Oligonucleotide delivery enhancing compounds, pharmaceutical compositions, and methods of use thereof

Abstract

Disclosed are compounds having a specific structure, which can significantly enhance the delivery efficiency of oligonucleotides to each in vitro and in vivo, and thus achieve an improvement in expression modulation of a target gene. Also disclosed are pharmaceutical compositions comprising the compounds and methods of using the pharmaceutical compositions to modulate expression of a target gene.

Description

Technical Field

[0001] The present invention relates to the field of genetic regulation technology, and in particular to unique compounds for enhancing the efficiency of oligonucleotide delivery in vitro and in vivo. Background Art

[0002] Oligonucleotide-based therapy has become an emerging technology because its mechanism of action provides for the regulation of expression of almost unlimited target genes. Giving oligonucleotides to patients, organs, tissues or cells can trigger or affect various biochemical reactions, and therefore achieve functions such as silencing, inhibition, activation and regulation of gene expression. The use of oligonucleotide-based therapy has great prospects and provides solutions to medical problems that traditional medicine cannot solve. However, one of the main obstacles to the commercialization of oligonucleotide-based medicine is the lack of an effective method for delivering it to the correct organ, tissue or cell. Oligonucleotide therapeutic agents typically have a molecular weight of 7kDa to 14kDa and contain a strong negative charge due to the inclusion of phosphodiester or thiophosphate in their backbone. This relatively large molecular weight and high negative charge density limit the transmission of oligonucleotides through the cell membrane. Many strategies have been developed to promote the delivery of oligonucleotides, but delivery efficiency remains a problem.

[0003] Therefore, there remains a long-standing need to develop unique technologies that can deliver oligonucleotides to a wider range of organs, tissues, and cells with excellent efficiency, especially organs, tissues, and cells that are almost inaccessible to oligonucleotides using existing technologies.

[0004] Through continuous exploration, we have developed unique delivery-enhancing compounds that can achieve the above goals. Summary of the Invention

[0005] The present disclosure provides an oligonucleotide delivery enhancing compound (DEC) comprising a nitrogen-containing five-membered heterocyclic moiety, wherein the DEC can be directly or indirectly attached to an oligonucleotide for enhancing the delivery efficiency of the oligonucleotide to a subject in vitro and in vivo. In a specific embodiment, the DEC has a structure represented by Formula AI or Formula AII

[0006]

[0007] In another specific embodiment, the oligonucleotide delivery enhancing compound comprises a moiety represented by Formula BI:

[0008]

[0009] In another specific embodiment, the oligonucleotide delivery enhancing compound comprises a moiety represented by Formula BII:

[0010]

[0011] Also provided herein is an oligonucleotide delivery agent comprising: a DEC portion derived from a DEC of the present disclosure and at least one oligonucleotide, wherein the DEC portion is directly or indirectly linked to the oligonucleotide through at least one linking portion. The oligonucleotide can be an antisense oligonucleotide (ASO), antisense RNA, short interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), double-stranded RNA (dsRNA), and small guide RNA (sgRNA).

[0012] Also provided herein is a pharmaceutical composition comprising the DEC of the present disclosure, which may optionally include additional ingredients such as pharmaceutically acceptable carriers, excipients, solvents, diluents, stabilizers, dispersants, buffers, extenders, preservatives, and combinations thereof.

[0013] Also provided herein is a method for regulating target gene expression in a subject in vitro or in vivo, wherein the method comprises: in the case of in vivo assays or therapeutic treatments, administering the pharmaceutical composition of the present disclosure to the subject, or in the case of in vitro assays, contacting the pharmaceutical composition with cells.

[0014] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0015] BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The features and advantages of the present invention may be better understood with reference to the following detailed description and accompanying drawings which illustrate exemplary embodiments in which the principles of the invention are employed, and in which:

[0017] Figure 1 The knockdown activity of siRNA conjugated with a delivery enhancing compound (ie, DEC-conjugated siRNA or DEC-siRNA) on mouse factor VII (mFVII) mRNA expression in primary mouse hepatocytes (PMH) is shown. PMH cells were transfected with lipofectamine TMRNAiMax uses 0.1nM and 1.0nM of each shown DEC coupling oligonucleotide (DCO) (i.e., RD-12339, RD-12585, RD-12586, RD-12710, RD-12711 and RD-12712) transfection, and continues 24 hours.Mock treatment is to carry out transfection in the absence of oligonucleotide.dsCon2 is used as non-specific double-stranded control.Use gene specific primer set to quantify mFVII mRNA level by RT-qPCR.Amplify Tbp with as internal reference.Show the mean value [mean ± standard error (SEM) of mean value of two replicate wells] of mFVII mRNA in the cell with respect to mock treatment after being standardized to Tbp.

[0018] Figure 2 Shown is the knockdown activity of DEC-coupled siRNA on mouse FVII mRNA expression by free uptake in PMH cells. Figure 1 RD-12339 (described RD-12585, RD-12586, RD-12710, RD-12711 and RD-12712) is directly added into PMH cell culture medium with 0.01nM, 0.05nM, 0.20nM, 0.78nM, 3.13nM, 12.50nM, 50nM and 200nM, continues 24 hours.Mock treatment carries out transfection (not shown) in the absence of oligonucleotide. dsCon2 is used as non-specific double-stranded control (not shown). Use gene specific primer set to carry out quantitative mFVIImRNA level by RT-qPCR. Amplification Tbp is used as internal reference. What is shown is the mean value [mean ± standard error of mean value (SEM) of two replicate holes] of mFVIImRNA in the cell with respect to mock treatment after being standardized to Tbp.

[0019] Figure 3 Figure 2 shows the in vivo knockdown activity of DEC-conjugated siRNA on mouse FVII mRNA expression by subcutaneous injection (SC) in C57BL / 6J mice. The indicated DCO (i.e., as shown) was administered to C57BL / 6J mice at postnatal day (PND) 40 at doses of 0.2 mg / kg, 1 mg / kg, and 5 mg / kg by SC injection. Figure 1RD-12339, RD-12585, RD-12586, RD-12710, RD-12711 and RD-12712). Physiological saline (saline) is injected as the baseline of vehicle control to establish mFVII mRNA expression. Give and put to death mice 3 days after, and use gene specific primer set to quantify the mFVII mRNA level in the total RNA isolated from liver tissue preparation by RT-qPCR. Amplification Tbp is used as internal reference. What is shown is the mean value [mean ± SEM of 3 animals in each group] of mFVII mRNA in the liver tissue of normal saline group after being standardized to Tbp.

[0020] Figure 4 Figure 2 shows the in vivo knockdown activity of DEC-conjugated siRNA on mouse FVII protein expression by SC injection in C57BL / 6J mice. The indicated DCO (i.e., as shown) was administered to C57BL / 6J mice at PND 40 at doses of 0.2 mg / kg, 1 mg / kg, and 5 mg / kg by SC injection. Figure 1 RD-12339, RD-12585, and RD-12586). Normal saline was injected as a vehicle control to establish a baseline for mFVII protein expression. Mice were sacrificed on day 3 after treatment, and mFVII protein levels in mouse plasma were quantified by ELISA. Shown are the average mFVII protein levels in the mouse plasma of each treatment group relative to the normal saline group by measuring OD values ​​[mean ± SEM of 3 animals in each group]. * represents p < 0.05; ** represents p < 0.01; *** represents p < 0.001; and **** represents p < 0.0001.

[0021] Figure 5 Shown is by carrying out SC injection in C57BL / 6J mice, the persistent period of activity of the DEC coupled siRNA to the low knockout of mouse FVII protein expression.Give the indicated DCO (that is, RD-12710 and RD-12712) of 3mg / kg to the C57BL / 6J mice of PND 40 by SC injection, continue 89 days.Inject RD-11706 with 3mg / kg and be used as control.Normal saline is injected to set up the baseline of mFVII protein expression as vehicle control.After processing, collect mouse plasma at 10th, 31st, 54th, 61st, 80th and 89th day and measure the mFVII protein level in mouse plasma by ELISA and carry out quantitative.Shown is with respect to normal saline group, by detecting the average mFVII protein level [mean ± SEM of 3 animals of each time point of every group] in the mouse plasma of 3 animals of each time point of each group of 3 animals.

[0022] Figures 6A-6B Figure 2 shows the in vitro knockdown activity of mouse Sod1 (Sod1) mRNA expression by free uptake of DEC-siRNA in PMH cells. DEC-siRNA (i.e., RD-13110, RD-13115, and RD-13118) was added to PMH cell culture medium at the indicated concentration gradients (i.e., 1.56 nM, 6.25 nM, 25 nM, 100 nM, 400 nM, and 1600 nM) to produce the following: Figure 6A Dose-response curves are shown. Expression data were normalized using treatment in the absence of oligonucleotides. After RNA isolation and RT reaction, Sod1 mRNA levels were quantified by RT-qPCR using gene-specific primer sets. Tbp was amplified as an internal control. Treatment with RD-12556 served as a non-conjugate control to compare dose-dependent knockdown in the absence of DEC conjugate, as shown in Figure 2. Figure 6B Shown are (mean ± SEM of duplicate wells).

[0023] Figure 7 Figure 2 shows the in vivo knockdown activity of different DEC-siRNAs on Sod1 mRNA expression by intracerebroventricular (ICV) injection in adult C57BL / 6J mice. The indicated DEC-siRNAs (i.e., RD-13110, RD-13115, and RD-13118) were administered by unilateral ICV injection at 200 μg. Normal saline was injected as a vehicle control to establish a baseline. RD-12556 was injected at 200 μg as a non-conjugate control. Mice were sacrificed 7 days after administration, and Sod1 mRNA knockdown in the brain (i.e., brain-frontal cortex, cerebrum, and brain-cerebellum), spinal cord (i.e., cervical, thoracic, and lumbar vertebrae), and peripheral tissues (i.e., liver) was quantified using gene-specific primer sets after RNA isolation and RT reaction. Tbp was amplified as an internal reference. Shown are mean Sod1 mRNA levels in each indicated tissue relative to the mRNA levels in the saline group after normalization to Tbp (mean ± SEM of 2-3 animals per group).

[0024] Figure 8Figure 2 shows the in vivo activity of different DEC-siRNAs in knocking down Sod1 mRNA expression after intravenous (IV) injection into the lateral tail vein of adult C57BL / 6J mice. The indicated DEC-siRNAs (i.e., RD-13110, RD-13115, and RD-13118) were given by IV injection at 20 mg / kg. Normal saline was injected as a vehicle control to establish a baseline. RD-12556 was injected at 20 mg / kg as a non-conjugate control. Mice were killed on day 7 after treatment, and Sod1 mRNA knockdown in selected peripheral tissues (i.e., heart, liver, spleen, lung, kidney, and bladder) was quantified using a gene-specific primer set by RT-qPCR after RNA isolation and RT reaction. Tbp was amplified as an internal reference. Shown is the average Sod1 mRNA level (mean ± SEM of 3 animals in each group) in each indicated tissue relative to the mRNA level in the normal saline group after standardization to Tbp.

[0025] Figure 9 Figure 2 shows the in vivo knockdown activity of different DEC-siRNAs on mRNA expression after IV injection into adult C57BL / 6J mice. The indicated DEC-siRNAs (i.e., RD-13110, RD-13115, and RD-13118) were administered by IV injection at 20 mg / kg. Normal saline was injected as a vehicle control to establish a baseline. RD-12556 was injected at 20 mg / kg as a non-conjugate control. Mice were sacrificed 7 days after administration, and the Sod1 mRNA levels in the skeletal muscle tissue of different positions (i.e., biceps, semitendinosus, platysma, and gluteal muscles) were quantified using a gene-specific primer set by RT-qPCR after RNA isolation and RT reaction. Tbp was amplified as an internal reference for RNA loading. Shown is the average Sod1 mRNA level (mean ± SEM) of 3 animals in the skeletal muscle tissue of each group relative to the mRNA level in the normal saline group after standardization to Tbp.

[0026] Figure 10The knockdown activity of different DEC-siRNAs on rat Sod1 mRNA expression by intravitreal (IVT) injection in adult SD rats is shown. The indicated DEC-siRNAs (i.e., RD-13115T and RD-13118) were administered by IVT injection of 30 μg per left eye. The right eye of each rat served as an uninjected naive eye. Normal saline was injected as a vehicle control to establish a baseline. RD-12556 was injected as a non-conjugate control. Rats were sacrificed on day 14 after treatment, and Sod1 mRNA levels in the eyes were quantified by RT-qPCR using a rat gene-specific primer set after RNA isolation and RT reaction. The geometric mean of the mRNA levels of Hprt1 and Hmbs was used as an internal control for RNA loading. Shown are the average Sod1 mRNA levels in retinal tissue of 3 animals in each group, relative to the mRNA levels in the normal saline group, after normalization to Hprt1 and Hmbs. Data are expressed as the mean ± SEM of 3 rats per group.

[0027] Figure 11 Shown are the saRNA concentrations of DEC-saRNA in the bladder of adult C57BL / 6J mice after intravesical (IVB) instillation. The indicated DEC-saRNA (i.e., RD-13520) was given by IVB injection of 3 mg. RD-10773 was injected as a non-conjugated saRNA control (i.e., in the absence of DEC). Mice were killed 2 hours, 6 hours, 12 hours, on the 1st day, and on the 4th day after treatment, and gene-specific primer sets (R1-40-AS-SL-RT, R1-40-AS-SL-F1, and SL-RT-qPCR-Uni-R2, see Table 13) were used to quantify the concentrations of RD-13520 and RD-10773 in bladder tissue by stem-loop RT-qPCRCF. The average concentrations (ng / g) (mean ± SEM) of saRNA in mouse bladder tissue samples from 2 animals (n=2) at the indicated time points are shown.

[0028] Figures 12A-12CDEC-siRNA injected by IV, weight change and Sod1 knockdown activity of adult C57BL / 6J mice are shown. Indicated siRNA (i.e., RD-15135, RD-15136, RD-15137 and RD-15138) were given to C57BL / 6J mice at 10 mg / kg. RD-15135 was used as a non-conjugate control. RD-15136 is a lipid (i.e., C16) coupled siRNA. RD-15137 with a typical DEC structure (i.e., C5X5) was used as a typical DEC-siRNA. RD-15138 with a typical DEC structure (i.e., C5X5) and lipid (i.e., C16) was used as a combination siRNA (combo siRNA) (i.e., DEC-C16-siRNA). Only treated with normal saline to be used as a vehicle control, thereby establishing baseline expression. Figure 12A Shown are the changes in body weight of C57BL / 6J mice up to day 28 after treatment. Figure 12B Shown are the remaining mouse Sod1 mRNA quantified by RT-qPCR 14 days after administration in peripheral (i.e., heart, liver, kidney, adipose tissue, pancreas, diaphragm), vascular (i.e., thoracic aorta with veins), and skeletal muscle (biceps, semitendinosus, platysma, and gluteal) tissues using gene-specific primer sets. Figure 12C Shown are the remaining mouse Sod1 mRNA quantified by RT-qPCR 28 days after administration in peripheral (i.e., heart, liver, kidney, adipose tissue, pancreas, diaphragm), vascular (i.e., thoracic aorta with veins), and skeletal muscle (biceps, semitendinosus, platysma, and gluteal) tissues using gene-specific primer sets. Rpl13a was amplified as an internal control. Average Sod1 mRNA levels in selected mouse tissues are shown relative to saline controls after normalization to Rpl13a. Data are presented as mean ± SEM of 3 mice per group.

[0029] Figures 13A-13CShown is the weight change and Sod1 knockdown activity of DEC-siRNA in adult SD female rats by intrathecal (IT) injection. With 0.9mg, indicated siRNA (i.e., RD-15135, RD-15136, RD-15137 and RD-15138) is given in C57BL / 6J mice. Injection RD-15135 is used as a non-conjugate control. RD-15136 is a lipid (i.e., C16) coupled siRNA. RD-15137 with typical DEC structure (i.e., C5X5) is used as typical DEC-siRNA. RD-15138 with typical DEC structure (i.e., C5X5) and lipid (i.e., C16) is used as combination siRNA (i.e., DEC-C16-siRNA). Only artificial cerebrospinal fluid (aCSF) is used as vehicle control to establish baseline expression. Figure 13A Shown are the changes in body weight of SD rats up to day 28 after treatment. Figure 13B Shown are the remaining rat Sod1 mRNA quantified by RT-qPCR using gene-specific primer sets in tissues of the brain (ie, frontal cortex, cerebellum, and cerebrum), spinal cord (ie, cervical, thoracic, and lumbar vertebrae), and periphery (ie, liver and kidney) 14 days after administration. Figure 13C Figure 2 shows the residual rat Sod1 mRNA quantified by RT-qPCR using gene-specific primer sets in tissues of the brain (i.e., frontal cortex, cerebellum, and cerebrum), spinal cord (i.e., cervical, thoracic, and lumbar vertebrae), and periphery (i.e., liver and kidney) 28 days after administration. The geometric mean of Actb and B2m mRNA levels was used as an internal control for RNA loading. Shown are the mean Sod1 mRNA levels in selected rat tissues relative to the mRNA levels in the aCSF group after normalization to Actb and B2m. Data are presented as the mean ± SEM of 3 rats per group.

[0030] Figures 14A-14B Figure 2 shows the in vitro knockdown activity of DEC-siRNA with helper oligonucleotides (i.e., DEC-siRNA-ACO) on human SOD1 (i.e., SOD1) mRNA expression in SK-N-AS and T98G cells. The indicated DEC-siRNA-ACOs (i.e., RD-16149, RD-16099, RD-16100, RD-16101, RD-16150, RD-16103, RD-16104, and RD-16105) were transfected into SK-N-AS and T98G cells at the indicated concentrations (i.e., 1.56 nM, 6.25 nM, 25 nM, 100 nM, 400 nM, and 1600 nM) to produce the following: Figures 14A-14BDose-response curves are shown. RD-16106 was transfected and served as an siRNA-ACO control. Mock treatment was performed in the absence of oligonucleotides (not shown). After RNA isolation and RT reaction, Sod1 mRNA levels were quantified by RT-qPCR using gene-specific primer sets. B2M was amplified as an internal control. Shown are the mean values ​​of the remaining SOD1 mRNA in cells relative to mock treatment after normalization to B2M [mean ± SEM of duplicate wells].

[0031] Figures 15A-15B Figure 2 shows the Sod1 knockdown activity and tissue concentration of siRNAs by ICV injection in adult hSOD1G93A mice. The indicated siRNAs (i.e., RD-14851, RD-12500, RD-16145, and RD-16334) were administered to hSOD1G93A mice at 200 μg. RD-14851, RD-12500, and RD-16145 were administered as siRNA-ACOs. RD-16334, which has a typical DEC structure (i.e., L17), was administered and used as a DEC-siRNA-ACO. ACSF-only treatment was used as a vehicle control to establish baseline expression. Figure 15A Figure 2 shows the residual SOD1 mRNA quantified by RT-qPCR using gene-specific primer sets in brain (i.e., frontal cortex, cerebellum, and cerebrum), spinal cord, and peripheral (i.e., liver) tissues 30 days after administration. Rpl13a was amplified as an internal control. Shown are the average SOD1 mRNA levels in selected mouse tissues relative to the mRNA levels in the aCSF group after normalization to Rpl13a. Figure 15B The concentration of the antisense strand of each siRNA in brain (i.e., frontal cortex, cerebellum, and cerebrum), spinal cord, and peripheral (i.e., liver) tissues 30 days after administration is shown using a gene-specific primer set (R17-02-AS-SL-RT, R17-02-AS-SL-F3, and SL-RT-qPCR-Uni-R1, see Table 13). The mean of siRNA concentrations for 5 animals (n=5) in each treatment is shown. Data are expressed as mean ± SEM of 5 mice per group.

[0032] Figures 16A-16BShown is the splicing activity of the "saRNA-ASO" DEC-conjugated dual-acting oligonucleotide (DEC-DAO) construct in converting SMN2 pre-mRNA to SMN2FL compared to the SMN2Δ7 mRNA isoform in GM03813 cells. The indicated DEC-DAO conjugates with an L21 linker (i.e., RD-16939 and RD-16940), DEC-saSMN2 (i.e., RD-16424), and DEC-antisense oligonucleotide (DEC-ASO) (i.e., RD-14644) were transfected into GM03813 cells at the indicated concentrations (i.e., 0.1 nM, 1 nM, and 10 nM) for 3 days. Mock treatment was performed in the absence of oligonucleotides. RD-16381 was transfected as a nonspecific DEC control. Combination treatments (ie, RD-16424 + RD-14644) and combination treatment controls (ie, RD-16381 + RD-16424, RD-16381 + RD-14644) were also transfected into GM03813 cells. Figures 16A-16B Shown are the mRNA levels of SMN2FL and SMN2Δ7 quantified by RT-qPCR using gene-specific primer sets in each PCR reaction. SDHA was amplified as an internal control for normalization of expression data. Data represent the mean expression level of SMN2FL or SMN2Δ7 relative to mock treatment after normalization to SDHA (mean ± SEM of duplicate transfected wells).

[0033] Figures 17A-17B The effects of "saRNA-siRNA" DEC-DAO constructs targeting two different human genes (SMN2 and SOD1) on SMN2 (SMN2FL and SMN2Δ7) and SOD1 expression in GM03813 cells are shown. The indicated DEC-DAO conjugates with an L21 linker (i.e., RD-16941), DEC-saSMN2 (i.e., RD-16424), and DEC-siSOD1 (RD-13115) were transfected into GM03813 cells at the indicated concentrations (i.e., 0.1 nM and 10 nM) for 3 days. Mock treatment was performed in the absence of oligonucleotides. RD-16381 was transfected as a nonspecific DEC control. Combination treatments (i.e., RD-16424+RD-13115) and combination treatment controls (i.e., RD-16381+RD-16424, RD-16381+RD-13115) were also transfected into GM03813 cells at the indicated concentrations (i.e., 0.1 nM, 1 nM, and 10 nM) for 3 days. Figures 17A-17B Shown are the mRNA levels of SMN2FL and SMN2Δ7 quantified by RT-qPCR using gene-specific primer sets in each PCR reaction. Figure 17C The remaining SOD1 mRNA levels were quantified by RT-qPCR using gene-specific primer sets in each PCR reaction. SDHA was amplified as an internal control for normalization of expression data. Data represent the mean expression level values ​​(mean ± SEM of duplicate transfection wells) of SMN2FL, SMN2Δ7, or SOD1 relative to mock treatment after normalization to SDHA.

[0034] Figures 18A-18B Shown is the knockdown activity of "siRNA-siRNA" DEC-DAO constructs targeting two different mouse genes (Sod1 and Ppig) on ​​mouse Sod1 and mouse Ppig expression in a mouse myoblast cell line (C2C12). The indicated DEC-DAO conjugates with an L21 linker (i.e., RD-16942), DEC-siSod1 (i.e., RD-13115), and DEC-siPpig (i.e., RD-14672) were transfected into C2C12 cells at the indicated concentrations (i.e., 0.01 nM, 0.1 nM, and 1 nM) for 24 hours. Mock treatment was performed in the absence of oligonucleotides. RD-16381 was transfected as a nonspecific DEC control. Combination treatments (i.e., RD-13115+RD-14672) and combination treatment controls (i.e., RD-16381+RD-13115, RD-16381+RD-14672) were also transfected into C2C12 cells at the indicated concentrations (i.e., 0.01 nM, 0.1 nM, and 1 nM) for 24 hours. Figure 18A Shown are the remaining mouse Sod1 mRNA levels quantified by RT-qPCR using gene-specific primer sets in each PCR reaction. Figure 18B Residual mouse Ppig mRNA levels quantified by RT-qPCR using gene-specific primer sets in each PCR reaction are shown. Mouse Rpl13a was amplified as an internal control for normalization of expression data. Data represent the mean expression levels of Sod1 and Ppig relative to mock treatment after normalization to Rpl13a (mean ± SEM of duplicate transfected wells).

[0035] Figure 19Shown is the knockdown activity of "siRNA-siRNA" DEC-DAO structures targeting two different mouse genes (Sod1 and Ppig) on ​​mouse Sod1 and mouse Ppig expression in adult C57BL / 6J mice. The indicated DEC-DAO conjugates with an L21 linker (i.e., RD-16942), DEC-siSod1 (i.e., RD-13115), and DEC-siPpig (i.e., RD-14672) were administered to C57BL / 6J mice at 10 mg / kg by IV injection. The combination treatments (i.e., RD-13115+RD-14672) were administered by IV injection at 10 mg / kg. Saline alone was used as a vehicle control to establish baseline expression. Residual mouse Sod1 mRNA was quantified by RT-qPCR using gene-specific primer sets in peripheral (i.e., heart, liver, kidney, adipose tissue, diaphragm), vascular (i.e., thoracic aorta with veins), and skeletal muscle (biceps, semitendinosus, platysma, and gluteal) tissues 14 days after administration. Tbp was amplified as an internal control for normalization of expression data. Shown are the mean Sod1 mRNA levels in selected mouse tissues relative to the mRNA levels in the saline group after normalization to Tbp. Data are presented as mean ± SEM of 3-4 mice per group.

[0036] Figures 20A-20B The oligonucleotide concentrations of DEC-saRNA and unconjugated saRNA in the retina and vitreous of adult SD rats after intravitreal (IVT) injection were compared. The indicated DEC-saRNA (i.e., RD-16447) and unconjugated saRNA (i.e., RD-12173) were administered by IV injection at 0.03 mg. Rats were sacrificed 1 hour, 1 day, 3 days, 7 days, 14 days, and 28 days after treatment, and the concentrations of RD-16447 and RD-12173 in the retina and vitreous were quantified by stem-loop RT-qPCRCF using gene-specific primer sets (R1C-OM4-AS-SL-RT, R1C-OM4-AS-SL-F4, and SL-RT-qPCR-Uni-R1, see Table 13). Shown are the mean values ​​of oligonucleotide concentrations for each group (mean ± SEM of 3 animals per group).

[0037] Figure 21Figure 2 shows the in vitro knockdown activity of DEC-siRNA on SOD1 mRNA expression in T98G cells. The indicated DEC-siRNA (i.e., RD-17138) was transfected into T98G cells at 0.1 nM and 1 nM. RD-11566 was transfected and served as a nonspecific double-stranded control. Mock treatment was performed in the absence of oligonucleotides. After RNA isolation and RT reaction, Sod1 mRNA levels were quantified by RT-qPCR using gene-specific primer sets. B2M was amplified as an internal control for normalization of expression data. Shown are the average values ​​of the remaining SOD1 mRNA in the cells relative to mock treatment after normalization to B2M (mean ± SEM of two replicate wells). DETAILED DESCRIPTION

[0038] Compared with the oligonucleotide delivery technology of prior art, the oligonucleotide delivery agent of new development can be delivered to the above-mentioned target tissue more effectively by the oligonucleotide of required amount or higher level, and therefore can improve biological activity and pharmacological properties (for example, biodistribution, bioavailability, pharmacokinetics, activity, effectiveness etc.).In some embodiments, the improvement of biological activity property can make cellular uptake improve, effectiveness is higher and duration / half-life is longer.In some embodiments, the improvement of pharmacological property can also obtain lower toxicity, lower dosage, lower frequency of administration and less undesirable immune response.In some embodiments, oligonucleotide delivery agent of the present disclosure relates to simpler synthesis process, therefore has better processability in manufacturing. In some embodiments, the oligonucleotide delivery agents of the present disclosure have the inherent pharmacological properties of free benzimidazole or benzimidazole derivatives, which target proton pumps (as reversible and irreversible proton pump inhibitors, PPIs), dopamine receptors (DRDs), angiotensin II type 1 receptors (AT1), histamine receptors (HRHs), dual-specificity mitogen-activated protein kinases (MEKs) and / or cyclin-dependent kinases (CDKs), etc. In some embodiments, the inherent pharmacological properties enable the oligonucleotide delivery agents of the present disclosure to be potentially used in medicine, including peptic ulcers, hypertension, schizophrenia, parasitic infections, bacterial infections, viral infections, cancer, etc.

[0039] In some embodiments, the newly developed oligonucleotide delivery agents disclosed herein can promote the delivery of an effective amount of oligonucleotides to achieve function in target tissues or cells, for example, in the central nervous system (for example, brain and spinal cord), liver, lungs, kidneys, intestines, pancreas, gall bladder, heart, lymph nodes, spleen, stomach, bladder, muscle and skeleton. In some embodiments, compared with the technology of the prior art, the regulatory activity of oligonucleotide delivery agents, such as up-regulating or down-regulating the expression of target genes in cells, can be improved. Therefore, according to the discovery provided herein, it will be understood by those skilled in the art that the use of oligonucleotide delivery agents as described herein can promote therapeutic oligonucleotides to have improved biodistribution in various targets as described above or cells, to prevent, treat and / or delay the onset of various diseases, obstacles and / or illnesses.

[0040] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. In addition, all publications, patent applications, patents and other references mentioned herein are incorporated by reference.

[0041] As disclosed herein, terms such as "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0042] As disclosed herein, the terms "approximately," "about," "substantially," and similar terms are intended to have the broadest meaning consistent with commonly accepted usage by one of ordinary skill in the art to which the presently disclosed subject matter pertains.

[0043] As disclosed herein, "and / or" means "and, or as an alternative." If any numerical range is given, the range includes any number within that range (including the upper and lower values), and also includes any subrange within that range. For example, a range from 1 to 3 may include any of the values ​​1, 2, and 3, as well as subranges from 1 to 2 and from 2 to 3.

[0044] The terms "oligonucleotide," "polynucleotide," or "oligomer" are used interchangeably and refer to a polymer of nucleotides, including but not limited to single-stranded, double-stranded, or partially double-stranded nucleic acid molecules of DNA, RNA, or DNA / RNA hybrids, oligonucleotide chains containing regular and irregular alternating deoxyribose and ribose moieties, as well as modified and naturally or non-naturally occurring frameworks for such oligonucleotides. In one embodiment, the oligonucleotide can be selected from antisense oligonucleotides (ASOs), antisense RNAs, short interfering RNAs (siRNAs), microRNAs (miRNAs), small activating RNAs (saRNAs), dsRNAs, and small guide RNAs (sgRNAs).

[0045] As used herein, the terms "oligonucleotide chain," "chain," and "oligonucleotide sequence" are used interchangeably and are general terms referring to short nucleotide sequences having less than 50 bases, e.g., less than 45, less than 40, less than 35 bases, e.g., 2-50 bases, or 5-45 bases, or 10-40 bases, or 15-35 bases, or 0-30 bases, including nucleotides in deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). In some non-limiting examples, the chain can be any length from 5 to 50 nucleotides, from 10 to 40 nucleotides, from 15 to 35 nucleotides, from 18 to 30 nucleotides, or from 20 to 25 nucleotides.

[0046] The term "target gene" as used herein may refer to a nucleic acid sequence, a transgenic, a viral or bacterial sequence, a chromosomal or extrachromosomal gene that is naturally present in an organism and / or that can be transiently or stably transfected or incorporated into a cell and / or its chromatin. The target gene may be a protein-coding gene or a non-protein-coding gene (such as a microRNA gene and a long non-coding RNA gene).

[0047] In an embodiment of the present application, a target gene is SOD1. By definition, a "target sequence" refers to a sequence segment that is homologous or complementary to a sense or antisense oligonucleotide of a siRNA or saRNA. For example, in certain embodiments, a SOD1 siRNA is homologous or complementary to a selected target sequence in a human SOD1 transcript.

[0048] As used herein, the term "guide strand" or "G strand" refers to the strand in the small RNA duplex assembled with the Argonaute (AGO) protein. The other strand that is partially or completely complementary to the guide strand is called the "passenger strand" or "P strand". Without being limited to any particular theory, the strand carrying a sequence complementary to the target is the antisense strand, which, if properly designed, will be preferentially selected as the guide strand. In this case, the passenger strand is the sense strand. However, only if the 5' end of the strand is captured within the MID domain of AGO2 can the strand be said to be a guide strand. Therefore, the sense strand can be selected as the guide strand, thereby generating an antisense passenger strand.

[0049] The term "LNA" as used herein refers to a locked nucleic acid in which the 2'-oxygen atom and the 4'-carbon atom are joined by an additional bridge. As used herein, the term "BNA" refers to a 2'-O and 4'-aminoethylene bridged nucleic acid, which may contain a five-membered or six-membered bridge structure with an N-O linkage. The term "PNA" as used herein refers to a nucleic acid mimetic having a pseudopeptide backbone comprising N-(2-aminoethyl)glycine units in which the nucleobases are linked to the glycine nitrogen via a carbonylmethylene linker.

[0050] As used herein, the term "antisense oligonucleotide" or "ASO" refers to a single-stranded oligonucleotide, etc., having, comprising, or consisting of a base sequence, etc., which allows the oligonucleotide, etc. to hybridize with a target molecule (e.g., another nucleic acid, a modified nucleic acid, or a nucleic acid analog), for example, by base pairing, such as Watson-Crick base pairing or non-Watson-Crick base pairing. In some embodiments, the antisense oligonucleotide is completely complementary or almost completely complementary to the target molecule. In some embodiments, any oligonucleotide of any type described herein or known in the art can be used as an antisense oligonucleotide. In various embodiments, antisense oligonucleotides can perform or participate in any of a variety of biological functions, including RNA interference, RNase H-mediated cleavage, exon skipping, prevention of exon skipping, enhancement or prevention of binding of an agent (e.g., a protein, RNA, a protein-RNA complex, or any other molecule) to another nucleic acid, or any other biological function performed by an antisense oligonucleotide, as described herein or known in the art.

[0051] As used herein, the terms "small interfering RNA," "siRNA," and "inhibitory RNA (iRNA)" are used interchangeably and refer to ribonucleic acid molecules that can downregulate, knock down, or silence target gene expression. They can be double-stranded nucleic acid molecules. They interfere with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, thereby preventing translation. siRNA binds primarily to target mRNA in the cytoplasm to downregulate gene expression after transcription through the RNA interference (RNAi) mechanism. siRNA can be designed to target the mRNA sequence of a gene to silence its expression through the RNAi mechanism (e.g., SOD1) for maximizing therapeutic outcomes, for example, for ALS patients. siRNA is a molecule with endogenous RNA bases or chemically modified nucleotides. The modification does not eliminate cellular activity, but rather increases stability and / or increases cellular efficacy. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotides, ribonucleotides containing 2'-OCH3, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, and combinations thereof. In some embodiments, siRNA can have different lengths (for example, 10-200bp) and structures (for example, hairpin, strand / double-strand / partial double-strand, protrusion, incision / gap, mispairing) and process in cells to provide active gene silencing. Double-stranded siRNA can have the same number of nucleotides at each chain (flat end) or asymmetric end (overhang). For example, the overhang of 1-2 nucleotide can be present in sense strand and / or antisense strand, and and be present in 5 ' end and / or 3 ' end of given chain. The length of siRNA molecule is generally about 10 to about 60, about 10 to about 50, about 15 to about 30, about 17 to about 29, about 18 to about 28, about 19 to about 27, about 20 to about 26, about 21 to about 25 and about 22 to about 24 base pairs, generally about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 23, about 25, about 30, about 40 or about 50 base pairs. Furthermore, the terms "small interfering RNA," "silencing RNA," and "siRNA" also encompass nucleic acids other than ribonucleotides, including but not limited to modified nucleotides or analogs.

[0052] As used herein, the terms “small activating RNA,” “saRNA,” and “small activating ribonucleic acid” are used interchangeably and refer to ribonucleic acid molecules that can upregulate the expression of a target gene. It can be a double-stranded nucleic acid molecule consisting of a first nucleic acid chain and a second nucleic acid chain, wherein the first nucleic acid chain contains a ribonucleotide sequence with sequence homology to a target gene non-coding nucleic acid sequence (such as a promoter and an enhancer), and the second nucleic acid chain contains a nucleotide sequence complementary to the first chain. saRNA can also be composed of a synthetic or vector-expressed single-stranded RNA molecule that is susceptible to forming a hairpin structure by two complementary regions within the molecule, wherein the first region contains a ribonucleotide sequence with sequence homology to the target sequence of the promoter of the gene, and the ribonucleotide sequence contained in the second region is complementary to the first region. The length of the duplex region of the siRNA molecule is typically about 10 to about 60, about 10 to about 50, about 10 to about 40, about 12 to about 30, about 14 to about 28, about 16 to about 26, about 18 to about 24, and about 20 to about 22 base pairs, typically about 10, about 13, about 15, about 17, about 18, about 19, about 20, about 21, about 22, about 25, about 30, about 40, about 50, or about 60 base pairs. In addition, the terms "small activating RNA," "saRNA," and "small activating ribonucleic acid" also include nucleic acids other than ribonucleotides, including but not limited to modified nucleotides or analogs.

[0053] As used herein, the terms "ODV" and "oligonucleotide delivery vector" are used interchangeably and refer to an oligonucleotide molecule comprising a duplex or double-stranded RNA (e.g., siRNA or saRNA) and a helper oligonucleotide (ACO) covalently linked to the duplex RNA via a linker.

