, and the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, P, and S. A 5-membered ring can 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. Heterocyclyl monocyclic heterocycles are linked to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include 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, Examples of heterocyclic heterocycles include, but are not limited to, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are bonded to the parent molecular moiety via any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls 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-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In some embodiments, the heterocyclyl group is optionally substituted with one or two groups, each independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted with one or two groups, each independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, 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 heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon or nitrogen atom contained within the base ring. In some embodiments, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic heterocyclyl groups 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.

[0057] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0058] The term "acyl," unless otherwise stated, means -C(O)R, in which 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.

[0059] The term "aryl," unless otherwise specified, refers to a polyunsaturated aromatic hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked. Fused-ring aryl refers to multiple rings fused together, in which at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (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(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, in which at least one of the fused rings is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, in which one ring has five members and the other ring has six members, and at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one having six members and the other having six members, with at least one ring being a heteroaryl ring. A 6,5-fused ring heteroarylene refers to two rings fused together, one having six members and the other having five members, with at least one ring being a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 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, 4-isoxazolyl, 5 ... Examples of aryl and heteroaryl groups include benzothiazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above 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 radicals derived from aryl and heteroaryl, respectively. Heteroaryl group substituents may be -O-bonded to a ring heteroatom nitrogen.

[0060] A fused-ring heterocycloalkyl(heterocyloalkyl)-aryl is an aryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused-ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Each fused-ring heterocycloalkyl-aryl, fused-ring heterocycloalkyl-heteroaryl, fused-ring heterocycloalkyl-cycloalkyl, or fused-ring heterocycloalkyl-heterocycloalkyl is independently unsubstituted or substituted with one or more of the substituents described herein.

[0061] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring may be the same or different. The individual rings within a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings within a set of spirocyclic rings. The possible substituents for the individual rings within a spirocyclic ring are the possible substituents for the same ring when not part of the spirocyclic ring (e.g., substituents for a cycloalkyl or heterocycloalkyl ring). The spirocyclic ring may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group may be any of the groups listed above, including when all rings are one type (e.g., all rings may be substituted heterocycloalkylene, and each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic and each ring can be a different ring. When referring to a spirocyclic ring, a substituted spirocyclic ring means that at least one ring is substituted and each substituent can optionally be different.

[0062] symbol [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0063] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.

[0064] The term "alkylsulfonyl," as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' can have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0065] The term "alkylarylene" refers to an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In some embodiments, the alkylarylene group has the formula [ka] It has.

[0066] The alkylarylene moiety can be optionally substituted (e.g., with a substituent) on the alkylene portion or on the arylene linker (e.g., at carbon 2, 3, 4, or 6) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH-SOH, -OSOH, -SONH, -NHNH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In some embodiments, the alkylarylene is unsubstituted.

[0067] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0068] Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) include, but are not limited to, -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R'''', -NR''C may be one or more of a variety of groups selected from (O)R', -NR-C(NR'R''R'')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)R', -S(O)NR'R'', -NRSOR', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO, -NR'SOR'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', ranging in number from 0 to (2m'+1) where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' preferably each independently represent 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 arylalkyl groups. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected, as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined 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.From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CHOCH3, etc.).

[0069] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′′, —NR″C(O)R′, —NR—C(NR′R″R′′)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSO2R′, —NR′NR″R′″, —ONR′R″, —NR′C(O)N R', R''', R''', -CN, -NO, -R', -N, -CH(Ph), fluoro(C-C)alkoxy, and fluoro(C-C)alkyl, -NR'S0R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from 0 to the total number of open valences on the aromatic ring system, and 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, for example, each of the R groups is independently selected, as are each R', R'', R''', and R''' group when more than one of these groups is present.

[0070] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as being on the ring rather than on a specific atom of the ring (commonly referred to as floating substituents). In such cases, the substituent may be attached to any of the ring atoms (subject to the rules of chemical valence); in the case of a fused or spirocyclic ring, a substituent depicted as being associated with one member of the fused or spirocyclic ring (floating substituent on a single ring) may be a substituent on any of the fused or spirocyclic rings (floating substituent on multiple rings). When a substituent is attached to a ring but not to a specific atom (floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may be different, as appropriate. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a flowing substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of either the fused or spirocyclic ring, subject to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms, and another flowing substituent (including, but not limited to, the point of attachment to the rest of the molecule) is shown on the ring, fused ring, or spirocyclic ring, this flowing substituent may be attached to the heteroatom. When, in a structure or formula containing a flowing substituent, a ring heteroatom is shown bonded to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), it is understood that when this heteroatom is bonded to a flowing substituent, this substituent replaces the hydrogen, subject to the rules of chemical valence.

[0071] Two or more substituents can optionally be bonded to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. These so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are bonded to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of the cyclic base structure result in a fused ring structure. In another embodiment, the ring-forming substituents are bonded to a single member of the base structure. For example, two ring-forming substituents attached to a single member of the cyclic base structure result in a spirocyclic structure. In yet another embodiment, the ring-forming substituents are bonded to non-adjacent members of the base structure.

[0072] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are of the formula -TC(O)-(CRR') q A ring of -U- may optionally be formed, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be a group of the formula -A-(CH2) r A and B may optionally be replaced with a substituent of the formula -B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be replaced with a double bond of the formula -(CRR') s -X'-(C''R''R'') dwhere s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. 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.

[0073] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0074] "Substituent" as used herein means a group selected from the following moieties:

[0075] (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2 , -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and

[0076] (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), substituted with at least one substituent selected from:

[0077] (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2 , -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and

[0078] (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), substituted with at least one substituent selected from:

[0079] (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2 , -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and

[0080] (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), substituted with at least one substituent selected from the following: oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHS02H, —NHC(O)H, —NHC(O)OH, —NHOH , -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0081] "Size-limited substituent" or "size-limited substituent group", as used herein, means a group selected from all of the substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20 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 C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0082] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituents," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0083] In some embodiments, each substituent described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each 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 described in the compounds herein 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-limiting substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower-rank substituent.

[0084] In another embodiment of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20 membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-8 membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0085] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C7 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section below, in a Figure, or in a Table.

[0086] In some embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In some embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene, respectively) is substituted (e.g., 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).

[0087] In some embodiments, a substituted moiety (e.g., 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, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In some embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0088] In some embodiments, a substituted moiety (e.g., 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-limiting substituent, and when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent can optionally be different. In some embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0089] In some embodiments, a substituted moiety (e.g., 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 substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent can optionally be different. In some embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0090] In some embodiments, a substituted moiety (e.g., 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, size-limiting substituent, or lower substituent; when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In some embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0091] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds, and stereoisomers, which may be defined in terms of absolute stereochemistry as enantiomers, racemates, diastereomers, tautomers, geometric isomers, (R)- or (S)-, or, for amino acids, (D)- or (L)-, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, both E- and Z-geometric isomers are intended to be included in the compounds, unless otherwise specified. In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 50% or greater, about 70% or greater, about 80% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In certain embodiments, the compound contains about 95% or greater of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the racemate.

[0092] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but that differ with respect to the structural arrangement or configuration of the atoms.

[0093] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0094] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0095] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0096] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by 13 C or 14 Compounds having the structures of the present disclosure except for the replacement by a C-rich carbon are within the scope of the present disclosure.

[0097] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain isotopes of, for example, 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 not, are encompassed within the scope of the present disclosure.

[0098] It should be noted that throughout this application, alternatives are written in Markush groups, e.g., at each nucleoside base position containing more than one possible nucleoside base. It is specifically contemplated that each member of a Markush group should be considered separately, thereby constituting a separate embodiment, and that a Markush group should not be read as a single unit.

[0099] With respect to any of the groups disclosed herein that contain one or more substituents, it is understood that such groups do not contain any substitutions or substitution patterns that are sterically impractical and / or synthetically infeasible. Additionally, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0100] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound provided herein, and one or more molecules of a solvent, 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 in a crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. 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.

[0101] As used herein, the term "cap analog" refers to a structural derivative of the 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), facilitates / improves translation and / or prevents degradation of the mRNA transcript (oligonucleotide).

[0102] As used herein, the terms "complement," "complementary," or "complementarity" refer to 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, complementarity between a capped oligonucleotide primer and one strand of a single-stranded DNA template or dsDNA template can be "complete" or "total," in which all of the nucleotide bases of the two nucleic acid strands match according to recognized base-pairing rules; "partial," in which only a portion of the nucleotide bases of the initiating capped oligonucleotide primer and the DNA template match according to recognized base-pairing rules; or "absent," in which none of the nucleotide bases of the two nucleic acid strands match according to recognized base-pairing rules. Complementarity can also be "substantial," in which the nucleotide bases of the two nucleic acids match according to recognized base-pairing rules but include one or more mismatches (e.g., one, two, three, or four) from total complementarity.

[0103] As used herein, a "deoxyribonuclease (DNase)" is an enzyme that catalyzes the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA.

[0104] As used herein, the terms "hybridize" or "specifically hybridize" refer to the process by which an initiating trinucleotide primer anneals to a DNA template under appropriately stringent conditions during a transcription reaction. In certain embodiments, hybridization to DNA is performed using an initiating capped oligonucleotide primer 3 to 10 nucleotides in length containing a 5'-5' inverted cap structure. Nucleic acid hybridization techniques are well known in the art (e.g., Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Press, Plainview, NY (1989); Ausubel, FM, et al., Current Protocols in Molecular Biology, John Wiley & Sons, Secaucus, NJ (1994)).

[0105] As used herein, "locked nucleic acid" (LNA) refers to a ribonucleotide, methylenebicyclonucleotide monomer having a bridge between the 2'0 and 4'C. The LNA moiety can have the following structure: [ka]

[0106] Use of the terms "comprising," "having," or "including," and variations thereof herein means to encompass the subsequently listed elements and equivalents thereof, as well as additional elements. Embodiments described as "comprising," "comprising," or "having" certain elements are also considered to "consist essentially of" and "consist of" those certain elements. As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, and when interpreted as alternatives ("or"), includes the absence of a combination.

[0107] Ranges can be expressed herein as from one particular value and / or to another particular value. When such ranges are expressed, unless the context specifically dictates otherwise, ranges from one particular value and / or to the other particular value are also specifically contemplated and considered disclosed. It should be understood that all individual values ​​and subranges of values ​​falling within an explicitly disclosed range are also specifically contemplated and considered disclosed, unless the context specifically dictates otherwise. Furthermore, all ranges should be understood to refer to both ranges described as ranges and ranges described as a set of individual numerical values, inclusive from a first endpoint to a second endpoint. In the latter case, it should be understood that any of the individual numerical values ​​can be selected as one form of the quantity, value, or feature to which the range refers. Thus, a range describes a set of numerical values ​​or values, inclusive from a first endpoint to a second endpoint, from which a single member of the set (i.e., a single numerical value) can be selected as the quantity, value, or feature to which the range refers.

[0108] As used herein, a "messenger RNA transcript" or "mRNA transcript" is a transcript transcribed from a DNA template that encodes a desired polypeptide. An mRNA transcript may contain coding and non-coding regions. For example, the DNA template may 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 also includes a nucleic acid sequence encoding a poly(A) tail.

[0109] 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 composed of two or more chemically synthesized oligonucleotides ligated together. Alternatively, a hybrid capped oligonucleotide may be composed of two or more oligonucleotides, where at least one oligonucleotide is chemically synthesized, another oligonucleotide may be generated by an in vitro transcription process, and then the two oligonucleotides are ligated. In some embodiments, chemically synthesized oligonucleotides may be modified to improve their stability. For example, chemically synthesized oligonucleotides may have modified internucleotide linkages, modified sugars, or modified nucleobases, as described herein. Various alternatives for ligation are described herein.

[0110] As used herein, the term "nucleoside" refers to a nitrogenous base linked to a 5-pentose sugar (e.g., ribose or deoxyribose). The term includes all forms of nucleoside bases and all nucleosides, including furanosides. Base rings include purine and pyrimidine rings. Purine rings include, for example, adenine, guanine, and N6-methyladenine. Pyrimidine rings include, for example, cytosine, thymine, 5-methylcytosine, and pseudouracil.

[0111] As used herein, the term "nucleoside triphosphate," "nucleoside 5' triphosphate," or "NTP" refers to a nucleoside linked to three phosphate groups. This term refers to natural NTPs (e.g., adenosine triphosphate (ATP), uridine triphosphate (UTP), guanine triphosphate (GTP), and cytosine triphosphate (CTP)), as well as modified NTPs (e.g., pseudouridine and N-terminal phosphate). 1-methylpseudouridine triphosphate).

[0112] "Inorganic pyrophosphatase" refers to an enzyme that catalyzes the conversion of one ion of pyrophosphate to two phosphate ions, thus inhibiting aggregation and, in some cases, preventing the interaction of pyrophosphate with magnesium ions during the T7 transcription reaction.

[0113] As used herein, the term "internucleotide linkage" refers to one or more bonds joining two nucleosides of an oligonucleotide or nucleic acid, and may be a natural phosphodiester linkage or a modified linkage.

[0114] As used herein, the term "substantially free" refers to a state in which there are little or no impurities (e.g., prematurely terminated RNA sequences, uncapped RNA, DNA, and / or double-stranded RNA) in a sample. "Substantially free of impurities" means that impurities are present in a sample at a level of less than approximately 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 a sample at a level of less than approximately 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 some embodiments, "substantially free of impurities" means that impurities are present at a level of less than approximately 5%. Impurities are present at a level of less than approximately 4%. Impurities are present at a level of less than approximately 3%. Impurities are present at a level of less than approximately 2%. Impurities are present at a level of less than approximately 1%. Impurities are present at a level of less than approximately 0.9%. Impurities are present at a level of less than approximately 0.8%. Impurities are present at a level of less than approximately 0.7%. Impurities are present at a level of less than approximately 0.6%. Impurities are present at a level of less than approximately 0.5%. Impurities are present at a level of less than approximately 0.4%. Impurities are present at a level of less than approximately 0.3%. Impurities are present at a level of less than approximately 0.2%. Impurities are present at a level of less than approximately 0.1%.

[0115] As used herein, the term "impurity" refers to a substance that differs from the chemical composition of the target material (e.g., mRNA transcript). Impurities are also called contaminants.

