Modified nucleoside compound and oligonucleotide prepared therefrom

Abstract

The present invention provides a nucleoside phosphoramidite compound represented by formula I. The nucleoside phosphoramidite compound of the present invention can be incorporated into the end of an oligonucleotide, enabling a modified oligonucleotide to hybridize with a portion of a target mRNA, thereby resulting in loss or downregulation of the normal function of the target mRNA.

Description

A modified nucleoside compound and oligonucleotides prepared therefrom Technical Field

[0001] This invention relates to the field of biopharmaceuticals, specifically to a modified nucleoside compound and oligonucleotides prepared therefrom. Background Technology

[0002] Oligonucleotides are polymers of nucleotides. As nucleic acid inhibitor molecules, oligonucleotides can regulate intracellular mRNA levels and have shown early promise in the treatment of genetic diseases, metabolic diseases, cancer, and viral infections. Nucleic acid inhibitor molecules can regulate mRNA expression through a different set of mechanisms, including RNA interference (RNAi).

[0003] RNAi is a conserved pathway found in most eukaryotes, in which a double-stranded RNA molecule (dsRNA) inhibits the expression of a target gene with a complementary sequence to the dsRNA. In a typical RNAi pathway, the longer dsRNA is cleaved by a nuclease (Dicer) into a shorter RNA duplex called small interfering RNA (“siRNA”). siRNA has been shown to associate with the nuclease, trans-activating response RNA-binding protein (TRBP), and Argonaute 2 (“Ago2”) to form a complex, sometimes referred to as the RNA-induced silencing complex (“RISC”). Ago2 is a nuclease that uses the antisense strand (also known as the guide strand) of the siRNA to guide the sequence-specific cleavage of the target mRNA.

[0004] Various double-stranded RNAi inhibitor molecular structures have been developed over the years. For example, early work on RNAi inhibitor molecules focused on double-stranded nucleic acid molecules mimicking natural siRNA, where each strand has 19-25 nucleotides and includes at least one 3' overhang with 1 to 5 nucleotides (see, for example, U.S. Patent No. 8,372,968). Subsequently, longer double-stranded RNAi inhibitor molecules were developed, which were cleaved in vivo by endonucleases into active RNAi inhibitor molecules (see, for example, U.S. Patent No. 8,883,996). Subsequent work developed extended double-stranded nucleic acid inhibitor molecules in which at least one end of at least one strand extends beyond the double-stranded target region of the molecule, one of the strands comprising a thermodynamically stable tetracyclic structure (see, for example, U.S. Patent Nos. 8,513,207, 8,927,705, WO 2010 / 033225, and WO 2016 / 100401). These structures include single-strand extensions (on one or both sides of the molecule) and double-strand extensions.

[0005] In recent years, many modified nucleosides have been used for RNAi, such as common 2'-fluorine modifications, 2'-methoxy modifications, 2'-methoxyethyl modifications, 2',3'-open-ring nucleotides, locked nucleic acids, ethylene glycol nucleic acids, and 5'-(E)-vinyl phosphates. In some cases, chemical modifications are introduced into nucleic acid inhibitor molecules to introduce properties that may be desired under specific conditions, such as those experienced after in vivo administration. These modifications include those designed, for example, to antagonize nucleases or other enzymes that interfere with the structure or activity of oligonucleotides, increase cellular uptake of oligonucleotides, or improve the pharmacokinetic properties of oligonucleotides.

[0006] For example, introducing long-chain lipids into nucleosides (see, for example, patent numbers: WO2023283434, WO2020006050) allows the modified nucleosides to be incorporated into the corresponding oligonucleotide sequences, improving the pharmacokinetic properties and bioavailability of oligonucleotide drugs in vivo. Further research is needed on the structural modification of oligonucleotide drugs to obtain those with superior properties in all aspects. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention aims to develop a nucleoside compound that, when applied to oligonucleotide molecules (including but not limited to siRNA, antisense nucleic acids, saRNA (small activating RNA), miRNA, and nucleic acid aptamers), can effectively enhance the activity of oligonucleotide molecules and improve their resistance to enzymatic digestion by phosphatases, exonucleases, and endonucleases. Furthermore, compared to ordinary nucleosides, this nucleoside compound can easily incorporate various functional groups with specific functions, such as various substituted alkyl lipids, without affecting their base pairing ability. This improves the cell membrane penetration ability of oligonucleotides and enhances the organ-targeting effect of nucleic acids. When this type of modified nucleoside is used in siRNA molecules, it can increase the enrichment of siRNA molecules in target organs and improve the pharmacokinetic properties of the drug.

[0008] This invention first provides a nucleoside compound of Formula I, or a stereoisomer thereof:

[0009] in,

[0010] R 1 R 2 R 3 They are independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C1-C6 alkoxy, and substituted C1-C6 alkoxy, respectively.

[0011] R 4 R 5 Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, and 4-6 membered heterocycle;

[0012] R 6 Selected from hydrogen, halogen, C1-C30 alkyl, substituted C1-C30 alkyl, C1-C30 alkoxy, substituted C1-C30 alkoxy, C2-C30 alkenyl, substituted C2-C30 alkenyl, C2-C30 alkynyl or, substituted C2-C30 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycle;

[0013] Nu is selected from hydrogen or nucleoside bases;

[0014] Z represents -O-, -S-, -NR Z1 -、-N(COR Z1 )-or-CR Z1 R Z2 -; where R is... Z1 and R Z2 Each of the following is independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl or substituted C2-C6 ynyl;

[0015] X 1 Selected from -(CH2) n O- or -(CH2) n S-; where n is any integer from 0 to 10;

[0016] X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) n -A-; where m is any integer from 0 to 10;

[0017] A is selected from 3-6 membered cycloalkyl, 4-6 membered heterocyclic, benzene ring, and 5-6 membered aromatic heterocyclic;

[0018] The substituents in the substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, and substituted C1-C6 alkoxy groups are selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(O)(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH(C1-C6 alkyl), and -C(O)N(C1-C6 alkyl)(C1-C6 alkyl).

[0019] Furthermore, the compounds of formula I are as shown in formula IIa or IIb:

[0020] Among them, Z and R 1 R 2 R 3 R 4 R 5 R 6 Nu, X 1 and X 2 As mentioned above.

[0021] Furthermore,

[0022] R 1 R 2 R 3 Each of the following is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, and ethoxy; preferably, R 1 R 2 R 3 All are hydrogen;

[0023] Z is selected from -O-, -S-, or -N(COR). Z1 )-; where R Z1 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; preferably, Z is -O-;

[0024] R 4 For hydrogen, R 5 Selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycle;

[0025] Or, R 5 For hydrogen, R4 Selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycle.

[0026] In some embodiments of the present invention, the compounds of formula I, IIa, or IIb are as shown in formula IIIa, IIIb, IIIc, and IIId:

[0027] Among them, R 4 R 5 R 6 Nu, X 1 and X 2 As mentioned above.

[0028] In some embodiments of the present invention, further,

[0029] X 1 Selected from -O- or -S-; preferably, X 1 -O-;

[0030] X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) m -A-; where m is selected from 0, 1, 2, 3, 4 or 5;

[0031] Preferably, X 2 It is selected from -O-, -CH2-, -CH2O-, -CH2S-, -CH2NH(CO)-, -(CO)NH- or -CH2OCH2- 5-membered aromatic heterocycle-; wherein the 5-membered aromatic heterocycle is preferably 1,2,4-triazole;

[0032] R 6 Selected from hydrogen, methyl, halogen, or C10-C18 alkyl; preferably, R 5 Selected from hydrogen, methyl, fluorine, C10 alkyl, C11 alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, or C18 alkyl; more preferably, R 5Selected from hydrogen, methyl, fluorine, C10 straight-chain alkyl, C11 straight-chain alkyl, C12 straight-chain alkyl, C13 straight-chain alkyl, C14 straight-chain alkyl, C15 straight-chain alkyl, C16 straight-chain alkyl, C17 straight-chain alkyl or C18 straight-chain alkyl;

[0033] R 4 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 4 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy,

[0034] R 5 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 5 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy,

[0035] In some embodiments of the present invention, Nu is further defined as a nucleoside base, wherein the nucleoside base is selected from:

[0036] In some embodiments of the present invention, preferably, the compound of formula I is as follows:

[0037] Among them, R 6 Nu, X 1 and X 2 As mentioned above.

[0038] In some embodiments of the present invention, preferably, the compound of formula I is as follows:

[0039] Among them, R 4 Nu and X 1 As mentioned above.

[0040] In some embodiments of the present invention, preferably, the nucleoside compound is a nucleoside compound as shown below:

[0041] Nu, as mentioned above.

[0042] In some specific embodiments of the present invention, the nucleoside compound is specifically:

[0043] The present invention also provides the use of any of the above-mentioned nucleoside compounds in the preparation of oligonucleotides; preferably, the present invention provides the use of any of the above-mentioned nucleoside compounds as intermediates in the preparation of oligonucleotides; more preferably, the oligonucleotide is siRNA, antisense nucleic acid, saRNA, miRNA or nucleic acid aptamer.

[0044] On the other hand, the present invention provides an oligonucleotide comprising at least one structure shown in Formula V, and through... Linked to the rest of the oligonucleotide;

[0045] in,

[0046] R 1 R 2 R 3 They are independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C1-C6 alkoxy, and substituted C1-C6 alkoxy, respectively.

[0047] R 4 R 5 Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, and 4-6 membered heterocycle;

[0048] R 6 Selected from hydrogen, halogen, C1-C30 alkyl, substituted C1-C30 alkyl, C1-C30 alkoxy, substituted C1-C30 alkoxy, C2-C30 alkenyl, substituted C2-C30 alkenyl, C2-C30 alkynyl or, substituted C2-C30 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycle;

[0049] Nu is selected from hydrogen or nucleoside bases;

[0050] Z represents -O-, -S-, -NR Z1 -、-N(COR Z1 )-or-CR Z1 RZ2 -; where R is... Z1 and R Z2 Each of the following is independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl or substituted C2-C6 ynyl;

[0051] X 1 Selected from -(CH2) n O- or -(CH2) n S-; where n is any integer from 0 to 10;

[0052] X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) n -A-; where m is any integer from 0 to 10;

[0053] X 3 Selected from O or S;

[0054] A is selected from 3-6 membered cycloalkyl, 4-6 membered heterocyclic, benzene ring, and 5-6 membered aromatic heterocyclic;

[0055] The substituents in the substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, and substituted C1-C6 alkoxy groups are selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(O)(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH(C1-C6 alkyl), and -C(O)N(C1-C6 alkyl)(C1-C6 alkyl).

[0056] Furthermore, the structure shown in equation V is as shown in equation VIa or equation VIb:

[0057] Among them, Z and R 1 R 2 R 3 R 4 R 5 R 6 Nu, X 1 X 2 and X 3 As mentioned above.

[0058] Furthermore,

[0059] R 1 R 2 R 3 Each of the following is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, and ethoxy; preferably, R 1 R 2 R 3 All are hydrogen;

[0060] Z is selected from -O-, -S-, or -N(COR). Z1 )-; where R Z1 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl;

[0061] R 4 For hydrogen, R 5 Selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycle;

[0062] Or, R 5 For hydrogen, R 4 Selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycle.

[0063] In some embodiments of the present invention, the structures represented by formulas V, VIa, and VIb are as shown in formulas VIIIa, VIIIb, VIIIc, and VIIId:

[0064] Among them, R 4 R 5 R 6 Nu, X 1 X 2 and X 3 As mentioned above.

[0065] In some embodiments of the present invention, further,

[0066] X1 Selected from -O- or -S-; preferably, X 1 Selected from -O-;

[0067] X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) m -A-; where m is selected from 0, 1, 2, 3, 4 or 5;

[0068] Preferably, X 2 It is selected from -O-, -CH2-, -CH2O-, -CH2S-, -CH2NH(CO)-, -(CO)NH- or -CH2OCH2- 5-membered aromatic heterocycle-; wherein the 5-membered aromatic heterocycle is preferably 1,2,4-triazole;

[0069] R 6 Selected from hydrogen, methyl, halogen, or C10-C18 alkyl; preferably, R 5 Selected from hydrogen, methyl, fluorine, C10 alkyl, C11 alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, or C18 alkyl; more preferably, R 5 Selected from hydrogen, methyl, fluorine, C10 straight-chain alkyl, C11 straight-chain alkyl, C12 straight-chain alkyl, C13 straight-chain alkyl, C14 straight-chain alkyl, C15 straight-chain alkyl, C16 straight-chain alkyl, C17 straight-chain alkyl or C18 straight-chain alkyl;

[0070] R 4 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 4 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy,

[0071] R 5 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 5 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy,

[0072] In some embodiments of the present invention, Nu is further defined as a nucleoside base selected from adenine, uracil, guanine, cytosine, thymine, or bases listed below:

[0073] In some embodiments of the present invention, the oligonucleotide provided by the present invention comprises at least one structure as shown in the following formula, and is obtained through... Linked to the rest of the oligonucleotide;

[0074] Among them, X 3 Selected from O or S. Preferably, X 3 Let it be S.

[0075] In some embodiments of the present invention, the oligonucleotide is siRNA, antisense nucleic acid, saRNA, miRNA, or a nucleic acid aptamer; preferably, the oligonucleotide is siRNA, wherein the siRNA comprises a sense strand and an antisense strand; more preferably, the structure shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc, or Formula VIIId is the first nucleotide at the 5' end of the sense strand of the siRNA, or the first nucleotide at the 5' end of the antisense strand of the siRNA; even more preferably, the structure shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc, or Formula VIIId is the first nucleotide at the 5' end of the sense strand of the siRNA.

[0076] In this invention, the siRNA has a double-stranded structure, comprising a sense strand and an antisense strand; wherein the antisense strand is 17-30 nucleotides in length; the sense strand is 17-30 nucleotides in length and is at least partially complementary to the antisense strand. Preferably, the sense strand and the antisense strand are complementary by at least 15, 16, 17, 18, 19, 20, or 21 nucleotides.

[0077] In some embodiments of the present invention, the antisense strand is 21 to 23 nucleotides long; the sense strand is 19 to 21 nucleotides long.

[0078] In some embodiments of the invention, the siRNA comprises one or more single-stranded nucleotide overhangs, such as 1, 2, 3, or 4 nucleotide overhangs. In some embodiments, the overhangs may be on the sense strand, the antisense strand, or any combination thereof. In some embodiments, the overhangs are present at the 5' end, 3' end, or both ends of the antisense or sense strand of the siRNA. Preferably, the 3' end of the antisense strand of the siRNA has a 2-nucleotide overhang.

[0079] In some embodiments of the present invention, the antisense strand is 23 nucleotides long and the sense strand is 21 nucleotides long; or the antisense strand is 22 nucleotides long and the sense strand is 20 nucleotides long; or the antisense strand is 21 nucleotides long and the sense strand is 21 nucleotides long; or the antisense strand is 21 nucleotides long and the sense strand is 19 nucleotides long; or the antisense strand is 19 nucleotides long and the sense strand is 19 nucleotides long.

[0080] In some embodiments of the present invention, in addition to nucleotides containing the structures shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc or Formula VIIId, the siRNA also contains at least one modifying nucleotide.

[0081] In some embodiments of the present invention, all nucleotides in the sense strand and / or antisense strand of the siRNA are modified nucleotides or nucleotide analogs.

[0082] In some embodiments of the present invention, the modified nucleotide is selected from 2'-methoxynucleotide, 2'-fluoronucleotide, 2'-deoxynucleotide, 2',3'-cleaved nucleotide analog, 2'-fluoroarabinonucleotide, 2'-methoxyethylnucleotide, 2'-amino-modified nucleotide, 2'-alkyl-modified nucleotide, 3'-methoxynucleotide, 2'-allyl-modified nucleotide, nucleotide containing a thiophosphate group, nucleotide containing a methylphosphonate group, nucleotide containing a 5'-phosphate, nucleotide containing a 5'-phosphate mimic, diol-modified nucleotide, debaseted nucleotide, morpholinonucleotide, locked nucleotide (LNA), unlocked nucleotide (UNA), glycerol nucleotide (GNA), or nucleotides with the structure shown in Formula V of the present invention, but the present invention is not limited thereto.

[0083] In some embodiments of the present invention, preferably, the first nucleotide at the 5' end of the siRNA positive strand has the structure shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc or Formula VIIId, and optionally further modified as follows: 1) the seventh nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 2) the ninth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 3) the tenth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 4) the eleventh nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide; more preferably, the nucleotides at the remaining positions of the siRNA positive strand are 2'-methoxynucleotides.

[0084] In some embodiments of the present invention, preferably, the first nucleotide at the 5' end of the siRNA positive strand has the structure shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc or Formula VIIId, and optionally further modified as follows: 1) the sixth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 2) the eighth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 3) the ninth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 4) the tenth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide; more preferably, the nucleotides at the remaining positions of the siRNA positive strand are 2'-methoxynucleotides.

[0085] In some embodiments of the present invention, preferably, the first nucleotide at the 5' end of the siRNA positive strand has the structure shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc or Formula VIIId, and optionally further modified as follows: 1) the fifth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 2) the seventh nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 3) the eighth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide, and / or 4) the ninth nucleotide at the 5' end of the positive strand is a 2'-fluoronucleotide; more preferably, the nucleotides at the remaining positions of the siRNA positive strand are 2'-methoxynucleotides.

[0086] In some embodiments of the present invention, preferably, the siRNA antisense strand is optionally modified as follows: 1) the second nucleotide at the 5' end of the antisense strand is a 2'-fluoronucleotide, and / or 2) the sixth nucleotide at the 5' end of the antisense strand is a 2'-fluoronucleotide, and / or 3) the fourteenth nucleotide at the 5' end of the antisense strand is a 2'-fluoronucleotide, and / or 4) the sixteenth nucleotide at the 5' end of the antisense strand is a 2'-fluoronucleotide; more preferably, the nucleotides at the remaining positions of the siRNA antisense strand are 2'-methoxynucleotides.

[0087] In some embodiments of the present invention, the siRNA is further linked to a targeting ligand.

[0088] In some embodiments of the present invention, the targeting ligand comprises one or more (e.g., 1, 2, 3 or 4) N-acetylgalactosamine (GalNAc) and / or its derivatives, for example, N-acetylgalactosamine is covalently conjugated to the sense and / or antisense strands in a monovalent, divalent, trivalent or tetravalent manner.

[0089] In some embodiments of the present invention, a targeting ligand is also attached to the 3' end of the siRNA positive strand.

[0090] In some embodiments of the present invention, the targeting ligand is L96, having the following structure:

[0091] In this invention, L96 can be prepared according to methods known in the art (e.g., the method described in patent application WO2014025805A1) and linked to siRNA molecules.

[0092] In some embodiments of the present invention, siRNA conjugates having the structure shown in the following formula are also provided:

[0093] in, This represents the oligonucleotide double strand of siRNA, where 3' represents the 3' end of the positive strand, and X is O or S.

[0094] The oligonucleotides provided by this invention are single-stranded or double-stranded nucleotide molecules, wherein each nucleotide in the double-stranded nucleotide molecule is a modified or unmodified nucleotide, and the double-stranded nucleotide sequence has 17-30 nucleotides; the antisense strand of the double-stranded nucleotide molecule is anticomplementary to at least 15 consecutive nucleotides in the target mRNA; at least one nucleotide in the sense or antisense strand of the double-stranded nucleotide molecule is prepared by using the nucleoside phosphoramidite compound provided by this invention as an intermediate; preferably, the first nucleotide at the 5' end of the sense strand of the double-stranded nucleotide molecule is prepared by using the nucleoside phosphoramidite compound provided by this invention as an intermediate.

[0095] The present invention also provides pharmaceutical compositions comprising the above-described oligonucleotides, said pharmaceutical compositions for inhibiting gene expression in cells, tissues, or organisms. In some embodiments, a therapeutically effective dose of the oligonucleotides or oligonucleotide compositions of the present invention is administered in vivo to inhibit the expression of target mRNAs in vivo.

[0096] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0097] The term "stereoisomer" in this application refers to compounds having the same chemical structure but different spatial arrangements of atoms or groups. The compounds of this invention may contain asymmetric centers or chiral centers, thus resulting in different stereoisomers. All stereoisomeric forms of the compounds of this invention, including but not limited to conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, blocked rotation isomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. These stereoisomers have the same chemical structure but different stereostructures. "Stereoisomer" includes enantiomers or diastereomers. Specific stereoisomers may be enantiomers, and mixtures of isomers are generally referred to as enantiomer mixtures.

[0098] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I mentioned in the groups and compounds described in this application include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen mentioned in the groups and compounds described in this application may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 127 iodine, 129 Iodine and 131 iodine.

[0099] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 30 carbon atoms, preferably an alkyl group with 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), more preferably an alkyl group with 1 to 6 carbon atoms or an alkyl group with 10 to 18 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, straight-chain or branched C 10-18 Alkyl group. The alkyl group may optionally be further substituted with one or more substituents.

[0100] "Alkoxy" refers to a group formed by the bonding of an alkyl group with an oxygen atom. The definition of alkyl is the same as that of "alkyl" as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, cyclobutoxy, and straight-chain or branched C-type groups. 10-18 Alkyl group. The alkoxy group may optionally be further substituted with one or more substituents.

[0101] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic system, preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The cycloalkyl group may optionally be further substituted by one or more substituents.

[0102] "Alkenyl" refers to an alkenyl group containing 1 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) carbon-carbon double bonds, consisting of 2 to 30 carbon atoms, preferably an alkenyl group with 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) carbon atoms, more preferably an alkenyl group with 2 to 8 carbon atoms or an alkenyl group with 10 to 18 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, undecen-3-yl, straight-chain or branched C 12-18Alkenyl group. The alkenyl group may optionally be further substituted with one or more substituents.