[0054] As used herein, the terms "delivery enhancing compound" and "DEC" are used interchangeably and refer to compounds of the present disclosure.

[0055] As used herein, the terms "DEC-conjugated oligonucleotide" and "DCO" are used interchangeably and refer to at least one moiety derived from DEC attached (e.g., covalently attached) to at least one oligonucleotide. Additionally, the DCO may further include at least one targeting moiety that helps the oligonucleotide target, accumulate, or reach a target site in a cell.

[0056] As used herein, the terms "administration", "parenteral administration", "administration", and "parenteral administration" have the meaning understood in the art, and refer to ordinary enteral administration, topical administration, and especially injection administration, and may include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0057] As used herein, the term "pharmaceutical composition" refers to an active agent optionally formulated with one or more pharmaceutically acceptable carriers and other additives. In some embodiments, the active agent is present in a unit dose that is suitable for administration in a treatment regimen and shows a statistically significant probability of achieving a predetermined therapeutic effect when used in a relevant population. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including those suitable for the following uses: oral administration, for example, soaks (aqueous or non-aqueous solutions or suspensions), tablets, such as those for buccal, sublingual and systemic absorption purposes, pills, powders, granules, pastes, for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection, such as sterile solutions or suspensions or sustained-release formulations; topical application, such as in the form of creams, ointments or controlled-release patches or sprays for administration to the skin, lungs or oral cavity; intravaginal or rectal, such as pessaries, creams or foams; sublingual; ophthalmic; transdermal; or nasal, lung and other mucosal surfaces.

[0058] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose / glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as ethylcellulose, cellulose acetate and sodium carboxymethylcellulose; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other nontoxic, compatible substances used in pharmaceutical formulations.

[0059] As used herein, the terms "subject," "test subject," and related terms used herein refer to any organism to which a compound or composition provided herein is administered according to the present invention, e.g., for experimental, diagnostic, preventive, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals, such as mice, rats, rabbits, non-human primates, and humans; fish; birds; insects; worms, etc.) and plants. In some embodiments, the subject may be suffering from a disease, disorder, and / or condition, and / or be susceptible to a disease, disorder, and / or condition. In some embodiments, the subject is a human or other mammal. In some embodiments, the subject may be male or female. In non-limiting embodiments, the animal is a vertebrate, such as a primate, a rodent, a captive animal, or a prey animal. In non-limiting examples, primates include chimpanzees, crab-eating macaques, spider monkeys, and macaques, such as rhesus macaques. Rodents include mice, rats, groundhogs, ferrets, rabbits, and hamsters. In non-limiting examples, domesticated animals include cattle, horses, pigs, deer, bison, buffalo, feline species such as domestic cats, canine species such as dogs, foxes, wolves, avian species such as chickens, emus, ostriches, and fish such as trout, catfish, and salmon. In certain embodiments of the aspects described herein, the subject is a mammal, such as a primate, such as a human. In non-limiting examples, the mammal can be a human, a non-primate, a mouse, a rat, a dog, a cat, a horse, or a cow, but is not limited to these examples. In some embodiments, mammals other than humans can be advantageously used as subjects to represent animal models of disorders associated with autoimmune diseases or infections. In some embodiments, the methods and compositions described herein can be used to treat domesticated animals and / or pets.

[0060] A "therapeutically effective amount" of a composition is an amount sufficient to achieve the desired therapeutic effect, and therefore does not require a cure or complete remission. In embodiments of the present application, therapeutic efficacy is an improvement in any disease indicator, and a therapeutically effective amount is sufficient to cause clinically significant improvement in symptoms / symptoms in the treated / treated individual. As used herein, the phrases "therapeutically effective amount" and "effective amount" mean sufficient to reduce the clinically significant deficits in activity, function, and response of the treated / treated individual by at least about 15%, preferably at least 50%, more preferably at least 90%, or increase by at least about 50%, at least about 100%, at least about 200%, more preferably at least about 500%. The effective amount may vary according to factors such as the size and weight of the subject, the type of disease, or the specific agent of the present application. For example, the choice of the agent of the present application may affect the composition of the "effective amount". One of ordinary skill in the art will be able to study the factors contained herein and determine the effective amount of the agent of the present application without excessive experimentation.

[0061] The dosage regimen can affect the composition of the effective amount. The medicaments of the present application can be administered to the subject before or after diagnosis of the disease or condition. In addition, several separate doses can be administered daily or sequentially, as well as staggered doses, or the dose can be continuously infused or bolus injected. In addition, the dosage of the agent of the present application can be increased or decreased proportionally according to the urgency of the treatment or prevention situation.

[0062] As used herein, the terms "treat," "treatment," "treatment method," or "therapy" have their meanings generally understood in the medical field and, therefore, do not require a cure or complete remission and include any beneficial or desired clinical outcome. Non-limiting examples of such beneficial or desired clinical outcomes include prolonged survival compared to the expected survival without treatment, alleviation of symptoms including one or more of the following: proximal skeletal muscle weakness and atrophy, inability to sit or walk independently, difficulty swallowing, difficulty breathing, and the like.

[0063] As used herein, "preventing" or "delaying" a disease refers to inhibiting the overall development of the disease.

[0064] The present disclosure is based on the unexpected discovery that compounds having a specific structure comprising a nitrogen-containing five-membered heterocyclic moiety can be directly or indirectly bonded to at least one oligonucleotide to facilitate delivery of the oligonucleotide to a subject, thereby achieving improved regulation of a target gene in vitro and / or in vivo. In one exemplary embodiment, the compounds disclosed herein can significantly enhance the efficiency of oligonucleotide delivery to the liver, in combination with endosomal escape and nuclear translocation designs, without the need for a delivery vector or formulation.

[0065] In exemplary embodiments, the ring portion of the nitrogen-containing five-membered heterocycle may have a core structure as shown in any of the following formulae, wherein all chemical bonds, atoms, and substituents connected to the ring atoms of the core structure are omitted for simplicity:

[0066]

[0067] The core structure shown in the above-mentioned includes different ring atoms, and the fused ring core structure can be electrically neutral or locally charged in the form of, for example, sulfonium or quaternary ammonium. As can be seen, due to the delocalized π electron conjugation effect, one or more unsaturated double bonds in the fused ring core structure may move, and all substituents, including any substituents that are present / non-existent, can change according to the category and valence of each ring atom that substituents are connected. For example, other substituents can be connected to sulfonium or the quaternary ammonium ion that exist as the ring atoms of the fused ring core structure. All of these variations are within the conception of the present disclosure.

[0068] In one embodiment, the compounds of the present disclosure include structures of formula BI, wherein X' is selected from carbon, nitrogen, oxygen, and sulfur; F', G', H', and I' are each independently selected from carbon, nitrogen, oxygen, and sulfur, and each asterisk refers to a site that is optionally directly or indirectly attached to at least one substituent or oligonucleotide.

[0069]

[0070] In one embodiment, the compounds of the present disclosure have a structure represented by Formula AI or Formula AII:

[0071]

[0072] Among them, each independently represent a covalent single or double bond; each occurrence of X is an atom selected from carbon, nitrogen, oxygen, and sulfur; and F, G, H, and I are each independently selected from carbon, nitrogen, oxygen, and sulfur.

[0073] In one embodiment, m is an integer of 1, 2, or 3, n is an integer of 1, 2, or 3, and m+n = 4. In some exemplary embodiments, m=1 and n=3; or m=2 and n=2; or m=3 and n=1.

[0074] In one embodiment, C at each occurrence is either absent or selected from: hydrogen; a halogen atom such as chlorine, chlorine, bromine or iodine; a hydroxyl group; (C1-C 25 )alkyl, such as -(C2-C 22 )alkyl, or -(C2-C 19 )alkyl, or -(C3-C 18 )alkyl, or -(C4-C 16 )alkyl, or -(C6-C 12 )alkyl, or -(C8-C 10 )alkyl; (C1-C 20 )alkoxy, for example, -(C2-C 19 )alkoxy, or -(C3-C 18 )alkoxy, or -(C4-C 16 )alkoxy, or -(C6-C 12 ) alkoxy; halo(C1-C 20 )alkyl, such as halo(C2-C 19 )alkyl, or halogenated (C3-C 18 )alkyl, or halogenated (C4-C 16 )alkyl, or halogenated (C6-C 12 )alkyl, or halogenated (C8-C 10 )alkyl; and halo(C1-C 20 ) alkoxy, such as halo(C1-C20 ) alkoxy, such as halo(C2-C 19 ) alkoxy, or halogenated (C3-C 18 ) alkoxy, or halogenated (C4-C 16 ) alkoxy, or halogenated (C6-C 12 ) alkoxy, or halogenated (C8-C 10 ) alkoxy; wherein, "halo" can be fluorinated, chloro, bromo, iodo or a combination thereof. In one embodiment, in the structure represented by Formula I, each B is connected to any one of F, G, H and I, and C is connected to the remaining F, G, H and I. In one embodiment, B is connected to H and three C are connected to each of F, G and I respectively. In another embodiment, B is connected to G and three C are connected to each of F, H and I respectively. In another embodiment, B is connected to F and three C are connected to each of G, H and I respectively. In another embodiment, B is connected to I and three C are connected to each of F, G and H respectively. In another embodiment, two B are connected to G and H respectively, and two C are connected to each of F and I respectively.

[0075] In one embodiment, B is independently selected at each occurrence from the group consisting of: hydroxy; -C(O)OH; -P(O)2-OH; -P(O)-OH; -P(O)(S)-OH; -CN; -(C1-C 22 )alkyl, such as -(C2-C 20 )alkyl, or -(C3-C 16 )alkyl, or -(C6-C 12 )alkyl; -O-(C1-C 22 )alkyl, such as -O-(C2-C 20 )alkyl, or -O-(C3-C 16 )alkyl, or -O-(C6-C 12 )alkyl; -(C1-C 22 )alkenyl, such as -(C2-C 20 )alkenyl, or -(C3-C 16 )alkenyl, or -(C6-C 12 )alkenyl; -(C1-C 22 )alkylene-OH, for example -(C2-C 20 )alkylene-OH, or -(C3-C 16 )alkylene-OH, or -(C6-C 12 )alkylene-OH; -(C3-C 22 )cycloalkylene-OH, for example -(C5-C 16 )cycloalkylene-OH, or -(C6-C 12)cycloalkylene-OH, or -(C6-C 10 )cycloalkylene-OH; -(C6-C 22 )arylene-OH; -(C6-C 22 )heteroarylene-OH; -(C1-C 22 )alkylene-C(O)OH, for example -(C2-C 18 )alkylene-C(O)OH, or -(C3-C 16 )alkylene-C(O)OH, or -(C6-C 12 )alkylene-C(O)OH;-(C3-C 22 )cycloalkylene-C(O)OH;-(C6-C 22 )arylene-C(O)OH;-(C5-C 22 )heteroarylene-C(O)OH;-OC(O)-(C1-C 22 )alkylene-C(O)NH2, for example -OC(O)-(C2-C 18 )alkylene-C(O)NH2, or -OC(O)-(C3-C 16 )alkylene-C(O)NH2, or -OC(O)-(C6-C 12 )alkylene-C(O)NH2;-(C1-C 22 )alkylene-OC(O)-(C1-C 22 )alkylene-C(O)NH2, for example -(C2-C 18 )alkylene-OC(O)-(C2-C 18 )alkylene-C(O)NH2, or -(C3-C 16 )alkylene-OC(O)-(C3-C 16 )alkylene-C(O)NH2, or -(C6-C 12 )alkylene-OC(O)-(C6-C 12 )alkylene-C(O)NH2;-OC(O)-(C1-C 22 )alkylene-C(O)OH;-(C1-C 22 )alkylene-OC(O)-(C1-C 22 )alkylene-C(O)OH; -C(O)-(C1-C 22 )alkylene-C(O)NH2;-(C1-C 22 )alkylene-C(O)-(C1-C 22 )alkylene-C(O)NH2; -C(O)-NH-(C1-C 22 )alkylene-OH; -C(O)-NH-(C1-C 22)alkylene-C(O)OH;-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)OH;-(C1-C 30 )alkylene-P(O)2-OH;-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, for example -(C2-C 18 )alkylene-OP(-N(C2-C 18 Alkyl)2)-O-(C2-C 18 )alkylene-CN, or -(C3-C 16 )alkylene-OP(-N(C3-C 16 Alkyl)2)-O-(C3-C 16 )alkylene-CN, or -(C6-C 12 )alkylene-OP(-N(C6-C 12 Alkyl)2)-O-(C6-C 12 )alkylene-CN; -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH; -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2;-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH;-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN; -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH; -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH;-C(O)-NH-(C1-C 22)alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2;-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN; -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH; -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH;-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2;-(C1-C 22 )alkylene-P(O)-OH;-(C1-C 22 )alkylene-P(O)(S)-OH and -(C1-C 22 ) alkylene-CN. (C1-C 22 )alkyl or (C1-C 22 ) alkylene groups may each be an alkyl or alkylene group containing 1 to 22 carbon atoms, or 2 to 20 carbon atoms, or 3 to 16 carbon atoms, or 4 to 12 carbon atoms, or 6 to 12 carbon atoms, or 8 to 10 carbon atoms.

[0076] In one embodiment, each of A1, A2 and A3 is either absent or is a substituent independently selected from the following: -H, -OH, -OR 1 、-SH、-(C1-C 25 )alkyl, halo-(C1-C 25 )alkyl, -(C2-C 22 )alkenyl, -(C1-C 22 )alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22)alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )alkylene-COOR 1 、-C(O)OR 1 、-O-(C1-C 22 )alkyl, -S-(C1-C 22 )alkyl, -C(O)-R 1 、-C(O)-(C1-C 22 )alkyl, -OC(O)-(C1-C 22 )alkyl, -OC(O)-R 1 、-(C1-C 22 )alkylene-OC(O)-R 1 、-C(O)-(C1-C 22 )alkylene-OH, -C(O)-(C1-C 22 )alkylene-R 1 、-C(O)-(C1-C 22 )alkylene-NH-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -R 1 、-OC(O)-(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 22 )alkylene-R 1 , -adamantyl, -(C1-C 22 )alkylene-adamantyl, -O-adamantyl, -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-C(O)-(C1-C 22 )alkylene-adamantyl, -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -CH(NH-CO-(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22)alkyl, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl]3, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 ]3, -CH(NH-CO-halogenated(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-(C1-C 22 )alkyl, -C(O)NH-R 1 、-C(O)NR 2 -R 1 、-C(O)NH-(C1-C 22 )alkylene-OH, -C(O)NH-(C1-C 22 )alkylene-COOH, -NH-C(O)-(C1-C 22 )alkyl, -NH-C(O)-R 1 、-NR 2 -C(O)-R 1 、-OP(O)2-OR 1 、-OP(O)(S)-OR 1 、-OP(O)-OR 1 、-NH-R 1 、-NR 2 -R1 、-(C1-C 22 )alkylene-NH-R 1 、-(C1-C 22 )alkylene-NR 2 -R 1 、-C(O)-(C1-C 22 )alkylene-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-C(O)OR 1 、-C(O)-(C1-C 22 )alkylene-NH-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -C(O)-R 1 、-(C1-C 22 )alkylene-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzothiazole, wherein when the ring indicated above is substituted, the substituent may include hydroxyl, a halogen atom (e.g., fluorine, chlorine, bromine or iodine), (C1-C 16 )alkyl, (C1-C 12 ) alkoxy; and a substituent represented by formula III:

[0077]

[0078] In one embodiment, Y is selected from carbon, nitrogen, oxygen, and sulfur; and each of P, Q, S, and T is independently selected from carbon, nitrogen, oxygen, and sulfur; and the asterisk refers to the position at which the substituent represented by Formula III is attached to the structure represented by Formula I or Formula II;

[0079] In one embodiment, R 3 、R 4 and R 5 Each of the or does not exist, or is a substituent independently selected from the group consisting of: -H, -OH, -OR 1 、-SH、-(C1-C 25 )alkyl, halo-(C1-C 25 )alkyl, -(C2-C 22 )alkenyl, -(C1-C 22 )alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22)alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )alkylene-COOR 1 、-C(O)OR 1 、-O-(C1-C 22 )alkyl, -S-(C1-C 22 )alkyl, -C(O)-R 1 、-C(O)-(C1-C 22 )alkyl, -OC(O)-(C1-C 22 )alkyl, -OC(O)-R 1 、-(C1-C 22 )alkylene-OC(O)-R 1 、-C(O)-(C1-C 22 )alkylene-OH, -C(O)-(C1-C 22 )alkylene-R 1 、-C(O)-(C1-C 22 )alkylene-NH-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -R 1 、-OC(O)-(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 22 )alkylene-R 1 , -adamantyl, -(C1-C 22 )alkylene-adamantyl, -O-adamantyl, -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-C(O)-(C1-C 22 )alkylene-adamantyl, -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -CH(NH-CO-(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl]3, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 ]3, -CH(NH-CO-halogenated(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-(C1-C 22 )alkyl, -C(O)NH-R 1 、-C(O)NR 2 -R 1 、-C(O)NH-(C1-C 22 )alkylene-OH, -C(O)NH-(C1-C 22 )alkylene-COOH, -NH-C(O)-(C1-C 22 )alkyl, -NH-C(O)-R 1 、-NR 2 -C(O)-R 1 、-OP(O)2-OR 1 、-OP(O)(S)-OR 1 、-OP(O)-OR 1 、-NH-R 1 、-NR 2 -R 1 、-(C1-C 22 )alkylene-NH-R 1、-(C1-C 22 )alkylene-NR 2 -R 1 、-C(O)-(C1-C 22 )alkylene-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-C(O)OR 1 、-C(O)-(C1-C 22 )alkylene-NH-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -C(O)-R 1 、-(C1-C 22 )alkylene-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22)alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22)alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole and substituted or unsubstituted benzothiazole, wherein, when the ring indicated above is substituted, the substituent may include hydroxyl, halogen atoms (e.g., fluorine, chlorine, bromine or iodine), (C1-C 16 )alkyl, (C1-C 12 )alkoxy.

[0080] In one embodiment, R 7 Each occurrence is connected to any one of P, Q, S and T and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 )alkyl and halo(C1-C 20 )alkoxy.

[0081] In one embodiment, M is an integer of 0, 1, 2 or 3.

[0082] In one embodiment, R 6 is connected to any one of P, Q, S and T, and is selected from a direct bond, -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-O-, -O-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22)alkylene-, -(C1-C 22 )alkylene-C(O)-, -C(O)-O-(C1-C 22 )alkylene-, -(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-OC(O)-, -C(O)-NH-(C1-C 22 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-O-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-O-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-C(O)-N((C1-C 22 )alkyl)-, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 22 )alkylene-、-NH-C(O)-(C1-C 22)alkylene-C(O)-O-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-O-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-、-N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-O-, -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-、-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-、-N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-N((C1-C 22 )alkyl)-C(O)-, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-P(O)2-O-, -(C1-C 22 )alkylene-OP(O)2-O-, -(C3-C 22 )cycloalkylene-, -(C3-C 22 )cycloalkylene-O-, -O-(C3-C 22 )cycloalkylene-, -(C6-C 22 )arylene-、-(C6-C 22 )arylene-O-, -O-(C6-C 22 )arylene-、-(C6-C 22 ) arylene-NH-, -NH-(C6-C 22 )arylene-、-C(O)-(C6-C 22 )arylene-、-(C6-C 22)arylene-C(O)-, -C(O)-O-(C6-C 22 )arylene-、-(C6-C 22 )arylene-C(O)-O-, -C(O)-NH-(C6-C 22 )arylene- and -C(O)-NH-(C6-C 22 )arylene-C(O)-O-.

[0083] In one embodiment, R 1 independently selected at each occurrence from hydrogen, hydroxy, -(C1-C 22 )alkyl, -(C3-C 22 )cycloalkyl, -(C6-C 22 )aryl, -(C1-C 22 )alkoxy, -(C3-C 22 )cycloalkoxy, -(C6-C 22 )aryloxy, -C(O)-(C1-C 22 )alkyl, -OC(O)(C1-C 22 )alkyl, -C(O)-O-(C1-C 22 )alkyl, -C(O)-(C3-C 22 )cycloalkyl, -OC(O)-(C3-C 22 )cycloalkyl, -C(O)-O-(C3-C 22 )cycloalkyl, -C(O)-(C6-C 22 )aryloxy, -OC(O)-(C6-C 22 )aryloxy, -C(O)-O-(C6-C 22 ) aryloxy, -C(O)-phosphate, phosphodiester, phosphoramidite, saturated fatty acid, unsaturated fatty acid, glucosyl, acetylglucosamine, acetylglucosamine, lipids, PEG, steroids, lipophilic substances, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine and alkaloids.

[0084] In one embodiment, R 2 independently selected at each occurrence from halogen atoms, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C1-C 12 ) alkoxycarbonyl, (C6-C 16 )aryl or (C6-C 16 ) aryloxycarbonyl.

[0085] In one embodiment, A1, A2, A3, B, C, R 1 、R 2 、R 3、R 4 、R 5 and R 7 One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained in the P Protection, terminal protecting group R P Selected from the following group: (C1-C 22 )alkyl, (C1-C 22 ) alkoxy, (C1-C 22 )alkylcarbonyl, (C1-C 22 ) alkoxycarbonyl, (C6-C 22 )aryl, (C6-C 22 ) aryloxy, (C6-C 22 ) arylcarbonyl, (C6-C 22 ) aryloxycarbonyl, tri((C1-C 22 )alkyl)silyl and tri((C1-C 22 )alkoxy)silyl, wherein the protecting group R p (C1-C 22 ) alkyl can be an alkyl group containing 1 to 22 carbon atoms, for example, 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p (C1-C 22 ) The alkoxy group may be an alkoxy group containing 1 to 22 carbon atoms, for example, 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p Contained in (C6-C 22 ) aryl can be an aryl group containing 6 to 22 carbon atoms, for example 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 atoms; and R p Contained in (C6-C 22 ) The aryloxy group can be an aryloxy group containing 6 to 22 carbon atoms, for example 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 atoms.

[0086] In one embodiment, A1, A2 and A3 are not hydrogen at the same time and R 3 、R 4 and R 5 In one exemplary embodiment, X is carbon, and A1, A2 and A 3- In another embodiment, X is nitrogen, A1 and A2 are present and A3 is absent. In another embodiment, X is a positively charged nitrogen (i.e., a quaternary ammonium), and A1, A2 and A3 are present. 3-In another embodiment, X is sulfur or oxygen, A1 and A3 are both absent and A2 is present. In another embodiment, X is a positively charged sulfur (i.e., sulfonium), A2 and A3 are both present and A1 is absent.

[0087] In one embodiment, A1, A2, A3, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 (C1-C 22 )alkyl or (C1-C 22 ) alkylene groups may each be an alkyl or alkylene group containing 1 to 22 carbon atoms, or 2 to 20 carbon atoms, or 3 to 16 carbon atoms, or 4 to 12 carbon atoms, or 6 to 12 carbon atoms, or 8 to 10 carbon atoms.

[0088] In one embodiment, A1, A2, A3, B, C, R 1 、R 2 、R 3 、R 4 、R 5 and R 7 The one or more hydroxyl, carboxyl, amino, nitrile, and phosphate groups contained in the solid material can be connected to a support material selected from the group consisting of silicon dioxide, silica gel, glass, ceramic, polymer, cellulose, and combinations thereof. In some embodiments, the solid material is in the form of beads. The beads can be made of any material, including but not limited to magnetic beads, paramagnetic beads, silica beads, agarose beads, and the like.

[0089] In another embodiment, the compounds of the present disclosure may have a structure represented by any one of Formula AIV to Formula AXIII:

[0090]

[0091] wherein A1, A2, A3, B, C, F, G, H, I, m and n are as defined above.

[0092] In one embodiment, the compounds of the present disclosure have a structure represented by Formula BII

[0093]

[0094] wherein X' is selected from carbon, nitrogen, oxygen, and sulfur; and each of F', G', H', and I' is independently selected from carbon, nitrogen, oxygen, and sulfur.

[0095] In another embodiment, each of A1', A2' and A3' is either absent or a substituent independently selected from the group consisting of: -H, -R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR 1 '、-OC(O)-R 1 ',-C(O)NH-R 1 ',-C(O)NR 2 '-R 1 ',-NH-C(O)-R 1 '、-NR 2 '-C(O)-R 1 ',-OP(O)2-OR 1 ',-OP(O)(S)-OR 1 '、-OP(O)-OR 1 ', -NH-R 1 '、-NR 2 '-R 1 '、-(CH2) r’ -NH-R 1 '、-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -R 1 ', -C(O)-(CH2) r’ -NH-R 1 ', -C(O)-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -C(O)-R 1 ', -C(O)-(CH2) r’ -C(O)OR 1 ', -C(O)-(CH2) r’ -NH-C(O)-R 1 ', -C(O)-(CH2) r’ -NR 2 '-C(O)-R 1 '、-(CH2) r’ -C(O)-R 1 ';-(CH2) r’ -C(O)OR 1 ';-(CH2) r’ -OC(O)-R 1'、-(CH2) r’ -R 1 '、-(CH2) r’ -NH-C(O)-R 1 '、-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NR 2 '-C(O)-(CH2) s’ -R 1 '、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 ')(-C(O)-NH-(CH2) q’ -R 3 '),-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’-NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’((CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)((CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’((CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)((CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3'), or A1' and A2' may be linked together so that A1', A2', the nitrogen atom linked to A1' and the carbon atom linked to A2' together form an unsubstituted or substituted heterocycle. (C1-C 22 ) alkylene groups can each be (C2-C 20 )alkylene, (C3-C 16 )alkylene, (C4-C 14 )alkylene, (C6-C 12 )alkylene, or (C8-C 10 ) alkylene. R 1 ' and R 3 ' are each independently selected from hydrogen; hydroxyl; -(C1-C 30 )alkyl, such as -(C2-C 25 )alkyl, or -(C2-C 22 )alkyl, or -(C3-C 18 )alkyl, or -(C4-C 16 )alkyl, or -(C6-C 12 )alkyl, or -(C8-C 10 )alkyl; -(C3-C 50 )cycloalkyl, for example -(C4-C 40 )cycloalkyl, or -(C5-C 30 )cycloalkyl, or -(C6-C 20 )cycloalkyl, or -(C6-C 16 )cycloalkyl; -(C6-C 50 ) aryl, for example -(C6-C 40 )aryl, or -(C6-C 30 )aryl, or -(C6-C 25 )aryl, or -(C6-C 22 )aryl, or -(C6-C 16 )aryl, or -(C6-C 12 )aryl; -(C1-C 30 )alkoxy, such as -(C2-C 22 )alkoxy, or -(C3-C 20 )alkoxy, or -(C4-C 16 )alkoxy, or -(C6-C 12 )alkoxy; -(C3-C 50 )cycloalkyloxy, for example -(C4-C 40 )cycloalkoxy, or -(C5-C 30 )cycloalkoxy, or -(C6-C 20 )cycloalkoxy, or -(C6-C 16 )cycloalkyloxy; -(C6-C 50) aryloxy, for example -(C6-C 40 )aryloxy, or -(C6-C 30 )aryloxy, or -(C6-C 25 )aryloxy, or -(C6-C 22 )aryloxy, or -(C6-C 16 )aryloxy, or -(C6-C 12 )aryloxy; -C(O)-(C1-C 30 )alkyl, such as -C(O)-(C2-C 22 )alkyl, or -C(O)-(C3-C 18 )alkyl, or -C(O)-(C4-C 16 )alkyl, or -C(O)-(C6-C 12 )alkyl, or -C(O)-(C8-C 10 )alkyl; -OC(O)(C1-C 30 )alkyl, such as -OC(O)(C2-C 22 )alkyl, or -OC(O)(C3-C 18 )alkyl, or -OC(O)(C4-C 16 )alkyl, or -OC(O)(C6-C 12 )alkyl, or -OC(O)(C8-C 10 )alkyl; -C(O)-O-(C1-C 30 )alkyl, such as -C(O)-O-(C2-C 22 )alkyl, or -C(O)-O-(C3-C 18 )alkyl, or -C(O)-O-(C4-C 16 )alkyl, or -C(O)-O-(C6-C 12 )alkyl, or -C(O)-O-(C8-C 10 )alkyl; -C(O)-(C3-C 50 )cycloalkyl, such as -C(O)-(C4-C 40 )cycloalkyl, or -C(O)-(C5-C 30 )cycloalkyl, or -C(O)-(C6-C 20 )cycloalkyl, or -C(O)-(C6-C 16 )cycloalkyl; -OC(O)-(C3-C 50 )cycloalkyl, for example -OC(O)-(C4-C 40 )cycloalkyl, or -OC(O)-(C5-C 30 )cycloalkyl, or -OC(O)-(C6-C 20 )cycloalkyl, or -OC(O)-(C6-C 16)cycloalkyl; -C(O)-O-(C3-C 50 )cycloalkyl, for example -C(O)-O-(C4-C 40 )cycloalkyl, or -C(O)-O-(C5-C 30 )cycloalkyl, or -C(O)-O-(C6-C 20 )cycloalkyl, or -C(O)-O-(C6-C 16 )cycloalkyl; -C(O)-(C6-C 50 ) aryloxy, such as -C(O)-(C6-C 40 )aryloxy, or -C(O)-(C6-C 30 )aryloxy, or -C(O)-(C6-C 25 )aryloxy, or -C(O)-(C6-C 22 )aryloxy, or -C(O)-(C6-C 16 )aryloxy, or -C(O)-(C6-C 12 )aryloxy; -OC(O)-(C6-C 50 ) aryloxy, such as -OC(O)-(C6-C 40 )aryloxy, or -OC(O)-(C6-C 30 )aryloxy, or -OC(O)-(C6-C 25 )aryloxy, or -OC(O)-(C6-C 22 )aryloxy, or -OC(O)-(C6-C 16 )aryloxy, or -OC(O)-(C6-C 12 ) aryloxy; -C(O)-O-(C6-C 50 ) aryloxy, such as -C(O)-O-(C6-C 40 ) aryloxy, or -C(O)-O-(C6-C 30 ) aryloxy, or -C(O)-O-(C6-C 25 ) aryloxy, or -C(O)-O-(C6-C 22 ) aryloxy, or -C(O)-O-(C6-C 16 )aryloxy, or -(C6-C 12 ) aryloxy; -C(O)-phosphate group, phosphodiester group, phosphoramidite group, saturated fatty acid group, unsaturated fatty acid group, glucosyl group, N-acetylglucosyl group, acetylgalactosamine, lipid, PEG, steroid, lipophilic substance, carbohydrate, cholesterol, adamantane, amino acid, peptide, ligand, nucleic acid, oligonucleotide, aptamer, small molecule, antibody, antibody fragment, chloroquine, alkaloid and targeting moiety described herein.

[0096] In some embodiments, one or more of substituents A1 ', A2 ' and A3 ' comprises at least one targeting moiety. The term "targeting moiety" as used herein refers to a molecular part or fragment that acts as a chemical signal, which binds a molecule or complex to a specific region of a cell, tissue or organ. Generally speaking, the targeting moiety changes one or more properties of the oligonucleotide of the present invention, including but not limited to pharmacodynamics, pharmacokinetics, binding, absorption, cellular distribution, cellular uptake, charge and removal. Targeting moieties are routinely used in the art and are directly or through optional linking moieties connected to a parent compound such as an oligomeric compound.

[0097] In some embodiments, the targeting moiety is selected from one or more of the following: part, peptide, nucleic acid, oligonucleotide, fit, small molecule, polyethylene glycol, amino acid, cholesterol, carbohydrate (such as glucose, galactosamine or N-acetylgalactosamine), antibody or antibody fragment and positioning signal, such as nuclear localization signal or mitochondrial positioning signal. In some embodiments, the targeting moiety is selected from: intercalating agent, reporter molecule, polyamine, polyamide, vitamin moiety, polyethylene glycol, thioether, polyether, thiocholesterol, bile acid moiety, folic acid, lipid, fatty acid, phospholipid, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescein, rhodamine, coumarin, fluorophore, luminescent protein and dyestuff. When the targeting moiety is fluorophore, any fluorophore that is considered useful can be used. Non-limiting examples of useful fluorescent proteins include, but are not limited to, GFP, EBFP, Azurite, Cerulean, mCFP, Turquoise, ECFP, mKeima-Red, TagCFP, AmCyan, mTFP, TurboGFP, TagGFP, EGFP, TagYFP, EYFP, Topaz, Venus, mCitrine, TurboYFP, mOrange, TurboRFP, tdTomato, TagRFP, dsRed2, mRFP, mCherry, mPlum, mRaspberry, mScarlet, etc. Examples of luminescent proteins include, but are not limited to, Cypridinia luciferase, Gaussia luciferase, Renilla luciferase, Phontinus luciferase, Luciola luciferase, Pyrophorus luciferase, Phrixothrix luciferase, etc.

[0098] In certain embodiments, the targeting moiety is selected from the group consisting of: a cell penetrating peptide, polyethylene glycol, an alkaloid, a tryptamine, a benzimidazole, a quinolone, an amino acid, cholesterol, a carbohydrate, and a ligand.

[0099] In one embodiment, the targeting moiety is a carbohydrate. The carbohydrate can be selected from monosaccharides, disaccharides, trisaccharides and polysaccharides. In some embodiments, the carbohydrate is a monosaccharide selected from the group consisting of dextrose, glucose, galactose, mannitol, D-mannose, sorbitol and sorbose. In another embodiment, the carbohydrate is a disaccharide selected from the group consisting of lactose, maltose, sucrose and trehalose. In one embodiment, the targeting moiety is a polysaccharide. In one embodiment, the targeting moiety is N-acetylgalactosamine.

[0100] In another embodiment, the targeting moiety is an amino acid. In one embodiment, the amino acid is a hydrophobic amino acid. In some embodiments, the hydrophobic amino acid is selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine. In another embodiment, the amino acid is a polar amino acid. In some embodiments, the amino acid is selected from the group consisting of arginine, histidine, lysine, cysteine, glycine, glutamine, serine, threonine, tyrosine, aspartic acid, and glutamic acid.

[0101] In one embodiment, the targeting moiety is selected from the group consisting of human serum albumin, alpha-lactalbumin, trypsinogen, and polyalanine.

[0102] In certain embodiments, the targeting moiety comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, benzothiadiazide, chlorothiazide, diazepam, Indomethacin, barbiturates, cephalosporins, sulfonamides, antidiabetic drugs, antibacterials, or antibiotics.

[0103] The targeting moieties disclosed herein can be used to increase the uptake, introduction, delivery, and targeted uptake of oligonucleotides into specific cells or tissue types, such as cells or tissues in the central nervous system (e.g., brain and spinal cord), liver, lungs, kidneys, intestines, pancreas, gall bladder, heart, lymph nodes, spleen, stomach, bladder, muscle, and skeleton. Preferred targeting moieties include those specifically provided in the Examples.

[0104] In one embodiment, R 1 ' and R 3 ' is a targeting moiety. In one embodiment, all R 1 ' are the targeting moieties as described above; in another embodiment, all R 3 ' are all targeting moieties as described above; in one embodiment, all R1 ' and R 3 ' are all targeting moieties as described above.

[0105] In some embodiments, in R 1 ' and R 3 'Each of the one or more hydroxyl, carboxyl and amino groups may be optionally protected, for example, by a terminal protecting group R selected from the group consisting of P Protection: (C1-C 22 )alkyl, (C1-C 22 ) alkoxy, (C1-C 22 )alkylcarbonyl, (C1-C 22 ) alkoxycarbonyl, (C6-C 22 )aryl, (C6-C 22 ) aryloxy, (C6-C 22 ) arylcarbonyl, (C6-C 22 ) aryloxycarbonyl, tri((C1-C 22 )alkyl)silyl and tri((C1-C 22 )alkoxy)silyl, wherein the protecting group R p (C1-C 22 ) alkyl can be an alkyl group containing 1 to 22 carbon atoms, for example, an alkyl group containing 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p (C1-C 22 ) The alkoxy group may be an alkoxy group containing 1 to 22 carbon atoms, for example, an alkoxy group containing 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p Contained in (C6-C 22 ) aryl may be an aryl containing 6 to 22 carbon atoms, for example, an aryl containing 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 carbon atoms; and R p Contained in (C6-C 22 ) The aryloxy group can be an aryloxy group containing 6 to 22 carbon atoms, for example, an aryloxy group containing 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 carbon atoms.