[0116] As used herein, the term "enzyme by-products" refers to undesired products from an IVT reaction, such as, for example, uncapped RNA, truncated RNA (RNA that is not fully synthesized or that lacks a tail end), dsRNA, etc. Enzyme by-products may be considered impurities.

[0117] As used herein, "tangential flow filtration (TFF)" refers to a type of filtration in which the material to be filtered flows tangentially through the filter rather than through it. In TFF, the undesired permeate passes through the filter, while the desired retentate flows 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 traditional membrane filtration or dead-end filtration.

[0118] As used herein, the term "in vitro" refers to a process that is carried out outside a living organism (e.g., a multicellular organism such as a human or non-human animal), e.g., in a test tube, culture dish, or other location outside the living organism.

[0119] As used herein, the term "in vivo" refers to events that occur within a living organism.

[0120] As used herein, the term "transcription" refers to the enzymatic production or synthesis of RNA complementary to a DNA template, thereby generating several RNA complements of the DNA sequence. The RNA molecule synthesized in a transcription reaction is an "RNA transcript," "primary transcript," or "transcription product." Transcription reactions involving the compositions and methods provided herein use an initiating capped oligonucleotide primer as described herein. Transcription of a DNA template can be exponential, nonlinear, 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.

[0121] As used herein, the term "modified oligonucleotide" includes, for example, oligonucleotides containing modified nucleosides, modified internucleotide linkages, or any combination of modified nucleosides and internucleotide linkages. Examples of internucleotide linkage modifications include phosphorothioates, phosphotriesters, and methylphosphonate derivatives (Stec, WJ, et al., Chem. Int. Ed. Engl., 33:709-722 (1994); Lebedev, AV, et al., E., Perspective. 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. Letters 6:2363-2366 (1996).

[0122] As used herein, "oligo dT purification" is an affinity chromatography method for purifying mRNA that is provided with or contains a polyA tail.

[0123] As used herein, "phosphorothioate linkage" refers to a linkage between nucleosides in which the phosphorodiester linkage has been modified by replacing one of the oxygen atoms bonded to the phosphorus atom with a sulfur atom.

[0124] As used herein, the term "prematurely terminated RNA transcript" refers to an incomplete product of an in vitro transcription reaction. Prematurely terminated RNA sequences can be of any length shorter than the intended length of the desired transcript.

[0125] The term "promoter," as used herein, refers to a nucleotide sequence within a DNA template that directs and controls the initiation of transcription of a particular DNA sequence. A promoter is typically located immediately adjacent to (or partially overlapping with) the DNA sequence to be transcribed. The promoter sequence is typically located immediately upstream or 5' of the transcription start site. The position of nucleotides within a promoter is specified relative to the transcription start site (position +1), where transcription of DNA begins.

[0126] 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, including all forms of nucleoside bases and furanosides. Base rings include purine and pyrimidine rings. Purine rings include, for example, adenine, guanine, and N6-methyladenine. Pyrimidine rings include, for example, cytosine, thymine, 5-methylcytosine, and pseudouracil. Other nucleosides include, but are not limited to, ribo, 2'-O-methyl, or 2'-deoxyribo derivatives of adenosine, guanosine, cytidine, thymidine, uridine, inosine, 7-methylguanosine, or pseudouridine. The term "natural nucleoside" refers to adenosine, guanosine, cytidine, uridine, and thymidine. 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), 1-methyladenosine, 2-methylthio-N6-hydroxynorvalylcarbamoyladenosine, 2-methyladenosine, 2-O-ribosylphosphate adenosine, N6-methyl-N6-threonylcarbamoyladenosine, N6-acetyladenosine, N6-glycinylcarbamoyladenosine, N6-isopentenyladenosine, N6-methyladenosine, N6-threonylcarbamoyladenosine, N6,N6-dimethyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, N6-hydroxynorvalylcarbamoyladenosine, 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-ribosylphosphate guanosine, 7-methylguanosine, undermodified hydroxywybutosine, 7-aminomethyl-7-deazaguanosine, 7-cyano-7-deazaguanosine, N2,N2-dimethylguanosine, 4-demethylwybutosine, epoxyqueuosine, hydroxywybutosine, isowybutosine, 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, peroxywybutosine, galactosyl-queuosine, mannosyl-queuosine, queuosine, archaeosine, wybutosine, methylwyosine, wyosine, 2-thiouridine, 3-(3-amino-3-carboxypropyl)uridine, 3-methyluridine, 4-thiouridine, 5-methyl-2-thiouridine, 5-methylaminomethyluridine, 5-carboxymethyluridine, 5-carboxymethyluridine, carboxymethylaminomethyluridine, 5-hydroxyuridine, 5-methyluridine, 5-taurinomethyluridine, 5-carbamoylmethyluridine, 5-(carboxyhydroxymethyl)uridine methyl ester, dihydrouridine, 5-methyldihydrouridine, 5-methylaminomethyl-2-thiouridine, 5-(carboxyhydroxymethyl)uridine, 5-(isopentenylaminomethyl)uridine, 5-(isopentenylaminomethyl)-2-thiouridine, 3,2-O-dimethyluridine, 5-carboxymethyl 5-(Isopentenylaminomethyl)-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, uridine 5-oxyacetic acid, 5-methoxycarbonylmethyluridine, uridine 5-oxyacetic acid methyl ester, 5-methoxyuridine, 5-aminomethyl-2-thiouridine, 5-carboxymethylaminomethyl There are 107 naturally occurring nucleosides, including 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 modified nucleobases thereof, can be a component of the nucleic acids of the present invention.

[0127] All other nucleosides (not including those described above as natural nucleosides or modified natural nucleosides) are unnatural nucleosides.

[0128] As used herein, the terms "nucleoside analog," "modified nucleoside," or "nucleoside derivative" include synthetic nucleosides described herein. Nucleoside derivatives also include nucleosides with modified bases or / and sugar moieties, with or without protecting groups, such as 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 base sugars substituted with non-natural heterocycles and substituted acyclic base sugars. Other nucleoside derivatives that may be utilized in the present disclosure include, for example, LNA nucleosides, halogen-substituted purines (e.g., 6-fluoropurine), halogen-substituted pyrimidines, N-substituted nucleosides, and the like. 6 -Ethyladenine, N 4 -(alkyl)cytosine, 5-ethylcytosine, and the like (for example, U.S. Pat. No. 6,762,298).

[0129] As used herein, the term "nucleoside base" or "nucleobase" refers to the base portion (nitrogenous base) of a nucleotide or nucleoside, and 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.

[0130] As used herein, the term "modified nucleoside base" or "modified nucleobase" describes naturally occurring modified nucleoside bases, including, but not limited to, pseudouracil, 5-methylcytosine, N6-methyladenine, hypoxanthine, 5-hydroxymethylcytosine, 5-carboxylcytosine, N4-acetylcytosine, N4-methylcytosine, N1-methyladenine, N2,N2-dimethylguanine, etc. See also the naturally occurring modified nucleosides listed above.

[0131] As used herein, the term "unnatural nucleoside base" or "unnatural nucleobase" refers to all nucleoside bases that are not natural (whether modified or not, see naturally occurring modified nucleosides above), including, but not limited to, for example, N1-methylpseudouracil, 7-deazaadenine, 2-aminoadenine, 5-methylisocytosine, 5-fluorouracil, 5-bromouracil, 5-iodouracil, 2-methylthioadenine, 2-thio-5-methyluracil, 2-amino-6-methylthiopurine, etc. Natural nucleosides are described above.

[0132] As used herein, the term "RNA polymerase" refers to an enzyme that synthesizes RNA using a DNA template. In vitro transcription methods typically use single-subunit phage RNA polymerases derived from T7, T3, SP6, K1-5, K1E, K1F, or K11 bacteriophages, or their variants. This polymerase family has a simple, minimal promoter sequence of approximately 17 nucleotides, which does not require accessory proteins and has minimal constraints on the initiation nucleotide sequence.

[0133] As used herein, the terms "purified" or "to purify" refer to the separation of a substance from at least some of the components (e.g., impurities or contaminants) with which it was originally associated when produced. For example, an RNA transcript is purified by removing contaminating proteins or other undesirable nucleic acid species (e.g., double-stranded RNA, DNA, and / or incomplete or interrupted 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 greater than 99% of the other components with which it was originally associated.

[0134] Salts of one or more compounds described herein can be used in the disclosed methods. The term "salt," as used herein, refers to derivatives of the compounds described herein prepared by reacting the acidic or basic portion of the compound with an inorganic or organic acid or base. Where appropriate, the salts may be pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts of the compounds described herein or their derivatives, and, where possible, zwitterionic forms of the compounds described herein, that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio and 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 its free base form with a suitable organic or inorganic acid and isolating the resulting salt. 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, naphthylate mesylate, glucoheptonate, lactobionate, methanesulfonate, and laurylsulfonate, etc. Salts may include cations based on alkali and alkaline earth metals, e.g., 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., J. Pharm. Sci. (1977) 66, 1 and Remington: The Science and Practice of Pharmacy, 23d Edition, Adejare et al. eds., Academic Press (2020), which are incorporated by reference in their entireties.)

[0135] References in this specification and the concluding claims to parts by weight of a particular element or component in a composition indicate the weight relationship between that element or component and any other element or component in the composition or article for which the parts by weight are expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in such ratio regardless of whether the compound contains additional components.

[0136] Weight percent (wt.%) of a component is based on the total weight of the formulation or composition in which the component is included, unless specifically stated to the contrary.

[0137] As used herein, the term "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where it does not occur.

[0138] As used herein, the term "subject" or "patient" can be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject 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 denote a particular age or sex. Thus, it is intended to cover adult and newborn subjects, whether male or female, as well as fetuses. 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 veterinary subjects.

[0139] The terms "immunization" or "vaccination" describe the process of treating a subject for therapeutic or prophylactic reasons.

[0140] As used herein, the term "treatment" refers to the medical management of a patient with the goal of curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder. The term includes active treatment, i.e., treatment specifically directed at ameliorating a disease, condition, or disorder, and also includes causal treatment, i.e., treatment directed at eliminating the cause of the associated disease, condition, or disorder. In addition, the term includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure the disease, condition, or disorder. In various embodiments, the term encompasses all treatments of a subject, including a mammal (e.g., a human), including (i) preventing a disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease, (ii) inhibiting a disease, i.e., halting the onset of the disease, or (iii) relieving a disease, i.e., causing regression of the disease. In one embodiment, the subject is a mammal, e.g., a primate, and in a further embodiment, the subject is a human.

[0141] As used herein, the term "prevent" or "preventing" means to prevent, avoid, remove, forestall, stop, or impede something from happening, especially by prior action. Where reduce, inhibit, or prevent are used herein, it is understood that the use of the other two words is also expressly disclosed unless specifically specified otherwise.

[0142] As used herein, the term "diagnosed" means having undergone a physical examination by a person skilled in the art, e.g., a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0143] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, intraocular administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, oral buccal administration, and parenteral administration, including injections, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various embodiments, the preparation can be administered therapeutically, i.e., to treat an existing disease or condition. In further various embodiments, the preparation can be administered prophylactically, i.e., to prevent a disease or condition.

[0144] As used herein, the terms "effective amount" and "effective quantity" refer to an amount sufficient to achieve a desired result or to affect an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to affect an undesired symptom, but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder, the specific composition used, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, the excretion rate of the specific compound used, the duration of treatment, drugs used in combination with or concomitantly with the specific compound used, and similar factors well known in the medical field. For example, it is within the skill of one of ordinary skill in the art to start a dose of a compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Consequently, a single-dose composition may contain such amounts or fractions thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary and can be administered in one or multiple daily doses over one or several days.For the appropriate dosage for a given class of pharmaceuticals, guidance can be found in literature.Furthermore, in various embodiments, the preparation can be administered in a "prophylactically effective amount", i.e., an amount that is effective for preventing disease or condition.

[0145] As used herein, "dosage form" refers to a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. The dosage form can include the disclosed compound of the present invention, the product of the disclosed method of preparation, or a salt, solvate, or polymorph thereof, in combination with pharmaceutically acceptable additives, such as preservatives, buffers, saline, or phosphate-buffered saline. The dosage form can be made using conventional pharmaceutical manufacturing and compounding techniques. The dosage form can contain inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjusters (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citric acid or acetate, amino acids and their salts). Antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonylphenol, sodium desoxycholate), solution and / or freeze / lyophilization stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmolality adjusters (e.g., salts or sugars), antimicrobial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymer stabilizers and viscosity adjusters (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose), and cosolvents (e.g., glycerol, polyethylene glycol, ethanol). Dosage forms formulated for injectable use can have the disclosed compounds, products of the disclosed methods of making, or salts, solvates or polymorphs thereof suspended in sterile saline for injection with a preservative.

[0146] As used herein, the terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" refer to sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into 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 (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. The absorption of injectable pharmaceutical forms can be prolonged by including agents such as aluminum monostearate and gelatin that delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0147] As used herein, the term "therapeutic agent" includes any synthetic or naturally occurring biologically active compound or composition of matter that, 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. Thus, the term encompasses compounds or chemicals traditionally considered to be drugs, vaccines, and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, and the like. Examples of therapeutic agents can be found in well-known references, e.g., the Merck Index (14 th edition), the Physicians' Desk Reference (64 th edition), and The Pharmacological Basis of Therapeutics (12 thedition), which include, but are not limited to, medicines, vitamins, mineral supplements, substances used in the treatment, prevention, diagnosis, cure, or mitigation of disease or illness, substances that affect the structure or function of the body, or prodrugs that become biologically active or more active after being placed in a physiological environment. For example, the term "therapeutic agent" includes adjuvants, anti-infectives such as antibiotics and antivirals, analgesics and analgesic combinations, appetite suppressants, anti-inflammatory agents, antiepileptics, local and general anesthetics, hypnotics, sedatives, antipsychotics, neuroleptics, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergics and cholinergic agents, antimuscarinics and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensives, hormones and nutrients, antiarthritics, antiasthmatics, anticonvulsants, antihistamines, antiemetics, antineoplastics, antipruritics, antipyretics, antispasmodics, cardiovascular preparations (including calcium channel blockers, beta blockers, beta agonists and antiarrythmics), antihypertensives, diuretics, vasodilators, central nervous system stimulants, cough suppressants and Included are compounds or compositions for use in all major therapeutic areas, including, but not limited to, cold remedies, decongestants, diagnostic agents, hormones, bone growth stimulants and bone resorption inhibitors, immunosuppressants, muscle relaxants, psychostimulants, sedatives, tranquilizers, proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized, or recombinantly produced), as well as nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA), including both 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 drugs can be bioactive agents used in medical applications, including veterinary medicine, and in agriculture, such as treating plants, and other fields.The term "therapeutic agent" also includes, but is not limited to, medicines, vitamins, mineral supplements, substances used to treat, prevent, diagnose, cure or alleviate a disease or disorder, or substances that affect the structure or function of the body, or prodrugs that become biologically active or more active after being placed in a given physiological environment.

