Lipid-modified nucleic acid compounds and methods

Abstract

To provide a nucleic acid compound for delivering a therapeutic nucleic acid to a cell.SOLUTION: Lipid-modified nucleic acid compounds having the following structure are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 678,013, filed May 30, 2018. No. 62 / 793,597, filed January 17, 2019. No. 60 / 699,999, filed on Oct. 1, 2003, which is incorporated herein in its entirety for all purposes.

[0002] "Sequence Listing", a table, or a computer program link submitted as an ASCII file Reference to the Appendix File 052974-502001WO_ST2 created on May 23, 2019 5.TXT (3,449 bytes, machine format IBM-PC, MS Window The sequence listing set forth in the operating system is incorporated herein by reference. do.

[0003] The present disclosure relates to the field of biologically active nucleic acid compounds. More specifically, the present disclosure relates to: The present invention relates to lipid-modified nucleic acid compounds, their preparation, and their uses. [Background technology]

[0004] Delivering therapeutic nucleic acids into cells remains a challenging area of ​​research. There is a need for improved nucleic acid compounds and strategies for introducing such compounds into cells. do. Summary of the Invention

[0005] In particular, provided herein are compounds or lipid-modified nucleic acid compounds having the following structure: It is served. [ka]

[0006] A is an oligonucleotide, a nucleic acid, a polynucleotide, a nucleotide or an analog thereof. In embodiments, A is an oligonucleotide, or a nucleoside or analog thereof. In embodiments, A is a nucleic acid. In embodiments, A is a polynucleotide. In embodiments, A is a nucleotide or analog thereof. In the formula, A is a nucleoside or analog thereof.

[0007] L 3 and L 4 are independently a bond, -NH-, -O-, -S-, -C(O)-, -N HC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)N H-, -OPO2-O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroaromatic hydrocarbons, alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene aryl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; be.

[0008] L 5 -L 5A -L 5B -L 5C -L 5D -L 5E - and L 6 -L 6A -L 6B -L 6C -L 6D -L 6E -It is. L 5A , L 5B , L 5C , L 5D , L 5E , L 6A , L 6B , L 6C , L 6D , and L6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, - OC(O)-, -C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted Heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene chloroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl It's Ren.

[0009] R 1 and R 2 are independently unsubstituted C1-C 25 alkyl, where R 1 and R 2 At least one of the following is an unsubstituted C9-C 19 alkyl, and R 3 But hydrogen, - NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NH C(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substitution or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl substituted or unsubstituted aryl; Or substituted or unsubstituted heteroaryl.

[0010] t is an integer of 1 to 5.

[0011] In embodiments, a lipid-conjugated compound having the structure of Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, and m have the values ​​described herein. Provided herein are compounds having either

[0012] In embodiments, a lipid-conjugated compound having the structure of Formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein A is any of the values ​​described herein. Provided herein are compounds having any of the following:

[0013] In embodiments, a lipid-conjugated compound having the structure of Formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein A, Z1 and Z2 have the values ​​described herein. Provided herein are compounds having any of the following:

[0014] In embodiments, cells containing the compounds disclosed and described herein are provided herein. It is served.

[0015] In an embodiment, the modified double-stranded oligonucleotide is introduced into a cell in vitro. A method for the preparation of a cell culture medium comprising contacting cells with a compound disclosed and described herein under free uptake conditions. A method is provided herein that includes contacting the

[0016] In an embodiment, the method is to introduce the modified double-stranded oligonucleotide ex vivo. Thus, cells are contacted with the compounds disclosed and described herein under free uptake conditions. A method is provided herein, comprising: [Brief explanation of the drawings]

[0017] [Figure 1] The structure of the synthesized DHA-conjugated siRNA is shown. [Figure 2] The structure of the synthesized DTx-01-08 conjugated siRNA is shown. [Figure 3] 1 shows the structure of PTEN siRNA synthesized with bound C10-C22 saturated fatty acids. [Figure 4] The structure of the synthesized C16 LCFA-conjugated siRNA is shown. [Figure 5] 1 shows the structure of PTEN siRNA synthesized with LCFA conjugation at both the 3′ and 5′ positions. [Figure 6] 1 shows the structure of PTEN siRNA synthesized with a conjugated C16 LCFA containing a terminal COOH group. [Figure 7] The structures of the synthesized DTx-01-08 conjugates DTxO-0038, DTxO-0033, and DTXO-0034 siRNAs are shown. [Figure 8] 1 shows the structure of DTxO-0003 siRNA conjugated to a motif with one or more unsaturated LCFAs. [Figure 9] 1 shows the structure of DTxO-0003 siRNA conjugated to a motif with a rigid linker. [Figure 10] 1 shows the structure of DTxO-0003 siRNA conjugated to a motif with three LCFAs. [Figure 11] 1 shows the structures of DTxO-0003 siRNA or DTxO-0038 siRNA conjugated to the DTx-01-08 motif at the 5' end of the passenger strand or the 3' end of the guide strand. [Figure 12A] 1 shows the structure of DTxO-0003 siRNA conjugated to a DTx-01-50, DTx-01-51, DTx-01-52, DTx-01-53, DTx-01-54, or DTx-01-55 motif. [Figure 12B]1 shows the structure of DTxO-0003 siRNA conjugated to a DTx-03-50, DTx-03-51, DTx-03-52, DTx-03-53, DTx-03-54, or DTx-03-55 motif. [Figure 12C] 1 shows the structure of DTxO-0003 siRNA conjugated to the DTx-06-50, DTx-06-51, DTx-06-52, DTx-06-53, DTx-06-54, or DTx-06-55 motif. [Figure 13] 1 shows the percentage of PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 7, 8, 26, and 1 for 48 hours compared to PBS control. [Figure 14] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in HEK293 cells after exposing the cells to various concentrations of compounds 2, 7, 8, 26, and 1 under free uptake conditions for 48 hours. [Figure 15] Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 7, 8, 26, and 1 under free uptake conditions for 48 hours. [Figure 16] Figure 1 shows a comparison of the effects of conjugates containing a rigid linker structure or conjugates containing three LCFAs on PTEN mRNA expression after compound transfection into HEK293 cells for 48 hours. [Figure 17] 1 shows a comparison of the effects of conjugates containing a rigid linker structure or three LCFAs on PTEN mRNA expression after free uptake of the compounds into HUVEC cells for 48 hours. [Figure 18] 1 shows the percentage of PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 9, and 1 for 48 hours compared to PBS control. [Figure 19]Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 9, and 1 under free uptake conditions for 48 hours. [Figure 20] 1 shows the effect of compounds with conjugate moieties attached to the 5′ or 3′ end of the passenger strand of two different siRNAs after transfection into HEK293 cells for 48 hours. [Figure 21] The effects of compounds with conjugate moieties attached to the 5' or 3' end of the passenger strand of two different siRNAs are shown after free uptake into HUVEC cells for 48 hours. [Figure 22] 1 shows the percent PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 25, 24, and 1 for 48 hours compared to PBS control. [Figure 23] 1 shows the percentage of PTEN mRNA expression in NIH3T3 cells after transfection with various concentrations of compounds 2, 25, 24, and 1 for 48 hours compared to PBS control. [Figure 24] Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 25, 24, and 1 under free uptake conditions for 48 hours. [Figure 25] Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 25, 24, and 1 under free uptake conditions for 96 hours. [Figure 26] 1 shows the percentage of PTEN mRNA expression in HEK293 cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 25, 24, and 1 under free uptake conditions for 48 hours. [Figure 27] 1 shows the percentage of PTEN mRNA expression in HEK293 cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 25, 24, and 1 under free uptake conditions for 96 hours. [Figure 28]1 shows the percentage of PTEN mRNA expression in NIH3T3 cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 25, 24, and 1 under free uptake conditions for 48 hours. [Figure 29] 1 shows the percentage of PTEN mRNA expression in NIH3T3 cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 25, 24, and 1 under free uptake conditions for 96 hours. [Figure 30] 1 shows the percentage of PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 20, 21, and 23 for 48 hours compared to PBS control. [Figure 31] 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 1, 2, 20, 21, and 23 under free uptake conditions for 48 hours. [Figure 32] 1 shows a comparison of the effects of conjugates containing saturated or unsaturated fatty acids on PTEN mRNA expression after transfection into HEK293 cells. [Figure 33] 1 shows a comparison of the effects of conjugates containing saturated or unsaturated fatty acids on PTEN mRNA expression after free uptake into HUVEC cells. [Figure 34] 1 shows the percentage of PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 10, 11, 12, and 1 for 48 hours compared to PBS control. [Figure 35] 1 shows the percentage of PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 13, 14, 15, and 1 for 48 hours compared to PBS control. [Figure 36] 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 10, 11, 12, and 1 under free uptake conditions for 48 hours. [Figure 37]1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 13, 14, 15, and 1 under free uptake conditions for 48 hours. [Figure 38] 1 shows the percent PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 16, 17, 18, and 1 for 48 hours compared to PBS control. [Figure 39] 1 shows the percentage of PTEN mRNA expression in HEK293 cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 16, 17, 18, and 1 under free uptake conditions for 48 hours. [Figure 40] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in differentiated SH-SY5Y cells after exposing the cells to various concentrations of compounds 2, 16, 17, 18, and 1 under free uptake conditions for 48 hours. [Figure 41] 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 16, 17, 18, and 1 under free uptake conditions for 48 hours. [Figure 42] Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 16, 17, 18, and 1 under free uptake conditions for 96 hours. [Figure 43] 1 shows the percentage of PTEN mRNA expression compared to PBS control in primary rat neurons after exposing cells to various concentrations of compounds 2, 16, 17, 18, and 1 under free uptake conditions for 96 hours. [Figure 44] 1 shows the percentage of PTEN mRNA expression compared to PBS control in primary rat neurons after exposure of cells to various concentrations of compounds 2, 16, 17, 18, and 1 under free uptake conditions for 7 days. [Figure 45A] 1 shows the percentage of VEGFR1 expression in HUVEC cells after transfection with various concentrations of compounds 3 and 1 for 48 hours compared to PBS control. [Figure 45B] 1 shows the percentage of PTEN mRNA expression in HUVEC cells after transfection with various concentrations of compounds 3 and 1 for 48 hours compared to PBS control. [Figure 46A] 1 shows the percentage of VEGFR2 expression in HUVEC cells after transfection with various concentrations of compounds 5 and 1 for 48 hours compared to PBS control. [Figure 46B] Shown is the percentage of PTEN in HUVEC cells after transfection with various concentrations of compounds 5 and 1 for 48 hours compared to PBS control. [Figure 47] 1 shows the percentage of VEGFR1 mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 4 and 3 under free uptake conditions for 48 hours. [Figure 48] Figure 1 shows the percentage of VEGFR2 mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 6 and 5 under free uptake conditions for 48 hours. [Figure 49] 1 shows the percentage of HTT mRNA expression in differentiated SH-SY5Y cells after transfection with various concentrations of compounds 29, 28, 27, 2, and 1 for 48 hours compared to PBS control. [Figure 50] 1 shows the percentage of HTT mRNA expression compared to PBS control in undifferentiated SH-SY5Y cells after exposing the cells to various concentrations of compounds 29, 28, 27, 2, and 1 under free uptake conditions for 48 hours. [Figure 51] 1 shows the percentage of HTT mRNA expression compared to PBS control in differentiated SH-SY5Y cells after exposing the cells to various concentrations of compounds 29, 28, 27, 2, and 1 under free uptake conditions for 48 hours. [Figure 52] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in differentiated 3T3L1 adipocytes after exposing the cells to various concentrations of compounds 2 and 1 under free uptake conditions for 48 hours. [Figure 53]Figure 1 shows the percentage of PTEN mRNA expression in the trabecular meshwork after 48 hours of exposure of cells to various concentrations of compounds 2 and 1 under free uptake conditions compared to PBS control. [Figure 54] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in differentiated primary human skeletal muscle cells after exposing the cells to various concentrations of compounds 2 and 1 under free uptake conditions for 96 hours. [Figure 55] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in primary human hepatocytes after exposing the cells to various concentrations of compounds 1, 2, 7, 8, and 9 under free uptake conditions for 48 hours. [Figure 56] Figure 1 shows the percent PTEN mRNA expression for compounds 1, 2, 7, 8, and 9 compared to the PBS control in primary human adipocytes after 7 days of incubation. [Figure 57] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in differentiated primary human skeletal muscle cells after exposing the cells to various concentrations of compounds 1, 2, 7, 8 and 9 under free uptake conditions for 96 hours. [Figure 58] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in primary human astrocytes after exposing the cells to various concentrations of compounds 1, 2, 7, 8, and 9 under free uptake conditions for 48 hours. [Figure 59] Figure 1 shows the percentage of PTEN mRNA expression compared to PBS control in human T cells after 96 hours of exposure of cells to various concentrations of compounds 2 and 9 under free uptake conditions. [Figure 60] 1 shows the percentage of PTEN mRNA expression 7 days after intravitreal injection of Compound 2 and Compound 37 in mice at various doses. [Figure 61] Quantitative in situ hybridization (RNAscope) is shown 7 days after intravitreal injection of Compound 2 in rats. (ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer; 10x, 10x magnification; 40x, 40x magnification). [Figure 62]1 shows the percentage of PTEN mRNA expression 7 days after intravitreal injection of Compound 2 in rats. [Figure 63] Figure 1 shows the percentage of PTEN mRNA expression after transfection of HEK293 cells with conjugated (compound 2) and unconjugated (compound 30) PTEN siRNA at various doses for 48 hours. [Figure 64] Figure 1 shows the percentage of mRNA expression 7 days after intravitreal injection of Compound 2 and Compound 33 into mice (One-way ANOVA, Tukey Post-hoc, ***p<0.001, ****p<0.0001, NS, not significant). [Figure 65] Figure 1 shows the percentage of HTT mRNA expression 7 days after intravitreal injection of Compound 2 and Compound 29 into mice (One-way ANOVA, Tukey Post-hoc, *p<0.05, ****p<0.0001, NS, not significant). [Figure 66] 1 shows the percentage of VEGFR2 mRNA expression after transfection of BEND cells with unconjugated VEGFR2 siRNA (compounds 31 and 32) at various doses for 48 hours. [Figure 67] Figure 1 shows the percentage of VEGFR2 mRNA expression 7 days after intravitreal injection of compounds 2, 34, and 35 into mice (One-way ANOVA, Tukey Post-hoc, ***p<0.001, ****p<0.0001, NS, not significant). [Figure 68] Figure 1 shows the percentage of VEGFR2 mRNA expression 7 days after intravitreal injection of compounds 2 and 34 in rats (One-way ANOVA, Tukey Post-hoc, ****p<0.0001, NS, not significant). [Figure 69] Figure 1 shows the percentage of PTEN mRNA expression 7 days after intravitreal injection of mice with compounds 2, 20, 21, and 1. (One-way ANOVA, Tukey Post-hoc, ***p<0.001, ****p<0.0001, NS, not significant). [Figure 70]Figure 1 shows the percentage of PTEN mRNA expression 7 days after intravitreal injection of mice with Compounds 11, 12, 2, 13, and Compound 1. (One-way ANOVA, Tukey Post-hoc, **p<0.01, ****p<0.0001, NS, not significant). [Figure 71] 1 shows the percentage of PTEN mRNA expression 7 days after intravitreal injection of compounds 1 and 2 into mice. [Figure 72] PTEN mRNA expression in the liver of C57B1 / 6 mice 7 days after subcutaneous (SQ) or intravenous (IV) administration of Compound 33. [Figure 73] PTEN mRNA expression in muscle, heart, adipose, lung, liver, kidney, and spleen tissues is shown 7 days after intravenous administration of Compound 33 to C57B1 / 6 mice. [Figure 74] 1 shows the percentage of PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 12, 54, 55, and 1 for 48 hours compared to PBS control. [Figure 75] 1 shows the percentage of PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 2, 13, 56, 57, and 1 for 48 hours compared to PBS control. [Figure 76] 1 shows the percent PTEN mRNA expression in HEK293 cells after transfection with various concentrations of compounds 12, 13, 58, 59, and 1 for 48 hours compared to PBS control. [Figure 77] Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 12, 54, 55, and 1 under free uptake conditions for 48 hours. [Figure 78] Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 2, 13, 56, 57, and 1 under free uptake conditions for 48 hours. [Figure 79]Figure 1 shows the percentage of PTEN mRNA expression in HUVEC cells compared to PBS control after exposing the cells to various concentrations of compounds 12, 13, 58, 59, and 1 under free uptake conditions for 48 hours. [Figure 80] 1 shows the structures of compounds 72-83, which have various combinations of saturated and unsaturated long-chain fatty acid motifs conjugated to the 3′ end of the passenger strand of siRNA. [Figure 81] 1 shows the structures of compounds 84-95, which have various combinations of saturated and unsaturated long-chain fatty acid motifs conjugated to the 3′ end of the passenger strand of siRNA. [Figure 82] 1 shows the structures of compounds 96-107, which have various combinations of saturated and unsaturated long-chain fatty acid motifs conjugated to the 3′ end of the passenger strand of an siRNA. [Figure 83] 1 shows the structures of compounds 108-113, which have various combinations of saturated and unsaturated long-chain fatty acid motifs conjugated to the 3′ end of siRNA. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition Unless otherwise defined, all technical, scientific, abbreviations, and chemical terms used herein are The structures and chemical formulas have the same meaning as commonly understood by one of ordinary skill in the art. The chemical structures and formulae set forth herein conform to standard rules of chemical valency known in the chemical arts. All patents, applications, published applications, and other publications referenced herein are hereby incorporated by reference. Articles are incorporated by reference in their entirety unless otherwise indicated. Unless otherwise specified, mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and Conventional methods of pharmacy and pharmacology are used. The terms "include," "includes," and " The use of other forms such as "include" is not limiting. "Comprise(s)" whether in a phrase or in the body of a claim and the term "comprising" is to be construed as having an open-ended meaning. That is, the term should be used in conjunction with "having at least" or "at least should be interpreted synonymously with the phrase "including" when used in the context of a process The term "comprising" means that the process consists of the listed steps. It means that the compound or composition includes at least one of the steps, but may include additional steps. or "comprising" when used in connection with a device The term refers to a compound, composition, or device that exhibits at least one of the recited features or components. "includes" means at least one of, but may include additional features or components.

[0019] When substituents are identified by their conventional chemical formula written from left to right, These substituents equally encompass chemically identical substituents whose structures are written from right to left. (For example, -CH2O- is equivalent to -OCH2-).

[0020] The term "alkyl," by itself or as part of another substituent, means any group, unless otherwise stated. Unless otherwise specified, they may be fully saturated, mono- or polyunsaturated, and may be mono-, di- and polyvalent. A straight (i.e., unbranched) or branched carbon chain (or carbon) which may contain groups , or a combination thereof. An alkyl can contain a specified number of carbons ( For example, C1-C10 means 1 to 10 carbons). Examples of saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, butyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, e.g. For example, homologs such as n-pentyl, n-hexyl, n-heptyl, and n-octyl, and Isomers are included. Unsaturated alkyl groups are those that have 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, etc. and higher homologs and isomers. Alkoxy is an alkyl group that is linked via an oxygen linker (-O The alkyl moiety is an alkenyl connected to the rest of the molecule via an alkyl group. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be an In addition to one or more double bonds, an alkenyl may have two or more divalent alkyl groups. It may contain double bonds and / or one or more triple bonds. Alkynyl is an alkyl group having one or more triple bonds. In addition, the alkyl group may contain two or more triple bonds and / or one or more double bonds.

[0021] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl. In embodiments, the monocyclic ring system contains 3 to 8 carbon atoms. Such groups may be saturated or unsaturated, but are not aromatic. In embodiments, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include: Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl. Examples of bicyclic rings include cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. A monocyclic ring is one in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkyl group of 1 to 3 additional carbon atoms. Xylene bridges (i.e., in the form (CH) w and w is 1, 2, or 3) Representative examples of bicyclic ring systems include: , including but 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 In embodiments, fused cyclo[4.2.1]nonane is used. Bicyclic cycloalkyl ring systems include phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl monocyclic cyclohexyl fused to either a monocyclic heterocyclyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl In embodiments, a bridged or fused bicyclic cycloalkyl contains a single cycloalkyl ring. The cyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the ring. In embodiments, the cycloalkyl group may have one or two groups that are independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is optionally substituted with a phenyl ring. , a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, 5- or 6-membered monocyclic heterocyclyl or 5- or 6-membered monocyclic heteroaryl a 5- or 6-membered monocyclic cycloalkyl ring fused to either The alkyl is optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the polycyclic cycloalkyl ring system is (i) a bicyclic aryl, a bicyclic hexacyclic Bicyclic cycloaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclo (ii) one ring system selected from the group consisting of phenyl, bicyclic aryl , monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or a bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl a monocyclic cycloalkyl ring fused to either of two other ring systems independently selected from the group In embodiments, polycyclic cycloalkyls are substituted with any carbon atom contained within the ring. is connected to the parent molecular moiety through a nitrogen atom. In embodiments, the polycyclic cycloalkyl ring system is (i) Bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloa one ring system selected from the group consisting of alkenyl, and bicyclic heterocyclyl, or ( ii) phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl and two other ring systems independently selected from the group consisting of monocyclic heterocyclyl. A monocyclic cycloalkyl ring (group ring) fused to either one of the following: Examples include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenanthiazolinone, perhydrophenoxazin-1-yl, and perhydrophenoxazin-1-yl.

[0022] In embodiments, the cycloalkyl is a cycloalkenyl. The term cycloalkane is used in accordance with its clear and ordinary meaning. In embodiments, the cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. Cyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing 3 to 8 carbon atoms, Groups such as are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond). Examples of monocyclic cycloalkenyl ring systems are cyclopentenyl and In embodiments, the bicyclic cycloalkenyl ring is a bridged monocyclic cycloalkenyl. In an embodiment, the bridged monocyclic ring is a fused bicyclic ring or a fused bicyclic ring. The non-adjacent carbon atoms are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., the form (C H2) w and w is 1, 2, or 3. Representative examples of bicyclic cycloalkenyls include, but are not limited to, , norbornenyl, and bicyclo[2.2.2]oct-2-enyl. In the present specification, the fused bicyclic cycloalkenyl ring system is phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, Fused to either a chloroalkenyl, monocyclic heterocyclyl, or monocyclic heteroaryl In embodiments, a bridged or fused bicyclic cycloalkenyl ring is The alkenyl can be attached to the parent molecule via any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl groups are independently oxo or thia. In embodiments, the polycyclic cycloalkane is optionally substituted with one or two groups. The aryl ring is (i) a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic one ring system selected from the group consisting of: cycloalkenyl, and bicyclic heterocyclyl or (ii) phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic Cyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic and two other ring systems independently selected from the group consisting of cyclic or bicyclic heterocyclyl. In some embodiments, the cycloalkenyl group contains a monocyclic cycloalkenyl ring (group ring) fused to either one of the rings. The formula cycloalkenyl can be attached to the parent molecular moiety through any carbon atom contained within the ring. In embodiments, the polycyclic cycloalkenyl ring is selected from the group consisting of (i) bicyclic aryl, bicyclic heterocyclic, bicyclic aryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclo or (ii) one ring system selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl a monocyclic cycloalkenyl fused to either of two ring systems independently selected from the group consisting of Contains a ring (base ring).

[0023] In embodiments, heterocycloalkyl is heterocyclyl. The term "heterocyclyl" means a monocyclic, bicyclic, or polycyclic heterocycle. Heterocyclyl monocyclic heterocycles are selected from the group consisting of O, N, and S. containing at least one heteroatom and the ring is saturated or unsaturated but not aromatic; The 3- or 4-membered ring is selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one heteroatom selected from O, and 1, 2, or 3 heteroatoms selected from the group consisting of N, and S. The 6- or 7-membered ring may have 0, 1, or 2 double bonds and may be composed of O, N, and S. and 1, 2 or 3 heteroatoms selected from the group consisting of: The formula heterocycle is a heterocyclyl monocyclic heterocycle, which is a heterocyclic ring, and is a heterocyclic ring. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through a nitrogen atom. Examples include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1, 3 dioxanyl, 1,3 dioxolanyl, 1,3 dithiolanyl, 1,3 dithianyl, imino Dazolinyl, Imidazolidinyl, Isothiazolinyl, Isothiazolidinyl, Isothiazol nyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyranyl Zolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetra Hydrothienyl, thiadiazolinyl, thiadiazolinyl, thiazolinyl, thiazolidinyl , thiomorpholinyl, 1,1dioxidethiomorpholinyl (thiomorpholine sulfone), Heterocyclyl bicyclic heterocycles include phenyl, thiopyranyl, and trithianyl. nyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic hexacyclic ring Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either heteroaryl or heteroaryl. , any carbon atom or any nitrogen atom contained within the monocyclic heterocyclic portion of the bicyclic ring system Representative examples of bicyclic heterocyclyls include, but are not limited to, However, 2,3-dihydrobenzofuran-2yl, 2,3-dihydrobenzofuran-3yl, Indolin-1yl, Indolin-2yl, Indolin-3yl, 2,3-dihydrobenzothien-2yl quinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro 1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is Optionally substituted with one or two groups which are independently oxo or thia. In embodiments, the bicyclic heterocyclyl is a phenyl ring, a 5- or 6-membered monocyclic cycloaza. alkyl, 5- or 6-membered monocyclic cycloalkenyl, 5- or 6-membered monocyclic heterocyclo aryl, or a 5- or 6-membered monocyclic heteroaryl fused to a 5- or 6-membered monocyclic heteroaryl heterocyclyl ring, and the bicyclic heterocyclyl is independently oxo or thia. The polycyclic heterocyclyl ring system is optionally substituted with one or two groups. Formula aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) phenyl aryl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cyclohexyl Cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic hexacyclic alkyl. a monocyclic ring fused to either of two other ring systems independently selected from the group consisting of tetracyclyl A polycyclic heterocyclyl is a heterocyclic ring (base ring). The polycyclic heterocycle may be connected to the parent molecular moiety through any carbon or nitrogen atom. Tetracyclyl ring systems include (i) bicyclic aryl, bicyclic heteroaryl, bicyclic cycloaryl, bicyclic cycloalkenyl, and bicyclic heterocyclyl one ring system, or (ii) phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl; A monocyclic heterocyclyl ring (base ring) fused to one of two other ring systems. Examples of 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]isoxy phenoxazin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydroxy dro-1H-carbazol-9-yl is an example.

[0024] The term "alkylene," by itself or as part of another substituent, means any group, unless otherwise defined. Unless otherwise specified, as exemplified by, but not limited to, -CHCHCHCHCH- It means a divalent group derived from alkyl. Typically, it is an alkyl (or alkylene) group. have 1 to 24 carbon atoms, and those groups having 10 or fewer carbon atoms are A "lower alkyl" or "lower alkylene" generally refers to a group having eight or fewer carbon atoms. A shorter chain alkyl or alkylene group having a substituted or unsubstituted alkyl group is called an "alkenylene." The term, by itself or as part of another substituent, is derived from an alkene, unless otherwise stated. means a divalent group having a substituent.