[0106] In some embodiments, R 2 '、R 4 '、R 5 ' and R 6 ' are each independently a halogen atom, for example, fluorine, chlorine, bromine or iodine; (C1-C 12)alkyl, such as (C1-C 10 )alkyl, or (C2-C8)alkyl, or (C3-C6)alkyl, or (C4-C5)alkyl; (C1-C 12 ) alkoxy, such as (C1-C 10 )alkoxy, or (C2-C8)alkoxy, or (C3-C6)alkoxy, or (C4-C5)alkoxy; (C1-C 12 ) alkoxycarbonyl, such as (C1-C 10 )alkoxycarbonyl, or (C2-C8)alkoxycarbonyl, or (C3-C6)alkoxycarbonyl, or (C4-C5)alkoxycarbonyl; (C6-C 16 ) aryl, for example -(C6-C 12 )aryl, or -(C6-C 10 ) aryl; or (C6-C 16 ) aryloxycarbonyl, for example (C6-C 12 ) aryloxycarbonyl, or (C6-C 10 )aryloxycarbonyl, or (C6-C8)aryloxycarbonyl.

[0107] In some embodiments, r', s', p' and q' are each an integer from 1 to 22, such as an integer from 2 to 20, or an integer from 3 to 18, an integer from 4 to 16, an integer from 6 to 12, or an integer from 8 to 10.

[0108] In another embodiment, when X' is oxygen, A3' does not exist, and A1', A2' and A3' are not hydrogen at the same time. In an exemplary embodiment, X' is carbon, and A1', A2' and A3' all exist. In another embodiment, X' is nitrogen, and A1' and A2' all exist and A3' does not exist. In another embodiment, X' is positively charged nitrogen (i.e., quaternary ammonium), and A1', A2' and A3' all exist. In another embodiment, X' is sulfur or oxygen, and A1' and A3' all do not exist and A2' exists. In another embodiment, X' is positively charged sulfur (i.e., sulfonium), and A2' and A3' all do not exist and A1' does not exist.

[0109] In another embodiment, each C' is linked to any one of F', G', H' and I' and is either absent or selected from the group consisting of: hydrogen; a halogen atom such as chlorine, chlorine, bromine or iodine; a hydroxyl group; -(C1-C 20 )alkyl, such as -(C2-C 19 )alkyl, or -(C3-C 18 )alkyl, or -(C4-C 16 )alkyl, or -(C6-C 12 )alkyl, or -(C8-C 10)alkyl; -(C1-C 20 )alkoxy, such as -(C2-C 19 )alkoxy, or -(C3-C 18 )alkoxy, or -(C4-C 16 )alkoxy, or -(C6-C 12 ) alkoxy; halo(C1-C 20 )alkyl, such as halo(C2-C 19 )alkyl, or halogenated (C3-C 18 )alkyl, or halogenated (C4-C 16 )alkyl, or halogenated (C6-C 12 )alkyl, or halogenated (C8-C 10 )alkyl; and halo(C1-C 20 ) alkoxy, such as halo(C1-C 20 ) alkoxy, such as halo(C2-C 19 ) alkoxy, or halogenated (C3-C 18 ) alkoxy, or halogenated (C4-C 16 ) alkoxy, or halogenated (C6-C 12 ) alkoxy, or halogenated (C8-C 10 )alkoxy; wherein "halo" can be fluorinated, chlorinated, brominated, iodinated or a combination thereof.

[0110] In one embodiment, m' is an integer of 1, 2, or 3, n' is an integer of 1, 2, or 3, and m'+n'=4. In some exemplary embodiments, m'=1 and n'=3; or m'=2 and n'=2; or m'=3 and n'=1.

[0111] In one embodiment, each B' is connected to any one of F', G', H', and I', while C' is connected to the remaining F', G', H', and I'. In one embodiment, B' is connected to H' and three C's are connected to each of F', G', and I', respectively. In another embodiment, B' is connected to G' and three C's are connected to each of F', H', and I', respectively. In another embodiment, B' is connected to F' and three C's are connected to each of G', H', and I', respectively. In another embodiment, B' is connected to I and three C's are connected to each of F', G', and H', respectively. In another embodiment, two B's are connected to G' and H', respectively, and two C's are connected to each of F' and I', respectively.

[0112] In another embodiment, each B' is independently selected from the group consisting of hydroxy, -C(O)OH, -(C1-C 30)alkoxy, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -H (wherein r' is an integer from 1 to 22), -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -(C1-C 30 )alkylene-C(O)-OH (wherein r' is an integer from 1 to 22), -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-(C6-C 50 )arylene-(C1-C 30 )alkylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50)arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 ) heteroarylene-CN, lipids, PEG, steroids, lipophilic substances, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine, alkaloids, and substituents represented by formula BIII:

[0113]

[0114] wherein Y' is selected from carbon, nitrogen, oxygen, and sulfur; and P', Q', S', and T' are each independently selected from carbon, nitrogen, oxygen, and sulfur. The asterisk indicates the position at which the substituent represented by Formula BIII is attached to any one of F', G', H', and I' of Formula BII.

[0115] In some embodiments, R 7 'Selected from the following group: -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-O-, -O-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-, -NH-(C1-C 30 )alkylene-, -C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-, -C(O)-O-(C1-C 30 )alkylene-, -(C1-C30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-O-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 30 )alkylene-、-NH-C(O)-(C1-C 30 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 30 )alkylene-C(O)-, -NH-C(O)-(C1-C 30 )alkylene-O-, -N((C1-C20 )alkyl)-C(O)-(C1-C 30 )alkylene-、-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-O-, -NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-、-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-、-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -(C1-C 30 )alkylene-P(O)2-O-, -(C1-C 30 )alkylene-OP(O)2-O-, -(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-O-, -O-(C3-C 50 )cycloalkylene-, -(C3-C 50 ) cycloalkylene-NH-, -NH-(C3-C 50 )cycloalkylene-, -C(O)-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-, -C(O)-O-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50)cycloalkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -(C3-C 50 )cycloalkylene-P(O)2-O-, -(C3-C 50 )cycloalkylene-OP(O)2-O-, -(C6-C 50 )arylene-、-(C6-C 50 )arylene-O-, -O-(C6-C 50 )arylene-、-(C6-C 50 ) arylene-NH-, -NH-(C6-C 50 )arylene-、-C(O)-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-, -C(O)-O-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-、-C(O)-NH-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C50 )arylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-、-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-O-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-、-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-, -(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -(C6-C 50 )arylene-P(O)2-O-, -(C6-C 50 )arylene-OP(O)2-O-, -(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-O-, -O-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-NH-, -NH-(C5-C 50 )heteroarylene-、-C(O)-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-C(O)-, -C(O)-O-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-、-C(O)-NH-(C5-C 50)heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-、-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-O-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-、-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-、-(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C6-C 50 )arylene-、-(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -(C5-C 50 )heteroarylene-P(O)2-O- and -(C5-C 50 )heteroarylene-OP(O)2-O-.

[0116] In some embodiments, R 8 ' and R 9 'Each or not exist or are independently selected from the following substituents: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50)cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 )alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C 50 )aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 )alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid. In some embodiments, in R 8 ' and R 9 Each of the one or more hydroxyl, carboxyl, amino and phosphate groups is optionally protected, for example, by a protecting group R as defined herein. P In one embodiment, R 8 ' and R 9 ' can be connected together so that R 8 '、R 9 ', and R 8 'The carbon atom connected to R 9 In another embodiment, when Y' is oxygen, R 9 'Does not exist.

[0117] In one embodiment, each R 10' is connected to any one of P', Q', S' and T', and is independently selected from the following group: hydroxyl, -C(O)OH, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30)alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30)alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 ) heteroarylene-CN, wherein R 10 One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained in ' are optionally replaced by R as defined herein p Protect or connect to support material.

[0118] In one embodiment, B', R 7 '、R 8 '、R 9 ' and R 10 'Contained in -(C1-C 30 )alkylene- may include -(C1-C 28 )alkylene-, or -(C1-C 26 )alkylene-, or -(C1-C 24 )alkylene-, or -(C2-C 22 )alkylene-, or -(C3-C 20 )alkylene-, or -(C4-C 18 )alkylene-, or -(C5-C 17 )alkylene-, or -(C6-C 16 )alkylene-, or -(C7-C 14 )alkylene-, or -(C8-C 12 )alkylene-. In another embodiment, B', R 7 '、R 8 '、R 9 ' and R 10'Contained in -(C3-C 50 )cycloalkylene- may include -(C3-C 40 )cycloalkylene-, or -(C3-C 30 )cycloalkylene-, or -(C3-C 22 )cycloalkylene-, or -(C4-C 20 )cycloalkylene-, or -(C5-C 18 )cycloalkylene-, or -(C6-C 16 )cycloalkylene-, or -(C7-C 14 )cycloalkylene-, or -(C8-C 12 In another embodiment, B', R 7 '、R 8 '、R 9 ' and R 10 'Contained in -(C6-C 50 )arylene- may include -(C6-C 40 )arylene-, or -(C6-C 30 )arylene-, or -(C6-C 22 )arylene-, or -(C6-C 20 )arylene-, or -(C6-C 18 )arylene-, or -(C6-C 16 )arylene-, or -(C6-C 12 In another embodiment, B', R 7 '、R 8 '、R 9 ' and R 10 'Contained in -(C5-C 50 )heteroarylene- may include -(C5-C 40 )heteroarylene-, or-(C5-C 30 )heteroarylene-, or-(C5-C 22 )heteroarylene-, or-(C5-C 18 )heteroarylene-, or -(C6-C 16 )heteroarylene-. In another embodiment, R 8 ' and R 9 ' In each of the substituents, the term "-(C1-C 30 )alkyl" may include -(C2-C 22 )alkyl, or -(C3-C 18 )alkyl, or -(C4-C 16 )alkyl, or -(C6-C 12 )alkyl, or -(C8-C 10 ) alkyl; the term "-(C3-C 50)cycloalkyl" may include -(C4-C 40 )cycloalkyl, or -(C5-C 30 )cycloalkyl, or -(C6-C 20 )cycloalkyl, or -(C6-C 16 )cycloalkyl; the term "-(C6-C 50 ) aryl" may include -(C6-C 40 )aryl, or -(C6-C 30 )aryl, or -(C6-C 25 )aryl, or -(C6-C 22 )aryl, or -(C6-C 16 )aryl, or -(C6-C 12 ) aryl; and the term "-(C6-C 50 ) aryloxy" may include -(C6-C 40 )aryloxy, or -(C6-C 30 )aryloxy, or -(C6-C 25 )aryloxy, or -(C6-C 22 )aryloxy, or -(C6-C 16 )aryloxy, or -(C6-C 12 )aryloxy group.

[0119] In another embodiment, each R 11 ' is connected to any one of P', Q', S' and T', and is either absent or selected from the group consisting of: hydrogen; a hydroxyl group; a halogen atom such as fluorine, chlorine, bromine or iodine; -(C1-C 20 )alkyl, such as -(C2-C 19 )alkyl, or -(C3-C 18 )alkyl, or -(C4-C 16 )alkyl, or -(C6-C 12 )alkyl, or -(C8-C 10 )alkyl; -(C1-C 20 )alkoxy, such as -(C2-C 19 )alkoxy, or -(C3-C 18 )alkoxy, or -(C4-C 16 )alkoxy, or -(C6-C 12 ) alkoxy; (C1-C 20 ) alkoxycarbonyl, such as (C1-C 16 ) alkoxycarbonyl, or (C2-C 12 )alkoxycarbonyl, or (C3-C8)alkoxycarbonyl, or (C4-C6)alkoxycarbonyl; halogenated (C1-C 20 )alkyl, such as halo(C2-C 19)alkyl, or halogenated (C3-C 18 )alkyl, or halogenated (C4-C 16 )alkyl, or halogenated (C6-C 12 )alkyl, or halogenated (C8-C 10 )alkyl; halo(C1-C 20 ) alkoxy, such as halo(C2-C 19 ) alkoxy, or halogenated (C3-C 18 ) alkoxy, or halogenated (C4-C 16 ) alkoxy, or halogenated (C6-C 12 ) alkoxy, or halogenated (C8-C 10 ) alkoxy; and halo(C1-C 20 ) alkoxycarbonyl, such as halo(C2-C 19 ) alkoxycarbonyl, or halogenated (C3-C 18 ) alkoxycarbonyl, or halogenated (C4-C 16 ) alkoxycarbonyl, or halogenated (C6-C 12 ) alkoxycarbonyl, or halogenated (C8-C 10 ) alkoxycarbonyl; wherein, "halo" can be fluorinated, chlorinated, brominated, iodinated or a combination thereof.

[0120] In another embodiment, when Y' is oxygen, R 9 ' is absent. In one exemplary embodiment, Y' is carbon, and R 8 ' and R 9 In another embodiment, Y' is nitrogen, R 8 'Exists and R 9 In another embodiment, Y' is a positively charged nitrogen (ie, a quaternary ammonium), R 8 ' and R 9 In another embodiment, Y' is sulfur or oxygen, and R 9 In another embodiment, Y' is a positively charged sulfur (ie, sulfonium), and R 9 'exist.

[0121] In one embodiment, M' is an integer of 1, 2, or 3, N' is an integer of 1, 2, or 3, and M'+N'=4. In some exemplary embodiments, M'=1 and N'=3; or M'=2 and N'=2; or M'=3 and N'=1.

[0122] In one embodiment, each R 10 ' is connected to any one of P', Q', S' and T', and R 11 Connected to the rest of P', Q', S' and T'. In one embodiment, R10 'Connect to S' and three R 11 ' are connected to each of P', Q' and T' respectively. In another embodiment, R 10 'Connect to Q' and three R's 11 ' are connected to each of P', S' and T' respectively. In another embodiment, R 10 'Connect to P' and three R 11 ' are connected to each of Q', S' and T' respectively. In another embodiment, R 10 'Connect to T' and three R 11 ' are connected to each of P', Q' and S' respectively. In another embodiment, two R 10 ' are connected to Q' and S' respectively, and the two R 11 ' are connected to each of P' and T' respectively.

[0123] In a specific embodiment, in R 8 '、R 9 ' and R 10 One or more hydroxyl, carboxyl, amino and phosphate groups contained in each of ' are optionally protected by a terminal protecting group R selected from the group consisting of P Protection: (C1-C 22 )alkyl, (C1-C 22 ) alkoxy, (C1-C 22 )alkylcarbonyl, (C1-C 22 ) alkoxycarbonyl, (C6-C 22 )aryl, (C6-C 22 ) aryloxy, (C6-C 22 ) arylcarbonyl, (C6-C 22 ) aryloxycarbonyl, tri((C1-C 22 )alkyl)silyl and tri((C1-C 22 )alkoxy)silyl, wherein the protecting group R p (C1-C 22 ) alkyl can be an alkyl group containing 1 to 22 carbon atoms, for example, an alkyl group containing 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p (C1-C 22 ) The alkoxy group may be an alkoxy group containing 1 to 22 carbon atoms, for example, an alkoxy group containing 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p Contained in (C6-C 22) aryl may be an aryl containing 6 to 22 carbon atoms, for example, an aryl containing 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 carbon atoms; and R p Contained in (C6-C 22 ) The aryloxy group can be an aryloxy group containing 6 to 22 carbon atoms, for example, an aryloxy group containing 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 carbon atoms.

[0124] In one exemplary embodiment, the connection to R 10 The support material can be selected from the group consisting of silica, silica gel, glass, ceramic, polymer, cellulose, and combinations thereof. In some embodiments, the solid material is in the form of beads. The beads can be made of any material, including but not limited to magnetic beads, paramagnetic beads, silica beads, agarose beads, and the like.

[0125] In another embodiment, the compounds of the present disclosure may have a structure represented by any one of Formula BIV to Formula BXIV:

[0126]

[0127] Among them, A1', A2', A3', B', C', F', G', H', I', R 7 '、R 8 '、R 10 '、R 11 ', P', Q', S', T', m', n', M' and N' are as defined herein.

[0128] In one embodiment, ring I can be formed by connecting A1' and A2' together, so it can be composed of a nitrogen atom connected to A1', a carbon atom connected to A2', at least a portion of A1' and at least a portion of A2'. Ring I can be a 4-, 5-, 6-, 7-, 8- or 9-membered ring, especially a ring fused to the core structure. For example, ring I can be composed of a nitrogen atom, a carbon atom and 2, 3, 4, 5, 6 or 7 additional ring atoms derived from A1' and A2' from the core structure, wherein each additional ring atom can be selected from carbon, nitrogen, oxygen, sulfur and combinations thereof. In another exemplary embodiment, all of the additional ring atoms can be carbon atoms.

[0129] A4' may be a substituent attached to any atom of Ring I, and A4', A5' and A6' are each independently selected from the group consisting of: -R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR1 ’、-O-C(O)-R 1 ’、-C(O)NH-R 1 ’、-C(O)NR 2 ’-R 1 ’、-NH-C(O)-R 1 ’、-NR 2 ’-C(O)-R 1 ’、-O-P(O)2-O-R 1 ’、-OP(O)(S)-O-R 1 ’、-O-P(O)-O-R 1 ’、-NH-R 1 ’、-NR 2 ’-R 1 ’、-(CH2) r’ -NH-R 1 ’、-(CH2) r’ -NR 2 ’-R 1 ’、-C(O)-(CH2) r’ -R 1 ’、-C(O)-(CH2) r’ -NH-R 1 ’、-C(O)-(CH2) r’ -NR 2 ’-R 1 ’、-C(O)-(CH2) r’ -C(O)-R 1 ’、-C(O)-(CH2) r’ -C(O)O-R 1 ’、-C(O)-(CH2) r’ -NH-C(O)-R 1 ’、-C(O)-(CH2) r’ -NR 2 ’-C(O)-R 1 ’、-(CH2) r’ -C(O)-R 1 ’;-(CH2) r’ -C(O)O-R 1 ’;-(CH2) r’ -O-C(O)-R 1 ’、-(CH2) r’ -R 1 ’、-(CH2) r’ -NH-C(O)-R 1 ’、-(CH2) r’ -NH-C(O)-(CH2) s’ -R1 ’、-(CH2) r’ -NR 2 ’-C(O)-(CH2) s’ -R 1 ’、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NR 6 ’-C(O)-(CH2) q’-R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '); where R 1 '、R 2 '、R 3 '、R 4 '、R 5 '、R 6 Each of ', r', s', p' and q' is as defined herein.

[0130] In one embodiment, ring II can be obtained by replacing R 8 ' and R 9 ' connected together to form, so it can be connected to R 9 ' nitrogen atom, connected to R 8 ' carbon atoms, at least some of the R 8 ' and at least part of R 9 '. Ring II can be a 4-, 5-, 6-, 7-, 8- or 9-membered ring, especially a ring fused to the core structure of substituent B'. For example, ring II can be composed of a nitrogen atom, a carbon atom and 2, 3, 4, 5, 6 or 7 atoms derived from the core structure of substituent B'. 8 ' and R 9 ' additional ring atoms, wherein each additional ring atom may be selected from carbon, nitrogen, oxygen, sulfur and combinations thereof. In another exemplary embodiment, all additional ring atoms may be carbon atoms.

[0131] In one embodiment, R 12 ' connected to any atom of ring II and selected from the group consisting of: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30)alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 )alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C 50 )aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 )alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid; wherein R 12 Each of the -(C1-C 30 )alkyl groups may include -(C2-C 22 )alkyl, or -(C3-C 18 )alkyl, or -(C4-C 16 )alkyl, or -(C6-C 12 )alkyl, or -(C8-C 10 )alkyl; wherein R 12 Each of the -(C3-C 50 )cycloalkyl may include -(C4-C 40)cycloalkyl, or -(C5-C 30 )cycloalkyl, or -(C6-C 20 )cycloalkyl, or -(C6-C 16 )cycloalkyl; R 12 Each of the -(C6-C 50 ) aryl groups may include -(C6-C 40 )aryl, or -(C6-C 30 )aryl, or -(C6-C 25 )aryl, or -(C6-C 22 )aryl, or -(C6-C 16 )aryl, or -(C6-C 12 ) aryl; R 12 Each of the -(C1-C 30 ) alkoxy may include -(C2-C 22 )alkoxy, or -(C3-C 20 )alkoxy, or -(C4-C 16 )alkoxy, or -(C6-C 12 ) alkoxy; R 12 Each of the -(C3-C 50 )cycloalkoxy may include -(C4-C 40 )cycloalkoxy, or -(C5-C 30 )cycloalkoxy, or -(C6-C 20 )cycloalkoxy, or -(C6-C 16 )cycloalkoxy; R 12 Each of the -(C6-C 50 )Aryloxy may include -(C6-C 40 )aryloxy, or -(C6-C 30 )aryloxy, or -(C6-C 25 )aryloxy, or -(C6-C 22 )aryloxy, or -(C6-C 16 )aryloxy, or -(C6-C 12 ) aryloxy; R 12 Each of the -(C1-C 30 )alkylene- may include -(C1-C 28 )alkylene-, or -(C1-C 26 )alkylene-, or -(C1-C 24 )alkylene-, or -(C2-C 22 )alkylene-, or -(C3-C 20 )alkylene-, or -(C4-C 18 )alkylene-, or -(C5-C 17)alkylene-, or -(C6-C 16 )alkylene-, or -(C7-C 14 )alkylene-, or -(C8-C 12 )alkylene-; R 12 'Contained in -(C3-C 50 )cycloalkylene- may include -(C3-C 40 )cycloalkylene-, or -(C3-C 30 )cycloalkylene-, or -(C3-C 22 )cycloalkylene-, or -(C4-C 20 )cycloalkylene-, or -(C5-C 18 )cycloalkylene-, or -(C6-C 16 )cycloalkylene-, or -(C7-C 14 )cycloalkylene-, or -(C8-C 12 )cycloalkylene-; R 12 'Contained in -(C6-C 50 )arylene- may include -(C6-C 40 )arylene-, or -(C6-C 30 )arylene-, or -(C6-C 22 )arylene-, or -(C6-C 20 )arylene-, or -(C6-C 18 )arylene-, or -(C6-C 16 )arylene-, or -(C6-C 12 )arylene-.

[0132] In one embodiment, R 12 One or more hydroxyl, carboxyl, amino and phosphate groups contained therein are optionally protected, for example, by a terminal protecting group R selected from the group consisting of P Protection: (C1-C 22 )alkyl, (C1-C 22 ) alkoxy, (C1-C 22 )alkylcarbonyl, (C1-C 22 ) alkoxycarbonyl, (C6-C 22 )aryl, (C6-C 22 ) aryloxy, (C6-C 22 ) arylcarbonyl, (C6-C 22 ) aryloxycarbonyl, tri((C1-C 22 )alkyl)silyl and tri((C1-C 22 )alkoxy)silyl, wherein the protecting group R p (C1-C 22) alkyl can be an alkyl group containing 1 to 22 carbon atoms, for example, an alkyl group containing 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p (C1-C 22 ) The alkoxy group may be an alkoxy group containing 1 to 22 carbon atoms, for example, an alkoxy group containing 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 6 to 12 carbon atoms; R p Contained in (C6-C 22 ) aryl may be an aryl containing 6 to 22 carbon atoms, for example, an aryl containing 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 carbon atoms; and R p Contained in (C6-C 22 ) The aryloxy group may be an aryloxy group containing 6 to 22 carbon atoms, for example, an aryloxy group containing 6 to 20 carbon atoms, or 6 to 18 carbon atoms, or 6 to 16 carbon atoms, or 6 to 12 carbon atoms, or 8-10 carbon atoms. In a specific embodiment, the protecting group R P The group may be selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butyldimethylsilyl (TBS), 4,4'-dimethoxytrityl (DMTr), tert-butyloxycarbonyl (Boc), benzyl (Bn) and benzyloxy (BnO).

[0133] In one embodiment, the compound of formula BI or formula BII may have one or more chiral centers, and each chiral center may independently be R chiral, S chiral, meso or racemic. For example, when one or more of A1', A2' and A3' is selected from -CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 ')(-C(O)-NH-(CH2) q’ -R 3 '),-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -NH-C(O)-(CH2)s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’((CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)((CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’((CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)((CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R3 '), wherein the central carbon atom contained therein may be a chiral center.

[0134] In some embodiments, the compounds of the present disclosure have a structure represented by any one of Formula BXV to Formula BXX:

[0135]

[0136]

[0137] Among them, A1', A2', B', R 7 '、R 8 ' and R 10 'As defined herein.

[0138] In another embodiment, when any one or more of the above-mentioned substituents contain at least one double bond, the double bond and the atom or moiety attached to the double bond can each be in the E form or the Z form.

[0139] In an exemplary embodiment, the compound of the present disclosure has a structure represented by the following molecular formula:

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] in represents a supporting material as defined above.

[0157] Another embodiment of the present disclosure provides an oligonucleotide delivery agent comprising a DEC compound disclosed herein and at least one oligonucleotide. It is fully understood that when DEC is directly linked to an oligonucleotide or is linked to an oligonucleotide via at least one linking moiety, one or more terminal atoms (e.g., hydrogen, halogen, nitrogen, oxygen, sulfur, phosphorus, etc.) or terminal groups (e.g., hydroxyl, amino, ester, ether, acyl, etc.) of DEC can be detached to provide an active site that can be linked to the linking moiety or the oligonucleotide.

[0158] In one embodiment, when a linking moiety is present, the linking moiety may be selected from the group consisting of: -O-, -S-, -C(O)-, -NH-, -N((C1-C 12 )alkyl)-, -N((C1-C 12 )Alkyl)-C(O)-O-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -C(O)-NH-, -OP(O)2O-, -P(O)(O - )O-, -OP(O)O-, -OP(O)(S)O-, -OS(O)2-O-, -S(O)2-O-, -S(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-C(O)-, -(C1-C 22 )alkylene-C(O)-O-, -C(O)-(C1-C 22 )alkylene-、-NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-C(O)-, -C(O)-(C1-C 22 )alkylene-C(O)-, -NH-(C1-C 22 )alkylene-NH-, -C(O)-(C1-C 22)alkylene-C(O)O-, -OC(O)-(C1-C 22 )alkylene-C(O)-O-, -C(O)-O-(C1-C 22 )alkylene-OC(O)-, -C(O)-(C1-C 22 )alkylene-NH-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-NH-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-OP(O)2O-, -(C1-C 22 )alkylene-OP(O)(O - )O-、-(C1-C 22 )alkylene-OP(O)(O - )O-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-OP(O)O-, -(C1-C 22 )alkylene-OP(O)(S)O-, -(C1-C 22 )alkylene-OS(O)2-O-, -(C1-C 22 )alkylene-S(O)2-O-, -(C1-C 22 )alkylene-S(O)-O-, -OP(O)2-O-(C1-C 22 )alkylene-OP(O)2O-, -OP(O)-O-(C1-C 22 )alkylene-OP(O)O-, -OP(O)(S)O-(C1-C 22 )alkylene-OP(O)(S)O-, -OS(O)2-O-(C1-C 22 )alkylene-OS(O)2-O-, -S(O)2-O-(C1-C 22 )alkylene-S(O)2-O- and -OS(O)-(C1-C 22 )alkylene-S(O)-O-; wherein the connecting portion contains -(C1-C 22 ) The alkylene group can be an alkylene group containing 1 to 22 carbon atoms, for example, an alkylene group containing 2 to 20 carbon atoms, or 3 to 18 carbon atoms, or 4 to 16 carbon atoms, or 5 to 12 carbon atoms, or 6 to 10 carbon atoms. In one embodiment, when the linking moiety is a direct bond, the delivery enhancing compound is directly linked to the oligonucleotide.

[0159] Another embodiment of the present disclosure provides a delivery enhancing compound (DEC)-coupled oligonucleotide comprising a structure represented by Formula AA, which can more effectively deliver the oligonucleotide in vitro and in vivo.

[0160]

[0161] The "delivery enhancing compound portion" shown in Formula AA is derived from any of the above-described DEC compounds of the present disclosure. It will be understood that one or more terminal atoms (e.g., hydrogen, halogen, nitrogen, oxygen, sulfur, phosphorus, etc.) or terminal groups (e.g., hydroxyl, amino, ester, ether, acyl, etc.) of the compounds of the present disclosure have been removed to provide an active site that can be attached to a targeting moiety or oligonucleotide, and thus, the "delivery enhancing compound" of Formula BA can be considered to be the portion obtained by subtracting the one or more terminal atoms or terminal groups from the compounds of the present disclosure.

[0162] In one embodiment of the present disclosure, the delivery enhancing compound (DEC)-conjugated oligonucleotide has a structure represented by Formula BB:

[0163]

[0164] Wherein, A1 ', A2 ', A3 ', X ', F ', G ', H ', I ', C ', m ' and n ' are as defined above separately. In one embodiment, at least one of A1 ', A2 ' and A3 ' comprises one or more targeting moieties, and DEC is connected to at least one oligonucleotide through B " group. As mentioned above, B " group can be by removing one or more terminal atoms (for example, hydrogen, halogen, nitrogen, oxygen, sulphur, phosphorus etc.) or one or more terminal groups (for example hydroxyl, amino, ester group, ether group, acyl group etc.) from the B " group comprised in formula BII and obtain.

[0165] In another embodiment of the present disclosure, the delivery enhancing compound (DEC)-conjugated oligonucleotide has a structure represented by Formula BC:

[0166]

[0167] Among them, A1', A2', A3', R 7 '、R 9 '、R 10 '、R 11 ', X', Y', F', G', H', I', C', R', Q', S', T', m', n', M' and N' are each as defined above. In one embodiment, at least one of A1', A2' and A3' comprises one or more targeting moieties, and DEC is activated by R 8 " group is attached to at least one oligonucleotide. As described above, R 8" group can be obtained by selecting R contained in BIII contained in formula BII 8 The group is obtained by removing one or more terminal atoms (eg, hydrogen, halogen, nitrogen, oxygen, sulfur, phosphorus, etc.) or one or more terminal groups (eg, hydroxyl, amino, ester, ether, acyl, etc.).

[0168] In one embodiment of the present disclosure, the delivery enhancing compound (DEC)-conjugated oligonucleotide has a structure represented by any one of Formulas E1 to E15:

[0169]

[0170]

[0171] Among them, A1', A2', R 7 ' and R 10 'Each is as defined above. In one embodiment, at least one of A1' and A2' comprises one or more targeting moieties, or A2' comprises one or more targeting moieties inserted into a member; and DEC is linked to a B" group or R 8 " group is attached to at least one oligonucleotide. As described above, R 8 "The group can be obtained by 8 The group is obtained by removing one or more terminal atoms (for example, hydrogen, halogen, nitrogen, oxygen, sulfur, phosphorus, etc.) or one or more terminal groups (for example, hydroxyl, amino, ester group, ether group, acyl group, etc.), and the B" group can be obtained by removing one or more terminal atoms (for example, hydrogen, halogen, nitrogen, oxygen, sulfur, phosphorus, etc.) or one or more terminal groups (for example, hydroxyl, amino, ester group, ether group, acyl group, etc.) from the B' group.

[0172] In one embodiment, the targeting moiety is included in the molecular structure of the DEC compound, for example, the moieties A1', A2' and A3', preferably R 1 ' or R 3 In another embodiment, the targeting moiety is independent of the DEC compound and is additionally added after or during the synthesis of the DEC compound.

[0173] In one embodiment, the targeting moiety and the delivery enhancing compound moiety can be connected to each other by a first linking moiety. In one embodiment, the delivery enhancing compound moiety and the oligonucleotide can be connected by a second linking moiety. Each of the first linking moiety and the second linking moiety can be selected from the group consisting of a direct bond, -O-, -S-, -C(O)-, -NH-, -N((C-C 12 )alkyl)-, -N((C1-C 12)Alkyl) -C(O)-O-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -C(O)-NH-, -OP(O)2O-, -OP(O)O-, -OP(O)(S)O-, -OS(O)2-O-, -S(O)2-O-, -S(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-C(O)-, -(C1-C 22 )alkylene-C(O)-O-, -C(O)-(C1-C 22 )alkylene-、-NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-C(O)-, -C(O)-(C1-C 22 )alkylene-C(O)-, -NH-(C1-C 22 )alkylene-NH-, -C(O)-(C1-C 22 )alkylene-C(O)O-, -OC(O)-(C1-C 22 )alkylene-C(O)-O-, -C(O)-O-(C1-C 22 )alkylene-OC(O)-, -C(O)-(C1-C 22 )alkylene-NH-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-NH-, -NH-(C1-C 22 )alkylene-OP(O)2O-, -NH-(C1-C 22 )alkylene-CH((C1-C 22 )alkylene-OH)-OP(O)2O-, -NH-(C1-C 22 )alkylene-CH((C1-C 22 )alkylene-OH)-(C1-C 22 )alkylene-OP(O)2O-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22)alkylene-OP(O)2O-, -(C1-C 22 )alkylene-OP(O)O-, -(C1-C 22 )alkylene-OP(O)(S)O-, -(C1-C 22 )alkylene-OS(O)2-O-, -(C1-C 22 )alkylene-S(O)2-O-, -(C1-C 22 )alkylene-S(O)-O-, -OP(O)2-O-(C1-C 22 )alkylene-OP(O)2O-, -OP(O)-O-(C1-C 22 )alkylene-OP(O)O-, -OP(O)(S)O-(C1-C 22 )alkylene-OP(O)(S)O-, -OS(O)2-O-(C1-C 22 )alkylene-OS(O)2-O-, -S(O)2-O-(C1-C 22 )alkylene-S(O)2-O- and -OS(O)-(C1-C 22 )alkylene-S(O)-O-; wherein the connecting portion contains -(C1-C 22 )alkylene-can be-(C1-C 20 )alkylene-, or -(C1-C 18 )alkylene-, or -(C1-C 16 )alkylene-, or -(C2-C 12 )alkylene-, or -(C3-C 10 In one embodiment, in the delivery enhancing compound (DEC) coupled oligonucleotide of formula A, when the linking moiety is a direct bond, the delivery enhancing compound portion is directly linked to the oligonucleotide. In one embodiment, in the delivery enhancing compound (DEC) coupled oligonucleotide of formula BA, when the linking moiety is a direct bond, the targeting moiety is directly linked to the delivery enhancing compound portion.

[0174] The oligonucleotide may include those disclosed above, and in particular may be selected from the group consisting of antisense oligonucleotides (ASOs), antisense RNAs, short interfering RNAs (siRNAs), microRNAs (miRNAs), saRNAs, dsRNAs, scRNAs, sgRNAs or any other oligonucleotide targeting at least one nucleotide sequence.

[0175] All nucleotides of the oligonucleotides described herein can be natural (i.e., not chemically modified) nucleotides or at least one nucleotide can be a chemically modified nucleotide. Non-limiting examples of chemical modifications include one or more of the following combinations:

[0176] 1) Modification of the phosphodiester bonds of nucleotides in oligonucleotide sequences.

[0177] 2) Modify the 2'-OH of the ribose sugar in nucleotides;

[0178] 3) Modify the bases in nucleotides;

[0179] 4) at least one nucleotide in the oligonucleotide sequence is a locked nucleic acid, and

[0180] 5) At least one nucleotide in the oligonucleotide sequence is deoxyribonucleic acid (DNA).

[0181] Chemical modifications of nucleotides or oligonucleotides in the present disclosure are well known to those skilled in the art, and modifications to phosphodiester bonds refer to modifications of oxygen in phosphodiester bonds, including phosphorothioate modifications and boronated phosphate modifications. Modifications disclosed herein stabilize oligonucleotide structures, maintaining high specificity and high affinity for base pairing. Modifications disclosed herein also stabilize nucleic acid structures and maintain their delivery-aiding properties, including bioavailability, biodistribution, and / or cellular uptake of oligonucleotide agents in various tissues, including the prefrontal cortex, cerebellum, spinal cord (e.g., neck, chest, waist), muscle, liver, and kidney.

[0182] In some embodiments, the chemical modification is the replacement of phosphodiester bonds with phosphorothioate (PS) bonds on the backbone of the oligonucleotides disclosed herein. In some embodiments, the oligonucleotides disclosed herein include at least one PS backbone modification in an oligonucleotide bond. In some embodiments, the oligonucleotides include at least 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 24, 28, 32, or 40 PS backbone modifications in an oligonucleotide bond.

[0183] In some embodiments, the nucleotides or oligonucleotides of the present disclosure include at least one chemically modified nucleotide, which is modified at the 2'-OH position in the pentose of the nucleotide, i.e., certain substituents are introduced at the hydroxyl position of the ribose, such as 2'-fluoro modification, 2'-oxymethyl modification, 2'-oxyethylenemethoxy modification, 2,4'-dinitrophenol modification, locked nucleic acid (LNA), 2'-amino modification or 2'-deoxy modification, e.g., 2'-deoxy-2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides.

[0184] In some embodiments, the nucleotides or oligonucleotides of the present application include at least one chemically modified nucleotide, which is modified at the base of the nucleotide, for example, 5'-bromouracil modification, 5'-iodouracil modification, N-methyluracil modification, or 2,6-diaminopurine modification.