[0148] As used herein, the term "derivative" refers to a compound having a structure derived from that of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to that disclosed herein that, based on that similarity, one skilled in the art would predict to exhibit the same or similar activity and utility as the compound, or, as a precursor, to induce the same or similar activity and utility as the compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0149] "Analog," or "analogue," is used according to its plain and ordinary meaning in chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., one atom is replaced by an atom of a different element, or a particular functional group is present, or one functional group is replaced by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0150] As used herein, the terms "hydrophobic moiety" or "hydrophobic group" are used interchangeably and can refer to a carbon-rich hydrophobic substituent or combination of hydrophobic substituents. The hydrophobicity of a substituent can be determined, measured, or calculated by its partition coefficient (log P) value. The partition coefficient (log P) of a substance defines the ratio of the substance's solubility in two immiscible solvents, usually octanol:water. This value is referred to as cLog P when calculated rather than measured. In some embodiments, a hydrophobic group has a cLog P of at least 2, or a combination of two, three, or four "hydrophobic moieties" has a collective cLog P value of at least 2. The nucleoside bases cytosine, thymine, uracil, adenine, and guanine, which have a cLog P of less than 2, are not considered "hydrophobic groups" as defined herein. Non-limiting examples of hydrophobic groups include C6-C 24 Alkyl, C4-C 24 Alkenyl, C4-C 24 Alkynyl, C3-C8 cycloalkyl, C6-C 10 These include aryl, trityl, silyl, lipid, and steroid. Fluoro substituents or fluoro-substituted groups can be used to increase the hydrophobicity of the hydrophobic group.

[0151] As used herein, the terms "cleavable hydrophobic moiety," "cleavable hydrophobic group," "removable hydrophobic moiety," or "removable hydrophobic group" are used interchangeably and refer to, for example, a C-C 20The term "5'-capped oligonucleotide" can refer to hydrophobic groups such as saturated alkyl groups, cycloalkyl rings, aryl rings, silyl, etc., of 5' or longer, which can be chemically or thermally removed from 5'-capped oligonucleotides using mild conditions. In some embodiments, such group(s) can be removed under mild acidic conditions at a pH of about 5 or higher (1 hour at room temperature). In some embodiments, such group(s) can be removed under mild basic conditions at a pH of about 9 or lower (1 hour at room temperature). In some embodiments, such group(s) can be removed by gentle heating at about 65°C or lower for 1 hour. In some embodiments, such group(s) can be removed by reductive amination. In some embodiments, such group(s) can be removed by desilylation. In some embodiments, such group(s) can be removed by oxidation. In some embodiments, such group(s) can be removed by photolysis. In some embodiments, these terms exclude photocleavable (photolabile) groups. In this application, a hydrophobic group is considered to be "cleavable" or "removable" if it can be removed under conditions that do not denature the 5'-capped RNA. In some embodiments, removal of these group(s) produces a highly pure, readily translatable 5'-capped oligonucleotide.

[0152] As used herein, the terms "non-cleavable hydrophobic moiety" or "non-cleavable hydrophobic group" are used interchangeably and refer to, for example, a C3-C 5′-capped oligonucleotide that cannot be readily removed from a 5′-capped oligonucleotide. 20 or longer saturated alkyl groups, C3-C8 cycloalkyl, C6-C 10This can refer to a hydrophobic group such as aryl. In some embodiments, the hydrophobic group cannot be removed using the mild conditions described above for cleavable hydrophobic groups. In some embodiments, the non-cleavable hydrophobic group cannot be removed at a pH between about 5 and about 9 (at room temperature for 1 hour). In some embodiments, the non-cleavable hydrophobic group cannot be removed by heating below about 65°C for 1 hour. In some embodiments, the non-cleavable hydrophobic group(s) do not interfere with translation of the 5'-capped oligonucleotide. In some embodiments, up to 5% of the non-cleavable hydrophobic group(s) are cleaved from the protected 5'-capped oligonucleotide. In some embodiments, up to 10% of the non-cleavable hydrophobic group(s) are cleaved from the protected 5'-capped oligonucleotide. In some embodiments, up to 15% of the non-cleavable hydrophobic group(s) are cleaved from the protected 5'-capped oligonucleotide. In some embodiments, up to 20% of the non-cleavable hydrophobic group(s) are cleaved from the protected 5'-capped oligonucleotide.

[0153] As used herein, the term "translationally permissive hydrophobic group" refers to any hydrophobic group that does not inhibit (or interfere with) translation of a 5'-capped RNA. Typically, most non-removable hydrophobic groups are translationally permissive. In some embodiments, removable hydrophobic groups may be translationally permissive. In such cases, the groups may not be allowed to remain in place, even though they are "removable."

[0154] As used herein, the terms "photocleavable group" or "photolabile group" are used interchangeably and can refer to groups such as, for example, nitrobenzyl, nitrobenzyl derivatives, phenacyl, benzyl, etc., which can be removed by irradiation with light of certain frequencies.

[0155] As used herein, the term "purification handle" refers to a hydrophobic group covalently linked to a 5'-capped oligonucleotide; such a group may be removable or non-removable. The purification handle allows for HPLC separation of a 5'-capped oligonucleotide containing a covalently linked purification handle from uncapped oligonucleotides and other truncated oligonucleotides. In some embodiments, the purification handle may be a protecting group. In some embodiments, the purification handle may include, for example, a C6-C 24 Alkyl, C4-C 24 Alkenyl, C4-C 24 Alkynyl, C3-C8 cycloalkyl, C6-C 10 These include, but are not limited to, aryl, silyl compounds, trityl compounds, vinyl ether compounds, modified and unmodified Fmoc compounds, etc. Typically, the hydrophobic group is a purification handle.

[0156] The term "protecting group" is used according to its ordinary meaning in organic chemistry to refer to a moiety covalently attached to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group. Typically, a protecting group is attached to a heteroatom (e.g., O or N) as part of a multi-step synthesis where reaction of the heteroatom with a reagent (e.g., chemical reduction) is undesirable. After protection, the protecting group can be removed (e.g., by adjusting pH or temperature). In some embodiments, 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 some embodiments, the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include trityl, monomethoxytrityl (MMT), dimethoxytrityl (DMT) or other modified trityl, dimethylcarbobenzyloxy (Cbz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), tert-butyldiphenylsilyl (TBDPS), and tosyl (Ts). II. 5' Capped Oligonucleotides

[0157] In one aspect, provided herein is an oligonucleotide comprising 50 to 12,000 nucleotides, the 5' end of which comprises a group represented by formula (I): [ka] 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, During the ceremony, B 1 and B 3 are each independently a natural, modified, or unnatural nucleoside base; Each B 2 are independently a natural, modified, or unnatural nucleoside base; Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-; Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se; R 1 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 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; R 3 is hydrogen, -C(O)R 3A , -C(O)OR3A , -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; Each R 7 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 7A , -NR 7A R 7B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 19A , -NR 19A R 19B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R 11 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 11A , -NR 11A R 11B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 11 and R 19together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R 1A , R 2A , R 3A , R 7A , R 7B , R 11A , R 11B , R 19A and R 19B are independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 bonded to the same nitrogen atom 7A and R 7B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 11A and R 11B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 19A and R 19B The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; Each R 101are independently hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O) OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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; 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. Here, and throughout this disclosure, [ka] indicates the point of attachment of the structure to the remainder of the oligonucleotide (eg, the body and the 3' end).

[0158] In some embodiments, R 1are independently hydrogen, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0159] In some embodiments, the substitution R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are independently substituted with at least one substituent, size-limiting substituent, or lower substituent, where the substituted R 1 When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1 When R is independently substituted, it is substituted with at least one substituent.1 When R is independently substituted, it is substituted with at least one size-limiting substituent. 1 When is independently substituted, it is substituted with at least one lower substituent.

[0160] In some embodiments, R 1 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 1 are independently hydrogen, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 1 are independently hydrogen. In some embodiments, R 1 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 1 is independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 1 are independently unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 1 are independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl).

[0161] In some embodiments, R 1are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, [ka] or a modified trityl.

[0162] R 1 are independently hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, [ka] or a modified trityl.

[0163] In some embodiments, R 1 is independently hydrogen or methyl. In some embodiments, R 1 are independently hydrogen or [ka] is.

[0164] In some embodiments, R 1 are independently hydrogen. In some embodiments, R 1 is independently methyl. In some embodiments, R 1 is independently ethyl. In some embodiments, R 1 is independently propyl. In some embodiments, R 1 is independently isopropyl. In some embodiments, R 1 is independently butyl. In some embodiments, R 1 is independently isobutyl. In some embodiments, R 1 is independently t-butyl. In some embodiments, R 1 is independently pentyl. In some embodiments, R 1is independently isopentyl. In some embodiments, R 1 is independently hexyl. In some embodiments, R 1 is independently phenyl. In some embodiments, R 1 is independently benzyl. In some embodiments, R 1 is, independently, [ka] In some embodiments, R 1 is, independently, [ka] In some embodiments, R 1 is, independently, [ka] In some embodiments, R 1 are independently modified trityl.

[0165] In some embodiments, R 2are independently hydrogen, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0166] In some embodiments, the substitution R 2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are independently substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 2 When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 2When R is independently substituted, it is substituted with at least one substituent. 2 When R is independently substituted, it is substituted with at least one size-limiting substituent. 2 When is independently substituted, it is substituted with at least one lower substituent.

[0167] In some embodiments, R 2 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 2 are independently hydrogen, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 2 are independently hydrogen. In some embodiments, R 2 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 2 is independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 2 are independently unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 2 are independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl).

[0168] In some embodiments, R 2 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, [ka] or a modified trityl.

[0169] R 1 are independently hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, [ka]

[0170] or a modified trityl.

[0171] In some embodiments, R 2 is independently hydrogen or methyl. In some embodiments, R 2 are independently hydrogen or [ka] is.

[0172] In some embodiments, R 2 are independently hydrogen. In some embodiments, R 2 is independently methyl. In some embodiments, R 2 is independently ethyl. In some embodiments, R 2 is independently propyl. In some embodiments, R 2 is independently isopropyl. In some embodiments, R 2 is independently butyl. In some embodiments, R 2 is independently isobutyl. In some embodiments, R 2 is independently t-butyl. In some embodiments, R 2is independently pentyl. In some embodiments, R 2 is independently isopentyl. In some embodiments, R 2 is independently hexyl. In some embodiments, R 2 is independently phenyl. In some embodiments, R 2 is independently benzyl. In some embodiments, R 2 is, independently, [ka] In some embodiments, R 2 is, independently, [ka] In some embodiments, R 2 is, independently, [ka] In some embodiments, R 2 are independently modified trityl.

[0173] In some embodiments, R 3is hydrogen, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0174] In some embodiments, the substitution R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 3 When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 3 When R is substituted, it is substituted with at least one substituent. 3When R is substituted, it is substituted with at least one size-limiting substituent. 3 When is substituted, it is substituted with at least one lower substituent.

[0175] In some embodiments, R 3 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. 3 is hydrogen, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 3 is a substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 3 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 3 is a substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl).

[0176] In some embodiments, R 3is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4-chlorobenzyl. 3 is methyl or 4-chlorobenzyl.

[0177] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is isobutyl. In some embodiments, R 3 is t-butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is isopentyl. In some embodiments, R 3 is hexyl. In some embodiments, R 3 is phenyl. In some embodiments, R 3 is benzyl. In some embodiments, R 3 is 4-chlorobenzyl.

[0178] In some embodiments, R 7 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 7A , -NR 7A R 7B, -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0179] In some embodiments, the substitution R 7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 7 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 7 When R is substituted, it is substituted with at least one substituent. 7When R is substituted, it is substituted with at least one size-limiting substituent. 7 When is substituted, it is substituted with at least one lower substituent.

[0180] In some embodiments, R 7 are independently hydrogen, halogen, or -OR 7A In some embodiments, R 7 are independently hydrogen. In some embodiments, R 7 is independently halogen. In some embodiments, R 7 are independently -OR 7A In some embodiments, R 7 is independently chloro. In some embodiments, R 7 is independently bromo. In some embodiments, R 7 is independently iodo. In some embodiments, R 7 is independently fluoro.

[0181] In some embodiments, R 7 is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In some embodiments, R 7 is independently hydroxy. In some embodiments, R 7 is independently methoxy. In some embodiments, R 7 is independently ethoxy. In some embodiments, R 7 is independently propoxy. In some embodiments, R 7 is independently butoxy. In some embodiments, R 7 is independently t-butoxy.

[0182] In some embodiments, R 7A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 7A is hydrogen. In some embodiments, R7A is substituted alkyl. In some embodiments, R 7A is an unsubstituted alkyl.

[0183] In some embodiments, R 7A is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0184] In some embodiments, the substitution R 7A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 7A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 7A When R is substituted, it is substituted with at least one substituent. 7A When R is substituted, it is substituted with at least one size-limiting substituent. 7A When is substituted, it is substituted with at least one lower substituent.

[0185] In some embodiments, R 7A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 7A is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 7A is hydrogen. In some embodiments, R 7Ais unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 7A is a substituted (eg, by a substituent, a size-limiting substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0186] In some embodiments, R 7A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 7A is hydrogen. In some embodiments, R 7A is methyl. In some embodiments, R 7A is ethyl. In some embodiments, R 7A is propyl. In some embodiments, R 7A is isopropyl. In some embodiments, R 7A is butyl. In some embodiments, R 7A is isobutyl. In some embodiments, R 7A is t-butyl. In some embodiments, R 7A is pentyl. In some embodiments, R 7A is hexyl.