[0025] The term "heteroalkyl," by itself or in combination with another term, Unless otherwise specified, at least one carbon atom and at least one heteroatom (e.g., O, Stable linear or branched chains, or combinations thereof, containing The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen hetero group may Atoms may be optionally quaternized. Heteroatom(s) (e.g., O, N , S, Si, or P) may be present at any interior position of a heteroalkyl group or at any position where the alkyl group is The heteroalkyl may be placed at any position that is attached to the remainder of the molecule. 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-CH2, -S(O)-CH3, -CH2- CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH 2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O- CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive. Examples include -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or or P). A heteroalkyl moiety may contain two optionally different heteroatoms (e.g., For example, O, N, S, Si, or P. The heteroalkyl moiety may contain three optional Optionally, different heteroatoms (e.g., O, N, S, Si, or P) may be included. The alkyl moiety may optionally contain four different heteroatoms (e.g., O, N, S, Si, or The heteroalkyl moiety may contain five optionally different heteroatoms (e.g., The heteroalkyl moiety may contain up to eight of any of the following: Optionally, different heteroatoms (e.g., O, N, S, Si, or P) may be included. The term "alkenyl", by itself or in combination with another term, unless otherwise specified, Unless otherwise specified, heteroalkyl refers to a heteroalkyl containing at least one double bond. optionally, in addition to one or more double bonds, two or more double bonds and / or one The term "heteroalkynyl" refers to a heterocyclic group or group that is heterocyclic or may contain one or more triple bonds. In conjunction with the term, unless otherwise specified, refers to a heteroaryl group containing at least one triple bond. Heteroalkynyl optionally includes, in addition to one or more triple bonds, It may contain two or more triple bonds and / or one or more double bonds.

[0026] Similarly, the term "heteroalkylene" by itself or as part of another substituent , unless otherwise specified, includes, but is not limited to, -CH2-CH2-S-CH2-CH2- and and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom is , or may occupy either or both of the chain ends (e.g., alkyleneoxy, alkylene alkylene, dialkylene, dialkylenediamino, etc.). For heteroalkylene and heteroalkylene linking groups, the orientation of the linking group depends on the direction in which the formula of the linking group is written. No orientation is implied. For example, the formula -C(O)2R' represents -C(O)2R'- and As described above, the heteroalkyl group of the present invention includes both -R'C(O)2- and -R'C(O)2-. As used herein, a group that is connected to the remainder of a molecule through a heteroatom, e.g., - C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. "Heteroalkyl" is shown, followed by the specific heteroalkyl group. When an alkyl group (e.g., -NR'R") is shown, the term heteroalkyl and -N It will be understood that R' and R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are provided for added clarity. The term "heteroalkyl" is used herein to refer to certain heteroalkyl groups such as -NR'R". This should not be construed as excluding alkyl groups.

[0027] The terms "cycloalkyl" and "heterocycloalkyl" may be used by themselves or as a group. In combination with these terms, unless otherwise specified, they are also referred to as "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heterocycloalkyl refer to cyclic forms of aromatic alkyl and heterocycloalkyl. Additionally, for heterocycloalkyl, the heteroatom must be a non-member of the heterocyclic ring that is the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, However, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclo Examples include hexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of alkyl 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, tetrahydrofuranyl tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-pipera "Cycloalkylene" and "heterocycloalkylene" are Alone or as part of another substituent, cycloalkyl and heterocycloalkyl, respectively. It means a divalent group derived from alkyl.

[0028] The terms "halo" or "halogen" by themselves or as part of another substituent include: Unless otherwise specified, it means a fluorine, chlorine, bromine, or iodine atom. 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, Oromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl , 4-chlorobutyl, 3-bromopropyl, and the like.

[0029] The term "acyl," unless otherwise specified, means --C(O)R, where R is , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted substituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl aryl, or substituted or unsubstituted heteroaryl.

[0030] The term "aryl", unless otherwise specified, refers to a polyunsaturated aromatic hydrocarbon substituent. aryls, which may be single rings, or fused together (i.e., fused ring aryls) or covalently bonded The fused ring aryl may be a ring consisting of multiple rings (for example, 1 to 3 rings) joined together. It refers to multiple fused rings, at least one of which is an aryl ring. The term "heteroaryl" refers to a group containing at least one heteroatom such as N, O, or S. and (b) an aryl group (or ring) having the nitrogen and sulfur atoms optionally oxidized; The nitrogen atom(s) are optionally quaternized. Hence, the term "heteroaryl." The term refers to a fused ring heteroaryl group (i.e., at least one of the fused rings is heteroaryl). 5,6-fused-ring heteroarylenes (multiple rings fused together that are aromatic rings). refers to two rings fused together, one ring having five members and the other ring having six members; At least one ring is a heteroaryl ring. Similarly, 6,6-fused ring heteroaryls A ring refers to two rings fused together, one ring having six members and the other having six members. and at least one ring is a heteroaryl ring. The 6,5-fused ring heteroarylene is Refers to two rings fused together, one ring having six members and the other having five members, At least one ring is a heteroaryl ring. A heteroaryl group is a group consisting of carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include: Typical examples include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazolyl, and the like. dinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl thiazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, Benzoxazoyl, benzimidazolyl, benzofuran, isobenzofuranyl, India aryl, 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, 5-isoxazolyl, 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thie nyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-Benzothiazolyl, Purinyl, 2-Benzimidazolyl, 5-Indolyl, 1-Iso Quinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Each of the above aryl and heteroaryl ring systems Substituents are selected from the group of acceptable substituents described below. "Arylene" and and "heteroarylene," alone or as part of another substituent, each represent an aryl group. Heteroaryl group substituents refer to divalent groups derived from aryl and heteroaryl. There may be an -O- attached to the heteroatom nitrogen.

[0031] Spirocyclic rings are two or more rings in which adjacent rings are connected through a single atom. The individual rings within a cyclic ring may be the same or different. Each ring of the spiro ring may be substituted or unsubstituted and may be different from each other ring in the set of spiro rings. The possible substituents for the individual rings in the spirocyclic ring are: , if not part of a spirocyclic ring, are possible substituents for the same ring (e.g., cyclohexyl Substituents for cycloalkyl or heterocycloalkyl rings. Spirocyclic rings are substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted substituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene; The individual rings in the spirocyclic group may be all of one type (e.g., all All rings are substituted heterocycloalkylene, and each ring may be the same or different substituted heterocycloalkylene. It can be any of the list immediately above, including cycloalkylene. When referring to a cyclic ring system, a heterocyclic spirocyclic ring is one in which at least one ring is a heterocyclic ring. , refers to a spirocyclic ring in which each ring may be a different ring. Spirocyclic rings have at least one ring substituted, and each ring is optionally different. This means that it is okay.

[0032] symbol [ka] indicates the point of attachment of a chemical moiety to the rest of the molecule or chemical formula.

[0033] The term "oxo" as used herein refers to an oxygen atom that is double bonded to a carbon atom. means.

[0034] an alkylene moiety (also referred to herein as an alkylene linker) covalently linked to the alkylene moiety; The term "alkylarylene" refers to an alkylene moiety. The olefin group has the formula [ka] It has.

[0035] The alkylarylene moiety may be an alkylene moiety or an arylene linker (e.g., a carbon 2, 3, 4, or 6) on (e.g., in a substituent) halogen, oxo, -N3, -CF 3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -CO OH, -CONH2, -NO2, -SH, -SO2CH3-SO3H, -OSO3H, - SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or non- substituted C1-C5 alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl In embodiments, the alkylarylene is unsubstituted.

[0036] The above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heteroalkyl" and "heteroalkyl") "cycloalkyl," "aryl," and "heteroaryl" are each as indicated Both substituted and unsubstituted forms of the radicals are included. Preferred substituents for each type of radical are provided below. do.

[0037] Substituents of alkyl and heteroalkyl groups (alkylene, alkenyl, heteroalkylene) alkynyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl groups commonly referred to as alkenyl, and heterocycloalkenyl) include, but are not limited to, ,-OR', =O, =NR', =N-OR', - with numbers ranging from zero to (2m'+1) NR'R”, -SR', -halogen, -SiR'R”R”', -OC(O)R', -C( O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O )R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR 'R"R"')=NR"", -NR-C(NR'R")=NR"', -S(O)R', - S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"'R"", -CN, -NO2, -NR' SO2R”, -NR'C(O)R”, -NR'C(O)-OR”, -NR'OR”, m' may be one or more of a variety of groups selected, and m' may be a carbon atom within such a group. R, R', R", R"', and R"" are each preferably independently and optionally hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl. , substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., 1 aryl substituted with up to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl When a compound described herein contains more than one R group, for example, each of the R groups This means that when two or more of these groups are present, they are each represented by R', R", R"', and R' and R" are independently selected to be groups. When R' and R" are attached to the same nitrogen atom, When combined with the nitrogen atom, they can form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" can include, but is not limited to, 1-pyrrolidinyl and 4- From the above discussion of substituents, the term "alkyl" is understood to mean a halo group. alkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)C -H3, -C(O)CF3, -C(O)CH2OCH3, etc.) Those skilled in the art will understand that this is meant to include groups containing carbon atoms other than the above.

[0038] The substituents for aryl and heteroaryl groups are similar to those described for alkyl groups. The substituents may vary, for example, in numbers ranging from zero to the total number of open valences on the aromatic ring system. -OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O )R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR”C(O)R’, -NR’-C(O)NR”R”’, -NR”C(O)2R’, - NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR"', -S (O)R', -S(O)2R', -S(O)2NR'R', -NRSO2R', -NR' NR”R”’, -ONR’R”, -NR’C(O)NR”NR”’R””, -CN, -N O2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, fluoro (C1-C4) alkyl, -NR'S02R", -NR'C(O)R", -NR'C( O) —OR″, —NR′OR″, wherein R′, R″, R′′, and R′″ are preferably independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups may be selected from the group consisting of: This means that when two or more of these groups are present, they are each represented by R', R", R"', and R"" groups are independently selected.

[0039] Rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) Substituents may be shown as substituents on the ring (generally floating atoms) rather than on specific atoms of the ring. In such cases, the substituent is May be attached to any ring atom (subject to chemical valency rules) and may be a fused or spiro ring In the case of a fused or spirocyclic ring, it is shown as being associated with one ring member of the ring. The substituents (floating substituents on a single ring) are substituted on either the fused or spirocyclic rings. The substituents may be attached to the ring rather than to a specific atom. (floating substituent), if the substituent subscript is an integer greater than 1, multiple substituents may be grouped together to form the same atom. They may be on the same atom, on the same ring, on different atoms, on different fused rings, or on different spirocyclic rings. Each substituent may optionally be different. The point of attachment of the ring to the rest of the molecule is a single atom. If not limited to a ring (floating substituent), the point of attachment may be any atom of the ring, and In the case of a ring or spirocyclic ring, fused rings or spirocyclic rings may be used, subject to the rules of chemical valency. The ring, fused ring, or spirocyclic ring may be any atom of one or more containing a ring heteroatom, and wherein the ring, fused ring, or spiro ring has one or more floating substituents; When a floating substituent is attached to a ring (including but not limited to the point of attachment to the rest of the molecule), the floating substituent is The ring heteroatom may be attached to one of the structures of the formula with a floating substituent. When shown bonded to more than one hydrogen atom (e.g., two bonds to a ring atom and one bond to a hydrogen atom), a ring nitrogen having a third bond to the heteroatom, and when the heteroatom is attached to a floating substituent, the substituent It will be understood that groups replace hydrogen while obeying the rules of chemical valency.

[0040] Optionally, two or more substituents may be linked to form an aryl, heteroaryl, cycloaryl, or Such so-called ring-forming substituents may form alkyl, or heterocycloalkyl groups. Typically, but not necessarily, they are found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent moieties of the base structure. Two ring-forming substituents attached to adjacent moieties of a base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single moiety of the base structure. For example, Two ring-forming substituents attached to a single moiety of the cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent moieties of the base structure. do.

[0041] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring are optionally , the formula -TC(O)-(CRR') q -U-, wherein T and U may form a ring of the formula: , independently represent -NR-, -O-, -CRR'-, or a single bond; q is an integer from 0 to 3; Alternatively, two of the substituents on adjacent atoms of an aryl or heteroaryl ring may be One optionally has the formula -A-(CH) r -B, 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 of 1 to 4. One of the single bonds of the new ring so formed may optionally be joined to a double bond. Alternatively, substitutions on adjacent atoms of the aryl or heteroaryl ring Two of the groups optionally have the formula -(CRR') s -X'-(C"R"R"') d - wherein s and d are independently an integer of 0 to 3. , X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S( O)NR'-. The substituents R, R', R" and R"' are preferably independently 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.

[0042] As used herein, the term "heteroatom" or "ring heteroatom" refers to an atom of an acid. It is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). It is illustrated.

[0043] As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CHF2 , -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2Br , -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -NO 2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, -NHNH2, - ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NH C(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCBr 3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -O CH2F, -OCH2Cl, -OCH2Br, -OCH2I, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heterocyclic heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl cycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl) alkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g. For example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl. teraryl), and (B) Alkyl, heteroaryl, substituted with at least one substituent selected from the following: alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (i) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CHF 2, -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2B r, -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, -N O2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -N HC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OCB r3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, - OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, unsubstituted alkyl (e.g. , C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted Heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or is 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl alkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted hetero Cycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloa alkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl ( For example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl heteroaryl), and (ii) alkyl, hetero, substituted with at least one substituent selected from the following: Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (a) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CH F2, -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2 Br, -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, - NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, -NHNH2 , -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, - NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OC Br3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, unsubstituted alkyl (e.g. For example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted Heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, if or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, alkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heteroalkyl Heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocyclo alkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6 -C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (For example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl ring heteroaryl), and (b) Oxo, halogen, -CF3, -CCl3, -CBr3, -CI3, -CH F2, -CHCl2, -CHBr2, -CHI2, -CH2F, -CH2Cl, -CH2 Br, -CH2I, -CN, -N3, -OH, -NH2, -COOH, -CONH2, - NO2, -SH, -SCH3, -SO3H, -SO4H, -SO2NH2, -NHNH2 , -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, - NHC(O)H, -NHC(O)OH, -NHOH, -OCF3, -OCCl3, -OC Br3, -OCI3, -OCHF2, -OCHCl2, -OCHBr2, -OCHI2, -OCH2F, -OCH2Cl, -OCH2Br, -OCH2I, unsubstituted alkyl (e.g. For example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted Heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, if or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, alkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heteroalkyl Heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocyclo alkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6 -C 10 Aryl, C 10aryl, or phenyl), or unsubstituted heteroaryl (For example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl substituted with at least one substituent selected from alkyl, heteroaryl, Tetraalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

[0044] "Size-limited substituents " or "size-limited substituents As used herein, a "substituent group" is defined above for a "substituent." Each substituted or unsubstituted alkyl refers to a group selected from all the substituents, and each substituted or unsubstituted alkyl refers to a group selected from the group consisting of substituted or unsubstituted alkyl. is unsubstituted C1-C 20 alkyl, and each substituted or unsubstituted heteroalkyl may be substituted or unsubstituted. or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, and each substituted or unsubstituted hetero The cycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, and each of the substituted Or unsubstituted aryl is substituted or unsubstituted C-C 10 aryl, and each substitution is The or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. .

[0045] "lower substituent" or "low As used herein, the term "substituted group" means a "Group" means a group selected from all of the substituents described above, and each substituted or unsubstituted The substituted alkyl is a substituted or unsubstituted C1-C8 alkyl, and each substituted or unsubstituted alkyl is Heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each of which is Unsubstituted cycloalkyl is substituted or unsubstituted C3-C7 cycloalkyl, and each substitution Alternatively, the unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl. each substituted or unsubstituted aryl is a substituted or unsubstituted C-C alkyl; 10 Ants each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl; It is a teraryl.

[0046] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted substituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl alkylene, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or represents unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) represents unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, alkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene aryl, unsubstituted arylene, and / or unsubstituted heteroarylene. In the present invention, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted alkyl) is substituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl chloroalkyl, 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 alkylene arylene, and / or substituted or unsubstituted heteroarylene) can be substituted ( For example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heteroalkyl, and substituted cycloalkyl, respectively. cycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroaryl alkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and and / or substituted heteroarylene).

[0047] In embodiments, substituted moieties (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, alkyl, 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 is optionally different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent may be a different It is.

[0048] In embodiments, substituted moieties (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, alkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) has at least one size limited When the substituted moiety is substituted with multiple size-limited substituents, In embodiments, each size-limited substituent may optionally be different. When a substituted moiety is substituted with multiple size-limited substituents, each size-limited substituent The bases are different.

[0049] In embodiments, substituted moieties (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, alkyl, 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. When a substituted moiety is substituted with multiple lower substituents, each lower substituent is optionally In embodiments, when a substituted moiety is substituted with multiple lower substituents, Each lower substituent is different.

[0050] In embodiments, substituted moieties (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, alkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) has at least one substituent, The substituted moiety is a substituent, a group having a size limit, or a lower substituent. When the alkyl group is substituted with multiple substituents selected from the above-mentioned substituents and lower substituents, each substituent The substituents, size-limited substituents, and / or lower substituents are optionally different. In embodiments, the substituted moiety may be a substituent, a size-limited substituent, or a low When substituted with multiple substituents selected from the same class of substituents, each substituent is limited in size. The substituents, and / or lower substituents are different.

[0051] In embodiments of the compounds herein, each substituted or unsubstituted alkyl may be substituted (e.g., substituted, size-limited, or lower substituents), or unsubstituted C1-C 20 alkyl, and each substituted or unsubstituted heteroalkyl may be substituted ( For example, substituted with a substituent, a size-limited substituent, or a lower substituent), and is an unsubstituted 2- to 20-membered heteroalkyl, and each substituted or unsubstituted cycloalkyl is Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted C3-C8 cycloalkyl, each of which is a substituted or unsubstituted heterocycloalkyl. The alkyl is substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent). substituted) or unsubstituted 3- to 8-membered heterocycloalkyl, The alkyl group may be substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent). substituted) or unsubstituted C6-C 10 aryl and / or each substituted or unsubstituted The unsubstituted or unsubstituted heteroaryl may be substituted (e.g., substituted, size-limited, if The present invention is a 5- to 10-membered heteroaryl, which is substituted with a lower substituent, or an unsubstituted 5- to 10-membered heteroaryl. In certain embodiments, each substituted or unsubstituted alkylene may be substituted (e.g., substituted, cycloalkyl). substituted with limited or lower substituents) or unsubstituted C1-C 20 alkylene, and each substituted or unsubstituted heteroalkylene may be substituted (e.g., substituted with size-limited or lower substituents) or unsubstituted 2-20 and each substituted or unsubstituted cycloalkylene is a substituted (e.g., substituted, substituted, size-limited, or lower substituents), or unsubstituted substituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene being , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted 3- to 8-membered heterocycloalkylene, each of which is substituted or unsubstituted aryl. The olefin may be substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent). substituted) or unsubstituted C6-C 10 and / or each substituent is The heteroarylene may be substituted (e.g., substituted, size-limited, or substituted by a lower substituent), or unsubstituted 5- to 10-membered heteroarylene .

[0052] In embodiments, each substituted or unsubstituted alkyl may be substituted (e.g., substituted, size-limited). or unsubstituted C1-C8 alkyl Each substituted or unsubstituted heteroalkyl may be substituted (e.g., substituted, cyclohexyl ... substituted with limited substituents or lower substituents) or unsubstituted 2-8 membered ring and each substituted or unsubstituted cycloalkyl is substituted (e.g., substituted, substituted with size-limited or lower substituents) or unsubstituted C3-C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl may be substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted substituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is substituted (e.g., substituted, size-limited, or lower substituents), or unsubstituted C6-C 10 aryl, and / or each substituted or unsubstituted heteroaryl The alkyl group may be substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent). In embodiments, each substituted or unsubstituted 5- to 9-membered heteroaryl is The unsubstituted or unsubstituted alkylene may be substituted (e.g., substituted, size-limited, or or unsubstituted C1-C8 alkylene, each substituted or An unsubstituted heteroalkylene is a substituted (e.g., substituted, size-limited, or is substituted with a lower substituent), or unsubstituted 2- to 8-membered heteroalkylene, Alternatively, the unsubstituted cycloalkylene may be substituted (e.g., substituted, size-limited substituents). or a lower substituent), or unsubstituted C3-C7 cycloalkylene Each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocyclic ring. cycloalkylene, and each substituted or unsubstituted arylene may be substituted (e.g., substituted with size-limited or lower substituents) or unsubstituted C6-C 10 arylene, and / or each substituted or unsubstituted heteroarylene is Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or an unsubstituted 5- to 9-membered heteroarylene. In an embodiment, the compound is The chemical species described in the Examples section, Figures, or Tables.

[0053] Certain compounds provided herein may have asymmetric carbon atoms (optical or chiral centers) or or double bond, and in terms of absolute stereochemistry, amino acids are either (R)- or (S)- or enantiomers, racemates, diastereomers which may be defined as (D)- or (L)- -, tautomers, geometric isomers, stereoisomeric forms, and individual isomers are within the scope of this disclosure. The compounds provided herein are too unstable to synthesize and / or The term "antibody" does not include those known in the art to be capable of being isolated or isolated. The compounds provided include compounds in racemic and optically pure forms. The (R)- and (S)-, or (D)- and (L)-isomers are also chiral synthons. or may be prepared using chiral reagents or resolved using conventional techniques. If the compounds described herein contain an olefinic bond or other center of geometric asymmetry, Where a compound is used, unless otherwise specified, the compound may include both E and Z geometric isomers. It is intended.

[0054] As used herein, the term "isomers" refers to compounds having the same number and kinds of atoms. , and therefore compounds that have the same molecular weight but differ in terms of the structural arrangement or configuration of atoms. Point.

[0055] The term "tautomer" as used herein refers to a compound that exists in equilibrium and is One of two or more structural isomers that is easily converted from one isomeric form to another Point.

[0056] Certain compounds provided herein may exist in tautomeric forms, and all of the compounds may be tautomeric. It will be apparent to one of ordinary skill in the art that all such tautomeric forms are within the scope of the present disclosure.

[0057] When the compounds disclosed herein have at least one chiral center, they may be , as individual enantiomers and diastereomers, or as such diastereomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers is not possible. This is accomplished by application of various methods well known to practitioners in the art. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Unless otherwise specified, structures shown herein are intended to be illustrative and not restrictive. It is also intended to include all stereochemical forms, i.e., the (R) and (S) configurations of each asymmetric center. Therefore, a single stereochemical isomer is generally recognized as stable by those skilled in the art. Enantiomeric and diastereomeric mixtures of the compounds are within the scope of this disclosure. be.

[0058] Unless otherwise stated, structures depicted herein also include one or more isotopically enriched atoms. It is meant to include compounds that differ only in the presence of, for example, deuterium or tritium. replacement of hydrogen by an element, 18 Replacement of fluoride with F, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure. be.

[0059] The compounds provided herein also contain a hydroxyl group at one or more of the atoms comprising such compounds. The compounds may contain unnatural proportions of atomic isotopes. For example, the compounds may contain, for example, tritiated water. Element ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C) and other radioisotopes All isotopic variations of the compounds provided herein may be radiolabeled. Whether or not it is included within this disclosure.

[0060] Throughout this application, alternatives are described in Markush groups, e.g., two or more It should be noted that each amino acid position is listed containing a possible amino acid. Each component of a cash group should be considered separately and therefore in separate practice. It should be noted that Markush groups should not be read as a single unit. Specifically, the following is envisaged.

[0061] "Analog" or "analogue" is a chemical and and is used in accordance with its obvious and ordinary meaning in biology and in relation to another compound (i.e., Structurally similar to the so-called "reference compound") but differing by e.g. one atom in the replacement of atoms with atoms of, or in the presence of certain functional groups, or in the presence of one functional group with another functional group, or to the absolute stereochemistry of one or more chiral centers of the reference compound. In the context of analogs, analogs refer to chemical compounds that differ in composition. Thus, analogs are compounds that are identical in function and appearance. Similar or equivalent in structure or origin to the reference compound It is not an equal compound.

[0062] The terms "a" or "an" as used herein mean one In addition, the phrase "replaced by one (a[n]) of" is used in the present specification. When used herein, a particular group may be selected from any or all of the specified substituents. For example, it means that a group such as an alkyl or hydroxyl group can be substituted. The heteroaryl group is "one (an) unsubstituted C-C 20 Alkyl or unsubstituted 2-2 When "substituted with 0-membered heteroalkyl," the group is substituted with one or more unsubstituted C-C 20 a The alkyl group may contain one or more unsubstituted alkyl groups, and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0063] When a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." If a moiety is R-substituted, then the moiety is substituted with at least one R substituent, and each The R substituents are optionally different. When a particular R group is present in a description of a chemical genus (such as formula (I)), If so, the Roman numeral decimal symbol may be used to distinguish between each appearance of that particular R group. For example, multiple R 13 When substituents are present, each R 13 The substituents are R 13.1 , R 1 3.2 , R 13.3 , R 13.4 may be distinguished as R 13.1 , R 13.2 , R 13.3 , R 13.4 etc. are R 13 Within the definition of and optionally The terms "a" or "an" are defined differently in this specification. When used in writing, it means one or more. In addition, "replaced by one (a[n]) of ~" The phrase "is" as used herein means that a particular group may be substituted with any one of the specified substituents. It means that a group may be substituted with one or more of any or all of the following: For example, an alkyl or heteroaryl group may be "one unsubstituted C-C 20 Archi When "substituted with 2- to 20-membered heteroalkyl, or unsubstituted 2- to 20-membered heteroalkyl," the group may be substituted with one or more Unsubstituted C1-C 20 alkyl, and / or one or more unsubstituted 2- to 20-membered heterocyclic rings It may contain alkyl.

[0064] The description of compounds provided herein is not limited by principles of chemical bonding known to those skilled in the art. Thus, a group may be substituted with one or more of several substituents. In this case, such substituents must comply with principles of chemical bonding and be not inherently unstable, and and / or under ambient conditions, e.g., aqueous, neutral, and several known physiological to give compounds that would be known to be likely to be unstable under environmental conditions. For example, heterocycloalkyl or heteroaryl may be selected from the group consisting of aryl, ... In accordance with the principles of chemical bonding, it is connected to the rest of the molecule through a ring heteroatom, thereby Avoid compounds that are inherently unstable.

[0065] The term "pharmaceutically acceptable salt" refers to a compound that retains the biological effectiveness and properties of a compound. and they are undesirable for biological or other pharmaceutical use. In many cases, the compounds herein contain an amino and / or carboxyl group. The presence of hydroxyl or groups similar thereto allows the formation of acid and / or base salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, Examples of organic acids from which salts can be derived include acetic acid, propionic acid, Glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, alcohol Taric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid , p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition Salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include: Examples include sodium, potassium, lithium, ammonium, calcium, magnesium, Examples include ammonium, iron, zinc, copper, manganese, and aluminum, and particularly preferred are ammonia. The salts are ammonium, potassium, sodium, calcium, and magnesium salts. Possible organic bases include, for example, primary, secondary, and tertiary amines, naturally occurring substituents, Substituted amines including substituted amines, cyclic amines, basic ion exchange resins, etc., For example, isopropylamine, trimethylamine, diethylamine, triethylamine, tri propylamine, and ethanolamine. Many of these salts are WO87 / 05297, published September 11, 1987, Johnston et al. 1., which is incorporated herein by reference in its entirety, It is known in the field.