[0185] In some embodiments, the chemical modification of the nucleotides or oligonucleotides of the present application is the addition of an (E)-vinylphosphonate moiety to the 5' end of the sense or antisense sequence. In some embodiments, the chemical modification of at least one chemically modified nucleotide is the addition of a 5'-methylcytosine moiety to the 5' end of the sense or antisense sequence. The oligonucleotides used in the present disclosure can be commercially available from different suppliers or synthesized on a laboratory scale or industrial scale. In an exemplary embodiment, the oligonucleotides can be synthesized using a commercial synthesizer or a specially customized synthesizer, such as a K&A DNA synthesizer purchased from K&A Laborgeraete of Schaffheim, Germany, using a common synthesis procedure, such as solid phase synthesis technology, which comprises the following steps: batches of raw materials (e.g., phosphoramidite monomers including various linkers and conjugates) are sequentially added to a solid support known in the art, and a preparation cycle consisting of four chemical reactions, detritylation, coupling, oxidation / thiolation, and capping, is performed for each base addition, thereby producing the desired full-length oligonucleotide.

[0186] The oligonucleotide delivery agent may comprise one, two, three, four, five, six or even more oligonucleotides, which are linked to one, two, three, four, five, six or even more delivery enhancing compounds via one, two, three, four, five, six or even more linking moieties, respectively. For example, the oligonucleotide delivery agent may have a structure represented by any one of the following formulae AAI to AAXXIV:

[0187]

[0188]

[0189] Wherein, L represents a linking moiety, ☆ represents an oligonucleotide delivery enhancing compound, and the symbol represents a double-stranded oligonucleotide, each end of which is independently symmetrical or asymmetrical; represents a single-stranded oligonucleotide, and a, b and c are each independently an integer from 1 to 50, such as an integer from 2 to 45, or an integer from 3 to 40, or an integer from 4 to 35, or an integer from 5 to 30, or an integer from 10 to 20. Each linking moiety, as well as the delivery enhancing compound, can be linked to the double-stranded or single-stranded oligonucleotide at the 3' end, the 5' end or any intermediate position, such as the nth nucleotide.

[0190] In one embodiment, one or more of the substituents A1, A2, A3, B, C, A1', A2', A3', B' and C' of the delivery enhancing compound can be linked to a linking moiety or to an oligonucleotide (when the linking moiety is a direct bond). For example, A1, A2, A3, B, A1', A2', A3', R 8 '、R 12 ' and B', preferably A2, A2', B, B', R 8 ' or R 12 'Connected to the linking moiety or oligonucleotide. Without being limited to any theory, one or more of the terminal groups in the above substituents (e.g., DMTrO-C1-C 22 Alkylene- or -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN) can be dead-end or hydrolyzed to expose the active site (e.g. -(C1-C 22 )alkylene-OH group), which is then connected by a linking moiety (e.g., -P(O)(O - )O-) is connected to the oligonucleotide. For example, the structure of an exemplary oligonucleotide delivery agent includes O1 to O25 as shown below:

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198] Where J represents O or S.

[0199] It can be seen that in all structures O1 to O25, the delivery enhancing compound is linked to the linker, e.g., –OP(O)2O-(–P(O)(O - )-O-), linked to a double-stranded RNA (dsRNA) duplex structure (including but not limited to siRNA and saRNA) and / or a single-stranded antisense oligonucleotide (ASO), connected at the 3' end or the 5' end of the passenger strand, wherein P is the passenger strand and G is the guide strand; and an electronic first rearrangement may also occur.

[0200] In some embodiments, at least one hydrogen atom (i.e., H) contained in the delivery enhancing compound, delivery enhancing compound portion, linking portion, and / or oligonucleotide is substituted with a deuterium atom (i.e., D). In an exemplary embodiment, at least one of the delivery enhancing compound, delivery enhancing compound portion, linking portion, and oligonucleotide contains 1 to 20 deuterium atoms, e.g., 1 to 15, or 1 to 12, or 1 to 10, or 1 to 8, or 1 to 6, or 1 to 3, or 1 to 2 deuterium atoms. In an exemplary embodiment, 1 mol% to 100 mol%, or 2 mol% to 90 mol%, or 5 mol% to 80 mol%, or 10 mol% to 70 mol%, or 20 mol% to 60 mol%, or 30 mol% to 50 mol%, or 40 mol% to 45 mol% of the hydrogen atoms contained in the delivery enhancing compound, delivery enhancing compound portion, linking portion, and / or oligonucleotide are substituted with deuterium atoms. In another exemplary embodiment, the deuterium substitution rate may be within a numerical range obtained by combining any two of the endpoint values ​​described above.

[0201] Another embodiment of the present disclosure provides a pharmaceutical composition comprising an oligonucleotide delivery agent. In another embodiment, the pharmaceutical composition may comprise one or more additional ingredients, such as a pharmaceutically acceptable carrier, excipient, solvent, diluent, stabilizer, dispersant, buffer, extender, preservative, and combinations thereof.

[0202] Another embodiment of the present disclosure provides a method for regulating the expression of a target gene in vitro or in vivo, the method comprising administering a pharmaceutical composition to a subject, or contacting cells of the subject with the pharmaceutical composition. For example, it is estimated that the oligonucleotide delivery agent and the pharmaceutical composition can be administered to various organs, tissues, and cells, such as the liver, lungs, kidneys, intestines, pancreas, gallbladder, heart, lymph nodes, spleen, stomach, bladder, muscle, bones, and central nervous system (CNS), and regulate the expression of one or more target genes in the cells thereof. DETAILED DESCRIPTION

[0204] In a specific embodiment, the present disclosure provides an oligonucleotide delivery-enhancing compound comprising a nitrogen-containing five-membered heterocyclic moiety and at least one substituent, which can be directly or indirectly linked to the oligonucleotide.

[0205] In another specific embodiment, the oligonucleotide delivery enhancing compound has a structure represented by Formula AI or Formula AII:

[0206]

[0207] Each of these independently represent a covalent single or double bond; X at each occurrence is an atom selected from carbon, nitrogen, oxygen, and sulfur; F, G, H, and I are each independently selected from carbon, nitrogen, oxygen, and sulfur;

[0208] wherein m is an integer of 1, 2, or 3, n is an integer of 1, 2, or 3, and m+n=4;

[0209] wherein C at each occurrence is either absent or selected from the group consisting of: hydrogen, halogen, hydroxyl, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 )alkyl and halo(C1-C 20 ) alkoxy;

[0210] wherein B is independently selected at each occurrence from the group consisting of hydroxy, -C(O)OH, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 22 )alkyl, -(C1-C 22 )alkenyl, -(C1-C 22 )alkylene-OH, -(C3-C 22 )cycloalkylene-OH, -(C6-C 22 )arylene-OH, -(C6-C 22 )heteroarylene-OH, -(C1-C 22 )alkylene-C(O)OH, -(C3-C 22 )cycloalkylene-C(O)OH, -(C6-C 22 )arylene-C(O)OH, -(C5-C 22 )heteroarylene-C(O)OH, -OC(O)-(C1-C 22 )alkylene-C(O)NH2, -(C1-C 22 )alkylene-OC(O)-(C1-C 22 )alkylene-C(O)NH2, -OC(O)-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-OC(O)-(C1-C 22 )alkylene-C(O)OH, -C(O)-(C1-C 22 )alkylene-C(O)NH2, -(C1-C 22 )alkylene-C(O)-(C1-C 22 )alkylene-C(O)NH2, -C(O)-NH-(C1-C 22 )alkylene-OH, -C(O)-NH-(C1-C 22)alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22 )alkylene-CN,

[0211] wherein A1, A2 and A3 are either absent or are independently selected from the following substituents: -H, -OH, -OR 1 、-SH、-(C1-C 25 )alkyl, halo-(C1-C 25 )alkyl, -(C2-C 22 )alkenyl, -(C1-C 22 )alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )alkylene-COOR 1 、-C(O)OR 1 、-O-(C1-C 22 )alkyl, -S-(C1-C 22 )alkyl, -C(O)-R 1 、-C(O)-(C1-C 22 )alkyl, -OC(O)-(C1-C 22 )alkyl, -OC(O)-R 1 、-(C1-C 22 )alkylene-OC(O)-R 1 、-C(O)-(C1-C22 )alkylene-OH, -C(O)-(C1-C 22 )alkylene-R 1 、-C(O)-(C1-C 22 )alkylene-NH-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -R 1 、-OC(O)-(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 22 )alkylene-R 1 , -adamantyl, -(C1-C 22 )alkylene-adamantyl, -O-adamantyl, -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-C(O)-(C1-C 22 )alkylene-adamantyl, -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -CH(NH-CO-(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl]3, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 ]3, -CH(NH-CO-halogenated(C1-C 22 )alkyl)-(C1-C 22)alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-(C1-C 22 )alkyl, -C(O)NH-R 1 、-C(O)NR 2 -R 1 、-C(O)NH-(C1-C 22 )alkylene-OH, -C(O)NH-(C1-C 22 )alkylene-COOH, -NH-C(O)-(C1-C 22 )alkyl, -NH-C(O)-R 1 、-NR 2 -C(O)-R 1 、-OP(O)2-OR 1 、-OP(O)(S)-OR 1 、-OP(O)-OR 1 、-NH-R 1 、-NR 2 -R 1 、-(C1-C 22 )alkylene-NH-R 1 、-(C1-C 22 )alkylene-NR 2 -R 1 、-C(O)-(C1-C 22 )alkylene-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-C(O)OR 1 、-C(O)-(C1-C 22 )alkylene-NH-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -C(O)-R 1 、-(C1-C 22 )alkylene-C(O)-R 1 、-(C1-C22 )alkylene-NH-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22)alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22)alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzothiazole, and substituents represented by Formula AIII:

[0212]

[0213] wherein Y is selected from carbon, nitrogen, oxygen, and sulfur; and each of P, Q, S, and T is independently selected from carbon, nitrogen, oxygen, and sulfur; and the asterisk refers to the position at which the substituent represented by Formula AIII is attached to the structure represented by Formula AI or Formula AII;

[0214] where R 3 、R 4 and R 5 Each of the or does not exist, or is a substituent independently selected from the group consisting of: -H, -OH, -OR 1 、-SH、-(C1-C 25 )alkyl, halo-(C1-C 25 )alkyl, -(C2-C 22 )alkenyl, -(C1-C 22 )alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )alkylene-COOR 1 、-C(O)OR 1 、-O-(C1-C 22 )alkyl, -S-(C1-C 22 )alkyl, -C(O)-R 1 、-C(O)-(C1-C 22 )alkyl, -OC(O)-(C1-C 22 )alkyl, -OC(O)-R 1 、-(C1-C22 )alkylene-OC(O)-R 1 、-C(O)-(C1-C 22 )alkylene-OH, -C(O)-(C1-C 22 )alkylene-R 1 、-C(O)-(C1-C 22 )alkylene-NH-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -R 1 、-OC(O)-(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 22 )alkylene-R 1 , -adamantyl, -(C1-C 22 )alkylene-adamantyl, -O-adamantyl, -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-C(O)-(C1-C 22 )alkylene-adamantyl, -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -CH(NH-CO-(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl]3, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1]3, -CH(NH-CO-halogenated(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-halo(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-(C1-C 22 )alkyl, -C(O)NH-R 1 、-C(O)NR 2 -R 1 、-C(O)NH-(C1-C 22 )alkylene-OH, -C(O)NH-(C1-C 22 )alkylene-COOH, -NH-C(O)-(C1-C 22 )alkyl, -NH-C(O)-R 1 、-NR 2 -C(O)-R 1 、-OP(O)2-OR 1 、-OP(O)(S)-OR 1 、-OP(O)-OR 1 、-NH-R 1 、-NR 2 -R 1 、-(C1-C 22 )alkylene-NH-R 1 、-(C1-C 22 )alkylene-NR 2 -R 1 、-C(O)-(C1-C 22 )alkylene-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-C(O)OR 1 、-C(O)-(C1-C 22 )alkylene-NH-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-NR 2 -C(O)-R 1、-(C1-C 22 )alkylene-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22)alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole and substituted or unsubstituted benzothiazole,

[0215] where R 7 is connected to any one of P, Q, S and T at each occurrence and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 )alkyl and halo(C1-C 20 ) alkoxy;

[0216] Wherein M is an integer of 0, 1, 2 or 3;

[0217] where R 6 is connected to any one of P, Q, S and T, and is selected from a direct bond, -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-O-, -O-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-C(O)-, -C(O)-O-(C1-C 22 )alkylene-, -(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-OC(O)-, -C(O)-NH-(C1-C 22)alkylene-OC(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-O-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-O-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-C(O)-N((C1-C 22 )alkyl)-, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 22 )alkylene-、-NH-C(O)-(C1-C 22 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-O-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-、-N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-O-, -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22)alkylene-、-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-、-N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-N((C1-C 22 )alkyl)-C(O)-, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-P(O)2-O-, -(C1-C 22 )alkylene-OP(O)2-O-, -(C3-C 22 )cycloalkylene-, -(C3-C 22 )cycloalkylene-O-, -O-(C3-C 22 )cycloalkylene-, -(C6-C 22 )arylene-、-(C6-C 22 )arylene-O-, -O-(C6-C 22 )arylene-、-(C6-C 22 ) arylene-NH-, -NH-(C6-C 22 )arylene-、-C(O)-(C6-C 22 )arylene-、-(C6-C 22 )arylene-C(O)-, -C(O)-O-(C6-C 22 )arylene-、-(C6-C 22 )arylene-C(O)-O-, -C(O)-NH-(C6-C 22 )arylene- and -C(O)-NH-(C6-C 22 )arylene-C(O)-O-;

[0218] where R 1 independently selected at each occurrence from hydrogen, hydroxy, -(C1-C 22 )alkyl, -(C3-C 22 )cycloalkyl, -(C6-C 22)aryl, -(C1-C 22 )alkoxy, -(C3-C 22 )cycloalkoxy, -(C6-C 22 )aryloxy, -C(O)-(C1-C 22 )alkyl, -OC(O)(C1-C 22 )alkyl, -C(O)-O-(C1-C 22 )alkyl, -C(O)-(C3-C 22 )cycloalkyl, -OC(O)-(C3-C 22 )cycloalkyl, -C(O)-O-(C3-C 22 )cycloalkyl, -C(O)-(C6-C 22 )aryloxy, -OC(O)-(C6-C 22 )aryloxy, -C(O)-O-(C6-C 22 ) aryloxy, -C(O)-phosphate group, phosphodiester group, phosphoramidite group, saturated fatty acid group, unsaturated fatty acid group, glucosyl, acetylglucosamine group, galactosamine, N-acetylgalactosamine, lipids, PEG, steroids, lipophilic substances, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine and alkaloids,

[0219] where R 2 independently selected at each occurrence from halogen atoms, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C1-C 12 ) alkoxycarbonyl, (C6-C 16 )aryl or (C6-C 16 ) aryloxycarbonyl;

[0220] Among them, A1, A2, A3, B, C, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained in are optionally attached to a support material or protected by a terminal protecting group; and

[0221] Provided that A1, A2 and A3 are not hydrogen at the same time and R 3 、R 4 and R 5 Not hydrogen at the same time.

[0222] In another specific embodiment, the oligonucleotide delivery enhancing compound according to claim 1 comprises a moiety represented by formula BI and at least one substituent, which can be directly or indirectly attached to the oligonucleotide,

[0223]

[0224] wherein X' is selected from carbon, nitrogen, oxygen, and sulfur; each of F', G', H', and I' is independently selected from carbon, nitrogen, oxygen, and sulfur; and each asterisk refers to a site that is optionally linked directly or indirectly to at least one substituent or oligonucleotide.

[0225] In another specific embodiment, the oligonucleotide delivery enhancing compound has the structure represented by Formula BII:

[0226]

[0227] wherein X' is selected from carbon, nitrogen, oxygen, and sulfur; and each of F', G', H', and I' is independently selected from carbon, nitrogen, oxygen, and sulfur;

[0228] wherein each of A1', A2' and A3' is either absent or a substituent independently selected from the group consisting of: -H, -R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR 1 '、-OC(O)-R 1 '、-C(O)NH-R 1 ',-C(O)NR 2 '-R 1 ',-NH-C(O)-R 1 '、-NR 2 '-C(O)-R 1 ',-OP(O)2-OR 1 ',-OP(O)(S)-OR 1 '、-OP(O)-OR 1 ', -NH-R 1 '、-NR 2 '-R 1 '、-(CH2) r’ -NH-R 1 '、-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -R 1 ', -C(O)-(CH2) r’ -NH-R 1 ', -C(O)-(CH2) r’ -NR 2 '-R 1', -C(O)-(CH2) r’ -C(O)-R 1 ', -C(O)-(CH2) r’ -C(O)OR 1 ', -C(O)-(CH2) r’ -NH-C(O)-R 1 ', -C(O)-(CH2) r’ -NR 2 '-C(O)-R 1 '、-(CH2) r’ -C(O)-R 1 ';-(CH2) r’ -C(O)OR 1 ';-(CH2) r’ -OC(O)-R 1 '、-(CH2) r’ -R 1 '、-(CH2) r’ -NH-C(O)-R 1 '、-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NR 2 '-C(O)-(CH2) s’ -R 1 '、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R3 ’)、-CH(-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 ’)(-C(O)-NH-(CH2) q’ -R 3 ’)、-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’((CH2) r’ -NR 5'-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '), or A1' and A2' are linked together so that A1', A2', the nitrogen atom linked to A1' and the carbon atom linked to A2' together form an unsubstituted or substituted heterocyclic ring; wherein R 1 ' and R 3 ' are each independently selected from hydrogen, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 )alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-phosphate, phosphodiester, phosphoramidite, saturated fatty acid, unsaturated fatty acid, glucosyl, acetylglucosamine, galactosamine, N-acetylgalactosamine, lipid, PEG, steroid, lipophilic substance, carbohydrate, cholesterol, adamantane, amino acid, peptide, ligand, nucleic acid, oligonucleotide, aptamer, small molecule, antibody, antibody fragment, chloroquine, alkaloid and targeting moiety, wherein R 1 ' and R 3'Each of the one or more hydroxyl, carboxyl and amino groups are optionally protected; wherein R 2 '、R 4 '、R 5 ' and R 6 ' are each independently a hydrogen atom, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C1-C 12 ) alkoxycarbonyl, (C6-C 16 )aryl or (C6-C 16 ) aryloxycarbonyl; wherein r', s', p' and q' are each an integer from 1 to 22; and provided that when X' is oxygen, A3' is absent, and A1', A2' and A3' are not simultaneously hydrogen;

[0229] wherein each C' is connected to any one of F', G', H' and I' and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 )alkyl and halo(C1-C 20 ) alkoxy;

[0230] wherein m' is an integer of 1, 2, or 3, n' is an integer of 1, 2, or 3, and m'+n'=4;

[0231] wherein each B' is connected to any one of F', G', H' and I' and is independently selected from the group consisting of hydroxy, -C(O)OH, -(C1-C 30 )alkoxy, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -H (wherein r' is an integer from 1 to 22), -C(O)-NH-[(C1-C30 )alkylene-O] r’ -(C1-C 30 )alkylene-C(O)-OH (wherein r' is an integer from 1 to 22), -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-(C6-C 50 )arylene-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30)alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50)arylene-CN, -(C5-C 50 ) heteroarylene-CN, lipids, PEG, steroids, lipophilic substances, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine, alkaloids, and substituents represented by formula BIII:

[0232]

[0233] wherein Y' is selected from carbon, nitrogen, oxygen, and sulfur; and P', Q', S', and T' are each independently selected from carbon, nitrogen, oxygen, and sulfur; and the asterisk refers to the position at which the substituent represented by Formula BIII is attached to any one of F', G', H', and I' of Formula BII;

[0234] where R 7 'Selected from the following group: -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-O-, -O-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-, -NH-(C1-C 30 )alkylene-, -C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-, -C(O)-O-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-O-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30)alkylene-, -C(O)-NH-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 30 )alkylene-、-NH-C(O)-(C1-C 30 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 30 )alkylene-C(O)-, -NH-C(O)-(C1-C 30 )alkylene-O-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-、-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-O-, -NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-、-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-、-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20)alkyl)-C(O)-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -(C1-C 30 )alkylene-P(O)2-O-, -(C1-C 30 )alkylene-OP(O)2-O-, -(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-O-, -O-(C3-C 50 )cycloalkylene-, -(C3-C 50 ) cycloalkylene-NH-, -NH-(C3-C 50 )cycloalkylene-, -C(O)-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-, -C(O)-O-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50)cycloalkylene-C(O)-N((C1-C 20 )alkyl)-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -(C3-C 50 )cycloalkylene-P(O)2-O-, -(C3-C 50 )cycloalkylene-OP(O)2-O-, -(C6-C 50 )arylene-、-(C6-C 50 )arylene-O-, -O-(C6-C 50 )arylene-、-(C6-C 50 ) arylene-NH-, -NH-(C6-C 50 )arylene-、-C(O)-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-, -C(O)-O-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-、-C(O)-NH-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-、-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-O-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-、-C(O)-N((C1-C 20 )alkyl)-(C6-C50 )arylene-C(O)-N((C1-C 20 )alkyl)-, -(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -(C6-C 50 )arylene-P(O)2-O-, -(C6-C 50 )arylene-OP(O)2-O-, -(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-O-, -O-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-NH-, -NH-(C5-C 50 )heteroarylene-、-C(O)-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-C(O)-, -C(O)-O-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-、-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-、-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-O-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-、-C(O)-N((C1-C 20)alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-、-(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C6-C 50 )arylene-、-(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -(C5-C 50 )heteroarylene-P(O)2-O-, -(C5-C 50 )heteroarylene-OP(O)2-O-; wherein R 8 ' and R 9 'Each or not exist or are independently selected from the following substituents: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 )alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C50 )aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 )alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid; wherein R 8 ' and R 9 'Each of which contains one or more hydroxyl, carboxyl, amino and phosphate groups, optionally protected by terminal protecting groups; or R 8 ' and R 9 'Connect together so that R 8 '、R 9 ', and R 8 'The carbon atom connected to R 9 The 'attached Y' atom forms an unsubstituted or substituted heterocyclic ring; provided that when Y' is oxygen or sulfur, R 9 'does not exist;

[0235] Each R 10 ' is connected to any one of P', Q', S' and T', and is independently selected from the following group: hydroxyl, -C(O)OH, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50)cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30)alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 )heteroarylene-CN, wherein R 10One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained therein are optionally attached to a support material or protected by a terminal protecting group;

[0236] Each R 11 ' is connected to any one of P', Q', S' and T' and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, (C1-C 20 ) alkoxycarbonyl, halo(C1-C 20 )alkyl and halo(C1-C 20 )alkoxycarbonyl; and

[0237] wherein M' is an integer of 1, 2, or 3, N' is an integer of 1, 2, or 3, and M'+N'=4.

[0238] In another specific embodiment, A1, A2, A3, B, C, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 1 '、R 2 '、R 3 '、R 4 '、R 5 '、R 6 '、R 7 '、R 8 '、R 9 '、R 10 ' and R 11 'Each of the one or more hydroxyl, carboxyl, amino, nitrile and phosphate groups are optionally selected from the group consisting of terminal protecting groups R P Protection: (C1-C 22 )alkyl, (C1-C 22 ) alkoxy, (C1-C 22 )alkylcarbonyl, (C1-C 22 ) alkoxycarbonyl, (C6-C 22 )aryl, (C6-C 22 ) aryloxy, (C6-C 22 ) arylcarbonyl, (C6-C 22 ) aryloxycarbonyl, glucosyl, acetylglucosamine, galactosamine, N-acetylgalactosamine, tri((C1-C 22 )alkyl)silyl and tri((C1-C 22 )alkoxy)silyl; and

[0239] The support material is selected from the group consisting of silicon dioxide, silica gel, glass, ceramic, polymer, cellulose and combinations thereof.

[0240] In another specific embodiment, the oligonucleotide delivery-enhancing compound has a structure represented by Formula AIV to Formula AXIII and Formula BIV to BXIV:

[0241]

[0242]

[0243] wherein A1, A2, A3, A4, F, G, H, I, B, C, P, Q, S, T, R6, R7, m, n, and M are as defined herein,

[0244] wherein Ring I and Ring II are each a 4-, 5-, 6-, 7-, 8-, or 9-membered ring;

[0245] wherein A4′ is attached to any atom in Ring I, and A4′, A5′ and A6′ are each independently selected from —R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR 1 '、-OC(O)-R 1 '、-C(O)NH-R 1 ',-C(O)NR 2 '-R 1 ',-NH-C(O)-R 1 '、-NR 2 '-C(O)-R 1 ',-OP(O)2-OR 1 ',-OP(O)(S)-OR 1 '、-OP(O)-OR 1 ', -NH-R 1 '、-NR 2 '-R 1 '、-(CH2) r’ -NH-R 1 '、-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -R 1 ', -C(O)-(CH2) r’ -NH-R 1 ', -C(O)-(CH2) r’ -NR 2 '-R1 ’、-C(O)-(CH2) r’ -C(O)-R 1 ’、-C(O)-(CH2) r’ -C(O)O-R 1 ’、-C(O)-(CH2) r’ -NH-C(O)-R 1 ’、-C(O)-(CH2) r’ -NR 2 ’-C(O)-R 1 ’、-(CH2) r’ -C(O)-R 1 ’;-(CH2) r’ -C(O)O-R 1 ’;-(CH2) r’ -O-C(O)-R 1 ’、-(CH2) r’ -R 1 ’、-(CH2) r’ -NH-C(O)-R 1 ’、-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’、-(CH2) r’ -NR 2 ’-C(O)-(CH2) s’ -R 1 ’、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1')(-NH-C(O)-(CH2) q’ -R 3 '),-CR 4 '(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')(-NR 6 '-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '); where R 1 ' and R 3 ' are each independently selected from hydrogen, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 )alkoxy, -(C3-C 50)cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-phosphate, phosphodiester, phosphoramidite, saturated fatty acid, unsaturated fatty acid, lipid, PEG, steroid, lipophilic substance, carbohydrate, cholesterol, adamantane, amino acid, peptide, ligand, nucleic acid, oligonucleotide, aptamer, small molecule, antibody, antibody fragment, polyethylene glycol, carbohydrate, antibody, antibody fragment, chloroquine, alkaloid and targeting moiety, wherein R 1 ' and R 3’ Each of the one or more hydroxyl, carboxyl and amino groups is optionally protected, wherein R 2 '、R 4 '、R 5 ' and R 6 ' are each independently a halogen atom, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C6-C 16 )aryl or (C6-C 16 ) aryloxy; wherein r', s', p' and q' are each an integer from 1 to 22; and

[0246] where R 12 ' is connected to any atom in ring II and is selected from the group consisting of: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C30 )alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 )alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C 50 )aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 )alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid; wherein R 12 One or more hydroxyl, carboxyl, amino and phosphate groups contained in ' are optionally protected.

[0247] In another specific embodiment, F, G, H and I are each carbon, m is 1 and n is 3, B is attached to G or H, P, Q, S and T are each carbon, R 6 Connect to either Q or S;

[0248] wherein the protecting group R P Selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butyldimethylsilyl (TBS), 4,4'-dimethoxytrityl (DMTr), tert-butyloxycarbonyl (Boc), benzyl (Bn) and benzyloxy (BnO);

[0249] wherein C is selected from the group consisting of hydrogen, halogen, hydroxyl, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, halogenated (C1-C 12 )alkyl and halo(C1-C12 ) alkoxy;

[0250] wherein B is selected from the group consisting of: -(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 16 )alkylene-C(O)NH2, -(C1-C 16 )alkylene-OC(O)-(C1-C 16 )alkylene-C(O)NH2, -OC(O)-(C1-C 16 )alkylene-C(O)OH, -(C1-C 16 )alkylene-OC(O)-(C1-C 16 )alkylene-C(O)OH, -C(O)-(C1-C 16 )alkylene-C(O)NH2, -(C1-C 16 )alkylene-C(O)-(C1-C 16 )alkylene-C(O)NH2, -C(O)-NH-(C1-C 16 )alkylene-OH, -C(O)-NH-(C1-C 16 )alkylene-C(O)OH, -(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-C(O)OH, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 )alkylene-CN, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 )alkylene-OH, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 )alkylene-NH2, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 )alkylene-C(O)OH and -C(O)-NH-(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 )alkylene-CN,

[0251] wherein A1, A2 and A3 are either absent or are substituents independently selected from the group consisting of: -H, -OH, linear or branched -(C6-C 22 )alkyl, linear or branched-(C2-C 22 )alkenyl, -(C1-C 22 )alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )alkylene-COOR 1 、-O-(C1-C 22 )alkyl, -(C6-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzothiazole, and a substituent represented by formula AIII,

[0252] wherein Y is selected from the group consisting of carbon, nitrogen, oxygen, and sulfur; and P, Q, S, and T are each carbon;

[0253] where R 3 、R 4 and R 5 Each of the above is either absent or a substituent independently selected from the group consisting of: -H, -OH, linear or branched -(C6-C 22 )alkyl, linear or branched-(C2-C 22 )alkenyl, -(C1-C 22 )alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )alkylene-COOR 1 、-O-(C1-C 22 )alkyl, -(C6-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-NR 2-C(O)-(C1-C 22 )alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, and substituted or unsubstituted benzothiazole,

[0254] where R 7 is connected to any one of P, Q, S and T at each occurrence and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halo(C1-C 20 )alkyl and halo(C1-C 20 ) alkoxy;

[0255] Wherein M is an integer of 0, 1, 2 or 3;

[0256] where R 6 Connected to any one of P, Q, S and T, and selected from the following group: -(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-O-, -O-(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-NH-, -NH-(C1-C 16 )alkylene-, -C(O)-(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-C(O)-, -C(O)-O-(C1-C 16 )alkylene-, -(C1-C16)alkylene-C(O)-O-, -C(O)-NH-(C1-C 16 )alkylene-, -C(O)-NH-(C1-C 16 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 16 )alkylene-OC(O)-, -C(O)-NH-(C1-C 16 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 16 )alkylene-O-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-O-, -C(O)-NH-(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-, -C(O)-NH-(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-, -C(O)-NH-(C1-C 16 )alkylene-C(O)-NH-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-C(O)-N((C1-C 16 )alkyl)-, -(C1-C 16 )alkylene-C(O)-NH-(C1-C16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 16 )alkylene-、-NH-C(O)-(C1-C 16 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 16 )alkylene-C(O)-, -NH-C(O)-(C1-C 16 )alkylene-O-, -N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-、-N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-O-, -NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-、-NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-, -N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-、-N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-N((C1-C 16 )alkyl)-C(O)-, -(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-.

[0257] In another specific embodiment, the oligonucleotide delivery-enhancing compound has a structure represented by any one of Formula BXV to Formula BXXIX:

[0258]

[0259]

[0260] wherein A1' and A2' are each a substituent independently selected from the group consisting of: -R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR 1 '、-OC(O)-R 1 '、-C(O)NH-R 1 ',-C(O)NR 2 '-R 1 ',-NH-C(O)-R 1 '、-NR 2 '-C(O)-R 1 ',-OP(O)2-OR 1 ',-OP(O)(S)-OR 1 '、-OP(O)-OR 1 ', -NH-R 1 '、-NR 2 '-R 1 '、-(CH2) r’ -NH-R 1 '、-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -R 1 ', -C(O)-(CH2) r’ -NH-R 1 ', -C(O)-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -C(O)-R 1 ', -C(O)-(CH2) r’ -C(O)OR 1 ', -C(O)-(CH2) r’ -NH-C(O)-R 1 ', -C(O)-(CH2) r’ -NR 2 '-C(O)-R 1 '、-(CH2) r’ -C(O)-R 1 ';-(CH2) r’ -C(O)OR 1 ';-(CH2) r’ -OC(O)-R 1 '、-(CH2) r’ -R1 '、-(CH2) r’ -NH-C(O)-R 1 '、-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NR 2 '-C(O)-(CH2) s’ -R 1 '、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 ')(-C(O)-NH-(CH2) q’ -R 3 '),-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NH-C(O)-(CH2) q’ -R3 '),-CR 4 '(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CR 4 '(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')(-NR 6 '-C(O)-(CH2) q’ -R 3 '),-CH(-(CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '), and -CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '); where R 1 ' and R 3 ' are each independently selected from hydrogen, hydroxyl, -(C1-C 30)alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 )alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-phosphate, phosphodiester, phosphoramidite, saturated fatty acid, unsaturated fatty acid, lipid, PEG, steroid, lipophilic substance, carbohydrate, cholesterol, adamantane, amino acid, peptide, ligand, nucleic acid, oligonucleotide, aptamer, small molecule, antibody, antibody fragment, polyethylene glycol, antibody, antibody fragment, chloroquine, alkaloid and targeting moiety, wherein R 1 ' and R 3 'Each of the one or more hydroxyl, carboxyl and amino groups are optionally protected; wherein R 2 '、R 4 '、R 5 ' and R 6 ' are each independently a halogen atom, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C1-C 12 ) alkoxycarbonyl, (C6-C 16 )aryl or (C6-C 16 ) aryloxycarbonyl; wherein r', s', p' and q' are each an integer from 1 to 22;

[0261] wherein m' is an integer of 1, 2, or 3, n' is an integer of 1, 2, or 3, and m'+n'=4;

[0262] Wherein each B' is independently selected from the group consisting of hydroxy, -C(O)OH, -(C1-C 30 )alkoxy, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 )alkylene-OH, -(C3-C50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -H (wherein r' is an integer from 1 to 22), -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -(C1-C 30 )alkylene-C(O)-OH (wherein r' is an integer from 1 to 22), -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-(C6-C 50 )arylene-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50)cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 ) heteroarylene-CN, lipids, PEG, steroids, lipophiles, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine, and alkaloids;

[0263] Each R 7 'Selected from the following group: -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-O-, -O-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-, -NH-(C1-C 30 )alkylene-, -C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-, -C(O)-O-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30)alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-O-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 30 )alkylene-、-NH-C(O)-(C1-C 30 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 30 )alkylene-C(O)-, -NH-C(O)-(C1-C 30 )alkylene-O-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-、-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-O-, -NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-、-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C20 )alkyl)-C(O)-(C1-C 30 )alkylene-、-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -(C1-C 30 )alkylene-P(O)2-O-, -(C1-C 30 )alkylene-OP(O)2-O-, -(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-O-, -O-(C3-C 50 )cycloalkylene-, -(C3-C 50 ) cycloalkylene-NH-, -NH-(C3-C 50 )cycloalkylene-, -C(O)-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-, -C(O)-O-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50)cycloalkylene-C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -(C3-C 50 )cycloalkylene-P(O)2-O-, -(C3-C 50 )cycloalkylene-OP(O)2-O-, -(C6-C 50 )arylene-、-(C6-C 50 )arylene-O-, -O-(C6-C 50 )arylene-、-(C6-C 50 ) arylene-NH-, -NH-(C6-C 50 )arylene-、-C(O)-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-, -C(O)-O-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-、-C(O)-NH-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-、-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-O-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C6-C50 )arylene-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-、-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-, -(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-、-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -(C6-C 50 )arylene-P(O)2-O-, -(C6-C 50 )arylene-OP(O)2-O-, -(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-O-, -O-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-NH-, -NH-(C5-C 50 )heteroarylene-、-C(O)-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-C(O)-, -C(O)-O-(C5-C 50 )heteroarylene-、-(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-、-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-、-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-O-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C3-C 50 )cycloalkylene-、-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -C(O)-N((C1-C 20)alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-、-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-、-(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C6-C 50 )arylene-、-(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -(C5-C 50 )heteroarylene-P(O)2-O-, -(C5-C 50 )heteroarylene-OP(O)2-O-; wherein each R 8 ' is a substituent independently selected from the group consisting of: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 )alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 )aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 )aryloxy, -C(O)-O-(C6-C 50 )aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 )alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid; wherein each R 8 One or more hydroxyl, carboxyl, amino and phosphate groups contained therein are optionally protected by terminal protecting groups; and

[0264] Each R 10 'Independently selected from the following group: hydroxyl, -C(O)OH, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 )alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30)alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30)alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 )heteroarylene-CN, wherein R 10 One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained in ' are optionally attached to a support material or protected by a terminal protecting group.

[0265] In another specific embodiment, the oligonucleotide delivery enhancing compound has the structure:

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283] in Indicates supporting material.

[0284] In another specific embodiment, at least one hydrogen atom contained in the oligonucleotide delivery-enhancing compound is replaced with a deuterium atom.

[0285] In another specific embodiment, the present disclosure provides an oligonucleotide delivery agent comprising a delivery enhancing compound (DEC) moiety derivable from an oligonucleotide delivery enhancing compound described herein and at least one oligonucleotide.