[0187] In some embodiments, R 11 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 7A , -NR 7A R 7B, -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0188] In some embodiments, the substitution R 11 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 11 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 11 When R is substituted, it is substituted with at least one substituent. 11When R is substituted, it is substituted with at least one size-limiting substituent. 11 When is substituted, it is substituted with at least one lower substituent.

[0189] In some embodiments, R 11 are independently hydrogen, halogen, or -OR 11A In some embodiments, R 11 are independently hydrogen. In some embodiments, R 11 is independently halogen. In some embodiments, R 11 are independently -OR 11A In some embodiments, R 11 is independently chloro. In some embodiments, R 11 is independently bromo. In some embodiments, R 11 is independently iodo. In some embodiments, R 11 is independently fluoro.

[0190] In some embodiments, R 11 is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. In some embodiments, R 11 is independently hydroxy. In some embodiments, R 11 is independently methoxy. In some embodiments, R 11 is independently ethoxy. In some embodiments, R 11 is independently propoxy. In some embodiments, R 11 is independently butoxy. In some embodiments, R 11 is independently t-butoxy.

[0191] In some embodiments, R 11A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 11A is hydrogen. In some embodiments, R11A is substituted alkyl. In some embodiments, R 1A is an unsubstituted alkyl.

[0192] In some embodiments, R 11A is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0193] In some embodiments, the substitution R 11A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 11A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 11A When R is substituted, it is substituted with at least one substituent. 11A When R is substituted, it is substituted with at least one size-limiting substituent. 11A When is substituted, it is substituted with at least one lower substituent.

[0194] In some embodiments, R 11A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 11A is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 11A is hydrogen. In some embodiments, R 11Ais unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 11A is a substituted (eg, by a substituent, a size-limiting substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0195] In some embodiments, R 11A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 11A is hydrogen. In some embodiments, R 11A is methyl. In some embodiments, R 11A is ethyl. In some embodiments, R 11A is propyl. In some embodiments, R 11A is isopropyl. In some embodiments, R 11A is butyl. In some embodiments, R 11A is isobutyl. In some embodiments, R 11A is t-butyl. In some embodiments, R 11A is pentyl. In some embodiments, R 11A is hexyl.

[0196] In some embodiments, R 19 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 19A , -NR 19A R 19B, -CONH2, -COOH, -NHC(O)OH, -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl ... substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0197] In some embodiments, the substitution R 19 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 19 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 19When R is substituted, it is substituted with at least one substituent. 19 When R is substituted, it is substituted with at least one size-limiting substituent. 19 When is substituted, it is substituted with at least one lower substituent.

[0198] In some embodiments, R 19 is hydrogen.

[0199] In some embodiments, R 7 and R 19 taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene. In some embodiments, R 7 and R 19 taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylene. In some embodiments, R 7 and R 19 taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocycloalkylene.

[0200] In some embodiments, R 7 and R 19 are taken together with the carbon atoms to which they are attached to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkylene (e.g., a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene). In some embodiments, R 7 and R 19 taken together with the carbon atoms to which they are attached form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).

[0201] In some embodiments, R together with the carbon atom to which they are attached 7 and R 19 The substituted heterocycloalkylene formed by the attachment of R is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkylene is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. In some embodiments, R together with the carbon atoms to which they are attached can be substituted with at least one substituent, size-limiting substituent, or lower substituent. 7 and R 19 When the heterocycloalkylene formed by the attachment of R is substituted, it is substituted with at least one substituent. In some embodiments, R together with the carbon atom to which they are attached 7 and R 19 If the heterocycloalkylene formed by the attachment of R is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R together with the carbon atom to which they are attached 7 and R 19 When the heterocycloalkylene formed by bonding is substituted, it is substituted with at least one lower substituent.

[0202] In some embodiments, R together with the carbon atom to which they are attached 7 and R 19 The substituted cycloalkylene formed by the attachment of R is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted cycloalkylene is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. In some embodiments, R together with the carbon atoms to which they are attached can be substituted with at least one substituent, size-limiting substituent, or lower substituent. 7 and R 19When the cycloalkylene formed by the bonding of R is substituted, it is substituted with at least one substituent. In some embodiments, R together with the carbon atom to which they are attached 7 and R 19 If the cycloalkylene formed by the attachment of R is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R together with the carbon atom to which they are attached 7 and R 19 When the cycloalkylene formed by bonding is substituted, it is substituted with at least one lower substituent.

[0203] In some embodiments, R 7 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. In some embodiments, R 7 and R 19 together with the carbon atoms to which they are attached form a substituted or unsubstituted 4-membered heterocycloalkylene.

[0204] In some embodiments, R 7 and R 19 taken together with the carbon atom to which they are attached form a substituted 4-membered heterocycloalkylene. In some embodiments, R 7 and R 19 together with the carbon atoms to which they are attached form an unsubstituted 4-membered heterocycloalkylene.

[0205] In some embodiments, R 7 and R 19 together with the carbon atom to which they are attached to form a locked nucleic acid (LNA).

[0206] In some embodiments, R 11 and R 19taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene. In some embodiments, R 11 and R 19 taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylene. In some embodiments, R 11 and R 19 taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocycloalkylene.

[0207] In some embodiments, R 11 and R 19 are taken together with the carbon atoms to which they are attached to form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkylene (e.g., a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene). In some embodiments, R 11 and R 19 taken together with the carbon atoms to which they are attached form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).

[0208] In some embodiments, R together with the carbon atom to which they are attached 11 and R 19 The substituted heterocycloalkylene formed by the attachment of R is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkylene is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. In some embodiments, R together with the carbon atoms to which they are attached can be substituted with at least one substituent, size-limiting substituent, or lower substituent. 11 and R 19When the heterocycloalkylene formed by the attachment of R is substituted, it is substituted with at least one substituent. In some embodiments, R together with the carbon atom to which they are attached 11 and R 19 If the heterocycloalkylene formed by the attachment of R is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R together with the carbon atom to which they are attached 11 and R 19 When the heterocycloalkylene formed by bonding is substituted, it is substituted with at least one lower substituent.

[0209] In some embodiments, R together with the carbon atom to which they are attached 11 and R 19 The substituted cycloalkylene formed by the attachment of R is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted cycloalkylene is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. In some embodiments, R together with the carbon atoms to which they are attached can be substituted with at least one substituent, size-limiting substituent, or lower substituent. 11 and R 19 When the cycloalkylene formed by the bonding of R is substituted, it is substituted with at least one substituent. In some embodiments, R together with the carbon atom to which they are attached 11 and R 19 If the cycloalkylene formed by the attachment of R is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R together with the carbon atom to which they are attached 11 and R 19 When the cycloalkylene formed by bonding is substituted, it is substituted with at least one lower substituent.

[0210] In some embodiments, R 11and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 6-membered heterocycloalkylene. In some embodiments, R 11 and R 19 together with the carbon atoms to which they are attached form a substituted or unsubstituted 4-membered heterocycloalkylene.

[0211] In some embodiments, R 11 and R 19 taken together with the carbon atom to which they are attached form a substituted 4-membered heterocycloalkylene. In some embodiments, R 11 and R 19 together with the carbon atoms to which they are attached form an unsubstituted 4-membered heterocycloalkylene.

[0212] In some embodiments, R 11 and R 19 together with the carbon atom to which they are attached to form a locked nucleic acid (LNA).

[0213] In some embodiments, each R 1A , R 2A , R 3A , R 7A , R 11A , R 11B , R 19A , and R 19Bare independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or is an unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0214] In some embodiments, 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. In some embodiments, each R 1A , R2A , R 3A , R 7A , R 11A , R 11B , R 19A , and R 19B is independently substituted with one or more size-limiting substituents. In some embodiments, 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 lower substituents.

[0215] In some embodiments, R 7A and R 7B Substituents can be optionally joined to form a substituted (e.g., with a substituent, size-limiting substituent, or 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., with a substituent, size-limiting substituent, or 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). In some embodiments, R 7A and R 7B The substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituted group, where when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituted groups, each substituent, size-limiting substituent, and / or lower-substituted group may optionally be different. In some embodiments, R 7A and R 7BWhen the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 7A and R 7B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 7A and R 7B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent. In some embodiments, R 7A and R 7B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 7A and R 7B If the heteroaryl formed by the attachment of the substituents is substituted, it is substituted with at least one size-limited substituent. In some embodiments, R 7A and R 7B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0216] In some embodiments, R 11A and R 11B Substituents can be optionally joined to form a substituted (e.g., with a substituent, size-limiting substituent, or 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., with a substituent, size-limiting substituent, or 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). In some embodiments, R 11A and R 11BThe substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituted group, where when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituted groups, each substituent, size-limiting substituent, and / or lower-substituted group may optionally be different. In some embodiments, R 11A and R 11B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 11A and R 11B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 11A and R 11B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent. In some embodiments, R 11A and R 11B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 11A and R 11B If the heteroaryl formed by the attachment of the substituents is substituted, it is substituted with at least one size-limited substituent. In some embodiments, R 11A and R 11B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0217] In some embodiments, R 19A and R 19BSubstituents can be optionally joined to form a substituted (e.g., with a substituent, size-limiting substituent, or 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., with a substituent, size-limiting substituent, or 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). In some embodiments, R 19A and R 19B The substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituted group, where when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituted groups, each substituent, size-limiting substituent, and / or lower-substituted group may optionally be different. In some embodiments, R 19A and R 19B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 17A and R 19B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 19A and R 19B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent. In some embodiments, R 19A and R 19B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 19A and R 19BIf the heteroaryl formed by the attachment of the substituents is substituted, it is substituted with at least one size-limited substituent. In some embodiments, R 19A and R 19B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0218] In some embodiments, B 1 and B 3 are each independently a natural, modified, or unnatural nucleoside base. In some embodiments, B 1 and B 3 are each independently a natural nucleoside base. In some embodiments, B 1 and B 3 are each independently a modified nucleoside base. In some embodiments, B 1 and B 3 are each independently an unnatural nucleoside base.

[0219] In some embodiments, B 1 and B 3 are each independently adenine, guanine, cytosine, uracil, or thymine. 1 is adenine. In some embodiments, B 1 is guanine. In some embodiments, B 1 is cytosine. In some embodiments, B 1 is uracil. In some embodiments, B 1 is thymine. In some embodiments, B 3 is adenine. In some embodiments, B 3 is guanine. In some embodiments, B 3 is cytosine. In some embodiments, B 3 is uracil. In some embodiments, B 3 is thymine.

[0220] In some embodiments, B 1 are independently 5-methylcytosine, pseudouracil, hypoxanthine, N1-methylpseudouracil, N6-methyladenine, N6-ethyladenine, 7-deazaadenine, N-(alkyl)-cytosine, or 5-ethylcytosine (U.S. Pat. No. 6,762,298).

[0221] In some embodiments, B 1 These include 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 cytosine, 6-azouracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and These include, but are not limited to, guanine, 5-halo, especially 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 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.

[0222] In some embodiments, B 3These include, but are not limited to, adenine, guanine, cytosine, uracil, pseudouracil, 5-methylcytosine, N6-methyladenine, hypoxanthine, 5-hydroxymethylcytosine, 5-carboxylcytosine, N4-acetylcytosine, N4-methylcytosine, N1-methyladenine, N2,N2-dimethylguanine, and the like.

[0223] In some embodiments, each B 2 is independently a natural, modified, or non-natural nucleoside base. In some embodiments, each B 2 are independently natural nucleoside bases. In some embodiments, each B 2 is independently a modified nucleoside base. In some embodiments, each B 2 are independently unnatural nucleoside bases.

[0224] In some embodiments, each B 2 is independently adenine, guanine, cytosine, uracil, or thymine. 2 is adenine. In some embodiments, B 2 is guanine. In some embodiments, B 2 is cytosine. In some embodiments, B 2 is uracil. In some embodiments, B 2 is thymine.

[0225] In some embodiments, each B 2 are independently 5-methylcytosine, pseudouracil, hypoxanthine, N1-methylpseudouracil, N6-methyladenine, N6-ethyladenine, 7-deazaadenine, N-(alkyl)-cytosine, or 5-ethylcytosine (U.S. Pat. No. 6,762,298).

[0226] In some embodiments, each B 2These include 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 cytosine, 6-azouracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and These include, but are not limited to, guanine, 5-halo, especially 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 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.

[0227] Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0228] In some embodiments, ring A is substituted or unsubstituted heterocycloalkylene. In some embodiments, ring A is substituted heterocycloalkylene. In some embodiments, ring A is unsubstituted heterocycloalkylene.

[0229] In some embodiments, ring A is substituted or unsubstituted heteroarylene. In some embodiments, ring A is substituted heteroarylene. In some embodiments, ring A is unsubstituted heteroarylene.

[0230] In some embodiments, ring A is a 3- to 10-membered substituted heterocycloalkylene. In some embodiments, ring A is a 3-membered substituted heterocycloalkylene. In some embodiments, ring A is a 4-membered substituted heterocycloalkylene. In some embodiments, ring A is a 5-membered substituted heterocycloalkylene. In some embodiments, ring A is a 6-membered substituted heterocycloalkylene. In some embodiments, ring A is a 7-membered substituted heterocycloalkylene. In some embodiments, ring A is an 8-membered substituted heterocycloalkylene. In some embodiments, ring A is a 9-membered substituted heterocycloalkylene. In some embodiments, ring A is a 10-membered substituted heterocycloalkylene.

[0231] In some embodiments, ring A is a 3- to 10-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is a 3-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is a 4-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is a 5-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is a 6-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is a 7-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is an 8-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is a 9-membered unsubstituted heterocycloalkylene. In some embodiments, ring A is a 10-membered unsubstituted heterocycloalkylene.

[0232] In some embodiments, ring A is substituted or unsubstituted tetrahydrofuranylene. In some embodiments, ring A is substituted tetrahydrofuranylene. In some embodiments, ring A is unsubstituted tetrahydrofuranylene. In some embodiments, ring A is substituted or unsubstituted morpholinylene. In some embodiments, ring A is substituted morpholinylene. In some embodiments, ring A is unsubstituted morpholinylene.