[0066] "Contacting" is used in accordance with its plain and ordinary meaning and includes at least two Different species (e.g., chemical compounds, biomolecules, or cells) react, interact, and refers to the process of bringing people into close enough proximity to make physical contact. The goal is to allow the compound to reach the cell in sufficient proximity to bind to the cell surface receptor. This includes processes that enable

[0067] As used herein, "contacting a cell" refers to the transfer of a compound or substance to a cell. Other compositions may be in direct contact with the cells or may induce a desired biological effect within the cells. It refers to a state that is close enough to

[0068] As used herein, the term "free incorporation conditions" refers to the incorporation of unmodified oligonucleotides. For example, such a free uptake condition refers to a condition in which the transfectant does not substantially enter the cell. transfection reagents, electroporation techniques, or other methods to enhance compound entry into cells There may be few or no other conditions used for this purpose. Free uptake conditions are conditions in which siRNA lacking lipid conjugation does not substantially enter cells. Incubation in standard media under standard conditions for a particular type of cell An example of a standard culture condition for free uptake is 0.5% to 10%, e.g. In another example, standard medium may contain fetal bovine serum (FBS) in the range of 1% to 5%. is serum-free.

[0069] The term "activator" refers to a compound capable of detecting the expression or activity of a given gene or protein. An activator refers to a compound, composition, or substance that can increase the activity of a specific molecule. For example, an activator is The expression or activity was increased by 10%, 20%, 30%, or 40% compared to the control in the absence of activator. %, 40%, 50%, 60%, 70%, 80%, 90% or more .

[0070] As defined herein, the terms "inhibit," "inhibit," "inhibiting," and the like mean , which adversely affects the activity or function compared to the activity or function in the absence of the inhibitor. In embodiments, inhibiting means causing (e.g., reducing) an effect in the absence of an inhibitor. The concentration or level of a biomolecule, such as a protein or mRNA, compared to that in the absence of It means to adversely affect (eg, decrease) the concentration or level of a biomolecule. For example, inhibiting includes decreasing the level of mRNA expression in the cell. Inhibition refers to the suppression of the activity of a particular biomolecular target, e.g., a protein target or an mRNA target. Thus, inhibition involves at least partial, partial, or complete blocking of a stimulus. reducing, preventing, or delaying activation or signal transduction or inactivating, desensitizing, or downregulating enzyme activity or the amount of a biomolecule. In embodiments, the inhibition includes the inhibition of the target biomolecule resulting from a direct interaction. It refers to a decrease in activity (e.g., an inhibitor binds to a target protein). In embodiments, inhibition refers to a decrease in the activity of a target biomolecule from an indirect interaction (e.g., an inhibitor is a molecule that acts on a target molecule). Binds to proteins that activate proteins, thereby preventing activation of the target protein do).

[0071] The term "inhibitor" also refers to a compound that detects the expression or activity of a given gene or protein. An inhibitor refers to a compound, composition, or substance that can reduce the activity of a protein. Increase expression or activity by 10%, 20%, or 30% compared to a control in the absence of an inhibitor. , 40%, 50%, 60%, 70%, 80%, 90%, or more. Inhibitors include, for example, synthetic molecules or biological molecules such as oligonucleotides. can be.

[0072] As used herein, the terms "expression" and "gene expression" refer to mRNA expression and refers to the steps involved in the translation of a nucleic acid into a protein, including transcription and protein expression. , nucleic acid or protein (e.g., PCR, ELISA, Southern blot, ting, Western blotting, flow cytometry, FISH, immunofluorescence, immunoassay The antibodies can be detected using conventional techniques for detecting antibodies (immunohistochemistry).

[0073] An "effective amount" is the amount of a compound that achieves a stated purpose compared to the absence of the compound. It is an amount sufficient to achieve the effect for which it is administered, to treat a disease, to inhibit enzymatic activity, etc. decrease activity, increase enzyme activity, decrease signal transduction pathways, or even cause disease (or alleviate one or more symptoms of a condition). is required to reduce the activity of the enzyme compared to its absence A "function-disrupting amount," as used herein, refers to the amount of an antagonist that required to disrupt enzyme or protein function compared to the absence of the This refers to the amount of antagonist administered.

[0074] The term "cell" is used herein in its ordinary sense as understood by those skilled in the art. The cells can be prokaryotic or eukaryotic. Prokaryotic cells include, but are not limited to: Eukaryotic cells include, but are not limited to, yeast cells, plant cells, and human cells. Cells can be characterized by, for example, the presence of an intact membrane, the ability to detect specific dyes, and the like. coloration, ability to produce offspring, or, in the case of gametes, the ability to produce viable offspring. and identifying the ability of the virus to combine with two gametes by methods well known in the art. In embodiments, the cells may be from an immortalized cell line. The cells may be primary cells. In embodiments, the cells are in vitro. In embodiments, In some embodiments, the cells are in vivo. In other embodiments, the cells are ex vivo.

[0075] As used herein, the term "in vivo" refers to a process that takes place inside a subject's body. Taste.

[0076] As used herein, the term "subject" refers to a human selected for treatment or therapy. Or a non-human animal. In an embodiment, the subject is a human.

[0077] As used herein, the term "ex vivo" refers to an organism in an isolated tissue or cell. refers to a process carried out in vitro using a method in which the treated tissue or cells are primary cells or As is known in the art, any medium used in this process may contain It can be aqueous and non-toxic so as not to render the tissue or cells non-viable. In ex vivo processes, the process is carried out in vitro using primary cells.

[0078] The term "administering" means providing an agent or composition to a subject, and is not intended to be used by a medical professional. This includes administration by a physician and self-administration.

[0079] The term "therapy" refers to a treatment or therapy for the improvement of at least one indication or disease or condition. It refers to the application of one or more specific procedures used. In an embodiment, the specific procedures are The administration of more than one drug.

[0080] The term "modulate" is used herein in its ordinary sense as understood by those skilled in the art. It refers to the act of using something and thus changing or altering one or more properties. For example, the properties or functions of a target molecule in terms of the effect of a modulator on the target molecule; The method involves adjusting the means to alter the amount of a target molecule by increasing or decreasing it. A disease modulator reduces the symptoms, causes, or characteristics of the target disease.

[0081] The terms "nucleic acid," "oligonucleotide," and "polynucleotide" are used together refers to a compound containing at least two nucleotide monomers covalently linked to each other. The term includes single-stranded and double-stranded nucleic acids, nucleic acids, oligonucleotides, and polynucleosides. It contains single-stranded DNA, double-stranded DNA, single-stranded RNA, double-stranded RNA, DNA and Single- and double-stranded molecules containing both nucleotides and RNA, and modifications thereof Oligonucleotides refer to polymers of shorter length, typically , approximately 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50, or more Nucleic acids and polynucleotides are , typically longer lengths, e.g., 200, 300, 500, 1000, 2000, Nucleic acids are polymers of 3000, 5000, 7000, and 10,000 nucleotides. A "residue" of a oligonucleotide, or polynucleotide, is a nucleotide molecule of that compound. "Residue" and "monomer" are used interchangeably herein. In embodiments, oligonucleotides are used for RNA silencing. In embodiments, the oligonucleotide may be DNA, locked nucleic acid (LNA), bicyclic nuclei, or the like. acid (BNA), or phosphorodiamidate morpholino oligomer (PMO), or These modifications and others may be included. In embodiments, the oligonucleotide comprises one or more 2'-O-methoxyethyl residue, 2'-O-methyl residue, and / or 2'-fluoro In embodiments, the oligonucleotide comprises a phosphorothioate linkage.

[0082] Non-limiting examples of oligonucleotides include double-stranded oligonucleotides, modified Double-stranded oligonucleotides, single-stranded oligonucleotides, modified single-stranded oligonucleotides Otides, antisense oligonucleotides, siRNA, microRNA mimics, stem Loop structure, single-stranded siRNA, RNase H oligonucleotide, anti-microRNA oligo oligonucleotides, sterically hindered oligonucleotides, CRISPR guide RNAs, and Examples include aptamers.

[0083] Non-limiting examples of polynucleotides include genes, gene fragments, exons, intros, and the like. DNA, intergenic DNA (including but not limited to heterochromatic DNA), messenger -RNA (mRNA), long non-coding RNA, transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, primers Examples include plasmids, vectors, isolated DNA sequences, and isolated RNA sequences. Polynucleotides useful in the disclosed methods include naturally occurring nucleic acid sequences and their barriers. The nucleic acid sequence may include a nucleic acid fragment, an artificial nucleic acid sequence, or a combination of such sequences.

[0084] "Nucleoside," as used herein, refers to a nucleic acid comprising a nucleobase and a five-membered ring sugar, e.g., It refers to glycosyl compounds consisting of nucleotides (either ribose or deoxyribose). The nucleotides may include bases such as A, C, G, T, U, or analogs thereof. The nucleoside may be modified at the base and / or sugar. In another embodiment, the nucleoside is a ribonucleoside. It is a creoside.

[0085] "Nucleotide" as used herein means a nucleoside-5'-polyphosphate refers to a compound, or structural analog thereof, that acts as a primer to a growing nucleic acid strand (e.g., a primer) It may be incorporated by a nucleic acid polymerase (e.g., a nucleoside) for extension. (It may be partially incorporated as 5'-monophosphate or its derivatives). Nucleotides may contain bases such as A, C, G, T, U, or their analogs. Often, there are 2, 3, 4, 5, 6, 7, 8, or more phosphate groups in the phosphate group. A nucleotide may contain a base, sugar, or phosphate group. The nucleotide may be modified in the ligand attached directly or via a linker. In one embodiment, the nucleotides are deoxyribonucleotides. In another embodiment, the nucleotide is a ribonucleotide.

[0086] As used herein, a "nucleotide analog" refers to a nucleotide that is present in a DNA or RNA polymerase. Recognized by enzymes (whichever applies) and DNA or RNA strands (whichever applies) analogs of A, G, C, T, or U (i.e., (i.e., nucleotide analogs containing the bases A, G, C, T, or U) Examples of nucleotide analogs include, but are not limited to, 7-deaza-adenine, 7-deaza-adenine, Aza-guanine, an analog of the deoxynucleotides shown herein, 5-position of cytosine or thymine or deaza-adenine or deaza-guanine through The label is attached to the 7-position of the anion, and the deoxyribonucleic acid is synthesized using a small chemical moiety. Nucleotide analogs and analogs that protect the OH group at the 3' position of the base are also included. and DNA polymerase-based DNA sequencing are also disclosed in U.S. Pat. No. 6,664,079. which is incorporated herein by reference in its entirety for all purposes. .

[0087] "Base" in the context of an oligonucleotide, nucleic acid, or polynucleotide, and As used herein, the term "nucleobase" refers to a base that is present in a nucleic acid (i.e., DNA or RNA). or a derivative thereof) In embodiments, a nucleobase refers to a naturally occurring DNA or RNA base (e.g., In embodiments, the nucleobase is optionally substituted. bases that are derivatives of naturally occurring DNA or RNA bases (e.g., base analogs) that In embodiments, the nucleobase is a hybridization base. The base is a hybridization base that may be optionally substituted. The nucleobase hybridizes to a complementary base. In embodiments, the nucleobase hybridizes to a complementary nucleic acid base. It is capable of forming at least one hydrogen bond with a base (e.g., adenosine with thymine). adenine hydrogen bonds with uracil, or guanine pairs with cytosine). Non-limiting examples of bases include cytosine or its derivatives (e.g., cytosine analogs). , guanine or a derivative thereof (e.g., a guanine analog), adenine or a derivative thereof (e.g., adenine analogs), thymine or its derivatives (e.g., thymine analogs), Uracil or its derivatives (e.g., uracil analogs), hypoxanthine or its derivatives conductors (e.g., hypoxanthine analogs), xanthine or its derivatives (e.g., xanthine guanine analogs), 7-methylguanine or its derivatives (e.g., 7-methylguanine analogs), deaza-adenine or its derivatives (e.g., deaza-adenine analogs) , deaza-guanine or a derivative thereof (e.g., deaza-guanine), deaza-hypoxal uridine or a derivative thereof, 5,6-dihydrouracil or a derivative thereof (e.g., 5,6 -dihydrouracil analogs), 5-methylcytosine or its derivatives (e.g., 5-methyl cytosine analog), or 5-hydroxymethylcytosine or its derivatives (e.g. In embodiments, the nucleic acid salt may be a 5-hydroxymethylcytosine analog moiety. The group may be adenine, guanine, hypoxanthine, chiral, or cyclohexyl, which may be optionally substituted or modified. In some embodiments, the compound is selected from the group consisting of santhin, theobromine, caffeine, uric acid, and isoguanine. , the nucleic acid base is [ka] and may be optionally substituted or modified.

[0088] Oligonucleotides, nucleic acids, and polynucleotides may contain non-specific sequences. As used herein, the term "non-specific sequence" refers to a sequence that is specific to any other sequence. A series of residues that are not designed to be completely complementary or only partially complementary For example, the two strands of a double-stranded oligonucleotide are One or more short (e.g., two) nucleotide overhangs on one or both ends As another example, non-specific nucleic acid sequences may be hybridized in a manner that results in The sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism. .

[0089] As used herein, the term "double-stranded oligonucleotide" refers to a double-stranded oligonucleotide that forms a double-stranded structure. refers to an oligonucleotide having a nucleic acid base sequence sufficiently complementary to form a double-stranded oligo. The nucleotide anneals the first oligonucleotide to the second complementary oligonucleotide. The double-stranded oligonucleotide may comprise a structure formed from ringing. Both oligonucleotides may be completely complementary over the length of the two. Double-stranded oligonucleotides contain short nucleotide oligonucleotides at one or both ends of the double-stranded structure. Such double-stranded oligonucleotides may have bar hangs. and microRNA mimics. Double-stranded oligonucleotides also include those with double-stranded structures. It contains a single oligonucleotide of sufficient length and self-complementarity to form a structure. Such double-stranded oligonucleotides may have a stem-loop structure. Double-stranded oligonucleotides may have naturally occurring ends, sugars, nucleobases, and / or nucleotides. It may contain one or more modifications to the interleucoside bond.

[0090] As used herein, the term "modified double-stranded oligonucleotide" refers to a naturally occurring One or more modifications to the terminal end, sugar, nucleobase, and / or internucleoside linkages present refers to a double-stranded oligonucleotide containing two separate complementary oligonucleotides. In the case of double-stranded oligonucleotides, one or both strands may contain naturally occurring termini, sugars, It may contain one or more modifications to the nucleobases and / or internucleoside linkages. stomach.

[0091] "Small interfering RNA," "short interfering RNA," "silencing RNA," and "si The terms "RNA" and "RNA" are used interchangeably herein and refer to the structure of mRNA prior to translation. The expression of specific genes by promoting their degradation (i.e., via the RNA interference pathway) siRNA refers to a group of double-stranded oligonucleotides that disrupt the target mRNA. The guide strand is targeted and incorporated into the RNA-induced silencing complex (RISC), and the guide strand is and a passenger strand that is complementary to the side strand and is typically degraded. siRNA molecules are typically about 15-50 nucleotides in length, more typically 20-30 nucleotides in length. The length of the nucleic acid fragment is 20-25 nucleotides, or 24-29 nucleotides. In this form, siRNAs are about 18-25 nucleotides in length. one or more modifications to the termini, sugars, nucleobases, and / or internucleoside linkages present may also include:

[0092] As used herein, the term "microRNA mimic" refers to a naturally occurring microRNA. MicroRNA mimics are synthetic forms of microRNAs that are complementary to one or more target mRNAs. A naturally occurring miRNA contains a guide strand and a passenger strand that is complementary to the guide strand. In a rRNA, the guide strand typically aligns partially with its target mRNA(s). The passenger strand is only partially complementary to the guide strand. RNA mimics are nucleic acid sequences that have 100% identity to naturally occurring microRNAs. or have less than 100% identity to a naturally occurring microRNA For example, the microRNA mimic may comprise a 100 nucleotide sequence in the guide strand. The microRNA mimic may contain a complementary passenger strand. one or more modifications to the termini, sugars, nucleobases, and / or internucleoside linkages that It may also contain.

[0093] As used herein, the term "single-stranded oligonucleotide" refers to an oligonucleotide that hybridizes to a complementary strand. A single-stranded oligonucleotide refers to an oligonucleotide that is not cleaved. one or more of the terminal, sugar, nucleobase, and / or internucleoside linkages present in The single-stranded oligonucleotide may include an antisense oligonucleotide. Single-stranded oligonucleotides contain nucleotides that fold into well-defined secondary structures. Also included are aptamers, which are single-stranded oligonucleotides.

[0094] As used herein, the term "modified single-stranded oligonucleotide" refers to a modified single-stranded oligonucleotide. and not hybridized to naturally occurring termini, sugars, nucleobases, and / or Refers to a single-stranded oligonucleotide containing one or more modifications to the internucleoside linkage. The modified single-stranded oligonucleotide may be a modified antisense oligonucleotide. Examples include nucleotides and aptamers.

[0095] "Antisense oligonucleotides" as referred to herein are oligonucleotides that target a small amount of a specific target nucleic acid. complementary to at least a portion of the nucleic acid and therefore selectively hybridizes to a particular target nucleic acid. and further reduce transcription of target nucleic acids (e.g., mRNA derived from DNA) and reduce translation of a nucleic acid (e.g., mRNA), alter transcript splicing, or single-stranded oligonucleotides that are further capable of otherwise interfering with the endogenous activity of Typically, antisense oligonucleotides are 15 to 25 bases long. Antisense oligonucleotides have naturally occurring termini, sugars, nucleobases, and / or It may contain one or more modifications to the internucleoside linkage. Nucleotides include, but are not limited to, anti-microRNA oligonucleotides (microRNAs) A), sterically hindered oligonucleotides (oligonucleotides that degrade target RNA) oligonucleotides that inhibit target RNA activity without inhibiting RNase H activity, and RNase H oligos Nucleotides (chemically modified oligonucleotides that induce RNase H-mediated degradation of target RNA) oligonucleotides).

[0096] One or more of the termini, phosphodiester bonds, sugars, or bases are modified from their native form. A nucleic acid, oligonucleotide, or polynucleotide is "modified" ( For example, nucleotides that are modified from their common forms in DNA or RNA to form nucleotide analogs For example, one or more of the phosphodiester bonds may be modified to form a sulfonamidate, phosphorothioate, phosphorodithioate, boranophosphonate, or or O-methyl phosphoramidite linkages, the nucleic acid is modified. (e.g., Eckstein, Oligonucleotides and Analogs gues:A Practical Approach, Oxford Univers (City Press). Modified Nucleic Acids, Oligonucleotides, and Polynucleotides These include those with cationic backbones, non-ionic backbones, and non-ribose backbones, e.g., U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, Carbohydr ate Modifications in Antisense Research, Modified nucleic acids, oligonucleotides, and the like are also described in the literature, including those described in Sanghui & Cook (eds.). Nucleotides and polynucleotides also include those in which one or more of the residues has been chemically modified. Ribose sugars, e.g., 2'-O-methylribose, 2'-deoxy-2'-fluoro-ribose ribose, and ribose "locked" by a covalent bond between the 2' and 4' carbons "Bicyclic nucleus" includes nucleic acids, oligonucleotides, and polynucleotides containing The "BNA" or "BNA" residue is located at the 4' carbon of the sugar ring, which essentially "locks" the structure into a rigid conformation. The 2' hydroxyl group of the ribose is connected to the sugar by a covalent bond. Bicyclic nucleic acids containing a methyleneoxy (4'-CH2-O-2') bridge between the aryl group and the 4' carbon The residue is a "locked nucleic acid" or "LNA." 4'-CH(CH3)-O-2' bridge The bicyclic nucleic acid residue containing is a "constrained ethyl" or "cEt" residue. " or "UNA" residues are acyclic nucleotides that lack a bond between the 2' and 3' carbons of the sugar ring. Additionally, modified nucleic acids, oligonucleotides, and polynucleotides The nucleotide may be modified at either or both of the 5' and 3' ends. For example, The oligonucleotide may contain a 5'-(E)-vinylphosphonate group at the end Nucleic acid modifications can be made for a variety of reasons, including to improve the stability and saturation of such molecules in physiological environments. This may be done to increase the half-life or to prevent immune stimulation.

[0097] In embodiments, the oligonucleotide is a single strand of locked nucleic acid (LNA), or a modified form thereof. It may consist of, consist essentially of, or include In embodiments, the oligonucleotide may be a phosphorodiamidate morpholino It may consist essentially of a single strand of a polymeric nucleotide oligomer (PMO), or modifications thereof, In embodiments, the oligonucleotide may be or include The peptides are DNA, siRNA, mRNA, locked nucleic acid (LNA), bicyclic nucleic acid (BNA), or phosphorodiamidate morpholino oligomers (PMOs), or modifications thereof, etc. At least 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68% %, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78 %, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88 %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 %, or 99%, or the oligonucleotide may contain any of the aforementioned values. The amount of DNA, siRNA, mRNA, locked nucleic acid (L NA), bicyclic nucleic acid (BNA), or phosphorodiamidate morpholino oligomer (PM O), or modifications thereof. is at least 1% of 2'-O-methoxyethyl / phosphorothioate (MOE), and 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, It may contain less than 10%, 9%, 8%, 7%, 6%, 5%, or 4%.

[0098] The term "complement," as used herein, refers to the complementary nucleotide or nucleotides. Nucleotides that can base pair with the nucleic acid sequence (e.g., RNA or DNA) A) or nucleotide sequence, as described herein and generally known in the art. As shown, the complementary (matching) nucleotide for adenosine is thymidine, and the complementary (matching) nucleotide for guanosine is thymidine. The complementary (matching) nucleotide for cytosine is cytosine. a sequence of nucleotides that base-pairs with corresponding complementary nucleotides in two nucleic acid sequences The complementary nucleotides may be partially or completely identical to the nucleotides of the second nucleic acid sequence. The complementary nucleotides may be identical to each nucleotide of the second nucleic acid sequence. If a perfect match is made with a complement, the complement will form base pairs with every nucleotide of the second nucleic acid sequence. A complementary sequence is one in which the nucleotides of the complementary sequence partially match the nucleotides of the second nucleic acid sequence. Only a portion of the nucleotides of the first nucleic acid sequence will base pair with the nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and non-coding sequences, where the non-coding sequences are complementary sequences. It contains nucleotides complementary to the coding sequence and therefore forms the complement of the coding sequence. Further examples of complementary sequences are sense and antisense sequences, The sequence contains nucleotides complementary to the antisense sequence and therefore It forms the complement of the sense sequence.

[0099] As described herein, sequence complementarity may be partial, with some of the nucleic acids Only the bases may be matched or perfect according to base pairing, and all nucleic acids may be base-paired. Therefore, two sequences that are complementary to each other are matched according to the nucleotide sequence. It may have a specific proportion of nucleotides that contribute to the About 60% complementarity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91% %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher (good complementarity).

[0100] "Hybridize" means to hybridize to a single molecule based on the well-understood principle of sequence complementarity. It is understood to mean the annealing of a single strand nucleic acid (such as a primer) to another nucleic acid. In embodiments, the other nucleic acid is a single-stranded nucleic acid. The degree of complementarity depends on the temperature and ionic strength of their environment, the length of the nucleic acids, and the degree of complementarity. The effect of these parameters on hybridization is discussed, for example, in Sambr ook J, Fritsch EF, Maniatis T., Molecular c. loning:a laboratory manual, Cold Spring H Arbor Laboratory Press, New York (1989) As used herein, a primer or a hybridization product of a DNA extension product and methylation can form phosphodiester bonds with these, respectively. Formation of a phosphodiester bond with any available nucleotide or nucleotide analog It can be extended by

[0101] A particular nucleic acid sequence also encompasses "splice variants." The specific protein encoded may be encoded by a splice variant of that nucleic acid. "Splice variant" refers to any protein that is an alternative splice of a gene. After transcription, the initial nucleic acid transcript can be split into different (alternative) nucleic acid splice products. may be spliced ​​to encode different polypeptides. The mechanisms for the production of variants vary but include alternative splicing of exons. Alternate polypeptides derived from the same nucleic acid by read-through transcription are also included in this definition. Any products of a splicing reaction (including recombinant forms of the splicing products) are included in this definition. Examples of potassium channel splice variants are the Leiche r,et al., J.Biol.Chem.273(52):35095-35101 (1998).

[0102] The terms "identical" or "percent identity" refer to the identity of two or more nucleic acid sequences or polypeptides. For sequences, BLAST or BLA using the default parameters described below As measured using the ST 2.0 sequence comparison algorithm or manual alignment and by visual inspection (see, for example, the NCBI website), are they the same? or a specific percentage of amino acid residues or nucleotides that are the same (i.e., comparison wins) When compared and aligned for maximum correspondence over a doe or a given region, At least 60% identity across a particular sequence, or at least 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or any of the preceding values refers to two or more sequences or subsequences that share a range of identity (within a range defined by the two This definition also refers to, or can be applied to, the complement of a test sequence. This definition also includes sequences that have deletions and / or additions, as well as sequences that have substitutions. As explained below, the preferred algorithm accounts for gaps, insertions, etc. Alignment for purposes of determining percent sequence identity can be performed using, for example, BL AST, BLAST-2, ALIGN, ALIGN-2, or Megaalign (DN Using publicly available computer software such as ASTAR software This can be achieved in a variety of ways within the skill of the art. Alignment, including any algorithms required to achieve maximal alignment Suitable parameters for measuring can be determined by known methods.

[0103] For sequence comparison, typically one sequence serves as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are compared in a computer The subsequence coordinates are specified if necessary, and the sequence algorithm program parameters are entered. Preferably, default program parameters can be used. The sequence comparison algorithm then compares the sequences against the reference sequence, based on the program parameters. Calculate the percent sequence identity of the test sequences.

[0104] A "comparison window," as used herein, is a window of 10 to 600, typically about 50 to about 200, more usually from about 100 to about 150, contains a reference to one of the segments, where the sequence is After being annotated, the sequence can be compared to a reference sequence for the same number of consecutive positions. Alignment methods are well known in the art. Examples of such cases include Smith & Waterman, Adv. Appl. Math. 2:4 82 (1981) local homology algorithm, Needleman & Wun Homology alignment of sch, J. Mol. Biol. 48:443 (1970) Algorithmically, Pearson & Lipman, Proc. Nat'l Acad These were identified by the similarity search method in Sci. USA 85:2444 (1988). Computer implementations of algorithms (GAP, BESTFIT, FASTA, and and Wisconsin Genetics Software Package, Gen etics Computer Group, 575 Science Dr., Maddie by TFASTA (by Son, WI) or by manual alignment and visual inspection Therefore (e.g., Current Protocols in Molecular Biology) (See Ausubel et al., eds., 1995, Supplement) good.

[0105] Compounds and Methods In one embodiment, a compound or lipid-modified oligonucleotide having the structure: It is a leotide compound. [ka]

[0106] A is an oligonucleotide, a nucleic acid, a polynucleotide, a nucleotide or an analog thereof. In embodiments, A is an oligonucleotide, or a nucleoside or analog thereof. In embodiments, A is a nucleic acid. In embodiments, A is a polynucleotide. In embodiments, A is a nucleotide or analog thereof. In the formula, A is a nucleoside or analog thereof.

[0107] L 3 and L 4 are independently a bond, -NH-, -O-, -S-, -C(O)-, -N HC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)N H-, -OPO2-O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroaromatic hydrocarbons, alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene aryl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; be.