[0103] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing 1 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) carbon-carbon triple bonds and composed of 2 to 30 carbon atoms, preferably an alkynyl group with 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) carbon atoms, more preferably an alkynyl group with 2 to 8 carbon atoms or an alkynyl group with 10 to 18 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyyn-1-yl, pentyyn-2-yl, hexyn-1-yl, 1-heptyyn-1-yl, heptyyn-3-yl, heptyyn-4-yl, octyyn-3-yl, nonyyn-3-yl, decantyyn-4-yl, undecyn-3-yl, dodecanyyn-4-yl, and straight-chain or branched C 13-18 The alkynyl group may optionally be further substituted by one or more substituents.

[0104] Halogens include F, Cl, Br and I.

[0105] An acyl group is a structure formed by a carbonyl functional group bonded to a hydrogen atom or a substituent group, written as -COR'. In this invention, R' represents alkyl, alkenyl, or alkynyl. The definitions of alkyl, alkenyl, and alkynyl are the same as those for "alkyl," "alkenyl," and "alkynyl" as described above. Non-limiting examples of acyl groups include formyl, acetyl, propionyl, and butyryl.

[0106] "Aryl" refers to an aromatic ring group having a conjugated planar ring system, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and can be a bridged ring or a spirocyclic ring. Non-limiting examples of aryl include phenyl and naphthyl. The aryl group may optionally be further substituted by one or more substituents.

[0107] "Heteroaryl" refers to an aromatic ring group having a conjugated planar ring system and containing heteroatoms. It can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S. Non-limiting examples of heteroaryl include triazolyl, pyridyl, furanyl, thiophene, pyranyl, pyrroloyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted by one or more substituents.

[0108] "Heterocyclic group" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. Non-limiting examples of "heterocyclic group" or "heterocycle" include oxoheterobutyl, azaheterobutyl, thioheterobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, azaheptanyl, oxoheptanyl, thioheptanyl, triazolyl, pyridyl, piperidinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentylyl Cycloyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyrroleyl, tetrahydroimidazoyl, tetrahydrothiazoyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl. The "heterocyclic group" or "heterocycle" may optionally be further substituted with one or more substituents.

[0109] In the chemical structural formula of this invention, "Bz" represents benzoyl group, and the structure is as follows: “iBu” represents isobutyryl, and its structure is as follows:

[0110] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Beneficial effects

[0111] This invention provides modified nucleoside compounds that can be incorporated into the heads and / or middles of oligonucleotides, allowing the modified oligonucleotides to hybridize with a portion of the target RNA, thereby causing loss or downregulation of the normal function of the target RNA. Such oligonucleotides can also be included in double-stranded compositions. Specifically, the nucleoside compounds of Formula I of this invention can be applied to oligonucleotides (including but not limited to siRNA, antisense nucleic acids, saRNA, miRNA, nucleic acid aptamers, etc.), effectively improving the activity of the oligonucleotides and simultaneously improving their resistance to enzymatic digestion by phosphatases, exonucleases, endonucleases, etc. Furthermore, compared to ordinary nucleosides, the nucleoside compounds of Formula I of this invention can easily introduce various functional groups with specific functions, such as various substituted alkyl lipids, without affecting their base pairing ability, improving the cell membrane penetration ability of the oligonucleotide sequence and enhancing the organ-targeting effect of the oligonucleotide (e.g., when such modified nucleosides are used in siRNA molecules, they can increase the enrichment of siRNA molecules in target organs, etc.). Cell and mouse experiments showed that the in vivo and in vitro activity, pharmacokinetic properties and bioavailability of oligonucleotide drugs prepared containing nucleoside compounds of Formula I of the present invention were significantly improved. Attached Figure Description

[0112] Figure 1 shows the TTR protein inhibition rate of 21-day-old wild mice in Example 44. Detailed Implementation

[0113] Unless otherwise specified, the instruments used in this invention are conventional instruments, and the reagents used are conventional reagents.

[0114] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0115] NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Broker Avance III 400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents and tetramethylsilane (TMS) as the internal standard.

[0116] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0117] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, and the diameter of the thin-layer chromatography separation and purification products is 0.4mm-0.5mm.

[0118] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0119] Oligo solid-phase synthesis was performed on an LK-48E synthesizer (Lingkun).

[0120] Explanation of the abbreviations used for materials in this invention:

[0121] In the siRNA nucleotide chain of this invention, SS represents the sense strand and AS represents the antisense strand. The modified nucleotides involved in the embodiments of this invention have the following basic sequences:

[0122] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0123] Example Section

[0124] Example 1: Synthesis of Compound 9 (LT110-A)

[0125] Synthesis of compound 2:

[0126] Compound 1 (20.0 g, 105.15 mmol, 1.0 eq.) was dissolved in DMF (200 mL). Imidazole (17.9 g, 262.88 mmol, 2.5 eq.) was added to the reaction system, and the reaction was cooled to 0 °C and stirred continuously for 30 minutes. Then, tert-butyldiphenylchlorosilane (31.79 g, 115.67 mmol, 1.1 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed, and the reaction was gradually restored to room temperature and allowed to proceed overnight at room temperature. The reaction was monitored by TLC, and compound 1 was found to be in complete reaction. Water was added to the reaction system, followed by extraction twice with ethyl acetate. The organic phases were combined and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 20 / 3) to give compound 2 (35.24 g, 82.29 mmol, 78.3% yield). ESI-MS: m / z 451.2 [M+Na] +

[0127] Synthesis of compound 3:

[0128] Compound 2 (35.24 g, 82.22 mmol, 1.0 eq.) was dissolved in DMF (350 mL), stirred until completely dissolved, and the reaction system was cooled to approximately 0 °C. NaH (4.93 g, 123.33 mmol, 1.5 eq.) was slowly added to the reaction system in portions, and the reaction system was stirred at 0 °C for 30 minutes after the addition was complete. Iodomethane (17.51 ​​g, 123.33 mmol, 1.5 eq.) was slowly added dropwise to the reaction system, maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction system was brought back to room temperature and reacted overnight at room temperature. TLC analysis showed that the reaction was complete, and compound 1 reacted completely. The reaction system was slowly poured into a saturated ammonium chloride aqueous solution at approximately 0 °C, and the mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 3 (45.21 g), which was directly used in the next reaction step. ESI-MS: m / z 443.2 [M+H] +

[0129] Synthesis of compound 4:

[0130] The crude compound 3 (45.21 g) was dissolved in THF (300 mL) and stirred until completely dissolved. TBAF (1 M in THF, 100 mL, 100 mmol, 1.22 eq.) was added to the reaction mixture, and the mixture was stirred overnight at room temperature until compound 3 reacted completely. The reaction solution was concentrated under reduced pressure to remove the solvent, and the crude product was subjected to column chromatography (PE / EA = 10 / 3) to give compound 4 (14.12 g, 69.14 mmol, two-step yield 84.09%). 1H NMR(400MHz, DMSO-d6)5.84(d,J=3.6Hz,1H),4.74(t,J=5.2Hz,1H),4.54–4.47(d,J=12Hz,1H),4.10 (m,1H),3.89(d,J=3.2Hz,1H),3.71–3.55(m,2H),3.41(s,3H),1.39(s,3H),1.26(s,3H).ESI-MS:m / z 205.1[M+H] +

[0131] Synthesis of compound 5:

[0132] Compound 4 (14.12 g, 69.14 mmol, 1.0 eq.) was dissolved in DMF (150 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. NaH (4.15 g, 103.71 mmol, 1.5 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 minutes. Bromododecane (20.68 g, 82.97 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was allowed to return to room temperature and reacted overnight at room temperature. TLC analysis showed that compound 4 reacted completely. The reaction mixture was slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude compound was obtained by desolventizing under reduced pressure. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 5 (22.98 g, 61.68 mmol, 89.21% yield). ESI-MS: m / z 373.3 [M+H] +

[0133] Synthesis of compound 6:

[0134] Compound 5 (22.98 g, 61.68 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (31.48 g, 308.40 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 5 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 6. Crude product 6 was subjected to column chromatography (PE / EA = 5 / 1) to give compound 6 (15.96 g, 38.32 mmol, 62.12% yield). ESI-MS: m / z 417.3 [M+H] +

[0135] Synthesis of compound 7:

[0136] Compound 6 (5.00 g, 12.00 mmol, 1.00 eq.) was added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (100 mL) was added and stirred to dissolve. Then, BSA (7.32 g, 36.00 mmol, 3.0 eq.) and ABz (5.74 g, 24.00 mmol, 2.0 eq.) were added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (2.67 g, 12.00 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 6 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution to the reaction system. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 7. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 7 (4.88 g, 8.19 mmol, 68.25% yield). 1H NMR (400MHz, DMSO-d6) δ11.24(s,1H),8.76(s,1H),8.42(s,1H),8.06(d,J=7.4Hz,2H ),7.65(t,J=7.4Hz,1H),7.55(t,J=7.6Hz,2H),6.31(d,J=1.7Hz,1H),4.78(d,J=11. 8Hz,1H),4.60(d,J=11.8Hz,1H),4.44(dd,J=10.3,4.6Hz,1H),3.46–3.39(m,5H),2. 13(s,3H),1.53–1.43(m,2H),1.32–1.16(m,20H),0.84(t,J=6.7Hz,3H).ESI-MS:m / z 596.3[M+H] +

[0137] Synthesis of compound 8:

[0138] Compound 7 (4.88 g, 8.19 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and THF (50 mL) was added to the reaction mixture. The mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (1.82 mL, 9.83 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 8 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 8. The crude compound 8 was subjected to column chromatography to obtain compound 8 (4.22 g, 7.62 mmol, 93.04% yield). ESI-MS: m / z 554.3 [M+H] +

[0139] Synthesis of compound 9:

[0140] The dried compound 8 (4.22 g, 7.62 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and 40 mL of ultra-dry dichloromethane was added and stirred until completely dissolved. DIPEA (1.97 g, 15.24 mmol, 2.0 eq.) and DMAP (185.7 mg, 1.52 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (2.71 g, 11.43 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 8 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 9. The crude product was purified by column chromatography to obtain compound 9 (4.39 g, 5.96 mmol, 78.22% yield). 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.76(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H),8. 05(d,J=7.7Hz,2H),7.65(t,J=7.3Hz,1H),7.55(t,J=7.6Hz,2H),6.22(dd,J=28.0,2.2 Hz,1H),4.99–4.88(m,1H),4.43(dt,J=9.0,4.4Hz,1H),4.10–3.97(m,1H),3.89–3.40( m,9H),2.80(t,J=5.9Hz,1H),2.67(t,J=6.0Hz,1H),1.49(dd,J=13.2,6.5Hz,2H),1.33 -1.19(m,21H),1.13(dd,J=10.9,4.2Hz,9H),0.99(d,J=6.7Hz,3H),0.84(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.83(s),149.68(s).ESI-MS:m / z 755.4[M+H] +

[0141] Example 2: Synthesis of Compound 17 (LT107-A)

[0142] Synthesis of Compound 10

[0143] Compound 2 (30.50 g, 71.16 mmol, 1.0 eq.) was dissolved and stirred in ultradry DCM (300 mL), and TCDI (25.36 g, 142.32 mmol, 2.0 eq.) was added. The system was stirred at room temperature. TLC analysis showed that compound 1 reacted completely. The system was directly concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 20) to give compound 10 (38 g, 70.54 mmol, 99.13% yield). ESI-MS: m / z 539.2 [M+H] +

[0144] Synthesis of Compound 11

[0145] Compound 10 (38 g, 70.54 mmol, 1.0 eq.) was dissolved in toluene (300 mL) and stirred. AIBN (0.35 g, 2.12 mmol, 0.03 eq.) and Bu3SnH (22.77 mL, 84.64 mmol, 1.2 eq.) were added, and the mixture was heated and stirred at 110 °C. The reaction was monitored by TLC, and compound 10 was found to be completely reacted. The mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 15) to give compound 11 (13.00 g, 31.51 mmol, 44.67% yield). ESI-MS: m / z 413.2 [M+H] +

[0146] Synthesis of Compound 12

[0147] Compound 11 (13.00 g, 31.51 mmol, 1.0 eq.) was dissolved and stirred in ultradry THF (150 mL). TBAF (43.63 mL, 43.63 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature. TLC analysis showed that compound 11 reacted completely. The mixture was quenched with water, extracted with ethyl acetate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 50) to give compound 12 (4.00 g, 22.96 mmol, 72.87% yield). ESI-MS: m / z 175.1 [M+H] +

[0148] Synthesis of Compound 13

[0149] Compound 12 (4.00 g, 22.96 mmol, 1.0 eq.) was dried in ultradry acetonitrile, then dissolved and stirred in ultradry DMF (100 mL). NaH (1.10 g, 27.56 mmol, 1.2 eq.) was added, and the mixture was stirred for 10 minutes. Bromododecane (8.25 mL, 34.44 mmol, 1.5 eq.) was then added, and the mixture was stirred at room temperature. TLC analysis showed that compound 12 reacted completely. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 8) to give compound 13 (5.50 g, 16.06 mmol, 69.95% yield). ESI-MS: m / z 343.3 [M+H] +

[0150] Synthesis of Compound 14

[0151] Compound 13 (5.50 g, 16.06 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (50 mL) and acetic anhydride (7.58 mL, 80.29 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5.0 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 13 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 14. Crude product 14 was subjected to column chromatography (PE / EA = 100 / 17) to give compound 14 (3.75 g, 9.70 mmol, 60.40% yield). ESI-MS: m / z 387.3 [M+H] +

[0152] Synthesis of Compound 15

[0153] Compound 14 (3.75 g, 9.70 mmol, 1.00 eq.) was added to a 250 mL round-bottom flask, and ABz (2.79 g, 11.64 mmol, 1.2 eq.) was added to the reaction flask and dissolved in ultra-dry acetonitrile (250 mL) with stirring. BSA (7.12 mL, 29.11 mmol, 3.0 eq.) was then added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (1.76 mL, 9.70 mmol, 1.00 eq.) was then added. 1.0 eq. was slowly added dropwise to the reaction system. After the addition was complete, the reaction was placed in an oil bath and slowly heated to 80°C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 14 reacted completely. The reaction was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the system was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 15. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 15 (3.30 g, 5.83 mmol, 60.13% yield). ESI-MS: m / z 566.3 [M+H] +

[0154] Synthesis of Compound 16

[0155] Compound 15 (3.30 g, 5.83 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and THF (10 mL) was added to the reaction mixture. The mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (1.296 mL, 7.000 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 15 was completely reacted. After the reaction was complete, the reaction mixture was concentrated under reduced pressure at 40 °C to obtain crude compound 16. The crude compound was subjected to column chromatography to obtain compound 16 (2.8 g, 5.35 mmol, 91.77% yield). ESI-MS: m / z 524.3 [M+H]+

[0156] Synthesis of Compound 17

[0157] The dried compound 16 (2.8 g, 5.35 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (30 mL) was added and stirred until completely dissolved. DIPEA (1.86 mL, 10.69 mmol, 2.0 eq.) and DMAP (0.13 g, 1.07 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (1.79 mL, 8.020 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 16 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 17. The crude product was purified by column chromatography to give compound 17 (2.5, 3.45 mmol, 64.60% yield). 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.76(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H),8. 05(d,J=7.7Hz,2H),7.65(t,J=7.3Hz,1H),7.55(t,J=7.6Hz,2H),6.22(dd,J=28.0,2.2 Hz,1H),4.99–4.88(m,1H),4.43(dt,J=9.0,4.4Hz,1H),4.10–3.97(m,1H),3.89–3.40( m,6H),2.80(t,J=5.9Hz,1H),2.67(t,J=6.0Hz,1H),1.49(dd,J=13.2,6.5Hz,2H),1.33 -1.19(m,21H),1.13(dd,J=10.9,4.2Hz,9H),0.99(d,J=6.7Hz,3H),0.84(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ148.68(s),148.20(s).ESI-MS:m / z 724.4[M+H] +

[0158] Example 3: Synthesis of compound 26 (LT119-A)

[0159] Synthesis of compound 19:

[0160] Compound 18 (10.6 g, 40.72 mmol, 1.0 eq.) was dissolved in DCM (100 mL). Pyridine (13.175 mL, 162.88 mmol, 4.0 eq.) was added to the reaction system, and the reaction was cooled to -20 °C and stirred continuously for 30 min. Trifluoromethanesulfonic anhydride (22.98 g, 81.448 mmol) was then slowly added dropwise to the reaction system. After the addition was complete, the reaction was maintained at -20 °C for 5 h. The reaction was monitored by TLC. After compound 18 had reacted completely, the reaction mixture was diluted with DCM and washed with HCl (2 M, 3 × 80 mL aqueous solution). The organic layer was dried, and the solvent was removed under vacuum to obtain crude intermediate trifluoromethanesulfonate. The crude intermediate trifluoromethanesulfonate was then dissolved in isopropanol (60 mL), followed by the addition of cesium fluoride (18.56 g, 122.17 mmol, 3.0 eq.). The reaction mixture was stirred at 80 °C for 24 hours until TLC (PE / EA = 5 / 1) showed complete reaction of the trifluoromethanesulfonate (intermediate). The reaction mixture was diluted with ethyl acetate (100 mL) and washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The aqueous layer was back-extracted using DCM (3 × 100 mL). The combined organic phases were dried, filtered, and concentrated under reduced pressure to obtain crude product 19. The crude product was subjected to column chromatography to give compound 19 (9.40 g, 35.84 mmol, 88.01% yield). 19 F NMR(377MHz,DMSO-d6)δ-206.65(s).ESI-MS:m / z263.1[M+H] +

[0161] Synthesis of compound 20:

[0162] Compound 19 (9.40 g, 35.840 mmol) was dissolved in methanol (40 mL), followed by the addition of 1% sulfuric acid solution (40 mL). The mixture was stirred at room temperature for 18 hours until compound 19 was completely reacted. The pH was then adjusted to neutral with triethylamine, and the solvent was removed under vacuum to obtain crude product 20. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 20 (6.60 g, 29.70 mmol, 82.87% yield). ESI-MS: m / z 223.1 [M+H] +

[0163] Synthesis of compound 21:

[0164] Compound 20 (6.60 g, 29.70 mmol, 1.0 eq.) was dissolved in a mixture of 1,4-dioxane (30 mL) and water (30 mL), followed by the addition of sodium periodate (7.62 g, 35.64 mmol, 1.2 eq.). The mixture was stirred at room temperature for 3 hours until compound 20 was completely reacted. Ethanol (25 mL) was then added and stirred for 20 minutes. The resulting white solid was removed by filtration. Sodium borohydride (1.12 g, 29.70 mmol, 1.2 eq.) was added to the filtrate and stirred for 2 hours until the intermediate was completely reacted. The pH of the reaction mixture was adjusted to 7 by adding acetic acid. The mixture was then dried and purified by column chromatography (PE / EA = 1 / 1) to give compound 21 (4.77 g, 24.82 mmol, 83.56% yield). 19 F NMR(377MHz,DMSO-d6)δ-208.56(s).ESI-MS:m / z 193.1[M+H] +

[0165] Synthesis of compound 22:

[0166] Compound 21 (4.77 g, 24.82 mmol, 1.0 eq) was dissolved in DMF (50 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. NaH (1.49 g, 37.23 mmol, 1.5 eq.) was slowly added to the reaction mixture in portions. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 minutes. Bromododecane (49.64 g, 49.64 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was allowed to return to room temperature and reacted overnight at room temperature. TLC analysis showed that compound 4 reacted completely. The reaction mixture was slowly poured into ice water to quench completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude compound was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 22 (8.50 g, 23.58 mmol, 95.00% yield). ESI-MS: m / z 361.3 [M+H] +

[0167] Synthesis of compound 23:

[0168] Compound 22 (8.50 g, 23.58 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (110 mL) and acetic anhydride (12.04 g, 117.89 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (1.1 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 22 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 23. Crude product 23 was subjected to column chromatography (PE / EA = 5 / 1) to give compound 23 (8.35 g, 20.64 mmol, 87.55% yield). ESI-MS: m / z 417.3 [M+H] +

[0169] Synthesis of compound 24:

[0170] Compound 23 (8.35 g, 20.64 mmol, 1.00 eq.) was added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (100 mL) was added and stirred to dissolve. Then, BSA (12.60 g, 61.93 mmol, 3.0 eq.) and ABz (7.41 g, 30.96 mmol, 1.5 eq.) were added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (6.88 g, 30.96 mmol, 1.5 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 6 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution to the reaction system. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 23. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 23 (7.70 g, 13.19 mmol, 63.91% yield). 19 F NMR(377MHz,DMSO-d6)δ-207.51(s).ESI-MS:m / z 584.3[M+H] +

[0171] Synthesis of compound 24:

[0172] Compound 23 (7.70 g, 13.19 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask, and THF (70 mL) was added to the reaction mixture. The mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (4.89 mL, 26.38 mmol, 2.0 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 23 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 24. The crude compound 24 was subjected to column chromatography to obtain compound 24 (11.63 g, 6.30 mmol, 88.17% yield). 19 F NMR(377MHz,DMSO-d6)δ-200.18(s).ESI-MS:m / z 542.3[M+H] +

[0173] Synthesis of compound 25:

[0174] The dried compound 24 (2.30 g, 4.25 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and 20 mL of ultradry dichloromethane was added and stirred until completely dissolved. DIPEA (1.10 g, 8.49 mmol, 2.0 eq.) and DMAP (104 mg, 0.85 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (1.51 g, 6.369 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 24 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 25. The crude product was purified by column chromatography to obtain compound 25 (4.39 g, 5.96 mmol, 78.22% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.78(d,J=6.7Hz,1H),8.52(d,J=2.3Hz,1H),8.06(d,J=7.7 Hz,2H),7.65(t,J=7.3Hz,1H),7.55(t,J=7.6Hz,2H),6.25(dd,J=26.9,3.1Hz,1H),5.49–5.10(m, 2H),4.60–4.45(m,1H),3.89–3.44(m,8H),2.80(t,J=5.9Hz,1H),2.69(t,J=6.0Hz,1H),1.54–1.4 9(m,2H),1.30–1.19(m,18H),1.12(t,J=6.3Hz,9H),0.96(d,J=6.8Hz,3H),0.84(t,J=6.8Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ150.89(s),150.57(s). 19 F NMR (377MHz, DMSO-d6) δ-200.11 (d, J=73.5Hz).ESI-MS: m / z 742.4[M+H] +

[0175] Example 4: Synthesis of compound 35 (LT116-A)

[0176] Synthesis of compound 27:

[0177] Compound 2 (15.20 g, 35.46 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask, and DCM (200 mL) was added to the reaction mixture. The mixture was stirred until completely dissolved. After cooling, Dys-Martin oxidant (24.07 g, 56.74 mmol, 1.6 eq.) was added, and the mixture was stirred at room temperature until compound 2 reacted completely. The reaction was quenched with a saturated sodium bicarbonate aqueous solution. The reactants were extracted twice with water and dichloromethane, and the combined organic phases were washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain crude product 27. The crude product was subjected to column chromatography to obtain compound 27 (14.80 g, 34.70 mmol, 97.86% yield). ESI-MS: m / z 427.2 [M+H] +

[0178] Synthesis of compound 28:

[0179] Triphenylmethylphosphine bromide (19.83 g, 55.51 mmol, 1.6 eq.) was dissolved in THF (150 mL), cooled, and then potassium tert-butoxide (6.23 g, 55.51 mmol, 1.6 eq.) was added and the mixture was stirred for 30 min. Then, compound 27 (14.80 g, 34.70 mmol, 1.0 eq.) was added to the reaction solution, and the mixture was stirred until compound 27 was completely reacted. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The reaction mixture was extracted twice with water and ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 28. The crude product was subjected to column chromatography to obtain compound 28 (9.00 g, 21.20 mmol, 61.09% yield). ESI-MS: m / z 425.2 [M+H] +

[0180] Synthesis of compound 29:

[0181] Compound 28 (9.00 g, 21.20 mmol, 1.0 eq.) was dissolved in methanol (90 mL), and 10% Pd / C (5% w, 450 mg) was added to replace the hydrogen atmosphere. The mixture was stirred until compound 28 was completely reacted. The reaction solution was filtered through diatomaceous earth and the solvent was removed under reduced pressure to obtain crude product 29. Crude product 29 was subjected to column chromatography to obtain compound 29 (6.31 g, 14.79 mmol, 69.76% yield). ESI-MS: m / z 427.2 [M+H] +

[0182] Synthesis of compound 30:

[0183] Compound 29 (6.31 g, 14.79 mmol, 1.0 eq.) was dissolved in THF (60 mL) and stirred until completely dissolved. TBAF (1 M in THF, 20 mL, 20 mmol, 1.35 eq.) was added to the reaction mixture, and the mixture was stirred overnight at room temperature until compound 29 reacted completely. The reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 10 / 3) to give compound 30 (2.28 g, 12.11 mmol, 84.09% yield). ESI-MS: m / z 189.1 [M+H] +

[0184] Synthesis of compound 31:

[0185] Compound 30 (2.28 g, 12.11 mmol, 1.0 eq.) was dissolved in DMF (30 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. NaH (687 mg, 18.17 mmol, 1.5 eq.) was slowly added to the reaction mixture in portions. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 minutes. Bromododecane (3.62 g, 14.53 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was allowed to return to room temperature and reacted overnight at room temperature. TLC analysis showed that compound 30 reacted completely. The reaction mixture was slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude compound was obtained by desolventizing under reduced pressure. The crude product was subjected to column chromatography (PE / EA = 10 / 1) to give compound 31 (4.03 g, 11.31 mmol, 93.39% yield). ESI-MS: m / z 357.3 [M+H] +

[0186] Synthesis of compound 32:

[0187] Compound 31 (4.03 g, 11.31 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (50 mL) and acetic anhydride (5.77 g, 56.55 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (1 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 31 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 32. Crude product 32 was subjected to column chromatography (PE / EA = 5 / 1) to give compound 32 (3.60 g, 8.98 mmol, 79.40% yield). ESI-MS: m / z 401.3 [M+H] +

[0188] Synthesis of compound 33:

[0189] Compound 32 (3.60 g, 8.98 mmol, 1.00 eq.) was added to a 100 mL three-necked round-bottom flask, and ultra-dry acetonitrile (40 mL) was added and stirred to dissolve. Then, BSA (5.48 g, 26.94 mmol, 3.0 eq.) and ABz (4.30 g, 17.96 mmol, 2.0 eq.) were added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (2.00 g, 8.98 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 32 reacted completely. The reaction system was then removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give crude product 33. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 33 (3.81 g, 6.57 mmol, 73.16% yield). ESI-MS: m / z 580.4 [M+H] +

[0190] Synthesis of compound 34:

[0191] Compound 33 (3.81 g, 6.57 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (40 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (1.46 mL, 7.88 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 33 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 34. The crude compound 34 was subjected to column chromatography to obtain compound 34 (3.13 g, 5.82 mmol, 88.58% yield). ESI-MS: m / z 538.3 [M+H] +

[0192] Synthesis of compound 35:

[0193] The dried compound 34 (3.13 g, 5.82 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (30 mL) was added and stirred until completely dissolved. DIPEA (1.50 g, 11.64 mmol, 2.0 eq.) and DMAP (142 mg, 1.16 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (2.07 g, 8.73 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 34 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 35. The crude product was purified by column chromatography to give compound 35 (3.22 g, 4.36 mmol, 74.91% yield). 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),8.73(d,J=7.3Hz,1H),8.42(d,J=5.9Hz,1H),8. 01(d,J=7.7Hz,2H),7.65(t,J=7.3Hz,1H),7.52(t,J=7.6Hz,2H),6.21(dd,J=28.0,2.2 Hz,1H),4.99–4.81(m,1H),4.42(dt,J=9.0,4.4Hz,1H),4.12–3.99(m,1H),3.88–3.41( m,8H),2.81(t,J=5.9Hz,1H),2.66(t,J=6.0Hz,1H),1.48(dd,J=13.2,6.5Hz,2H),1.32 -1.18(m,21H),1.12(dd,J=10.9,4.2Hz,9H),0.98(d,J=6.7Hz,3H),0.83(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.33(s),148.98(s).ESI-MS:m / z 738.5[M+H] +

[0194] Example 5: Synthesis of compound 44 (LT132-A)

[0195] Synthesis of compound 37:

[0196] Compound 36 (20.0 g, 133.22 mmol, 1.0 eq.) was dissolved in DMF (200 mL). Imidazole (22.67 g, 333.06 mmol, 2.5 eq.) was added to the reaction system, and the reaction was cooled to 0 °C and stirred continuously for 30 minutes. Then, tert-butyldiphenylchlorosilane (40.28 g, 146.54 mmol, 1.1 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed, and the reaction was heated to 60 °C and allowed to proceed overnight. The reaction was monitored by TLC, and compound 36 was found to be completely reacted. Water was added to the reaction system, followed by extraction twice with ethyl acetate. The organic phases were combined and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 35.38 g of crude intermediate. The crude intermediate was dissolved in acetone (300 mL), and p-toluenesulfonic acid (1.15 g, 6.66 mmol, 0.05 eq.) was added, followed by 2,2-dimethoxypropane (69.37 g, 666.1 mmol, 5.0 eq.). After the addition was complete, the reaction was stirred at room temperature. TLC analysis showed that the intermediate had completely reacted. Sodium bicarbonate solid was added to quench the p-toluenesulfonic acid, the solid was removed by filtration, and the mixture was concentrated to obtain 38.24 g of crude product 37. Crude product 37 was subjected to column chromatography (PE / EA = 20 / 3) to give compound 2 (19.27 g, 44.96 mmol, 33.75% yield). ESI-MS: m / z 451.2 [M + Na] +

[0197] Synthesis of compound 38:

[0198] Compound 37 (19.27 g, 44.96 mmol, 1.0 eq.) was dissolved in DMF (200 mL), stirred until completely dissolved, and the reaction system was cooled to approximately 0 °C. NaH (2.70 g, 67.44 mmol, 1.5 eq.) was slowly added to the reaction mixture in portions. After the addition was complete, the reaction system was stirred at 0 °C for 30 minutes. Iodomethane (9.57 g, 67.44 mmol, 1.5 eq.) was slowly added dropwise to the reaction system, maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction system was brought back to room temperature and reacted overnight at room temperature. TLC analysis showed that the reaction was complete, and compound 37 reacted completely. The reaction mixture was slowly poured into a saturated ammonium chloride aqueous solution at approximately 0 °C. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 38 (22.21 g), which was directly used in the next reaction step. ESI-MS: m / z 443.2 [M+H] +

[0199] Synthesis of compound 39:

[0200] Crude compound 38 (22.21 g) was dissolved in THF (200 mL) and stirred until completely dissolved. TBAF (1 M in THF, 50 mL, 50 mmol, 1.11 eq.) was added to the reaction mixture, and the mixture was stirred overnight at room temperature until compound 38 reacted completely. The reaction solution was concentrated under reduced pressure to remove the solvent, and the crude product was subjected to column chromatography (PE / EA = 10 / 3) to give compound 39 (7.12 g, 34.86 mmol, two-step yield 77.54%). 1 H NMR(400MHz, DMSO-d6)δ5.83(d,J=3.6Hz,1H),4.75(t,J=5.2Hz,1H),4.55–4.44(d,J=12Hz,1H),4.18–4 .03(m,1H),3.88(d,J=3.2Hz,1H),3.72–3.56(m,2H),3.42(s,3H),1.38(s,3H),1.27(s,3H).ESI-MS:m / z 205.1[M+H] +

[0201] Synthesis of compound 40:

[0202] Compound 39 (7.12 g, 34.86 mmol, 1.0 eq.) was dissolved in DMF (70 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. NaH (2.09 g, 52.29 mmol, 1.5 eq.) was slowly added to the reaction mixture in portions. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 minutes. Bromododecane (10.43 g, 41.83 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was allowed to return to room temperature and reacted overnight at room temperature. TLC analysis showed that compound 39 reacted completely. The reaction mixture was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude compound was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 5 (11.68 g, 31.35 mmol, 89.93% yield). ESI-MS: m / z 373.3 [M+H] +

[0203] Synthesis of compound 41:

[0204] Compound 40 (11.68 g, 31.35 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (160 mL) and acetic anhydride (17.53 g, 171.75 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (1.6 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 40 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 41. Crude product 41 was subjected to column chromatography (PE / EA = 5 / 1) to give compound 6 (8.52 g, 20.45 mmol, 65.23% yield). ESI-MS: m / z 417.3 [M+H] +

[0205] Synthesis of compound 42:

[0206] Compound 41 (5.00 g, 12.00 mmol, 1.00 eq.) was added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (100 mL) was added and stirred to dissolve. Then, BSA (7.32 g, 36.00 mmol, 3.0 eq.) and ABz (5.74 g, 24.00 mmol, 2.0 eq.) were added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (2.67 g, 12.00 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 41 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution to the reaction system. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 42. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 42 (4.75 g, 7.79 mmol, 64.92% yield). 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),8.75(s,1H),8.41(s,1H),8.05(d,J=7.4Hz,2H ),7.66(t,J=7.4Hz,1H),7.56(t,J=7.6Hz,2H),6.32(d,J=1.7Hz,1H),4.79(d,J=11. 8Hz,1H),4.61(d,J=11.8Hz,1H),4.45(dd,J=10.3,4.6Hz,1H),3.45–3.38(m,5H),2. 12(s,3H),1.53–1.42(m,2H),1.33–1.15(m,20H),0.85(t,J=6.7Hz,3H).ESI-MS:m / z 596.3[M+H] +

[0207] Synthesis of compound 43:

[0208] Compound 42 (4.75 g, 7.79 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and THF (50 mL) was added to the reaction mixture. The mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (1.73 mL, 9.83 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 42 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 43. The crude compound 43 was subjected to column chromatography to obtain compound 43 (4.15 g, 7.50 mmol, 96.28% yield). ESI-MS: m / z 554.3 [M+H] +

[0209] Synthesis of compound 44:

[0210] The dried compound 43 (4.15 g, 7.50 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (1.94 g, 15.00 mmol, 2.0 eq.) and DMAP (183 mg, 1.50 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. Compound CEP-Cl (2.66 g, 11.25 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 43 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 44. The crude product was purified by column chromatography to give compound 44 (4.25 g, 5.77 mmol, 76.93% yield). 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.74(d,J=7.3Hz,1H),8.45(d,J=5.9Hz,1H),8. 04(d,J=7.7Hz,2H),7.66(t,J=7.3Hz,1H),7.55(t,J=7.6Hz,2H),6.23(dd,J=28.0,2.2 Hz,1H),4.98–4.87(m,1H),4.44(dt,J=9.0,4.4Hz,1H),4.11–3.95(m,1H),3.88–3.41( m,9H),2.81(t,J=5.9Hz,1H),2.62(t,J=6.0Hz,1H),1.48(dd,J=13.2,6.5Hz,2H),1.34 -1.18(m,21H),1.14(dd,J=10.9,4.2Hz,9H),0.98(d,J=6.7Hz,3H),0.85(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.91(s),148.86(s).ESI-MS:m / z 755.4[M+H] +

[0211] Example 6: Synthesis of compound 52 (LT131-A)

[0212] Synthesis of Compound 45

[0213] Compound 37 (30.00 g, 70.00 mmol, 1.0 eq.) was dissolved and stirred in ultradry DCM (300 mL), and TCDI (24.95 g, 140.00 mmol, 2.0 eq.) was added. The system was stirred at room temperature. TLC analysis showed that compound 37 reacted completely. The system was directly concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 45 (34.23 g, 63.54 mmol, 90.77% yield). ESI-MS: m / z 539.2 [M+H] +

[0214] Synthesis of Compound 46

[0215] Compound 45 (34.23 g, 63.54 mmol, 1.0 eq.) was dissolved in toluene (300 mL) and stirred. AIBN (0.52 g, 3.18 mmol, 0.05 eq.) and Bu3SnH (27.74 g, 95.31 mmol, 1.5 eq.) were added, and the mixture was heated and stirred at 110 °C. The reaction was monitored by TLC, and compound 45 was found to be completely reacted. The mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 15) to give compound 46 (17.23 g, 41.76 mmol, 65.72% yield). ESI-MS: m / z 413.2 [M+H] +

[0216] Synthesis of Compound 47

[0217] Compound 46 (17.23 g, 41.76 mmol, 1.0 eq.) was dissolved and stirred in ultradry THF (170 mL), and then TBAF (50.00 mL, 50.00 mmol, 1.2 eq.) was added. The mixture was stirred at room temperature. TLC analysis showed that compound 46 reacted completely. The mixture was quenched with water, extracted with ethyl acetate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 50) to give compound 47 (6.23 g, 35.76 mmol, 85.63% yield). ESI-MS: m / z 175.1 [M+H] +

[0218] Synthesis of Compound 48

[0219] Compound 17 (6.23 g, 35.76 mmol, 1.0 eq.) was dried in ultradry acetonitrile, then dissolved and stirred in ultradry DMF (70 mL). NaH (1.72 g, 42.91 mmol, 1.2 eq.) was added, and the mixture was stirred for 10 minutes. Bromododecane (13.37 g, 53.64 mmol, 1.5 eq.) was then added, and the mixture was stirred at room temperature. TLC analysis showed that compound 47 reacted completely. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 8) to give compound 48 (10.06 g, 29.37 mmol, 84.49% yield). ESI-MS: m / z 343.3 [M+H] +

[0220] Synthesis of Compound 49

[0221] Compound 48 (10.06 g, 29.37 mmol, 1.0 eq) was added to a 250 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (14.99 g, 146.85 mmol, 5.0 eq) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (1.5 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 48 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 49. Crude product 49 was subjected to column chromatography (PE / EA = 100 / 17) to give compound 49 (6.11 g, 15.81 mmol, 53.83% yield). ESI-MS: m / z 387.3 [M+H] +

[0222] Synthesis of Compound 50

[0223] Compound 49 (6.11 g, 15.81 mmol, 1.00 eq.) was added to a 250 mL round-bottom flask, followed by ABz (4.54 g, 18.97 mmol, 1.2 eq.). After dissolving the ABz in 250 mL of ultra-dry acetonitrile with stirring, BSA (9.65 g, 47.43 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred for 1 hour under nitrogen protection. After the reaction was complete, the mixture was stirred in an ice-water bath at 0 °C for 30 minutes, and TMSOTf (3.51 g, 15.81 mmol, 1.0 eq.) was slowly added dropwise. Following the addition, the mixture was slowly heated to 80 °C in an oil bath and reacted overnight. TLC and LCMS analysis confirmed that compound 49 had reacted completely. The reaction mixture was then removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 50. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 50 (5.98 g, 10.57 mmol, 66.86% yield). ESI-MS: m / z 566.3 [M+H] +

[0224] Synthesis of Compound 51

[0225] Compound 50 (5.98 g, 10.57 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (60 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.35 mL, 12.68 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 50 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 51. The crude compound 51 was subjected to column chromatography to obtain compound 51 (5.24 g, 10.01 mmol, 94.70% yield). ESI-MS: m / z 524.3 [M+H] +

[0226] Synthesis of Compound 52

[0227] The dried compound 51 (5.24 g, 10.01 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (2.59 g, 20.02 mmol, 2.0 eq.) and DMAP (0.24 g, 2.00 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (3.55 g, 15.02 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 51 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 52. The crude product was purified by column chromatography to give compound 52 (5.35 g, 7.39 mmol, 73.83% yield). 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.75(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H),8. 07(d,J=7.7Hz,2H),7.63(t,J=7.3Hz,1H),7.56(t,J=7.6Hz,2H),6.23(dd,J=28.0,2.2 Hz,1H),4.98–4.87(m,1H),4.42(dt,J=9.0,4.4Hz,1H),4.11–3.98(m,1H),3.86–3.41( m,6H),2.81(t,J=5.9Hz,1H),2.68(t,J=6.0Hz,1H),1.48(dd,J=13.2,6.5Hz,2H),1.34 -1.20(m,21H),1.14(dd,J=10.9,4.2Hz,9H),0.98(d,J=6.7Hz,3H),0.85(t,J=6.7Hz,3H). 31 P NMR (162MHz, DMSO-d6) δ149.49,148.20, ESI-MS: m / z 724.4[M+H] +

[0228] Example 7: Synthesis of compound 59 (LT134-A)

[0229] Synthesis of Compound 53

[0230] Compound 37 (30.00 g, 70.00 mmol, 1.0 eq.) was dissolved and stirred in ultradry DCM (300 mL). Pyridine (55.37 g, 700.00 mmol, 10.0 eq.) was added, and the mixture was cooled to -78 °C. Then, pyridine hydrogen fluoride (13.86 g, 140.00 mmol, 2.0 eq.) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred. The reaction was monitored by TLC, and compound 37 was found to be completely reacted. After the reaction was complete, the reaction mixture was extracted twice with water and dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 53 (25.22 g). ESI-MS: m / z 431.2 [M+H] +

[0231] Synthesis of Compound 54

[0232] The crude compound 53 (25.22 g) was dissolved and stirred in ultradry THF (150 mL), and then TBAF (84.00 mL, 84.00 mmol, 1.2 eq.) was added. The mixture was stirred at room temperature. TLC analysis showed that compound 53 reacted completely. The mixture was quenched with water, extracted with ethyl acetate, and concentrated under reduced pressure to obtain the crude product. Column chromatography (PE / EA = 100 / 40) yielded compound 54 (5.64 g, 29.35 mmol, overall yield: 41.93%). 19 F NMR(377MHz,DMSO-d6)δ-208.67(s).ESI-MS:m / z193.1[M+H] +

[0233] Synthesis of Compound 55

[0234] Compound 54 (5.64 g, 29.35 mmol, 1.0 eq.) was dried in ultradry acetonitrile, then dissolved and stirred in ultradry DMF (60 mL). NaH (1.41 g, 35.22 mmol, 1.2 eq.) was added, and the mixture was stirred for 10 minutes. Bromododecane (10.97 g, 44.03 mmol, 1.5 eq.) was then added, and the mixture was stirred at room temperature. TLC analysis showed that compound 54 reacted completely. The mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (PE / EA = 100 / 10) to give compound 55 (8.91 g, 24.71 mmol, 84.19% yield). ESI-MS: m / z 361.3 [M+H] +

[0235] Synthesis of Compound 56

[0236] Compound 55 (8.91 g, 24.71 mmol, 1.0 eq) was added to a 250 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (12.61 g, 123.55 mmol, 5.0 eq) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (1.2 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 55 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 56. Crude product 56 was subjected to column chromatography (PE / EA = 100 / 20) to give compound 56 (4.11 g, 10.16 mmol, 41.12% yield). ESI-MS: m / z 405.3 [M+H] +