[0233] In some embodiments, ring A is [ka] In some embodiments, Ring A is [ka] In some embodiments, ring A is [ka] is.

[0234] In some embodiments, X 1 and X 2 are each independently -O-, -CH2-, -CX2-, -N(R 101 )-, -BH-, or -S-.

[0235] In some embodiments, X 1 is -O-, -CH2-, or -CX2-. In some embodiments, X 1 is —O—, —CH—, or —CF—. In some embodiments, X 1 is —O—. In some embodiments, X 1 is -CH-. In some embodiments, X 1 In some embodiments, X is -CX-. 1 is -CF-. In some embodiments, X 1 is -N(R 101 In some embodiments, X 1 is -NH-. In some embodiments, X 1 is -BH-. In some embodiments, X 1 is -S-.

[0236] In some embodiments, X 2 -O-, -CH2-, -CX2-, -N(R 101)-, -BH-, or -S-. In some embodiments, X 2 is -O-, -CH2-, -CF2-, -NH-, -BH-, or -S-. In some embodiments, X 2 is —O—, —CH—, or —NH—. In some embodiments, X 2 is -CH2- or -NH-.

[0237] In some embodiments, X 2 is —O—. In some embodiments, X 2 is -CH-. In some embodiments, X 2 In some embodiments, X is -CX-. 2 is -CF-. In some embodiments, X 2 is -N(R 101 In some embodiments, X 2 is -NH-. In some embodiments, X 2 is -BH-. In some embodiments, X 2 is -S-.

[0238] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O, S, or Se. In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 are each independently O, S, or Se. In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently O or S. In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 are each independently O or S. In some embodiments, Y 1 , Y2 , Y 3 , Y 4 , and Y 5 are each independently O. In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 are each independently O. In some embodiments, Y 1 is O. In some embodiments, Y 1 is S. In some embodiments, Y 1 is Se. In some embodiments, Y 2 is O. In some embodiments, Y 2 is S. In some embodiments, Y 2 is Se. In some embodiments, Y 3 is O. In some embodiments, Y 3 is S. In some embodiments, Y 3 is Se. In some embodiments, Y 4 is O. In some embodiments, Y 4 is S. In some embodiments, Y 4 is Se. In some embodiments, Y 5 is O or S. In some embodiments, Y 5 is O. In some embodiments, Y 5 is S. In some embodiments, Y 5 is Se.

[0239] In some embodiments, each R is independently selected from hydrogen, oxo, halogen, —CCl, —CBr, —CF, —CI, —CHCl, —CHBr, —CHF, —CHI, —CHCl, —CHBr, —CHF, —CHI, —CN, —OH, —NH, —COOH, —CONH, —NO, —SH, —SOH, —SOH, —SONH, —NHNH, —ONH, —NHC(O)NHNH, —NHC(O) NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl , C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., with a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). In some embodiments, R 101is substituted with one or more substituents. In some embodiments, R 101 is substituted with one or more size-limiting substituents. In some embodiments, R 101 is substituted with one or more lower substituents.

[0240] In some embodiments, each X is independently -Cl, -Br, -I, or -F. In some embodiments, X is independently -Cl. In some embodiments, X is independently -Br. In some embodiments, X is independently -I. In some embodiments, X is independently -F.

[0241] In some embodiments, n is an integer from 0 to 3. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0242] In some embodiments, m is an integer from 0 to 8. In some embodiments, m is 0 or 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8.

[0243] In some embodiments, formula (IA) [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, During the ceremony, B 3 is a natural nucleoside base, R 4 is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; R 6 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 6A , -NR 6A R 6B, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 14A , -NR 14A R 14B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 14A , and R 14Bare independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 attached to the same nitrogen atom 6A and R 6B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 14A and R 14B The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. 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 herein, including in the embodiments.

[0244] In some embodiments, R 4 are independently hydrogen, -C(O)R 4A , -C(O)OR 4A , -OR 4A, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0245] In some embodiments, the substitution R 4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are independently substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 4 When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 4 When R is independently substituted, it is substituted with at least one substituent.4 When R is independently substituted, it is substituted with at least one size-limiting substituent. 4 When is independently substituted, it is substituted with at least one lower substituent.

[0246] In some embodiments, R 4 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In some embodiments, R 4 are independently hydrogen, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 4 are independently hydrogen. In some embodiments, R 4 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 4 is independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 4 are independently unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 4 are independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl).

[0247] In some embodiments, R 4are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4-chlorobenzyl.

[0248] In some embodiments, R 4 are independently hydrogen. In some embodiments, R 4 is independently methyl. In some embodiments, R 4 is independently ethyl. In some embodiments, R 4 is independently propyl. In some embodiments, R 4 is independently isopropyl. In some embodiments, R 4 is independently butyl. In some embodiments, R 4 is independently isobutyl. In some embodiments, R 4 is independently t-butyl. In some embodiments, R 4 is independently pentyl. In some embodiments, R 4 is independently isopentyl. In some embodiments, R 4 is independently hexyl. In some embodiments, R 4 is independently phenyl. In some embodiments, R 4 is independently benzyl. In some embodiments, R 4 is independently 4-chlorobenzyl.

[0249] In some embodiments, R 5 are independently hydrogen, -C(O)R 5A , -C(O)OR 5A , -OR 5A, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0250] In some embodiments, the substitution R 5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are independently substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 5 When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 5 When R is independently substituted, it is substituted with at least one substituent.5 When R is independently substituted, it is substituted with at least one size-limiting substituent. 5 When is independently substituted, it is substituted with at least one lower substituent.

[0251] In some embodiments, R 5 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In some embodiments, R 5 are independently hydrogen, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 5 are independently hydrogen. In some embodiments, R 5 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 5 is independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 5 are independently unsubstituted aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In some embodiments, R 5 are independently substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl).

[0252] In some embodiments, R 5are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4-chlorobenzyl.

[0253] In some embodiments, R 5 are independently hydrogen. In some embodiments, R 5 is independently methyl. In some embodiments, R 5 is independently ethyl. In some embodiments, R 5 is independently propyl. In some embodiments, R 5 is independently isopropyl. In some embodiments, R 5 is independently butyl. In some embodiments, R 5 is independently isobutyl. In some embodiments, R 5 is independently t-butyl. In some embodiments, R 5 is independently pentyl. In some embodiments, R 5 is independently isopentyl. In some embodiments, R 5 is independently hexyl. In some embodiments, R 5 is independently phenyl. In some embodiments, R 5 is independently benzyl. In some embodiments, R 5 is independently 4-chlorobenzyl.

[0254] In some embodiments, R 6 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 6A , -NR 6A R 6B, -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0255] In some embodiments, the substitution R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 6 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 6 When R is substituted, it is substituted with at least one substituent. 6When R is substituted, it is substituted with at least one size-limiting substituent. 6 When is substituted, it is substituted with at least one lower substituent.

[0256] In some embodiments, R 6 is hydrogen, halogen, or -NR 6A R 6B In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is halogen. In some embodiments, R 6 is -NR 6A R 6B In some embodiments, R 6 is -Cl. In some embodiments, R 6 is -Br. In some embodiments, R 6 is -I. In some embodiments, R 6 is -F. In some embodiments, R 6 is -NHMe. In some embodiments, R 6 is -NH. In some embodiments, R 6 is -NMe2.

[0257] In some embodiments, R 6 is hydrogen, -F, -NHMe, -NH, or -NMe. In some embodiments, R 6 is hydrogen or -NHMe. In some embodiments, R 6 is hydrogen.

[0258] In some embodiments, R 6A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 6A is hydrogen. In some embodiments, R 6A is substituted alkyl. In some embodiments, R 6A is unsubstituted alkyl. In some embodiments, R 6Bis hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 6B is hydrogen. In some embodiments, R 6B is substituted alkyl. In some embodiments, R 6B is an unsubstituted alkyl.

[0259] In some embodiments, R 6A is hydrogen, substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 6B is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0260] In some embodiments, the substitution R 6A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 6A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 6A When R is substituted, it is substituted with at least one substituent. 6A When R is substituted, it is substituted with at least one size-limiting substituent. 6A When R is substituted, it is substituted with at least one lower substituent. In some embodiments, the substituted R 6B(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 6B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 6B When R is substituted, it is substituted with at least one substituent. 6B When R is substituted, it is substituted with at least one size-limiting substituent. 6B When is substituted, it is substituted with at least one lower substituent.

[0261] In some embodiments, R 6A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 6A is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 6A is hydrogen. In some embodiments, R 6A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 6A is a substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 6B is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 6Bis hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 6B is hydrogen. In some embodiments, R 6B is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 6B is a substituted (eg, by a substituent, a size-limited substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0262] In some embodiments, R 6A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 6A is hydrogen. In some embodiments, R 6A is methyl. In some embodiments, R 6A is ethyl. In some embodiments, R 6A is propyl. In some embodiments, R 6A is isopropyl. In some embodiments, R 6A is butyl. In some embodiments, R 6A is isobutyl. In some embodiments, R 6A is t-butyl. In some embodiments, R 6A is pentyl. In some embodiments, R 6A is hexyl. In some embodiments, R 6B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 6B is hydrogen. In some embodiments, R 6B is methyl. In some embodiments, R 6B is ethyl. In some embodiments, R6B is propyl. In some embodiments, R 6B is isopropyl. In some embodiments, R 6B is butyl. In some embodiments, R 6B is isobutyl. In some embodiments, R 6B is t-butyl. In some embodiments, R 6B is pentyl. In some embodiments, R 6B is hexyl.

[0263] In some embodiments, R 14 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 14A , -NR 14A R 14B , -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0264] In some embodiments, the substitution R 14 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 14 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 14 When R is substituted, it is substituted with at least one substituent. 14 When R is substituted, it is substituted with at least one size-limiting substituent. 14 When is substituted, it is substituted with at least one lower substituent.

[0265] In some embodiments, R 14 is hydrogen, halogen, or -NR 14A R 14B In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is halogen. In some embodiments, R 14 is -NR 14A R 14B In some embodiments, R 14 is -Cl. In some embodiments, R 14 is -Br. In some embodiments, R 14 is -I. In some embodiments, R 14 is -F. In some embodiments, R 14is -NHMe. In some embodiments, R 14 is -NH. In some embodiments, R 14 is -NMe2.

[0266] In some embodiments, R 14 is hydrogen, -F, -NHMe, -NH, or -NMe. In some embodiments, R 14 is hydrogen or -NH. In some embodiments, R 14 is hydrogen.

[0267] In some embodiments, R 14A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 14A is hydrogen. In some embodiments, R 14A is substituted alkyl. In some embodiments, R 14A is unsubstituted alkyl. In some embodiments, R 14B is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 14B is hydrogen. In some embodiments, R 14B is substituted alkyl. In some embodiments, R 6B is an unsubstituted alkyl.

[0268] In some embodiments, R 14A is hydrogen, substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 14B is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0269] In some embodiments, the substitution R 14A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 14A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 14A When R is substituted, it is substituted with at least one substituent. 14A When R is substituted, it is substituted with at least one size-limiting substituent. 14A When R is substituted, it is substituted with at least one lower substituent. In some embodiments, the substituted R 14B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 14B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 14B When R is substituted, it is substituted with at least one substituent. 14B When R is substituted, it is substituted with at least one size-limiting substituent. 14B When is substituted, it is substituted with at least one lower substituent.

[0270] In some embodiments, R 14A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 14Ais hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 14A is hydrogen. In some embodiments, R 14A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 14A is a substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 14B is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 14B is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 14B is hydrogen. In some embodiments, R 14B is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 14B is a substituted (eg, by a substituent, a size-limited substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0271] In some embodiments, R 14A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 14A is hydrogen. In some embodiments, R 14A is methyl. In some embodiments, R 14A is ethyl. In some embodiments, R 14A is propyl. In some embodiments, R 14Ais isopropyl. In some embodiments, R 14A is butyl. In some embodiments, R 14A is isobutyl. In some embodiments, R 14A is t-butyl. In some embodiments, R 14A is pentyl. In some embodiments, R 6A is hexyl. In some embodiments, R 14B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 14B is hydrogen. In some embodiments, R 14B is methyl. In some embodiments, R 14B is ethyl. In some embodiments, R 14B is propyl. In some embodiments, R 14B is isopropyl. In some embodiments, R 14B is butyl. In some embodiments, R 14B is isobutyl. In some embodiments, R 14B is t-butyl. In some embodiments, R 14B is pentyl. In some embodiments, R 14B is hexyl.

[0272] In some embodiments, each R 4A , R 5A , R 6A , R 6B , R 14A , and R 14Bare independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or is an unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0273] In some embodiments, each R 4A , R 5A , R 6A , R 6B , R 14A , and R 14B is independently substituted with one or more substituents. In some embodiments, each R 4A , R 5A , R 6A , R6B , R 14A , and R 14B is independently substituted with one or more size-limiting substituents. In some embodiments, each R 4A , R 5A , R 6A , R 6B , R 14A , and R 14B is independently substituted with one or more lower substituents.

[0274] In some embodiments, R 6A and R 6B Substituents can be optionally joined to form a substituted (e.g., with a substituent, size-limiting substituent, or 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., with a substituent, size-limiting substituent, or 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). In some embodiments, R 6A and R 6B The substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituted group, where when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituted groups, each substituent, size-limiting substituent, and / or lower-substituted group may optionally be different. In some embodiments, R 6A and R 6B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 6A and R 6BIf the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 6A and R 6B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent. In some embodiments, R 6A and R 6B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 6A and R 6B If the heteroaryl formed by the attachment of the substituents is substituted, it is substituted with at least one size-limited substituent. In some embodiments, R 6A and R 6B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0275] In some embodiments, R 14A and R 14B Substituents can be optionally joined to form a substituted (e.g., with a substituent, size-limiting substituent, or 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., with a substituent, size-limiting substituent, or 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). In some embodiments, R 14A and R 14BThe substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituted group, where when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituted groups, each substituent, size-limiting substituent, and / or lower-substituted group may optionally be different. In some embodiments, R 14A and R 14B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 14A and R 14B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 14A and R 14B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent. In some embodiments, R 14A and R 14B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 14A and R 14B If the heteroaryl formed by the attachment of the substituents is substituted, it is substituted with at least one size-limited substituent. In some embodiments, R 14A and R 14B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0276] In some embodiments, each X is independently -Cl, -Br, -I, or -F. In some embodiments, X is independently -Cl. In some embodiments, X is independently -Br. In some embodiments, X is independently -I. In some embodiments, X is independently -F.