[0108] L 5 -L 5A -L 5B -L 5C -L 5D -L 5E - and L 6 -L 6A -L 6B -L 6C -L 6D -L 6E -It is. L 5A , L 5B , L 5C , L 5D , L 5E , L 6A , L 6B , L 6C , L 6D , and L 6E are independently a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, - OC(O)-, -C(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted Heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene chloroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl It's Ren.

[0109] R 1 and R 2 are independently unsubstituted C-C 25 alkyl, where R 1 and R 2 At least one of the following is an unsubstituted C9-C 19 In embodiments, R 1 and R 2 are independently unsubstituted C-C 20 alkyl, where R 1 and R 2 At least one of the following is an unsubstituted C9-C 19 It is alkyl.

[0110] R 3 are hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NH C(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O )H, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or is unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0111] t is an integer of 1 to 5.

[0112] In embodiments, t is 1. In embodiments, t is 2. In embodiments, t is In an embodiment, t is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,

[0113] In embodiments, A is a double-stranded oligonucleotide or a single-stranded oligonucleotide. In an embodiment, A is a double-stranded oligonucleotide. In an embodiment, A is a modified oligonucleotide. In embodiments, A is a modified double-stranded oligonucleotide, a modified single-stranded oligonucleotide, or In embodiments, A is a modified double-stranded oligonucleotide. In an embodiment, A is a modified single-stranded oligonucleotide.

[0114] In embodiments, A is an siRNA, a microRNA mimic, a stem-loop structure, a single stranded siRNA, RNase H oligonucleotides, anti-microRNA oligonucleotides, sterically hindered oligonucleotides, CRISPR guide RNAs, or aptamers.

[0115] In an embodiment, one L 3 is a double-stranded or single-stranded oligonucleotide. In one embodiment, one L 3 is a double-stranded oligonucleotide In one embodiment, one L 3 is a single-stranded oligonucleotide In one embodiment, one L 3 double-stranded oligonucleotides or attached to the 3' carbon of the 3' terminal nucleotide of a single-stranded oligonucleotide. In terms of form, one L 3 is the 3' carbon atom of the 3' terminal nucleotide of the double-stranded oligonucleotide In one embodiment, one L 3 is the 3'-terminal nucleotide of a single-stranded oligonucleotide. It is attached to the 3' carbon of the nucleotide.

[0116] In an embodiment, one L 3 is a double-stranded or single-stranded oligonucleotide. In one embodiment, one L 3 is a double-stranded oligonucleotide In one embodiment, one L 3 is a single-stranded oligonucleotide In one embodiment, one L 3 double-stranded oligonucleotides or attached to the 5' carbon of the 5' terminal nucleotide of a single-stranded oligonucleotide. In terms of form, one L 3 is the 5' carbon atom of the 5' terminal nucleotide of the double-stranded oligonucleotide In one embodiment, one L 3 is the 5'-terminal nucleotide of a single-stranded oligonucleotide. It is attached to the 5' carbon of the nucleotide.

[0117] In an embodiment, one L 3 is attached to the 2' carbon of the nucleotide in the double-stranded oligonucleotide. In one embodiment, one L 3 is the nucleotide of a single-stranded oligonucleotide In embodiments, the 2' carbon is connected to the 2' carbon of an internal nucleotide. be.

[0118] In an embodiment, one L 3 is a double-stranded or single-stranded oligonucleotide. In embodiments, one L 3 is a double-stranded oligonucleotide In one embodiment, one L 3 is a single-stranded oligonucleotide is connected to the nucleic acid base.

[0119] In an embodiment, L 3 and L 4 are independently a bond, -NH-, -O-, -S-, or -C (O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)- , -C(O)NH-, -OPO2-O-, substituted or unsubstituted alkylene, or substituted or unsubstituted alkylene. or unsubstituted heteroalkylene. In embodiments, L 3 are independently a bond, -NH -, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C( -O)O-, -OC(O)-, -C(O)NH-, -OPO2-O-, substituted or unsubstituted In embodiments, L is an alkylene, or a substituted or unsubstituted heteroalkylene. 4 teeth Independently, the bond -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, -OPO2- O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. do.

[0120] In an embodiment, L 3 is independently a bond. 3 is, independently, - In embodiments, L 3 is independently —O—. In embodiments, L 3 teeth , independently -S-. In embodiments, L 3 are independently -C(O)-. In this embodiment, L 3 is independently —NHC(O)—. In embodiments, L 3 is independent and -NHC(O)NH-. In embodiments, L 3 are independently -C(O)O- In an embodiment, L 3 is independently -OC(O)-. In embodiments, L 3 is independently —C(O)NH—. In embodiments, L 3 are independently -OPO2 In an embodiment, L 3 is independently substituted or unsubstituted alkylene. In an embodiment, L 3 is independently substituted or unsubstituted heteroalkylene.

[0121] In an embodiment, L 3 are independently substituted or unsubstituted alkylene (e.g., C1-C2 0, C1-C12 , C1-C8, C1-C6, C1-C4, or C1-C2). In an embodiment, L 3 are independently substituted alkylene (e.g., C-C 20 , C1-C1 2, C1-C8, C1-C6, C1-C4, or C1-C2). L 3 are independently unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C 8, C1-C6, C1-C4, or C1-C2). 3 is independent and substituted or unsubstituted C1-C 20 In embodiments, L is alkylene. 3 is independent Substitution C1-C 20 In embodiments, L is alkylene. 3 are independently unsubstituted C1 -C 20 In embodiments, L is alkylene. 3 are independently substituted or unsubstituted C1- C 12 In embodiments, L is alkylene. 3 are independently substituted C1-C 12 Alkire In an embodiment, L 3 are independently unsubstituted C-C 12 It is an alkylene. In this embodiment, L 3 is independently a substituted or unsubstituted C1-C8 alkylene. In this state, L 3 is independently a substituted C1-C8 alkylene. 3 teeth, In an embodiment, L is independently an unsubstituted C1-C8 alkylene. 3 are independently replaced by or unsubstituted C1-C6 alkylene. In embodiments, L 3 independently, substitution C1 In an embodiment, L 3 are independently unsubstituted C1-C6 alkylene In an embodiment, L 3 are independently substituted or unsubstituted C1-C4 alkylene; In an embodiment, L 3 is independently a substituted C1-C4 alkylene. L 3 is independently an unsubstituted C1-C4 alkylene. 3 is German In one embodiment, L is substituted or unsubstituted ethylene. 3 are independently substituted ethene In an embodiment, L 3 is independently unsubstituted ethylene. L 3 is independently substituted or unsubstituted methylene. 3 independently , substituted methylene. In embodiments, L 3 is independently unsubstituted methylene.

[0122] In an embodiment, L 3 are independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4 In one embodiment, L 3 is independently a substituted heteroalkylene (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or is a 4- to 5-membered ring). 3 are independently unsubstituted heteroalkylene (e.g., For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, and 2- to 3-membered rings or a 4- or 5-membered ring). 3 are independently substituted or unsubstituted 2 In one embodiment, L is a 20-membered heteroalkylene. 3 are independently a substituted 2- to 20-membered ring In embodiments, L is heteroalkylene. 3 are independently unsubstituted 2- to 20-membered heterocyclic rings In embodiments, L is alkylene. 3 are independently substituted or unsubstituted 2- to 8-membered ring heterocycles. In one embodiment, L is 1,2,3,4-trimethylsilyl. 3 are independently a substituted 2- to 8-membered heteroalkyl group. In an embodiment, L 3 are independently unsubstituted 2- to 8-membered heteroalkylene In an embodiment, L 3 are independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In an embodiment, L 3 are independently substituted 2- to 6-membered heteroalkylene. In this state, L 3 is independently an unsubstituted 2- to 6-membered heteroalkylene. L 3 are independently substituted or unsubstituted 4- to 6-membered heteroalkylene. , L 3 are independently substituted 4- to 6-membered heteroalkylene. 3 teeth, In an embodiment, L is an unsubstituted 4- to 6-membered heteroalkylene. 3 independently , substituted or unsubstituted 2- to 3-membered heteroalkylene. 3 is independent In an embodiment, L is a substituted 2- or 3-membered heteroalkylene. 3 are independently unsubstituted In one embodiment, L is a 2- or 3-membered heteroalkylene. 3 are independently substituted or non-substituted. In one embodiment, L is a substituted 4- or 5-membered heteroalkylene. 3 are independently substituted 4- to 5-membered In one embodiment, L is a heterocyclic heteroalkylene. 3 are independently unsubstituted 4- or 5-membered heterocyclic rings It is alkylene.

[0123] In an embodiment, L 4 is independently a bond. 4 is, independently, - In embodiments, L 4 is independently —O—. In embodiments, L 4 teeth , independently -S-. In embodiments, L 4 are independently -C(O)-. In this embodiment, L 4 is independently —NHC(O)—. In embodiments, L 4 is independent and -NHC(O)NH-. In embodiments, L 4 are independently -C(O)O- In an embodiment, L 4 is independently -OC(O)-. In embodiments, L 4 is independently —C(O)NH—. In embodiments, L 4 are independently -OPO2 In an embodiment, L 4 is independently substituted or unsubstituted alkylene. In an embodiment, L 4 is independently substituted or unsubstituted heteroalkylene.

[0124] In an embodiment, L 4 are independently substituted or unsubstituted alkylene (e.g., C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In an embodiment, L 4 are independently substituted alkylene (e.g., C-C 20 , C1-C1 2, C1-C8, C1-C6, C1-C4, or C1-C2). L 4 are independently unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C 8, C1-C6, C1-C4, or C1-C2). 4 is independent and substituted or unsubstituted C1-C 20 In embodiments, L is alkylene. 4 is independent Substitution C1-C 20 In embodiments, L is alkylene. 4 are independently unsubstituted C1 -C 20 In embodiments, L is alkylene. 4 are independently substituted or unsubstituted C1- C 12 In embodiments, L is alkylene. 4 are independently substituted C1-C 12 Alkire In an embodiment, L 4 are independently unsubstituted C-C 12 It is an alkylene. In this embodiment, L 4 is independently a substituted or unsubstituted C1-C8 alkylene. In this state, L 4 is independently a substituted C1-C8 alkylene. 4 teeth, In an embodiment, L is independently an unsubstituted C1-C8 alkylene. 4 are independently replaced by or unsubstituted C1-C6 alkylene. In embodiments, L 4 independently, substitution C1 In an embodiment, L 4 are independently unsubstituted C1-C6 alkylene In an embodiment, L 4 are independently substituted or unsubstituted C1-C4 alkylene; In an embodiment, L 4 is independently a substituted C1-C4 alkylene. L 4 is independently an unsubstituted C1-C4 alkylene. 4 is German In one embodiment, L is substituted or unsubstituted ethylene. 4 are independently substituted ethene In an embodiment, L 4 is independently unsubstituted ethylene. L 4 is independently substituted or unsubstituted methylene. 4 independently , substituted methylene. In embodiments, L 4 is independently unsubstituted methylene.

[0125] In an embodiment, L 4 are independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4 In one embodiment, L 4 is independently a substituted heteroalkylene (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or is a 4- to 5-membered ring). 4 are independently unsubstituted heteroalkylene (e.g., For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, and 2- to 3-membered rings or a 4- or 5-membered ring). 4 are independently substituted or unsubstituted 2 In one embodiment, L is a 20-membered heteroalkylene. 4 are independently a substituted 2- to 20-membered ring In embodiments, L is heteroalkylene. 4 are independently unsubstituted 2- to 20-membered heterocyclic rings In embodiments, L is alkylene. 4 are independently substituted or unsubstituted 2- to 8-membered ring heterocycles. In one embodiment, L is 1,2,3,4-trimethylsilyl. 4 are independently a substituted 2- to 8-membered heteroalkyl group. In an embodiment, L 4 are independently unsubstituted 2- to 8-membered heteroalkylene In an embodiment, L 4 are independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In an embodiment, L 4 are independently substituted 2- to 6-membered heteroalkylene. In this state, L 4 is independently an unsubstituted 2- to 6-membered heteroalkylene. L 4 are independently substituted or unsubstituted 4- to 6-membered heteroalkylene. , L 4 are independently substituted 4- to 6-membered heteroalkylene. 4 teeth, In an embodiment, L is an unsubstituted 4- to 6-membered heteroalkylene. 4 independently , substituted or unsubstituted 2- to 3-membered heteroalkylene. 4 is independent In an embodiment, L is a substituted 2- or 3-membered heteroalkylene. 4 are independently unsubstituted In one embodiment, L is a 2- or 3-membered heteroalkylene. 4 are independently substituted or non-substituted. In one embodiment, L is a substituted 4- or 5-membered heteroalkylene. 4 are independently substituted 4- to 5-membered In one embodiment, L is a heterocyclic heteroalkylene. 4 are independently unsubstituted 4- or 5-membered heterocyclic rings It is alkylene.

[0126] In an embodiment, L 3 is, independently, [ka] In an embodiment, L 3 is independently -OPO2-O-. In embodiments, L 3 are independently -O-.

[0127] In an embodiment, L 4 are independently substituted or unsubstituted alkylene or substituted or In embodiments, L is an unsubstituted heteroalkylene. 4 independently, -L 7 -NH-C( O)- or -L 7 In embodiments, L 7 are independently replaced by or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C 6, C1-C4, or C1-C2). In embodiments, L 7 are independently substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4 , or C1-C2). In an embodiment, L 7 are independently unsubstituted alkylene (e.g. For example, C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1 -C2).

[0128] In an embodiment, L 4 are independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered ring, 2-12-membered ring, 2-10-membered ring, 2-8-membered ring, 2-6-membered ring, or 2-4-membered ring) In an embodiment, L 4 are independently substituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, or 2- to 4-membered ring) In an embodiment, L 4 are independently oxo-substituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, or 2- to 4-membered ring) In an embodiment, L 4 are independently unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, or 2- to 4-membered ring).

[0129] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7 are independently substituted or unsubstituted alkylene (e.g., C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In an embodiment, L 4 independently, -L 7 -NH-C(O)-, and L 7 independently , substituted or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C In embodiments, L 4 is, independently, -L 7 -C(O)-NH-, and L 7 are independently substituted or unsubstituted alkylene (e.g. For example, C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1 -C2).

[0130] In an embodiment, L 7are independently substituted or unsubstituted alkylene (e.g., C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In an embodiment, L 7 are independently substituted alkylene (e.g., C-C 20 , C1-C1 2, C1-C8, C1-C6, C1-C4, or C1-C2). L 7 are independently unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C 8, C1-C6, C1-C4, or C1-C2). 7 is independent and substituted or unsubstituted C1-C 20 In embodiments, L is alkylene. 7 is independent Substitution C1-C 20 In embodiments, L is alkylene. 7 are independently hydroxy (OH)substituted C1-C 20 In embodiments, L is alkylene. 7 are independently hydrochloride Oxymethyl-substituted C1-C 20 In embodiments, L is alkylene. 7 is independent and non-placed Exchange C1-C 20 In embodiments, L is alkylene. 7 are independently substituted or unsubstituted C1-C 12 In embodiments, L is alkylene. 7 are independently substituted C1-C 12 a In one embodiment, L 7 are independently hydroxy (OH) substituted C1-C1 2 alkylene. In embodiments, L 7 are independently hydroxymethyl-substituted C1-C 12In embodiments, L is alkylene. 7 are independently unsubstituted C-C 12 Alkire In an embodiment, L 7 are independently substituted or unsubstituted C1-C8 alkylene; In an embodiment, L 7 is independently a substituted C1-C8 alkylene. L 7 is independently a hydroxy (OH) substituted C1-C8 alkylene. Well, L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. Well, L 7 is independently an unsubstituted C1-C8 alkylene. 7 teeth, In an embodiment, L is independently substituted or unsubstituted C1-C6 alkylene. 7 is independent and substituted C1-C6 alkylene. 7 are independently hydroxy (OH) substituted C1-C6 alkylene. 7 are independently hydroxyl In one embodiment, L is a methyl-substituted C1-C6 alkylene. 7 are independently unsubstituted C In embodiments, L 7 are independently substituted or unsubstituted C1- In an embodiment, L 7 are independently substituted C1-C4 alkylene; In an embodiment, L 7 are independently hydroxy (OH) substituted C1-C4 alkylene In an embodiment, L 7 are independently hydroxymethyl-substituted C1-C4 alkylene In an embodiment, L 7 is independently an unsubstituted C1-C4 alkylene. In this state, L7 is independently a substituted or unsubstituted C1-C2 alkylene. L 7 is independently a substituted C1-C2 alkylene. 7 is independent and hydroxy (OH) substituted C1-C2 alkylene. 7 is German In one embodiment, L is a hydroxymethyl-substituted C1-C2 alkylene. 7 is German and unsubstituted C1-C2 alkylene.

[0131] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7 are independently substituted or unsubstituted alkylene (e.g., C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)- NH- and L 7 are independently substituted or unsubstituted C1-C8 alkylene. In terms of form, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH - and L 7 is independently a substituted C1-C8 alkylene. 4 teeth , independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 teeth , independently, hydroxy (OH)-substituted C1-C8 alkylene. In embodiments, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 is independently unsubstituted C1-C8 alkylene.

[0132] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7 are independently substituted or unsubstituted C3-C8 alkylene. In this embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-N H- and L 7 is independently a substituted C-C alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 is independently a hydroxy (OH) substituted C-C alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C-C alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7-C(O)-NH-, and L 7 is independently an unsubstituted C3-C8 alkylene.

[0133] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7 are independently substituted or unsubstituted C5-C8 alkylene. In this embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-N H- and L 7 is independently a substituted C5-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 is independently a hydroxy (OH) substituted C5-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 is independently an unsubstituted C5-C8 alkylene.

[0134] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7is independently substituted or unsubstituted octylene. , L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH- , L 7 is independently a substituted octylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 are independently hydrochloride In embodiments, L is an oxy(OH)-substituted octylene. 4 independently, -L 7 -NH- C(O)- or -L 7 -C(O)-NH-, and L 7 are independently unsubstituted octyl In an embodiment, L 4 independently, -L 7 -NH-C(O)-, and L 7 teeth , independently, hydroxy (OH)-substituted octylene. In embodiments, L 4 is independent Te, -L 7 -NH-C(O)-, and L 7 are independently hydroxymethyl-substituted octyl In an embodiment, L 4 independently, -L 7 -NH-C(O), and L 7 teeth , independently, unsubstituted octylene.

[0135] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7 is independently substituted or unsubstituted heptylene. , L 4independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH- , L 7 is independently a substituted heptylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 are independently hydrochloride In embodiments, L is an oxy(OH)-substituted heptylene. 4 independently, -L 7 -NH- C(O)- or -L 7 -C(O)-NH-, and L 7 are independently unsubstituted hexyl In an embodiment, L 4 independently, -L 7 -NH-C(O)-, and L 7 teeth , independently, hydroxy (OH)-substituted heptylene. In embodiments, L 4 is independent Te, -L 7 -NH-C(O)-, and L 7 are independently hydroxymethyl-substituted hydroxymethyl groups. In an embodiment, L 4 independently, -L 7 -NH-C(O), and L 7 teeth , are independently unsubstituted heptylene.

[0136] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7 is independently substituted or unsubstituted hexylene. , L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH- , L 7 is independently a substituted hexylene. 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 are independently hydrochloride In embodiments, L is an alkoxy(OH)-substituted hexylene. 4 independently, -L 7 -NH- C(O)- or -L 7 -C(O)-NH-, and L 7 are independently unsubstituted hexyl In an embodiment, L 4 independently, -L 7 -NH-C(O)-, and L 7 teeth , independently, hydroxy (OH)-substituted hexylene. In embodiments, L 4 is independent Te, -L 7 -NH-C(O)-, and L 7 are independently hydroxymethyl-substituted hexyl In an embodiment, L 4 independently, -L 7 -NH-C(O), and L 7 teeth , independently, unsubstituted hexylene.

[0137] In an embodiment, L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O) -NH- and L 7 is independently substituted or unsubstituted pentylene. , L 4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH- , L 7 is independently a substituted pentylene.4 independently, -L 7 -NH-C(O)- or -L 7 -C(O)-NH-, and L 7 are independently hydrochloride In embodiments, L is an oxy(OH)-substituted pentylene. 4 independently, -L 7 -NH- C(O)- or -L 7 -C(O)-NH-, and L 7 are independently unsubstituted pentylene In an embodiment, L 4 independently, -L 7 -NH-C(O)-, and L 7 teeth , independently, hydroxy (OH)-substituted pentylene. In embodiments, L 4 is independent Te, -L 7 -NH-C(O)-, and L 7 are independently hydroxymethyl-substituted pentyl groups. In an embodiment, L 4 independently, -L 7 -NH-C(O), and L 7 teeth , independently, unsubstituted pentylene.

[0138] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] is.

[0139] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] In an embodiment, L 4 is, independently, [ka] is.

[0140] In an embodiment, -L 3 -L 4 - is independently, -L 7-NH-C(O)- or -L 7 In embodiments, L 7 are independently substituted or unsubstituted heterocyclic groups. Alkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring) In one embodiment, L 7 are independently substituted heteroalkyl groups. olefins (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 10-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, or a 2- to 4-membered ring). 7 are independently oxo-substituted heteroalkyl groups; olefins (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 10-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, or a 2- to 4-membered ring). 7 are independently unsubstituted heteroalkylene (For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 10-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, or is a 2- to 4-membered ring). 7 are independently substituted or unsubstituted heteroaryl groups. kenylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring) In one embodiment, L 7 are independently substituted heteroalkenyl groups; olefins (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 10-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, or a 2- to 4-membered ring). 7 are independently an oxo-substituted heteroalkene; Nylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring) or a 2- to 4-membered ring). 7 are independently unsubstituted heteroalkenyl olefins (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 10-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, or 2- to 4-membered ring).

[0141] In an embodiment, L 7 are independently substituted or unsubstituted 2- to 20-membered heteroalkylene rings. In an embodiment, L 7 are independently substituted 2- to 20-membered heteroalkylene rings. In this embodiment, L 7 are independently an oxo-substituted 2- to 20-membered heteroalkylene. In terms of form, L 7 is independently an unsubstituted 2- to 20-membered heteroalkylene. L 7 are independently substituted or unsubstituted 2- to 12-membered heteroalkylene. In this state, L 7 is independently a substituted 2- to 12-membered heteroalkylene. L 7 is independently an oxo-substituted 2- to 12-membered heteroalkylene. 7 is independently an unsubstituted 2- to 12-membered heteroalkylene. 7 teeth, In an embodiment, L is independently a substituted or unsubstituted 2- to 10-membered heteroalkylene. 7 is independently a substituted 2- to 10-membered heteroalkylene. 7 is independent and oxo-substituted 2- to 10-membered heteroalkylene. 7 is independent In one embodiment, L is an unsubstituted 2- to 10-membered heteroalkylene. 7 is independently placed In one embodiment, L is a substituted or unsubstituted 2- to 8-membered heteroalkylene. 7 is, independently, In one embodiment, L is a substituted 2- to 8-membered heteroalkylene. 7 are independently oxo-substituted In one embodiment, L is a 2- to 8-membered heteroalkylene. 7are independently unsubstituted 2- to 8-membered In one embodiment, L is a heterocyclic heteroalkylene. 7 are independently substituted or unsubstituted 2 to 6 In one embodiment, L is a membered heteroalkylene. 7 are independently substituted 2- to 6-membered heterocyclic rings In embodiments, L is alkylene. 7 are independently an oxo-substituted 2- to 6-membered heteroaryl ring. In one embodiment, L 7 are independently unsubstituted 2- to 6-membered heteroalkylene. In an embodiment, L 7 are independently substituted or unsubstituted 2- to 4-membered heteroalkylene In an embodiment, L 7 are independently substituted 2- to 4-membered heteroalkylene. In this embodiment, L 7 are independently oxo-substituted 2- to 4-membered heteroalkylene. In this state, L 7 are independently unsubstituted 2- to 4-membered heteroalkylene.

[0142] In an embodiment, L 7 are independently substituted or unsubstituted 2- to 20-membered heteroalkenylene. In an embodiment, L 7 are independently a substituted 2- to 20-membered heteroalkenylene. In an embodiment, L 7 are independently an oxo-substituted 2- to 20-membered heteroalkenylene. In an embodiment, L 7 are independently unsubstituted 2- to 20-membered heteroalkenylene. In this embodiment, L 7 are independently substituted or unsubstituted 2- to 12-membered heteroalkenylene. In an embodiment, L 7 are independently substituted 2- to 12-membered heteroalkenylene. In this embodiment, L 7are independently an oxo-substituted 2- to 12-membered heteroalkenylene. In this embodiment, L 7 are independently unsubstituted 2- to 12-membered heteroalkenylene. In this state, L 7 are independently substituted or unsubstituted 2- to 10-membered heteroalkenylene. In an embodiment, L 7 are independently substituted 2- to 10-membered heteroalkenylene. In this state, L 7 are independently an oxo-substituted 2- to 10-membered heteroalkenylene. In this state, L 7 are independently unsubstituted 2- to 10-membered heteroalkenylene. L 7 are independently substituted or unsubstituted 2- to 8-membered heteroalkenylene. In this state, L 7 are independently substituted 2-8 membered heteroalkenylene. L 7 is independently an oxo-substituted 2-8 membered heteroalkenylene. 7 is independently an unsubstituted 2-8 membered heteroalkenylene. 7 teeth, In an embodiment, L is independently a substituted or unsubstituted 2- to 6-membered heteroalkenylene. 7 are independently substituted 2- to 6-membered heteroalkenylene. 7 is independent and oxo-substituted 2- to 6-membered heteroalkenylene. 7 is independent In one embodiment, L is an unsubstituted 2- to 6-membered heteroalkenylene. 7 is independently placed In one embodiment, L is a substituted or unsubstituted 2- to 4-membered heteroalkenylene. 7 independently , substituted 2- to 4-membered heteroalkenylene.7 are independently oxo In one embodiment, L is a substituted 2- to 4-membered heteroalkenylene. 7 are independently unsubstituted 2 ~ 4-membered heteroalkenylene.

[0143] In embodiments, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)- or - Office Lady 7 In embodiments, L 7 are independently substituted or non-substituted. Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2). In embodiments, -L 3 -L 4 - is independently -O- L 7 -NH-C(O)- or -OL 7 -C(O)-NH-, and L 7 independently , substituted or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C In embodiments, -L 3 -L 4 -teeth, Independently, -OL 7 -NH-C(O), and L 7 are independently substituted or unsubstituted alkyl groups. alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4 , or C1-C2). In embodiments, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2 )

[0144] In embodiments, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently placed In one embodiment, -L is a C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 are independently hydroxy (OH) substituted C1-C8 alkyl groups. In one embodiment, -L is alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)- NH- and L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently unsubstituted C1-C8 alkylene.

[0145] In embodiments, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, L 7is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently placed In one embodiment, -L is a C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 are independently hydroxy (OH) substituted C3-C8 alkyl groups. In one embodiment, -L is alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)- NH- and L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently an unsubstituted C3-C8 alkylene.

[0146] In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently placed In one embodiment, -L is a C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7are independently hydroxy (OH) substituted C5-C8 alkyl groups. In one embodiment, -L is alkylene. 3 -L 4 - is, independently, -OL 7 -C(O)- NH- and L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L 3 -L 4 - is, independently, -OL 7 -C(O)-NH-, and L 7 is independently an unsubstituted C5-C8 alkylene.