[0237] Synthesis of Compound 57

[0238] Compound 56 (4.11 g, 10.16 mmol, 1.00 eq.) was added to a 250 mL round-bottom flask, followed by ABz (2.92 g, 12.19 mmol, 1.2 eq.). After dissolving the ABz in ultra-dry acetonitrile (250 mL) with stirring, BSA (6.20 g, 30.48 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred for 1 hour under nitrogen protection. After the reaction was complete, the mixture was stirred in an ice-water bath at 0 °C for 30 minutes, and TMSOTf (2.26 g, 10.16 mmol, 1.0 eq.) was slowly added dropwise. Following the addition, the mixture was slowly heated to 80 °C in an oil bath and reacted overnight. TLC and LCMS analysis confirmed that compound 56 had reacted completely. The reaction mixture was then removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 57. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 57 (4.01 g, 6.87 mmol, 67.62% yield). ESI-MS: m / z 584.3 [M+H] +

[0239] Synthesis of Compound 58

[0240] Compound 57 (4.01 g, 6.87 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. 40 mL of THF was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (1.53 mL, 8.24 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 57 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 58. The crude compound was subjected to column chromatography to obtain compound 58 (3.43 g, 6.33 mmol, 92.14% yield). ESI-MS: m / z 542.3 [M+H] +

[0241] Synthesis of Compound 59

[0242] The dried compound 58 (3.43 g, 6.33 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (1.64 g, 12.66 mmol, 2.0 eq.) and DMAP (0.16 g, 1.27 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (2.25 g, 9.50 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 58 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 59. The crude product was purified by column chromatography to give compound 59 (3.33 g, 4.49 mmol, 70.93% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.76(d,J=7.3Hz,1H),8.45(d,J=5.9Hz,1H),8. 02(d,J=7.7Hz,2H),7.66(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.21(dd,J=28.0,2.2 Hz,1H),4.99–4.85(m,1H),4.43(dt,J=9.0,4.4Hz,1H),4.12–3.97(m,1H),3.87–3.40( m,6H),2.80(t,J=5.9Hz,1H),2.64(t,J=6.0Hz,1H),1.46(dd,J=13.2,6.5Hz,2H),1.36 -1.21(m,21H),1.13(dd,J=10.9,4.2Hz,9H),0.99(d,J=6.7Hz,3H),0.87(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ150.49,149.21. 19 F NMR (377MHz, DMSO-d6) δ-200.13 (d, J=73.5Hz).ESI-MS: m / z 742.4[M+H] +

[0243] Example 8: Synthesis of compound 68 (LT133-A)

[0244] Synthesis of compound 60:

[0245] Compound 37 (30.00 g, 70.00 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask, and DCM (300 mL) was added to the reaction mixture. The mixture was stirred until completely dissolved. After cooling, Dys-Martin oxidant (47.50 g, 112.00 mmol, 1.6 eq.) was added, and the mixture was stirred at room temperature until compound 37 was completely reacted. The reaction was quenched with a saturated sodium bicarbonate aqueous solution. The reactants were extracted twice with water and dichloromethane, and the organic phases were combined. The organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 60. The crude product was subjected to column chromatography to obtain compound 60 (27.83 g, 65.24 mmol, 93.20% yield). ESI-MS: m / z 427.2 [M+H] +

[0246] Synthesis of compound 61:

[0247] Triphenylmethylphosphine bromide (37.29 g, 104.38 mmol, 1.6 eq.) was dissolved in THF (380 mL). After cooling, potassium tert-butoxide (11.71 g, 104.38 mmol, 1.6 eq.) was added and the mixture was stirred for 30 min. Then, compound 60 (27.83 g, 65.24 mmol, 1.0 eq.) was added to the reaction solution, and the reaction was continued until compound 60 was completely reacted. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The reaction mixture was extracted twice with water and ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 61. The crude product was subjected to column chromatography to obtain compound 61 (18.14 g, 42.72 mmol, 65.48% yield). ESI-MS: m / z 425.2 [M+H] +

[0248] Synthesis of compound 62:

[0249] Compound 61 (18.14 g, 42.72 mmol, 1.0 eq.) was dissolved in methanol (180 mL), and 10% Pd / C (5% w, 907 mg) was added to displace hydrogen gas. The mixture was stirred until compound 61 was completely reacted. The reaction solution was filtered through diatomaceous earth and the solvent was removed under reduced pressure to obtain crude product 62. Crude product 62 was subjected to column chromatography to obtain compound 62 (9.21 g, 21.59 mmol, 50.54% yield). ESI-MS: m / z 427.2 [M+H] +

[0250] Synthesis of compound 63:

[0251] Compound 62 (9.21 g, 21.59 mmol, 1.0 eq.) was dissolved in THF (90 mL) and stirred until completely dissolved. TBAF (1 M in THF, 25.91 mL, 25.91 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred overnight at room temperature until compound 62 reacted completely. The reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 10 / 3) to give compound 63 (3.58 g, 19.02 mmol, 88.10% yield). ESI-MS: m / z 189.1 [M+H] +

[0252] Synthesis of compound 64:

[0253] Compound 63 (3.58 g, 19.02 mmol, 1.0 eq.) was dissolved in DMF (40 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. NaH (1.14 g, 28.53 mmol, 1.5 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 minutes. Bromododecane (5.69 g, 22.82 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was allowed to return to room temperature and reacted overnight at room temperature. TLC analysis showed that compound 63 reacted completely. The reaction mixture was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude compound was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 10 / 1) to give compound 64 (5.82 g, 16.32 mmol, 85.80% yield). ESI-MS: m / z 357.3 [M+H] +

[0254] Synthesis of compound 65:

[0255] Compound 64 (5.82 g, 16.32 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (60 mL) and acetic anhydride (8.33 g, 81.60 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (1.0 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 64 was completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 65. Crude product 65 was subjected to column chromatography (PE / EA = 5 / 1) to give compound 65 (3.60 g, 8.99 mmol, 55.09% yield). ESI-MS: m / z 401.3 [M+H] +

[0256] Synthesis of compound 66:

[0257] Compound 65 (3.60 g, 8.99 mmol, 1.00 eq.) was added to a 100 mL three-necked round-bottom flask, and ultra-dry acetonitrile (40 mL) was added and stirred to dissolve. Then, BSA (5.49 g, 26.97 mmol, 3.0 eq.) and ABz (2.58 g, 10.79 mmol, 1.2 eq.) were added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (2.00 g, 8.99 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 65 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 66. The crude product was subjected to column chromatography (PE / EA = 1 / 1) to give compound 66 (3.71 g, 6.40 mmol, 71.19% yield). ESI-MS: m / z 580.4 [M+H] +

[0258] Synthesis of compound 67:

[0259] Compound 66 (3.71 g, 6.40 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (40 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (1.42 mL, 7.68 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 66 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 67. The crude compound 67 was subjected to column chromatography to obtain compound 67 (3.04 g, 5.65 mmol, 88.28% yield). ESI-MS: m / z 538.3 [M+H] +

[0260] Synthesis of compound 68:

[0261] The dried compound 67 (3.04 g, 5.65 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (30 mL) was added and stirred until completely dissolved. DIPEA (1.46 g, 11.30 mmol, 2.0 eq.) and DMAP (138 mg, 1.13 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (2.00 g, 8.48 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 67 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 68. The crude product was purified by column chromatography to give compound 68 (3.31 g, 4.49 mmol, 79.47% yield). 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.74(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H),8. 03(d,J=7.7Hz,2H),7.63(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.23(dd,J=28.0,2.2 Hz,1H),4.98–4.80(m,1H),4.43(dt,J=9.0,4.4Hz,1H),4.12–3.97(m,1H),3.86–3.42( m,8H),2.82(t,J=5.9Hz,1H),2.67(t,J=6.0Hz,1H),1.49(dd,J=13.2,6.5Hz,2H),1.32 -1.19(m,21H),1.13(dd,J=10.9,4.2Hz,9H),0.99(d,J=6.7Hz,3H),0.82(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.22(s),148.47(s).ESI-MS:m / z 738.5[M+H] +

[0262] Example 9: Synthesis of Compound 74 (LT135-A)

[0263] Synthesis of compound 69:

[0264] Compound 12 (30.00 g, 172.22 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (41.04 g, 602.77 mmol, 3.5 eq.), triphenylphosphine (54.20 g, 206.66 mmol, 1.2 eq.), and iodine (52.45 g, 206.66 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred and reacted for 3 hours. TLC and LCMS analysis showed that compound 12 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 69. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 69 (41.91 g, 147.52 mmol, 85.66% yield). ESI-MS: m / z 285.0 [M+H] +

[0265] Synthesis of compound 70:

[0266] Compound 69 (41.91 g, 147.52 mmol, 1.0 eq.) was dissolved in MeOH (400 mL), followed by the addition of potassium carbonate (20.39 g, 147.52 mmol, 1.0 eq.) and palladium on carbon (10% W, 4.19 g). The mixture was stirred at room temperature until compound 69 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 70. Crude product 70 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 70 (21.29 g, 134.58 mmol, 91.23% yield). ESI-MS: m / z 159.1 [M+H] +

[0267] Synthesis of compound 71:

[0268] Compound 70 (21.29 g, 134.58 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (68.70 g, 672.90 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction system was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (10.0 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 70 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 71. Crude product 71 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 71 (14.48 g, 71.61 mmol, 53.21% yield). ESI-MS: m / z 203.1 [M+H] +

[0269] Synthesis of compound 72:

[0270] Compound 71 (14.48 g, 71.61 mmol, 1.0 eq.) and N6-benzoyladenine (20.56 g, 85.93 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (150 mL) was added and stirred to dissolve. Then, BSA (43.70 g, 214.83 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (15.92 g, 71.61 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 71 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 72. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 72 (19.42 g, 50.92 mmol, 71.11% yield). ESI-MS: m / z 382.2 [M+H] +

[0271] Synthesis of compound 73:

[0272] Compound 72 (19.42 g, 50.92 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (200 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (11.31 mL, 61.10 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 72 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 73. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to give compound 73 (15.42 g, 45.44 mmol, 89.24% yield). ESI-MS: m / z 340.1 [M+H] +

[0273] Synthesis of compound 74:

[0274] The dried compound 73 (5.00 g, 14.73 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.81 g, 29.46 mmol, 2.0 eq.) and DMAP (360 mg, 2.95 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (5.23 g, 22.10 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 73 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 74. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 74 (6.22 g, 11.53 mmol, 78.28% yield). 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.46(,J=7.3Hz,1H),8.33(d,J=5.9Hz,1 H),7.98–7.90(m,2H),7.68–7.48(m,3H),6.25(dd,J=28.0,2.2Hz,1H),4.59–4. 37(m,1H),4.12–3.80(m,3H),2.95–2.70(m,2H),2.68–2.55(m,2H),1.96–1.50 (m,2H),1.33–1.19(m,3H),1.14(dd,J=10.9,4.2Hz,9H),0.98(d,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.40(s),148.56(s).ESI-MS:m / z 540.3[M+H] +

[0275] Example 10: Synthesis of Compound 80 (LT136-A)

[0276] Synthesis of compound 75:

[0277] Compound 4 (30.00 g, 146.90 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (35.00 g, 514.15 mmol, 3.5 eq.), triphenylphosphine (46.24 g, 176.28 mmol, 1.2 eq.), and iodine (44.74 g, 176.28 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred for 3 hours. TLC and LCMS analysis showed that compound 4 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 75. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 75 (37.89 g, 120.62 mmol, 82.11% yield). ESI-MS: m / z 315.0 [M+H] +

[0278] Synthesis of compound 76:

[0279] Compound 75 (37.89 g, 120.62 mmol, 1.0 eq.) was dissolved in MeOH (400 mL), followed by the addition of potassium carbonate (16.67 g, 120.62 mmol, 1.0 eq.) and palladium on carbon (10% W, 3.79 g). The mixture was stirred at room temperature until compound 75 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 76. Crude product 76 was subjected to column chromatography (PE / EA = 4 / 1) to obtain compound 76 (20.53 g, 109.10 mmol, 90.45% yield). ESI-MS: m / z 189.1 [M+H] +

[0280] Synthesis of compound 77:

[0281] Compound 76 (20.53 g, 109.10 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (55.69 g, 545.50 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction system was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5.0 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 76 was completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 77. Crude compound 77 was subjected to column chromatography (PE / EA = 4 / 1) to yield compound 77 (12.49 g, 53.78 mmol, 49.29% yield). ESI-MS: m / z 233.1 [M+H] +

[0282] Synthesis of compound 78:

[0283] Compound 77 (12.49 g, 53.78 mmol, 1.0 eq.) and N6-benzoyladenine (15.44 g, 64.54 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (150 mL) was added and stirred to dissolve. Then, BSA (32.82 g, 161.34 mmol, 3.0 eq.) was added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (11.95 g, 53.78 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 77 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 78. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 78 (15.54 g, 37.78 mmol, 70.25% yield). ESI-MS: m / z 412.2 [M+H] +

[0284] Synthesis of compound 79:

[0285] Compound 78 (15.54 g, 37.78 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (8.40 mL, 45.34 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 78 was completely dissolved. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 79. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 79 (12.78 g, 34.60 mmol, 91.58% yield). ESI-MS: m / z 370.1 [M+H] +

[0286] Synthesis of compound 80:

[0287] The dried compound 79 (5.00 g, 13.54 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.50 g, 27.08 mmol, 2.0 eq.) and DMAP (331 mg, 2.71 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.81 g, 20.31 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 79 was completely reacted. The reaction system was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 80. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 80 (5.82 g, 10.22 mmol, 75.48% yield). 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.47(,J=7.3Hz,1H),8.35(d,J=5.9Hz,1H),7 .99–7.91(m,2H),7.69–7.47(m,3H),6.17(dd,J=28.0,2.2Hz,1H),4.59–4.37(m,1H) ,4.12–3.99(m,1H),3.96–3.46(m,4H),2.95–2.71(m,2H),2.69–2.56(m,2H),1.91– 1.51(m,2H),1.32–1.20(m,3H),1.13(dd,J=10.9,4.2Hz,9H),0.99(d,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.32(s),148.29(s).ESI-MS:m / z 570.3[M+H] +

[0288] Example 11: Synthesis of Compound 86 (LT137-A)

[0289] Synthesis of compound 81:

[0290] Compound 30 (30.00 g, 159.39 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (37.98 g, 557.87 mmol, 3.5 eq.), triphenylphosphine (50.17 g, 191.27 mmol, 1.2 eq.), and iodine (48.55 g, 191.27 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred for 3 hours. TLC and LCMS analysis showed that compound 30 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 81. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 81 (39.80 g, 133.50 mmol, 83.76% yield). ESI-MS: m / z 299.0 [M+H] +

[0291] Synthesis of compound 82:

[0292] Compound 81 (39.80 g, 133.50 mmol, 1.0 eq.) was dissolved in MeOH (400 mL). Potassium carbonate (18.45 g, 133.50 mmol, 1.0 eq.) and palladium on carbon (10% W, 3.98 g) were then added to the reaction solution, and the mixture was stirred at room temperature until compound 81 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 82. Crude product 82 was subjected to column chromatography (PE / EA = 4 / 1) to obtain compound 82 (20.37 g, 118.28 mmol, 88.60% yield). ESI-MS: m / z 173.1 [M+H] +

[0293] Synthesis of compound 83:

[0294] Compound 82 (20.37 g, 118.28 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (60.38 g, 591.40 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction system was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 82 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 83. Crude product 83 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 83 (12.46 g, 57.62 mmol, 48.71% yield). ESI-MS: m / z 217.1 [M+H] +

[0295] Synthesis of compound 84:

[0296] Compound 83 (12.46 g, 57.62 mmol, 1.0 eq.) and N6-benzoyladenine (16.54 g, 69.14 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (150 mL) was added and stirred to dissolve. Then, BSA (35.16 g, 172.86 mmol, 3.0 eq.) was added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (12.81 g, 57.62 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 83 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 84. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 84 (15.54 g, 39.30 mmol, 68.21% yield). ESI-MS: m / z 396.2 [M+H] +

[0297] Synthesis of compound 85:

[0298] Compound 84 (15.54 g, 39.30 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (8.73 mL, 47.16 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 84 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 85. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 85 (12.16 g, 34.41 mmol, 87.56% yield). ESI-MS: m / z 354.2 [M+H] +

[0299] Synthesis of compound 86:

[0300] The dried compound 85 (5.00 g, 14.15 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.66 g, 28.30 mmol, 2.0 eq.) and DMAP (346 mg, 2.83 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (5.02 g, 21.23 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 85 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 86. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 86 (5.94 g, 10.73 mmol, 75.83% yield). 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),8.48(,J=7.3Hz,1H),8.29(d,J=5.9Hz,1H),7.98–7.90(m,2H),7.68–7.48(m,3H),6.07(dd,J=28.0,2.2Hz ,1H),4.58–4.38(m,1H),3.95–3.74(m,3H),2.96–2.70(m,2H),1.20–1. 09(m,12H),0.99(d,J=6.7Hz,3H),1.20–1.09(m,3H),0.93–0.76(m,3H). 31P NMR(162MHz,DMSO-d6)δ149.51(s),148.64(s).ESI-MS:m / z554.3[M+H] +

[0301] Example 12: Synthesis of compound 92 (LT138-A)

[0302] Synthesis of compound 87:

[0303] Compound 21 (30.00 g, 156.10 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (37.20 g, 546.35 mmol, 3.5 eq.), triphenylphosphine (49.13 g, 187.32 mmol, 1.2 eq.), and iodine (47.54 g, 187.32 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred for 3 hours. TLC and LCMS analysis showed that compound 21 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 87. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 87 (35.59 g, 117.82 mmol, 75.48% yield). ESI-MS: m / z 303.0 [M+H] +

[0304] Synthesis of compound 88:

[0305] Compound 87 (35.59 g, 117.82 mmol, 1.0 eq.) was dissolved in MeOH (400 mL), followed by the addition of potassium carbonate (16.28 g, 133.50 mmol, 1.0 eq.) and palladium on carbon (10% W, 3.60 g). The mixture was stirred at room temperature until compound 87 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 88. Crude product 88 was subjected to column chromatography (PE / EA = 4 / 1) to obtain compound 88 (18.50 g, 105.00 mmol, 89.12% yield). ESI-MS: m / z 177.1 [M+H] +

[0306] Synthesis of compound 89:

[0307] Compound 88 (18.50 g, 105.00 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (53.60 g, 525.00 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 88 was completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 89. Crude product 89 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 89 (12.79 g, 58.08 mmol, 55.31% yield). ESI-MS: m / z 221.1 [M+H] +

[0308] Synthesis of compound 90:

[0309] Compound 89 (12.79 g, 58.08 mmol, 1.0 eq.) and N6-benzoyladenine (16.67 g, 69.70 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (150 mL) was added and stirred to dissolve. Then, BSA (35.45 g, 174.24 mmol, 3.0 eq.) was added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (12.91 g, 58.08 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 89 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the system was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 90. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 90 (16.60 g, 41.56 mmol, 71.56% yield). ESI-MS: m / z 400.1 [M+H] +

[0310] Synthesis of compound 91:

[0311] Compound 90 (16.60 g, 41.56 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (160 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (9.24 mL, 49.87 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 90 was completely dissolved. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 91. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 91 (13.09 g, 36.63 mmol, 88.14% yield). ESI-MS: m / z 358.1 [M+H] +

[0312] Synthesis of compound 92:

[0313] The dried compound 91 (5.00 g, 14.00 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.62 g, 28.00 mmol, 2.0 eq.) and DMAP (342 mg, 2.80 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.97 g, 21.00 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 91 was completely reacted. The reaction system was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 92. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 92 (5.45 g, 9.77 mmol, 69.79% yield). 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.49(,J=7.3Hz,1H),8.21(d,J=5.9Hz,1H),7.99–7.89(m,2H),7.67–7.46(m,3H),6.11(dd,J=28 .0,2.2Hz,1H),5.67–5.33(m,1H),3.95–3.74(m,3H),2.96–2.70(m,2H),1.20–1.09(m,12H),0.99(d,J=6.7Hz,3H),1.20–1.09(m,3H). 19F NMR(377MHz,DMSO-d6)δ-208.56(s),-208.33(s). 31 P NMR(162MHz,DMSO-d6)δ149.62(s),148.32(s).ESI-MS:m / z 558.3[M+H] +

[0314] Example 13: Synthesis of Compound 97 (LT139-A)

[0315] Synthesis of compound 93:

[0316] Compound 12 (10.00 g, 57.41 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (2.76 g, 68.89 mmol, 1.2 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (12.22 g, 86.12 mmol, 1.5 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and reacted overnight at room temperature. TLC analysis showed that compound 12 reacted completely. The reaction system was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 93 (9.47 g, 50.31 mmol, 87.63% yield). ESI-MS: m / z 189.1 [M+H] +

[0317] Synthesis of compound 94:

[0318] Compound 93 (9.47 g, 50.31 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (25.68 g, 251.55 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 93 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 94. Crude product 94 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 94 (6.76 g, 29.11 mmol, 57.86% yield). ESI-MS: m / z 233.1 [M+H] +

[0319] Synthesis of Compound 95:

[0320] Compound 94 (6.76 g, 29.11 mmol, 1.0 eq.) and N6-benzoyladenine (8.36 g, 34.93 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (70 mL) was added and stirred to dissolve. Then, BSA (17.77 g, 87.33 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (6.47 g, 29.11 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 94 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 95. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 95 (7.88 g, 19.15 mmol, 65.82% yield). ESI-MS: m / z 412.2 [M+H] +

[0321] Synthesis of compound 96:

[0322] Compound 95 (7.88 g, 19.15 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (80 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (4.26 mL, 22.98 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 95 was completely dissolved. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 96. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to give compound 96 (6.38 g, 17.27 mmol, 90.18% yield). ESI-MS: m / z 370.2 [M+H] +

[0323] Synthesis of compound 97:

[0324] The dried compound 96 (6.38 g, 17.27 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask, and ultra-dry dichloromethane (70 mL) was added and stirred until completely dissolved. DIPEA (4.46 g, 34.54 mmol, 2.0 eq.) and DMAP (421 mg, 3.45 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (6.13 g, 25.91 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 96 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 97. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 97 (7.03 g, 12.34 mmol, 71.45% yield). 1H NMR (400MHz, DMSO-d6) δ11.20 (s, 1H), 8.76 (d, J = 7.3Hz, 1H), 8.43 (d, J = 5.9Hz, 1H),8.05(d,J=7.7Hz,2H),7.65(t,J=7.3Hz,1H),7.55(t,J=7.6Hz,2H),6.22(d d,J=28.0,2.2Hz,1H),4.99–4.88(m,1H),4.43(dt,J=9.0,4.4Hz,1H),4.10–3. 97(m,1H),3.89–3.40(m,8H),2.80(t,J=5.9Hz,1H),2.67(t,J=6.0Hz,1H),1.33 -1.19(m,2H),1.13(dd,J=10.9,4.2Hz,9H),0.84(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.51(s),148.32(s).ESI-MS:m / z 570.3[M+H] +

[0325] Example 14: Synthesis of Compound 102 (LT140-A)

[0326] Synthesis of compound 98:

[0327] Compound 1 (10.00 g, 52.58 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (5.05 g, 126.19 mmol, 2.4 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (18.66 g, 131.45 mmol, 2.5 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and reacted overnight at room temperature. TLC analysis showed that Compound 1 reacted completely. The reaction system was slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 98 (10.00 g, 45.82 mmol, 87.14% yield). ESI-MS: m / z 219.1 [M+H] +

[0328] Synthesis of Compound 99:

[0329] Compound 98 (10.00 g, 45.82 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (23.39 g, 229.10 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 98 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 99. Crude product 99 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 99 (7.28 g, 27.76 mmol, 60.58% yield). ESI-MS: m / z 263.1 [M+H] +

[0330] Synthesis of Compound 100:

[0331] Compound 99 (7.28 g, 27.76 mmol, 1.0 eq.) and N6-benzoyladenine (7.97 g, 33.31 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (70 mL) was added and stirred to dissolve. Then, BSA (16.94 g, 83.28 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (6.17 g, 27.76 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 99 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. A saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 100. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 100 (7.02 g, 15.90 mmol, 57.28% yield). ESI-MS: m / z 442.2 [M+H] +

[0332] Synthesis of compound 101:

[0333] Compound 100 (7.02 g, 15.90 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (70 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (3.53 mL, 19.08 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 100 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 101. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 101 (5.83 g, 14.60 mmol, 91.82% yield). ESI-MS: m / z 400.2 [M+H] +

[0334] Synthesis of compound 102:

[0335] The dried compound 101 (5.83 g, 14.60 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask, and ultra-dry dichloromethane (70 mL) was added and stirred until completely dissolved. DIPEA (3.77 g, 29.20 mmol, 2.0 eq.) and DMAP (357 mg, 2.92 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (5.18 g, 21.90 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 101 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 102. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 102 (6.33 g, 10.56 mmol, 72.33% yield). 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.74(d,J=7.3Hz,1H),8.45(d,J=5.9Hz,1H),8.0 4(d,J=7.7Hz,2H),7.63(t,J=7.3Hz,1H),7.52(t,J=7.6Hz,2H),6.21(dd,J=28.0,2.2H z,1H),4.91–4.56(m,1H),3.97–3.72(m,3H),3.65–3.50(m,1H),3.44–3.20(m,7H),2.9 8–2.66(m,2H),2.70–2.41(m,2H),1.13(dd,J=10.9,4.2Hz,9H),0.99(d,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.71(s),148.56(s).ESI-MS:m / z 600.3[M+H] +

[0336] Example 15: Synthesis of Compound 107 (LT141-A)

[0337] Synthesis of compound 103:

[0338] Compound 30 (10.00 g, 53.13 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (2.55 g, 63.76 mmol, 1.2 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (9.05 g, 63.76 mmol, 1.2 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and allowed to proceed overnight at room temperature. TLC analysis showed that compound 30 reacted completely. The reaction system was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 103 (9.46 g, 46.77 mmol, 88.03% yield). ESI-MS: m / z 203.1 [M+H] +

[0339] Synthesis of compound 104:

[0340] Compound 103 (9.46 g, 46.77 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (23.87 g, 233.85 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 103 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 104. Crude product 104 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 104 (6.53 g, 26.52 mmol, 56.70% yield). ESI-MS: m / z 247.1 [M+H] +

[0341] Synthesis of compound 105:

[0342] Compound 104 (6.53 g, 26.52 mmol, 1.0 eq.) and N6-benzoyladenine (7.61 g, 31.82 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (70 mL) was added and stirred to dissolve. Then, BSA (16.18 g, 79.56 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (5.89 g, 26.52 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 104 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 105. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 105 (6.01 g, 14.13 mmol, 53.28% yield). ESI-MS: m / z 426.2 [M+H] +

[0343] Synthesis of compound 106:

[0344] Compound 105 (6.01 g, 14.13 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (60 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (3.14 mL, 16.96 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 105 was completely dissolved. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 106. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 106 (4.81 g, 12.55 mmol, 88.82% yield). ESI-MS: m / z 384.2 [M+H] +

[0345] Synthesis of compound 107:

[0346] The dried compound 106 (4.81 g, 12.55 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.24 g, 25.10 mmol, 2.0 eq.) and DMAP (307 mg, 2.51 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.46 g, 18.83 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 106 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 107. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 107 (6.33 g, 10.56 mmol, 72.33% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.75(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H ),8.03(d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.51(t,J=7.6Hz,2H),6.17(dd,J =28.0,2.2Hz,1H),5.21–4.89(m,1H),4.10–3.73(m,3H),3.64–3.14(m,5H),2.99 –2.65(m,4H),2.17–1.91(m,1H),1.12(dd,J=10.9,4.2Hz,9H),1.01–0.82(m,6H). 31 P NMR(162MHz,DMSO-d6)δ149.81(s),148.68(s).ESI-MS:m / z 584.3[M+H] +

[0347] Example 16: Synthesis of Compound 112 (LT142-A)

[0348] Synthesis of compound 108:

[0349] Compound 21 (10.00 g, 52.03 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (2.50 g, 62.44 mmol, 1.2 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (8.86 g, 62.44 mmol, 1.2 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and allowed to proceed overnight at room temperature. TLC analysis showed that compound 21 reacted completely. The reaction system was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 108 (9.36 g, 45.39 mmol, 87.24% yield). ESI-MS: m / z 207.1 [M+H] +

[0350] Synthesis of compound 109:

[0351] Compound 108 (9.36 g, 45.39 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (23.17 g, 226.95 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 108 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 109. Crude product 109 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 109 (5.53 g, 22.10 mmol, 48.69% yield). ESI-MS: m / z 251.1 [M+H] +

[0352] Synthesis of compound 110:

[0353] Compound 109 (5.53 g, 22.10 mmol, 1.0 eq.) and N6-benzoyladenine (6.34 g, 26.52 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (60 mL) was added and stirred to dissolve. Then, BSA (13.49 g, 66.30 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (4.91 g, 22.10 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 109 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the system was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 110. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 110 (6.01 g, 14.13 mmol, 53.28% yield). ESI-MS: m / z 430.2 [M+H] +

[0354] Synthesis of compound 111:

[0355] Compound 110 (6.01 g, 14.13 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (60 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (3.14 mL, 16.96 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 110 was completely dissolved. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 111. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 111 (4.63 g, 11.95 mmol, 84.57% yield). ESI-MS: m / z 388.1 [M+H] +

[0356] Synthesis of compound 112:

[0357] Dry compound 111 (4.63 g, 11.92 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultradry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.08 g, 23.84 mmol, 2.0 eq.) and DMAP (290 mg, 2.38 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. Compound CEP-Cl (4.23 g, 17.88 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 111 was completely reacted. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 112. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 112 (5.39 g, 9.17 mmol, 76.93% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.75(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H) ,8.03(d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.51(t,J=7.6Hz,2H),6.17(dd,J=2 8.0,2.2Hz,1H),5.26–4.91(m,1H),4.85–4.54(m,1H),4.10–3.73(m,3H),3.67–3. 17(m,5H),3.00–2.60(m,4H),1.12(dd,J=10.9,4.2Hz,9H),0.85(t,J=6.7Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-201.22 (d, J = 73.5Hz). 31 P NMR(162MHz,DMSO-d6)δ149.21(s),148.03(s).ESI-MS:m / z 588.3[M+H] +

[0358] Example 17: Synthesis of Compound 117 (LT143-A)

[0359] Synthesis of compound 113:

[0360] The dried compound 12 (15.00 g, 86.11 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. 2,4,6-Trimethylpyridine (20.87 g, 172.22 mmol, 2.0 eq.) was then added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (16.66 g, 103.33 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 12 had completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 113. Crude product 113 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 113 (7.33 g, 41.60 mmol, 48.31% yield). ESI-MS: m / z 177.1 [M+H] +

[0361] Synthesis of compound 114:

[0362] Compound 113 (7.33 g, 41.60 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (75 mL) and acetic anhydride (21.23 g, 208.00 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 113 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 114. Crude compound 114 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 114 (4.71 g, 21.41 mmol, 51.47% yield). ESI-MS: m / z 221.1 [M+H] +

[0363] Synthesis of compound 115:

[0364] Compound 114 (4.71 g, 21.41 mmol, 1.0 eq.) and N6-benzoyladenine (6.15 g, 25.69 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (60 mL) was added and stirred to dissolve. Then, BSA (13.07 g, 64.23 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (4.76 g, 21.41 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 114 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 115. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 115 (5.00 g, 12.52 mmol, 58.48% yield). ESI-MS: m / z 400.1 [M+H] +

[0365] Synthesis of compound 116:

[0366] Compound 115 (5.00 g, 12.52 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (50 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.78 mL, 15.02 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 115 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 116. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 116 (4.03 g, 11.28 mmol, 90.10% yield). ESI-MS: m / z 358.1 [M+H] +

[0367] Synthesis of compound 117:

[0368] The dried compound 116 (4.03 g, 11.28 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (2.92 g, 22.56 mmol, 2.0 eq.) and DMAP (276 mg, 2.26 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.00 g, 16.92 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 116 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 117. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 117 (4.25 g, 7.62 mmol, 67.55% yield). 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.76(d,J=7.3Hz,1H),8.45(d,J=5.9Hz ,1H),8.04(d,J=7.7Hz,2H),7.63(t,J=7.3Hz,1H),7.52(t,J=7.6Hz,2H),6.1 3(dd,J=28.0,2.2Hz,1H),5.01–4.21(m,3H),4.09–3.76(m,3H),2.95–2.66(m ,4H),2.16–1.65(m,2H),1.12(dd,J=10.9,4.2Hz,9H),0.81(t,J=6.7Hz,3H). 19 F NMR(377MHz, DMSO)δ-227.23(s),-227.32(s). 31 P NMR (162MHz, DMSO) δ151.29 (d, J = 55.5Hz), 149.36 (d, J = 42.7Hz). ESI-MS: m / z 558.2 [M+H] +

[0369] Example 18: Synthesis of Compound 123 (LT144-A)

[0370] Synthesis of compound 118:

[0371] The dried compound 4 (15.00 g, 73.45 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. 2,4,6-Trimethylpyridine (17.80 g, 146.90 mmol, 2.0 eq.) was then added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (14.21 g, 88.14 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 4 had completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 118. Crude product 118 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 118 (7.76 g, 37.63 mmol, 51.23% yield). ESI-MS: m / z 207.1 [M+H] +

[0372] Synthesis of compound 119:

[0373] Compound 118 (7.76 g, 37.63 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (75 mL) and acetic anhydride (19.21 g, 188.15 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for another 8 hours until compound 118 had completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 119. Crude product 119 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 119 (3.95 g, 15.79 mmol, 41.96% yield). ESI-MS: m / z 251.1 [M+H] +

[0374] Synthesis of compound 120:

[0375] Compound 119 (3.95 g, 15.79 mmol, 1.0 eq.) and N6-benzoyladenine (4.53 g, 18.95 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (50 mL) was added and stirred to dissolve. Then, BSA (9.64 g, 47.37 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (3.51 g, 15.79 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 119 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution. The system was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 120. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 120 (4.21 g, 9.80 mmol, 62.06% yield). ESI-MS: m / z 430.2 [M+H] +

[0376] Synthesis of compound 121:

[0377] Compound 120 (4.21 g, 9.80 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (40 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.18 mL, 11.76 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 120 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 121. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 121 (3.39 g, 8.75 mmol, 89.29% yield). ESI-MS: m / z 388.1 [M+H] +

[0378] Synthesis of compound 122:

[0379] The dried compound 121 (3.39 g, 8.75 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (2.26 g, 17.50 mmol, 2.0 eq.) and DMAP (214 mg, 1.75 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (3.11 g, 13.13 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 121 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 122. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 122 (3.05 g, 5.19 mmol, 59.31% yield). 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.73(d,J=7.3Hz,1H),8.41(d,J=5.9Hz,1H) ,8.03(d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.09(dd,J=2 8.0,2.2Hz,1H),5.47–4.22(m,3H),4.01–3.80(m,2H),3.68–3.35(m,4H),2.98–2. 67(m,1H),2.55–2.40(m,1H),1.15(dd,J=10.9,4.2Hz,9H),0.83(t,J=6.7Hz,3H). 19 F NMR(377MHz, DMSO)δ-226.53(s),-226.22(s). 31 P NMR (162MHz, DMSO) δ151.11 (d, J = 55.5Hz), 149.31 (d, J = 42.7Hz). ESI-MS: m / z 588.3 [M+H] +

[0380] Example 19: Synthesis of Compound 127 (LT145-A)

[0381] Synthesis of compound 123:

[0382] The dried compound 30 (15.00 g, 79.69 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. 2,4,6-Trimethylpyridine (19.31 g, 159.38 mmol, 2.0 eq.) was then added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (15.41 g, 95.63 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 30 had completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 123. Crude product 123 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 123 (8.01 g, 42.11 mmol, 52.84% yield). ESI-MS: m / z 191.1 [M+H] +

[0383] Synthesis of compound 124:

[0384] Compound 123 (8.01 g, 42.11 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (80 mL) and acetic anhydride (21.50 g, 210.55 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 123 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 124. Crude compound 124 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 124 (4.22 g, 18.02 mmol, 42.79% yield). ESI-MS: m / z 235.1 [M+H] +

[0385] Synthesis of compound 125:

[0386] Compound 124 (4.22 g, 18.02 mmol, 1.0 eq.) and N6-benzoyladenine (5.17 g, 21.62 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (50 mL) was added and stirred to dissolve. Then, BSA (11.00 g, 54.06 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (4.01 g, 18.02 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 124 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 125. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 125 (4.78 g, 11.56 mmol, 64.15% yield). ESI-MS: m / z 414.2 [M+H] +

[0387] Synthesis of compound 126:

[0388] Compound 125 (4.78 g, 11.56 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (50 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.57 mL, 13.87 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 125 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 126. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 126 (3.89 g, 10.47 mmol, 90.57% yield). ESI-MS: m / z 372.2 [M+H] +

[0389] Synthesis of compound 127:

[0390] The dried compound 126 (3.89 g, 10.47 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (2.71 g, 20.94 mmol, 2.0 eq.) and DMAP (255 mg, 2.09 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (3.72 g, 15.71 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 126 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 127. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 127 (4.33 g, 7.58 mmol, 72.39% yield). 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.73(d,J=7.3Hz,1H),8.41(d,J=5.9Hz,1H) ,8.03(d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.09(dd,J=2 8.0,2.2Hz,1H),5.47–4.22(m,3H),4.01–3.80(m,2H),3.68–3.35(m,4H),2.98–2. 67(m,1H),2.55–2.40(m,1H),1.15(dd,J=10.9,4.2Hz,9H),0.84(t,J=6.7Hz,3H). 19 F NMR(377MHz, DMSO)δ-227.13(s),-226.92(s). 31 P NMR (162MHz, DMSO) δ151.25 (d, J = 55.5Hz), 149.46 (d, J = 42.7Hz). ESI-MS: m / z 572.3 [M+H] +

[0391] Example 20: Synthesis of Compound 132 (LT146-A)

[0392] Synthesis of compound 128:

[0393] The dried compound 21 (15.00 g, 78.05 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. 2,4,6-Trimethylpyridine (18.92 g, 156.10 mmol, 2.0 eq.) was then added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (15.10 g, 93.66 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 21 had completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 128. Crude product 128 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 128 (7.62 g, 39.24 mmol, 50.28% yield). ESI-MS: m / z 195.1 [M+H] +

[0394] Synthesis of compound 129:

[0395] Compound 128 (7.62 g, 39.24 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (80 mL) and acetic anhydride (20.03 g, 196.20 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 128 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 129. Crude product 129 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 129 (4.12 g, 17.30 mmol, 44.09% yield). ESI-MS: m / z 239.1 [M+H] +

[0396] Synthesis of compound 130:

[0397] Compound 129 (4.12 g, 17.30 mmol, 1.0 eq.) and N6-benzoyladenine (4.97 g, 20.76 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (50 mL) was added and stirred to dissolve. Then, BSA (10.56 g, 51.90 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (3.85 g, 17.30 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 129 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the system was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 130. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 130 (4.62 g, 11.07 mmol, 63.99% yield). ESI-MS: m / z 418.1 [M+H] +

[0398] Synthesis of compound 131:

[0399] Compound 130 (4.62 g, 11.07 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (50 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.46 mL, 13.28 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 130 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 131. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to give compound 131 (3.65 g, 9.72 mmol, 87.80% yield). ESI-MS: m / z 376.1 [M+H] +

[0400] Synthesis of compound 132:

[0401] The dried compound 131 (3.65 g, 9.72 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (2.51 g, 19.44 mmol, 2.0 eq.) and DMAP (237 mg, 1.94 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (3.45 g, 14.58 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 131 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 132. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 132 (4.03 g, 7.00 mmol, 72.02% yield). 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.73(d,J=7.3Hz,1H),8.41(d,J=5.9Hz,1H) ,8.03(d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.09(dd,J=2 8.0,2.2Hz,1H),5.52–5.10(m,1H),4.97–4.55(m,3H),4.07–3.75(m,3H),2.99–2. 70(m,2H),2.63–2.47(m,2H),1.15(dd,J=10.9,4.2Hz,9H),0.84(t,J=6.7Hz,3H). 19 F NMR(377MHz, DMSO)δ-201.11(s),-201.35(s),-227.13(s),-226.92(s). 31 P NMR (162MHz, DMSO) δ151.31 (d, J = 55.5Hz), 149.56 (d, J = 42.7Hz). ESI-MS: m / z 576.2 [M+H] +

[0402] Example 21: Synthesis of compound 138 (LT147-A)

[0403] Synthesis of compound 133:

[0404] Compound 47 (30.00 g, 172.22 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (41.04 g, 602.77 mmol, 3.5 eq.), triphenylphosphine (54.20 g, 206.66 mmol, 1.2 eq.), and iodine (52.45 g, 206.66 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred for 3 hours. TLC and LCMS analysis showed that compound 47 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 133. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 133 (42.33 g, 149.00 mmol, 86.52% yield). ESI-MS: m / z 285.0 [M+H] +

[0405] Synthesis of compound 134:

[0406] Compound 133 (42.33 g, 149.00 mmol, 1.0 eq.) was dissolved in MeOH (400 mL). Potassium carbonate (20.59 g, 149.00 mmol, 1.0 eq.) and palladium on carbon (10% W, 4.23 g) were then added to the reaction solution, and the mixture was stirred at room temperature until compound 133 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 134. Crude product 134 was subjected to column chromatography (PE / EA = 4 / 1) to obtain compound 134 (20.33 g, 128.51 mmol, 86.25% yield). ESI-MS: m / z 159.1 [M+H] +

[0407] Synthesis of compound 135:

[0408] Compound 134 (20.33 g, 128.51 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (65.60 g, 642.55 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction system was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (6.0 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 134 was completely reacted. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 135. Crude compound 135 was subjected to column chromatography (PE / EA = 4 / 1) to yield compound 135 (13.58 g, 67.16 mmol, 52.26% yield). ESI-MS: m / z 203.1 [M+H] +

[0409] Synthesis of compound 136:

[0410] Compound 135 (13.58 g, 67.16 mmol, 1.0 eq.) and N6-benzoyladenine (19.28 g, 80.59 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (150 mL) was added and stirred to dissolve. Then, BSA (40.99 g, 201.48 mmol, 3.0 eq.) was added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (14.93 g, 67.16 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 135 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the system was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 136. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 136 (18.11 g, 47.48 mmol, 70.70% yield). ESI-MS: m / z 382.2 [M+H] +

[0411] Synthesis of compound 137:

[0412] Compound 136 (18.11 g, 47.48 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (200 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (10.55 mL, 56.98 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 136 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 137. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 137 (14.39 g, 42.40 mmol, 89.30% yield). ESI-MS: m / z 340.1 [M+H] +

[0413] Synthesis of compound 138:

[0414] The dried compound 137 (5.00 g, 14.73 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.81 g, 29.46 mmol, 2.0 eq.) and DMAP (360 mg, 2.95 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (5.23 g, 22.10 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 137 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 138. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 138 (6.01 g, 11.14 mmol, 75.63% yield). 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.74(d,J=7.3Hz,1H),8.40(d,J=5.9Hz,1H),8.0 1(d,J=7.7Hz,2H),7.61(t,J=7.3Hz,1H),7.52(t,J=7.6Hz,2H),6.08(dd,J=28.0,2.2H z,1H),4.47–4.17(m,1H),4.09–3.79(m,3H),2.99–2.68(m,2H),2.63–2.48(m,2H),2.3 4–2.01(m,1H),1.41–1.16(m,4H),1.13(dd,J=10.9,4.2Hz,9H),0.84(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO)δ151.23(s),149.41(s).ESI-MS:m / z 540.3[M+H] +

[0415] Example 22: Synthesis of compound 144 (LT148-A)

[0416] Synthesis of compound 139:

[0417] Compound 39 (30.00 g, 146.90 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (35.00 g, 514.15 mmol, 3.5 eq.), triphenylphosphine (46.24 g, 176.28 mmol, 1.2 eq.), and iodine (44.74 g, 176.28 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred and reacted for 3 hours. TLC and LCMS analysis showed that compound 39 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 139. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 139 (36.13 g, 115.02 mmol, 78.30% yield). ESI-MS: m / z 315.0 [M+H] +

[0418] Synthesis of compound 140:

[0419] Compound 139 (36.13 g, 115.02 mmol, 1.0 eq.) was dissolved in MeOH (400 mL), followed by the addition of potassium carbonate (15.90 g, 115.02 mmol, 1.0 eq.) and palladium on carbon (10% W, 3.61 g). The mixture was stirred at room temperature until compound 139 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 140. Crude product 140 was subjected to column chromatography (PE / EA = 4 / 1) to obtain compound 140 (19.10 g, 101.48 mmol, 88.23% yield). ESI-MS: m / z 189.1 [M+H] +

[0420] Synthesis of compound 141:

[0421] Compound 140 (19.10 g, 101.48 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (51.80 g, 507.40 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5.0 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 140 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 141. Crude compound 141 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 141 (10.79 g, 46.46 mmol, 45.78% yield). ESI-MS: m / z 233.1 [M+H] +

[0422] Synthesis of compound 142:

[0423] Compound 141 (10.79 g, 46.46 mmol, 1.0 eq.) and N6-benzoyladenine (13.34 g, 55.75 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (150 mL) was added and stirred to dissolve. Then, BSA (28.35 g, 139.38 mmol, 3.0 eq.) was added. The reaction system was placed in an oil bath and heated to 80 °C, and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (10.33 g, 46.46 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 141 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 142. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 142 (13.84 g, 33.64 mmol, 72.41% yield). ESI-MS: m / z 412.2 [M+H] +

[0424] Synthesis of compound 143:

[0425] Compound 142 (13.84 g, 33.64 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (7.48 mL, 40.37 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 142 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 143. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 143 (11.11 g, 30.07 mmol, 89.39% yield). ESI-MS: m / z 370.1 [M+H] +

[0426] Synthesis of compound 144:

[0427] The dried compound 143 (5.00 g, 13.54 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.50 g, 27.08 mmol, 2.0 eq.) and DMAP (331 mg, 2.71 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.81 g, 20.31 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 143 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 144. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 144 (5.33 g, 9.36 mmol, 69.13% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.74(d,J=7.3Hz,1H),8.40(d,J=5.9Hz,1 H),8.01(d,J=7.7Hz,2H),7.61(t,J=7.3Hz,1H),7.52(t,J=7.6Hz,2H),6.08(dd ,J=28.0,2.2Hz,1H),4.54–4.23(m,1H),4.09–3.78(m,3H),3.53–3.25(m,4H),2 .95–2.70(m,2H),2.47–2.29(m,2H),1.18–1.00(m,12H),0.84(t,J=6.7Hz,3H). 31 P NMR (162MHz, DMSO) δ151.11 (s), 149.29 (s). 31 P NMR(162MHz,DMSO-d6)δ149.02(s),148.37(s).ESI-MS:m / z570.3[M+H] +

[0428] Example 23: Synthesis of Compound 150 (LT149-A)

[0429] Synthesis of compound 145:

[0430] Compound 63 (30.00 g, 159.39 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (37.98 g, 557.87 mmol, 3.5 eq.), triphenylphosphine (50.17 g, 191.27 mmol, 1.2 eq.), and iodine (48.55 g, 191.27 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred for 3 hours. TLC and LCMS analysis showed that compound 63 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 145. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 145 (36.88 g, 123.71 mmol, 77.61% yield). ESI-MS: m / z 299.0 [M+H] +

[0431] Synthesis of compound 146:

[0432] Compound 145 (36.88 g, 123.71 mmol, 1.0 eq.) was dissolved in MeOH (400 mL), followed by the addition of potassium carbonate (17.10 g, 133.50 mmol, 1.0 eq.) and palladium on carbon (10% W, 3.69 g). The mixture was stirred at room temperature until compound 145 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 146. Crude product 146 was subjected to column chromatography (PE / EA = 4 / 1) to obtain compound 146 (18.91 g, 109.80 mmol, 88.76% yield). ESI-MS: m / z 173.1 [M+H] +

[0433] Synthesis of compound 147:

[0434] Compound 146 (18.91 g, 109.80 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (200 mL) and acetic anhydride (56.05 g, 549.00 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 146 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 147. Crude compound 147 was subjected to column chromatography (PE / EA = 4 / 1) to yield compound 147 (13.58 g, 62.80 mmol, 57.19% yield). ESI-MS: m / z 217.1 [M+H] +

[0435] Synthesis of compound 148:

[0436] Compound 147 (13.58 g, 62.80 mmol, 1.0 eq.) and N6-benzoyladenine (18.03 g, 75.36 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (150 mL) was added and stirred to dissolve. Then, BSA (38.33 g, 188.40 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (13.96 g, 62.80 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 147 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the system was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 148. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 148 (16.11 g, 40.74 mmol, 64.87% yield). ESI-MS: m / z 396.2 [M+H] +

[0437] Synthesis of compound 149:

[0438] Compound 148 (16.11 g, 40.74 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (160 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (9.05 mL, 48.89 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 148 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 149. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to give compound 149 (13.06 g, 36.96 mmol, 90.72% yield). ESI-MS: m / z 354.2 [M+H] +

[0439] Synthesis of Compound 150:

[0440] The dried compound 149 (5.00 g, 14.15 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.66 g, 28.30 mmol, 2.0 eq.) and DMAP (346 mg, 2.83 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. Compound CEP-Cl (5.02 g, 21.23 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 85 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 86. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 86 (5.39 g, 9.74 mmol, 68.83% yield). 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.75(d,J=7.3Hz,1H),8.41(d,J=5.9Hz,1H ),8.03(d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.07(dd,J =28.0,2.2Hz,1H),4.30–3.97(m,2H),3.97–3.76(m,2H),2.98–2.55(m,4H),1.85 –1.49(m,1H),1.16–0.97(m,12H),0.88(d,J=13.2Hz,3H),0.81(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO)δ151.18(s),149.32(s).ESI-MS:m / z 554.3[M+H] +

[0441] Example 24: Synthesis of Compound 157 (LT150-A)

[0442] Synthesis of compound 152:

[0443] Compound 54 (30.00 g, 156.10 mmol, 1.0 eq.) was added to a 1000 mL round-bottom flask, and toluene (300 mL) was added to the reaction flask and stirred to dissolve. Then, imidazole (37.20 g, 546.35 mmol, 3.5 eq.), triphenylphosphine (49.13 g, 187.32 mmol, 1.2 eq.), and iodine (47.54 g, 187.32 mmol, 1.2 eq.) were added. After the addition was complete, the reaction system was placed in an oil bath and heated to 110 °C. The mixture was stirred and reacted for 3 hours. TLC and LCMS analysis showed that compound 54 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding an aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 152. The crude product was subjected to column chromatography (PE / EA = 1 / 4) to give compound 152 (32.39 g, 107.22 mmol, 68.69% yield). ESI-MS: m / z 303.0 [M+H] +

[0444] Synthesis of compound 153:

[0445] Compound 152 (32.39 g, 107.22 mmol, 1.0 eq.) was dissolved in MeOH (320 mL). Potassium carbonate (14.82 g, 107.22 mmol, 1.0 eq.) and palladium on carbon (10% W, 3.24 g) were then added to the reaction solution, and the mixture was stirred at room temperature until compound 152 was completely reacted. The system was filtered through diatomaceous earth, concentrated, extracted twice with ethyl acetate, filtered to remove salt, and concentrated under reduced pressure to obtain crude product 153. Crude product 153 was subjected to column chromatography (PE / EA = 4 / 1) to obtain compound 153 (17.20 g, 97.62 mmol, 91.05% yield). ESI-MS: m / z 177.1 [M+H] +

[0446] Synthesis of compound 154:

[0447] Compound 153 (17.20 g, 97.62 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (170 mL) and acetic anhydride (49.83 g, 488.10 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (5.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 153 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 154. Crude compound 154 was subjected to column chromatography (PE / EA = 4 / 1) to yield compound 154 (10.93 g, 49.64 mmol, 50.85% yield). ESI-MS: m / z 221.1 [M+H] +

[0448] Synthesis of compound 155:

[0449] Compound 154 (10.93 g, 49.64 mmol, 1.0 eq.) and N6-benzoyladenine (14.25 g, 59.57 mmol, 1.2 eq.) were added to a 500 mL three-necked round-bottom flask, and ultra-dry acetonitrile (120 mL) was added and stirred to dissolve. Then, BSA (30.29 g, 148.92 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (11.03 g, 49.64 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 154 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 155. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 155 (13.56 g, 33.95 mmol, 68.39% yield). ESI-MS: m / z 400.1 [M+H] +

[0450] Synthesis of compound 156:

[0451] Compound 155 (13.56 g, 33.95 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. THF (140 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (7.54 mL, 40.74 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 155 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 156. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 156 (10.62 g, 29.72 mmol, 87.54% yield). ESI-MS: m / z 358.1 [M+H] +

[0452] Synthesis of compound 157:

[0453] The dried compound 156 (5.00 g, 14.00 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.62 g, 28.00 mmol, 2.0 eq.) and DMAP (342 mg, 2.80 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.97 g, 21.00 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 156 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 157. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 157 (5.65 g, 10.13 mmol, 72.36% yield). 1H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.73(d,J=7.3Hz,1H),8.42(d,J=5.9Hz,1 H),8.01(d,J=7.7Hz,2H),7.65(t,J=7.3Hz,1H),7.55(t,J=7.6Hz,2H),6.09(dd ,J=28.0,2.2Hz,1H),5.01–4.63(m,1H),4.56–4.21(m,1H),4.10–3.68(m,3H),2 .98–2.68(m,2H),2.52–2.20(m,2H),1.22–0.96(m,12H),0.83(t,J=6.7Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-204.23 (d, J = 73.5Hz). 31 P NMR(162MHz,DMSO)δ151.33(s),149.41(s).ESI-MS:m / z 558.3[M+H] +

[0454] Example 25: Synthesis of Compound 162 (LT151-A)

[0455] Synthesis of compound 157:

[0456] Compound 47 (10.00 g, 57.41 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (2.76 g, 68.89 mmol, 1.2 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (12.22 g, 86.12 mmol, 1.5 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and allowed to proceed overnight at room temperature. TLC analysis showed that compound 47 reacted completely. The reaction system was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 157 (9.60 g, 51.00 mmol, 88.83% yield). ESI-MS: m / z 189.1 [M+H] +

[0457] Synthesis of compound 158:

[0458] Compound 157 (9.60 g, 51.00 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (26.03 g, 255.00 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 157 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 158. Crude compound 158 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 158 (7.32 g, 31.52 mmol, 61.80% yield). ESI-MS: m / z 233.1 [M+H] +

[0459] Synthesis of compound 159:

[0460] Compound 158 (7.32 g, 31.52 mmol, 1.0 eq.) and N6-benzoyladenine (9.05 g, 37.82 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (80 mL) was added and stirred to dissolve. Then, BSA (19.24 g, 94.56 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (7.01 g, 31.52 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 158 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 159. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 159 (8.28 g, 20.13 mmol, 63.86% yield). ESI-MS: m / z 412.2 [M+H] +

[0461] Synthesis of compound 160:

[0462] Compound 159 (8.28 g, 20.13 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (80 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (4.47 mL, 24.16 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 159 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 160. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 160 (6.74 g, 18.25 mmol, 90.66% yield). ESI-MS: m / z 370.2 [M+H] +

[0463] Synthesis of compound 161:

[0464] The dried compound 160 (6.74 g, 18.25 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask, and ultra-dry dichloromethane (70 mL) was added and stirred until completely dissolved. DIPEA (4.72 g, 36.50 mmol, 2.0 eq.) and DMAP (446 mg, 3.65 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (6.48 g, 27.38 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 160 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 161. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 161 (7.63 g, 13.40 mmol, 73.42% yield). 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.75(d,J=7.3Hz,1H),8.41(d,J=5.9Hz,1H) ,8.02(d,J=7.7Hz,2H),7.66(t,J=7.3Hz,1H),7.51(t,J=7.6Hz,2H),6.07(dd,J=2 8.0,2.2Hz,1H),4.34–4.03(m,2H),3.96–3.81(m,2H),3.61–3.18(m,5H),2.96–2. 64(m,2H),2.40–2.01(m,4H),1.15(dd,J=10.9,4.2Hz,9H),0.83(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO)δ151.11(s),149.28(s).ESI-MS:m / z 570.3[M+H] +

[0465] Example 26: Synthesis of Compound 166 (LT152-A)

[0466] Synthesis of compound 162:

[0467] Compound 39 (10.00 g, 48.97 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (2.35 g, 58.76 mmol, 1.2 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (8.34 g, 58.76 mmol, 1.2 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and allowed to proceed overnight at room temperature. TLC analysis showed that compound 39 reacted completely. The reaction system was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 162 (9.83 g, 45.04 mmol, 91.97% yield). ESI-MS: m / z 219.1 [M+H] +

[0468] Synthesis of compound 163:

[0469] Compound 162 (9.83 g, 45.04 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (22.99 g, 225.20 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 162 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 163. Crude product 163 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 163 (6.88 g, 26.23 mmol, 58.24% yield). ESI-MS: m / z 263.1 [M+H] +

[0470] Synthesis of compound 164:

[0471] Compound 163 (6.88 g, 26.23 mmol, 1.0 eq.) and N6-benzoyladenine (6.67 g, 27.88 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (70 mL) was added and stirred to dissolve. Then, BSA (16.01 g, 78.69 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (5.83 g, 26.23 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 163 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 164. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 164 (7.21 g, 16.33 mmol, 62.26% yield). ESI-MS: m / z 442.2 [M+H] +

[0472] Synthesis of compound 165:

[0473] Compound 164 (7.21 g, 16.33 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (70 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (3.63 mL, 19.60 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 164 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 165. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 165 (5.92 g, 14.82 mmol, 90.75% yield). ESI-MS: m / z 400.2 [M+H] +

[0474] Synthesis of compound 166:

[0475] The dried compound 165 (5.92 g, 14.82 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask, and 60 mL of ultradry dichloromethane was added and stirred until completely dissolved. DIPEA (3.83 g, 29.64 mmol, 2.0 eq.) and DMAP (362 mg, 2.96 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (5.26 g, 22.23 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 165 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 166. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 166 (6.45 g, 10.76 mmol, 72.60% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.71(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H) ,8.01(d,J=7.7Hz,2H),7.61(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.01(dd,J=2 8.0,2.2Hz,1H),4.86–4.59(m,1H),4.07–3.81(m,3H),3.67–3.20(m,9H),2.94–2. 65(m,2H),2.44–2.17(m,2H),1.12(dd,J=10.9,4.2Hz,9H),0.81(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO)δ151.19(s),149.31(s).ESI-MS:m / z 600.3[M+H] +

[0476] Example 27: Synthesis of Compound 171 (LT153-A)

[0477] Synthesis of compound 167:

[0478] Compound 63 (10.00 g, 53.13 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (2.55 g, 63.76 mmol, 1.2 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (9.05 g, 63.76 mmol, 1.2 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and allowed to proceed overnight at room temperature. TLC analysis showed that compound 63 reacted completely. The reaction system was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 167 (9.86 g, 48.75 mmol, 91.76% yield). ESI-MS: m / z 203.1 [M+H] +

[0479] Synthesis of compound 168:

[0480] Compound 167 (9.86 g, 48.75 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (24.88 g, 243.75 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 167 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 168. Crude compound 168 was subjected to column chromatography (PE / EA = 4 / 1) to yield compound 168 (6.22 g, 25.26 mmol, 51.82% yield). ESI-MS: m / z 247.1 [M+H] +

[0481] Synthesis of compound 169:

[0482] Compound 168 (6.22 g, 25.26 mmol, 1.0 eq.) and N6-benzoyladenine (7.25 g, 30.31 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (70 mL) was added and stirred to dissolve. Then, BSA (15.42 g, 75.78 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (5.61 g, 25.26 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 168 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 169. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 169 (6.01 g, 14.13 mmol, 55.94% yield). ESI-MS: m / z 426.2 [M+H] +

[0483] Synthesis of compound 170:

[0484] Compound 169 (6.01 g, 14.13 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (60 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (3.14 mL, 16.96 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 169 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 170. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to give compound 170 (4.92 g, 12.83 mmol, 90.80% yield). ESI-MS: m / z 384.2 [M+H] +

[0485] Synthesis of compound 171:

[0486] The dried compound 170 (4.92 g, 12.83 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (3.32 g, 25.66 mmol, 2.0 eq.) and DMAP (313 mg, 2.56 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.56 g, 19.25 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 170 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 171. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 171 (5.73 g, 9.82 mmol, 76.54% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.71(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H),8.01 (d,J=7.7Hz,2H),7.61(t,J=7.3Hz,1H),7.53(t,J=7.6Hz,2H),6.01(dd,J=28.0,2.2Hz, 1H),4.22–3.76(m,4H),3.61–3.18(m,5H),2.98–2.71(m,2H),2.41–2.15(m,2H),1.95–1 .69(m,1H),1.12(dd,J=10.9,4.2Hz,9H),0.88(d,J=13.1Hz,3H),0.81(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO)δ151.25(s),149.41(s).ESI-MS:m / z 584.3[M+H] +

[0487] Example 28: Synthesis of Compound 176 (LT154-A)

[0488] Synthesis of compound 172:

[0489] Compound 54 (10.00 g, 52.03 mmol, 1.0 eq.) was dissolved in DMF (100 mL) and stirred until homogeneous. The reaction mixture was cooled to 0 °C and stirred for 30 minutes. Then, 60% NaH (2.50 g, 62.44 mmol, 1.2 eq.) was added to the reaction mixture and stirred for 30 minutes. Compound CH3I (8.86 g, 62.44 mmol, 1.2 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to return to room temperature and allowed to proceed overnight at room temperature. TLC analysis showed that compound 54 reacted completely. The reaction system was then slowly poured into ice water to quench the reaction completely. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the crude product was removed under reduced pressure to remove the solvent. The crude product was subjected to column chromatography (PE / EA = 100 / 9) to give compound 172 (9.01 g, 43.69 mmol, 83.97% yield). ESI-MS: m / z 207.1 [M+H] +

[0490] Synthesis of compound 173:

[0491] Compound 172 (9.01 g, 43.69 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (100 mL) and acetic anhydride (22.30 g, 218.45 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.50 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 172 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 173. Crude product 173 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 173 (5.08 g, 20.30 mmol, 46.46% yield). ESI-MS: m / z 251.1 [M+H] +

[0492] Synthesis of compound 174:

[0493] Compound 173 (5.08 g, 20.30 mmol, 1.0 eq.) and N6-benzoyladenine (5.83 g, 24.36 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (60 mL) was added and stirred to dissolve. Then, BSA (12.39 g, 60.90 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (4.51 g, 20.30 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 173 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 174. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 174 (5.49 g, 12.78 mmol, 62.96% yield). ESI-MS: m / z 430.2 [M+H] +

[0494] Synthesis of compound 175:

[0495] Compound 174 (5.49 g, 12.78 mmol, 1.0 eq.) was added to a 250 mL round-bottom flask. THF (60 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.84 mL, 15.34 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 174 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 175. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 175 (4.33 g, 11.18 mmol, 86.95% yield). ESI-MS: m / z 388.1 [M+H] +

[0496] Synthesis of compound 176:

[0497] The dried compound 175 (4.33 g, 11.18 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (50 mL) was added and stirred until completely dissolved. DIPEA (2.89 g, 22.36 mmol, 2.0 eq.) and DMAP (274 mg, 2.24 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (3.97 g, 16.77 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 175 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 176. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 176 (5.01 g, 8.53 mmol, 76.30% yield). 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.73(d,J=7.3Hz,1H),8.41(d,J=5.9Hz,1H),8.03( d,J=7.7Hz,2H),7.62(t,J=7.3Hz,1H),7.57(t,J=7.6Hz,2H),6.03(dd,J=28.0,2.2Hz,1H ),5.71(d,J=92.6Hz,1H),5.03–4.59(m,1H),4.09–3.67(m,4H),3.42–3.14(m,4H),2.99– 2.58(m,4H),1.13(dd,J=10.9,4.2Hz,9H),0.83(d,J=13.1Hz,3H),0.81(t,J=6.7Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-203.18 (d, J = 73.5Hz). 31 P NMR(162MHz,DMSO)δ151.31(s),149.52(s).ESI-MS:m / z 588.3[M+H] +

[0498] Example 29: Synthesis of Compound 182 (LT155-A)