[0286] In another specific embodiment, the oligonucleotide delivery enhancing compound portion is linked to the oligonucleotide via at least one linking moiety selected from the group consisting of a direct bond, -O-, -S-, -C(O)-, -NH-, -N((C1-C 12 )alkyl)-, -N((C1-C 12)Alkyl)-C(O)-O-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -C(O)-NH-, -OP(O)2O-, -P(O)(O - )O-, -OP(O)O-, -OP(O)(S)O-, -OS(O)2-O-, -S(O)2-O-, -S(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-C(O)-, -(C1-C 22 )alkylene-C(O)-O-, -C(O)-(C1-C 22 )alkylene-、-NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-C(O)-, -C(O)-(C1-C 22 )alkylene-C(O)-, -NH-(C1-C 22 )alkylene-NH-, -C(O)-(C1-C 22 )alkylene-C(O)O-, -OC(O)-(C1-C 22 )alkylene-C(O)-O-, -C(O)-O-(C1-C 22 )alkylene-OC(O)-, -C(O)-(C1-C 22 )alkylene-NH-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-NH-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-OP(O)2O-, -(C1-C 22 )alkylene-OP(O)(O - )O-、-(C1-C 22 )alkylene-OP(O)(O - )O-(C1-C 22 )alkylene-, -(C1-C 22)alkylene-OP(O)O-, -(C1-C 22 )alkylene-OP(O)(S)O-, -(C1-C 22 )alkylene-OS(O)2-O-, -(C1-C 22 )alkylene-S(O)2-O-, -(C1-C 22 )alkylene-S(O)-O-, -OP(O)2-O-(C1-C 22 )alkylene-OP(O)2O-, -OP(O)-O-(C1-C 22 )alkylene-OP(O)O-, -OP(O)(S)O-(C1-C 22 )alkylene-OP(O)(S)O-, -OS(O)2-O-(C1-C 22 )alkylene-OS(O)2-O-, -S(O)2-O-(C1-C 22 )alkylene-S(O)2-O- and -OS(O)-(C1-C 22 )alkylene-S(O)-O-; and

[0287] The oligonucleotide is selected from the group consisting of antisense oligonucleotide (ASO), antisense RNA, short interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), double-stranded RNA (dsRNA) and small guide RNA (sgRNA).

[0288] In another specific embodiment, the oligonucleotide comprises at least a portion of the sequence set forth in SEQ ID NOs 1 to 53.

[0289] In another specific embodiment, the oligonucleotide delivery agent comprises a structure represented by formula AA:

[0290]

[0291] wherein the delivery enhancing compound (DEC) portion is derived from the oligonucleotide delivery enhancing compound of any one of claims 1 to 9 and is directly or indirectly linked to at least one oligonucleotide.

[0292] In another specific embodiment, DEC is linked to the oligonucleotide via at least one first linking moiety.

[0293] In another specific embodiment, TM is linked to DEC via at least one second linking moiety.

[0294] In another specific embodiment, the first linking portion and the second linking portion are each independently selected from: a direct bond, -O-, -S-, -C(O)-, -NH-, -N((C1-C12 )alkyl)-, -N((C1-C 12 )Alkyl) -C(O)-O-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -C(O)-NH-, -OP(O)2O-, -OP(O)O-, -OP(O)(S)O-, -OS(O)2-O-, -S(O)2-O-, -S(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-C(O)-, -(C1-C 22 )alkylene-C(O)-O-, -C(O)-(C1-C 22 )alkylene-、-NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 )alkylene-NH-, -NH-(C1-C 22 )alkylene-C(O)-, -C(O)-(C1-C 22 )alkylene-C(O)-, -NH-(C1-C 22 )alkylene-NH-, -C(O)-(C1-C 22 )alkylene-C(O)O-, -OC(O)-(C1-C 22 )alkylene-C(O)-O-, -C(O)-O-(C1-C 22 )alkylene-OC(O)-, -C(O)-(C1-C 22 )alkylene-NH-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-NH-, -NH-(C1-C 22 )alkylene-OP(O)2O-, -NH-(C1-C 22 )alkylene-CH((C1-C 22 )alkylene-OH)-OP(O)2O-, -NH-(C1-C 22 )alkylene-CH((C1-C 22 )alkylene-OH)-(C1-C 22 )alkylene-OP(O)2O-, -C(O)-NH-(C1-C22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-OP(O)2O-, -(C1-C 22 )alkylene-OP(O)O-, -(C1-C 22 )alkylene-OP(O)(S)O-, -(C1-C 22 )alkylene-OS(O)2-O-, -(C1-C 22 )alkylene-S(O)2-O-, -(C1-C 22 )alkylene-S(O)-O-, -OP(O)2-O-(C1-C 22 )alkylene-OP(O)2O-, -OP(O)-O-(C1-C 22 )alkylene-OP(O)O-, -OP(O)(S)O-(C1-C 22 )alkylene-OP(O)(S)O-, -OS(O)2-O-(C1-C 22 )alkylene-OS(O)2-O-, -S(O)2-O-(C1-C 22 )alkylene-S(O)2-O- and -OS(O)-(C1-C 22 )alkylene-S(O)-O-; and / or

[0295] wherein the oligonucleotide is selected from the group consisting of short interfering RNA (siRNA), small activating RNA (saRNA), microRNA (miRNA), antisense oligonucleotide (ASO) and small guide RNA (sgRNA).

[0296] In another specific embodiment, the targeting moiety is selected from one or more of the following: a ligand, a peptide, a nucleic acid, an oligonucleotide, an aptamer, a lipid, a fatty acid, a small molecule, polyethylene glycol, an amino acid, cholesterol, a carbohydrate, and an antibody or antibody fragment.

[0297] In another specific embodiment, the oligonucleotide delivery agent has a structure represented by any one of Formulas AAI to AAXXIV:

[0298]

[0299]

[0300]

[0301] Wherein, L represents a linking moiety, ☆ represents an oligonucleotide delivery enhancing compound, and the symbol represents a double-stranded oligonucleotide, in which each strand represents an interchangeable sense strand or antisense strand, and each end is independently symmetrical or asymmetrical; the symbol represents a single-stranded oligonucleotide, and a, b and c are each independently an integer from 1 to 50.

[0302] In another specific embodiment, at least one hydrogen atom contained in the delivery enhancing compound moiety, linking moiety, targeting moiety and / or oligonucleotide is replaced with a deuterium atom.

[0303] In another specific embodiment, the present disclosure provides a pharmaceutical composition comprising: a) an oligonucleotide delivery agent as described herein; and b) optionally, one or more ingredients selected from the group consisting of a pharmaceutically acceptable carrier, excipient, solvent, diluent, stabilizer, dispersant, buffer, extender, preservative, and combinations thereof.

[0304] In another specific embodiment, the present disclosure provides a method for regulating the expression of a target gene in a subject, the method comprising administering to the subject a pharmaceutical composition as described herein.

[0305] In another specific embodiment, the oligonucleotide or target gene comprises at least a portion of the sequence set forth in SEQ ID NOs 1 to 53.

[0306] In another specific embodiment, the pharmaceutical composition increases the expression of the target gene. In another specific embodiment, the pharmaceutical composition reduces the expression of the target gene. In another specific embodiment, the subject is a mammal. In another specific embodiment, the subject is a rodent. In another specific embodiment, the rodent is a mouse. In another specific embodiment, the rodent is a rat. In another specific embodiment, the mammal is a non-human primate. In another specific embodiment, the mammal is a human. In another specific embodiment, the target gene is associated with a disease or disorder. In another specific embodiment, the target gene is associated with a disease or disorder in the central nervous system (CNS), brain, spinal cord, liver, lung, kidney, intestine, pancreas, gall bladder, heart, lymph nodes, spleen, stomach, bladder, muscle or skeleton. In another specific embodiment, the disease is cancer.

[0307] In another specific embodiment, the present disclosure provides a method for regulating the expression of a target gene, the method comprising contacting a cell with the pharmaceutical composition described herein.

[0308] In another specific embodiment, the oligonucleotide or target gene comprises at least a portion of the sequence set forth in SEQ ID NOs 1 to 53.

[0309] In another specific embodiment, the pharmaceutical composition increases the expression of the target gene. In another specific embodiment, the pharmaceutical composition reduces the expression of the target gene. In another specific embodiment, the cell is a mammalian cell. In another specific embodiment, the mammalian cell is a mouse cell. In another specific embodiment, the mammalian cell is a rat cell. In another specific embodiment, the mammalian cell is a non-human primate cell. In another specific embodiment, the mammalian cell is a human cell. In another specific embodiment, the target gene is associated with a disease or disorder. In another specific embodiment, the target gene is associated with a disease or disorder in the central nervous system (CNS), brain, spinal cord, liver, lung, kidney, intestine, pancreas, gall bladder, heart, lymph nodes, spleen, stomach, bladder, muscle or bone. In another specific embodiment, the disease is cancer.

[0310] Example

[0311] Some embodiments of the present invention will now be described in the following examples, wherein, unless otherwise specified, all parts and percentages are by weight. However, the scope of the present disclosure is certainly not limited to the formulations described in these examples. More specifically, the examples are merely inventive embodiments of the present disclosure.

[0312] The following examples are provided for the purpose of fully disclosing and describing how to make and use the present invention to one of ordinary skill in the art, and are not intended to limit the scope of what the inventors believe to be their invention, nor do they represent that the experiments described below are all or the only experiments performed. Efforts have been made to ensure the accuracy of the values ​​used (such as amounts, temperatures, etc.), but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. Standard abbreviations may be used, for example, bp: base pair; kb: kilobase; nM: nanomole; s or sec: second; min: minute; h or hr: hour; aa: amino acid; nt: nucleotide; im: intramuscular; ip: intraperitoneal; sc: subcutaneous; ivt or IVT: intravitreal; iv or IV: tail vein, intravenous; icv or icv or ICV: intracerebroventricular, etc.

[0313] Unless otherwise noted, all starting materials, reagents and solvents used below were obtained from commercial sources and used as is. Purification of the reaction products was performed using silica gel column chromatography, including silica gel (200-300 mesh) and hexane / ethyl acetate, DCM / MeOH eluents. Thin layer chromatography (TLC) was performed using pre-coated silica gel GF plates and visualized using KMnO 4 staining. CDCl 3 and TMS were used, and the chromatograms were recorded at 400 or 500 MHz (Varian). 1 H-NMR spectroscopy. High-resolution mass spectra (HRMS) were recorded by ESI or matrix-assisted laser desorption / ionization (MALDI) on a LC / MS (Agilent Technologies 1260 Infinity II / 6120 quadrupole) and time-of-flight mass spectrometer.

[0314] Example 1: Preparation of Compound A1 of the present disclosure

[0315] In this example, compound A1 was prepared using the following procedure:

[0316]

[0317] (1) Preparation of Compound A62

[0318]

[0319] To a solution of Fmoc-L-hydroxyproline A61 (13.3 g, 37.6 mmol, 1.0 equiv) in anhydrous THF (250 mL) was slowly added borane-methyl sulfide complex (8.0 mL, 10 M in THF, 80 mmol, 2.1 equiv) at room temperature. The reaction mixture was stirred at room temperature for 5 min and then heated to reflux for approximately 1 h. Methanol (15 mL) was carefully added to the reaction mixture and allowed to reflux for 15 min. Subsequently, the reaction mixture was concentrated under reduced pressure. The crude product was then evaporated three times with methanol (100 mL of methanol each time). The crude product A62 was used directly in the next step without further purification.

[0320] (2) Preparation of Compound A63

[0321]

[0322] Under ice bath, DMTrCl (14 g, 41.4 mmol, 1.1 eq) was slowly added to a solution of compound A62 (37.6 mmol, 1.0 eq) in anhydrous pyridine (200 mL). The reaction was stirred overnight under nitrogen atmosphere and then concentrated under reduced pressure. The crude product was dissolved in dry MeCN (300 mL), and then Et3N (15.6 mL, 113 mmol, 3.0 eq) was added to the mixture and heated to 60 ° C for 4 h. After concentration under reduced pressure, the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-8% MeOH / DCM) to provide the desired product A63 (7.57 g, 48% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 419.21; MW found: 303.2 [DMT] - . 1 H NMR(400MHz, CDCl3) δ7.41(d,J=7.4Hz,2H),7.30(d,J=8.8Hz,4H),7.28–7.2 2(m,2H),7.18(t,J=7.2Hz,1H),6.80(d,J=8.8Hz,4H),4.34(s,1H),3.75(d, J=11.1Hz,6H),3.60(dd,J=12.7,6.7Hz,1H),3.10–2.92(m,5H),2.86(d,J=1 1.5Hz, 1H), 1.85 (dd, J=13.5, 7.1Hz, 1H), 1.63 (ddd, J=13.7, 7.9, 5.9Hz, 1H).

[0323] (3) Preparation of Compound A66

[0324]

[0325] Under nitrogen atmosphere, to compound A64 (1.4g, 7.2mmol, 2.0 equivalents) solution in DCM (30mL) add compound A65 (1.0g, 3.6mmol, 1.0 equivalents), O-benzotriazole-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU) (2.7g, 7.2mmol, 2.0 equivalents) and N, N-diisopropylethylamine (DIPEA) (0.93g, 7.2mmol, 2.0 equivalents). The reaction mixture was stirred at room temperature overnight. Then 30mLH2O was added to the reaction mixture, and the mixture was extracted with DCM (3*30mL). The organic phase was merged, dried over Na2SO4, and concentrated. The residue obtained was purified using flash chromatography (silica gel, gradient elution: 1-5% MeOH / DCM) to provide compound A66 (1.7g, 94% yield), which was a colorless oil. The products were analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 453.31; MW found: 454.29 [M+H] + . 1 H NMR (400MHz, CDCl3) δ3.69–3.61(m,5H),3.59-3.53(m,8H),3.48(t,J=5.2Hz,2H),3.35(dd,J=10.7,5.3Hz, 2H), 3.15 (qd, J=7.4, 4.4Hz, 3H), 2.43 (t, J=6.4Hz, 2H), 1.92–1.85 (m, 5H), 1.54-1.52 (m, 4H), 1.37 (s, 12H).

[0326] (4) Preparation of Compound A67

[0327]

[0328] To a solution of compound A66 (0.8g, 1.7mmol, 1.0 equivalent) in DCM (10mL) was added HCl / dioxane (4M, 10mL). The reaction mixture was stirred at room temperature for 3h, then concentrated under reduced pressure to provide a crude product, which was a yellow oil. The crude product was dissolved in DCM (10mL), and compound A63 (583mg, 1.7mmol, 1.0 equivalent), HBTU (1.28g, 3.4mmol, 2.0 equivalent) and DIPEA (439mg, 3.4mmol, 2.0 equivalent) were then added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. Then 10mL H o was added to the reaction mixture, and the mixture was extracted with DCM (3*20mL). The organic phase was merged, dried over Na sO , and concentrated. The resulting residue was purified using flash chromatography (silica gel, gradient eluent: 10% MeOH / DCM) to provide compound A67 (261 mg, 21% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 798.45; MW found: 303.31 [DMT] - ,519.62[DMT off+Na] + . 1 H NMR(400MHz, CDCl3)δ7.36(d,J=7.7Hz,2H),7.26–7.23(m,6H),7.17(t,J=7.0Hz,1H),6 .81(dd,J=11.4,5.1Hz,4H),3.85–3.81(m,1H),3.77(s,6H),3.62–3.56(m,8H),3.53(dd ,J=9.1,4.5Hz,2H),3.44–3.32(m,4H),2.73(q,J=7.2Hz,6H),2.45–2.33(m,1H),2.26–2 .16(m,1H),2.15–2.02(m,1H),1.99–1.90(m,5H),1.72–1.66(m,3H),1.63–1.58(m,9H).

[0329] (5) Preparation of Compound A68

[0330]

[0331] Under a nitrogen atmosphere, succinic anhydride (282 mg, 2.76 mmol, 3.0 equiv) was added to a solution of compound A67 (666 mg, 0.92 mmol, 1.0 equiv) and DMAP (393 mg, 3.22 mmol, 3.5 equiv) in DCM (6 mL). The reaction mixture was stirred at room temperature overnight, and then H2O (10 mL) was added to the reaction. The mixture was extracted with DCM (3*10 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A68 (447 mg, 59% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 898.46; MW found: 303.15 [DMT] - ,597.98[DMT off+H] + . 1 H NMR (400MHz, CDCl3) δ7.36–7.32(m,2H),7.27–7.25(m,6H),7.19-7.16(m,1H),6.85–6.76(m,4H ),5.46–5.32(m,1H),3.82(d,J=6.3Hz,1H),3.77(s,6H),3.60(dd,J=9.3,4.5Hz,8H),3.53(t,J= 5.0Hz,2H),3.44–3.40(m,2H),3.14(dd,J=9.2,2.9Hz,1H),2.99–2.93(m,6H),2.62–2.45(m,5H) ,2.34-2.28(m,1H),2.19–2.04(m,1H),1.96–1.92(m,5H),1.69–1.66(m,3H),1.62–1.58(m,9H).

[0332] (6) Preparation of Compound A1

[0333]

[0334] Under a nitrogen atmosphere, HBTU (169 mg, 0.446 mmol, 2.0 equiv) was added to a solution of compound A68 (200 mg, 0.223 mmol, 1.0 equiv), controlled pore glass (CPG) (3.9 g), and DIPEA (111 μL, 0.669 mmol, 3.0 equiv) in acetonitrile (30 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (12 mL), pyridine (28 mL), and NEt3 (401 μL) in acetonitrile (18 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A1 (3.67 g) of the present disclosure.

[0335] Example 2: Preparation of Compound A2 of the present disclosure

[0336] In this example, the following procedure was used to prepare compound A2:

[0337]

[0338] (1) Preparation of Compound A70

[0339]

[0340] To a solution of methyl 4-fluoro-3-nitrobenzoate A69 (8.0 g, 40.2 mmol, 1.0 equiv) and KCO (5.5 g, 40.2 mmol) in anhydrous DMF (100 mL) was added benzyl (3-aminopropyl)carbamate (8.3 g, 40.2 mmol, 1.0 equiv) under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 6 h, and then cold water (100 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phase was then washed three times with saturated LiCl solution and once with brine. It was then dried over NaSO and concentrated under reduced pressure to form compound A70 as a yellow solid, which was used directly in the next step without further purification.

[0341] (2) Preparation of Compound A72

[0342]

[0343] Under an ice bath, HCOONH4 (9.78 g, 155.04 mmol, 6.0 equivalents) and Zn powder (10.14 g, 155.04 mmol, 6.0 equivalents) were added to a solution of compound A70 (10 g, 25.84 mmol, 1.0 equivalents) in THF / H2O (9:1, 100 mL). After 10 minutes, the reaction mixture was moved to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Water (100 mL) was subsequently added to the mixture, followed by extraction with ethyl acetate three times, and the organic phase was washed once with brine. After drying over anhydrous Na2SO4 and concentrating under reduced pressure, a light red solid compound A72 was formed, which was then used directly in the next step without further purification.

[0344] (3) Preparation of compound A73.

[0345]

[0346] To a solution of compound A72 (8.0 g, 22.5 mmol, 1.0 equiv) in EtOH (200 mL) under nitrogen atmosphere were added 3-((tert-butyldimethylsilyl)oxy)propanal (4.2 g, 22.5 mmol, 1.0 equiv) and AcOH (5.1 mL, 90 mmol, 4.0 equiv). The reaction mixture was stirred at 80°C overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (100 mL) was then added and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue, compound A73, was used directly in the next step without further purification. Compound A73 was characterized by mass spectrometry. MW calculated: 525.27; MW found: 526.59 [M+H] + .

[0347] (4) Preparation of Compound A74

[0348]

[0349] Under a nitrogen atmosphere, 1M TBAF THF solution (14.25 mL, 14.25 mmol, 1.5 equivalents) was added to a solution of compound A73 (5.0 g, 9.5 mmol, 1.0 equivalents) in anhydrous THF (50 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. Water (100 mL) was then added and the mixture was extracted three times with DCM. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was dissolved in 50 mL of pyridine and DMTrCl (3.86 g, 11.4 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 6 h. After concentration under reduced pressure, the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A74 (4.1 g, 60% yield) as a yellow solid. The product was purified by mass spectrometry and 1 H NMR characterization. MW calculated: 713.31; MW found: 303.17 [DMT]-, 412.36 [DMT off + H] + . 1 H NMR(400MHz, CDCl3)δ8.39(d,J=1.1Hz,1H),7.96(dd,J=8.5,1.3Hz,1H),7.38–7.27(m,8H),7.20(dq,J=6.7,2.5Hz,7H),6.76–6.70(m,4H),5.10 (s,2H),4.19(t,J=7.3Hz,2H),3.94(s,3H),3.74(s,6H),3.65(t,J=6.6 Hz, 2H), 3.20 (d, J = 6.3 Hz, 2H), 3.09 (t, J = 6.4 Hz, 2H), 2.00–1.90 (m, 2H).

[0350] (5) Preparation of Compound A75

[0351]

[0352] Under a nitrogen atmosphere and an ice bath, to a solution of compound A74 (4.0 g, 5.6 mmol, 1.0 equiv) in anhydrous THF (50 mL) was added LiAlH4 (319 mg, 8.4 mmol, 1.5 equiv). After 10 minutes, the mixture was moved to room temperature and stirred for 1 h. The reaction was then moved to an ice bath, and a saturated solution of potassium sodium tartrate (30 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et2O, and the organic phases were combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was dissolved in 50 mL of DMF, followed by the addition of imidazole (572 mg, 8.4 mmol, 1.5 equiv) and TBSCl (1.27 g, 8.4 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A75 (4.03 g, 90% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 HNMR characterization: MW calculated: 799.40; MW found: 303.17 [DMT]. 1 H NMR(400MHz, CDCl3)δ7.65(s,1H),7.38–7.29(m,7H),7.19(ddd,J=8.4,7.9,3.7Hz,9H),6.78–6.71(m,4H),5.10(s,2H),4.84(s,2H),4.16(t,J= 7.2Hz,2H),3.75(s,6H),3.61(t,J=6.8Hz,2H),3.18(d,J=6.3Hz,2H),3. 07(t,J=6.4Hz,2H),2.95(s,1H),2.88(s,1H),0.94(s,9H),0.10(s,6H).

[0353] (6) Preparation of Compound A78

[0354]

[0355] Under a nitrogen atmosphere, Pd / C (22 mg) was slowly added to a solution of compound A75 (220 mg, 0.276 mmol, 1.0 equivalent) in MeOH (8 mL). The reaction atmosphere was then replaced three times with hydrogen. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (8 mL), and then compound A77 (64 mg, 0.33 mmol, 1.2 equivalents), HBTU (209 mg, 0.552 mmol, 2.0 equivalents) and DIPEA (155 μL, 0.938 mmol, 3.4 equivalents) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. H2O (10 mL) was then added to the reaction, and the mixture was extracted with DCM (3*10 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A78 (199 mg, 86% yield) as a yellow oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 841.48; MW found: 303.2 [DMT] - ,540.3[DMT Off+H] + . 1 H NMR(400MHz, CDCl3)δ7.64(d,J=6.5Hz,1H),7.34–7.27(m,4H),7.22–7.17(m,6H) ,6.83(dd,J=8.1,2.7Hz,1H),6.81–6.65(m,4H),4.84(d,J=3.3Hz,2H),4.23–4.15 (m,2H),3.87–3.78(m,2H),3.77(s,6H),3.72–3.48(m,2H),3.29–3.19(m,2H),3. 17–3.06(m,2H),1.87–1.81(m,6H),1.68–1.57(m,11H),0.95(s,9H),0.11(s,6H).

[0356] (7) Preparation of Compound A79

[0357]

[0358] Under a nitrogen atmosphere, a solution of compound A78 (165 mg, 0.196 mmol, 1.0 equivalent) in anhydrous THF (5 mL) was added 1M TBAF THF solution (1.18 mL, 1.18 mmol, 6.0 equivalents). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (8 mL), followed by the addition of DMAP (84 mg, 0.686 mmol, 3.5 equivalents) and succinic anhydride (39 mg, 0.392 mmol, 2.0 equivalents) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then H2O (10 mL) was added to the reaction, the mixture was extracted with DCM (3*10 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-8% MeOH / DCM) to provide compound A79 (97 mg, 60% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 827.41; MW found: 303.2 [DMT] - ,527.3[DMT Off+H] + . 1 H NMR(400MHz, CDCl3)δ7.66(d,J=4.4Hz,1H),7.33–7.29(m,2H),7.24(s,2H),7.23–7.14 (m,7H),6.75(dd,J=8.1,5.6Hz,4H),5.22(s,2H),4.18(s,2H),3.75(s,6H),3.61(t,J=6 .7Hz,2H),3.23(s,2H),3.08(d,J=13.2Hz,2H),2.95(dd,J=14.6,7.3Hz,2H),2.71–2.55 (m,4H),1.98–1.92(m,4H),1.85(d,J=3.6Hz,2H),1.70–1.59(m,6H),1.33–1.16(m,5H).

[0359] (8) Preparation of Compound A2

[0360]

[0361] Under a nitrogen atmosphere, HBTU (78 mg, 0.206 mmol, 2.0 equiv) was added to a solution of compound A79 (85 mg, 0.103 mmol, 1.0 equiv), controlled pore glass (CPG) (1.8 g), and DIPEA (51 μL, 0.31 mmol, 3.0 equiv) in acetonitrile (14 mL). The reaction mixture was stirred overnight at 25 ° C. and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, the crude solid support was added to a solution of acetic anhydride (6.2 mL), pyridine (12 mL), and NEt3 (186 μL) in acetonitrile (7.9 mL). The reaction mixture was stirred overnight at 25 ° C. and then washed with DCM and diethyl ether to produce compound A2 (1.62 g) of the present disclosure.

[0362] Example 3: Preparation of Compound A3 of the present disclosure.

[0363] In this example, the following procedure was used to prepare Compound A3 of the present disclosure:

[0364]

[0365] (1) Preparation of Compound A81

[0366]

[0367] Under a nitrogen atmosphere, Pd / C (144 mg) was slowly added to a solution of compound A75 (1.44 g, 1.8 mmol, 1.0 equivalent) in MeOH (30 mL). The reaction atmosphere was then replaced three times with hydrogen. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (40 mL), and then palmitic acid (508 mg, 1.98 mmol, 1.1 equivalents), HBTU (1.36 g, 3.6 mmol, 2.0 equivalents) and DIPEA (1.01 mL, 6.12 mmol, 3.4 equivalents) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. Then H2O (30 mL) was added to the reaction, and the mixture was extracted with DCM (3*40 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A81 (1.43 g, 88% yield) as a yellow oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 903.59; MW found: 303.2 [DMT] - ,488.4[DMT and TBS off (off DMT and TBS) + H] + . 1H NMR(400MHz, CDCl3)δ7.62(d,J=4.7Hz,1H),7.33–7.27(m,4H),7.22–7.16(m, 7H),6.74(dd,J=8.1,5.6Hz,4H),4.83(s,2H),4.23–4.16(m,2H),3.76(s,6H), 3.62(dd,J=11.9,5.3Hz,2H),3.27–3.21(m,2H),3.15(d,J=6.9Hz,2H),2.11– 2.05(m,2H),2.03–1.90(m,2H),1.34-1.25(m,29H),0.95(s,9H),0.11(s,6H).

[0368] (2) Preparation of Compound A82

[0369]

[0370] Under a nitrogen atmosphere, a solution of compound A81 (1.4 g, 1.55 mmol, 1.0 equivalent) in anhydrous THF (30 mL) was added 1M TBAF THF solution (4.65 mL, 4.65 mmol, 3.0 equivalents). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (40 mL), and DMAP (660 mg, 5.4 mmol, 3.5 equivalents) and succinic anhydride (465 mg, 4.65 mmol, 3.0 equivalents) were then added thereto under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, and then H2O (30 mL) was added to the reaction. The mixture was extracted with DCM (3*30 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-8% MeOH / DCM) to provide compound A82 (827 mg, 60% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 889.52; MW found: 303.1 [DMT] - ,588.3[DMT Off+H] + . 1H NMR(400MHz, CDCl3)δ7.65(d,J=4.5Hz,1H),7.34–7.28(m,2H),7.25–7.14(m,9H) ,6.74(dd,J=8.1,5.5Hz,4H),5.21(s,2H),4.34–3.90(m,2H),3.74(s,6H),3.60( dd,J=12.1,5.4Hz,2H),3.22-3.16(m,2H),3.09–3.04(m,2H),2.63–2.60(m,4H), 2.16–2.01(m,2H),1.97–1.84(m,2H),1.33–1.23(m,26H),0.87(t,J=6.7Hz,3H).

[0371] (3) Preparation of Compound A3

[0372]

[0373] Under a nitrogen atmosphere, HBTU (99 mg, 0.26 mmol, 2.0 equiv) was added to a solution of compound A82 (120 mg, 0.13 mmol, 1.0 equiv), controlled pore glass (CPG) (2.29 g), and DIPEA (65 μL, 0.39 mmol, 3.0 equiv) in acetonitrile (15 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (7.8 mL), pyridine (15 mL), and NEt3 (234 μL) in acetonitrile (10 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A3 (2.1 g) of the present disclosure.

[0374] Example 4: Preparation of Compound A4 and Compound A5 of the present disclosure

[0375] In this example, Compound A4 and Compound A5 were prepared using the following procedure:

[0376]

[0377] (1) Preparation of Compound A85

[0378]

[0379] Under a nitrogen atmosphere, to a solution of methyl 2-(4-fluoro-3-nitrophenyl)acetate A84 (17.3 g, 81 mmol, 1.0 equivalent) and K2CO3 (11.2 g, 81 mmol) in anhydrous DMF (200 mL) was added compound A83 (19.56 g, 81 mmol, 1.0 equivalent). The reaction mixture was stirred at 55 ° C for 6 h and then cold water (100 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phase was then washed three times with a saturated LiCl solution and washed once with brine. The mixture was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to form compound A85 as a yellow oil, which was used directly in the next step without further purification.

[0380] (2) Preparation of Compound A86

[0381]

[0382] To a solution of compound A85 (35.18 g, 81 mmol, 1.0 equiv) in THF / H2O (9:1, 280 mL) in an ice bath were added HCOONH4 (30.67 g, 486 mmol, 6.0 equiv) and Zn powder (31.78 g, 486 mmol, 6.0 equiv). After 10 minutes, the reaction mixture was brought to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Subsequently, water (200 mL) was added to the mixture, followed by extraction three times with ethyl acetate, and the organic phase was washed once with brine. After drying over anhydrous Na2SO4 and concentration under reduced pressure, product A86 was formed and then used directly in the next step without further purification. Compound A86 was characterized by mass spectrometry. MW calculated: 404.34; MW found: 405.3 [M+H] + .

[0383] (3) Preparation of Compound A88

[0384]

[0385] Under a nitrogen atmosphere, to a solution of compound A86 (19.36 g, 48 mmol, 1.0 equiv) in EtOH (200 mL) was added 3-((tert-butyldimethylsilyl)oxy)propanal A87 (9.0 g, 48 mmol, 1.0 equiv) and AcOH (11 mL, 192 mmol, 4.0 equiv). The reaction mixture was stirred at 80°C overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (100 mL) was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residual compound A88 was used directly in the next step without further purification.

[0386] (4) Preparation of Compound A89

[0387]

[0388] Under a nitrogen atmosphere, 1M TBAF THF solution (26.3 mL, 26.3 mmol, 1.5 equivalents) was added to a solution of compound A88 (10 g, 17.5 mmol, 1.0 equivalents) in anhydrous THF (50 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. Water (100 mL) was then added and the mixture was extracted three times with DCM. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was dissolved in 50 mL of pyridine and DMTrCl (7.12 g, 21 mmol, 1.2 equivalents) was added thereto. The reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-3% MeOH / DCM) to provide compound A89 (8.1 g, 61% yield) as a yellow solid. The product was characterized by mass spectrometry and 1 H NMR characterization. MW calculated: 760.48; MW found: 761.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.59–7.53(m,1H),7.38–7.31(m,2H),7.23-7.19(m,6H),7.18–7.14(m,3H),6.76(dd,J=7.8,5.6Hz,4H),4.17–4. 02(m,2H),3.76(s,6H),3.73(s,2H),3.67(s,3H),3.59(t,J=7.0Hz,2H),3.19–3.05(m,2H),1.29–1.25(m,28H),0.88(t,J=6.5Hz,3H).

[0389] (5) Preparation of Compound A90

[0390]

[0391] To a solution of compound A89 (2.7 g, 3.55 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added LiAlH₄ (202 mg, 5.33 mmol, 1.5 equiv) under a nitrogen atmosphere and an ice bath. After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then moved to an ice bath, and saturated potassium sodium tartrate solution (20 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined, washed with brine, dried over Na₂SO₄, and concentrated. The crude product (300 mg, 0.41 mmol, 1.0 equiv) was dissolved in DCM (10 mL), and DMAP (175 g, 1.44 mmol, 3.5 equiv) and succinic anhydride (123 mg, 1.23 mmol, 3.0 equiv) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then H2O (10 mL) was added to the reaction, the mixture was extracted with DCM (3*20 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A90 (113 mg, 33% yield), which was a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 832.50; MW found: 303.2 [DMT] - ,531.3[DMT Off+H] + . 1 H NMR (400MHz, CDCl3) δ7.63 (s, 1H), 7.31 (dd, J = 7.6, 4.1Hz, 2H), 7.28–7.11 ( m,9H),6.74(dd,J=7.9,5.6Hz,4H),4.35–4.32(m,2H),4.12–4.08(m,2H),3 .75(s,6H),3.59(dd,J=11.8,5.1Hz,2H),3.24–3.10(m,2H),3.09–2.96(m, 2H), 2.63 (dd, J=7.2, 3.0Hz, 4H), 1.37–1.25 (m, 28H), 0.88 (t, J=6.5Hz, 3H).

[0392] (6) Preparation of Compound A4

[0393]

[0394] Under a nitrogen atmosphere, HBTU (82 mg, 0.216 mmol, 2.0 equiv) was added to a solution of compound A90 (90 mg, 0.108 mmol, 1.0 equiv), controlled pore glass (CPG) (1.89 g), and DIPEA (54 μL, 0.324 mmol, 3.0 equiv) in acetonitrile (14 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (6.5 mL), pyridine (12.6 mL), and NEt3 (195 μL) in acetonitrile (8.3 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A4 (1.7 g) of the present disclosure.

[0395] (7) Preparation of Compound A5

[0396]

[0397] To a solution of compound A89 (2.7 g, 3.55 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added LiAlH₄ (202 mg, 5.33 mmol, 1.5 equiv) under a nitrogen atmosphere and an ice bath. After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then returned to an ice bath, and saturated potassium sodium tartrate solution (20 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined, washed with brine, dried over Na₂SO₄, and concentrated. The crude product (300 mg, 0.41 mmol, 1.0 equiv) was dissolved in anhydrous DCM (5 mL), followed by the addition of DIPEA (204 μL, 1.23 mmol, 3.0 equiv) and 3-((chloro(diisopropylamino)phosphino)oxy)propionitrile (274 μL, 1.23 mmol, 3.0 equiv) at 25°C under a nitrogen atmosphere. The reaction mixture was stirred for 1 h. The mixture was extracted twice with DCM, then washed with brine and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM, 1% Et3N) to provide compound A5 (299 mg, 78% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 946.61; MW found: 303.2 [DMT] - . 1H NMR (400MHz, CDCl3) δ7.62 (s, 1H), 7.32 (dd, J = 7.6, 4.1Hz, 2H), 7.27–7.11 (m, 9H), 6. 73(dd,J=7.9,5.6Hz,4H),4.34–4.31(m,2H),4.10–4.06(m,2H),3.75(s,6H),3.64–3. 61(m,2H),3.58(dd,J=11.8,5.1Hz,2H),3.24–3.18(m,2H),3.09–2.88(m,4H),2.65– 2.55(m,4H),1.37–1.28(m,28H),1.22(dd,J=6.8,3.2Hz,12H),0.88(t,J=6.5Hz,3H).

[0398] Example 5: Preparation of Compound A6 of the present disclosure

[0399] In this example, compound A6 was prepared using the following procedure:

[0400]

[0401] (1) Preparation of Compound A92

[0402]

[0403] Under a nitrogen atmosphere, 5-((tert-butyldimethylsilyl)oxy)pentanal A91 (5.4 g, 24.84 mmol, 1.0 equiv) and AcOH (5.73 mL, 99.36 mmol, 4.0 equiv) were added to a solution of compound A72 (8.87 g, 24.84 mmol, 1.0 equiv) in EtOH (220 mL). The reaction mixture was stirred at 80 ° C overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (100 mL) was then added thereto and the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A92 (6.3 g, 46% yield) as a red solid. The product was analyzed by mass spectrometry, 1 H NMR and 13 C NMR characterization. MW calculated: 553.30; MW found: 554.29 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.42 (d, J=0.8Hz, 1H), 7.95 (dd, J=8.5, 1.1Hz, 1H), 7.44 –7.28(m,5H),7.26(d,J=6.8Hz,1H),5.12(s,2H),4.16(dd,J=12.6,5.3Hz,2H) ,3.93(s,3H),3.67(t,J=6.3Hz,2H),3.28(d,J=6.2Hz,2H),2.87(t,J=7.6Hz,2 H), 2.04–1.88 (m, 4H), 1.67 (dd, J = 14.7, 6.6Hz, 2H), 0.88 (s, 9H), 0.04 (s, 6H). 13 C NMR (100MHz, CDCl3) δ167.72,156.63,142.35,138.19,136.30,128.60,128.24,124.10,123.87,121.63,1 08.66,66.96,62.71,60.41,52.06,41.31,38.57,32.46,30.43,27.30,25.97,24.15,21.07,18.34,14.21.