[0147] In embodiments, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, L 7 is independently a substituted or unsubstituted C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 is independently placed In one embodiment, -L is a C1-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 are independently hydroxy (OH) substituted C1-C8 alkyl groups. In one embodiment, -L is alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C( O)- and L 7 is independently a hydroxymethyl-substituted C1-C8 alkylene. In embodiments, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 is independently unsubstituted C1-C8 alkylene.

[0148] In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, L 7 is independently a substituted or unsubstituted C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 is independently placed In one embodiment, -L is a C3-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 are independently hydroxy (OH) substituted C3-C8 alkyl groups. In one embodiment, -L is alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C( O)- and L 7 is independently a hydroxymethyl-substituted C3-C8 alkylene. In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 is independently an unsubstituted C3-C8 alkylene.

[0149] In an embodiment, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, L 7 is independently a substituted or unsubstituted C5-C8 alkylene. 3 -L 4- is, independently, -OL 7 -NH-C(O)-, and L 7 is independently placed In one embodiment, -L is a C5-C8 alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 are independently hydroxy (OH) substituted C5-C8 alkyl groups. In one embodiment, -L is alkylene. 3 -L 4 - is, independently, -OL 7 -NH-C( O)- and L 7 is independently a hydroxymethyl-substituted C5-C8 alkylene. In embodiments, -L 3 -L 4 - is, independently, -OL 7 -NH-C(O)-, and L 7 is independently an unsubstituted C5-C8 alkylene.

[0150] In embodiments, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] is.

[0151] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O) -or-OPO2-OL 7 In embodiments, L 7 is independent and substituted or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8 , C1-C6, C1-C4, or C1-C2). In embodiments, -L 3 -L 4 - are independently -OPO2-OL 7 -NH-C(O)- or -OPO2-OL 7 - C(O)-NH-, and L 7 is independently a substituted or unsubstituted alkylene. In terms of form, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O) , L 7 is independently substituted or unsubstituted alkylene. In embodiments, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-, and L 7 is, independently, In embodiments, -L is a substituted or unsubstituted alkylene. 3 -L 4 - is independently -O PO2-OL 7 -NH-C(O)- or -OPO2-OL 7 -C(O)-NH- Yes, L 7 are independently substituted or unsubstituted alkylene (e.g., C-C 20 , C1- C12 , C1-C8, C1-C6, C1-C4, or C1-C2). -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-, and L 7 are independently substituted or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-, and L 7 is German and substituted or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C 8, C1-C6, C1-C4, or C1-C2).

[0152] In embodiments, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH - and L 7 is independently a substituted or unsubstituted C1-C8 alkylene. So, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-, L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 -teeth , independently, -OPO2-OL 7 -C(O)-NH-, and L 7 is independently In one embodiment, -L is an alkylene group selected from the group consisting of hydroxy(OH)-substituted C1-C8 alkylene. 3 -L 4- is German Standing, -OPO2-OL 7 -C(O)-NH-, and L 7 are independently hydroxyl In one embodiment, -L is a methyl-substituted C1-C8 alkylene. 3 -L 4 - is independently , -OPO2-OL 7 -C(O)-NH-, and L 7 are independently unsubstituted C-C 8 alkylene.

[0153] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH - and L 7 is independently a substituted or unsubstituted C3-C8 alkylene. So, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-, L 7 is independently a substituted C-C alkylene. 3 -L 4 -teeth , independently, -OPO2-OL 7 -C(O)-NH-, and L 7 is independently In one embodiment, -L is an alkylene group selected from the group consisting of hydroxy(OH)-substituted C3-C8 alkylene. 3 -L 4 - is German Standing, -OPO2-OL 7 -C(O)-NH-, and L 7 are independently hydroxyl In one embodiment, -L is a dimethyl-substituted C3-C8 alkylene. 3 -L 4 - is independently , -OPO2-OL 7 -C(O)-NH-, and L 7 are independently unsubstituted C3-C 8 alkylene.

[0154] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH - and L 7 is independently a substituted or unsubstituted C5-C8 alkylene. So, -L 3 -L 4 - is independently -OPO2-OL 7 -C(O)-NH-, L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 -teeth , independently, -OPO2-OL 7 -C(O)-NH-, and L 7 is independently In one embodiment, -L is an alkylene group selected from the group consisting of hydroxy(OH)-substituted C5-C8 alkylene. 3 -L 4 - is German Standing, -OPO2-OL 7 -C(O)-NH-, and L 7 are independently hydroxyl In one embodiment, -L is a dimethyl-substituted C5-C8 alkylene. 3 -L 4 - is independently , -OPO2-OL 7 -C(O)-NH-, and L 7 are independently unsubstituted C5-C 8 alkylene.

[0155] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O) - and L 7 is independently a substituted or unsubstituted C1-C8 alkylene. So, -L 3 -L4 - is independently -OPO2-OL 7 -NH-C(O)-, L 7 is independently a substituted C1-C8 alkylene. 3 -L 4 -teeth , independently, -OPO2-OL 7 -NH-C(O)-, and L 7 is independently In one embodiment, -L is an alkylene group selected from the group consisting of hydroxy(OH)-substituted C1-C8 alkylene. 3 -L 4 - is German Standing, -OPO2-OL 7 -NH-C(O)-, and L 7 are independently hydroxyl In one embodiment, -L is a methyl-substituted C1-C8 alkylene. 3 -L 4 - is independently , -OPO2-OL 7 -NH-C(O)-, and L 7 are independently unsubstituted C-C 8 alkylene.

[0156] In an embodiment, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O) - and L 7 is independently a substituted or unsubstituted C3-C8 alkylene. So, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-, L 7 is independently a substituted C-C alkylene. 3 -L 4 -teeth , independently, -OPO2-OL 7 -NH-C(O)-, and L 7 is independently In one embodiment, -L is an alkylene group selected from the group consisting of hydroxy(OH)-substituted C3-C8 alkylene. 3 -L 4 - is German Standing, -OPO2-OL 7 -NH-C(O)-, and L 7 are independently hydroxyl In one embodiment, -L is a dimethyl-substituted C3-C8 alkylene. 3 -L 4 - is independently , -OPO2-OL 7 -NH-C(O)-, and L 7 are independently unsubstituted C3-C 8 alkylene.

[0157] In embodiments, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O) - and L 7 is independently a substituted or unsubstituted C5-C8 alkylene. So, -L 3 -L 4 - is independently -OPO2-OL 7 -NH-C(O)-, L 7 is independently a substituted C5-C8 alkylene. 3 -L 4 -teeth , independently, -OPO2-OL 7 -NH-C(O)-, and L 7 is independently In one embodiment, -L is an alkylene group selected from the group consisting of hydroxy(OH)-substituted C5-C8 alkylene. 3 -L 4 - is German Standing, -OPO2-OL 7 -NH-C(O)-, and L 7 are independently hydroxyl In one embodiment, -L is a dimethyl-substituted C5-C8 alkylene. 3 -L 4 - is independently , -OPO2-OL 7 -NH-C(O)-, and L 7 are independently unsubstituted C5-C 8 alkylene.

[0158] In an embodiment, -L 3 -L 4 - is independently [ka] In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 3' carbon of the double-stranded or single-stranded oligonucleotide. are. In an embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 2' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is connected to the nucleobase of a double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 3' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 2' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is connected to the nucleobase of a double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 3' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4- is independently [ka] and is attached to the 2' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is connected to the nucleobase of a double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 3' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 5' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is attached to the 2' carbon of the double-stranded or single-stranded oligonucleotide. In one embodiment, -L 3 -L 4 - is independently [ka] and is connected to the nucleobase of a double-stranded or single-stranded oligonucleotide. are.

[0159] In embodiments, R 3 are independently hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, - C(O)OH, -OC(O)H, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted substituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl chloroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl In an embodiment, R 3 are independently hydrogen. In embodiments, R 3 is independent In one embodiment, R 3 is independently —OH. R 3 is independently -SH. In an embodiment, R 3 are independently -C(O)H In an embodiment, R 3 is independently —C(O)NH. In embodiments, R 3 teeth , independently -NHC(O)H. In embodiments, R 3 are independently -NHC(O )OH. In embodiments, R 3 are independently —NHC(O)NH. In this state, R 3 is independently —C(O)OH. In embodiments, R 3 is, independently, In an embodiment, R 3 are independently -N3.

[0160] In embodiments, R 3 are independently substituted or unsubstituted alkyl (e.g., C-C 20 , C1-C 12, C1-C8, C1-C6, C1-C4, or C1-C2). In the embodiment, R 3 are independently substituted or unsubstituted C-C 20 It is alkyl. In this state, R 3 are independently substituted C1-C 20 In embodiments, R 3 teeth, independently, unsubstituted C1-C 20 In embodiments, R 3 are independently replaced by or unsubstituted C1-C 12 In embodiments, R 3 independently, substitution C1 -C 12 In embodiments, R 3 are independently unsubstituted C-C 12 Archi In an embodiment, R 3 are independently substituted or unsubstituted C1-C8 alkyl. In an embodiment, R 3 is independently substituted C1-C8 alkyl. R 3 is independently unsubstituted C1-C8 alkyl. In embodiments, R 3 independently , substituted or unsubstituted C1-C6 alkyl. In embodiments, R 3 are independently replaced by In an embodiment, R 3 are independently unsubstituted C1-C6 alkyl In an embodiment, R 3 are independently substituted or unsubstituted C1-C4 alkyl. In an embodiment, R 3 is independently substituted C1-C4 alkyl. R 3 is independently unsubstituted C1-C4 alkyl. In embodiments, R 3 independently , substituted or unsubstituted ethyl. In embodiments, R 3 are independently substituted ethyl In embodiments, R 3 is independently unsubstituted ethyl. In embodiments, R 3 is independent and substituted or unsubstituted methyl. In embodiments, R 3 are independently substituted methyl In an embodiment, R 3 is independently unsubstituted methyl.

[0161] In an embodiment, L 6 is independently —NHC(O)—. In embodiments, L 6 teeth, Independently, -C(O)NH-. In embodiments, L 6 are independently substituted or non-substituted. In one embodiment, L is a substituted alkylene. 6 are independently substituted or unsubstituted heteroalkyl groups. It's Ren.

[0162] In an embodiment, L 6 are independently substituted or unsubstituted alkylene (e.g., C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In an embodiment, L 6 are independently substituted alkylene (e.g., C-C 20 , C1-C1 2, C1-C8, C1-C6, C1-C4, or C1-C2). L 6 are independently unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C 8, C1-C6, C1-C4, or C1-C2). 6 is independent and substituted or unsubstituted C1-C 20 In embodiments, L is alkylene.6 is independent Substitution C1-C 20 In embodiments, L is alkylene. 6 are independently unsubstituted C1 -C 20 In embodiments, L is alkylene. 6 are independently substituted or unsubstituted C1- C 12 In embodiments, L is alkylene. 6 are independently substituted C1-C 12 Alkire In an embodiment, L 6 are independently unsubstituted C-C 12 It is an alkylene. In this embodiment, L 6 is independently a substituted or unsubstituted C1-C8 alkylene. In this state, L 6 is independently a substituted C1-C8 alkylene. 6 teeth, In an embodiment, L is independently an unsubstituted C1-C8 alkylene. 6 are independently replaced by or unsubstituted C1-C6 alkylene. In embodiments, L 6 independently, substitution C1 In an embodiment, L 6 are independently unsubstituted C1-C6 alkylene In an embodiment, L 6 are independently substituted or unsubstituted C1-C4 alkylene; In an embodiment, L 6 is independently a substituted C1-C4 alkylene. L 6 is independently an unsubstituted C1-C4 alkylene. 6 is German In one embodiment, L is substituted or unsubstituted ethylene. 6 are independently substituted ethene In an embodiment, L 6is independently unsubstituted ethylene. L 6 is independently substituted or unsubstituted methylene. 6 independently , substituted methylene. In embodiments, L 6 is independently unsubstituted methylene.

[0163] In an embodiment, L 6 are independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4 In one embodiment, L 6 is independently a substituted heteroalkylene (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or is a 4- to 5-membered ring). 6 are independently unsubstituted heteroalkylene (e.g., For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, and 2- to 3-membered rings or a 4- or 5-membered ring). 6 are independently substituted or unsubstituted 2 In one embodiment, L is a 20-membered heteroalkylene. 6 are independently a substituted 2- to 20-membered ring In embodiments, L is heteroalkylene. 6 are independently unsubstituted 2- to 20-membered heterocyclic rings In embodiments, L is alkylene. 6 are independently substituted or unsubstituted 2- to 8-membered ring heterocycles. In one embodiment, L is 1,2,3,4-trimethylsilyl. 6 are independently a substituted 2- to 8-membered heteroalkyl group. In an embodiment, L 6 are independently unsubstituted 2- to 8-membered heteroalkylene In an embodiment, L 6 are independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In an embodiment, L 6 are independently substituted 2- to 6-membered heteroalkylene. In this state, L 6 is independently an unsubstituted 2- to 6-membered heteroalkylene. L 6 are independently substituted or unsubstituted 4- to 6-membered heteroalkylene. , L 6 are independently substituted 4- to 6-membered heteroalkylene. 6 teeth, In an embodiment, L is an unsubstituted 4- to 6-membered heteroalkylene. 6 independently , substituted or unsubstituted 2- to 3-membered heteroalkylene. 6 is independent In an embodiment, L is a substituted 2- or 3-membered heteroalkylene. 6 are independently unsubstituted In one embodiment, L is a 2- or 3-membered heteroalkylene. 6 are independently substituted or non-substituted. In one embodiment, L is a substituted 4- or 5-membered heteroalkylene. 6 are independently substituted 4- to 5-membered In one embodiment, L is a heterocyclic heteroalkylene. 6 are independently unsubstituted 4- or 5-membered heterocyclic rings It is alkylene.

[0164] In an embodiment, L 6A are independently a bond or unsubstituted alkylene; L 6B teeth, independently a bond, —NHC(O)—, or unsubstituted arylene; L 6C is independent is a bond, unsubstituted alkylene, or unsubstituted arylene; 6D is independent and is substituted or unsubstituted alkylene; L 6E are independently a bond or -NHC(O)- In an embodiment, L6A is independently a bond or unsubstituted alkylene. In this state, L 6B are independently a bond, —NHC(O)—, or unsubstituted arylene; In an embodiment, L 6C are independently a bond, an unsubstituted alkylene, or an unsubstituted aryl. In an embodiment, L 6D are independently a bond or unsubstituted alkylene. In this embodiment, L 6E are independently a bond or —NHC(O)—.

[0165] In an embodiment, L 6A are independently a bond or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, L 6A are independently unsubstituted C-C 20 It is alkylene. Well, L 6A are independently unsubstituted C-C 12 In embodiments, L is alkylene. 6 A is independently an unsubstituted C1-C8 alkylene. 6A is independent and unsubstituted C1-C6 alkylene. In embodiments, L 6A are independently unsubstituted C In embodiments, L is 1-C4 alkylene. 6A are independently unsubstituted ethylene In an embodiment, L 6A is independently unsubstituted methylene. 6A teeth , independently, is a bond.

[0166] In an embodiment, L 6B is independently a bond.6B independently , -NHC(O)-. In embodiments, L 6B are independently unsubstituted arylene (e.g. For example, C6-C 12 , C6-C 10 , or phenyl). In embodiments, L 6B teeth , independently, unsubstituted C6-C 12 In one embodiment, L 6B independently , unsubstituted C6-C 10 In one embodiment, L 6B are independently unsubstituted fluoresceins. In one embodiment, L is phenylene. 6B is independently unsubstituted naphthylene.

[0167] In an embodiment, L 6C are independently a bond or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, L 6C are independently unsubstituted C-C 20 It is alkylene. Well, L 6C are independently unsubstituted C-C 12 In embodiments, L is alkylene. 6 C is independently an unsubstituted C1-C8 alkylene. 6C are independently unsubstituted C2 In embodiments, L is -C alkynylene. 6C are independently unsubstituted C1-C6 alkyl In one embodiment, L 6C are independently unsubstituted C1-C4 alkylene In an embodiment, L 6C is independently unsubstituted ethylene. In embodiments, L 6C teeth , independently, are unsubstituted methylene. In embodiments, L 6C are independently bonded or non-bonded. Substituted alkynylene (e.g., C-C 20 , C2-C 12 , C2-C8, C2-C6, C 2-C4, or C2-C2). In an embodiment, L 6C are independently unsubstituted C2 -C 20 In one embodiment, L is alkynylene. 6C are independently unsubstituted C2-C 12 In one embodiment, L is alkynylene. 6C are independently unsubstituted C2-C8 alkynyl In an embodiment, L 6C is independently unsubstituted C2-C6 alkynylene. In an embodiment, L 6C is independently unsubstituted C2-C4 alkynylene. L 6C is independently unsubstituted ethynylene. In embodiments, L 6C independently , unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl). In an embodiment, L 6C are independently unsubstituted C6-C 12 In one embodiment, L 6C are independently unsubstituted C6-C 10 In one embodiment, L 6C is independently unsubstituted phenylene. 6C are independently unsubstituted na In one embodiment, L 6C are independently bonds.

[0168] In an embodiment, L 6D are independently a bond or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, L 6D are independently unsubstituted C-C 20 It is alkylene. Well, L 6D are independently unsubstituted C-C 12 In embodiments, L is alkylene. 6 A is independently an unsubstituted C1-C8 alkylene. 6D is independent and unsubstituted C1-C6 alkylene. In embodiments, L 6D are independently unsubstituted C In embodiments, L is 1-C4 alkylene. 6D are independently unsubstituted ethylene In an embodiment, L 6D is independently unsubstituted methylene. 6D teeth , independently, is a bond.

[0169] In an embodiment, L 6E is independently a bond. 6E independently , -NHC(O)-.

[0170] In an embodiment, L 6A is independently a bond or unsubstituted C1-C8 alkylene. In an embodiment, L 6B are independently a bond, -NHC(O)-, or unsubstituted phenylene. In an embodiment, L 6C are independently a bond, unsubstituted C2-C8 alkynylene, or or unsubstituted phenylene. In embodiments, L 6D are independently a bond or an unsubstituted C In embodiments, L 6E are independently a bond or -NHC( O)-.

[0171] In an embodiment, L 6 are independent, combined, [ka] In an embodiment, L 6 is independently a bond. 6 is independent hand, [ka] In an embodiment, L 6 is, independently, [ka] In an embodiment, L 6 is, independently, [ka] In an embodiment, L 6 is, independently, [ka] In an embodiment, L 6 is, independently, [ka] is.

[0172] In an embodiment, L 5 is independently —NHC(O)—. In embodiments, L 5 teeth, Independently, -C(O)NH-. In embodiments, L 5 are independently substituted or non-substituted. In one embodiment, L is a substituted alkylene. 5 are independently substituted or unsubstituted heteroalkyl groups. It's Ren.

[0173] In an embodiment, L 5 are independently substituted or unsubstituted alkylene (e.g., C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In an embodiment, L 5 are independently substituted alkylene (e.g., C-C 20 , C1-C1 2, C1-C8, C1-C6, C1-C4, or C1-C2). L 5 are independently unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C 8, C1-C6, C1-C4, or C1-C2). 5 is independent and substituted or unsubstituted C1-C 20 In embodiments, L is alkylene. 5 is independent Substitution C1-C 20 In embodiments, L is alkylene. 5 are independently unsubstituted C1 -C 20 In embodiments, L is alkylene. 5 are independently substituted or unsubstituted C1- C 12 In embodiments, L is alkylene. 5 are independently substituted C1-C 12 Alkire In an embodiment, L 5 are independently unsubstituted C-C 12 It is an alkylene. In this embodiment, L 5 is independently a substituted or unsubstituted C1-C8 alkylene. In this state, L 5 is independently a substituted C1-C8 alkylene. 5 teeth, In an embodiment, L is independently an unsubstituted C1-C8 alkylene. 5are independently replaced by or unsubstituted C1-C6 alkylene. In embodiments, L 5 independently, substitution C1 In an embodiment, L 5 are independently unsubstituted C1-C6 alkylene In an embodiment, L 5 are independently substituted or unsubstituted C1-C4 alkylene; In an embodiment, L 5 is independently a substituted C1-C4 alkylene. L 5 is independently an unsubstituted C1-C4 alkylene. 5 is German In one embodiment, L is substituted or unsubstituted ethylene. 5 are independently substituted ethene In an embodiment, L 5 is independently unsubstituted ethylene. L 5 is independently substituted or unsubstituted methylene. 5 independently , substituted methylene. In embodiments, L 5 is independently unsubstituted methylene.

[0174] In an embodiment, L 5 are independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4 In one embodiment, L 5 is independently a substituted heteroalkylene (e.g., 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or is a 4- to 5-membered ring). 5 are independently unsubstituted heteroalkylene (e.g., For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, and 2- to 3-membered rings or a 4- or 5-membered ring). 5 are independently substituted or unsubstituted 2 In one embodiment, L is a 20-membered heteroalkylene. 5 are independently a substituted 2- to 20-membered ring In embodiments, L is heteroalkylene. 5 are independently unsubstituted 2- to 20-membered heterocyclic rings In embodiments, L is alkylene. 5 are independently substituted or unsubstituted 2- to 8-membered ring heterocycles. In one embodiment, L is 1,2,3,4-trimethylsilyl. 5 are independently a substituted 2- to 8-membered heteroalkyl group. In an embodiment, L 5 are independently unsubstituted 2- to 8-membered heteroalkylene In an embodiment, L 5 are independently substituted or unsubstituted 2- to 6-membered heteroalkylene. In an embodiment, L 5 are independently substituted 2- to 6-membered heteroalkylene. In this state, L 5 is independently an unsubstituted 2- to 6-membered heteroalkylene. L 5 are independently substituted or unsubstituted 4- to 6-membered heteroalkylene. , L 5 are independently substituted 4- to 6-membered heteroalkylene. 5 teeth, In an embodiment, L is an unsubstituted 4- to 6-membered heteroalkylene. 5 independently , substituted or unsubstituted 2- to 3-membered heteroalkylene. 5 is independent In an embodiment, L is a substituted 2- or 3-membered heteroalkylene. 5 are independently unsubstituted In one embodiment, L is a 2- or 3-membered heteroalkylene. 5 are independently substituted or non-substituted. In one embodiment, L is a substituted 4- or 5-membered heteroalkylene. 6 are independently substituted 4- to 5-membered In one embodiment, L is a heterocyclic heteroalkylene. 6 are independently unsubstituted 4- or 5-membered heterocyclic rings It is alkylene.

[0175] In an embodiment, L 5A are independently a bond or unsubstituted alkylene; L 5B teeth, independently a bond, —NHC(O)—, or unsubstituted arylene; L 5C is independent is a bond, unsubstituted alkylene, or unsubstituted arylene; 5D is independent and is substituted or unsubstituted alkylene; L 5E are independently a bond or -NHC(O)- In an embodiment, L 5A is independently a bond or unsubstituted alkylene. In this state, L 5B are independently a bond, —NHC(O)—, or unsubstituted arylene; In an embodiment, L 5C are independently a bond, an unsubstituted alkylene, or an unsubstituted aryl. In an embodiment, L 5D are independently a bond or unsubstituted alkylene. In this embodiment, L 5E are independently a bond or —NHC(O)—.

[0176] In an embodiment, L 5A are independently a bond or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, L 5A are independently unsubstituted C-C 20 It is alkylene. Well, L5A are independently unsubstituted C-C 12 In embodiments, L is alkylene. 5 A is independently an unsubstituted C1-C8 alkylene. 5A is independent and unsubstituted C1-C6 alkylene. In embodiments, L 5A are independently unsubstituted C In embodiments, L is 1-C4 alkylene. 5A are independently unsubstituted ethylene In an embodiment, L 5A is independently unsubstituted methylene. 5A teeth , independently, is a bond.

[0177] In an embodiment, L 5B is independently a bond. 5B independently , -NHC(O)-. In embodiments, L 5B are independently unsubstituted arylene (e.g. For example, C6-C 12 , C6-C 10 , or phenyl). In embodiments, L 5B teeth , independently, unsubstituted C6-C 12 In one embodiment, L 5B independently , unsubstituted C6-C 10 In one embodiment, L 5B are independently unsubstituted fluoresceins. In one embodiment, L is phenylene. 5B is independently unsubstituted naphthylene.

[0178] In an embodiment, L 5C are independently a bond or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, L 5C are independently unsubstituted C-C 20 It is alkylene. Well, L 5C are independently unsubstituted C-C 12 In embodiments, L is alkylene. 5 C is independently an unsubstituted C1-C8 alkylene. 5C are independently unsubstituted C2 In embodiments, L is -C alkynylene. 5C are independently unsubstituted C1-C6 alkyl In one embodiment, L 5C are independently unsubstituted C1-C4 alkylene In an embodiment, L 5C is independently unsubstituted ethylene. In embodiments, L 5C teeth , independently, are unsubstituted methylene. In embodiments, L 5C are independently bonded or non-bonded. Substituted alkynylene (e.g., C-C 20 , C2-C 12 , C2-C8, C2-C6, C 2-C4, or C2-C2). In an embodiment, L 5C are independently unsubstituted C2 -C 20 In one embodiment, L is alkynylene. 5C are independently unsubstituted C2-C 12 In one embodiment, L is alkynylene. 5C are independently unsubstituted C2-C8 alkynyl In an embodiment, L 5C is independently unsubstituted C2-C6 alkynylene. In an embodiment, L 5C is independently unsubstituted C2-C4 alkynylene. L 5C is independently unsubstituted ethynylene. In embodiments, L 5C independently , unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl). In an embodiment, L 5C are independently unsubstituted C6-C 12 In one embodiment, L 5C are independently unsubstituted C6-C 10 In one embodiment, L 5C is independently unsubstituted phenylene. 5C are independently unsubstituted na In one embodiment, L 5C are independently bonds.

[0179] In an embodiment, L 5D are independently a bond or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, L 5D are independently unsubstituted C-C 20 It is alkylene. Well, L 5D are independently unsubstituted C-C 12 In embodiments, L is alkylene. 5 A is independently an unsubstituted C1-C8 alkylene. 5D is independent and unsubstituted C1-C6 alkylene. In embodiments, L 5D are independently unsubstituted C In embodiments, L is 1-C4 alkylene. 5D are independently unsubstituted ethylene In an embodiment, L 5D is independently unsubstituted methylene. 5D teeth , independently, is a bond.

[0180] In an embodiment, L 5E is independently a bond. 5E independently , -NHC(O)-.

[0181] In an embodiment, L 5A is independently a bond or unsubstituted C1-C8 alkylene. In an embodiment, L 5B are independently a bond, -NHC(O)-, or unsubstituted phenylene. In an embodiment, L 5C are independently a bond, unsubstituted C2-C8 alkynylene, or or unsubstituted phenylene. In embodiments, L 5D are independently a bond or an unsubstituted C In embodiments, L 5E are independently a bond or -NHC( O)-.

[0182] In an embodiment, L 5 are independent, combined, [ka] In an embodiment, L 5 is independently a bond. 5 is independent hand, [ka] In an embodiment, L 5 is, independently, [ka] In an embodiment, L 5 is, independently, [ka] In an embodiment, L 5is, independently, [ka] In an embodiment, L 5 is, independently, [ka] is.