[0499] Synthesis of compound 177:

[0500] The dried compound 47 (15.00 g, 86.11 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. 2,4,6-Trimethylpyridine (20.87 g, 172.22 mmol, 2.0 eq.) was then added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (16.66 g, 103.33 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 47 was completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 177. Crude product 177 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 177 (7.06 g, 40.07 mmol, 46.53% yield). ESI-MS: m / z 177.1 [M+H] +

[0501] Synthesis of compound 178:

[0502] Compound 177 (7.06 g, 40.07 mmol, 1.0 eq.) was added to a 500 mL round-bottom three-necked flask, and acetic acid (75 mL) and acetic anhydride (20.45 g, 200.35 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 177 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 178. Crude compound 178 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 178 (4.93 g, 22.39 mmol, 55.88% yield). ESI-MS: m / z 221.1 [M+H] +

[0503] Synthesis of compound 179:

[0504] Compound 178 (4.93 g, 22.39 mmol, 1.0 eq.) and N6-benzoyladenine (6.43 g, 26.87 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (60 mL) was added and stirred to dissolve. Then, BSA (13.66 g, 67.17 mmol, 3.0 eq.) was added. The reaction mixture was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (4.98 g, 22.39 mmol, 1.0 eq.) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 178 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the system was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 179. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 179 (5.36 g, 13.42 mmol, 59.94% yield). ESI-MS: m / z 400.1 [M+H] +

[0505] Synthesis of compound 180:

[0506] Compound 179 (5.36 g, 13.42 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (50 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.98 mL, 16.10 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 179 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 180. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 180 (4.25 g, 11.89 mmol, 88.60% yield). ESI-MS: m / z 358.1 [M+H] +

[0507] Synthesis of compound 181:

[0508] The dried compound 180 (4.25 g, 11.89 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (45 mL) was added and stirred until completely dissolved. DIPEA (3.07 g, 23.78 mmol, 2.0 eq.) and DMAP (291 mg, 2.386 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.22 g, 17.84 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 180 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 181. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 181 (4.66 g, 8.36 mmol, 70.31% yield). 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),8.73(d,J=7.3Hz,1H),8.43(d,J=5.9Hz,1H) ,8.01(d,J=7.7Hz,2H),7.61(t,J=7.3Hz,1H),7.58(t,J=7.6Hz,2H),6.07(dd,J=2 8.0,2.2Hz,1H),4.96–4.46(m,2H),4.43–4.10(m,1H),4.08–3.75(m,3H),2.97–2. 60(m,4H),2.37–2.07(m,2H),1.11(dd,J=10.9,4.2Hz,9H),0.83(t,J=6.7Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-225.18 (d, J = 73.5Hz). 31 P NMR (162MHz, DMSO) δ151.33 (d, J = 55.5Hz), 149.45 (d, J = 42.7Hz). ESI-MS: m / z 558.2 [M+H] +

[0509] Example 30: Synthesis of Compound 186 (LT156-A)

[0510] Synthesis of compound 182:

[0511] The dried compound 39 (15.00 g, 73.45 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. 2,4,6-Trimethylpyridine (17.80 g, 146.90 mmol, 2.0 eq.) was then added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (14.21 g, 88.14 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 39 had completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 182. Crude product 182 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 182 (8.12 g, 39.38 mmol, 53.61% yield). ESI-MS: m / z 207.1 [M+H] +

[0512] Synthesis of compound 183:

[0513] Compound 182 (8.12 g, 39.38 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (80 mL) and acetic anhydride (20.10 g, 196.90 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 182 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 183. Crude product 183 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 183 (4.99 g, 19.94 mmol, 50.63% yield). ESI-MS: m / z 251.1 [M+H] +

[0514] Synthesis of compound 184:

[0515] Compound 183 (4.99 g, 19.94 mmol, 1.0 eq.) and N6-benzoyladenine (5.72 g, 23.93 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (50 mL) was added and stirred to dissolve. Then, BSA (13.78 g, 59.82 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (4.43 g, 19.94 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 183 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 184. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 184 (5.87 g, 13.67 mmol, 68.61% yield). ESI-MS: m / z 430.2 [M+H] +

[0516] Synthesis of compound 185:

[0517] Compound 184 (5.87 g, 13.67 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (60 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (3.04 mL, 16.40 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 184 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 185. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 185 (4.78 g, 12.34 mmol, 90.27% yield). ESI-MS: m / z 388.1 [M+H] +

[0518] Synthesis of compound 186:

[0519] The dried compound 185 (4.78 g, 12.34 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (3.19 g, 24.68 mmol, 2.0 eq.) and DMAP (302 mg, 2.47 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (4.38 g, 18.51 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 185 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 186. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 186 (5.33 g, 9.07 mmol, 73.50% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.71(d,J=7.3Hz,1H),8.42(d,J=5.9Hz,1H) ,8.01(d,J=7.7Hz,2H),7.63(t,J=7.3Hz,1H),7.51(t,J=7.6Hz,2H),6.07(dd,J=2 8.0,2.2Hz,1H),5.48–4.21(m,3H),4.00–3.81(m,2H),3.66–3.36(m,4H),2.99–2. 67(m,1H),2.56–2.40(m,1H),1.13(dd,J=10.9,4.2Hz,9H),0.81(t,J=6.7Hz,3H). 19 F NMR(377MHz, DMSO)δ-225.53(s),-225.31(s). 31 P NMR (162MHz, DMSO) δ151.23 (d, J = 55.5Hz), 149.48 (d, J = 42.7Hz). ESI-MS: m / z 588.3 [M+H] +

[0520] Example 31: Synthesis of Compound 191 (LT157-A)

[0521] Synthesis of compound 187:

[0522] The dried compound 63 (15.00 g, 79.69 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. Then, 2,4,6-trimethylpyridine (19.31 g, 159.38 mmol, 2.0 eq.) was added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (15.41 g, 95.63 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 63 had completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 187. Crude product 187 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 187 (8.36 g, 43.95 mmol, 55.15% yield). ESI-MS: m / z 191.1 [M+H] +

[0523] Synthesis of compound 188:

[0524] Compound 187 (8.36 g, 43.95 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (80 mL) and acetic anhydride (22.43 g, 219.75 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 187 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 188. Crude compound 188 was subjected to column chromatography (PE / EA = 4 / 1) to yield compound 188 (4.33 g, 18.49 mmol, 42.07% yield). ESI-MS: m / z 235.1 [M+H] +

[0525] Synthesis of compound 189:

[0526] Compound 188 (4.33 g, 18.49 mmol, 1.0 eq.) and N6-benzoyladenine (5.31 g, 22.19 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (50 mL) was added and stirred to dissolve. Then, BSA (11.28 g, 55.47 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour. The entire reaction was carried out under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (4.11 g, 18.49 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 188 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 189. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 189 (5.03 g, 12.17 mmol, 65.82% yield). ESI-MS: m / z 414.2 [M+H] +

[0527] Synthesis of compound 190:

[0528] Compound 189 (5.03 g, 12.17 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (50 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.70 mL, 14.60 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 189 was completely reacted. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 190. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 190 (4.07 g, 10.96 mmol, 90.06% yield). ESI-MS: m / z 372.2 [M+H] +

[0529] Synthesis of compound 191:

[0530] The dried compound 190 (4.07 g, 10.96 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (2.83 g, 21.92 mmol, 2.0 eq.) and DMAP (268 mg, 2.19 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (3.89 g, 16.44 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 190 was completely reacted. The reaction system was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 191. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 191 (4.55 g, 7.96 mmol, 72.63% yield). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.72(d,J=7.3Hz,1H),8.42(d,J=5.9Hz,1H) ,8.01(d,J=7.7Hz,2H),7.63(t,J=7.3Hz,1H),7.51(t,J=7.6Hz,2H),6.07(dd,J=2 8.0,2.2Hz,1H),5.48–4.21(m,3H),4.03–3.81(m,2H),3.69–3.36(m,4H),2.98–2. 68(m,1H),2.55–2.41(m,1H),1.15(dd,J=10.9,4.2Hz,9H),0.83(t,J=6.7Hz,3H). 19 F NMR(377MHz, DMSO)δ-226.98(s),-226.12(s). 31 P NMR (162MHz, DMSO) δ151.19 (d, J = 55.5Hz), 149.27 (d, J = 42.7Hz). ESI-MS: m / z 572.3 [M+H] +

[0531] Example 32: Synthesis of compound 196 (LT158-A)

[0532] Synthesis of compound 192:

[0533] The dried compound 54 (15.00 g, 78.05 mmol, 1.0 eq.) was added to a 500 mL round-bottom flask. DCM (150 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. 2,4,6-Trimethylpyridine (18.92 g, 156.10 mmol, 2.0 eq.) was then added to the reaction mixture. The reaction mixture was cooled to -78 °C and stirred at this temperature for 30 minutes. Diethylaminosulfur trifluoride (15.10 g, 93.66 mmol, 1.2 eq.) was slowly added dropwise to the reaction mixture, maintaining the temperature at -78 °C. After the addition was complete, the reaction mixture was allowed to return to room temperature and stirred for 8 hours until compound 54 had completely reacted. The reaction mixture was cooled to approximately -5 °C and neutralized to approximately pH 7 with a saturated sodium bicarbonate aqueous solution. Water was added to the reaction mixture, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 192. Crude product 192 was subjected to column chromatography (PE / EA = 8 / 1) to give compound 192 (7.01 g, 36.10 mmol, 46.25% yield). ESI-MS: m / z 195.1 [M+H] +

[0534] Synthesis of compound 193:

[0535] Compound 192 (7.01 g, 36.10 mmol, 1.0 eq.) was added to a 250 mL round-bottom three-necked flask, and acetic acid (70 mL) and acetic anhydride (18.43 g, 180.50 mmol, 5.0 eq.) were added to the reaction system, and the mixture was stirred until completely dissolved. The reaction mixture was cooled to 0 °C and stirred at this temperature for 30 minutes. Concentrated sulfuric acid (2.00 mL) was slowly added dropwise to the reaction system, maintaining the temperature between 0 and 5 °C. After the addition was complete, the reaction system was allowed to return to room temperature and stirred for 8 hours until compound 192 reacted completely. The reaction system was cooled to approximately -5 °C and neutralized with ammonia to a pH of approximately 7. Water was added to the reaction system, and the reaction mixture was extracted twice with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 193. Crude product 193 was subjected to column chromatography (PE / EA = 4 / 1) to give compound 193 (4.00 g, 16.79 mmol, 46.51% yield). ESI-MS: m / z 239.1 [M+H] +

[0536] Synthesis of compound 194:

[0537] Compound 193 (4.00 g, 16.79 mmol, 1.0 eq.) and N6-benzoyladenine (4.82 g, 20.15 mmol, 1.2 eq.) were added to a 250 mL three-necked round-bottom flask, and ultra-dry acetonitrile (50 mL) was added and stirred to dissolve. Then, BSA (10.25 g, 50.37 mmol, 3.0 eq.) was added. The reaction system was heated to 80 °C in an oil bath and stirred at this temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction system was placed in an ice-water bath at 0 °C and stirred for 30 minutes. TMSOTf (3.73 g, 16.79 mmol, 1.0 eq.) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was placed in an oil bath and slowly heated to 80 °C, and reacted overnight at this temperature. TLC and LCMS analysis showed that compound 193 reacted completely. The reaction mixture was removed from the oil bath and cooled to room temperature. The reaction was quenched by adding a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 194. The crude product was subjected to column chromatography (PE / EA = 3 / 7) to give compound 194 (4.78 g, 11.45 mmol, 68.20% yield). ESI-MS: m / z 418.1 [M+H] +

[0538] Synthesis of compound 195:

[0539] Compound 194 (4.78 g, 11.45 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask. THF (50 mL) was added to the reaction mixture, and the mixture was stirred until completely dissolved. A 5.4 mol / L sodium methoxide solution (2.54 mL, 13.74 mmol, 1.2 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature until compound 194 was completely dissolved. After the reaction was complete, the reactants were extracted twice with water and ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude compound 195. The crude compound was subjected to column chromatography (PE / EA = 1 / 4) to obtain compound 195 (3.68 g, 9.80 mmol, 85.59% yield). ESI-MS: m / z 376.1 [M+H] +

[0540] Synthesis of compound 196:

[0541] The dried compound 195 (3.68 g, 9.80 mmol, 1.0 eq.) was added to a 100 mL round-bottom flask, and ultra-dry dichloromethane (40 mL) was added and stirred until completely dissolved. DIPEA (2.53 g, 19.60 mmol, 2.0 eq.) and DMAP (239 mg, 1.96 mmol, 0.2 eq.) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction system was purged with nitrogen and carried out under nitrogen protection. CEP-Cl (3.48 g, 14.70 mmol, 1.5 eq.) was added dropwise to the reaction mixture at room temperature, and the reaction was carried out at room temperature for 30–60 minutes until compound 195 was completely reacted. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude product 196. The crude product was purified by column chromatography (PE / EA = 2 / 3) to give compound 196 (4.29 g, 7.45 mmol, 76.02% yield). 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),8.75(d,J=7.3Hz,1H),8.45(d,J=5.9Hz,1H) ,8.01(d,J=7.7Hz,2H),7.63(t,J=7.3Hz,1H),7.52(t,J=7.6Hz,2H),6.01(dd,J=2 8.0,2.2Hz,1H),5.51–5.11(m,1H),4.97–4.56(m,3H),4.07–3.72(m,3H),2.89–2. 63(m,2H),2.61–2.42(m,2H),1.12(dd,J=10.9,4.2Hz,9H),0.85(t,J=6.7Hz,3H). 19 F NMR(377MHz, DMSO)δ-202.13(s),-202.37(s),-226.89(s),-227.08(s). 31 P NMR (162MHz, DMSO) δ151.22 (d, J = 55.5Hz), 149.38 (d, J = 42.7Hz). ESI-MS: m / z 576.2 [M+H] +

[0542] Example 33: Synthesis of compound 199 (LT110-G)

[0543] The synthetic route for compound 199 is the same as in Example 1, except that the substrate ABz (N6-benzoyladenine) used in the synthesis of compound 7 from compound 6 in Example 1 is changed to compound G-iBu (N2-isobutyrylguanine). The remaining steps are similar to those in Example 1. The NMR data of the obtained nucleoside compound 199 are shown below:

[0544] 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),11.51(s,1H),7.45(s,1H),5.67(d,J=5.9Hz,1H),4.92– 4.66(m,1H),4.16–3.77(m,3H),3.70–3.51(m,3H),3.50–3.19(m,5H),2.97–2.39(m,5H),1.33 -1.19(m,20H),1.13(m,15H),0.99(d,J=6.7Hz,3H),0.84(t,J=6.7Hz,3H). 31 P NMR(162MHz,DMSO-d6)δ149.92(s),149.61(s).ESI-MS:m / z 736.5[M+H]+

[0545] Example 34: Synthesis of compound 202 (LT131-G)

[0546] The synthetic route for compound 202 is the same as in Example 6, except that the substrate ABz (N6-benzoyladenine) used in the synthesis of compound 50 from compound 49 in Example 6 is changed to compound G-iBu (N2-isobutyrylguanine). The remaining steps are similar to those in Example 6. The NMR data of the obtained nucleoside compound 202 are shown below:

[0547] 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),11.51(s,1H),7.45(s,1H),5.67(d,J=5.9Hz,1H),4.98–4.87(m,1H),4.42(dt,J=9.0,4 .4Hz,1H),4.11–3.98(m,1H),3.86–3.41(m,6H),2.81(t,J=5.9Hz,1H),2.81–2.61(m,2H),1.48(dd,J=13.2,6.5Hz,2H),1.34 -1.20(m,21H),1.14(m,15H),0.98(d,J=6.7Hz,3H),0.85(t,J=6.7Hz,3H). 31 P NMR (162MHz, DMSO-d6) δ149.38,148.51, ESI-MS: m / z 706.4[M+H] +

[0548] Example 35: Synthesis of compound 205 (LT137-G)

[0549] The synthetic route for compound 205 is the same as in Example 11, except that the substrate ABz (N6-benzoyladenine) used in the synthesis of compound 84 from compound 83 in Example 11 is changed to compound G-iBu (N2-isobutyrylguanine). The remaining steps are similar to those in Example 11. The NMR data of the obtained nucleoside compound 205 are shown below:

[0550] 1H NMR (400MHz, DMSO-d6) δ12.07(s,1H),11.52(s,1H),7.46(s,1H),5.68(d,J=5.9Hz,1H),4.57–4.37(m,1H),3.96– 3.75(m,3H),2.95–2.60(m,3H),1.21–1.08(m,18H),1.21–1.08(m,3H),0.98(d,J=6.7Hz,3H),0.91–0.76(m,3H). 31 P NMR(162MHz,DMSO-d6)δ149.51(s),148.64(s).ESI-MS:m / z 536.3[M+H] +

[0551] Example 36: Synthesis of compound 208 (LT142-G)

[0552] The synthetic route for compound 208 is the same as in Example 16, except that the substrate ABz (N6-benzoyladenine) used in the synthesis of compound 110 from compound 109 in Example 16 is changed to compound G-iBu (N2-isobutyrylguanine). The remaining steps are similar to those in Example 16. The NMR data of the obtained nucleoside compound 208 are shown below:

[0553] 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),11.52(s,1H),7.46(s,1H),5.68(d,J=5.9Hz,1H),5.21–4.91(m,1H),4.85–4.54 (m,1H),4.10–3.73(m,3H),3.68–3.16(m,5H),3.00–2.61(m,5H),1.13(dd,J=10.9,4.2Hz,15H),0.83(t,J=6.7Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-202.11 (d, J = 73.5Hz). 31 P NMR(162MHz,DMSO-d6)δ149.33(s),148.45(s).ESI-MS:m / z 570.3[M+H] +

[0554] Example 37: Synthesis of compound 211 (LT148-G)

[0555] The synthetic route for compound 211 is the same as in Example 22, except that the substrate ABz (N6-benzoyladenine) used in the synthesis of compound 142 from compound 141 in Example 22 is changed to compound G-iBu (N2-isobutyrylguanine). The remaining steps are similar to those in Example 22. The NMR data of the obtained nucleoside compound 214 are shown below:

[0556] 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),11.51(s,1H),7.45(s,1H),5.67(d,J=5.9Hz,1H),4.55–4.24(m,1H),4.08– 3.77(m,3H),3.54–3.25(m,4H),2.96–2.57(m,3H),2.47–2.28(m,2H),1.19–1.00(m,18H),0.83(t,J=6.7Hz,3H). 31 P NMR (162MHz, DMSO) δ151.11(s), 149.29(s). 31 P NMR(162MHz,DMSO-d6)δ149.32(s),148.44(s).ESI-MS:m / z 552.3[M+H] +

[0557] Example 38: Synthesis of compound 214 (LT152-G)

[0558] The synthetic route for compound 214 is the same as in Example 26, except that the substrate ABz (N6-benzoyladenine) used in the synthesis of compound 164 from compound 163 in Example 26 is changed to compound G-iBu (N2-isobutyrylguanine). The remaining steps are similar to those in Example 26. The NMR data of the obtained nucleoside compound 214 are shown below:

[0559] 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),11.52(s,1H),7.46(s,1H),5.62(d,J=5.9Hz,1H),4.85–4.56(m,1H),4.06–3.82 (m,3H),3.65–3.21(m,9H),2.95–2.61(m,3H),2.45–2.18(m,2H),1.13(dd,J=10.9,4.2Hz,15H),0.82(t,J=6.7Hz,3H). 31P NMR(162MHz,DMSO)δ149.29(s),148.38(s).ESI-MS:m / z 582.3[M+H] +

[0560] Example 39: Targeting Mouse TTR siRNA Sequence and Synthesis

[0561] The synthesis of oligonucleotide single strands is no different from the usual phosphoramide solid-phase synthesis method. When synthesizing single-stranded oligonucleotides with a compound of formula I at the 5'-end, the phosphoramide monomer synthesized above is used to replace the original nucleotide of the parent sequence.

[0562] The synthesis process is briefly described as follows: Using a Universal CPG (Dinaxinke) carrier as the starting material, nucleoside phosphoramide monomers were linked one by one according to the synthesis program on an LK-48E synthesizer (Lingkun). Except for the modified nucleoside compounds LT107-A~LT158-A and (LT110-G)~(LT152-G) as described above, the remaining nucleoside monomer raw materials, such as 2'-F RNA and 2'-O-methyl RNA, were purchased from Shanghai Zhaowei. 5'-Ethylthio-1H-tetrazole (ETT) was used as the activator (0.6M acetonitrile solution), 0.22M PADS dissolved in a 1:1 volume ratio of trimethylpyridine (Suzhou Kelama) solution was used as the sulfiding agent, and iodopyridine / water solution (Kelama) was used as the oxidizing agent.

[0563] After solid-phase synthesis, the oligonucleotides were cleaved from the solid support and soaked in a 3:1 solution of 28% ammonia and ethanol at 50°C for 16 hours. After centrifugation, the supernatant was transferred to another centrifuge tube, concentrated, and evaporated to dryness. Purification was then performed using C18 reversed-phase chromatography with 0.1M TEAA and acetonitrile as the mobile phase, and DMTr was removed using 3% trifluoroacetic acid solution. The target oligonucleotides were collected, lyophilized, identified as the target product by LCMS, and quantified by UV (260 nm) spectroscopy.

[0564] The obtained single-stranded oligonucleotides and sodium acetate were ultrafiltered and salt-replaced using a 3KD ultrafiltration tube. According to the equimolar ratio and complementary pairing, they were annealed. Finally, the double-stranded siRNAs shown in Table 1 were dissolved in water and adjusted to the required concentration for the experiment.