[0404] (2) Preparation of Compound A93

[0405]

[0406] Under a nitrogen atmosphere, 1M TBAF THF solution (17.1 mL, 17.1 mmol, 1.5 equivalents) was added to a solution of compound A92 (6.3 g, 11.4 mmol, 1.0 equivalents) in anhydrous THF (50 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. Water (100 mL) was then added and the mixture was extracted three times with DCM. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was dissolved in 50 mL of pyridine and DMTrCl (4.6 g, 13.68 mmol, 1.2 equivalents) was added thereto. The reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A93 (6.23 g, 74% yield) as a yellow solid. The product was analyzed by mass spectrometry, 1 H NMR and 13 C NMR characterization. MW calculated: 741.34; MW found: 303.11 [DMT]-, 440.14 [DMT off + H] + . 1H NMR (400MHz, CDCl3) δ8.63(dd,J=5.7,1.5Hz,1H),8.43(d,J=1.0Hz,1H),7.97(dd,J=8.5,1.1Hz ,1H),7.45(d,J=7.4Hz,2H),7.37–7.28(m,11H),7.21(dd,J=8.1,6.1Hz,1H),6.83(t,J=5.9Hz,4 H),5.13(s,2H),4.12(t,J=7.2Hz,2H),3.95(s,3H),3.79(s,6H),3.24(d,J=6.2Hz,2H),3.14(t, J=6.2Hz, 2H), 2.83 (t, J=7.4Hz, 2H), 2.01 (dd, J=16.0, 8.5Hz, 4H), 1.79 (dd, J=14.1, 6.6Hz, 2H). 13 C NMR (100MHz, CDCl3) δ167.81,158.43,156.64,149.95,145.34,142.43,138.26,136.57,136.05,130.11,128.69,128.39,128.26,128.23 ,127.84,126.75,124.17,123.89,121.70,113.11,108.75,85.93,67 .02,62.90,55.31,52.16,41.37,38.64,30.50,29.76,27.30,24.53.

[0407] (3) Preparation of Compound A94

[0408]

[0409] Under nitrogen atmosphere and ice bath, to a solution of compound A93 (5.0 g, 6.74 mmol, 1.0 equivalent) in anhydrous THF (60 mL) was added LiAlH4 (384 mg, 10.11 mmol, 1.5 equivalents). After 10 minutes, the mixture was then transferred to room temperature and stirred for about 1 hour. The reaction was then transferred to an ice bath, and saturated potassium sodium tartrate solution (30 mL) was slowly added to the mixture. After 30 minutes of reaction, the reaction was extracted three times with Et2O, and the organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was dissolved in 20 mL of DMF, followed by the addition of imidazole (688 mg, 10.11 mmol, 1.5 equivalents) and TBSCl (1.524 g, 10.11 mmol, 1.5 equivalents). The reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A94 (4.78 g, 86% yield) as a yellow solid. The product was analyzed by mass spectrometry, 1 H NMR and 13 C NMR characterization. MW calculated: 827.43; MW found: 303.16 [DMT]-, 526.50 [DMT off + H] + . 1 H NMR(400MHz, CDCl3)δ7.69(s,1H),7.47–7.42(m,2H),7.40–7.28(m,11H),7.22 (t,J=3.5Hz,3H),6.86–6.80(m,4H),5.13(s,2H),4.86(s,2H),4.15(dd,J=14.3 ,7.2Hz,2H),3.79(s,6H),3.13(t,J=6.3Hz,2H),2.82(t,J=7.5Hz,2H),2.05–1 .94(m,4H),1.81–1.74(m,2H),1.29(t,J=7.1Hz,2H),0.97(s,9H),0.13(s,6H). 13CNMR(100MHz,CDCl3)δ171.27,158.45,156.60,154.95,145.40,142.93,13 6.66,135.52,134.14,130.14,128.70,128.37,128.28,127.85,126.74,120 .93,117.18,113.13,108.73,85.93,67.00,65.53,63.00,60.51,55.32,53.55,41.19,38.74,30.51,29.85,27.33,26.14,24.78,21.17,18.57,14.33.

[0410] (4) Preparation of Compound A96

[0411]

[0412] Under a nitrogen atmosphere, Pd / C (16 mg) was slowly added to a solution of compound A94 (264 mg, 0.319 mmol, 1.0 equivalent) in MeOH (5 mL). The reaction atmosphere was then replaced three times with hydrogen. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (8 mL), and then compound A77 (74 mg, 0.38 mmol, 1.2 equivalents), HBTU (242 mg, 0.64 mmol, 2.0 equivalents) and DIPEA (179 μL, 1.08 mmol, 3.4 equivalents) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. Then H2O (10 mL) was added to the reaction and the mixture was extracted with DCM (3*10 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A96 (236 mg, 85% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 869.52; MW found: 303.2 [DMT] - ,568.4[DMT Off+H] + . 1H NMR(400MHz, CDCl3)δ7.67(s,1H),7.44–7.39(m,2H),7.32–7.27(m,5H),7.26–7.14(m,4 H),6.83–6.78(m,4H),4.83(s,2H),4.11(t,J=7.4Hz,2H),3.78(s,6H),3.25(dd,J=13.2 ,6.7Hz,2H),3.10(t,J=6.2Hz,2H),2.86(dd,J=9.5,5.9Hz,2H),1.97(d,J=13.0Hz,6H), 1.85(s,2H),1.74–1.65(m,6H),1.59(dd,J=13.7,7.1Hz,9H),0.94(s,9H),0.10(s,6H).

[0413] (5) Preparation of Compound A97

[0414]

[0415] Under a nitrogen atmosphere, a solution of compound A96 (223 mg, 0.26 mmol, 1.0 equivalent) in anhydrous THF (7 mL) was added 1M TBAF THF solution (1.54 mL, 1.54 mmol, 6.0 equivalents). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (10 mL), followed by the addition of DMAP (110 mg, 0.90 mmol, 3.5 equivalents) and succinic anhydride (52 mg, 0.52 mmol, 2.0 equivalents) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then H2O (10 mL) was added to the reaction, the mixture was extracted with DCM (3*10 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A97 (116 mg, 53% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 855.45; MW found: 303.2 [DMT] - ,554.3[DMT Off+H] + . 1H NMR(400MHz, CDCl3)δ7.62(s,1H),7.42(dd,J=7.0,1.5Hz,2H),7.37(s,1H),7.32–7.2 6(m,6H),7.18(t,J=7.2Hz,2H),6.82–6.79(m,4H),5.19(s,2H),4.28–4.12(m,2H),3.7 8(s,6H),3.24(s,2H),3.09(t,J=6.2Hz,2H),2.88–2.83(m,2H),2.64(t,J=3.9Hz,4H) ,1.96(d,J=13.0Hz,6H),1.84(s,2H),1.73–1.66(m,6H),1.57(dd,J=13.7,7.1Hz,9H).

[0416] (6) Preparation of Compound A6

[0417]

[0418] Under a nitrogen atmosphere, HBTU (89 mg, 0.234 mmol, 2.0 equivalents) was added to a solution of compound A97 (100 mg, 0.117 mmol, 1.0 equivalents), controlled pore glass (CPG) (2.05 g), and DIPEA (58 μL, 0.35 mmol, 3.0 equivalents) in acetonitrile (16 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (7.02 mL), pyridine (13.5 mL), and NEt3 (211 μL) in acetonitrile (9 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A6 (1.76 g) of the present disclosure.

[0419] Example 6: Preparation of Compound A7 of the present disclosure

[0420] In this example, compound A7 was prepared using the following procedure:

[0421]

[0422] (1) Preparation of Compound A99

[0423]

[0424] Under a nitrogen atmosphere, to a solution of methyl 4-fluoro-3-nitrobenzoate A69 (8.0 g, 40.2 mmol, 1.0 equivalent) and K2CO3 (5.5 g, 40.2 mmol, 1.0 equivalent) in anhydrous DMF (100 mL) was added compound A98 (8.57 g, 40.2 mmol, 1.0 equivalent). The reaction mixture was stirred at 25 ° C for 6 h, and then cold water (100 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phase was then washed three times with a saturated LiCl solution and washed once with brine. The mixture was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to form compound A99 as a brown oil, which was used directly in the next step without further purification.

[0425] (2) Preparation of Compound A100

[0426]

[0427] To a solution of compound A99 (15.76 g, 40.17 mmol, 1.0 equiv) in THF / H2O (9:1, 165 mL) in an ice bath were added HCOONH4 (15.21 g, 241 mmol, 6.0 equiv) and Zn powder (15.76 g, 241 mmol, 6.0 equiv). After 10 minutes, the reaction mixture was brought to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Subsequently, water (100 mL) was added to the mixture, followed by extraction three times with ethyl acetate, and the organic phase was washed once with brine. After drying over anhydrous Na2SO4 and concentration under reduced pressure, compound A100 was formed as a brown oil, which was then used directly in the next step without further purification. The compound was characterized by mass spectrometry. MW calculated: 362.29; MW found: 363.4 [M+H] + .

[0428] (3) Preparation of Compound A102

[0429]

[0430] Under nitrogen atmosphere, to a solution of compound A100 (6.0 g, 16.56 mmol, 1.0 equiv) in EtOH (100 mL) was added compound A101 (1.69 g, 16.56 mmol, 1.0 equiv) and AcOH (3.8 mL, 66.24 mmol, 4.0 equiv). The reaction mixture was stirred at 80°C overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (100 mL) was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was used directly in the next step without further purification. The compound was characterized by mass spectrometry. MW calculated: 444.34; MW found: 445.4 [M+H] + .

[0431] The resulting residue (1.0 g, 2.25 mol, 1.0 eq) was dissolved in 10 mL of DCM, and Et3N (0.47 mL, 3.37 mmol, 1.5 eq) and DMTrCl (915 mg, 2.7 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. The resulting residue was used directly in the next step without further purification. The product A102 was characterized by mass spectrometry. MW calculated: 746.47; MW found: 303.2 [DMT] - .

[0432] (4) Preparation of Compound A103

[0433]

[0434] To a solution of compound A102 (1.6 g, 2.16 mmol, 1.0 equiv) in anhydrous THF (13 mL) was added LiAlH₄ (123 mg, 3.24 mmol, 1.5 equiv) under a nitrogen atmosphere and an ice bath. After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then returned to an ice bath, and saturated potassium sodium tartrate solution (10 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined, washed with brine, dried over Na₂SO₄, and concentrated. The crude product (500 mg, 0.70 mmol, 1.0 equiv) was dissolved in DCM (10 mL), and DMAP (298 mg, 2.45 mmol, 3.5 equiv) and succinic anhydride (140 mg, 1.40 mmol, 2.0 equiv) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then H2O (10 mL) was added to the reaction, the mixture was extracted with DCM (3*10 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A103 (285 mg, 53% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 818.49; MW found: 303.2 [DMT] - ,517.4[DMT off+H] + . 1 H NMR (400MHz, CDCl3) δ7.81 (s, 1H), 7.41 (d, J = 7.6Hz, 2H), 7.30 (d, J = 8.8Hz, 5H), 7.2 5–7.15(m,4H),6.80(d,J=8.8Hz,4H),5.26(s,2H),4.04(d,J=7.2Hz,2H),3.77(s,6H ),3.11(t,J=6.1Hz,2H),2.90(t,J=7.7Hz,2H),2.69(dd,J=8.4,4.5Hz,4H),2.02–1 .95(m,2H),1.74(dd,J=13.4,6.9Hz,4H),1.28–1.24(m,22H),0.87(t,J=6.7Hz,3H).

[0435] (5) Preparation of Compound A7

[0436]

[0437] Under a nitrogen atmosphere, HBTU (115 mg, 0.30 mmol, 2.0 equiv) was added to a solution of compound A103 (124 mg, 0.15 mmol, 1.0 equiv), controlled pore glass (CPG) (2.66 g), and DIPEA (75 μL, 0.45 mmol, 3.0 equiv) in acetonitrile (20 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (9.06 mL), pyridine (17.4 mL), and NEt3 (272 μL) in acetonitrile (11.6 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A7 (2.4 g) of the present disclosure.

[0438] Example 7: Preparation of Compound A8 of the present disclosure

[0439] In this example, compound A8 was prepared using the following procedure:

[0440]

[0441] (1) Preparation of Compound A105

[0442]

[0443] Under a nitrogen atmosphere, to a solution of methyl 4-fluoro-3-nitrobenzoate A104 (15 g, 75.3 mmol, 1.0 equivalent) and K2CO3 (10.4 g, 75.3 mmol, 1.0 equivalent) in anhydrous DMF (240 mL) was added compound A69 (18.18 g, 75.3 mmol, 1.0 equivalent). The reaction mixture was stirred at 25 ° C for 6 h, and then cold water (100 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phase was then washed three times with a saturated LiCl solution and washed once with brine. The mixture was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to form compound A105 as a brown oil, which was used directly in the next step without further purification.

[0444] (2) Preparation of Compound A106

[0445]

[0446] Under ice bath, to compound A105 (31.65g, 75.3mmol, 1.0 equivalent) in THF / H2O (9:1, 300mL) solution HCOONH4 (28.5g, 451.8mmol, 6.0 equivalent) and Zn powder (29.5g, 451.8mmol, 6.0 equivalent). After 10 minutes, the reaction mixture was moved to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Subsequently, water (100mL) was added to the mixture, followed by extraction with ethyl acetate three times, and the organic phase was washed once with salt water. After drying with anhydrous Na2SO4 and concentrating under reduced pressure, brown solid compound A106 was formed, which was directly used in the next step without further purification.

[0447] (3) Preparation of Compound A107

[0448]

[0449] To a solution of compound A106 (6.0 g, 15.4 mmol, 1.0 equiv) in EtOH (90 mL) under a nitrogen atmosphere were added compound A101 (1.57 g, 15.4 mmol, 1.0 equiv) and AcOH (3.54 mL, 61.6 mmol, 4.0 equiv). The reaction mixture was stirred at 80°C overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (80 mL) was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was used directly in the next step without further purification. The resulting residue was characterized by mass spectrometry. MW calculated: 472.37; MW found: 473.4 [M+H] + .

[0450] The resulting residue (1.0 g, 2.12 mol, 1.0 equivalent) was dissolved in 10 mL of DCM, and Et3N (0.44 mL, 3.17 mmol, 1.5 equivalents) and DMTrCl (860 mg, 2.54 mmol, 1.2 equivalents) were added thereto. The reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A107 (1.27 g, 77% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 774.50; MW found: 303.2 [DMT] - ,473.4[DMT Off+H] + . 1H NMR (400MHz, CDCl3) δ8.42(d,J=0.9Hz,1H),7.97(dd,J=8.5,1.4Hz,1H),7.42(d,J=7.4Hz ,2H),7.33–7.28(m,5H),7.25(d,J=6.8Hz,2H),7.19(t,J=7.3Hz,1H),6.80(dd,J=9.4,2.4 Hz,4H),4.05(t,J=7.5Hz,2H),3.93(s,3H),3.78(s,6H),3.12(t,J=6.3Hz,2H),2.92–2.8 0(m,2H),2.07–1.97(m,2H),1.82–1.71(m,4H),1.28-1.24(m,26H),0.88(t,J=6.8Hz,3H).

[0451] (4) Preparation of Compound A108

[0452]

[0453] To a solution of compound A107 (1.27 g, 1.64 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added LiAlH₄ (93 mg, 2.46 mmol, 1.5 equiv) under a nitrogen atmosphere and an ice bath. After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then transferred to an ice bath, and saturated potassium sodium tartrate solution (10 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined, washed with brine, dried over Na₂SO₄, and concentrated. The crude product (500 mg, 0.67 mmol, 1.0 equiv) was dissolved in DCM (10 mL), and DMAP (286 mg, 2.34 mmol, 3.5 equiv) and succinic anhydride (134 mg, 1.34 mmol, 2.0 equiv) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then H2O (10 mL) was added to the reaction, the mixture was extracted with DCM (3*10 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A108 (425 mg, 62% yield), which was a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 846.52; MW found: 303.2 [DMT] - ,545.4[DMT Off+H] + . 1H NMR (400MHz, CDCl3) δ7.81 (s, 1H), 7.42 (d, J = 7.5Hz, 2H), 7.30 (d, J = 8.8Hz, 4H), 7.25 (d, J = 7 .6Hz,3H),7.19(dd,J=14.9,7.9Hz,2H),6.80(d,J=8.8Hz,4H),5.26(s,2H),4.03(t,J=7.4Hz ,2H),3.77(s,6H),3.11(t,J=6.1Hz,2H),2.90(t,J=7.7Hz,2H),2.73–2.66(m,4H),1.99(dt, J=15.3,7.7Hz,2H),1.74(dd,J=13.5,6.9Hz,4H),1.29–1.25(m,26H),0.87(t,J=6.7Hz,3H).

[0454] (5) Preparation of Compound A8

[0455]

[0456] Under a nitrogen atmosphere, HBTU (102 mg, 0.268 mmol, 2.0 equivalents) was added to a solution of compound A108 (114 mg, 0.134 mmol, 1.0 equivalents), controlled pore glass (CPG) (2.36 g), and DIPEA (67 μL, 0.4 mmol, 3.0 equivalents) in acetonitrile (18 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (8.04 mL), pyridine (15.5 mL), and NEt3 (241 μL) in acetonitrile (10 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A8 (2.2 g) of the present disclosure.

[0457] Example 8: Preparation of Compound A9 of the Present Disclosure

[0458] In this example, compound A9 was prepared using the following procedure:

[0459]

[0460] (1) Preparation of Compound A110

[0461]

[0462] Under a nitrogen atmosphere, to a solution of methyl 4-fluoro-3-nitrobenzoate A69 (8.0 g, 40.2 mmol, 1.0 equivalent) and K2CO3 (5.55 g, 40.2 mmol) in anhydrous DMF (128 mL) was added compound A109 (10.83 g, 40.2 mmol, 1.0 equivalent). The reaction mixture was stirred at 25 ° C for 6 h, and then cold water (100 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phase was then washed three times with a saturated LiCl solution and washed once with brine. The mixture was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to form compound A110 as a brown oil, which was used directly in the next step without further purification.

[0463] (2) Preparation of Compound A111

[0464]

[0465] To a solution of compound A110 (13 g, 29 mmol, 1.0 equiv) in THF / H2O (9:1, 120 mL) was added HCOONH4 (10.98 g, 174 mmol, 6.0 equiv) and Zn powder (11.38 g, 174 mmol, 6.0 equiv) under an ice bath. After 10 minutes, the reaction mixture was brought to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Subsequently, water (100 mL) was added to the mixture, followed by extraction three times with ethyl acetate, and the organic phase was washed once with brine. After drying over anhydrous Na2SO4 and concentration under reduced pressure, compound A111 was formed as a brown solid, which was then used directly in the next step without further purification.

[0466] (3) Preparation of Compound A112

[0467]

[0468] Under a nitrogen atmosphere, compound A111 (6.0 g, 14.34 mmol, 1.0 equiv) was added to a solution of EtOH (80 mL) with compound A101 (1.46 g, 14.34 mmol, 1.0 equiv) and AcOH (3.3 mL, 57.36 mmol, 4.0 equiv). The reaction mixture was stirred at 80 ° C overnight and then concentrated under reduced pressure. Saturated NaHCO 3 solution (80 mL) was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na 2 SO 4, and concentrated. The resulting residue was used directly in the next step without further purification. The resulting residue was characterized by mass spectrometry. MW calculated: 500.40; MW found: 501.4 [M+H] + .

[0469] The resulting residue (1.5 g, 3.0 mol, 1.0 eq) was dissolved in 10 mL of DCM, and Et3N (0.625 mL, 4.5 mmol, 1.5 eq) and DMTrCl (1.2 g, 3.6 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. The resulting residue was used directly in the next step without further purification. The product A112 was characterized by mass spectrometry. MW calculated: 802.53; MW found: 303.2 [DMT] - .

[0470] (4) Preparation of Compound A113

[0471]

[0472] To a solution of compound A112 (1.7 g, 2.12 mmol, 1.0 equiv) in anhydrous THF (15 mL) was added LiAlH₄ (121 mg, 3.18 mmol, 1.5 equiv) under a nitrogen atmosphere and an ice bath. After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then moved to an ice bath, and saturated potassium sodium tartrate solution (10 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O, and the organic phases were combined, washed with brine, dried over Na₂SO₄, and concentrated. The crude product (500 mg, 0.65 mmol, 1.0 equiv) was dissolved in DCM (10 mL), and DMAP (276 mg, 2.27 mmol, 3.5 equiv) and succinic anhydride (129 mg, 1.29 mmol, 2.0 equiv) were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then H2O (10 mL) was added to the reaction, the mixture was extracted with DCM (3*10 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A113 (340 mg, 60% yield), which was a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 874.55; MW found: 303.2 [DMT] - ,573.4[DMT off+H] + . 1H NMR (400MHz, CDCl3) δ7.79(s,1H),7.42(d,J=7.5Hz,2H),7.30(d,J=8.8Hz,4H),7.26–7.22( m,4H),7.17(d,J=8.0Hz,1H),6.81(t,J=5.8Hz,4H),5.26(s,2H),4.02(t,J=7.4Hz,2H),3.77 (s,6H),3.11(t,J=6.1Hz,2H),2.88(t,J=7.7Hz,2H),2.69(dt,J=10.5,5.3Hz,4H),1.97(dd, J=15.0,7.6Hz,2H),1.74(dd,J=13.5,6.9Hz,4H),1.28-1.25(m,30H),0.87(t,J=6.8Hz,3H).

[0473] (5) Preparation of Compound A9

[0474]

[0475] Under a nitrogen atmosphere, HBTU (86 mg, 0.228 mmol, 2.0 equivalents) was added to a solution of compound A113 (100 mg, 0.114 mmol, 1.0 equivalents), controlled pore glass (CPG) (2.0 g), DIPEA (57 μL, 0.342 mmol, 3.0 equivalents) in acetonitrile (15 mL). The reaction mixture was stirred overnight at 25 ° C, then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (6.8 mL), pyridine (13 mL), NEt3 (210 μL) in acetonitrile (9 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C, then washed with DCM and diethyl ether to produce compound A9 (1.87 g) of the present disclosure.

[0476] Example 9: Preparation of Compounds A10 and A13 of the Present Disclosure

[0477] In this example, compounds A10 and A13 were prepared using the following procedure:

[0478]

[0479] (1) Preparation of Compound A115

[0480]

[0481] Under a nitrogen atmosphere, compound A106 (2.0 g, 5.12 mmol, 1.0 equiv) was added to a solution of EtOH (30 mL) with compound A114 (790 mg, 5.12 mmol, 1.0 equiv) and AcOH (1.18 mL, 20.48 mmol, 4.0 equiv) . The reaction mixture was stirred at 80 ° C overnight and then concentrated under reduced pressure. Saturated NaHCO 3 solution (20 mL) was then added and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na 2 SO 4 , and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-25% EA / hexane) to provide compound A115 (1.46 g, 54% yield) as a yellow oil. The product was characterized by mass spectrometry. MW calculated: 524.43; MW actual: 525.5 [M+H] + .

[0482] (2) Preparation of Compound A116

[0483]

[0484] To a solution of compound A115 (500 mg, 0.95 mmol, 1.0 equivalent) in MeOH (18 mL) was added 18 mL of 0.5 M NaOH aqueous solution at room temperature. The mixture was stirred overnight. The reaction was then acidified with 2 M HCl and extracted three times with Et2O. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The organic layer was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A116 of the present disclosure (400 mg, 82% yield) as a white solid. The product was characterized by mass spectrometry. MW calculated: 510.42; MW actual: 511.4 [M+H] + .

[0485] (3) Preparation of Compound A117

[0486]

[0487] Under a nitrogen atmosphere, Pd / C (30 mg) was slowly added to a solution of compound A94 (298 mg, 0.36 mmol, 1.0 equivalent) in MeOH (5 mL). The reaction atmosphere was then replaced three times with hydrogen. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was then filtered and concentrated under reduced pressure to provide a crude product A95. The crude product A95 was dissolved in DCM (5 mL), and compound A116 (220 mg, 0.432 mmol, 1.2 equivalents), HBTU (273 mg, 0.72 mmol, 2.0 equivalents) and DIPEA (203 μL, 1.224 mmol, 3.4 equivalents) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. H2O (10 mL) was then added to the reaction, and the mixture was extracted with DCM (3*10 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A117 (400 mg, 94% yield) as a yellow oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 1185.80; MW found: 303.2 [DMT] - . 1 H NMR(400MHz, CDCl3)δ8.05(d,J=1.3Hz,1H),7.43–7.40(m,2H),7.32–7.26(m,8H),7.23(dd,J=11.0,4.3Hz,3H),7.18(dd,J=7 .9,1.8Hz,1H),6.81–6.78(m,4H),6.38(t,J=5.8Hz,1H),5.09(t,J=7.0Hz,1H),4.83(s,2H),4.18(t,J=7.3Hz,2H),4.11–4.0 7(m,2H),3.76(s,6H),3.49(dd,J=13.0,6.6Hz,2H),3.09(t,J=6.2Hz,2H),2.91–2.83(m,4H),2.14–2.01(m,5H),1.80–1.73( m,4H),1.67(s,3H),1.59(s,3H),1.32-1.25(m,30H),0.99(d,J=6.6Hz,3H),0.94(s,9H),0.87(d,J=4.6Hz,3H),0.10(s,6H).

[0488] (4) Preparation of Compound A118

[0489]

[0490] Under a nitrogen atmosphere, a solution of compound A117 (400 mg, 0.337 mmol, 1.0 equivalent) in anhydrous THF (8 mL) was added 1M TBAF THF solution (2.02 mL, 2.02 mmol, 6.0 equivalents). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (10 mL), and DMAP (144 mg, 1.18 mmol, 3.5 equivalents) and succinic anhydride (67 mg, 0.674 mmol, 2.0 equivalents) were then added thereto under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, and then H2O (10 mL) was added to the reaction. The mixture was extracted with DCM (3*20 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A118 (235 mg, 60% yield) as a white solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 1171.73; MW found: 303.2 [DMT] - ,871.3[DMT Off+H] + . 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.65(s,1H),7.41(d,J=7.6Hz,2H),7.31–7.24(m,9H),7.18(dd,J=7.9,5.6H z,2H),6.80(d,J=8.8Hz,4H),5.20(s,2H),5.07(d,J=6.3Hz,1H),4.13(dt,J=15.1,7.1Hz,4H),3.76(s,6H),3. 33(dd,J=11.3,5.6Hz,4H),3.09(t,J=6.2Hz,2H),2.83(t,J=7.6Hz,2H),2.72-2.68(m,4H),2.15–2.04(m,5H), 1.76(dd,J=15.1,7.9Hz,4H),1.67(s,3H),1.60(s,3H),1.31–1.26(m,30H),0.96(s,3H),0.87(d,J=7.0Hz,3H).

[0491] (5) Preparation of Compound A10

[0492]

[0493] Under a nitrogen atmosphere, HBTU (110 mg, 0.29 mmol, 2.0 equiv) was added to a solution of compound A118 (170 mg, 0.145 mmol, 1.0 equiv), controlled pore glass (CPG) (2.54 g), and DIPEA (72 μL, 0.435 mmol, 3.0 equiv) in acetonitrile (15 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (8.67 mL), pyridine (16.8 mL), and NEt3 (260 μL) in acetonitrile (11 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A10 (2.38 g) of the present disclosure.

[0494] (6) Preparation of Compound A13

[0495]

[0496] To a solution of compound A116 (400 mg, 0.76 mmol, 1.0 equiv) in anhydrous THF (5 mL) under a nitrogen atmosphere and an ice bath was added LiAlH₄ (43 mg, 1.14 mmol, 1.5 equiv). After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then transferred to an ice bath, and saturated potassium sodium tartrate solution (10 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined and washed with brine, dried over Na₂SO₄, and concentrated to yield the crude product. To a solution of the crude compound and DIPEA (378 μL, 2.28 mmol, 3.0 equiv) in anhydrous DCM (5 mL) at 25°C under a nitrogen atmosphere was added 3-((chloro(diisopropylamino)phosphino)oxy)propionitrile (540 mg, 2.28 mmol, 3.0 equiv). The reaction mixture was stirred for 1 hour. The mixture was extracted twice with DCM, then washed with brine and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM, 1% NEt3) to provide compound A13 (397 mg, 75% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 696.55; MW found: 614.4 [M-diisopropylamine + 2H] + . 1H NMR(400MHz, CDCl3) δ7.68(s,1H),7.25(dd,J=8.6,3.9Hz,2H),4.85(dd,J=11.9,8.3Hz,1 H),4.75(dd,J=11.9,9.0Hz,1H),4.10–4.04(m,2H),3.90–3.78(m,2H),3.73–3.60(m,2H), 2.73(d,J=7.2Hz,2H),2.61(td,J=6.5,1.4Hz,2H),1.98–1.92(m,1H),1.88–1.52(m,8H),1 .36–1.23(m,31H),1.21(dd,J=6.8,0.7Hz,12H),1.15–0.98(m,3H),0.88(t,J=6.8Hz,3H).

[0497] Example 10: Preparation of Compounds A11 and A15 of the Present Disclosure

[0498] In this example, compounds A11 and A15 were prepared using the following procedure:

[0499]

[0500] (1) Preparation of Compound A120

[0501]

[0502] Under nitrogen atmosphere, to a solution of compound A106 (2.0 g, 5.12 mmol, 1.0 equiv) in EtOH (30 mL) was added compound A119 (958 mg, 5.12 mmol, 1.0 equiv) and AcOH (1.18 mL, 20.48 mmol, 4.0 equiv). The reaction mixture was stirred at 80 ° C overnight and then concentrated under reduced pressure. Saturated NaHCO 3 solution (30 mL) was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na 2 SO 4, and concentrated. The resulting residual compound A120 was used directly in the next step without further purification. Compound A120 was characterized by mass spectrometry. MW calculated: 557.36; MW found: 558.4 [M+H] + .

[0503] (2) Preparation of Compound A122

[0504]

[0505] To a solution of compound A121 (500 mg, 0.9 mmol, 1.0 equiv) in MeOH (18 mL) was added 18 mL of 0.5 M NaOH aqueous solution at room temperature. The mixture was stirred overnight. The reaction was then acidified with 2 M HCl and extracted three times with Et2O. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The organic layer was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A122 of the present disclosure (330 mg, 68% yield) as a white solid. The product was characterized by mass spectrometry. MW calculated: 543.35; MW actual: 544.5 [M+H] + .

[0506] (3) Preparation of Compound A123

[0507]

[0508] Under a nitrogen atmosphere, Pd / C (27 mg) was slowly added to a solution of compound A94 (273 mg, 0.33 mmol, 1.0 equivalent) in MeOH (5 mL). The reaction atmosphere was then replaced three times with hydrogen. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was then filtered and concentrated under reduced pressure to provide a crude product A95. The crude product A95 was dissolved in DCM (5 mL), and compound A122 (229 mg, 0.33 mmol, 1.0 equivalent), HBTU (250 mg, 0.66 mmol, 2.0 equivalent) and DIPEA (186 μL, 1.12 mmol, 3.4 equivalent) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. H2O (5 mL) was then added to the reaction, and the mixture was extracted with DCM (3*10 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A123 (249 mg, 62% yield) as a white solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 1218.73; MW found: 303.2 [DMT] - . 1H NMR(400MHz, CDCl3)δ9.19(s,1H),8.28(s,1H),7.73–7.69(m,2H),7.56(s,1H),7.29(d,J=7.0Hz,3H),7.18– 7.15(m,6H),7.07(dt,J=9.2,8.5Hz,6H),6.67(d,J=8.9Hz,4H),4.72(s,2H),4.12–4.05(m,2H),3.96(t,J=7 .0Hz,2H),3.64(s,6H),3.12(d,J=6.4Hz,2H),2.95(t,J=6.3Hz,2H),2.70–2.63(m,7H),1.82(dd,J=17.3,10 .5Hz,4H),1.59(dd,J=12.8,6.9Hz,4H),1.18–1.04(m,24H),0.83(s,9H),0.75(d,J=7.0Hz,3H),0.03(s,6H).

[0509] (4) Preparation of Compound A124

[0510]

[0511] Under a nitrogen atmosphere, a solution of compound A123 (230 mg, 0.19 mmol, 1.0 equivalent) in anhydrous THF (5 mL) was added 1M TBAF THF solution (1.13 mL, 1.13 mmol, 6.0 equivalents). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (6 mL), and then DMAP (81 mg, 0.66 mmol, 3.5 equivalents) and succinic anhydride (38 mg, 0.38 mmol, 2.0 equivalents) were added thereto under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, and then H2O (10 mL) was added to the reaction. The mixture was extracted with DCM (3*10 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A124 (126 mg, 55% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 1204.66; MW found: 303.2 [DMT] - . 1H NMR (400MHz, CDCl3) δ8.55(s,1H),8.07(d,J=8.2Hz,2H),7.73(d,J=8.1Hz,1H),7.63(d,J=10.8Hz,2H),7 .38(d,J=11.5Hz,4H),7.28(t,J=8.1Hz,6H),7.16(t,J=6.8Hz,4H),6.79(d,J=8.7Hz,4H),5.16(s,2H),4. 30–4.20(m,4H),3.75(s,6H),3.58(d,J=5.1Hz,2H),3.43–3.41(m,7H),3.07(s,2H),2.86(t,J=7.2Hz,2H ), 2.61 (d, J = 3.4Hz, 4H), 2.21–2.15 (m, 2H), 1.98–1.93 (m, 2H), 1.27–1.20 (m, 26H), 0.86 (d, J = 7.0Hz, 3H).

[0512] (5) Preparation of Compound A11

[0513]

[0514] Under a nitrogen atmosphere, HBTU (79 mg, 0.208 mmol, 2.0 equiv) was added to a solution of compound A124 (126 mg, 0.104 mmol, 1.0 equiv), controlled pore glass (CPG) (1.83 g), DIPEA (52 μL, 0.312 mmol, 3.0 equiv) in acetonitrile (12 mL). The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (6.2 mL), pyridine (12 mL), and NEt3 (186 μL) in acetonitrile (7.9 mL) was added to the crude solid support. The reaction mixture was stirred overnight at 25 ° C and then washed with DCM and diethyl ether to produce compound A11 (1.7 g) of the present disclosure.

[0515] (6) Preparation of Compound A15

[0516]

[0517] To a solution of compound A121 (300 mg, 0.538 mmol, 1.0 equiv) in anhydrous THF (5 mL) under a nitrogen atmosphere and an ice bath was added LiAlH₄ (31 mg, 0.8 mmol, 1.5 equiv). After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then moved to an ice bath, and saturated potassium sodium tartrate solution (5 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined and washed with brine, dried over Na₂SO₄, and concentrated to yield the crude product. To a solution of the crude compound and DIPEA (265 μL, 1.6 mmol, 3.0 equiv) in anhydrous DCM (5 mL) at 25°C under a nitrogen atmosphere was added 3-((chloro(diisopropylamino)phosphino)oxy)propionitrile (379 mg, 1.6 mmol, 3.0 equiv). The reaction mixture was stirred for 1 hour. The mixture was extracted twice with DCM, then washed with brine and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM, 1% NEt3) to provide compound A15 (274 mg, 70% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 729.47; MW found: 669.5 [M-diisopropylamine + Na] + . 1 H NMR(400MHz, CDCl3)δ8.28(s,1H),7.73-7.68(m,2H),7.56(s,1H),7.18–7.15(m,4H),4.72(s,2H),4.12–4.05(m,4 H), 2.70–2.63 (m, 7H), 1.92–1.88 (m, 2H), 1.27–1.23 (m, 26H), 1.21 (dd, J = 6.8, 0.7Hz, 12H), 0.88 (t, J = 6.8Hz, 3H).