[0183] In embodiments, R 1 is an unsubstituted alkyl (e.g., C-C 25 , C1-C 20 , C1 -C 17 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, R 1 is an unsubstituted unbranched alkyl (e.g., C-C 25 , C1-C 20 , C1-C 17 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1 In an embodiment, R 1 is an unsubstituted unbranched saturated alkyl (e.g., C-C 25 , C1-C 20 , C1-C 17 , C1-C 12 , C1-C8, C1-C6, C1-C 4, or C1-C2).

[0184] In embodiments, R 1 is unsubstituted C1-C 17 In embodiments, R 1 teeth, unsubstituted C 11 -C 17 In embodiments, R 1 is the unsubstituted C 13 -C 17 a In an embodiment, R 1 is the unsubstituted C 15In embodiments, R 1 is an unsubstituted unbranched C1-C 17 In embodiments, R 1 is an unsubstituted unbranched C 11 -C 17 In embodiments, R 1 is an unsubstituted unbranched C 13 -C 17 a In an embodiment, R 1 is an unsubstituted unbranched C 15 In one embodiment, is R 1 is an unsubstituted unbranched saturated C1-C 17 In embodiments, R 1 is non Substituted unbranched saturated C 11 -C 17 In embodiments, R 1 is an unsubstituted unbranched Japanese C 13 -C 17 In embodiments, R 1 is an unsubstituted unbranched saturated C 15 Al In an embodiment, R 1 is an unsubstituted unbranched unsaturated C1-C 17 It is alkyl. In embodiments, R 1 is an unsubstituted unbranched unsaturated C 11 -C 17 In one embodiment, is R 1 is an unsubstituted unbranched unsaturated C 13 -C 17 In embodiments, R 1 teeth , unsubstituted unbranched unsaturated C 15 It is alkyl.

[0185] In embodiments, R 2 is an unsubstituted alkyl (e.g., C-C 25 , C1-C 20 , C1 -C17 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, R 2 is an unsubstituted unbranched alkyl (e.g., C-C 25 , C1-C 20 , C1-C 17 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1 In an embodiment, R 2 is an unsubstituted unbranched saturated alkyl (e.g., C-C 25 , C1-C 20 , C1-C 17 , C1-C 12 , C1-C8, C1-C6, C1-C 4, or C1-C2).

[0186] In embodiments, R 2 is unsubstituted C1-C 17 In embodiments, R 2 teeth, unsubstituted C 11 -C 17 In embodiments, R 2 is the unsubstituted C 13 -C 17 a In an embodiment, R 2 is the unsubstituted C 15 In embodiments, R 2 is an unsubstituted unbranched C1-C 17 In embodiments, R 2 is an unsubstituted unbranched C 11 -C 17 In embodiments, R 2 is an unsubstituted unbranched C 13 -C 17 a In an embodiment, R 2 is an unsubstituted unbranched C 15 In one embodiment, is R2 is an unsubstituted unbranched saturated C1-C 17 In embodiments, R 2 is non Substituted unbranched saturated C 11 -C 17 In embodiments, R 2 is an unsubstituted unbranched Japanese C 13 -C 17 In embodiments, R 2 is an unsubstituted unbranched saturated C 15 Al In an embodiment, R 2 is an unsubstituted unbranched unsaturated C1-C 17 It is alkyl. In embodiments, R 2 is an unsubstituted unbranched unsaturated C 11 -C 17 In one embodiment, is R 2 is an unsubstituted unbranched unsaturated C 13 -C 17 In embodiments, R 2 teeth , unsubstituted unbranched unsaturated C 15 It is alkyl.

[0187] In embodiments, R 1 and R 2 At least one of the groups is unsubstituted C1-C 19 Archi In an embodiment, R 1 and R 2 At least one of the C9-C1 9 alkyl. In embodiments, R 1 and R 2 At least one of 11 -C 19 In embodiments, R 1 and R 2 At least one of , unsubstituted C 13 -C 19 It is alkyl.

[0188] In embodiments, R 1 is unsubstituted C1-C 19 In embodiments, R 1 teeth, unsubstituted C9-C 19 In embodiments, R 1 is the unsubstituted C 11 -C 19 Al In an embodiment, R 1 is the unsubstituted C 13 -C 19 In one embodiment, is R 1 is an unsubstituted unbranched C1-C 19 In embodiments, R 1 is a non-permutation Unbranched C9-C 19 In embodiments, R 1 is an unsubstituted unbranched C 11 -C1 9 alkyl. In embodiments, R 1 is an unsubstituted unbranched C 13 -C 19 is alkyl In embodiments, R 1 is an unsubstituted unbranched saturated C1-C 19 In embodiments, , R 1 is an unsubstituted unbranched saturated C9-C 19 In embodiments, R 1 is non-placed conversion unbranched saturated C 11 -C 19 In embodiments, R 1 is an unsubstituted, unbranched, saturated C 13 -C 19 In embodiments, R 1 is an unsubstituted unbranched unsaturated C1-C1 9 alkyl. In embodiments, R 1 is an unsubstituted unbranched unsaturated C9-C 19 With alkyl In an embodiment, R 1is an unsubstituted unbranched unsaturated C 11 -C 19 It is an alkyl. In terms of form, R 1 is an unsubstituted unbranched unsaturated C 13 -C 19 It is alkyl.

[0189] In embodiments, R 2 is unsubstituted C1-C 19 In embodiments, R 2 teeth, unsubstituted C9-C 19 In embodiments, R 2 is the unsubstituted C 11 -C 19 Al In an embodiment, R 2 is the unsubstituted C 13 -C 19 In one embodiment, is R 2 is an unsubstituted unbranched C1-C 19 In embodiments, R 2 is a non-permutation Unbranched C9-C 19 In embodiments, R 2 is an unsubstituted unbranched C 11 -C1 9 alkyl. In embodiments, R 2 is an unsubstituted unbranched C 13 -C 19 is alkyl In embodiments, R 2 is an unsubstituted unbranched saturated C1-C 19 In embodiments, , R 2 is an unsubstituted unbranched saturated C9-C 19 In embodiments, R 2 is non-placed conversion unbranched saturated C 11 -C 19 In embodiments, R 2 is an unsubstituted, unbranched, saturated C 13 -C 19 In embodiments, R2 is an unsubstituted unbranched unsaturated C1-C1 9 alkyl. In embodiments, R 2 is an unsubstituted unbranched unsaturated C9-C 19 With alkyl In an embodiment, R 2 is an unsubstituted unbranched unsaturated C 11 -C 19 It is an alkyl. In terms of form, R 2 is an unsubstituted unbranched unsaturated C 13 -C 19 It is alkyl.

[0190] In embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, the oligonucleotide is an siRNA. In embodiments, the oligonucleotide is a stem-loop In an embodiment, the oligonucleotide is a single-stranded siRNA. In one embodiment, the oligonucleotide is an RNase H oligonucleotide. In some embodiments, the oligonucleotide is an anti-microRNA oligonucleotide. The oligonucleotide is a sterically hindered oligonucleotide. In embodiments, the oligonucleotide is an aptamer. It is an id RNA.

[0191] In embodiments, the oligonucleotide is a modified oligonucleotide.

[0192] In embodiments, the oligonucleotide comprises a nucleotide analog.

[0193] In embodiments, the oligonucleotides contain locked nucleic acid (LNA) residues, constrained ethyl (cE t) residue, bicyclic nucleic acid (BNA) residue, unlocked nucleic acid (UNA) residue, phosphorodiamide Peptide morpholino oligomer (PMO) monomer, peptide nucleic acid (PNA) monomer, 2' -O-methyl (2'-OMe) residue, 2'-O-methyoxyethyl residue, 2'-deoxy -2'-fluoro residue, 2'-O-methoxyethyl / phosphorothioate residue, phosphora amidate, phosphorodiamidate, phosphorothioate, phosphorodithioate, phospho carboxylic acids, phosphonocarboxylates, phosphonoacetic acids, phosphonoformic acids, methylphosphonic acids In embodiments, the compound includes a phosphate, a boron phosphonate, or an O-methyl phosphoramidite. In embodiments, the oligonucleotide comprises a bicyclic nucleic acid (BNA) residue. In embodiments, the bicyclic nucleic acid (BNA) residue is a constrained ethoxylated In embodiments, the oligonucleotide is an unlocked nucleic acid (UN In embodiments, the oligonucleotide comprises a phosphorodiamidate morpholino group A) residue. In embodiments, the oligonucleotide comprises a peptide moiety (PMO) monomer. In embodiments, the oligonucleotide comprises a 2'-O-mer nucleic acid (PNA) monomer. In embodiments, the oligonucleotide contains a 2'-O-methyl (2'-OMe) residue. In embodiments, the oligonucleotide comprises a 2'-deoxy-2'-thiol group. In embodiments, the oligonucleotide comprises a 2'-O-methoxy group. In embodiments, the oligonucleotide contains a phosphoryl / phosphorothioate residue. In embodiments, the oligonucleotide comprises a phosphorodiamidate. In embodiments, the oligonucleotide comprises a phosphorothioate. In embodiments, the oligonucleotide comprises a phosphorodithioate. In embodiments, the oligonucleotide comprises a phosphonocarboxylic acid. In embodiments, the oligonucleotide comprises a phosphonoacetic acid. In an embodiment, the oligonucleotide comprises phosphonoformic acid. In embodiments, the oligonucleotide comprises a boron phosphonate. In embodiments, the oligonucleotide comprises an O-methyl phosphoramidite. .

[0194] In embodiments, a compound having the structure of Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. conjugated to the moiety, X1, [ka] and L1 is -(CH2) n -, -(CH2) n L2(CH2) n - or a combination L2 is -C(=O)NH- and each m is independently an integer of 10 to 18; Provided herein are compounds wherein each n is independently an integer from 1 to 6. , X1 is, [ka] In an embodiment, X1 is [ka] and each m is 10 and n is 3. In an embodiment, X1 is [ka] and each m is 11 and n is 3. In an embodiment, X1 is [ka] and each m is 12 and n is 3. In an embodiment, X1 is [ka] and each m is 13 and n is 3. In an embodiment, X1 is [ka] and each m is 14 and n is 3. In an embodiment, X1 is [ka] and each m is 15 and n is 3. In an embodiment, X1 is [ka] and each m is 16 and n is 3. In an embodiment, X1 is [ka] and each m is 17 and n is 3. In an embodiment, X1 is [ka] and each m is 18 and n is 3. In an embodiment, X1 is [ka] and each m is 10. In an embodiment, X1 is [ka] and each m is 11. In an embodiment, X1 is [ka] and each m is 12. In an embodiment, X1 is [ka] and each m is 13. In an embodiment, X1 is [ka] and each m is 14. In an embodiment, X1 is [ka] and each m is 15. In an embodiment, X1 is [ka] and each m is 16. In an embodiment, X1 is [ka] and each m is 17. In an embodiment, X1 is [ka] and each m is 18.

[0195] In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 10. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 11. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 12. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 13. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 14. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 15. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 16. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 17. In an embodiment, X1 is [ka] L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is 18. do.

[0196] In embodiments, L1 is a bond and each m is independently an integer from 10 to 16. In one embodiment, L1 is a bond and each m is independently an integer from 12 to 16. L1 is a bond and each m is independently an integer from 12 to 14. In an embodiment, L1 is a bond. and each m is 14. In an embodiment, L1 is -(CH2) n L2(CH2) n -, L2 is -C(=O)NH-, and each m is independently an integer of 10 to 16. and each n is independently an integer from 1 to 6. In an embodiment, L1 is -(CH2) n L2(CH2) n -, L2 is -C(=O)NH-, and each m is independently 1 is an integer from 2 to 16, and each n is independently an integer from 1 to 6. In an embodiment, L1 is , -(CH2) n L2(CH2) n -, L2 is -C(=O)NH-, and each m are independently an integer from 12 to 14, and each n is independently an integer from 1 to 6. In the form L1 is -(CH2) n L2(CH2) n - and L2 is -C(=O)N H-, each m is independently 14, and each n is independently an integer from 1 to 6. In embodiments, L1 is —(CH2)3C(═O)NH(CH2)5—, and each m is independently In one embodiment, L1 is -(CH2)3C(=O)N H(CH2)5-, and each m is independently an integer from 12 to 16. L1 is -(CH2)3C(=O)NH(CH2)5-, and each m is independently 12 In an embodiment, L1 is -(CH2)3C(=O)NH(CH2) 5- and each m is 14. In an embodiment, each m is 14.

[0197] In embodiments, a compound having the structure of Formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. provided herein are compounds conjugated to a moiety, wherein m is an integer from 10 to 18. The moiety of formula Ia above, represented by: [ka] is a portion of the lipid-containing moiety of formula Ia.

[0198] In embodiments, a compound having the structure of Formula Ib: cet or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. provided herein are compounds conjugated to a moiety, wherein m is an integer from 10 to 18. The moiety of formula Ib above, represented by: [ka] is a portion of the lipid-containing moiety of formula Ib.

[0199] In embodiments of compounds having the structure of Formula I, Ia, or Ib, each m is 12 to 16. In an embodiment, each m is an integer from 12 to 14. In an embodiment, each m is 1 0 and L1 is -(CH2) n - and n is 3. In an embodiment, each m is 11. L1 is -(CH2) n - and n is 3. In embodiments, each m is 12 , L1 is -(CH2) n - and n is 3. In an embodiment, each m is 13 and L 1 is -(CH2) n - and n is 3. In an embodiment, each m is 14 and L1 is -(CH2) n - and n is 3. In an embodiment, each m is 15 and L1 is -( CH2) n - and n is 3. In an embodiment, each m is 16 and L is -(CH 2) n - and n is 3. In embodiments, each m is 17 and L is -(CH) n - and n is 3. In embodiments, each m is 18 and L is -(CH) n - and n is 3.

[0200] In embodiments, a lipid-conjugated compound having the structure of Formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. Provided herein are compounds conjugated to a moiety represented by: The moiety of formula II above [ka] is a portion of the lipid-containing moiety of formula II.

[0201] In embodiments, a lipid-conjugated compound having the structure of Formula IIa: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. Provided herein are compounds conjugated to a moiety represented by: The moiety of formula IIa above [ka] is the portion of the lipid-containing moiety of formula IIa.

[0202] In embodiments, a lipid-conjugated compound having the structure of Formula IIb: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. Provided herein are compounds conjugated to a moiety represented by: The moiety of formula IIb above [ka] is the portion of the lipid-containing moiety of formula IIb.

[0203] In embodiments, a lipid-conjugated compound having the structure of Formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide. modified double-stranded oligonucleotides. The modified double-stranded oligonucleotide is Z1 at the 3' end of one strand of the modified single-stranded oligonucleotide or the 3' end of the modified single-stranded oligonucleotide Conjugated, Z1 [ka] and p is an integer from 10 to 18; The modified double-stranded oligonucleotide is conjugated to Z2 at the 5' end of the strand or the 5' end of the modified single-stranded oligonucleotide Gated, Z2, [ka] and q is an integer from 10 to 18. , p is 14 and q is 14.

[0204] In embodiments, a lipid-conjugated compound having the structure of Formula IIIa: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. portion [ka] and a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide conjugated to The oligonucleotide is attached to the 5' end of one strand of the modified double-stranded oligonucleotide or Lipid-containing moieties at the 5' ends of modified single-stranded oligonucleotides [ka] Provided herein are compounds conjugated to

[0205] In embodiments, a lipid-conjugated compound having the structure of Formula IIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. portion [ka] modified double-stranded or single-stranded oligonucleotides conjugated to The nucleotide is attached to the 5' end of one strand of a modified double-stranded oligonucleotide or Lipid-containing moiety at the 5' end of a single-stranded oligonucleotide [ka] Provided herein are compounds conjugated to

[0206] In embodiments, L1 is a bond, a substitution (e.g., a substituent, a size-limited substituent, or or lower substituted) or unsubstituted alkylene (e.g., C-C 20 , C1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), or substitution (e.g. For example, substituted with a substituent, a size-limited substituent, or a lower substituent) or non- Substituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring) , 4- to 6-membered ring, 2- to 3-membered ring, or 4- to 5-membered ring). For example, substituted with a substituent, a size-limited substituent, or a lower substituent) or Unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C 1-C4, or C1-C2), or substituted (e.g., substituents, size-limited substitutions or a lower substituent) or unsubstituted heteroalkylene (e.g., 2 to 2 0-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4- In embodiments, L1 is a substituted (e.g., a substituent, a size-limited substituent). alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), or substituted (e.g. , substituted with a substituent, a size-limited substituent, or a lower substituent) olefins (e.g., 2-20 membered rings, 2-12 membered rings, 2-8 membered rings, 2-6 membered rings, 4-6 membered rings, 2 In an embodiment, L1 is an unsubstituted alkylene (e.g., For example, C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1- C2), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 1-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4- to 5-membered ring). In one embodiment, L is substituted with a substituent. In embodiments, L1 is substituted with a size-limited substituent. When is substituted, L1 is substituted with a lower substituent.

[0207] In embodiments, L is a bond. In embodiments, L is -(CH) n -,Also Ha-(CH2) n L2(CH2) n In an embodiment, L is -(CH) n - In an embodiment, L1 is -(CH2) n L2(CH2) n In an embodiment In some embodiments, n is 1 to 6. In some embodiments, n is 1 to 5. In some embodiments, n is 1 In an embodiment, n is 1 to 4. In an embodiment, n is 1 to 3. In an embodiment, n is 1 to 2. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, where n is 6.

[0208] In embodiments, each occurrence of n (i.e., n' and n") may be the same or In an embodiment, each occurrence (i.e., n' and and n") may be the same. In an embodiment, each occurrence of n (i.e., n' and n") may be different. In embodiments, n' is 1 to 6. In an embodiment, n' is 1 to 5. In an embodiment, n' is 1 to 4. In an embodiment, n In an embodiment, n' is 1 to 3. In an embodiment, n' is 1 to 2. In an embodiment, n' is 1 In an embodiment, n' is 2. In an embodiment, n' is 3. In some embodiments, n' is 4. In some embodiments, n' is 5. In some embodiments, n' is 6 In an embodiment, n" is 1 to 6. In an embodiment, n" is 1 to 5. In an embodiment, n" is 1 to 4. In an embodiment, n" is 1 to 3. In the embodiment, n" is 1 to 2. In the embodiment, n" is 1. In the embodiment, n" is In an embodiment, n" is 3. In an embodiment, n" is 4. In some embodiments, n" is 5. In some embodiments, n" is 6.

[0209] In one embodiment, m is 10 to 18. In another embodiment, m is 10 to 17. In an embodiment, m is 10 to 16. In an embodiment, m is 10 to 15. In one embodiment, m is 10 to 14. In one embodiment, m is 10 to 13. In one embodiment, m is 10 to 13. In the embodiment, m is 10 to 12. In the embodiment, m is 10 to 11. In the embodiment, In an embodiment, m is 10. In an embodiment, m is 11. In an embodiment, m is 12. In an embodiment, m is 13. In an embodiment, m is 14. In an embodiment, m is 15. In an embodiment, m is 16. In an embodiment, m is 17 In an embodiment, m is 18.

[0210] In embodiments, L2 is -C(=O)NH-, -C(=O)O-, -OC(=O)O- , -NHC(=O)O-, -NHC(=O)NH-, -C(=S)NH-, -C(=O) In an embodiment, L2 is -C( In an embodiment, L2 is -C(=O)O-. In an embodiment, L2 is -C(=O)O-. L2 is -OC(=O)O-. In an embodiment, L2 is -NHC(=O)O-. In embodiments, L2 is -NHC(=O)NH-. In embodiments, L2 is - In an embodiment, L2 is -C(=O)S-. In an embodiment, L2 is -C(=O)S-. , L2 is -NH-. In an embodiment, L2 is O (oxygen). In an embodiment, L2 is S (sulfur).

[0211] L 3 are independently a bond, -NH-, -O-, -S-, -C(O)-, or -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, -O PO2-O-, substituted (e.g., substituted, size-limited, or lower-substituted) substituted with), or unsubstituted alkylene (e.g., C-C20 , C1-C 12 , C1 -C8, C1-C6, C1-C4, or C1-C2), substitution (e.g., substituents, size is substituted with limited or lower substituents), or unsubstituted heteroalkyl (e.g., 2-20 membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2- 3-membered ring, or 4-5-membered ring), substitution (e.g., substituents, size-limited substituents, if or lower substituted), or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, substituted with size-limited or lower substituents) or unsubstituted heterocyclic Chloroalkylene (e.g., 3-10 membered ring, 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring) 1-membered ring, or 5-6-membered ring), substitution (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted arylene (e.g., C-C 12 , C6- C 10 , or phenyl), or substituted (e.g., substituents, size-limited substituents or lower substituents), or unsubstituted heteroarylene (e.g., 5 to 1 In an embodiment, L is a 2-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. 3 teeth Independently, the bond -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, -OPO2- O-, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C 1-C4, or C1-C2), substituted (e.g., substituted, size-limited substituents, or lower substituent) heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring), substituted (e.g. For example, a cycloaza that is substituted with a substituent, a size-limited substituent, or a lower substituent. alkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5- C6), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4 1 to 6-membered ring, 4 to 5-membered ring, or 5 to 6-membered ring), substitution (e.g., substituents, size-limited arylene (e.g., C6-C substituted with a substituent or a lower substituent); 12 , C6 -C 10 , or phenyl), or substituted (e.g., substituted, size-limited substituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 12-membered ring, substituted with a group or lower substituent) In one embodiment, L 3 is, independently, Bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)N H-, -C(O)O-, -OC(O)-, -C(O)NH-, -OPO2-O-, unsubstituted Alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C 4, or C1-C2), unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4- to 5-membered ring), unsubstituted silyl ring Chloroalkylene (e.g., C3-C10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3-10 membered ring, 3-8 membered ring, 3 to 6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), unsubstituted arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene (e.g. For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. Well, L 3 If is substituted, L 3 is substituted with a substituent. 3 but If substituted, L 3 is substituted with size-limited substituents. L 3 If is substituted, L 3 is substituted with a lower substituent.

[0212] L 4 are independently a bond, -NH-, -O-, -S-, -C(O)-, or -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, -O PO2-O-, substituted (e.g., substituted, size-limited, or lower-substituted) substituted with), or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1 -C8, C1-C6, C1-C4, or C1-C2), substitution (e.g., substituents, size is substituted with limited or lower substituents), or unsubstituted heteroalkyl (e.g., 2-20 membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2- 3-membered ring, or 4-5-membered ring), substitution (e.g., substituents, size-limited substituents, if or lower substituted), or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, substituted with size-limited or lower substituents) or unsubstituted heterocyclic Chloroalkylene (e.g., 3-10 membered ring, 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring) 1-membered ring, or 5-6-membered ring), substitution (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted arylene (e.g., C-C 12 , C6- C 10 , or phenyl), or substituted (e.g., substituents, size-limited substituents or lower substituents), or unsubstituted heteroarylene (e.g., 5 to 1 In an embodiment, L is a 2-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. 4 teeth , bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O) NH-, -C(O)O-, -OC(O)-, -C(O)NH-, -OPO2-O-, substitution (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Kiren (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituted, size-limited, or lower Heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, substituted by a substituent) 1-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), substituted (e.g., substituted cycloalkylene (substituted with a group, a size-limited substituent, or a lower substituent) For example, C3-C 10, C3-C8, C3-C6, C4-C6, or C5-C6), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4-5 membered ring, or 5-6 membered ring), substitution (e.g., substituents, size-limited substituents, or lower substituted) arylene (e.g., C-C 12 , C6-C 10 , or phenyl), or substituted (e.g., substituted, size-limited, or is substituted by a lower substituent) heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, In one embodiment, L 4 is a bond, -NH-, -O -, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O- , -OC(O)-, -C(O)NH-, -OPO2-O-, unsubstituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2 ), unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- 6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted cycloalkylene (e.g., For example, C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted Heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring) , 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g., C6-C 12 , C6- C 10 , or phenyl), or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, In an embodiment, L 4 is replaced If so, L 4 is substituted with a substituent. 4 If is replaced, L 4 is substituted with size-limited substituents. 4 is replaced If, L 4 is substituted with a lower substituent.

[0213] L 5 are independently a bond, -NH-, -O-, -S-, -C(O)-, or -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substitution (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent), or or unsubstituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6 , C1-C4, or C1-C2), substituted (e.g., substituents, size-limited substituents or lower substituents), or unsubstituted heteroalkylene (e.g., 2 to 2 0-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4- 5-membered ring), substituted (e.g., substituted, size-limited, or lower-rank substituents) substituted), or unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3 -C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituted or lower substituted), or unsubstituted heterocycloalkylene (e.g. For example, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 4- to 5-membered ring, or a 5- to 6-membered ring. -membered ring), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) substituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl), or substituted (e.g., substituted, size-limited, or lower-substituted substituted with a group), or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered In one embodiment, L 5 are independent, combined, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size alkylene (e.g., C1-C2 substituted with limited or lower substituents) 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substitution ( For example, heterocyclic groups (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Alkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring) ring, 2-3 membered ring, or 4-5 membered ring), substitution (e.g., substituents, size-limited substitutions cycloalkylene (e.g., C-C substituted with a group or a lower substituent) 10 , C3 -C8, C3-C6, C4-C6, or C5-C6), substitution (e.g., substituents, size Heterocycloalkylene (e.g., substituted with limited or lower substituents) For example, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 4- to 5-membered ring, or a 5- to 6-membered ring. ring), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6-C10 , or phenyl), or Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 9-membered ring, or 5- to 6-membered ring) In one embodiment, L 5 are independently a bond, -NH-, -O-, -S-, or -C (O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)- , —C(O)NH—, unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g. , 2-20 membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or or 4-5 membered ring), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3 -C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl), or Unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 9-membered ring, or 5 In one embodiment, L 5 If is substituted, L 5 is substituted with a substituent In an embodiment, L 5 If is substituted, L 5 is a size-limited substituent In embodiments, L 5 If is substituted, L 5 is substituted with a lower substituent do.

[0214] L 5A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 5A is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 5A are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unplaced Substituted alkylene (e.g., C1-C 20 , C1-C12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 5A If is substituted, L 5A is substituted with a substituent. L 5A If is substituted, L 5A is substituted with size-limited substituents. In terms of form, L 5A If is substituted, L 5A is substituted with a lower substituent.

[0215] L 5B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 5B is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 5B are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unplaced Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 5B If is substituted, L 5B is substituted with a substituent. L 5B If is substituted, L 5B is substituted with size-limited substituents. In terms of form, L 5B If is substituted, L 5B is substituted with a lower substituent.

[0216] L 5C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 5C is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 5C are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unplaced Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 5C If is substituted, L 5C is substituted with a substituent. L 5C If is substituted, L 5Cis substituted with size-limited substituents. In terms of form, L 5C If is substituted, L 5C is substituted with a lower substituent.

[0217] L 5D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 5D is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 5Dare bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unplaced Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 5D If is substituted, L 5D is substituted with a substituent. L 5D If is substituted, L 5D is substituted with size-limited substituents. In terms of form, L 5D If is substituted, L 5D is substituted with a lower substituent.

[0218] L 5E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 5E is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 5E are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unfixed Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10, C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 5E If is substituted, L 5E is substituted with a substituent. L 5E If is substituted, L 5E is substituted with size-limited substituents. In terms of form, L 5E If is substituted, L 5E is substituted with a lower substituent.