[0277] In some embodiments, [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, During the ceremony, R 8 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 8A , -NR 8A R 8B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R 8A , -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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’represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 8’A , -NR 8’A R 8’B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R 8’A , -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 9A , -NR 9A R 9B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)R 9A , -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 9or R 8’ and R 9 together with the carbon atom to which they are attached form a substituted or unsubstituted heterocycloalkylene; R 10 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 10A , -NR 10A R 10B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R 8A , R 8B , R 8’A , R 8’B , R 9A , R 9B , R 10A , and R 10Bare independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 attached to the same nitrogen atom 8A and R 8B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 8’A and R 8’B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 9A and R 9B The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R 10A and R 10B The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. 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 herein, inclusive in embodiments.

[0278] In some embodiments, R 8 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 8A , -NR 8A R 8B , -CONH2, -COOH, -NHC(O)R 8A , -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0279] In some embodiments, the substitution R8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 8 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 8 When R is substituted, it is substituted with at least one substituent. 8 When R is substituted, it is substituted with at least one size-limiting substituent. 8 When is substituted, it is substituted with at least one lower substituent.

[0280] In some embodiments, R 8 are independently hydrogen, halogen, -OR 8A , or -NHC(O)R 8A In some embodiments, R 8 are independently hydrogen. In some embodiments, R 8 is independently halogen. In some embodiments, R 8 are independently -OR 8A In some embodiments, R 8 are independently -NHC(O)R 8A In some embodiments, R 8 is independently chloro. In some embodiments, R 8 is independently bromo. In some embodiments, R 8 is independently iodo. In some embodiments, R 8 is independently fluoro.

[0281] In some embodiments, R 8is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. 8 is independently hydrogen or hydroxy.

[0282] In some embodiments, R 8 is independently hydroxy. In some embodiments, R 8 is independently methoxy. In some embodiments, R 8 is independently ethoxy. In some embodiments, R 8 is independently propoxy. In some embodiments, R 8 is independently butoxy. In some embodiments, R 8 is independently t-butoxy.

[0283] In some embodiments, R 8A are independently hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 8A is hydrogen. In some embodiments, R 8A is substituted alkyl. In some embodiments, R 8A is an unsubstituted alkyl.

[0284] In some embodiments, R 8A is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0285] In some embodiments, the substitution R 8A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 8AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 8A When R is substituted, it is substituted with at least one substituent. 8A When R is substituted, it is substituted with at least one size-limiting substituent. 8A When is substituted, it is substituted with at least one lower substituent.

[0286] In some embodiments, R 8A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 8A is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 8A is hydrogen. In some embodiments, R 8A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 8A is a substituted (eg, by a substituent, a size-limited substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0287] In some embodiments, R 8A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 8A is hydrogen. In some embodiments, R 8A is methyl. In some embodiments, R 8A is ethyl. In some embodiments, R 8A is propyl. In some embodiments, R 8Ais isopropyl. In some embodiments, R 8A is butyl. In some embodiments, R 8A is isobutyl. In some embodiments, R 8A is t-butyl. In some embodiments, R 8A is pentyl. In some embodiments, R 8A is hexyl.

[0288] In some embodiments, R 8’ are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 8’A , -NR 8’A R 8’B , -CONH2, -COOH, -NHC(O)R 8’A , -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0289] In some embodiments, the substitution R 8’ (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 8’ When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 8’ When R is substituted, it is substituted with at least one substituent. 8’ When R is substituted, it is substituted with at least one size-limiting substituent. 8’ When is substituted, it is substituted with at least one lower substituent.

[0290] In some embodiments, R 8’ are independently hydrogen, halogen, -OR 8’A , or -NHC(O)R 8’A In some embodiments, R 8’ are independently hydrogen. In some embodiments, R 8’ is independently halogen. In some embodiments, R 8’ are independently -OR 8’A In some embodiments, R 8’ are independently -NHC(O)R 8’A In some embodiments, R 8’ is independently chloro. In some embodiments, R 8’ is independently bromo. In some embodiments, R8’ is independently iodo. In some embodiments, R 8’ is independently fluoro.

[0291] In some embodiments, R 8’ is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy. 8’ is independently hydrogen or hydroxy.

[0292] In some embodiments, R 8’ is independently hydroxy. In some embodiments, R 8’ is independently methoxy. In some embodiments, R 8’ is independently ethoxy. In some embodiments, R 8’ is independently propoxy. In some embodiments, R 8’ is independently butoxy. In some embodiments, R 8’ is independently t-butoxy.

[0293] In some embodiments, R 8’A are independently hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 8’A is hydrogen. In some embodiments, R 8’A is substituted alkyl. In some embodiments, R 8’A is an unsubstituted alkyl.

[0294] In some embodiments, R 8’A is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0295] In some embodiments, the substitution R 8’A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 8’A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 8’A When R is substituted, it is substituted with at least one substituent. 8’A When R is substituted, it is substituted with at least one size-limiting substituent. 8’A When is substituted, it is substituted with at least one lower substituent.

[0296] In some embodiments, R 8’A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 8’A is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 8’A is hydrogen. In some embodiments, R 8’A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 8’A is a substituted (eg, by a substituent, a size-limiting substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0297] In some embodiments, R 8’A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 8’A is hydrogen. In some embodiments, R8’A is methyl. In some embodiments, R 8’A is ethyl. In some embodiments, R 8’A is propyl. In some embodiments, R 8’A is isopropyl. In some embodiments, R 8’A is butyl. In some embodiments, R 8’A is isobutyl. In some embodiments, R 8’A is t-butyl. In some embodiments, R 8’A is pentyl. In some embodiments, R 8’A is hexyl.

[0298] In some embodiments, R 9 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 9A , -NR 9A R 9B , -CONH2, -COOH, -NHC(O)R 9A, -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0299] In some embodiments, the substitution R 9 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 9 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 9 When R is substituted, it is substituted with at least one substituent. 9When R is substituted, it is substituted with at least one size-limiting substituent. 9 When is substituted, it is substituted with at least one lower substituent.

[0300] In some embodiments, R 9 are independently hydrogen, halogen, -OR 9A , or -NHC(O)R 9A In some embodiments, R 9 are independently hydrogen. In some embodiments, R 9 is independently halogen. In some embodiments, R 9 are independently -OR 9A In some embodiments, R 9 are independently -NHC(O)R 9A In some embodiments, R 9 is independently chloro. In some embodiments, R 9 is independently bromo. In some embodiments, R 9 is independently iodo. In some embodiments, R 9 is independently fluoro.

[0301] In some embodiments, R 9 is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

[0302] In some embodiments, R 9 are independently hydrogen. In some embodiments, R 9 is independently hydroxy. In some embodiments, R 9 is independently methoxy. In some embodiments, R 9 is independently ethoxy. In some embodiments, R 9 is independently propoxy. In some embodiments, R 9 is independently butoxy. In some embodiments, R 9is independently t-butoxy.

[0303] In some embodiments, R 9A are independently hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9A is hydrogen. In some embodiments, R 9A is substituted alkyl. In some embodiments, R 9A is an unsubstituted alkyl.

[0304] In some embodiments, R 9A is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0305] In some embodiments, the substitution R 9A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 9A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 9A When R is substituted, it is substituted with at least one substituent. 9A When R is substituted, it is substituted with at least one size-limiting substituent. 9A When is substituted, it is substituted with at least one lower substituent.

[0306] In some embodiments, R 9A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 9Ais hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 9A is hydrogen. In some embodiments, R 9A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 9A is a substituted (eg, by a substituent, a size-limiting substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0307] In some embodiments, R 9A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. 9A is hydrogen. In some embodiments, R 9A is methyl. In some embodiments, R 9A is ethyl. In some embodiments, R 9A is propyl. In some embodiments, R 9A is isopropyl. In some embodiments, R 9A is butyl. In some embodiments, R 9A is isobutyl. In some embodiments, R 9A is t-butyl. In some embodiments, R 9A is pentyl. In some embodiments, R 9A is isopentyl. In some embodiments, R 9A is hexyl.

[0308] In some embodiments, (R 8 and R 9 ) or (R 8’ and R 9) taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocycloalkylene. In some embodiments, (R 8 and R 9 ) or (R 8’ and R 9 ), taken together with the carbon atom to which they are attached, form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkylene (e.g., a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene).

[0309] In some embodiments, (R 8 and R 9 ) or (R 8’ and R 9 The substituted heterocycloalkylene formed by the attachment of (R) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkylene is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. In some embodiments, (R) together with the carbon atoms to which they are attached can be substituted with at least one substituent, size-limiting substituent, or lower substituent. 8 and R 9 ) or (R 8’ and R 9 When the heterocycloalkylene formed by the attachment of (R) is substituted, it is substituted with at least one substituent. In some embodiments, (R) together with the carbon atom to which they are attached can be substituted with at least one substituent. 8 and R 9 ) or (R 8’ and R 9 When the heterocycloalkylene formed by the attachment of (R) is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, (R) together with the carbon atom to which they are attached 8 and R 9 ) or (R 8’ and R9 When the heterocycloalkylene formed by bonding of (a) and (b) is substituted, it is substituted with at least one lower substituent.

[0310] In some embodiments, (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 5- to 6-membered heterocycloalkylene. In some embodiments, (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 5-membered heterocycloalkylene. In some embodiments, (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 6-membered heterocycloalkylene.

[0311] In some embodiments, (R 8 and R 9 ) or (R 8’ and R 9 ) together with the carbon atom to which they are attached form a substituted 5-membered heterocycloalkylene. In some embodiments, (R 8 and R 9 ) or (R 8’ and R 9 ) together with the carbon atom to which they are attached form an unsubstituted 5-membered heterocycloalkylene. In some embodiments, (R 8 and R 9 ) or (R 8’ and R 9 ) together with the carbon atom to which they are attached form a substituted 6-membered heterocycloalkylene. In some embodiments, (R 8 and R 9 ) or (R 8’and R 9 ) together with the carbon atom to which they are attached form an unsubstituted 6-membered heterocycloalkylene.

[0312] In some embodiments, R 10 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 10A , -NR 10A R 10B , -CONH2, -COOH, -NHC(O)OH, -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl ... substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted by at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0313] In some embodiments, the substitution R 10(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 10 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 10 When R is substituted, it is substituted with at least one substituent. 10 When R is substituted, it is substituted with at least one size-limiting substituent. 10 When is substituted, it is substituted with at least one lower substituent.

[0314] In some embodiments, R 10 is hydrogen.

[0315] In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 ), taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene. In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 ) taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkylene. In some embodiments, (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 heterocycloalkylene.

[0316] In some embodiments, (R 8 and R 10) or (R 8’ and R 10 ), taken together with the carbon atom to which they are attached, form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkylene (e.g., a 3-8 membered heterocycloalkylene, a 3-6 membered heterocycloalkylene, or a 5-6 membered heterocycloalkylene). In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 ), taken together with the carbon atom to which they are attached, form a substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene).

[0317] In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 The substituted heterocycloalkylene formed by the attachment of (R) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkylene is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. In some embodiments, (R) together with the carbon atoms to which they are attached can be substituted with at least one substituent, size-limiting substituent, or lower substituent. 8 and R 10 ) or (R 8’ and R 10 When the heterocycloalkylene formed by the attachment of (R) is substituted, it is substituted with at least one substituent. In some embodiments, (R) together with the carbon atom to which they are attached can be substituted with at least one substituent. 8 and R 10 ) or (R 8’ and R 10When the heterocycloalkylene formed by the attachment of (R) is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, (R) together with the carbon atom to which they are attached 8 and R 10 ) or (R 8’ and R 10 When the heterocycloalkylene formed by bonding of (a) and (b) is substituted, it is substituted with at least one lower substituent.

[0318] In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 The substituted cycloalkylene formed by the attachment of (R) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted cycloalkylene is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. In some embodiments, (R) together with the carbon atoms to which they are attached can be substituted with at least one substituent, size-limiting substituent, or lower substituent. 8 and R 10 ) or (R 8’ and R 10 When the cycloalkylene formed by bonding (R ) is substituted, it is substituted with at least one substituent. In some embodiments, (R ) together with the carbon atom to which they are attached can be substituted with at least one substituent. 8 and R 10 ) or (R 8’ and R 10 When the cycloalkylene formed by the attachment of (R) is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, (R) together with the carbon atom to which they are attached 8 and R 10 ) or (R 8’ and R 10When the cycloalkylene formed by bonding of (a) and (b) is substituted, it is substituted with at least one lower substituent.

[0319] In some embodiments, (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 3- to 6-membered heterocycloalkylene. In some embodiments, (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 4-membered heterocycloalkylene.

[0320] In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 ) together with the carbon atom to which they are attached form a substituted 4-membered heterocycloalkylene. In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 ) together with the carbon atom to which they are attached form an unsubstituted 4-membered heterocycloalkylene.

[0321] In some embodiments, (R 8 and R 10 ) or (R 8’ and R 10 ) together with the carbon atom to which they are attached form a locked nucleic acid (LNA).

[0322] In some embodiments, each R 8A , R 8B , R 8’A , R 8’B , R 9A , R 9B , R 10A , and R 10Bare independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or is an unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0323] In some embodiments, 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. In some embodiments, each R 8A , R8B , R 8’A , R 8’B , R 9A , R 9B , R 10A , and R 10B is independently substituted with one or more size-limiting substituents. In some embodiments, 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 lower substituents.

[0324] In some embodiments, R 8A and R 8B Substituents may be optionally combined to form a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl), or a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0325] In some embodiments, R 8’A and R 8’B Substituents may be optionally combined to form a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl), or a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0326] In some embodiments, R 8A and R 8B The substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituent, and when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituents, each substituent, size-limiting substituent, and / or lower-substituent can be optionally different.