[0518] Example 11: Preparation of Compound A12 of the Present Disclosure

[0519] In this example, compound A12 was prepared using the following procedure:

[0520]

[0521] (1) Preparation of Compound A126

[0522]

[0523] Under a nitrogen atmosphere, Pd / C (30 mg) was slowly added to a solution of compound A94 (298 mg, 0.36 mmol, 1.0 equivalent) in MeOH (5 mL). The reaction atmosphere was then replaced three times with hydrogen. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was then filtered and concentrated under reduced pressure to provide a crude product A95. The crude product A95 was dissolved in DCM (5 mL), and then compound A125 (111 mg, 0.43 mmol, 1.2 equivalents), HBTU (273 mg, 0.72 mmol, 2.0 equivalents) and DIPEA (203 μL, 1.22 mmol, 3.4 equivalents) were added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. H2O (5 mL) was then added to the reaction, and the mixture was extracted with DCM (3*10 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound A126 (295 mg, 88% yield) as a yellow oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 931.63; MW found: 303.2 [DMT] - . 1 H NMR (400MHz, CDCl3) δ7.68(s,1H),7.47–7.39(m,2H),7.32–7.23(m,9H),6.83–6.77(m,4 H),4.83(s,2H),4.10(t,J=7.3Hz,2H),3.78(s,6H),3.24(dd,J=13.2,6.7Hz,2H),3.11( t,J=6.2Hz,2H),2.06(dd,J=12.4,4.5Hz,2H),2.02–1.93(m,4H),1.79–1.72(m,2H),1.5 6(d,J=7.0Hz,2H),1.29-1.23(m,26H),0.94(s,9H),0.87(d,J=7.0Hz,3H),0.10(s,6H).

[0524] (2) Preparation of Compound A127

[0525]

[0526] Under a nitrogen atmosphere, a solution of compound A126 (270 mg, 0.29 mmol, 1.0 equivalent) in anhydrous THF (6 mL) was added 1M TBAF THF solution (1.74 mL, 1.74 mmol, 6.0 equivalents). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (10 mL), and DMAP (124 mg, 1.02 mmol, 3.5 equivalents) and succinic anhydride (58 mg, 0.58 mmol, 2.0 equivalents) were then added thereto under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, and then H2O (10 mL) was added to the reaction. The mixture was extracted with DCM (3*10 mL) and the organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-10% MeOH / DCM) to provide compound A127 (120 mg, 45% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 917.56; MW found: 303.2 [DMT] - . 1 H NMR (400MHz, CDCl3) δ7.64 (s, 1H), 7.46–7.40 (m, 3H), 7.31 (d, J = 8.8Hz, 4H), 7.25 (d, J = 7. 8Hz,2H),7.20(t,J=7.7Hz,2H),6.80(d,J=8.8Hz,4H),5.18(s,2H),4.31–4.18(m,2H),3. 78(s,6H),3.42–3.40(m,4H),3.09(t,J=6.3Hz,2H),2.87(t,J=7.5Hz,2H),2.67–2.62(m, 4H), 2.34(t,J=7.6Hz,2H), 2.05–1.92(m,4H), 1.29–1.23(m,26H), 0.88(t,J=6.8Hz,3H).

[0527] (3) Preparation of Compound A12

[0528]

[0529] Under a nitrogen atmosphere, HBTU (99 mg, 0.26 mmol, 2.0 equivalents) was added to a solution of compound A127 (120 mg, 0.13 mmol, 1.0 equivalents), controlled pore glass (CPG) (2.29 g), DIPEA (65 μL, 0.39 mmol, 3.0 equivalents) in acetonitrile (15 mL). The reaction mixture was stirred overnight at 25 ° C, then washed with DCM and ether to produce a crude solid support. Under a nitrogen atmosphere, a solution of acetic anhydride (7.8 mL), pyridine (15 mL), NEt3 (234 μL) in acetonitrile (10 mL) was added to a crude solid support. The reaction mixture was stirred overnight at 25 ° C, then washed with DCM and ether to produce compound A12 (2.1 g) of the present disclosure.

[0530] Example 12: Preparation of Compound A14 of the Present Disclosure

[0531] In this example, compound A14 was prepared using the following procedure:

[0532]

[0533] (1) Preparation of compound A129:

[0534]

[0535] Under nitrogen atmosphere, to a solution of compound A106 (1.55 g, 3.96 mmol, 1.0 equiv) in EtOH (20 mL) was added compound A128 (500 mg, 3.96 mmol, 1.0 equiv) and AcOH (913 μL, 15.84 mmol, 4.0 equiv). The reaction mixture was stirred at 80°C overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (20 mL) was then added, and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residual compound A129 was used directly in the next step without further purification. Compound A129 was characterized by mass spectrometry. MW calculated: 496.40; MW found: 497.5 [M+H] + .

[0536] (2) Preparation of Compound A14

[0537]

[0538] To a solution of compound A129 (400 mg, 0.806 mmol, 1.0 equiv) in anhydrous THF (5 mL) under a nitrogen atmosphere and an ice bath was added LiAlH₄ (46 mg, 1.2 mmol, 1.5 equiv). After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then transferred to an ice bath, and saturated potassium sodium tartrate solution (5 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined and washed with brine, dried over Na₂SO₄, and concentrated to yield the crude product. To a solution of the crude compound and DIPEA (401 μL, 2.42 mmol, 3.0 equiv) in anhydrous DCM (5 mL) at 25°C under a nitrogen atmosphere was added 3-((chloro(diisopropylamino)phosphino)oxy)propionitrile (573 mg, 2.42 mmol, 3.0 equiv). The reaction mixture was stirred for 1 hour. The mixture was extracted twice with DCM, then washed with brine and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-3% MeOH / DCM, 1% NEt3) to provide compound A14 (339 mg, 63% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 668.52; MW found: 607.4 [M-diisopropylamine + Na] + . 1 H NMR (400MHz, CDCl3) δ7.62 (s, 1H), 7.19 (dd, J = 6.9, 2.8Hz, 2H), 5.03 (t, J = 7.0Hz, 1H), 4.81–4. 79(m,1H),4.71–4.66(m,1H),4.04–3.98(m,2H),3.79(dd,J=6.9,2.8Hz,1H),3.60(ddd,J=13.6 ,6.8,3.4Hz,2H),2.82–2.78(m,1H),2.61–2.53(m,3H),1.63–1.60(m,3H),1.54–1.52(m,3H), 1.33–1.17(m,30H),1.14(dd,J=6.8,2.0Hz,12H),0.92(d,J=6.6Hz,3H),0.82(t,J=6.8Hz,3H).

[0539] Example 13: Preparation of Compound B1 of the Present Disclosure

[0540] In this example, compound B1 was prepared using the following procedure:

[0541]

[0542] Compound B1

[0543] (1) Preparation of compound B12 from 4-fluoro-3-nitrobenzoic acid:

[0544]

[0545] Under a nitrogen atmosphere, benzyl bromide (35.6 g, 207.98 mmol, 1.1 equiv) was slowly added to a solution of 4-fluoro-3-nitrobenzoic acid (35 g, 189.1 mmol, 1.0 equiv) and Na2CO3 (30.6 g, 283.6 mmol, 1.5 equiv) in anhydrous DMF (500 mL). The reaction mixture was stirred at 45°C for 3 h, after which cold water (200 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phase was then washed three times with saturated LiCl and once with brine. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to form a yellow oil (Compound B12), which was used directly in the next step without further purification.

[0546] (2) Compound B13 was prepared from Compound B12 by SNAr reaction of tert-butyl (3-aminopropyl)carbamate.

[0547]

[0548] Under nitrogen atmosphere, to a solution of compound B12 (52g, 189.1mmol, 1.0 equivalent) and KCO (26.13g, 189.1mmol, 1.0 equivalent) in anhydrous DMF (500mL) was added tert-butyl (3-aminopropyl) carbamate (32.9g, 189.1mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 3h, then cold water (200mL) was added. The mixture was extracted 3 times with ethyl acetate, and then the organic phase was washed 3 times with saturated LiCl and 1 time with brine. After drying with anhydrous NaSO and concentrating under reduced pressure, a yellow solid B13 was formed, which was then directly used in the next step without further purification.

[0549] (3) Compound B14 is produced by reducing compound B13.

[0550]

[0551] Under ice bath, to the solution of compound B13 (81.16g, 189.1mmol, 1.0 equivalent) in THF / H2O (9:1, 666mL) was added HCOONH4 (71.58g, 1.134mol, 6.0 equivalent) and Zn powder (74.19g, 1.134mol, 6.0 equivalent). After 10 minutes, the reaction mixture was moved to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Subsequently, water (200mL) was added to the mixture, and then the mixture was extracted 3 times with ethyl acetate and the organic phase was washed once with brine. The organic phase was dried over anhydrous NaSO4 and concentrated under reduced pressure to form a light red solid (compound B14), which was used directly in the next step without further purification.

[0552] (4) Compound B15 is produced by acylation of compound B14 with N2,N6-bis(tert-butoxycarbonyl)-L-lysine.

[0553]

[0554] Under a nitrogen atmosphere, to a solution of compound B14 (16.8 g, 42 mmol, 1.0 equivalent) in DCM (300 mL) was added N2, N6-bis(tert-butoxycarbonyl)-L-lysine (21.82 g, 63 mmol, 1.5 equivalents), EDCI (12.08 g, 63 mmol, 1.5 equivalents) and DMAP (2.565 g, 21 mmol, 0.5 equivalents). The reaction mixture was stirred at room temperature overnight. 200 mL of H2O was then added to the reaction mixture and the mixture was extracted with DCM (3*100 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified using flash chromatography (silica gel, gradient eluent: 1-50% EA / hexane) to provide compound 15 (27.5 g, 90% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 727.42; MW found: 728.47 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.88(dd,J=8.6,1.9Hz,1H),7.79(s,1H),7.35(ddt,J=9.8,7.1,5.5Hz,5H),6.62(d,J=8.6Hz,1H), 5.29(s,2H),4.16(s,1H),3.37–2.97(m,6H),1.78(d,J=25.4Hz,4H),1.51(s,2H),1.48–1.35(m,27H),1.36–1.13(m,2H).

[0555] (5) Compound B16 includes a benzimidazole structure and is prepared from compound B15.

[0556]

[0557] Under a nitrogen atmosphere, compound B15 (20 g, 27.5 mmol, 1.0 equivalent) was added to AcOH (100 mL). The reaction mixture was stirred at 95 ° C for 4 h. Saturated NaHCO3 solution (100 mL) was then added thereto, the mixture was extracted 3 times with ethyl acetate, the organic phases were combined and washed with saturated NaHCO3 solution (3*100 mL), dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-50% EA / hexane) to provide compound B16 (8.78 g, 45% yield) as a white solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 709.41; MW found: 710.57 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.50(s,1H),8.04(dd,J=8.5,1.4Hz,1H),7.46(d,J=7.0Hz,2H),7.41(s,1H),7.38–7.34(m,3H),5. 39(s,2H),5.02(dd,J=15.8,7.7Hz,1H),3.20-3.10(m,6H),2.08-1.96(m,4H),1.57–1.48(m,4H),1.41(d,J=8.6Hz,27H).

[0558] (6) Compound B17 was prepared by using (2S,3R,4R,5R,6R)-3-acetamido-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate as the starting material.

[0559]

[0560] Under a nitrogen atmosphere, TMSOTf (15.3 mL, 84.7 mmol, 1.1 equiv) was added to a solution of (2S, 3R, 4R, 5R, 6R) -3-acetylamino-6- (acetoxymethyl) tetrahydro -2H- pyran-2,4,5-triyl triacetate (30 g, 77 mmol, 1.0 equiv) in DCM (300 mL). The reaction mixture was stirred at room temperature for 6 h. NaHCO3 solution (21 g NaHCO3 in 200 mL water) was then added under an ice bath, and the reaction was transferred to room temperature. After stirring for 30 minutes, the mixture was extracted 3 times with DCM, and the organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-50% EA / hexane) to provide compound B17 (19.8 g, 78% yield). The product was separated by mass spectrometry and 1 H NMR characterization. MW calculated: 329.11; MW found: 330.33 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.97(d,J=9.5Hz,1H),5.39(s,1H),5.26(dd,J=11.4,3.2Hz,1H),4.53(td,J=11.4,3.4H z,1H),4.43(t,J=6.5Hz,1H),4.27(s,1H),4.11–4.08(m,1H),2.17(s,3H),2.05(s,3H),2.00(d,J=7.3Hz,6H).

[0561] (7) An alkoxy group having a terminal vinyl group is connected to compound B17.

[0562]

[0563] Under a nitrogen atmosphere, to a solution of compound B17 (15 g, 45.6 mmol, 1.0 equivalent) in DCE (200 mL) was added dec-9-en-1-ol (8.5 g, 54.7 mmol, 1.2 equivalent) and TMSOTf (1.6 mL, 9.1 mmol, 0.2 equivalent). The reaction mixture was stirred at room temperature for 6 h. Saturated NaHCO3 solution (100 mL) was then added thereto, the mixture was extracted 3 times with DCM, the organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound B20 (19.6 g, 89% yield). The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 485.26; MW found: 486.48 [M+H] + .1 H NMR (400MHz, CDCl3) δ5.84-5.74(m,1H),5.49(d,J=8.5Hz,1H),5.35(d,J=2.7Hz,1H), 5.33–5.25(m,2H),5.01–4.88(m,2H),4.70(d,J=8.4Hz,1H),4.20–4.07(m,2H),3.94– 3.80(m,3H),3.47(dt,J=9.5,6.9Hz,1H),2.13(s,3H),2.03(s,3H),1.98(d,J=9.7Hz, 3H), 1.95 (d, J = 10.1Hz, 3H), 1.56 (d, J = 6.4Hz, 2H), 1.35 (d, J = 6.7Hz, 2H), 1.27 (s, 8H).

[0564] (8) The terminal vinyl group of compound B20 is oxidized to a carboxyl group.

[0565]

[0566] Under ice bath, to a solution of compound B20 (19.6 g, 40.4 mmol, 1.0 equiv) in ACN / DCM / H2O (50 mL / 50 mL / 60 mL) was added NaIO4 (34.6 g, 161.6 mol, 4.0 equiv) and RuCl3·3H2O (1.66 g, 8.0 mol, 0.2 equiv). After 10 minutes, the reaction mixture was transferred to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Subsequently, water (50 mL) was added to the mixture, and the mixture was extracted 3 times with DCM, and the organic phase was washed once with brine. After drying over anhydrous Na2SO4 and concentrating under reduced pressure, the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-8% MeOH / DCM) to provide compound B21 (17 g, 84% yield). The product was identified by mass spectrometry and 1 H NMR characterization. MW calculated: 503.24; MW found: 504.49 [M+H] + . 1H NMR (400MHz, CDCl3) δ5.65(d,J=8.7Hz,1H),5.35(d,J=2.8Hz,1H),5.31(d,J=6.1Hz,1H),4.68(d,J=8.3Hz,1H),4.18–4.12(m,2H),3.91(dd,J=11 .8,5.4Hz,2H),3.48(dd,J=9.7,6.7Hz,1H),2.35(t,J=7.2Hz,2H),2.15( s,3H),2.05(s,3H),2.01(s,3H),1.96(s,3H),1.63(s,2H),1.32(s,10H).

[0567] (9) Compounds B16 and B21 are linked together.

[0568]

[0569] To a solution of compound B16 (4.56g, 6.4mmol, 1.0 equivalent) in DCM (10mL) was added HCl / dioxane (4M, 30mL). The reaction mixture was stirred at room temperature for 3h, then concentrated under reduced pressure to provide a crude product as a yellow solid. The crude product was dissolved in 50mL DCM, and then under a nitrogen atmosphere, compound 21 (9.66g, 19.2mmol, 3.0 equivalents), HBTU (8.49g, 22.4mmol, 3.5 equivalents) and DIPEA (12.72mL, 76.8mmol, 12.0 equivalents) were added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. 50mLH2O was then added to the reaction mixture, and the mixture was extracted with DCM (3*50mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-8% MeOH / DCM) to provide compound B22 (10.4 g, 87% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 H NMR characterization. MW calculated: 1864.93; MW found: 1895.54 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.45(s,1H),8.04(dd,J=8.5,1.4Hz,1H),7.46(d,J=7.1Hz,2H),7.36(dd,J=13.2,7.3Hz,4 H),5.39(s,2H),5.35(d,J=3.2Hz,4H),5.29(s,6H),4.75–4.63(m,4H),4.14(qd,J=11.1,6.8Hz,9H),3.92(dd,J= 13.0,6.4Hz,6H),3.64(dd,J=13.0,6.6Hz,4H),3.49–3.42(m,4H),3.12–3.06(m,3H),2.19(dd,J=11.6,7.5Hz,6 H),2.13(s,9H),2.03(s,9H),1.99(s,9H),1.93(d,J=2.6Hz,9H),1.54–1.50(m,12H),1.45(s,6H),1.25(s,18H).

[0570] (10) Reducing compound B22 to produce compound B1 of the present disclosure.

[0571]

[0572] Under a nitrogen atmosphere, Pd / C (100 mg) was slowly added to a solution of compound B22 (1.4 g, 0.75 mmol, 1.0 equivalent) in MeOH (25 mL). The reaction atmosphere was then replaced with hydrogen three times. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was then filtered and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-15% MeOH / DCM) to provide compound B1 (1.2 g, 90% yield) as a colorless oil. The product was analyzed by mass spectrometry and 1 The product was characterized by mass spectrometry and 1 H NMR characterization. MW calculated: 1774.88; MW found: 1775.32 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.73(s,1H),8.18(d,J=8.4Hz,1H),7.55(d,J=8.6Hz,1H),5.36–5.27(m,6H),4.69(d,J= 7.9Hz,2H),4.56–4.37(m,2H),4.17–4.08(m,6H),4.00–3.88(m,6H),3.88–3.77(m,3H),3.65(dd,J=13.3,6.6H z,2H),3.50–3.39(m,4H),3.11–3.03(m,2H),2.20(dd,J=17.0,9.2Hz,8H),2.13(d,J=1.5Hz,9H),2.04–2.02(m ,9H),1.98(d,J=1.9Hz,9H),1.94–1.89(m,9H),1.60–1.52(m,16H),1.44(d,J=6.4Hz,6H),1.31–1.20(m,24H).

[0573] Example 14: Preparation of Compound B2 of the Present Disclosure

[0574] In this example, compound B2 was prepared using the following procedure:

[0575]

[0576] Compound B2

[0577] (1) This step involves preparing compound B38 from methyl 4-fluoro-3-nitrobenzoate.

[0578]

[0579] Under a nitrogen atmosphere, to a solution of 4-fluoro-3-nitrobenzoic acid methyl ester (8.0 g, 40.2 mmol, 1.0 equivalent) and K2CO3 (5.5 g, 40.2 mmol) in anhydrous DMF (100 mL) was added (3-aminopropyl) benzyl carbamate (8.3 g, 40.2 mmol, 1.0 equivalent). The reaction mixture was stirred at 25 ° C for 6 h, and then cold water (100 mL) was added. The mixture was extracted with ethyl acetate 3 times, and then the organic phase was washed 3 times with saturated LiCl and 1 time with brine. It was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to form a yellow solid (Compound B38), which was used directly in the next step without further purification.

[0580] (2) Converting compound B38 into compound B39.

[0581]

[0582] Under ice bath, to the solution of compound B38 (10g, 25.84mmol, 1.0 equivalent) in THF / H2O (9:1, 100mL) was added HCOONH4 (9.78g, 155.04mmol, 6.0 equivalent) and Zn powder (10.14g, 155.04mmol, 6.0 equivalent). After 10 minutes, the reaction mixture was moved to room temperature and stirred overnight. The reaction mixture was then filtered and concentrated under reduced pressure. Subsequently, water (100mL) was added to the mixture, which was then extracted 3 times with ethyl acetate and the organic phase was washed once with brine. After drying over anhydrous Na2SO4 and concentrating under reduced pressure, a light red solid (compound B39) was formed, which was then used directly in the next step without further purification.

[0583] (3) Compound B40 containing a benzimidazole structure is formed from compound B39.

[0584]

[0585] To a solution of compound B39 (8.0 g, 22.5 mmol, 1.0 equiv) in EtOH (200 mL) under a nitrogen atmosphere were added 3-((tert-butyldimethylsilyl)oxy)propanal (4.2 g, 22.5 mmol, 1.0 equiv) and AcOH (5.1 mL, 90 mmol, 4.0 equiv). The reaction mixture was stirred at 80°C overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (100 mL) was then added and the mixture was extracted three times with ethyl acetate. The organic phases were then combined and washed with brine, dried over Na2SO4, and concentrated. The resulting residue (compound B40) was used directly in the next step without further purification. Compound B40 was characterized by mass spectrometry. MW calculated: 525.27; MW found: 526.59 [M+H] + .

[0586] (4) The tert-butyldimethylsilyl (TBS) protecting group contained in compound B40 was replaced with a 4,4'-dimethoxytrityl (DMT) group.

[0587]

[0588] Under a nitrogen atmosphere, 1M TBAF THF solution (14.25 mL, 14.25 mmol, 1.5 equivalents) was added to a solution of compound B40 (5.0 g, 9.5 mmol, 1.0 equivalents) in anhydrous THF (50 mL). The reaction mixture was stirred at room temperature for about 1 h and then concentrated under reduced pressure. Water (100 mL) was then added and the mixture was extracted 3 times with DCM, followed by combining the organic phases and washing with brine, drying over Na2SO4, and concentrating. The resulting residue was dissolved in 50 mL of pyridine and DMTrCl (3.86 g, 11.4 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 6 h and, after concentration under reduced pressure, the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound B41 (4.1 g, 60% yield) as a yellow solid. The product was characterized by mass spectrometry and 1 H NMR characterization. MW calculated: 713.31; MW found: 303.17 [DMT]-, 412.36 [DMT off + H] + . 1 H NMR(400MHz, CDCl3)δ8.39(d,J=1.1Hz,1H),7.96(dd,J=8.5,1.3Hz,1H),7.38–7.27(m,8H),7.20(dq,J=6.7,2.5Hz,7H),6.76–6.70(m,4H),5.10 (s,2H),4.19(t,J=7.3Hz,2H),3.94(s,3H),3.74(s,6H),3.65(t,J=6.6 Hz, 2H), 3.20 (d, J = 6.3 Hz, 2H), 3.09 (t, J = 6.4 Hz, 2H), 2.00–1.90 (m, 2H).

[0589] (5) The carbonyloxy group contained in compound B41 is reduced to a methyleneoxy group to produce compound B42.

[0590]

[0591] To a solution of compound B41 (4.0 g, 5.6 mmol, 1.0 equiv) in anhydrous THF (50 mL) was added LiAlH₄ (319 mg, 8.4 mmol, 1.5 equiv) under a nitrogen atmosphere and an ice bath. After 10 minutes, the mixture was brought to room temperature and stirred for 1 hour. The reaction was then moved to an ice bath, and a saturated solution of potassium sodium tartrate (30 mL) was slowly added to the mixture. After 30 minutes, the reaction was extracted three times with Et₂O. The organic phases were then combined, washed with brine, dried over Na₂SO₄, and concentrated. The resulting residue was dissolved in 50 mL of DMF, followed by the addition of imidazole (572 mg, 8.4 mmol, 1.5 equiv) and TBSCl (1.27 g, 8.4 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 1 h, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound B42 (4.03 g, 90% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 HNMR characterization: MW calculated: 799.40; MW found: 303.17 [DMT]. 1 H NMR(400MHz, CDCl3)δ7.65(s,1H),7.38–7.29(m,7H),7.19(ddd,J=8.4,7.9,3.7Hz,9H),6.78–6.71(m,4H),5.10(s,2H),4.84(s,2H),4.16(t,J= 7.2Hz,2H),3.75(s,6H),3.61(t,J=6.8Hz,2H),3.18(d,J=6.3Hz,2H),3. 07(t,J=6.4Hz,2H),2.95(s,1H),2.88(s,1H),0.94(s,9H),0.10(s,6H).

[0592] (6) Compound B22 was derived from steps (1) to (9) of Example 13.

[0593] (7) Compound B43 derived from the reduction of Compound B42 is linked to Compound B22.

[0594]

[0595] Under a nitrogen atmosphere, Pd / C (136 mg) was slowly added to a solution of compound B22 (1.36 g, 0.732 mmol, 1.1 equivalents) in MeOH (15 mL). The reaction atmosphere was then replaced three times with hydrogen. Subsequently, the reaction mixture was stirred overnight by purging with a hydrogen balloon at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to provide a crude product. The crude product was dissolved in DCM (15 mL), and then HBTU (508 mg, 1.34 mmol, 2.0 equivalents) and DIPEA (375 μL, 2.28 mmol, 3.4 equivalents) were added to the reaction mixture under a nitrogen atmosphere. After 5 minutes, compound B43 (446 mg, 0.67 mmol, 1.0 equivalents) produced by reducing compound B42 was added to the reaction. The reaction mixture was stirred at room temperature overnight. Then H2O (20 mL) was added to the reaction and the mixture was extracted with DCM (3*50 mL). The organic phases were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by flash chromatography (silica gel, gradient eluent: 1-5% MeOH / DCM) to provide compound B24 (1.5 g, 93% yield) as a yellow solid. The product was analyzed by mass spectrometry and 1 H NMR characterization: MW calculated:...

Claims

1. An oligonucleotide delivery enhancing compound comprising a nitrogen-containing five-membered heterocyclic moiety and at least one substituent capable of being directly or indirectly linked to an oligonucleotide.

2. The oligonucleotide delivery enhancing compound according to claim 1, which has a structure represented by Formula AI or Formula AII: Each of these independently represents a covalent single or double bond; X at each occurrence is an atom selected from carbon, nitrogen, oxygen and sulfur; F, G, H and I are each independently selected from carbon, nitrogen, oxygen and sulfur; wherein m is an integer of 1, 2, or 3, n is an integer of 1, 2, or 3, and m+n=4; wherein C at each occurrence is either absent or selected from: hydrogen, a halogen atom, a hydroxyl group, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 ) alkyl and halogenated (C1-C 20 ) alkoxy; wherein B is independently selected at each occurrence from the group consisting of hydroxy, -C(O)OH, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 22 )alkyl, -(C1-C 22 )alkenyl, -(C1-C 22 ) alkylene-OH, -(C3-C 22 )cycloalkylene-OH, -(C6-C 22 )arylene-OH, -(C6-C 22 )heteroarylene-OH, -(C1-C 22 )alkylene-C(O)OH, -(C3-C 22 )cycloalkylene-C(O)OH, -(C6-C 22 )arylene-C(O)OH, -(C5-C 22 )heteroarylene-C(O)OH, -OC(O)-(C1-C 22 )alkylene-C(O)NH2, -(C1-C 22 )alkylene-OC(O)-(C1-C 22 )alkylene-C(O)NH2, -OC(O)-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-OC(O)-(C1-C 22 )alkylene-C(O)OH, -C(O)-(C1-C 22 )alkylene-C(O)NH2, -(C1-C 22 )alkylene-C(O)-(C1-C 22 )alkylene-C(O)NH2, -C(O)-NH-(C1-C 22 ) alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22 ) alkylene-CN, wherein each of A1, A2 and A3 is either absent or a substituent independently selected from the group consisting of: -H, -OH, -OR 1 ,-SH,-(C1-C 25 )alkyl, halo-(C1-C 25 )alkyl, -(C2-C 22 )alkenyl, -(C1-C 22 ) alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )Alkylene-COOR 1 、-C(O)OR 1 、-O-(C1-C 22 )alkyl, -S-(C1-C 22 )alkyl, -C(O)-R 1 、-C(O)-(C1-C 22 )alkyl, -OC(O)-(C1-C 22 )alkyl, -OC(O)-R 1 、-(C1-C 22 )alkylene-OC(O)-R 1 、-C(O)-(C1-C 22 )alkylene-OH, -C(O)-(C1-C 22 )alkylene-R 1 、-C(O)-(C1-C 22 )alkylene-NH-R 1 、-C(O)-(C1-C 22 )Alkylene-NR 2 -R 1 、-OC(O)-(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 22 )alkylene-R 1 , -adamantyl, -(C1-C 22 )alkylene-adamantyl, -O-adamantyl, -C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-C(O)-(C1-C 22 ) alkylene-adamantyl, -NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-halogeno(C1-C 22 )alkyl, -CH(NH-CO-(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl]3, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 ]3. -CH(NH-CO-halogenated(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-halogeno(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )Alkylene-NR 2 -C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -C(O)NH-(C1-C 22 )alkyl, -C(O)NH-R 1 、-C(O)NR 2 -R 1 、-C(O)NH-(C1-C 22 )alkylene-OH, -C(O)NH-(C1-C 22 )alkylene-COOH, -NH-C(O)-(C1-C 22 )alkyl, -NH-C(O)-R 1 、-NR 2 -C(O)-R 1 、-OP(O)2-OR 1 、-OP(O)(S)-OR 1 、-OP(O)-OR 1 、-NH-R 1 、-NR 2 -R 1 、-(C1-C 22 )alkylene-NH-R 1 、-(C1-C 22 )Alkylene-NR 2 -R 1 、-C(O)-(C1-C 22 )alkylene-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-C(O)OR 1 、-C(O)-(C1-C 22 )alkylene-NH-C(O)-R 1 、-C(O)-(C1-C 22 )Alkylene-NR 2 -C(O)-R 1 、-(C1-C 22 )alkylene-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )Alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzothiazole, and a substituent represented by formula AIII, wherein Y is selected from carbon, nitrogen, oxygen, and sulfur; and each of P, Q, S, and T is independently selected from carbon, nitrogen, oxygen, and sulfur; and the asterisk refers to the position at which the substituent represented by Formula AIII is attached to the structure represented by Formula AI or Formula AII; Where R 3 , R 4 and R 5 Each of is either absent or is a substituent independently selected from the group consisting of: -H, -OH, -OR 1 ,-SH,-(C1-C 25 )alkyl, halo-(C1-C 25 )alkyl, -(C2-C 22 )alkenyl, -(C1-C 22 ) alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )Alkylene-COOR 1 、-C(O)OR 1 、-O-(C1-C 22 )alkyl, -S-(C1-C 22 )alkyl, -C(O)-R 1 、-C(O)-(C1-C 22 )alkyl, -OC(O)-(C1-C 22 )alkyl, -OC(O)-R 1 、-(C1-C 22 )alkylene-OC(O)-R 1 、-C(O)-(C1-C 22 )alkylene-OH, -C(O)-(C1-C 22 )alkylene-R 1 、-C(O)-(C1-C 22 )alkylene-NH-R 1 、-C(O)-(C1-C 22 )Alkylene-NR 2 -R 1 、-OC(O)-(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 22 )alkylene-R 1 , -adamantyl, -(C1-C 22 )alkylene-adamantyl, -O-adamantyl, -C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-C(O)-(C1-C 22 ) alkylene-adamantyl, -NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-halogeno(C1-C 22 )alkyl, -CH(NH-CO-(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl]3, -C(O)-(C1-C 22 )alkylene-C(O)-NH-C[-(C1-C 22 )alkylene-O-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 ]3. -CH(NH-CO-halogenated(C1-C 22 )alkyl)-(C1-C 22 )alkylene-NH-C(O)-halogeno(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )Alkylene-NR 2 -C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -C(O)NH-(C1-C 22 )alkyl, -C(O)NH-R 1 、-C(O)NR 2 -R 1 、-C(O)NH-(C1-C 22 )alkylene-OH, -C(O)NH-(C1-C 22 )alkylene-COOH, -NH-C(O)-(C1-C 22 )alkyl, -NH-C(O)-R 1 、-NR 2 -C(O)-R 1 、-OP(O)2-OR 1 、-OP(O)(S)-OR 1 、-OP(O)-OR 1 、-NH-R 1 、-NR 2 -R 1 、-(C1-C 22 )alkylene-NH-R 1 、-(C1-C 22 )Alkylene-NR 2 -R 1 、-C(O)-(C1-C 22 )alkylene-C(O)-R 1 、-C(O)-(C1-C 22 )alkylene-C(O)OR 1 、-C(O)-(C1-C 22 )alkylene-NH-C(O)-R 1 、-C(O)-(C1-C 22 )Alkylene-NR 2 -C(O)-R 1 、-(C1-C 22 )alkylene-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )Alkylene-NR 2 -C(O)-(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-P(O)-OH, -(C1-C 22 )alkylene-P(O)(S)-OH, -(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole and substituted or unsubstituted benzothiazole, Where R 7 is connected to any one of P, Q, S and T at each occurrence and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 ) alkyl and halogenated (C1-C 20 ) alkoxy; Wherein M is an integer of 0, 1, 2 or 3; Where R 6 is connected to any one of P, Q, S and T, and is selected from a direct bond, -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-O-, -O-(C1-C 22 )alkylene-, -(C1-C 22 ) alkylene-NH-, -NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-C(O)-, -C(O)-O-(C1-C 22 )alkylene-, -(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-OC(O)-, -C(O)-NH-(C1-C 22 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 22 )alkylene-O-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-O-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-, -C(O)-N((C1-C 22 )alkyl)-(C1-C 22 )alkylene-C(O)-N((C1-C 22 )alkyl)-, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 22 )alkylene-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-O-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-O-, -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-, -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-, -N((C1-C 22 )alkyl)-C(O)-(C1-C 22 )alkylene-N((C1-C 22 )alkyl)-C(O)-, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-P(O)2-O-, -(C1-C 22 )alkylene-OP(O)2-O-, -(C3-C 22 )cycloalkylene-, -(C3-C 22 )cycloalkylene-O-, -O-(C3-C 22 )cycloalkylene-, -(C6-C 22 )arylene-, -(C6-C 22 )arylene-O-, -O-(C6-C 22 )arylene-, -(C6-C 22 )arylene-NH-, -NH-(C6-C 22 )arylene-, -C(O)-(C6-C 22 )arylene-, -(C6-C 22 )arylene-C(O)-, -C(O)-O-(C6-C 22 )arylene-, -(C6-C 22 )arylene-C(O)-O-, -C(O)-NH-(C6-C 22 )arylene- and -C(O)-NH-(C6-C 22 )arylene-C(O)-O-; Where R 1 is independently selected at each occurrence from hydrogen, hydroxy, -(C1-C 22 )alkyl, -(C3-C 22 )cycloalkyl, -(C6-C 22 )aryl, -(C1-C 22 ) alkoxy, -(C3-C 22 )cycloalkoxy, -(C6-C 22 ) aryloxy, -C(O)-(C1-C 22 )alkyl, -OC(O)(C1-C 22 )alkyl, -C(O)-O-(C1-C 22 )alkyl, -C(O)-(C3-C 22 )cycloalkyl, -OC(O)-(C3-C 22 )cycloalkyl, -C(O)-O-(C3-C 22 )cycloalkyl, -C(O)-(C6-C 22 )aryloxy, -OC(O)-(C6-C 22 ) aryloxy, -C(O)-O-(C6-C 22 ) aryloxy, -C(O)-phosphate, phosphodiester, phosphoramidite, saturated fatty acid, unsaturated fatty acid, glucosyl, acetylglucosyl, galactosamine, N-acetylgalactosamine, lipids, PEG, steroids, lipophilic substances, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine and alkaloids, Where R 2 is independently selected at each occurrence from halogen atoms, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C1-C 12 ) alkoxycarbonyl, (C6-C 16 )aryl or (C6-C 16 ) aryloxycarbonyl; Among them, A1, A2, A3, B, C, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained in are optionally attached to a support material or protected by a terminal protecting group; and Provided that A1, A2 and A3 are not simultaneously hydrogen and R 3 , R 4 and R 5 Not at the same time as hydrogen.

3. The oligonucleotide delivery enhancing compound according to claim 1, comprising a moiety represented by formula BI and at least one substituent capable of being directly or indirectly attached to an oligonucleotide, wherein X' is selected from carbon, nitrogen, oxygen and sulfur; each of F', G', H' and I' is independently selected from carbon, nitrogen, oxygen and sulfur; and each asterisk refers to a site optionally linked directly or indirectly to at least one substituent or oligonucleotide.