[0219] L 6 are independently a bond, -NH-, -O-, -S-, -C(O)-, or -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substitution (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent), or or unsubstituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6 , C1-C4, or C1-C2), substituted (e.g., substituents, size-limited substituents or lower substituents), or unsubstituted heteroalkylene (e.g., 2 to 2 0-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4- 5-membered ring), substituted (e.g., substituted, size-limited, or lower-rank substituents) substituted), or unsubstituted cycloalkylene (e.g., C3-C10 , C3-C8, C3 -C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituted or lower substituted), or unsubstituted heterocycloalkylene (e.g. For example, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 4- to 5-membered ring, or a 5- to 6-membered ring. -membered ring), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) substituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl), or substituted (e.g., substituted, size-limited, or lower-substituted substituted with a group), or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered In one embodiment, L 6 are independent, combined, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size alkylene (e.g., C1-C2 substituted with limited or lower substituents) 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substitution ( For example, heterocyclic groups (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Alkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, 4- to 6-membered ring) ring, 2-3 membered ring, or 4-5 membered ring), substitution (e.g., substituents, size-limited substitutions cycloalkylene (e.g., C-C substituted with a group or a lower substituent) 10 , C3 -C8, C3-C6, C4-C6, or C5-C6), substitution (e.g., substituents, size Heterocycloalkylene (e.g., substituted with limited or lower substituents) For example, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 4- to 5-membered ring, or a 5- to 6-membered ring. ring), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 9-membered ring, or 5- to 6-membered ring) In one embodiment, L 6 are independently a bond, -NH-, -O-, -S-, or -C (O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)- , —C(O)NH—, unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1- C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkylene (e.g. , 2-20 membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or or 4-5 membered ring), unsubstituted cycloalkylene (e.g., C3-C 10 , C3-C8, C3 -C6, C4-C6, or C5-C6), unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl), or Unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 9-membered ring, or 5 In one embodiment, L 6 If is substituted, L 6 is substituted with a substituent In an embodiment, L 6 If is substituted, L 6 is a size-limited substituent In embodiments, L 6 If is substituted, L 6 is substituted with a lower substituent do.

[0220] L 6A is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 6A is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 6A are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unplaced Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 6A If is substituted, L 6A is substituted with a substituent. L 6A If is substituted, L 6A is substituted with size-limited substituents. In terms of form, L 6A If is substituted, L 6A is substituted with a lower substituent.

[0221] L 6B is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 6B is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 6B are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unfixed Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 6B If is substituted, L 6B is substituted with a substituent. L 6B If is substituted, L 6B is substituted with size-limited substituents. In terms of form, L 6B If is substituted, L 6B is substituted with a lower substituent.

[0222] L 6C is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 6C is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 6C are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unfixed Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 6C If is substituted, L 6C is substituted with a substituent. L 6C If is substituted, L 6C is substituted with size-limited substituents. In terms of form, L 6C If is substituted, L 6C is substituted with a lower substituent.

[0223] L 6D is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 6D is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 6D are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unfixed Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 6D If is substituted, L 6D is substituted with a substituent. L 6D If is substituted, L 6D is substituted with size-limited substituents. In terms of form, L 6D If is substituted, L 6D is substituted with a lower substituent.

[0224] L6E is a bond, -NH-, -O-, -S-, -C(O)-, -NHC(O)-, -N HC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g. substituted, substituted, size-limited, or lower substituents), or unsubstituted Substituted alkylene (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1- C4, or C1-C2), substituted (e.g., substituents, size-limited substituents, or is substituted with a lower substituent), or unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring) , substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) ), or unsubstituted cycloalkylene (e.g., C-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted heterocycloalkylene (e.g., 3 10-membered ring, 3-8-membered ring, 3-6-membered ring, 4-6-membered ring, 4-5-membered ring, or 5-6-membered ring), Substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) , or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl) or substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroarylene (e.g., 5- to 12-membered ring, 5- to 10-membered ring, 5- to 12-membered ring, In one embodiment, L 6E is a bond, -NH-, -O- , -S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substituted (e.g., substituents, size-limited substituents) , or lower substituted) alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substituted (e.g., substituents, Heteroalkylene (e.g., substituted with size-limited or lower substituents) For example, 2- to 20-membered rings, 2- to 12-membered rings, 2- to 8-membered rings, 2- to 6-membered rings, 4- to 6-membered rings, 2- to 3-membered rings, or 4-5 membered ring), substituted (e.g., substituted, size-limited, or lower substituted) cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C 6, C4-C6, or C5-C6), substituted (e.g., substituents, size-limited substitutions heterocycloalkylene (e.g., 3- to 10-membered rings substituted with a group or a lower substituent) , 3-8 membered ring, 3-6 membered ring, 4-6 membered ring, 4-5 membered ring, or 5-6 membered ring), substituted (e.g. substituted, size-limited, or lower substituent) arylene (e.g., C6-C 12 , C6-C 10 , or phenyl), or substituted (e.g., Heteroarylene (substituted with a substituent, a size-limited substituent, or a lower substituent) (For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring). In terms of form, L 6E are bonds, -NH-, -O-, -S-, -C(O)-, -NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, unfixed Substituted alkylene (e.g., C1-C 20 , C1-C12 , C1-C8, C1-C6, C1- C4, or C1-C2), unsubstituted heteroalkylene (e.g., 2-20 membered ring, 2-12 1-membered ring, 2-8-membered ring, 2-6-membered ring, 4-6-membered ring, 2-3-membered ring, or 4-5-membered ring), unsubstituted Cycloalkylene (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, and is C5-C6), unsubstituted heterocycloalkylene (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted arylene (e.g. , C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroarylene ( For example, a 5- to 12-membered ring, a 5- to 10-membered ring, a 5- to 9-membered ring, or a 5- to 6-membered ring. In this state, L 6E If is substituted, L 6E is substituted with a substituent. L 6E If is substituted, L 6E is substituted with size-limited substituents. In terms of form, L 6E If is substituted, L 6E is substituted with a lower substituent.

[0225] In an embodiment, L 7 are independently substituted (e.g., substituents, size-limited substituents) or lower substituents) or unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In terms of form, L 7 are independently substituted (e.g., substituents, size-limited substituents, if or lower substituted) alkylene (e.g., C-C 20 , C1-C12 , C1 In embodiments, L 7 teeth, Independently, unsubstituted alkylene (e.g., C-C 20 , C1-C 12 , C1-C8, C1 -C6, C1-C4, or C1-C2).

[0226] In an embodiment, L 7 are independently substituted (e.g., substituents, size-limited substituents) or lower substituent) or unsubstituted heteroalkylene (e.g., 2 to 20 2-membered ring, 2- to 12-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, or 2- to 4-membered ring) In an embodiment, L 7 are independently substituted (e.g., substituents, size-limited substitutions) heteroalkylene (e.g., 2- to 20-membered ring, 2- to 20-membered ring, substituted with a group or a lower substituent) 12-membered ring, 2-10-membered ring, 2-8-membered ring, 2-6-membered ring, or 2-4-membered ring). In this state, L 7 are independently unsubstituted heteroalkylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, 1-membered ring, 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, or 2- to 4-membered ring). L 7 are independently substituted (e.g., substituted, size-limited, or low substituted with 2- to 20-membered rings) or unsubstituted heteroalkenylene (e.g., 2- to 20-membered rings, 2- to 20-membered rings) 12-membered ring, 2-10-membered ring, 2-8-membered ring, 2-6-membered ring, or 2-4-membered ring). In this state, L 7 are independently substituted (e.g., substituted, size-limited, or is substituted with a lower substituent) heteroalkenylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring) , 2- to 10-membered ring, 2- to 8-membered ring, 2- to 6-membered ring, or 2- to 4-membered ring). L 7 are independently unsubstituted heteroalkenylene (e.g., 2- to 20-membered ring, 2- to 12-membered ring, In an embodiment, L is a 2- to 10-membered ring, a 2- to 8-membered ring, a 2- to 6-membered ring, or a 2- to 4-membered ring. 7 If is substituted, L 7 is substituted with a substituent. 7 is replaced If so, L 7 is substituted with size-limited substituents. 7 Place If it is replaced, L 7 is substituted with a lower substituent.

[0227] In embodiments, R 1 is an unsubstituted alkyl (e.g., C-C 25 , C1-C 20 , C1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). So, R 1 is unsubstituted C1-C 25 In embodiments, R 1 is an unsubstituted C1 -C 20 In embodiments, R 1 is unsubstituted C1-C 12 It is alkyl. In embodiments, R 1 is unsubstituted C1-C8 alkyl. In embodiments, R 1 is non-placed In one embodiment, R 1 is unsubstituted C1-C4 alkyl In embodiments, R 1 is an unsubstituted C1-C2 alkyl.

[0228] In embodiments, R 1 is an unsubstituted branched alkyl (e.g., C-C25 , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In terms of form, R 1 is an unsubstituted branched C1-C 25 In embodiments, R 1 is non Substitution branch C1-C 20 In embodiments, R 1 is an unsubstituted branched C1-C 12 In embodiments, R 1 is an unsubstituted branched C1-C8 alkyl. In this state, R 1 is an unsubstituted branched C1-C6 alkyl. In embodiments, R 1 is a non-permutation In an embodiment, R 1 is an unsubstituted branched C1-C2 alkyl is.

[0229] In embodiments, R 1 is an unsubstituted unbranched alkyl (e.g., C-C 25 , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In the embodiment, R 1 is an unsubstituted unbranched C1-C 25 In embodiments, R 1 teeth , unsubstituted unbranched C1-C 20 In embodiments, R 1 is an unsubstituted unbranched C1 -C 12 In embodiments, R 1 is an unsubstituted unbranched C1-C8 alkyl In an embodiment, R 1 is an unsubstituted unbranched C1-C6 alkyl. In embodiments, R 1is an unsubstituted unbranched C1-C4 alkyl. In embodiments, R 1 is an unsubstituted unbranched C It is 1-C2 alkyl.

[0230] In embodiments, R 1 is an unsubstituted branched saturated alkyl (e.g., C-C 25 , C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 1 is an unsubstituted branched saturated C1-C 25 In embodiments, R 1 is an unsubstituted branched saturated C1-C 20 In embodiments, R 1 is a non-substituted branch Saturation C1-C 12 In embodiments, R 1 is an unsubstituted branched saturated C1-C8 alkyl In an embodiment, R 1 is an unsubstituted branched saturated C1-C6 alkyl. In terms of form, R 1 is an unsubstituted branched saturated C1-C4 alkyl. In embodiments, R 1 teeth, It is an unsubstituted branched saturated C1-C2 alkyl.

[0231] In embodiments, R 1 is an unsubstituted branched unsaturated alkyl (e.g., C-C 25 , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In embodiments, R 1 is an unsubstituted branched unsaturated C1-C 25 In embodiments, , R 1 is an unsubstituted branched unsaturated C1-C 20 In embodiments, R 1 is non-placed Substituted branched unsaturated C1-C 12 In embodiments, R 1 is an unsubstituted branched unsaturated C 1-C8 alkyl. In embodiments, R 1 is an unsubstituted branched unsaturated C1-C6 alkyl In an embodiment, R 1 is an unsubstituted branched unsaturated C1-C4 alkyl. So, R 1 is an unsubstituted branched saturated C1-C2 alkyl.

[0232] In embodiments, R 1 is an unsubstituted unbranched saturated alkyl (e.g., C-C 25 , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In embodiments, R 1 is an unsubstituted unbranched saturated C1-C 25 In embodiments, , R 1 is an unsubstituted unbranched saturated C1-C 20 In embodiments, R 1 is non-placed Converting unbranched saturated C1-C 12 In embodiments, R 1 is an unsubstituted unbranched saturated C 1-C8 alkyl. In embodiments, R 1 is an unsubstituted unbranched saturated C1-C6 alkyl In an embodiment, R 1 is an unsubstituted unbranched saturated C1-C4 alkyl. So, R 1 is an unsubstituted unbranched saturated C1-C2 alkyl.

[0233] In embodiments, R 1 is an unsubstituted unbranched unsaturated alkyl (e.g., C-C 25 , C1- C 20 , C1-C 12, C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, R 1 is an unsubstituted unbranched unsaturated C1-C 25 alkyl. So, R 1 is an unsubstituted unbranched unsaturated C1-C 20 In embodiments, R 1 teeth , unsubstituted unbranched unsaturated C1-C 12 In embodiments, R 1 is a non-substitutive non-divisible In an embodiment, R 1 is an unsubstituted unbranched unsaturated C1- In an embodiment, R 1 is an unsubstituted unbranched unsaturated C1-C4 alkyl In an embodiment, R 1 is an unsubstituted unbranched unsaturated C1-C2 alkyl.

[0234] In embodiments, R 1 is unsubstituted C9-C 19 In embodiments, R 1 teeth, Unsubstituted branch C9-C 19 In embodiments, R 1 is an unsubstituted unbranched C9-C 19 In embodiments, R 1 is an unsubstituted branched saturated C9-C 19 It is alkyl In an embodiment, R 1 is an unsubstituted branched unsaturated C9-C 19 In one embodiment, is R 1 is an unsubstituted unbranched saturated C9-C 19 In embodiments, R 1 is non Substituted unbranched unsaturated C9-C 19 It is alkyl.

[0235] In embodiments, R2 is an unsubstituted alkyl (e.g., C-C 25 , C1-C 20 , C1 -C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). So, R 2 is unsubstituted C1-C 25 In embodiments, R 2 is an unsubstituted C1 -C 20 In embodiments, R 2 is unsubstituted C1-C 12 It is alkyl. In embodiments, R 2 is unsubstituted C1-C8 alkyl. In embodiments, R 2 is non-placed In one embodiment, R 2 is unsubstituted C1-C4 alkyl In embodiments, R 2 is an unsubstituted C1-C2 alkyl.

[0236] In embodiments, R 2 is an unsubstituted branched alkyl (e.g., C-C 25 , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In terms of form, R 2 is an unsubstituted branched C1-C 25 In embodiments, R 2 is non Substitution branch C1-C 20 In embodiments, R 2 is an unsubstituted branched C1-C 12 In embodiments, R 2 is an unsubstituted branched C1-C8 alkyl. In this state, R 2 is an unsubstituted branched C1-C6 alkyl. In embodiments, R 2 is a non-permutation In an embodiment, R 2 is an unsubstituted branched C1-C2 alkyl is.

[0237] In embodiments, R 2 is an unsubstituted unbranched alkyl (e.g., C-C 25 , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In the embodiment, R 2 is an unsubstituted unbranched C1-C 25 In embodiments, R 2 teeth , unsubstituted unbranched C1-C 20 In embodiments, R 2 is an unsubstituted unbranched C1 -C 12 In embodiments, R 2 is an unsubstituted unbranched C1-C8 alkyl In an embodiment, R 2 is an unsubstituted unbranched C1-C6 alkyl. In embodiments, R 2 is an unsubstituted unbranched C1-C4 alkyl. In embodiments, R 2 is an unsubstituted unbranched C It is 1-C2 alkyl.

[0238] In embodiments, R 2 is an unsubstituted branched saturated alkyl (e.g., C-C 25 , C1-C2 0, C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, R 2 is an unsubstituted branched saturated C1-C 25 In embodiments, R 2 is an unsubstituted branched saturated C1-C 20 In embodiments, R 2 is a non-substituted branch Saturation C1-C12 In embodiments, R 2 is an unsubstituted branched saturated C1-C8 alkyl In an embodiment, R 2 is an unsubstituted branched saturated C1-C6 alkyl. In terms of form, R 2 is an unsubstituted branched saturated C1-C4 alkyl. In embodiments, R 2 teeth, It is an unsubstituted branched saturated C1-C2 alkyl.

[0239] In embodiments, R 2 is an unsubstituted branched unsaturated alkyl (e.g., C-C 25 , C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In embodiments, R 2 is an unsubstituted branched unsaturated C1-C 25 In embodiments, , R 2 is an unsubstituted branched unsaturated C1-C 20 In embodiments, R 2 is non-placed Substituted branched unsaturated C1-C 12 In embodiments, R 2 is an unsubstituted branched unsaturated C 1-C8 alkyl. In embodiments, R 2 is an unsubstituted branched unsaturated C1-C6 alkyl In an embodiment, R 2 is an unsubstituted branched unsaturated C1-C4 alkyl. So, R 2 is an unsubstituted branched unsaturated C1-C2 alkyl.

[0240] In embodiments, R 2 is an unsubstituted unbranched saturated alkyl (e.g., C-C 25 , C1-C 20 , C1-C 12, C1-C8, C1-C6, C1-C4, or C1-C2) In embodiments, R 2 is an unsubstituted unbranched saturated C1-C 25 In embodiments, , R 2 is an unsubstituted unbranched saturated C1-C 20 In embodiments, R 2 is non-placed Converting unbranched saturated C1-C 12 In embodiments, R 2 is an unsubstituted unbranched saturated C 1-C8 alkyl. In embodiments, R 2 is an unsubstituted unbranched saturated C1-C6 alkyl In an embodiment, R 2 is an unsubstituted unbranched saturated C1-C4 alkyl. So, R 2 is an unsubstituted unbranched saturated C1-C2 alkyl.

[0241] In embodiments, R 2 is an unsubstituted unbranched unsaturated alkyl (e.g., C-C 25 , C1- C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C1-C2) In an embodiment, R 2 is an unsubstituted unbranched unsaturated C1-C 25 alkyl. So, R 2 is an unsubstituted unbranched unsaturated C1-C 20 In embodiments, R 2 teeth , unsubstituted unbranched unsaturated C1-C 12 In embodiments, R 2 is a non-substitutive non-divisible In an embodiment, R 2 is an unsubstituted unbranched unsaturated C1- In an embodiment, R 2 is an unsubstituted unbranched unsaturated C1-C4 alkyl In an embodiment, R 2 is an unsubstituted unbranched unsaturated C1-C2 alkyl.

[0242] In embodiments, R 2 is unsubstituted C9-C 19 In embodiments, R 2 teeth, Unsubstituted branch C9-C 19 In embodiments, R 2 is an unsubstituted unbranched C9-C 19 In embodiments, R 2 is an unsubstituted branched saturated C9-C 19 It is alkyl In an embodiment, R 2 is an unsubstituted branched unsaturated C9-C 19 In one embodiment, is R 2 is an unsubstituted unbranched saturated C9-C 19 In embodiments, R 2 is non Substituted unbranched unsaturated C9-C 19 It is alkyl.

[0243] In embodiments, R 3 are hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O) NH2, -NHC(O)H, -NHC(O)OH, -NHC(O)NH2, -C(O)O H, -OC(O)H, -N3, substitution (e.g., substituents, size-limited substituents, if or lower substituted), or unsubstituted alkyl (e.g., C-C 20 , C1- C 12 , C1-C8, C1-C6, C1-C4, or C1-C2), substitution (e.g., substitution substituted, size-limited, or lower substituents), or unsubstituted Tetraalkyl (e.g., 2-20 membered ring, 2-12 membered ring, 2-8 membered ring, 2-6 membered ring, 4-6 1-membered ring, 2-3-membered ring, or 4-5-membered ring), substitution (e.g., substituents, size-limited substituents or lower substituents), or unsubstituted cycloalkyl (e.g., C3 -C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), substituted (e.g., substituted, size-limited, or lower substituents), or unsubstituted Heterocycloalkyl (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring, 4-5 membered ring, or 5-6 membered ring), substitution (e.g., substituents, size-limited substituents, or lower substituted), or unsubstituted aryl (e.g., C-C 12 , C 6-C 10 , or phenyl), or substituted (e.g., substituents, size-limited substituents or lower substituted), or unsubstituted heteroaryl (e.g., 5- In an embodiment, R 3 are hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O )H, -NHC(O)OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) alkyl (e.g., C1-C 20 , C1-C 12 , C1-C8, C1-C6, C 1-C4, or C1-C2), substituted (e.g., substituted, size-limited substituents, or lower substituted) heteroalkyl (e.g., 2- to 20-membered ring, 2- to 12-membered ring, , 2-8 membered ring, 2-6 membered ring, 4-6 membered ring, 2-3 membered ring, or 4-5 membered ring), substituted (e.g. cycloalkanes, substituted with a substituent, a size-limited substituent, or a lower substituent; Kill (e.g., C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6 ), substituted (e.g., substituted with a substituent, a size-limited substituent, or a lower substituent) Heterocycloalkyl (for example, 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring) ring, 4- to 5-membered ring, or 5- to 6-membered ring), substitution (e.g., substituents, size-limited substitutions aryl (e.g., C-C substituted with a group or lower substituent); 12 , C6-C 10 , or phenyl), or substituted (e.g., substituents, size-limited substituents, if heteroaryl (e.g., 5- to 12-membered ring, 5- to 10-membered ring, In one embodiment, R 3 are hydrogen, -NH2, -O H, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O)OH , -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, unsubstituted alkyl ( For example, C1-C 20 , C1-C 12 , C1-C8, C1-C6, C1-C4, or C 1-C2), unsubstituted heteroalkyl (e.g., 2-20 membered ring, 2-12 membered ring, 2-8 membered ring , 2- to 6-membered ring, 4- to 6-membered ring, 2- to 3-membered ring, or 4- to 5-membered ring), unsubstituted cycloalkyl ( For example, C3-C 10 , C3-C8, C3-C6, C4-C6, or C5-C6), non Substituted heterocycloalkyl (e.g., 3- to 10-membered ring, 3- to 8-membered ring, 3- to 6-membered ring, 4- to 6-membered ring) ring, 4- to 5-membered ring, or 5- to 6-membered ring), unsubstituted aryl (e.g., C6-C 12 , C6- C10 , or phenyl), or unsubstituted heteroaryl (e.g., 5- to 12-membered ring, 5 In an embodiment, R 3 is replaced If so, R 3 is substituted with a substituent. In an embodiment, R 3 If is substituted, R 3 is substituted with size-limited substituents. In embodiments, R 3 If is replaced If, R 3 is substituted with a lower substituent.

[0244] In embodiments, the lipid-modified nucleic acid compound is a compound according to any of the aspects, embodiments, and claims. , drawings (e.g., Figures 1 to 83, especially Figures 1 to 12, and Figures 80 to 83), tables (e.g., Table 1), Examples, or Schemes (e.g., Schemes I, II, and III) In embodiments, the lipid-modified nucleic acid compound comprises a motif as described herein, comprising: In an embodiment, the lipid comprises a motif selected from any one of the motifs in Table 1 below. The modified nucleic acid compound comprises the DTx-01-01 motif of Table 1. In an embodiment, The lipid-modified nucleic acid compound comprises the DTx-01-03 motif of Table 1. In an embodiment, In some embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-06 motif of Table 1. The lipid-modified nucleic acid compound comprises the DTx-01-07 motif of Table 1. In the embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-08 motif of Table 1. In one embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-09 motif of Table 1. In one embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-11 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-12 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-13 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-30 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-31 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-32 motif of Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-33 motif of Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-34 motif of Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-35 model of Table 1. In an embodiment, the lipid-modified nucleic acid compound is DTx-01-36 in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-3 motif in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises DTx-01-9 motif in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises DTx-01 in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises a DTx-0 or DTx-1 or DTx-2 motif. In an embodiment, the lipid-modified nucleic acid compound comprises a DTx-1-45 motif. In embodiments, the lipid-modified nucleic acid compound comprises a DTx 01-46 motif. In embodiments, the lipid-modified nucleic acid compound comprises a DT-01-50 motif. In embodiments, the lipid-modified nucleic acid compound comprises a D In embodiments, the lipid-modified nucleic acid compound comprises a Tx-01-52 motif. In embodiments, the lipid-modified nucleic acid compound comprises a DTx-01-53 motif. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-54 motif of Table 1 In an embodiment, the lipid-modified nucleic acid compound comprises a DTx-01-55 motif of The lipid-modified nucleic acid compound comprises the DTx-03-06 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound , comprising the DTx-03-50 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound The DTx-03-51 motif of Table 1 is included. In an embodiment, the lipid-modified nucleic acid compound The product comprises the DTx-03-52 motif of Table 1. In an embodiment, the lipid-modified nucleic acid The compound comprises the DTx-03-53 motif of Table 1. In an embodiment, the lipid-modified nucleic acid The compound comprises the DTx-03-54 motif of Table 1. In an embodiment, the lipid-modified nucleus The acid compound comprises the DTx-03-55 motif of Table 1. In an embodiment, a lipid-modified The nucleic acid compound comprises the DTx-04-01 motif of Table 1. In embodiments, the nucleic acid compound is a lipid-modified The nucleic acid compound comprises the DTx-05-01 motif of Table 1. In an embodiment, the lipid-modified The nucleic acid compound comprises the DTx-06-06 motif of Table 1. In an embodiment, the lipid-modified The modified nucleic acid compound comprises the DTx-06-50 motif of Table 1. In an embodiment, the lipid-modified The lipid-modified nucleic acid compound comprises the DTx-06-51 motif of Table 1. In an embodiment, The modified nucleic acid compound comprises the DTx-06-52 motif of Table 1. In an embodiment, The modified nucleic acid compound comprises the DTx-06-53 motif of Table 1. In an embodiment, The lipid-modified nucleic acid compound comprises the DTx-06-54 motif of Table 1. In an embodiment, In some embodiments, the lipid-modified nucleic acid compound comprises the DTx-06-55 motif of Table 1. The lipid-modified nucleic acid compound comprises the DTx-08-01 motif of Table 1. In the embodiment, the lipid-modified nucleic acid compound comprises the DTx-09-01 motif of Table 1. In one embodiment, the lipid-modified nucleic acid compound comprises the DTx-10-01 motif of Table 1. In one embodiment, the lipid-modified nucleic acid compound comprises the DTx-11-01 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-60 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-61 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-62 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-63 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-64 motif of Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-65 motif of Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-66 motif of Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-67 model of Table 1. In an embodiment, the lipid-modified nucleic acid compound is DTx-01-68 in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-6 motif in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises DTx-01-9 motif in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises DTx-01 in Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises a DTx-0-71 motif. In an embodiment, the lipid-modified nucleic acid compound comprises a DTx-1-72 motif. In embodiments, the lipid-modified nucleic acid compound comprises a DTx 01-73 motif. In an embodiment, the lipid-modified nucleic acid compound comprises a DT-01-74 motif. In embodiments, the lipid-modified nucleic acid compound comprises a D In embodiments, the lipid-modified nucleic acid compound comprises a Tx-01-76 motif. In embodiments, the lipid-modified nucleic acid compound comprises a DTx-01-77 motif. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-78 motif of Table 1. In an embodiment, the lipid-modified nucleic acid compound comprises a DTx-01-79 motif of The lipid-modified nucleic acid compound comprises the DTx-01-80 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound , comprising the DTx-01-81 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-82 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound The product comprises the DTx-01-83 motif of Table 1. In an embodiment, the lipid-modified nucleic acid The compound comprises the DTx-01-84 motif of Table 1. In an embodiment, the lipid-modified nucleic acid The compound comprises the DTx-01-85 motif of Table 1. In an embodiment, the lipid-modified nucleus The acid compound comprises the DTx-01-86 motif of Table 1. In an embodiment, a lipid-modified The nucleic acid compound comprises the DTx-01-87 motif of Table 1. In embodiments, the nucleic acid compound is a lipid-modified The nucleic acid compound comprises the DTx-01-88 motif of Table 1. In an embodiment, the lipid-modified The selected nucleic acid compound comprises the DTx-01-89 motif of Table 1. In an embodiment, the lipid-modified The modified nucleic acid compound comprises the DTx-01-90 motif of Table 1. In an embodiment, the lipid-modified The lipid-modified nucleic acid compound comprises the DTx-01-91 motif of Table 1. In an embodiment, The modified nucleic acid compound comprises the DTx-01-92 motif of Table 1. In an embodiment, The modified nucleic acid compound comprises the DTx-01-93 motif of Table 1. In an embodiment, The lipid-modified nucleic acid compound comprises the DTx-01-94 motif of Table 1. In an embodiment, In some embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-95 motif of Table 1. The lipid-modified nucleic acid compound comprises the DTx-01-96 motif of Table 1. In the embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-97 motif of Table 1. In one embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-98 motif of Table 1. In one embodiment, the lipid-modified nucleic acid compound comprises the DTx-01-99 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-100 motif of Table 1. In embodiments, the lipid-modified nucleic acid compound comprises the DTx-01-101 motif of Table 1. include.