[0327] In some embodiments, R 8’A and R 8’B The substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituent, and when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituents, each substituent, size-limiting substituent, and / or lower-substituent can be optionally different.

[0328] In some embodiments, R 8A and R 8B If the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 8A and R 8B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 8A and R 8B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0329] In some embodiments, R 8’A and R8’B If the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 8’A and R 8’B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 8’A and R 8’B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0330] In some embodiments, R 8A and R 8B If the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 8A and R 8B If the heteroaryl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 8A and R 8B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0331] In some embodiments, R 8’A and R 8’B If the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 8’A and R 8’B If the heteroaryl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 8’A and R8’B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0332] In some embodiments, R 9A and R 9B Substituents may be optionally combined to form a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl), or a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0333] In some embodiments, R 9A and R 9B The substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituent, and when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituents, each substituent, size-limiting substituent, and / or lower-substituent can be optionally different.

[0334] In some embodiments, R 9A and R 9B If the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 9A and R 9B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 9A and R9B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0335] In some embodiments, R 9A and R 9B If the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 9A and R 9B If the heteroaryl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 9A and R 9B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0336] In some embodiments, R 10A and R 10B Substituents may be optionally combined to form a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl), or a substituted (e.g., by a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0337] In some embodiments, R 10A and R 10BThe substituted heterocycloalkyl or substituted heteroaryl formed by the bonding of substituents is substituted with at least one substituent, size-limiting substituent, or lower-substituent, and when the substituted heterocycloalkyl or substituted heteroaryl is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituents, each substituent, size-limiting substituent, and / or lower-substituent can be optionally different.

[0338] In some embodiments, R 10A and R 10B If the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 10A and R 10B If the heterocycloalkyl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 10A and R 10B When the heterocycloalkyl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0339] In some embodiments, R 10A and R 10B If the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one substituent. In some embodiments, R 10A and R 10B If the heteroaryl formed by the bonding of the substituents is substituted, it is substituted with at least one size-limiting substituent. In some embodiments, R 10A and R 10B When the heteroaryl formed by bonding of the substituents is substituted, it is substituted with at least one lower substituent.

[0340] In some embodiments, each X is independently -Cl, -Br, -I, or -F. In some embodiments, X is independently -Cl. In some embodiments, X is independently -Br. In some embodiments, X is independently -I. In some embodiments, X is independently -F.

[0341] In some embodiments, the formula (IC): [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, 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 herein, inclusive in embodiments.

[0342] In some embodiments, the formula (ID): [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, During the ceremony, R 12 is 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 4 and R 5 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; Each R 12A and R 13A are independently hydrogen, —CX, —CHX, CHX, —C(O)OH, —C(O)NH, —CN, —OH, —NH, —COOH, —CONH, —NO, —SH, —SOH, —SOH, —SONH, —NHNH, —ONH, —NHC═(O)NHNH, —NHC═(O)NH, —NHSOH, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCX, —OCHX, —OCHX, 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. R1 , 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 , ring A, and n are each as defined herein, including in the embodiments.

[0343] In some embodiments, R 12 are independently hydrogen, -C(O)R 12A , -C(O)OR 12A , -OR 12A , substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0344] In some embodiments, the substitution R 12 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are independently substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 12 When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 12 When R is independently substituted, it is substituted with at least one substituent. 12 When R is independently substituted, it is substituted with at least one size-limiting substituent. 12 When is independently substituted, it is substituted with at least one lower substituent.

[0345] In some embodiments, R 12 are independently hydrogen or substituted or unsubstituted alkyl.

[0016] In some embodiments, R 12 are independently hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 12 are independently hydrogen. In some embodiments, R 12 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 12is independently substituted (eg, by a substituent, a size-limiting substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0346] In some embodiments, R 12 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

[0347] In some embodiments, R 12 is independently hydrogen or methyl.

[0348] In some embodiments, R 12 are independently hydrogen. In some embodiments, R 12 is independently methyl. In some embodiments, R 12 is independently ethyl. In some embodiments, R 12 is independently propyl. In some embodiments, R 12 is independently isopropyl. In some embodiments, R 12 is independently butyl. In some embodiments, R 12 is independently isobutyl. In some embodiments, R 12 is independently t-butyl. In some embodiments, R 12 is independently pentyl. In some embodiments, R 12 is independently isopentyl. In some embodiments, R 12 is independently hexyl.

[0349] In some embodiments, R 13 are independently hydrogen, -C(O)R 13A , -C(O)OR 13A , -OR 13A, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0350] In some embodiments, the substitution R 13 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are independently substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 13 When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 13 When R is independently substituted, it is substituted with at least one substituent.13 When R is independently substituted, it is substituted with at least one size-limiting substituent. 13 When is independently substituted, it is substituted with at least one lower substituent.

[0351] In some embodiments, R 13 are independently hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 13 are independently hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 13 are independently hydrogen. In some embodiments, R 13 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 13 is independently substituted (eg, by a substituent, a size-limiting substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0352] In some embodiments, R 13 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

[0353] In some embodiments, R 13 is independently hydrogen or methyl.

[0354] In some embodiments, R 13 are independently hydrogen. In some embodiments, R 13 is independently methyl. In some embodiments, R 13 is independently ethyl. In some embodiments, R 13 is independently propyl. In some embodiments, R13 is independently isopropyl. In some embodiments, R 13 is independently butyl. In some embodiments, R 13 is independently isobutyl. In some embodiments, R 13 is independently t-butyl. In some embodiments, R 13 is independently pentyl. In some embodiments, R 13 is independently isopentyl. In some embodiments, R 13 is independently hexyl.

[0355] In some embodiments, each R 12A and R 13A are independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or is an unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., by substituents, size-limiting substituents, or lower substituents) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), or substituted (e.g., by a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl).

[0356] In some embodiments, each R 12A and R 13A is independently substituted with one or more substituents. In some embodiments, each R 12A and R 13A is independently substituted with one or more size-limiting substituents. In some embodiments, each R 12A and R 13A is independently substituted with one or more lower substituents.

[0357] In some embodiments, each X is independently -Cl, -Br, -I, or -F. In some embodiments, X is independently -Cl. In some embodiments, X is independently -Br. In some embodiments, X is independently -I. In some embodiments, X is independently -F.

[0358] In some embodiments, the formula (IE): [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8’ , R 9 , R 10 , R 11 , R12 , 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 herein, inclusive in embodiments.

[0359] In some embodiments, the formula (IF): [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, 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 herein, inclusive in embodiments.

[0360] In some embodiments, the formula (IG): [ka] or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, During the ceremony, R 15 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OR 15A , -NR 15A R 15B , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF5, 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 is 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 15A , R 15B , and R 16Aare independently hydrogen, -CX, -CHX, -CHX, -C(O)OH, -C(O)NH, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 attached to the same nitrogen atom 15A and R 15B The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. 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 herein, including in the embodiments.

[0361] In some embodiments, R 15 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 15A , -NR 15A R 15B, -NO2, -SH, substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent), substituted) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0362] In some embodiments, the substitution R 15 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 15 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 15 When R is substituted, it is substituted with at least one substituent. 15When R is substituted, it is substituted with at least one size-limiting substituent. 15 When is substituted, it is substituted with at least one lower substituent.

[0363] In some embodiments, R 15 is hydrogen, halogen, or -NR 15A R 15B In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is halogen. In some embodiments, R 15 is -NR 15A R 15B In some embodiments, R 15 is -Cl. In some embodiments, R 15 is -Br. In some embodiments, R 15 is -I. In some embodiments, R 15 is -F. In some embodiments, R 15 is -NHMe. In some embodiments, R 15 is -NH. In some embodiments, R 15 is -NMe2.

[0364] In some embodiments, R 15 is hydrogen, -F, -NHMe, -NH, or -NMe. In some embodiments, R 15 is hydrogen, -NHMe, or -NH2.

[0365] In some embodiments, R 15A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 15A is hydrogen. In some embodiments, R 15A is substituted alkyl. In some embodiments, R 15A is unsubstituted alkyl. In some embodiments, R 15B is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R15B is hydrogen. In some embodiments, R 15B is substituted alkyl. In some embodiments, R 15B is an unsubstituted alkyl.

[0366] In some embodiments, R 15A is hydrogen, substituted (e.g., substituted with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 15B is hydrogen, substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0367] In some embodiments, the substitution R 15A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 15A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 15A When R is substituted, it is substituted with at least one substituent. 15A When R is substituted, it is substituted with at least one size-limiting substituent. 15A When R is substituted, it is substituted with at least one lower substituent. In some embodiments, the substituted R 15B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 15BWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 15B When R is substituted, it is substituted with at least one substituent. 15B When R is substituted, it is substituted with at least one size-limiting substituent. 15B When is substituted, it is substituted with at least one lower substituent.

[0368] In some embodiments, R 15A is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 15A is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 15A is hydrogen. In some embodiments, R 15A is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 15A is a substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 15B is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 15B is hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 15B is hydrogen. In some embodiments, R 15B is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R15B is a substituted (eg, by a substituent, a size-limited substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0369] In some embodiments, R 15A is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 15A is hydrogen. In some embodiments, R 15A is methyl. In some embodiments, R 15A is ethyl. In some embodiments, R 15A is propyl. In some embodiments, R 15A is isopropyl. In some embodiments, R 15A is butyl. In some embodiments, R 15A is isobutyl. In some embodiments, R 15A is t-butyl. In some embodiments, R 15A is pentyl. In some embodiments, R 15A is hexyl. In some embodiments, R 15B is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. 15B is hydrogen. In some embodiments, R 15B is methyl. In some embodiments, R 15B is ethyl. In some embodiments, R 15B is propyl. In some embodiments, R 15B is isopropyl. In some embodiments, R 15B is butyl. In some embodiments, R 15B is isobutyl. In some embodiments, R 15B is t-butyl. In some embodiments, R 15B is pentyl. In some embodiments, R15B is hexyl.

[0370] In some embodiments, R 16 are independently hydrogen, -C(O)R 16A , -C(O)OR 16A , -OR 16A , substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., substituted with at least one substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0371] In some embodiments, the substitution R 16 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are independently substituted with at least one substituent, size-limiting substituent, or lower substituent, and the substituted R 16When R is independently substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can be optionally different. 16 When R is independently substituted, it is substituted with at least one substituent. 16 When R is independently substituted, it is substituted with at least one size-limiting substituent. 16 When is independently substituted, it is substituted with at least one lower substituent.

[0372] In some embodiments, R 16 are independently hydrogen or substituted or unsubstituted alkyl. In some embodiments, R 16 are independently hydrogen or substituted (e.g., by a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In some embodiments, R 16 are independently hydrogen. In some embodiments, R 16 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 16 is independently substituted (eg, by a substituent, a size-limiting substituent, or a lower substituent) alkyl (eg, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0373] In some embodiments, R 16 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-...

Claims

1. An oligonucleotide comprising 50 to 12,000 nucleotides, the 5' end of which comprises the structure of formula (I) 【Chemistry 206】 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 [In the formula, B １ and B ３ are each independently a natural, modified, or unnatural nucleoside base; Each B ２ are independently a natural, modified, or unnatural nucleoside base; Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X １ and X ２ are each independently —O—, —CH ２ -, -CX ２ -, -N(R １０１ )-, -BH-, or -S-; Y １ , Y ２ , Y ３ , Y ４ , and Y ５ are each independently 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 they are attached form a substituted or unsubstituted heteroaryl or 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; Each R ７ are independently hydrogen, halogen, or —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, or —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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R １１ are independently hydrogen, halogen, or —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 , 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 １１ and R １９ together with the carbon atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R １Ａ , R ２Ａ , R ３Ａ , R ７Ａ , R ７Ｂ , R １１Ａ , R １１Ｂ , 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; Or R bonded to the same nitrogen atom ７Ａ and R ７Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １１Ａ and R １１Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １９Ａ and R １９Ｂ The substituents can be optionally combined 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; m is an integer from 0 to 8; n is an integer from 0 to 3, each X is independently -Cl, -Br, -I, or -F.

2. An oligonucleotide comprising 50 to 12,000 nucleotides, the 5' end of which comprises the structure of formula (II) 【Chemistry 207】 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 [In the formula, B １ and B ２ are each independently a natural, modified, or unnatural nucleoside base; Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X １ and X ２ are each independently —O—, —CH ２ -, -CX ２ -, -N(R １０１ )-, -BH-, or -S-; Y １ , Y ２ , Y ３ , and Y ４ are each independently O, S, or Se; R １ 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 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 they are attached form a substituted or unsubstituted heteroaryl or 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 ７ 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 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, or —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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R １１ are independently hydrogen, halogen, or —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 , 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 １１ and R １９ together with the carbon atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; Each R １Ａ , R ２Ａ , R ３Ａ , R ７Ａ , R ７Ｂ , R １１Ａ , R １１Ｂ , 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; Or R bonded to the same nitrogen atom ７Ａ and R ７Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １１Ａ and R １１Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １９Ａ and R １９Ｂ The substituents can be optionally combined 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; However, R １１ is not OH].

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

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

5. The oligonucleotide of claim 4, wherein the oligonucleotide comprises three or more modified nucleosides at its 3' end.

6. 5. The oligonucleotide of claim 4, wherein the oligonucleotide comprises two or more nucleotides linked together at its 3' end by a modified internucleotide linkage.