[0565] Table 1: Sequences containing protected compounds

[0566] Example 40: In vitro silencing efficacy of TTR target mRNA with modified nucleoside duplexes

[0567] Activity screening steps

[0568] Cell culture and transfection:

[0569] Hepa1-6 cells (ATCC, cat#CRL1830) were cultured at 37°C and 5% CO2 until near confluence in DMEM (Invitrogen, cat#11965092) containing 10% FBS (Ausgenex, cat#FBS500-S) and 1% penicillin-streptomycin. The cells were then digested and resuspended in seeding medium (DMEM + 10% FBS), and 5000 cells / well / 90 μL were seeded into 96-well cell culture plates (Corning, cat#3904) and incubated overnight at 37°C and 5% CO2. Transfection conditions were as follows: 4.6 μL of Opti-MEM (Gibco, cat#31985-070) and 0.4 μL of Lipofectamine RNAiMax (Invitrogen, CarlsbadCA, cat#13778-150) were mixed with 5 μL of siRNA per well and incubated at room temperature for 15 minutes. The mixture was then added to each well of a 96-well plate prepared the previous day at 10 μL. The plates were incubated at 37°C with 5% CO2 for 48 h. The final concentrations of siRNAs used in the experiments were 10 nM, 1 nM, and 0.1 nM.

[0570] RNA extraction and reverse transcription into cDNA:

[0571] Cell lysis to extract RNA was performed according to the Cells-to-Ct bulk lysis reagents (Invitrogen #4391851C) manufacturer's instructions. 1) Aspirate the old culture medium from each well and wash twice with 100 μL PBS. 2) Carefully aspirate the PBS. Add 50 μL of lysis buffer to each well. 3) Vortex at 500 rpm for 5 minutes at room temperature. 4) Add 5 μL of stop solution to each well and vortex at 500 rpm for 2 minutes at room temperature. If cDNA synthesis is to be performed immediately, the plate should be placed on ice.

[0572] Reverse transcription was performed according to the Cells-to-CT Bulk Fast Advanced RT Reagent (Invitrogen #A39110) manufacturer's instructions: Mixtures were prepared (per well: 25 μL 2×Fast Advanced RT Buffer, 2.5 μL 20×RT Fast Advanced Enzyme Mix, and 22.5 μL total RNA). cDNA was synthesized using Biometra TAdvanced96SG (analytikjena) following these steps: 37°C for 30 min, 95°C for 5 min, and incubation at 4°C. The cDNA was stored at -20°C or immediately analyzed by real-time PCR.

[0573] Real-time PCR:

[0574] 4.33 μL of cDNA and 0.17 μL of 60X GAPDH TaqMan probe (Invitrogen cat, cat#4448491), 0.5 μL of 20X TTR TaqMan probe (Invitrogen, cat#4351370), and 5 μL of... FAST PCR Master Mix (Applied Biosystems, cat#4444965) was mixed and added to a 96-well plate (Axygen, cat#PCR-96-FLT-C) for real-time PCR detection. The instrument used was... 7 (Applied Biosystems), the system program is: 50℃ for 2 min, 95℃ for 20 s, and 40 cycles of 90℃ for 1 s and 60℃ for 20 s. Unless otherwise specified, each siRNA should be transfected in 3 replicates.

[0575] Data analysis was performed using the ΔΔCt method to analyze real-time data, which was then normalized using mock datasets. The specific calculation method was: ΔCt = Ct(target gene) – Ct(GAPDH), ΔΔCt = ΔCt(detection sample) - ΔCt(Mock), Relative mRNA expression to Mock = 2. -ΔΔCt %Inhibition vsMock = {1 - Expression fold(sample tested) / Expression fold(Mock)} * 100. The final results are shown in Table 2. The siRNA with the modified nucleoside of this invention was essentially identical to or better than the parent sequence siRNA in the in vitro silencing test.

[0576] Table 2: q-PCR in vitro activity screening data

[0577] Example 41: Synthesis of oligonucleotide single strands for 5'-exonuclease stability evaluation

[0578] The synthesis of oligonucleotide single strands is no different from the usual phosphoramide solid-phase synthesis method. When synthesizing single-stranded oligonucleotides with Formula I modification at the 5'-end, the phosphoramide monomer synthesized above is used to replace the original nucleotide of the parent sequence.

[0579] The synthesis process is briefly described as follows: Using a Universal CPG (Dinaxinke) carrier as the starting material, nucleoside phosphoramide monomers were linked one by one according to the synthesis program on an LK-48E synthesizer (Lingkun). Except for LT107-A, LT134-A, LT136-A, LT141-A, LT148-A, LT110-A, and LT119-A, which were synthesized as described above, the remaining nucleoside monomer raw materials, such as 2'-F RNA and 2'-O-methyl RNA, were purchased from Shanghai Zhaowei. 5'-Ethylthio-1H-tetrazole (ETT) was used as the activator (0.6M acetonitrile solution), 0.22M PADS dissolved in a 1:1 volume ratio of trimethylpyridine (Suzhou Kelama) solution was used as the sulfiding agent, and iodopyridine / aqueous solution (Kelama) was used as the oxidizing agent.

[0580] After solid-phase synthesis, the oligonucleotides were cleaved from the solid support and soaked in a 3:1 solution of 28% ammonia and ethanol at 50°C for 16 hours. After centrifugation, the supernatant was transferred to another centrifuge tube, concentrated, and evaporated to dryness. Purification was then performed using C18 reversed-phase chromatography with 0.1M TEAA and acetonitrile as the mobile phase, and DMTr was removed using 3% trifluoroacetic acid solution. The target oligonucleotides were collected, lyophilized, identified as the target product by LCMS, and quantified by UV (260 nm). The obtained single-stranded oligonucleotides, as shown in Table 3, were dissolved in 1xPBS and adjusted to the required concentration for future experiments.

[0581] Among them, SM0512-1000, which was not modified with nucleoside compounds compared to other groups, served as the control group.

[0582] Table 3: Oligonucleotide sequences used to examine 5'-exonuclease stability

[0583] Example 42: Stability test of 5'-exonuclease in single-stranded sequences

[0584] Stability evaluation operation steps:

[0585] The samples (oligonucleotide molecules SM0512-1000, SM0512-1001, SM0512-1002, SM0512-1003, SM0512-1004, SM0512-1005, SM0512-1006, SM0512-1007) were dissolved in PBS (BOSTER, Lot. 17F24C21), and the concentration of the compounds was determined using an ELISA reader. The working solution was diluted with PBS to 300 ng / μL.

[0586] Co-incubation of test sample and enzyme system: Add 43 μL of enzyme system (Sigma, Lot. P4506) and 7 μL of test sample (two replicates per sample) to an EP tube, vortex to mix, and incubate at 37°C.

[0587] Termination of reaction: At each time point of the stability study, 50 μL of the incubation tube was taken out and transferred to another EP tube, 5 μL of EDTA (0.5 M) solution was added, mixed well, and immediately placed in liquid nitrogen for rapid cooling to terminate the reaction.

[0588] Biological sample pretreatment: After thawing the frozen samples at room temperature, add 10 μL of internal standard compound (a quality control compound, i.e., siRNA sequence: antisense strand CmsUfsCmGmGfUmAfCmAmUmGmCfAmAfUmCmsCmsCm; sense strand GmsGmGmAmUmUfGmCfAfUfGmUmAmAmCmCmGmsAmsGm), 150 μL of Tris, and 150 μL of extraction solvent (phenol:chloroform:isoamyl alcohol = 25:24:1) to each tube. After vortexing and mixing, centrifuge for 10 minutes, and take the supernatant for high-resolution liquid chromatography-mass spectrometry detection. The remaining amount of the test sample at each time point is shown in Table 4.

[0589] Table 4: Remaining amount of test samples at each time point

[0590] The above results indicate that when the nucleoside compound of the present invention is introduced into the 5' end of an oligonucleotide single strand, it can significantly improve the stability of the oligonucleotide single strand to 5'-exonuclease.

[0591] Example 43: Synthesis of siRNA sequences for in vivo evaluation in wild-type mice

[0592] The synthesis of siRNA is no different from the usual phosphoramide solid-phase synthesis method. When synthesizing nucleotides modified at various positions of the SS and AS chains, the original nucleotides of the parent sequence are replaced with the phosphoramide monomers synthesized above.

[0593] The synthesis process is briefly described as follows: Using a Universal CPG (Dinaxinke) carrier as the starting material, nucleoside phosphoramide monomers were linked one by one according to the synthesis program on an LK-48E synthesizer (Lingkun). Except for LT107-A~LT158-A and (LT110-G)~(LT152-G) synthesized as described above, the remaining nucleoside monomer raw materials, such as 2'-F RNA and 2'-O-methyl RNA, were purchased from Shanghai Zhaowei, and L96 was purchased from WuXi AppTec. 5'-Ethylthio-1H-tetrazole (ETT) was used as the activator (0.6M acetonitrile solution), 0.22M PADS dissolved in a 1:1 volume ratio of trimethylpyridine (Suzhou Kelama) solution was used as the sulfiding agent, and iodopyridine / water solution (Kelama) was used as the oxidizing agent.

[0594] After solid-phase synthesis, the oligonucleotides were cleaved from the solid support and soaked in a 3:1 solution of 28% ammonia and ethanol at 50°C for 16 hours. After centrifugation, the supernatant was transferred to another centrifuge tube, concentrated, and evaporated to dryness. Purification was then performed using C18 reversed-phase chromatography with 0.1M TEAA and acetonitrile as the mobile phase, and DMTr was removed using 3% trifluoroacetic acid solution. The target oligonucleotides were collected, lyophilized, identified as the target product by LCMS, and quantified by UV (260 nm) spectroscopy.

[0595] The obtained single-stranded oligonucleotides and sodium acetate were ultrafiltered and salt-replaced using a 3KD ultrafiltration tube. According to the equimolar ratio and complementary pairing, they were annealed. Finally, the double-stranded siRNAs shown in Table 5 were dissolved in water and adjusted to the required concentration for the experiment.

[0596] Table 5. siRNA sequences used for in vivo evaluation

[0597] Example 44: In vivo activity evaluation in wild-type mice

[0598] The in vivo activity of the above compounds (see Table 5) was evaluated using wild-type C57BL / 6 mice (Speford (Beijing) Biotechnology Co., Ltd.).

[0599] Six- to eight-week-old C57BL / 6 mice were subcutaneously injected with a single dose of the compound at 1 mg / kg. Orbital blood was collected in EP tubes before administration and on days 7, 14, and 21 after administration. After the blood samples were allowed to stand at room temperature for two hours, they were centrifuged at 5500 rpm for 10 min at 4°C to separate and collect serum for the detection of TTR levels in the animal serum.

[0600] Serum TTR levels were analyzed using a TTR enzyme-linked immunosorbent assay (ELISA). The Abcam mouse Prealbumin ELISA kit (ab282297) was used for ELISA, and all samples were tested according to the kit instructions. Absorbance at 450 nm was read on a Tecan SPARK microplate reader, and the data from the standards (from the aforementioned ELISA kit) were fitted to a parametric standard curve to determine serum TTR protein levels (in μg / mL). The protein content of each animal was compared with its corresponding pre-drug serum protein content to determine the percentage of TTR remaining relative to pre-drug levels. Some experimental results are shown in Figure 1. The siRNAs with the modified nucleosides of this invention produced a silencing effect in vivo, which was essentially consistent with or better than the parent siRNA sequence; in particular, the silencing effects of LM0512-1001, LM0512-1002, and LM0512-1004 were significantly better than those of the parent siRNA sequence.

Claims

1. A nucleoside compound of Formula I, or a stereoisomer thereof: in, R 1 R 2 R 3 They are independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C1-C6 alkoxy, and substituted C1-C6 alkoxy, respectively. R 4 R 5 Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, and 4-6 membered heterocycle; R 6 Selected from hydrogen, halogen, C1-C30 alkyl, substituted C1-C30 alkyl, C1-C30 alkoxy, substituted C1-C30 alkoxy, C2-C30 alkenyl, substituted C2-C30 alkenyl, C2-C30 alkynyl or, substituted C2-C30 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycle; Nu is selected from hydrogen or nucleoside bases; Z represents -O-, -S-, -NR Z1 -、-N(COR Z1 )-or-CR Z1 R Z2 -; where R is... Z1 and R Z2 Each of the following is independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl or substituted C2-C6 ynyl; X 1 Selected from -(CH2) n O- or -(CH2) n S-; where n is any integer from 0 to 10; X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) n -A-; where m is any integer from 0 to 10; A is selected from 3-6 membered cycloalkyl, 4-6 membered heterocyclic, benzene ring, and 5-6 membered aromatic heterocyclic; The substituents in the substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, and substituted C1-C6 alkoxy groups are selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(O)(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH(C1-C6 alkyl), and -C(O)N(C1-C6 alkyl)(C1-C6 alkyl).

2. The nucleoside compound according to claim 1, characterized in that: Nucleoside compounds represented by Formula I are shown as those represented by Formula IIa or Formula IIb: Among them, Z and R 1 R 2 R 3 R 4 R 5 R 6 Nu, X 1 and X 2 As described in claim 1.

3. The nucleoside compound according to any one of claims 1-2, characterized in that: R 1 R 2 R 3 Each of the following is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, and ethoxy; preferably, R 1 R 2 R 3 All are hydrogen; Z is selected from -O-, -S-, or -N(COR). Z1 )-; where R Z1 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; preferably, Z is -O-; R 4 For hydrogen, R 5 Selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycle; Or, R 5 For hydrogen, R 4 Selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycle.

4. The nucleoside compound according to any one of claims 1-3, characterized in that: The compounds of formula I, IIa, or IIb are shown in formulas IIIa, IIIb, IIIc, and IIId: Among them, R 4 R 5 R 6 Nu, X 1 and X 2 As described in claim 1.

5. The nucleoside compound according to any one of claims 1-4, characterized in that: X 1 Selected from -O- or -S-; preferably, X 1 -O-; X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) m -A-; where m is selected from 0, 1, 2, 3, 4 or 5; Preferably, X 2 It is selected from -O-, -CH2-, -CH2O-, -CH2S-, -CH2NH(CO)-, -(CO)NH- or -CH2OCH2- 5-membered aromatic heterocycle-; wherein the 5-membered aromatic heterocycle is preferably 1,2,4-triazole; R 6 Selected from hydrogen, methyl, halogen, or C10-C18 alkyl; preferably, R 5 Selected from hydrogen, methyl, fluorine, C10 alkyl, C11 alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, or C18 alkyl; more preferably, R 5 Selected from hydrogen, methyl, fluorine, C10 straight-chain alkyl, C11 straight-chain alkyl, C12 straight-chain alkyl, C13 straight-chain alkyl, C14 straight-chain alkyl, C15 straight-chain alkyl, C16 straight-chain alkyl, C17 straight-chain alkyl or C18 straight-chain alkyl; R 4 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 4 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy, R 5 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 5 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy, 6. The nucleoside compound according to any one of claims 1-5, characterized in that: Nu is a nucleoside base, and the nucleoside base is selected from:

7. The nucleoside compound according to any one of claims 1-6, characterized in that: The nucleoside compound is as follows: Wherein, Nu is as described in claim 1 or claim 6.

8. The nucleoside compound according to any one of claims 1-7, characterized in that: The nucleoside compound is specifically:

9. Use of the nucleoside compound of any one of claims 1-8 in the preparation of oligonucleotides; preferably, use of the nucleoside compound of any one of claims 1-8 as an intermediate in the preparation of oligonucleotides; more preferably, the oligonucleotide is siRNA, antisense nucleic acid, saRNA, miRNA or nucleic acid aptamer.

10. An oligonucleotide comprising at least one structure of formula V, and wherein... Linked to the rest of the oligonucleotide; in, R 1 R 2 R 3 They are independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, C1-C6 alkoxy, and substituted C1-C6 alkoxy, respectively. R 4 R 5 Each of the following is independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl, substituted C2-C6 ynyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, -S (C1-C6 alkyl), -S (substituted C1-C6 alkyl), 3-6 membered cycloalkyl, and 4-6 membered heterocycle; R 6 Selected from hydrogen, halogen, C1-C30 alkyl, substituted C1-C30 alkyl, C1-C30 alkoxy, substituted C1-C30 alkoxy, C2-C30 alkenyl, substituted C2-C30 alkenyl, C2-C30 alkynyl or, substituted C2-C30 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycle; Nu is selected from hydrogen or nucleoside bases; Z represents -O-, -S-, -NR Z1 -、-N(COR Z1 )-or-CR Z1 R Z2 -; where R is... Z1 and R Z2 Each of the following is independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 ynyl or substituted C2-C6 ynyl; X 1 Selected from -(CH2) n O- or -(CH2) n S-; where n is any integer from 0 to 10; X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) n -A-; where m is any integer from 0 to 10; X 3 Selected from O or S; A is selected from 3-6 membered cycloalkyl, 4-6 membered heterocyclic, benzene ring, and 5-6 membered aromatic heterocyclic; The substituents in the substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, and substituted C1-C6 alkoxy groups are selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(O)(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)NH(C1-C6 alkyl), and -C(O)N(C1-C6 alkyl)(C1-C6 alkyl).

11. The oligonucleotide according to claim 10, characterized in that: The structures shown in equation V are as shown in equations VIIIa, VIIIb, VIIIc, and VIIId: Among them, R 4 R 5 R 6 Nu, X 1 X 2 and X 3 As described in claim 10.

12. The oligonucleotide according to any one of claims 10-11, characterized in that: X 1 Selected from -O- or -S-; preferably, X 1 Selected from -O-; X 2 Selected from -(CH2) m O-, -(CH2) m -、-(CH2) m S-, -(CH2) m NH(CO)-, -(CH2) m (CO)NH- or -(CH2) m O(CH2) m -A-; where m is selected from 0, 1, 2, 3, 4 or 5; Preferably, X 2 It is selected from -O-, -CH2-, -CH2O-, -CH2S-, -CH2NH(CO)-, -(CO)NH- or -CH2OCH2- 5-membered aromatic heterocycle-; wherein the 5-membered aromatic heterocycle is preferably 1,2,4-triazole; R 6 Selected from hydrogen, methyl, halogen, or C10-C18 alkyl; preferably, R 5 Selected from hydrogen, methyl, fluorine, C10 alkyl, C11 alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, or C18 alkyl; more preferably, R 5 Selected from hydrogen, methyl, fluorine, C10 straight-chain alkyl, C11 straight-chain alkyl, C12 straight-chain alkyl, C13 straight-chain alkyl, C14 straight-chain alkyl, C15 straight-chain alkyl, C16 straight-chain alkyl, C17 straight-chain alkyl or C18 straight-chain alkyl; R 4 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 4 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy, R 5 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl. Preferably, R 5 Selected from hydrogen, fluorine, methyl, methoxy, ethoxy, 13. The oligonucleotide according to any one of claims 10-12, characterized in that: Nu is a nucleoside base, which is selected from adenine, uracil, guanine, cytosine, thymine, or the bases shown below:

14. The oligonucleotide according to any one of claims 10-13, characterized in that: The oligonucleotide comprises at least one structure as shown in the following formula, and is obtained through... Linked to the rest of the oligonucleotide; Among them, X 3 Selected from O or S; preferably, X 3 Let it be S.

15. The oligonucleotide according to any one of claims 10-14, characterized in that: The oligonucleotide is siRNA, wherein the siRNA comprises a sense strand and an antisense strand; preferably, the structure shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc or Formula VIIId is the first nucleotide at the 5' end of the sense strand of the siRNA, or the first nucleotide at the 5' end of the antisense strand of the siRNA; more preferably, the structure shown in Formula V, Formula VIIIa, Formula VIIIb, Formula VIIIc or Formula VIIId is the first nucleotide at the 5' end of the sense strand of the siRNA.

16. The siRNA according to claim 15, characterized in that: The antisense strand is 17 to 30 nucleotides long; the sense strand is 17 to 30 nucleotides long and is at least partially complementary to the antisense strand; preferably, the sense strand and the antisense strand are complementary by at least 15, 16, 17, 18, 19, 20 or 21 nucleotides.

17. The siRNA according to claim 16, characterized in that: The antisense strand is 21–23 nucleotides long; the sense strand is 19–21 nucleotides long.

18. The siRNA according to claim 16, characterized in that: The siRNA contains one or more single-stranded nucleotide overhangs; preferably, the antisense strand of the siRNA has a two-nucleotide overhang at its 3' end.

19. The siRNA according to claim 16, characterized in that: All nucleotides in the sense and / or antisense strands of the siRNA are modified nucleotides or nucleotide analogs; preferably, the modified nucleotides are selected from 2'-methoxynucleotides, 2'-fluoronucleotides, 2'-deoxynucleotides, 2',3'-cleaved nucleotide analogs, 2'-fluoroarabinonucleotides, 2'-methoxyethylnucleotides, 2'-amino-modified nucleotides, 2'-alkyl-modified nucleotides, 3'-methoxynucleotides, 2'-allyl-modified nucleotides, nucleotides containing thiophosphate groups, nucleotides containing methylphosphonate groups, nucleotides containing 5'-phosphates, nucleotides containing 5'-phosphate mimics, diol-modified nucleotides, abase nucleotides, morpholinonucleotides, locked nucleotides (LNA), unlocked nucleotides (UNA), glycerol nucleotides (GNA), or nucleotides with the structure shown in Formula V of the present invention.

20. The siRNA according to any one of claims 15-19, characterized in that: The siRNA is also linked to a targeting ligand; preferably, the 3' end of the siRNA's positive strand is linked to a targeting ligand.

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