[0245] Structure of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb In an embodiment of the compound having the formula: In one embodiment, the modified The decorated double-stranded oligonucleotide has a lipid-containing moiety at the 3' end of its guide strand. In embodiments, the modified double-stranded oligonucleotide is conjugated to At the 3' end of the passenger strand, it is conjugated to a portion of the lipid-containing moiety.

[0246] Structure of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb In an embodiment of the compound having the formula: In one embodiment, the modified The decorated double-stranded oligonucleotide has a lipid-containing moiety at the 5' end of its guide strand. In embodiments, the modified double-stranded oligonucleotide is conjugated to At the 5' end of the passenger strand, it is conjugated to a portion of the lipid-containing moiety.

[0247] In embodiments having the structure of Formula I, Ia, Ib, II, IIa, or IIb, Conjugation to the end occurs via a phosphodiester bond. In embodiments having the structure Ib, II, IIa, or IIb, The jugation occurs via a phosphodiester bond.

[0248] In an embodiment of Formula III, IIIa, or IIIb, A is a modified double-stranded oligo Z1 is a passenger strand of a modified double-stranded oligonucleotide. Z2 is a modified double-stranded oligonucleotide It is conjugated to the 5' end of the sender strand.

[0249] In an embodiment of Formula III, IIIa, or IIIb, A is a modified double-stranded oligo Z1 is a nucleotide at the 3' end of the guide strand of the modified double-stranded oligonucleotide. Z2 is a passenger of the modified double-stranded oligonucleotide. The 5' end of the first strand is conjugated to the 5' end of the second strand.

[0250] In embodiments, a compound of formula I, Ia, Ib, II, IIa, Ib, IIb, IIc, IId, IIe, IIf, IIg, IIh, IIi, IIj ... Ib, III, IIIa, or IIIb lipid-conjugated compounds, or The modified double-stranded oligonucleotide is prepared by contacting the oligonucleotide with a corresponding pharmaceutically acceptable salt of Provided herein are methods for introducing nucleotides into cells in vitro. In some embodiments, the compound is in direct contact with the cell. In some embodiments, the cell is a mammalian cell. In embodiments, the cells are human cells. In embodiments, the cells are mouse cells. In embodiments, the cells are fibroblast cells. In embodiments, the cells are kidney cells. In embodiments, the cells are HEK293 In embodiments, the cells are endothelial cells. In embodiments, the cells are HUVE cells. In an embodiment, the cell is an adipose cell. In an embodiment, the cells are differentiated 3T3L1 cells. In an embodiment, the cell is a phage cell. In an embodiment, the cell is a RAW264.7 cell. In some embodiments, the cells are neuronal cells. In some embodiments, the cells are primary rat neurons. In embodiments, the cells are SH-SY5Y cells. In embodiments, the cells are muscle cells. In embodiments, the cells are differentiated primary human musculoskeletal cells. In embodiments, the cells are In embodiments, the cells may be derived from an immortalized cell line. In some embodiments, the cells may be derived from primary cells. In some embodiments, the cells may be adipocytes (adipose cells). In an embodiment, the cells are human adipocyte cells. In embodiments, the cells are hepatocyte cells. In embodiments, the cells are human hepatocyte cells. In embodiments, the cell is a T cell.

[0251] In embodiments, a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or A lipid-conjugated compound of formula IIIb, or its corresponding pharmaceutically acceptable salt. The modified double-stranded oligonucleotides were introduced into cells in vivo by intravitreal injection of Provided herein are methods for performing the same. In embodiments, the cells are ocular cells. The cells of the eye are photoreceptors, bipolar cells, ganglion cells, horizontal cells, amacrine cells, and corneal In an embodiment, the corneal epithelial cells are basal cells, corneal endothelial cells, and corneal stromal cells. , wing cells, or squamous cells.

[0252] In embodiments, the modified double-stranded oligonucleotide is administered in vivo by intrathecal administration. In embodiments, the modified ATP is delivered to cells by intraventricular administration. Provided herein are methods for introducing decorated double-stranded oligonucleotides into cells.

[0253] In embodiments, a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or A lipid-conjugated compound of formula IIIb, or its corresponding pharmaceutically acceptable salt. The modified double-stranded oligonucleotide is administered in vivo by contacting the modified double-stranded oligonucleotide with the systemic administration of Provided herein are methods for introducing the vector into cells.

[0254] In embodiments, a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or A lipid-conjugated compound of formula IIIb, or its corresponding pharmaceutically acceptable salt. In embodiments, the cells are provided with a method for introducing either an in vivo or in vivo recombinant vector into a cell. In embodiments, the cells are in vitro. In embodiments, the cells are ex vivo. In embodiments, the cells are in vivo. It's Bibo.

[0255] In embodiments, a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or A lipid-conjugated compound of formula IIIb, or its corresponding pharmaceutically acceptable salt. The subject may have an eye, brain, liver, kidney, or the like. The patient may have a disease or disorder of the heart, adipose tissue, lungs, muscles, or spleen.

[0256] In embodiments, the eye disease or disorder is blepharitis, cataract, chalazion, conjunctivitis, diabetic ophthalmopathy, or retinal edema. Membrane, dry eye, glaucoma, keratitis, keratoconus, macular degeneration, eye allergies, high intraocular pressure, eyelid The condition is macula, presbyopia, pterygium, retinoblastoma, subconjunctival hemorrhage, or uveitis.

[0257] In embodiments, the disease or disorder is a neurological disease or disorder, a metabolic disease or disorder, In an embodiment, the subject has a cancer.

[0258] In either in vivo administration or subject-related embodiments, administration is systemic administration. These include, but are not limited to, subcutaneous, intravenous, intramuscular, and oral administration. In either the in vivo administration or subject-related embodiments, the administration may include , local administration, including but not limited to intravitreal administration, intrathecal administration, and intravenous administration. Intravenous administration may be included.

[0259] In an embodiment, the method is to introduce the modified double-stranded oligonucleotide ex vivo. Therefore, under free uptake conditions, cells and the formula I, Ia, Ib, II, IIa, IIb, II I, IIIa, or IIIb, or a corresponding pharmaceutically acceptable salt thereof. In embodiments, the cell is a neuroblastoma cell. The cells are TBM cells, skeletal muscle cells, adipocyte cells or hepatocyte cells.

[0260] In embodiments, a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or contains a compound having the structure IIIb, or a corresponding pharmaceutically acceptable salt thereof Provided herein are cells. In embodiments, the cells are mammalian cells. In embodiments, In some embodiments, the cells are human cells. In some embodiments, the cells are mouse cells. In some embodiments, the cells are fibroblast cells. In some embodiments, the cells are NIH3T3 cells. In embodiments, the cells are kidney cells. In embodiments, the cells are HEK293 cells. In embodiments, the cells are endothelial cells. In embodiments, the cells are HUVEC cells. In an embodiment, the cells are adipose cells. In some embodiments, the cells are differentiated 3T3L1 cells. In some embodiments, the cells are macrophage cells. In an embodiment, the cells are RAW264.7 cells. In an embodiment, the cells are In an embodiment, the cells are primary rat neurons. In some embodiments, the cells are SH-SY5Y cells. In some embodiments, the cells are muscle cells. In one embodiment, the cells are differentiated primary human musculoskeletal cells. In another embodiment, the cells are derived from the trabecular meshwork. In embodiments, the cells may be from an immortalized cell line. The cells may be derived from primary cells. In embodiments, the cells are adipocytes. In an embodiment, the cells are human adipocytes. In some embodiments, the cells are hepatocyte cells. In some embodiments, the cells are human hepatocyte cells. In embodiments, the cells are primary human adipocytes. VEC cells. In embodiments, the cells are primary human hepatocyte cells.

[0261] In embodiments, the cells are treated with a compound having the structure of Formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is Z1 at the 3' end of one strand of the modified single-stranded oligonucleotide or the 3' end of the modified single-stranded oligonucleotide The Z1 is [ka] and The modified double-stranded oligonucleotide is conjugated to Z2 at the 5' end of the strand or the 5' end of the modified single-stranded oligonucleotide Gated, Z2, [ka] The compound contains a compound in which

[0262] In embodiments, the cells are treated with a compound having the structure of Formula IIIa: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. portion [ka] and a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide conjugated to The oligonucleotide is attached to the 5' end of one strand of the modified double-stranded oligonucleotide or Lipid-containing moieties at the 5' ends of modified single-stranded oligonucleotides [ka] The compound contains a compound conjugated to the

[0263] In embodiments, the cells are treated with a compound having the structure of Formula IIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide, The modified double-stranded oligonucleotide is or a lipid-containing nucleotide at the 3' end of one strand of a modified single-stranded oligonucleotide. portion [ka] modified double-stranded or single-stranded oligonucleotides conjugated to The nucleotide is attached to the 5' end of one strand of a modified double-stranded oligonucleotide ...

Claims

1. The following structure 【Chemistry 1】 (In the formula, A is an oligonucleotide; L ３ and L ４ are independently a bond, —NH—, —O—, —S—, —C(O)—, —N HC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)N H-, -OPO ２ -O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroaromatic group alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene aryl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; can be, L ５ But, -L ５Ａ -L ５Ｂ -L ５Ｃ -L ５Ｄ -L ５Ｅ - and L ６ But, -L ６Ａ -L ６Ｂ -L ６Ｃ -L ６Ｄ -L ６Ｅ - and L ５Ａ L ５Ｂ L ５Ｃ L ５Ｄ L ５Ｅ L ６Ａ L ６Ｂ L ６Ｃ L ６Ｄ 、および L ６Ｅ are independently a bond, —NH—, —O—, —S—, —C(O)—, or —NHC(O) -, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)NH-, substitution or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted Cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted alkylene arylene, or substituted or unsubstituted heteroarylene; R １ and R ２ are independently unsubstituted C １ -C ２５ alkyl, wherein R １ and R ２ At least one of ９ -C １９ is alkyl, R ３ is hydrogen, -NH ２ , -OH, -SH, -C(O)H, -C(O)NH ２ , -NH C(O)H、-NHC(O)OH、-NHC(O)NH ２ 、-C(O)OH、-OC(O ) H, —N ３ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or is unsubstituted aryl, or substituted or unsubstituted heteroaryl; and t is an integer from 1 to 5.

2. The compound of claim 1, wherein t is 1.

3. The compound of claim 1, wherein t is 2.

4. The compound of claim 1, wherein t is 3.

5. 1, wherein A is a double-stranded oligonucleotide or a single-stranded oligonucleotide. The compound described in

6. The compound of claim 1 , wherein the oligonucleotide of A is modified.

7. One L ３ is the 3' of the double-stranded or single-stranded oligonucleotide The compound of claim 5 , wherein the carbon is attached to

8. One L ３ is the 5' of the double-stranded or single-stranded oligonucleotide The compound of claim 5 , wherein the carbon is attached to

9. One L ３ The nucleic acid of the double-stranded oligonucleotide or single-stranded oligonucleotide The compound of claim 5 , which is connected to a base.

10. L ３ and L ４ are independently a bond, —NH—, —O—, —S—, —C(O)—, —N HC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -C(O)N H-, -OPO ２ -O-, substituted or unsubstituted alkylene, or substituted or unsubstituted heptane The compound of claim 1 which is a terephthaloalkylene.

11. L ３ But independently, 【Chemistry 2】 2. The compound of claim 1, wherein:

12. L ３ But independently, -OPO ２ The compound of claim 1, wherein the aryl group is —O—.

13. L ３ The compound of claim 1 , wherein is independently —O—.

14. L ４ are independently substituted or unsubstituted alkylene, or substituted or unsubstituted hetoe 2. The compound of claim 1, wherein the compound is a methyl group.

15. L ４ But independently, -L ７ -NH-C(O)- or -L ７ -C(O)-NH- , L ７ The compound of claim 1 , wherein is substituted or unsubstituted alkylene.

16. L ４ But independently, 【Transformation 3】 2. The compound of claim 1, wherein:

17. L ４ But independently, 【Chemistry 4】 2. The compound of claim 1, wherein:

18. -L ３ -L ４ - is independent, -OL ７ —NH—C(O)— or —O—L ７ -C ( O) —NH—, and L ７ are independently substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted heteroalkenylene.

1. The compound according to claim 1.

19. -L ３ -L ４ - is independent, -OL ７ —NH—C(O)—, and L ７ But independent and substituted or unsubstituted C ５ -C ８ The compound of claim 1 which is an alkylene.

20. -L ３ -L ４ - but independently, 【Transformation 5】 2. The compound of claim 1, wherein:

21. -L ３ -L ４ - but independently, -OPO ２ -O-L ７ —NH—C(O)— or —OP O ２ -O-L ７ —C(O)—NH—, and L ７ are independently substituted or unsubstituted alkyl The compound of claim 1 , wherein the compound is cyclohexane.

22. -L ３ -L ４ - but independently, -OPO ２ -O-L ７ —NH—C(O)—, and L ７ are independently substituted or unsubstituted C ５ -C ８ The compound of claim 1, which is an alkylene. 。

23. -L ３ -L ４ - but independently, 【Transformation 6】 2. The compound of claim 1, wherein:

24. -L ３ -L ４ - but independently, 【Transformation 7】 and attached to the 3' carbon of the double-stranded or single-stranded oligonucleotide 2. The compound of claim 1 ,

25. -L ３ -L ４ - but independently, 【Transformation 8】 and attached to the 5' carbon of the double-stranded or single-stranded oligonucleotide 2. The compound of claim 1 ,

26. -L ３ -L ４ - but independently, 【Chemistry 9】 and connected to a nucleotide base of the double-stranded or single-stranded nucleic acid. The compound described in

27. R ３ The compound of claim 1 , wherein is independently hydrogen.

28. L ６ are independently —NHC(O)—, —C(O)NH—, substituted or unsubstituted alkyl 2. The compound of claim 1, wherein the alkylene is substituted or unsubstituted heteroalkylene.

29. L ６ The compound of claim 1, wherein is independently -NHC(O)-.

30. L ６Ａ is independently a bond or unsubstituted alkylene; L ６Ｂ are independently a bond, —NHC(O)—, or unsubstituted arylene; L ６Ｃ are independently a bond, unsubstituted alkylene, or unsubstituted arylene; L ６Ｄ is independently a bond or unsubstituted alkylene; L ６Ｅ is independently a bond or -NHC(O)-.

31. L ６Ａ are independently a bond or an unsubstituted C １ -C ８ is alkylene, L ６Ｂ are independently a bond, —NHC(O)—, or unsubstituted phenylene; L ６Ｃ are independently a bond, an unsubstituted C ２ -C ８ Alkynylene, or unsubstituted phenylene and L ６Ｄ are independently a bond or an unsubstituted C １ -C ８ is alkylene, L ６Ｅ is independently a bond or -NHC(O)-.

32. L ６ But independently, combined, 【Chemistry 10】 2. The compound of claim 1, wherein:

33. L ５ are independently —NHC(O)—, —C(O)NH—, substituted or unsubstituted alkyl 2. The compound of claim 1, wherein the alkylene is substituted or unsubstituted heteroalkylene.

34. L ５ The compound of claim 1, wherein is independently -NHC(O)-.

35. L ５Ａ is independently a bond or unsubstituted alkylene; L ５Ｂ are independently a bond, —NHC(O)—, or unsubstituted arylene; L ５Ｃ are independently a bond, unsubstituted alkylene, or unsubstituted arylene; L ５Ｄ is independently a bond or unsubstituted alkylene; L ５Ｅ is independently a bond or -NHC(O)-.

36. L ５Ａ are independently a bond or an unsubstituted C １ -C ８ is alkylene, L ５Ｂ are independently a bond, —NHC(O)—, or unsubstituted phenylene; L ５Ｃ are independently a bond, an unsubstituted C ２ -C ８ Alkynylene, or unsubstituted phenylene and L ５Ｄ are independently a bond or an unsubstituted C １ -C ８ is alkylene, L ５Ｅ is independently a bond or -NHC(O)-.

37. L ５ But independently, combined, 【Chemistry 11】 2. The compound of claim 1, wherein:

38. R １ is unsubstituted C １ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

39. R １ is unsubstituted C １１ -C １７ The compound of claim 1 , wherein the compound is alkyl.

40. R １ is unsubstituted C １３ -C １７ The compound of claim 1 , wherein the compound is alkyl.

41. R １ is unsubstituted C １５ The compound of claim 1 , wherein the compound is alkyl.

42. R １ is an unsubstituted unbranched C １ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

43. R １ is an unsubstituted unbranched C １１ -C １７ The compound of claim 1 , wherein the compound is alkyl.

44. R １ is an unsubstituted unbranched C １３ -C １７ The compound of claim 1 , wherein the compound is alkyl.

45. R １ is an unsubstituted unbranched C １５ The compound of claim 1 , wherein the aryl group is alkyl.

46. R １ is an unsubstituted unbranched saturated C １ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

47. R １ is an unsubstituted unbranched saturated C １１ -C １７ The compound of claim 1 , wherein the compound is alkyl.

48. R １ is an unsubstituted unbranched saturated C １３ -C １７ The compound of claim 1 , wherein the compound is alkyl.

49. R １ is an unsubstituted unbranched saturated C １５ The compound of claim 1 , wherein the aryl group is alkyl.

50. R ２ is unsubstituted C １ -C １７ The compound of claim 1 , wherein the compound is alkyl.

51. R ２ is unsubstituted C １１ -C １７ The compound of claim 1 , wherein the compound is alkyl.

52. R ２ is unsubstituted C １３ -C １７ The compound of claim 1 , wherein the compound is alkyl.

53. R ２ is unsubstituted C １５ The compound of claim 1 , wherein the aryl group is alkyl.

54. R ２ is an unsubstituted unbranched C １ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

55. R ２ is an unsubstituted unbranched C １１ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

56. R ２ is an unsubstituted unbranched C １３ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

57. R ２ is an unsubstituted unbranched C １５ The compound of claim 1 , wherein the aryl group is alkyl.

58. R ２ is an unsubstituted unbranched saturated C １ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

59. R １ is an unsubstituted unbranched saturated C １１ -C １７ The compound of claim 1 , wherein the compound is alkyl.

60. R ２ is an unsubstituted unbranched saturated C １３ -C １７ The compound of claim 1 , wherein the aryl group is alkyl.

61. R ２ is an unsubstituted unbranched saturated C １５ The compound of claim 1 , wherein the compound is alkyl.

62. The oligonucleotide may be an siRNA, a microRNA mimic, a stem-loop structure, Single-stranded siRNA, RNase H oligonucleotide, anti-microRNA oligonucleotide oligonucleotides, sterically hindered oligonucleotides, CRISPR guide RNAs, or aptamers. The compound of claim 1 .

63. The compound of claim 1 , wherein the oligonucleotide is modified.

64. The compound of claim 1 , wherein the oligonucleotide comprises a nucleotide analog.

65. The oligonucleotide may contain a locked nucleic acid (LNA) residue, a bicyclic nucleic acid (BNA) residue, a constrained hexaethyl (cEt) residue, unlocked nucleic acid (UNA) residue, phosphorodiamidate morpho Peptide oligomer (PMO) monomer, peptide nucleic acid (PNA) monomer, 2'-O-methyl 2'-O-methyloxyethyl residue, 2'-deoxy-2'-furan residue, phosphorothioate residue, 2'-O-methoxyethyl / phosphorothioate residue, phosphoramidate, Phosphorodiamidates, phosphorothioates, phosphorodithioates, phosphonocarbones Acid, phosphonocarboxylate, phosphonoacetic acid, phosphonoformic acid, methylphosphonic acid, boro 10. The compound of claim 1, comprising a phosphonate, or an O-methyl phosphoramidite. 。

66. The compound is a lipid-conjugated compound having the structure of Formula I: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, wherein: A is a modified double-stranded oligonucleotide or a modified single-stranded oligonucleotide and the modified double-stranded oligonucleotide or the modified single-stranded oligonucleotide is The oligonucleotide is attached to the 3' end of one strand of the modified double-stranded oligonucleotide or conjugated to a lipid-containing moiety at the 3' end of the single-stranded nucleic acid; X １ but, 【Chemistry 13】 and L １ But -(CH ２ ) ｎ -, -(CH ２ ) ｎ L ２ (CH ２ ) ｎ - or a bond, L ２ が、-C(=O)NE-、-C(=O)N�EC( =O)O-, -NHC(=O)NH-, -C(=S)NH-, -C(=O)S-, -NH -, O (oxygen), or S (sulfur), and each m is independently an integer from 10 to 18; 2. The compound of claim 1, wherein each n is independently an integer from 1 to 6.

67. Each m is 10, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

68. Each m is 11, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

69. Each m is 12, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

70. Each m is 13, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

71. Each m is 14, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

72. Each m is 15, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

73. Each m is 16, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

74. Each m is 17, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

75. Each m is 18, and L １ Ga-(CH ２ ) ｎ - and n is 3. Compound.

76. each m is independently an integer from 12 to 16, and each n is independently an integer from 1 to 6; The compound according to claim 66.

77. each m is independently an integer from 12 to 14, and each n is independently an integer from 1 to 6; The compound according to claim 66.

78. L １ is a bond and each m is independently an integer from 12 to 16. compound.

79. L １ But -(CH ２ ) ３ C(=O)NH(CH ２ ) ５ -, and each m is independently 12 67. The compound of claim 66, wherein R is an integer from 1 to 16.

80. 79. The compound of claim 78, wherein each m is 14.

81. The modified double-stranded oligonucleotide or the modified single-stranded oligonucleotide 67. The compound of claim 66, wherein:

82. The modified double-stranded oligonucleotide or the modified single-stranded oligonucleotide 67. The compound of claim 66, wherein: contains at least one 2'-O-methyl residue.

83. The modified double-stranded oligonucleotide or the modified single-stranded oligonucleotide contains at least one 2'-deoxy-2'-fluoro residue. The compounds listed above.

84. The modified double-stranded oligonucleotide or the modified single-stranded oligonucleotide 67. The compound of claim 66, wherein comprises a bicyclic nucleic acid (BNA) residue.

85. The bicyclic nucleic acid residue of the oligonucleotide is a locked nucleic acid (LNA) residue or a constrained ethoxylate residue.

85. The compound of claim 84, wherein the residue is a cEt residue.

86. The modified double-stranded oligonucleotide or the modified single-stranded oligonucleotide comprises a phosphorodiamidate morpholino oligomer (PMO) monomer. The compound described in

87. The modified double-stranded oligonucleotide is an siRNA or a microRNA mimic.

67. The compound of claim 66, wherein:

88. a lipid moiety attached to the 3' end of the passenger strand of the siRNA or microRNA mimic; 88. The compound of claim 87, wherein the compound is connected to an end.

89. 67. The compound of claim 66, wherein A is an antisense oligonucleotide.

90. A cell containing the compound of claim 1.

91. 91. The cell of claim 90, wherein the cell is a primary cell.

92. The cells may be adipocyte cells, hepatocyte cells, fibroblast cells, or the like. Cells, endothelial cells, kidney cells, human umbilical vein endothelial cells (HUVEC), adipocytes (adipocytes e cell), macrophage cells, nerve cells, muscle cells, or differentiated primary human muscle-bone cells.

92. The cell of claim 91, which is a blastocyst cell.

93. 93. The cell of claim 92, wherein the cell is a human umbilical vein endothelial cell.

94. 91. The cell of claim 90, wherein the cell is an immortalized cell.

95. The cells may be NIH3T3 cells, differentiated 3T3L1 cells, RAW264.7 cells, or or SH-SY5Y cells.

96. 91. The cell of claim 90, wherein the cell is an adipocyte or a hepatocyte.

97. 10. A method for introducing an oligonucleotide into a cell, the method comprising: with a compound of formula (I).

98. A method for introducing oligonucleotides into cells in vitro, comprising the steps of:

10. A method comprising contacting said cells with a compound of claim 1 at 200°C.

99. 99. The method of claim 98, wherein the method is ex vivo and the cells are primary cells. 。

100. The cells may be adipocyte cells, hepatocyte cells, fibroblast cells, or the like. Cells, endothelial cells, kidney cells, human umbilical vein endothelial cells (HUVEC), adipocytes (adipocytes e cell), macrophage cells, nerve cells, rat neurons, muscle cells, or 100. The method of claim 99, wherein the cells are primary human musculoskeletal cells.

101. 100. The method of claim 99, wherein the cells are human umbilical vein endothelial cells.

102. 99. The method of claim 98, wherein the cell is an immortalized cell.

103. The cells may be NIH3T3 cells, differentiated 3T3L1 cells, RAW264.7 cells, or or SH-SY5Y cells.

104. 99. The method of claim 98, wherein the cell is an adipocyte or a hepatocyte.

105. 1. A method for introducing an oligonucleotide into a cell ex vivo, comprising obtaining the cell; and contacting the cells with the compound of claim 1 under free uptake conditions. ,method.

106. The cells are neurons, TBM cells, skeletal muscle cells, adipocyte cells or hepatocyte cells. The method of claim 105, wherein the cell is a cell.

107. 106. The method of claim 105, wherein the cells are human umbilical vein endothelial cells.

108. A method for introducing an oligonucleotide into a cell in vivo, comprising the steps of: with a compound as described above.

109. The cells may be adipocyte cells, hepatocyte cells, fibroblast cells, or the like. cells, endothelial cells, renal cells, adipose cells, macrophage cells, 109. The method of claim 108, wherein the cell is a neuron, a muscle cell, or a musculoskeletal cell.

110. A method comprising contacting a cell with a compound of claim 1.

111. 111. The method of claim 110, wherein the contacting is performed in vitro.

112. 111. The method of claim 110, wherein said contacting is performed ex vivo.

113. 111. The method of claim 110, wherein said contacting is performed in vivo.

114. A method comprising administering to a subject a compound of claim 1.

115. the subject has a disease or disorder of the eye, liver, kidney, heart, adipose tissue, lung, muscle, or spleen. The method of claim 114, wherein the method is harmful.

116. 10. A compound according to claim 1 for use in therapy.

117. 10. A compound according to claim 1 for use in the preparation of a medicament.

118. 1. A method for introducing an oligonucleotide into a cell in a subject, said method comprising: A method comprising administering a compound of claim 1.

119. A cell comprising the compound of claim 1.

120. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1.

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