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 5' end has the formula (IA): 【Chemistry 208】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, B ３ is a natural nucleoside base, R ４ is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , 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 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １４Ａ and R １４Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

10. The 5' end has the formula (IB): 【Chemistry 209】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

11. The 5' end has the formula (IC): 【Chemistry 210】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

12. The 5' end has the formula (ID): 【Chemistry 211】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ４ is 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 １２ and R １３ together with the nitrogen atom to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , 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 is 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 ４ and R ５ together with the nitrogen atom to which they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , -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 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １４Ａ and R １４Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

13. The 5' end has the formula (IE): 【Chemistry 212】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

14. The 5' end has the formula (IF): 【Chemistry 213】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

15. The 5' end has the formula (IG): 【Chemical 214】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ４ is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , 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 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 is 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 ４Ａ , R ５Ａ , 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １５Ａ and R １５Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

16. The 5' end has the formula (IH): 【Chemistry 215】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

17. The 5' end has the formula (IJ): 【Chemistry 216】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

18. The 5' end has the formula (IK): 【Chemistry 217】 The oligonucleotide of claim 1, comprising the structure 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 [In the formula, 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 , 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 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １４Ａ and R １４Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

19. The 5' end has the formula (IL): 【Chemical 218】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

20. The 5' end has the formula (IM): 【Chemical 219】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

21. The 5' end has the formula (IN): 【Chemistry 220】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, 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 , 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 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 is 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １５Ａ and R １５Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

22. The 5' end has the formula (IO): 【Chemical 221】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

23. The 5' end has the formula (IP): 【Chemical 222】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

24. The 5' end has the formula (IQ): 【Chemical Formula 223】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ４ is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , 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 is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １５Ａ and R １５Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

25. The 5' end has the formula (IR): 【Chemical 224】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

26. The 5' end has the formula (IS): 【Chemical 225】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

27. The 5' end has the formula (IT): 【Chemical 226】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, 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 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 is 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 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 is 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 , 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, 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 attached to the same nitrogen atom １５Ａ and R １５Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １７Ａ and R １７Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

28. The 5' end has the formula (IU): 【Chemical 227】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

29. The 5' end has the formula (IV): 【Chemical 228】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

30. The 5' end has the formula (IW): 【Chemical 229】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, 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 , -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 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 is 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 attached to the same nitrogen atom １４Ａ and R １４Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １７Ａ and R １７Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

31. The 5' end has the formula (IX): 【Chemistry 230】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

32. The 5' end has the formula (IY): 【Chemistry 231】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

33. The 5' end has the formula (IZ): 【Chemical 232】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ４ is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; R １４ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , C.H. 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 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 attached to the same nitrogen atom １４Ａ and R １４Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １７Ａ and R １７Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

34. The 5' end has the formula (IAA): 【Chemical formula 233】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

35. The 5' end has the formula (IBB): 【Chemical 234】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

36. The 5' end has the formula (IIA): 【Chemistry 235】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ４ is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , 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 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １４Ａ and R １４Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

37. The 5' end has the formula (IIB): 【Chemical 236】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

38. The 5' end has the formula (IIC): 【Chemical 237】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

39. The 5' end has the formula (ICC): 【Chemical 238】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X １ and X ２ are each independently —O—, —CH ２ -, -CX ２ -, -N(R １０１ )-, -BH-, or -S-; Y １ , Y ２ , Y ３ , and Y ５ are each independently O, S, or Se; R １ 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 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 they are attached form a substituted or unsubstituted heteroaryl or 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 is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , 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 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 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, or —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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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, and R are attached to the same nitrogen atom. ６Ａ and R ６Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ７Ａ and R ７Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １９Ａ and R １９Ｂ The substituents can be optionally combined 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 5' end has the formula (IDD): 【Chemical 239】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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 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 , 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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

41. The 5' end has the formula (IEE): 【Chemistry 240】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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 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 , 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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

42. The 5' end has the formula (IFF): 【Chemical 241】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ４ is 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 they are attached form a substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl; 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 , 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 , and R ６Ｂ , 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, 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 attached to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

43. The 5' end has the formula (IGG): 【Chemical 242】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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 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 , 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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

44. The 5' end has the formula (IHH): 【Chemical 243】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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 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 , 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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

45. The 5' end has the formula (IJJ): 【Chemical 244】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, 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 , 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 Each R ６Ａ and R ６Ｂ 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, or R bonded to the same nitrogen atom ６Ａ and R ６Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

46. The 5' end has the formula (IKK): 【Chemistry 245】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [In the formula, R ８ 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 , 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’ 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 , 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 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 , 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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

47. The 5' end has the formula (ILL): 【Chemical 246】 or a pharmaceutically acceptable salt, solvate or hydrate thereof. [R ８ 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 , 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’ 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 , 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 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 , 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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 atoms to which they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

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

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

50. R １ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, 【Chemical 247】 or a modified trityl.

51. R １ are independently hydrogen, butyl, or 【Chemical 248】 51. The oligonucleotide of claim 50, wherein:

52. R １ are independently hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, 【Chemical 249】 or a modified trityl.

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

54. R ２ is independently hydrogen, methyl, or ethyl.

55. Propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, 【Chemistry 250】 【Chemistry 251】 or modified trityl.

56. R ２ are independently hydrogen, butyl, or 【Chemical 252】 55. The oligonucleotide of claim 54, wherein:

57. R ２ are independently hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, 【Chemistry 253】 or a modified trityl.

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

59. R ３ 58. The oligonucleotide of claim 57, wherein is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4-chlorobenzyl.

60. R ３ is methyl or 4-chlorobenzyl.

61. R ４ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

62. R ４ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4-chlorobenzyl.

63. R ４ 62. The oligonucleotide of claim 61, wherein:

64. R ５ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

65. R ５ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, phenyl, benzyl, or 4-chlorobenzyl.

66. R ５ 65. The oligonucleotide of claim 64, wherein: are independently hydrogen.

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

68. R ６ is hydrogen, -F, -NHMe, -NH ２ , or -NMe ２ 67. The oligonucleotide of claim 66,

69. R ６ 68. The oligonucleotide of claim 67, wherein is hydrogen or -NHMe.

70. R ６ 69. The oligonucleotide of claim 68, wherein is hydrogen.

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

72. R ７ is independently hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

73. R ７ is independently methoxy.

74. R ８ are independently hydrogen, halogen, or —OR ８Ａ or -NHC(O)R ８Ａ 73. The oligonucleotide of 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,

75. R ８Ａ is independently hydrogen or substituted or unsubstituted alkyl.

76. R ８ is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

77. R ８ is independently hydrogen or hydroxy.

78. R ８’ are independently hydrogen, halogen, or —OR ８’Ａ or -NHC(O)R ８’Ａ 77. The oligonucleotide of 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,

79. R ８’Ａ is independently hydrogen or substituted or unsubstituted alkyl.

80. R ８’ is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

81. R ８’ 80. The oligonucleotide of claim 79, wherein is independently hydrogen or hydroxy.

82. R ９ are independently hydrogen, halogen, or —OR ９Ａ or -NHC(O)R ９Ａ 81. The oligonucleotide of 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,

83. R ９Ａ is independently hydrogen or substituted or unsubstituted alkyl.

84. R ９ is independently hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

85. R ９ is independently methoxy.

86. R １０ 85. The oligonucleotide of 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 49-84, wherein

87. 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 heterocycloalkylene.

88. R ８ and R １０ , or R ８’ and R １０ together with the carbon atom to which they are attached form a locked nucleic acid (LNA).

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

90. R ７ and R １９ together with the carbon atom to which they are attached form a locked nucleic acid (LNA).

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

92. R １１ is independently methoxy, ethoxy, propoxy, butoxy, or t-butoxy.

93. R １１ is independently methoxy.

94. R １２ is independently hydrogen or substituted or unsubstituted alkyl.

95. R １２ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

96. R １２ is independently hydrogen or methyl.

97. R １３ is independently hydrogen or substituted or unsubstituted alkyl.

98. R １３ is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

99. R １３ is independently hydrogen or methyl.

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

101. R １４ is hydrogen, -F, -NHMe, -NH ２ , or -NMe ２ 100. The oligonucleotide of claim 99, wherein:

102. R １４ is hydrogen or -NH ２ The oligonucleotide of claim 100,

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

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

105. R １５ is hydrogen, —NHMe, or —NH ２ The oligonucleotide of claim 103,

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

107. R １６ The oligonucleotide of any one of claims 15-17, 21-23, 27-29, or 48-105, wherein is hydrogen or substituted or unsubstituted alkyl.

108. R １６ 107. The oligonucleotide of claim 106, wherein is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

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

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

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

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

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

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

115. R １８ 114. The oligonucleotide of claim 113, wherein is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl.

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

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

118. X １ However, -O-, -CH ２ - or -CF ２ The oligonucleotide of claim 116, wherein

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

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

121. X ２ However, -O-, -CH ２ -, -CF ２ 120. The oligonucleotide of claim 119, wherein said oligonucleotide is -, -NH-, or -BH-.

122. X ２ The oligonucleotide of claim 120, wherein is -O-.

123. Y １ , Y ２ , Y ３ , and Y ４ is each independently O or S.

124. Y １ , Y ２ , Y ３ , and Y ４ The oligonucleotide of claim 122, wherein each independently is O.

125. Y ５ is O or S.

126. Y ５ The oligonucleotide of claim 124, wherein

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

128. 127. The oligonucleotide of claim 126, wherein n is 1.

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

130. B ３ is a natural nucleoside base.

131. The 5' end has the following structure: 【Chemical 254】 or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, comprising the compound of:

132. The 5' end has the following structure: 【Chemistry 255】 or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, comprising the compound of:

133. The 5' end has the following structure: 【256】 or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof, comprising the compound of:

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

135. 134. The oligonucleotide of claim 133, wherein the pharmaceutically acceptable salt is a sodium salt.

136. The one or more removable hydrophobic groups are G nucleobases of structure of formula (I) or formula (II) 【Chemistry 257】 and / or ring A and / or nucleobase B １ The oligonucleotide of claim 7, wherein the oligonucleotide is linked to

137. The one or more removable hydrophobic groups are G nucleobases of structure of formula (I) or formula (II) 【Chemical 258】 The oligonucleotide of claim 135, wherein the oligonucleotide is linked to

138. 136. The oligonucleotide of claim 135, wherein the one or more removable hydrophobic groups are attached to ring A of the structure of formula (I) or formula (II).

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

140. 138. The oligonucleotide of claim 137, wherein the one or more removable hydrophobic groups are attached to ring A, and ring A is a morpholino ring.

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

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

143. 8. The oligonucleotide of claim 7, wherein each removable hydrophobic group is independently silyl, 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.

144. 143. The oligonucleotide of claim 142, wherein each removable hydrophobic group is independently silyl, trityl, substituted ethyl ether, fluorenylmethyloxycarbonyl (Fmoc), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), dimethoxytrityl (DMT), monomethoxytrityl (MMT), or modified trityl.

145. 144. The oligonucleotide of claim 143, wherein each removable hydrophobic group is independently MMT.

146. The one or more non-removable hydrophobic groups are G nucleobases of structure of formula (I) or formula (II) 【Chemical 259】 and / or ring A. The oligonucleotide of claim 8.

147. The one or more non-removable hydrophobic groups are G nucleobases of structure of formula (I) or formula (II) 【Chemistry 260】 The oligonucleotide of claim 145, wherein the oligonucleotide is linked to

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

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

150. 148. The oligonucleotide of claim 147, wherein the one or more non-removable hydrophobic groups are attached to ring A, and ring A is a morpholino ring.

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

152. 9. The oligonucleotide of claim 8, wherein each non-removable hydrophobic group is independently 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.

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

154. The one or more non-removable hydrophobic groups are nucleobases B having the structure of formula (I) or formula (II) １ The oligonucleotide of claim 8, wherein the oligonucleotide is linked to

155. 154. The oligonucleotide of claim 153, wherein each non-removable hydrophobic group is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

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

157. 156. The oligonucleotide of claim 155, wherein each non-removable hydrophobic group is independently ethyl, propyl, butyl, iso-propyl, or acetyl.

158. Formula (III): 【Chemical 261】 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. [In the formula, Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X １ is -O-, -CH ２ -, -CX ２ -, -N(R １０１ )-, -BH-, or -S-; Y １ and Y ２ are each independently O, S, or Se; R １ 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 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 they are attached form a substituted or unsubstituted heteroaryl or 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; Each R １Ａ , R ２Ａ , and R ３Ａ 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; 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, and each X is independently -Cl, -Br, -I, or -F. 5'-phosphate-oligonucleotide 【Chemical 262】 2. The protected 5'-capped oligonucleotide of claim 1, prepared by reaction with

159. Formula (IIIA): 【Chemical 263】 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. [In the formula, R ８ 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 , 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’ 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 , 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, or —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 they are attached form a substituted or unsubstituted heterocycloalkylene; 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 , 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 they are attached form a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; 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 attached to the same nitrogen atom ８Ａ and R ８Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ８’Ａ and R ８’Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R ９Ａ and R ９Ｂ The substituents can be optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R １０Ａ and R １０Ｂ The substituents can be optionally combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. 5'-phosphate-oligonucleotide 【Chemical 264】 11. The protected 5'-capped oligonucleotide of claim 10, prepared by reaction with

160. Compound of formula (IIIB) 【Chemical 265】 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; 5'-phosphate-oligonucleotide 【Chemical 266】 12. The protected 5'-capped oligonucleotide of claim 11 prepared by reaction with

161. 160. The protected 5'-capped oligonucleotide of any one of claims 157 to 159, wherein the 5'-phosphate-oligonucleotide is prepared by chemical synthesis.

162. 160. A 5' capped oligonucleotide prepared by removing the protecting group(s) of the protected 5' capped oligonucleotide of any one of claims 7 or 157-159.

163. 162. The oligonucleotide of claim 161, which is substantially free of enzyme by-products.

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

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

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

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

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

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

170. 161. A composition comprising the chemically synthesized oligonucleotide of claim 160, wherein the composition is substantially free of enzymatic by-products.

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

173. A process for preparing an oligonucleotide containing 50 to 12,000 nucleotides, the 5' end of which is a compound of formula (I) 【Chemical 267】 Or formula (II): 【Chemical 268】 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, (a) Formula (III) 【Chemical 269】 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 [In the formula, Ring A is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; X １ is -O-, -CH ２ -, -CX ２ -, -N(R １０１ )-, -BH-, or -S-; Y １ and Y ２ are each independently O, S, or Se; R １ 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 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 they are attached form a substituted or unsubstituted heteroaryl or 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; Each R １Ａ , R ２Ａ , and R ３Ａ 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; 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; each X is independently -Cl, -Br, -I, or -F. 5'-phosphate-oligonucleotide 【Chemistry 270】 and reacting with (b) optionally removing removable hydrophobic groups; The process includes:

174. 173. The method of claim 172, wherein the 5' capped oligonucleotide is prepared by chemical synthesis.

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

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

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

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

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

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

181. R １ 180. The oligonucleotide of claim 179, wherein are independently removable hydrophobic groups.

182. R ２ 180. The oligonucleotide of claim 179, wherein are independently removable hydrophobic groups.

183. R ３ is a removable hydrophobic group.

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