4. The oligonucleotide delivery enhancing compound according to claim 3, which has a structure represented by formula BII: wherein X' is selected from carbon, nitrogen, oxygen and sulfur; and each of F', G', H' and I' is independently selected from carbon, nitrogen, oxygen and sulfur; wherein each of A1', A2' and A3' is either absent or a substituent independently selected from the group consisting of: -H, -R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR 1 '、-OC(O)-R 1 ', -C(O)NH-R 1 '、-C(O)NR 2 '-R 1 ',-NH-C(O)-R 1 '、-NR 2 '-C(O)-R 1 '、-OP(O)2-OR 1 ',-OP(O)(S)-OR 1 '、-OP(O)-OR 1 ', -NH-R 1 '、-NR 2 '-R 1 '、-(CH2) r’ -NH-R 1 '、-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -R 1 ', -C(O)-(CH2) r’ -NH-R 1 ', -C(O)-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -C(O)-R 1 ', -C(O)-(CH2) r’ -C(O)OR 1 ', -C(O)-(CH2) r’ -NH-C(O)-R 1 ', -C(O)-(CH2) r’ -NR 2 '-C(O)-R 1 '、-(CH2) r’ -C(O)-R 1 ';-(CH2) r’ -C(O)OR 1 ';-(CH2) r’ -OC(O)-R 1 '、-(CH2) r’ -R 1 '、-(CH2) r’ -NH-C(O)-R 1 '、-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NR 2 '-C(O)-(CH2) s’ -R 1 '、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 ')、-CH(-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 ')(-C(O)-NH-(CH2) q’ -R 3 ')、-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 ')、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’((CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)((CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’((CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)((CH2) p’ -NR 6 ’-C(O)-(CH2) q’ -R 3 '), or A1' and A2' are linked together so that A1', A2', the nitrogen atom linked to A1' and the carbon atom linked to A2' together form an unsubstituted or substituted heterocyclic ring; wherein R 1 ' and R 3 Each of ' is independently selected from hydrogen, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 ) alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 ) aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 ) aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-phosphate, phosphodiester, phosphoramidite, saturated fatty acid, unsaturated fatty acid, glucosyl, acetylglucosyl, galactosamine, N-acetylgalactosamine, lipid, PEG, steroid, lipophilic substance, carbohydrate, cholesterol, adamantane, amino acid, peptide, ligand, nucleic acid, oligonucleotide, aptamer, small molecule, antibody, antibody fragment, chloroquine, alkaloid and targeting moiety, wherein R 1 ' and R 3 'Each of which contains one or more hydroxyl, carboxyl and amino groups, which are optionally protected; wherein R 2 '、R 4 '、R 5 ' and R 6 ' are each independently a halogen atom, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C1-C 12 ) alkoxycarbonyl, (C6-C 16 )aryl or (C6-C 16 ) aryloxycarbonyl; wherein r', s', p' and q' are each an integer from 1 to 22; provided that when X' is oxygen, A3' is absent, and A1', A2' and A3' are not simultaneously hydrogen; wherein each C' is connected to any one of F', G', H' and I' and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 ) alkyl and halogenated (C1-C 20 ) alkoxy; wherein m' is an integer of 1, 2, or 3, n' is an integer of 1, 2, or 3, and m'+n'=4; wherein each B' is connected to any one of F', G', H' and I', and is independently selected from the group consisting of hydroxyl, -C(O)OH, -(C1-C 30 )alkoxy, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 ) alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -H (wherein r' is an integer from 1 to 22), -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -(C1-C 30 )alkylene-C(O)-OH (wherein r' is an integer from 1 to 22), -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-(C6-C 50 )arylene-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 )heteroarylene-CN, lipids, PEG, steroids, lipophilic substances, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine, alkaloids, and substituents represented by Formula BIII: wherein Y' is selected from carbon, nitrogen, oxygen and sulfur; and P', Q', S' and T' are each independently selected from carbon, nitrogen, oxygen and sulfur; and the asterisk refers to the position at which the substituent represented by formula BIII is attached to any one of F', G', H' and I' of formula BII; Where R 7 'Selected from the following group: -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-O-, -O-(C1-C 30 )alkylene-, -(C1-C 30 ) alkylene-NH-, -NH-(C1-C 30 )alkylene-, -C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-, -C(O)-O-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-O-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 30 )alkylene-, -NH-C(O)-(C1-C 30 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 30 )alkylene-C(O)-, -NH-C(O)-(C1-C 30 )alkylene-O-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-O-, -NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -(C1-C 30 )alkylene-P(O)2-O-, -(C1-C 30 )alkylene-OP(O)2-O-, -(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-O-, -O-(C3-C 50 )cycloalkylene-, -(C3-C 50 ) cycloalkylene-NH-, -NH-(C3-C 50 )cycloalkylene-, -C(O)-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-, -C(O)-O-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -(C3-C 50 )cycloalkylene-P(O)2-O-, -(C3-C 50 )cycloalkylene-OP(O)2-O-, -(C6-C 50 )arylene-, -(C6-C 50 )arylene-O-, -O-(C6-C 50 )arylene-, -(C6-C 50 )arylene-NH-, -NH-(C6-C 50 )arylene-, -C(O)-(C6-C 50 )arylene-, -(C6-C 50 )arylene-C(O)-, -C(O)-O-(C6-C 50 )arylene-, -(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-, -C(O)-NH-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-O-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-, -(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-, -(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -(C6-C 50 )arylene-P(O)2-O-, -(C6-C 50 )arylene-OP(O)2-O-, -(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-O-, -O-(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-NH-, -NH-(C5-C 50 )heteroarylene-, -C(O)-(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-C(O)-, -C(O)-O-(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-O-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-, -(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C6-C 50 )arylene-, -(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -(C5-C 50 )heteroarylene-P(O)2-O-, -(C5-C 50 )heteroarylene-OP(O)2-O-; wherein R 8 ' and R 9 'Each or not exist or are independently selected from the following substituents: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 ) alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C 30 ) alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 ) alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 ) aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 ) aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 ) alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid; wherein R 8 ' and R 9 'Each of which contains one or more hydroxyl, carboxyl, amino and phosphate groups, which are optionally protected by terminal protecting groups; or R 8 ' and R 9 'Connect together so that R 8 '、R 9 ', and R 8 'The carbon atom connected to R 9 The Y' atom to which it is attached forms an unsubstituted or substituted heterocyclic ring; provided that when Y' is oxygen or sulfur, R 9 'Does not exist; Each R 10 ' is connected to any one of P', Q', S' and T', and is independently selected from the following group: hydroxyl, -C(O)OH, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 ) alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 ) alkylene-OH, -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 ) alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 )heteroarylene-CN, wherein R 10 One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained therein are optionally attached to a support material or protected by a terminal protecting group; Each R 11 ' is connected to any one of P', Q', S' and T' and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, (C1-C 20 ) alkoxycarbonyl, halo(C1-C 20 ) alkyl and halogenated (C1-C 20 )alkoxycarbonyl; and wherein M' is an integer of 1, 2, or 3, N' is an integer of 1, 2, or 3, and M'+N'=4.

5. The oligonucleotide delivery enhancing compound according to claim 2 or 4, wherein A1, A2, A3, B, C, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 1 '、R 2 '、R 3 '、R 4 '、R 5 '、R 6 '、R 7 '、R 8 '、R 9 '、R 10 ' and R 11 'Each of the one or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained therein is optionally selected from the group consisting of terminal protecting groups R P Protection: (C1-C 22 )alkyl, (C1-C 22 ) alkoxy, (C1-C 22 )alkylcarbonyl, (C1-C 22 ) alkoxycarbonyl, (C6-C 22 ) aryl, (C6-C 22 ) aryloxy, (C6-C 22 ) arylcarbonyl, (C6-C 22 ) aryloxycarbonyl, glucosyl, acetylglucosyl, galactosamine, N-acetylgalactosamine, tri((C1-C 22 )alkyl)silyl and tri((C1-C 22 )alkoxy)silyl; and The supporting material is selected from the group consisting of silicon dioxide, silica gel, glass, ceramic, polymer, cellulose and combinations thereof.

6. The oligonucleotide delivery enhancing compound according to claim 2 or 4, having a structure represented by Formula AIV to Formula AXIII and Formula BIV to BXIV: wherein A1, A2, A3, A4, F, G, H, I, B, C, P, Q, S, T, R6, R7, m, n and M are as defined in claim 2, wherein Ring I and Ring II are each a 4-, 5-, 6-, 7-, 8-, or 9-membered ring; wherein A4' is attached to any atom in Ring I, and A4', A5' and A6' are each independently selected from -R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR 1 '、-OC(O)-R 1 ', -C(O)NH-R 1 '、-C(O)NR 2 '-R 1 ',-NH-C(O)-R 1 '、-NR 2 '-C(O)-R 1 '、-OP(O)2-OR 1 ',-OP(O)(S)-OR 1 '、-OP(O)-OR 1 ', -NH-R 1 '、-NR 2 '-R 1 '、-(CH2) r’ -NH-R 1 '、-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -R 1 ', -C(O)-(CH2) r’ -NH-R 1 ', -C(O)-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -C(O)-R 1 ', -C(O)-(CH2) r’ -C(O)OR 1 ', -C(O)-(CH2) r’ -NH-C(O)-R 1 ', -C(O)-(CH2) r’ -NR 2 '-C(O)-R 1 '、-(CH2) r’ -C(O)-R 1 ';-(CH2) r’ -C(O)OR 1 ';-(CH2) r’ -OC(O)-R 1 '、-(CH2) r’ -R 1 ’、-(CH2) r’ -NH-C(O)-R 1 ’、-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’、-(CH2) r’ -NR 2 ’-C(O)-(CH2) s’ -R 1 ’、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-NH-C(O)-(CH2) q’ -R 3 ’)、-CR 4 ’(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ’)(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 ’-C(O)-(CH2) s’ -R 1 ’)(-NR 6 ’-C(O)-(CH2) q’ -R 3 ’)、-CH(-(CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '); where R 1 ' and R 3 ' are each independently selected from hydrogen, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 ) alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 ) aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 ) aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-phosphate group, phosphodiester group, phosphoramidite group, saturated fatty acid group, unsaturated fatty acid group, lipid, PEG, steroid, lipophilic substance, carbohydrate, cholesterol, adamantane, amino acid, peptide, ligand, nucleic acid, oligonucleotide, aptamer, small molecule, antibody, antibody fragment, polyethylene glycol, carbohydrate, antibody, antibody fragment, chloroquine, alkaloid and targeting moiety, wherein R 1 ' and R 3’ One or more hydroxyl groups, carboxyl groups and amino groups each of which are optionally protected; wherein R 2 '、R 4 '、R 5 ' and R 6 ' are each independently a halogen atom, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C6-C 16 )aryl or (C6-C 16 ) aryloxy; wherein r', s', p' and q' are each an integer from 1 to 22; and Where R 12 ' is connected to any atom in ring II and is selected from the group consisting of: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 ) alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C 30 ) alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 ) alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 ) aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 ) aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 ) alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid; wherein R 12 One or more hydroxyl, carboxyl, amino and phosphate groups contained in ' are optionally protected.

7. The oligonucleotide delivery enhancing compound of claim 2, wherein F, G, H and I are each carbon, m is 1 and n is 3, B is attached to G or H, P, Q, S and T are each carbon, R 6 Connect to either Q or S; The protecting group R P Selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butyldimethylsilyl (TBS), 4,4'-dimethoxytrityl (DMTr), tert-butyloxycarbonyl (Boc), benzyl (Bn) and benzyloxy (BnO); wherein C at each occurrence is selected from the group consisting of hydrogen, halogen atoms, hydroxyl groups, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, halogenated (C1-C 12 ) alkyl and halogenated (C1-C 12 ) alkoxy; Wherein B is selected from the following group at each occurrence: -(C1-C 22 )alkylene-OH, -OC(O)-(C1-C 16 )alkylene-C(O)NH2, -(C1-C 16 )alkylene-OC(O)-(C1-C 16 )alkylene-C(O)NH2, -OC(O)-(C1-C 16 )alkylene-C(O)OH, -(C1-C 16 )alkylene-OC(O)-(C1-C 16 )alkylene-C(O)OH, -C(O)-(C1-C 16 )alkylene-C(O)NH2, -(C1-C 16 )alkylene-C(O)-(C1-C 16 )alkylene-C(O)NH2, -C(O)-NH-(C1-C 16 ) alkylene-OH, -C(O)-NH-(C1-C 16 )alkylene-C(O)OH, -(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-C(O)OH, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 )alkylene-CN, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 ) alkylene-OH, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 ) alkylene-NH2, -(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 )alkylene-C(O)OH, and -C(O)-NH-(C1-C 16 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 16 ) alkylene-CN, wherein A1, A2 and A3 are either absent or are substituted independently from the following groups: -H, -OH, straight chain or branched -(C6-C 22 )alkyl, linear or branched-(C2-C 22 )alkenyl, -(C1-C 22 ) alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )Alkylene-COOR 1 、-O-(C1-C 22 )alkyl, -(C6-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )Alkylene-NR 2 -C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted benzothiazole, and a substituent represented by formula AIII, wherein Y is selected from the group consisting of carbon, nitrogen, oxygen and sulfur; and P, Q, S and T are each carbon; Where R 3 , R 4 and R 5 Each of the above is either absent or is a substituent independently selected from the group consisting of -H, -OH, a linear or branched -(C6-C 22 )alkyl, linear or branched-(C2-C 22 )alkenyl, -(C1-C 22 ) alkylene-OH, -(C3-C 22 )cycloalkyl, -(C3-C 22 )cycloalkenyl, -(C1-C 22 )alkylene-(C3-C 22 )cycloalkyl, -(C1-C 22 )alkylene-R 1 、-(C1-C 22 )alkylene-OR 1 、-(C1-C 22 )Alkylene-COOR 1 、-O-(C1-C 22 )alkyl, -(C6-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 )alkyl, -(C1-C 22 )alkylene-NH-C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )Alkylene-NR 2 -C(O)-(C1-C 22 ) alkylene-adamantyl, -(C1-C 22 )alkylene-(C1-C6 epoxyalkyl) (1-20) -NH-C(O)-(C1-C 22 )alkylene-adamantyl, -C(O)NH-R 1 、-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-OH, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 ) alkylene-NH2, -(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-C(O)OH, -C(O)-NH-(C1-C 22 )alkylene-OP(-N(C1-C 22 Alkyl)2)-O-(C1-C 22 )alkylene-CN, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrroline, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazole, substituted or unsubstituted pyrazoline, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiazole, substituted or unsubstituted benzopyrrole, substituted or unsubstituted benzopyrroline, substituted or unsubstituted benzopyrrolidine, substituted or unsubstituted benzopyrazole, substituted or unsubstituted benzopyrazoline, substituted or unsubstituted benzopyrazolidine, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole and substituted or unsubstituted benzothiazole, Where R 7 is connected to any one of P, Q, S and T at each occurrence and is absent or selected from hydrogen, halogen atoms, hydroxyl groups, (C1-C 20 )alkyl, (C1-C 20 ) alkoxy, halogenated (C1-C 20 ) alkyl and halogenated (C1-C 20 ) alkoxy; Wherein M is an integer of 0, 1, 2 or 3; Where R 6 Connected to any one of P, Q, S and T, and selected from the following group: -(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-O-, -O-(C1-C 16 )alkylene-, -(C1-C 16 ) alkylene-NH-, -NH-(C1-C 16 )alkylene-, -C(O)-(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-C(O)-, -C(O)-O-(C1-C 16 )alkylene-, -(C1-C16)alkylene-C(O)-O-, -C(O)-NH-(C1-C 16 )alkylene-, -C(O)-NH-(C1-C 16 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 16 )alkylene-OC(O)-, -C(O)-NH-(C1-C 16 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 16 )alkylene-O-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-O-, -C(O)-NH-(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-, -C(O)-NH-(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-, -C(O)-NH-(C1-C 16 )alkylene-C(O)-NH-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-, -C(O)-N((C1-C 16 )alkyl)-(C1-C 16 )alkylene-C(O)-N((C1-C 16 )alkyl)-, -(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-C(O)-NH-(C1-C 16 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 16 )alkylene-, -NH-C(O)-(C1-C 16 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 16 )alkylene-C(O)-, -NH-C(O)-(C1-C 16 )alkylene-O-, -N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-, -N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-O-, -NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-, -NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-, -N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-, -N((C1-C 16 )alkyl)-C(O)-(C1-C 16 )alkylene-N((C1-C 16 )alkyl)-C(O)-, -(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-, -(C1-C 16 )alkylene-NH-C(O)-(C1-C 16 )alkylene-NH-C(O)-.

8. The oligonucleotide delivery enhancing compound according to claim 4, which has a structure represented by any one of Formula BXV to Formula BXXIX: Wherein A1' and A2' are each independently selected from the following substituents: -R 1 '、-OR 1 '、-SR 1 ',-C(O)-R 1 '、-C(O)OR 1 '、-OC(O)-R 1 ', -C(O)NH-R 1 '、-C(O)NR 2 '-R 1 ',-NH-C(O)-R 1 '、-NR 2 '-C(O)-R 1 '、-OP(O)2-OR 1 ',-OP(O)(S)-OR 1 '、-OP(O)-OR 1 ', -NH-R 1 '、-NR 2 '-R 1 '、-(CH2) r’ -NH-R 1 '、-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -R 1 ', -C(O)-(CH2) r’ -NH-R 1 ', -C(O)-(CH2) r’ -NR 2 '-R 1 ', -C(O)-(CH2) r’ -C(O)-R 1 ', -C(O)-(CH2) r’ -C(O)OR 1 ', -C(O)-(CH2) r’ -NH-C(O)-R 1 ', -C(O)-(CH2) r’ -NR 2 '-C(O)-R 1 '、-(CH2) r’ -C(O)-R 1 ';-(CH2) r’ -C(O)OR 1 ';-(CH2) r’ -OC(O)-R 1 '、-(CH2) r’ -R 1 '、-(CH2) r’ -NH-C(O)-R 1 '、-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NH-C(O)-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-C(O)-NH-(CH2) s’ -R 1 '、-(CH2) r’ -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-(CH2) s’ -R 1 '、-(CH2) r’ -NR 2 '-C(O)-(CH2) s’ -R 1 '、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 ')、-CH(-(CH2) r’ -C(O)-NH-(CH2) s’ -R 1 ')(-C(O)-NH-(CH2) q’ -R 3 ')、-N(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 ')、-CH(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 '),-CR 4 '(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-NH-C(O)-(CH2) q’ -R 3 '),-CR 4 '(-(CH2) r’ -NH-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NH-C(O)-(CH2) q’ -R 3 ')、-CH(-(CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')(-NR 6 '-C(O)-(CH2) q’ -R 3 ')、-CH(-(CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')(-(CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '),-CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '), and -CR 4 '((CH2) r’ -NR 5 '-C(O)-(CH2) s’ -R 1 ')((CH2) p’ -NR 6 '-C(O)-(CH2) q’ -R 3 '); where R 1 ' and R 3 ' are each independently selected from hydrogen, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 ) alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 ) aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 ) aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-phosphate group, phosphodiester group, phosphoramidite group, saturated fatty acid group, unsaturated fatty acid group, lipid, PEG, steroid, lipophilic substance, carbohydrate, cholesterol, adamantane, amino acid, peptide, ligand, nucleic acid, oligonucleotide, aptamer, small molecule, antibody, antibody fragment, polyethylene glycol, antibody, antibody fragment, chloroquine, alkaloid and targeting moiety, wherein R 1 ' and R 3 'Each of which contains one or more hydroxyl, carboxyl and amino groups which are optionally protected; wherein R 2 '、R 4 '、R 5 ' and R 6 ' are each independently a halogen atom, (C1-C 12 )alkyl, (C1-C 12 ) alkoxy, (C1-C 12 ) alkoxycarbonyl, (C6-C 16 )aryl or (C6-C 16 ) aryloxycarbonyl; wherein r', s', p' and q' are each an integer from 1 to 22; wherein m' is an integer of 1, 2, or 3, n' is an integer of 1, 2, or 3, and m'+n'=4; Wherein each B' is independently selected from the group consisting of hydroxyl, -C(O)OH, -(C1-C 30 )alkoxy, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 ) alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OH, -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -H (wherein r' is an integer from 1 to 22), -C(O)-NH-[(C1-C 30 )alkylene-O] r’ -(C1-C 30 )alkylene-C(O)-OH (wherein r' is an integer from 1 to 22), -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-(C6-C 50 )arylene-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 ) heteroarylene-CN, lipids, PEG, steroids, lipophiles, carbohydrates, cholesterol, adamantane, amino acids, peptides, chloroquine, and alkaloids; Each R 7 'Selected from the following group: -O-, -C(O)O-, -OC(O)-, -P(O)2-O-, -OP(O)2-O-, -P(O)(S)-O-, -OP(O)(S)-O-, -OP(O)-O-, -(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-O-, -O-(C1-C 30 )alkylene-, -(C1-C 30 ) alkylene-NH-, -NH-(C1-C 30 )alkylene-, -C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-, -C(O)-O-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-, -C(O)-NH-(C1-C 30 )alkylene-OC(O)-O-, -C(O)-NH-(C1-C 30 )alkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-O-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-, -C(O)-N((C1-C 20 )alkyl)-(C1-C 30 )alkylene-C(O)-N((C1-C 20 )alkyl)-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)-NH-, -NH-C(O)-(C1-C 30 )alkylene-, -NH-C(O)-(C1-C 30 )alkylene-C(O)-O-, -NH-C(O)-(C1-C 30 )alkylene-C(O)-, -NH-C(O)-(C1-C 30 )alkylene-O-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-O-, -NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-, -N((C1-C 20 )alkyl)-C(O)-(C1-C 30 )alkylene-N((C1-C 20 )alkyl)-C(O)-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-, -(C1-C 30 )alkylene-NH-C(O)-(C1-C 30 )alkylene-NH-C(O)-, -(C1-C 30 )alkylene-P(O)2-O-, -(C1-C 30 )alkylene-OP(O)2-O-, -(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-O-, -O-(C3-C 50 )cycloalkylene-, -(C3-C 50 ) cycloalkylene-NH-, -NH-(C3-C 50 )cycloalkylene-, -C(O)-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-, -C(O)-O-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-O-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-, -C(O)-N((C1-C 20 )alkyl)-(C3-C 50 )cycloalkylene-C(O)-N((C1-C 20 )alkyl)-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -(C3-C 50 )cycloalkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)-NH-, -(C3-C 50 )cycloalkylene-P(O)2-O-, -(C3-C 50 )cycloalkylene-OP(O)2-O-, -(C6-C 50 )arylene-, -(C6-C 50 )arylene-O-, -O-(C6-C 50 )arylene-, -(C6-C 50 )arylene-NH-, -NH-(C6-C 50 )arylene-, -C(O)-(C6-C 50 )arylene-, -(C6-C 50 )arylene-C(O)-, -C(O)-O-(C6-C 50 )arylene-, -(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-, -C(O)-NH-(C6-C 50 )arylene-C(O)-O-, -C(O)-NH-(C6-C 50 )arylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-O-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-, -C(O)-N((C1-C 20 )alkyl)-(C6-C 50 )arylene-C(O)-N((C1-C 20 )alkyl)-, -(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-, -(C6-C 50 )arylene-C(O)-NH-(C6-C 50 )arylene-C(O)-NH-, -(C6-C 50 )arylene-P(O)2-O-, -(C6-C 50 )arylene-OP(O)2-O-, -(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-O-, -O-(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-NH-, -NH-(C5-C 50 )heteroarylene-, -C(O)-(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-C(O)-, -C(O)-O-(C5-C 50 )heteroarylene-, -(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-O-, -C(O)-NH-(C5-C 50 )heteroarylene-O-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-O-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C3-C 50 )cycloalkylene-, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-, -C(O)-N((C1-C 20 )alkyl)-(C5-C 50 )heteroarylene-C(O)-N((C1-C 20 )alkyl)-, -(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-(C6-C 50 )arylene-, -(C5-C 50 )heteroarylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)-NH-, -(C5-C 50 )heteroarylene-P(O)2-O-, -(C5-C 50 )heteroarylene-OP(O)2-O-; wherein each R 8 ' is a substituent independently selected from the following group: -H, hydroxyl, -(C1-C 30 )alkyl, -(C3-C 50 )cycloalkyl, -(C6-C 50 )aryl, -(C1-C 30 ) alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C1-C 30 ) alkylene-NH2, -(C3-C 50 ) cycloalkylene-NH2, -(C6-C 50 ) arylene-NH2, -(C1-C 30 ) alkoxy, -(C3-C 50 )cycloalkoxy, -(C6-C 50 ) aryloxy, -C(O)-(C1-C 30 )alkyl, -OC(O)(C1-C 30 )alkyl, -C(O)-O-(C1-C 30 )alkyl, -C(O)-(C3-C 50 )cycloalkyl, -OC(O)-(C3-C 50 )cycloalkyl, -C(O)-O-(C3-C 50 )cycloalkyl, -C(O)-(C6-C 50 )aryloxy, -OC(O)-(C6-C 50 ) aryloxy, -C(O)-O-(C6-C 50 ) aryloxy, -C(O)-NH-(C1-C 30 )alkyl, -C(O)-NH-(C3-C 50 )cycloalkyl, -C(O)-NH-(C6-C 50 )aryl, -(C1-C 30 ) alkylene-phosphoric acid, -(C3-C 50 ) cycloalkylene-phosphoric acid, -(C6-C 50 ) arylene-phosphoric acid; wherein each R 8 One or more hydroxyl, carboxyl, amino and phosphate groups contained therein are optionally protected by terminal protecting groups; and Each R 10 'Independently selected from the following group: hydroxyl, -C(O)OH, -P(O)2-OH, -P(O)-OH, -P(O)(S)-OH, -CN, -(C1-C 30 ) alkylene-OH, -(C3-C 50 )cycloalkylene-OH, -(C6-C 50 )arylene-OH, -(C5-C 50 )heteroarylene-OH, -(C1-C 30 )alkylene-C(O)OH, -(C3-C 50 )cycloalkylene-C(O)OH, -(C6-C 50 )arylene-C(O)OH, -(C5-C 50 )heteroarylene-C(O)OH, -C(O)-NH-(C1-C 30 ) alkylene-OH, -C(O)-NH-(C3-C 50 )cycloalkylene-OH, -C(O)-NH-(C6-C 50 )arylene-OH, -C(O)-NH-(C5-C 50 )heteroarylene-OH, -C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -C(O)-NH-(C6-C 50 )arylene-C(O)OH, -C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-OC(O)-(C1-C 30 ) alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C3-C 50 )cycloalkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C6-C 50 )arylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C5-C 50 )heteroarylene-C(O)OH, -(C1-C 30 )alkylene-P(O)2-OH, -(C3-C 50 )cycloalkylene-P(O)2-OH, -(C6-C 50 )arylene-P(O)2-OH, -(C5-C 50 )heteroarylene-P(O)2-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-CN, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 )alkylene-C(O)OH, -(C1-C 30 )alkylene-C(O)-NH-(C1-C 30 )alkylene-OP(-N(C1-C 16 Alkyl)2)-O-(C1-C 30 ) alkylene-NH2, -(C1-C 30 )alkylene-P(O)-OH, -(C3-C 50 )cycloalkylene-P(O)-OH, -(C6-C 50 )arylene-P(O)-OH, -(C5-C 50 )-heteroarylene-P(O)-OH, -(C1-C 30 )alkylene-P(O)(S)-OH, -(C3-C 50 )cycloalkylene-P(O)(S)-OH, -(C6-C 50 )arylene-P(O)(S)-OH, -(C5-C 50 )heteroarylene-P(O)(S)-OH, -(C1-C 30 )alkylene-CN, -(C3-C 50 )cycloalkylene-CN, -(C6-C 50 )arylene-CN, -(C5-C 50 )heteroarylene-CN, wherein R 10 One or more hydroxyl, carboxyl, amino, nitrile and phosphate groups contained in the ' are optionally attached to a supporting material or protected by a terminal protecting group.

9. The oligonucleotide delivery enhancing compound according to claim 2 or claim 4, which has the following structure: in Stands for Supporting Materials.

10. The oligonucleotide delivery enhancing compound according to any one of claims 1 to 9, wherein at least one hydrogen atom contained in the oligonucleotide delivery enhancing compound is substituted with a deuterium atom.

11. An oligonucleotide delivery agent comprising a delivery enhancing compound (DEC) portion derived from the oligonucleotide delivery enhancing compound of any one of claims 1 to 10 and at least one oligonucleotide.

12. The oligonucleotide delivery agent according to claim 11, wherein the oligonucleotide delivery enhancing compound portion is linked to the oligonucleotide via at least one linking portion selected from the group consisting of a direct bond, -O-, -S-, -C(O)-, -NH-, -N((C1-C 12 )alkyl)-, -N((C1-C 12 )Alkyl)-C(O)-O-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -C(O)-NH-, -OP(O)2O-, -P(O)(O - )O-, -OP(O)O-, -OP(O)(S)O-, -OS(O)2-O-, -S(O)2-O-, -S(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 ) alkylene-NH-, -NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-C(O)-, -(C1-C 22 )alkylene-C(O)-O-, -C(O)-(C1-C 22 )alkylene-, -NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 ) alkylene-NH-, -NH-(C1-C 22 )alkylene-C(O)-, -C(O)-(C1-C 22 )alkylene-C(O)-, -NH-(C1-C 22 )alkylene-NH-, -C(O)-(C1-C 22 )alkylene-C(O)O-, -OC(O)-(C1-C 22 )alkylene-C(O)-O-, -C(O)-O-(C1-C 22 )alkylene-OC(O)-, -C(O)-(C1-C 22 ) alkylene-NH-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-NH-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-OP(O)2O-, -(C1-C 22 )alkylene-OP(O)(O - )O-、-(C1-C 22 )alkylene-OP(O)(O - )O-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-OP(O)O-, -(C1-C 22 )alkylene-OP(O)(S)O-, -(C1-C 22 )alkylene-OS(O)2-O-, -(C1-C 22 )alkylene-S(O)2-O-, -(C1-C 22 )alkylene-S(O)-O-, -OP(O)2-O-(C1-C 22 )alkylene-OP(O)2O-, -OP(O)-O-(C1-C 22 )alkylene-OP(O)O-, -OP(O)(S)O-(C1-C 22 )alkylene-OP(O)(S)O-, -OS(O)2-O-(C1-C 22 )alkylene-OS(O)2-O-, -S(O)2-O-(C1-C 22 )alkylene-S(O)2-O- and -OS(O)-(C1-C 22 )alkylene-S(O)-O-; and The oligonucleotide is selected from the group consisting of antisense oligonucleotide (ASO), antisense RNA, short interfering RNA (siRNA), micro RNA (miRNA), small activating RNA (saRNA), double-stranded RNA (dsRNA) and small guide RNA (sgRNA).

13. The oligonucleotide delivery agent according to claim 11, wherein The oligonucleotide comprises at least a portion of the sequence as set forth in SEQ ID NOs 1 to 53.

14. The oligonucleotide delivery agent according to claim 11, comprising a structure represented by formula AA: in, The delivery enhancing compound (DEC) moiety is derived from the oligonucleotide delivery enhancing compound of any one of claims 1 to 9 and is directly or indirectly linked to at least one oligonucleotide.

15. The oligonucleotide delivery agent according to claim 14, wherein DEC is linked to the oligonucleotide via at least one first linking moiety.

16. The oligonucleotide delivery agent according to claim 14, wherein TM is linked to DEC via at least one second linking moiety.

17. The oligonucleotide delivery agent according to any one of claims 14 to 16, wherein the first linking portion and the second linking portion are each independently selected from: a direct bond, -O-, -S-, -C(O)-, -NH-, -N((C1-C 12 )alkyl)-, -N((C1-C 12 )Alkyl) -C(O)-O-, -OC(O)-, -C(O)-O-, -OC(O)-O-, -C(O)-NH-, -OP(O)2O-, -OP(O)O-, -OP(O)(S)O-, -OS(O)2-O-, -S(O)2-O-, -S(O)-O-, -(C1-C 22 )alkylene-, -(C1-C 22 ) alkylene-NH-, -NH-(C1-C 22 )alkylene-, -(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-C(O)-, -(C1-C 22 )alkylene-C(O)-O-, -C(O)-(C1-C 22 )alkylene-, -NH-C(O)-(C1-C 22 )alkylene-, -C(O)-NH-(C1-C 22 )alkylene-, -C(O)-(C1-C 22 ) alkylene-NH-, -NH-(C1-C 22 )alkylene-C(O)-, -C(O)-(C1-C 22 )alkylene-C(O)-, -NH-(C1-C 22 )alkylene-NH-, -C(O)-(C1-C 22 )alkylene-C(O)O-, -OC(O)-(C1-C 22 )alkylene-C(O)-O-, -C(O)-O-(C1-C 22 )alkylene-OC(O)-, -C(O)-(C1-C 22 ) alkylene-NH-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-, -NH-C(O)-(C1-C 22 )alkylene-C(O)-NH-, -NH-(C1-C 22 )alkylene-OP(O)2O-, -NH-(C1-C 22 )alkylene-CH((C1-C 22 )alkylene-OH)-OP(O)2O-, -NH-(C1-C 22 )alkylene-CH((C1-C 22 )alkylene-OH)-(C1-C 22 )alkylene-OP(O)2O-, -C(O)-NH-(C1-C 22 )alkylene-NH-C(O)-, -(C1-C 22 )alkylene-OP(O)2O-, -(C1-C 22 )alkylene-OP(O)O-, -(C1-C 22 )alkylene-OP(O)(S)O-, -(C1-C 22 )alkylene-OS(O)2-O-, -(C1-C 22 )alkylene-S(O)2-O-, -(C1-C 22 )alkylene-S(O)-O-, -OP(O)2-O-(C1-C 22 )alkylene-OP(O)2O-, -OP(O)-O-(C1-C 22 )alkylene-OP(O)O-, -OP(O)(S)O-(C1-C 22 )alkylene-OP(O)(S)O-, -OS(O)2-O-(C1-C 22 )alkylene-OS(O)2-O-, -S(O)2-O-(C1-C 22 )alkylene-S(O)2-O- and -OS(O)-(C1-C 22 )alkylene-S(O)-O-; and / or in, The oligonucleotide is selected from the group consisting of short interfering RNA (siRNA), small activating RNA (saRNA), micro RNA (miRNA), antisense oligonucleotide (ASO) and small guide RNA (sgRNA).

18. The oligonucleotide delivery agent according to any one of claims 14 to 16, wherein the targeting moiety is selected from one or more of the following: a ligand, a peptide, a nucleic acid, an oligonucleotide, an aptamer, a lipid, a fatty acid, a small molecule, polyethylene glycol, an amino acid, cholesterol, a carbohydrate, and an antibody or an antibody fragment.

19. The oligonucleotide delivery agent according to claim 13, which has a structure represented by any one of formulas AAI to AAXXIV: in, L represents the connecting part, stands for oligonucleotide delivery enhancing compound, symbol represents a double-stranded oligonucleotide, in which each strand represents an interchangeable sense strand or antisense strand, and each end of which is independently symmetrical or asymmetrical; the symbol represents a single-stranded oligonucleotide, and a, b and c are each independently an integer from 1 to 50.

20. The oligonucleotide delivery agent according to any one of claims 11 to 19, wherein at least one hydrogen atom contained in the delivery enhancing compound moiety, the linking moiety, the targeting moiety and / or the oligonucleotide is substituted with a deuterium atom.

21. A pharmaceutical composition, comprising: a) the oligonucleotide delivery agent according to any one of claims 11 to 20; and b) optionally, one or more ingredients selected from the group consisting of a pharmaceutically acceptable carrier, excipient, solvent, diluent, stabilizer, dispersant, buffer, extender, preservative, and combinations thereof.

22. A method for regulating the expression of a target gene in a subject, the method comprising the step of administering the pharmaceutical composition according to claim 21 to the subject.

23. The method according to claim 22, wherein: The oligonucleotide or target gene comprises at least a portion of the sequence as set forth in SEQ ID NOs 1 to 53.

24. The method according to claim 22, wherein: The pharmaceutical composition increases the expression of a target gene.

25. The method according to claim 22, wherein: The pharmaceutical composition reduces the expression of a target gene.

26. The method according to any one of claims 22 to 24, wherein: The subject is a mammal.

27. The method according to claim 26, wherein: The mammal is a rodent.

28. The method according to claim 27, wherein: The rodent is a mouse.

29. The method according to claim 27, wherein: The rodent is a rat.

30. The method according to claim 26, wherein: Mammals are non-human primates.

31. The method according to claim 26, wherein: Mammals are humans.

32. The method according to any one of claims 22 to 24, wherein: The target gene is associated with a disease or disorder.

33. The method of claim 32, wherein the target gene is associated with a disease or disorder in the central nervous system (CNS), brain, spinal cord, liver, lung, kidney, intestine, pancreas, gallbladder, heart, lymph node, spleen, stomach, bladder, muscle or bone.

34. The method of claim 33, wherein the disease is cancer.

35. A method for regulating the expression of a target gene, the method comprising contacting a cell with the pharmaceutical composition of claim 21.

36. The method according to claim 35, wherein: The oligonucleotide or target gene comprises at least a portion of the sequence as set forth in SEQ ID NOs 1 to 53.

37. The method according to claim 35, wherein: The pharmaceutical composition increases the expression of a target gene.

38. The method according to claim 35, wherein: The pharmaceutical composition reduces the expression of a target gene.

39. The method of claim 35, wherein the cell is a mammalian cell.

40. The method of claim 39, wherein the mammalian cell is a mouse cell.

41. The method of claim 39, wherein the mammalian cells are rat cells.

42. The method according to claim 39, wherein: Mammalian cells are non-human primate cells.

43. The method of claim 39, wherein the mammalian cell is a human cell.

44. The method according to any one of claims 35 to 43, wherein: The target gene is associated with a disease or disorder.

45. The method of claim 44, wherein the target gene is associated with a disease or disorder in the central nervous system (CNS), brain, spinal cord, liver, lung, kidney, intestine, pancreas, gallbladder, heart, lymph node, spleen, stomach, bladder, muscle or bone.

46. ​​The method of claim 44, wherein the disease is cancer.

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