TWI827720B - Cyclic dinucleotide compounds and uses thereof - Google Patents

Abstract

The present invention discloses a compound of　formula (I), an optical isomer thereof,　a pharmaceutically acceptable salt thereof, and an use of the compound as a STING agonist.

Description

Cyclic dinucleotide compounds and their applications

The present invention relates to the compound represented by formula (I), its optical isomers and pharmaceutically acceptable salts thereof, as well as the use of the compound as a STING agonist.

This application claims the following priority rights: CN201811301854.8, application date November 2, 2018; CN201811367721.0, application date: November 16, 2018; CN201910129734.2, application date: February 21, 2019; CN201910463705.X, application date: May 30, 2019; CN201910999403.4, application date October 18, 2019.

For a long time, researchers have been trying to activate patients' immune systems so that their own immune systems can effectively fight tumors and completely eliminate tumor cells. However, the probability of spontaneous tumor remission is extremely low, so the vast majority of patients will not benefit from it. In the 1960s and 1970s, treatment methods such as BCG injection and non-specific strengthening of immune system function emerged. In the 1980s, interferon and IL-2, which can activate T cells and NK cells, were also tried to be used in cancer treatment. However, these methods still have many limitations, such as the very short half-life of exogenous cytokines in the blood. , which must be compensated for by frequent dosing and high doses. Non-specific activation of the immune system leads to inflammatory responses in normal tissues, cytokine storms, etc. Therefore, many therapies have very strong toxic side effects. As immunomodulators that trigger the production of specific therapeutically beneficial cytokines in the body, therapies targeting STING bring hope to resolve this dilemma.

It is currently known that human STING is activated in three ways: 1) By binding to exogenous (3', 3') cyclic dinucleotides (c-diGMP, c-diAMP and c-GAMP) released by invading bacteria or archaea. Activated, which shows that STING has a role in innate immune activation in anti-infection; 2) activated by binding to (2' 3') cyclic guanosine monophosphate adenosine monophosphate (2', 3' c-GAMP), It is endogenously produced by cyclic GMP-AMP dinucleotide synthase (cGAS) induced in the presence of exogenous double-stranded DNA (e.g., released by invading bacteria, viruses, or protozoa) or self-DNA in mammals. Source cyclic dinucleotide, which shows that STING has the function of activating innate immunity induced by endogenous or exogenous DNA; 3) activated by binding synthetic ligands.

STING acts as a sensor for DNA in the cytoplasm, and its activation can lead to the activation of the downstream IRF3 and NF-κB pathways to activate the immune system. Activation of the NF-κB pathway leads to the activation of a series of downstream inflammatory cytokines, while activation of the IRF3 pathway leads to the activation of type 1 interferons (IFN-α/β), dendritic cells, cytotoxic cells, NK cells, etc. activation, thereby exerting anti-tumor effects.

DNA in the human body usually does not activate the STING protein, because normally DNA can only exist in the nucleus (except for mitochondrial DNA). However, if DNA leaks into the cytoplasm, STING will be activated and trigger an immune response. Recently, it has been found that radiotherapy and chemotherapy can also activate STING. This may also be due to the leakage of DNA in dead tumor cells, which causes STING to be activated.

The present invention provides compounds represented by formula (I), optical isomers thereof and pharmaceutically acceptable salts thereof, Among them, R ₁ and R _1a are independently selected from , , , , , , and ; T ₁ , T ₂ , _{T 3} , T ₄ , T 5 , T ₆ , T ₇ , T ₈ , T ₉ , T ₁₀ , T ₁₁ , T ₁₂ , and T ₁₃ are each independently selected from -C(R)- and -N-; L ₁ and L ₂ are independently selected from -O-, -N(R)-, -C(RR)- and -C(=O)-; R are independently selected from H, halogen ,OH,NH ₂ ,CN, , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylthio and C _1-6 alkylamino are optionally substituted by 1, 2 or 3 R';R' is selected from F, Cl, Br, I, OH, NH ₂ and CH ₃ ; R ₂ and R _2a respectively Independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkyne group, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are optionally substituted by 1, 2 or 3 R ; R ₃ and R _3a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkyl Amino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are optionally replaced by 1 , 2 or 3 R substituted; R ₄ and R _4a are independently selected from H, halogen, OH, NH ₂ , CN, N ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylthio group, C _1-6 alkylamino group and C _2-6 alkynyl group, wherein C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, C _1-6 alkynyl group and C _2-6 alkynyl is optionally substituted by 1, 2 or 3 R; R ₅ and R _5a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 Alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are optionally substituted by 1, 2 or 3 R; R ₆ and R _6a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino are optionally substituted by 1, 2 or 3 R; R ₇ and R _7a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino is optionally substituted by 1, 2 or 3 R; R ₁₀ and R _10a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 Alkoxy, C _1-6 alkylthio and C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino are any optionally substituted by 1, 2 or 3 R; alternatively, R ₇ and R ₁₀ are connected together to form a C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl group, the C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl is optionally substituted by 1, 2 or 3 R; R _7a and R _10a are joined together to form a C _3-6 Cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl, the C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl is optionally replaced by 1, 2 or 3 R substitutions; R ₈ is selected from BH ₃ ^- and -S(R ₉ ); R ₉ is selected from H, CH ₂ OC(=O)R ₁₁ , CH ₂ OC(=O)OR ₁₁ , CH ₂ CH ₂ SC(=O)R ₁₁ and CH ₂ CH ₂ SSCH ₂ R ₁₁ ; R ₁₁ is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heterocycloalkyl and C ₁ - ₂₀ alkyl, the C ₁ - ₂₀ alkyl is optionally substituted by 1, 2, 3, 4 or 5 C _6-10 aryl, C _3-10 cycloalkyl, OH and F; Or, R ₄ and R ₆ or R _4a and R _6a are connected together to form a 5~6-membered heterocycloalkyl group; X ₁ and X _1a are independently selected from -NH-, -O-, -S- and -CH ₂ -; X ₂ and X _2a are independently selected from -NH-, -O-, -S- and -CH ₂ -; X ₃ and X _3a are independently selected from -O- _and -S-; is selected from -O-, -S-, -CH ₂ - and -C(=CH ₂ )-; the 5 to 6-membered heterocycloalkyl, 5 to 10-membered heteroaryl or C _1-6 heterocycle The alkyl group contains 1, 2 or 3 independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, - S(=O) ₂ - and N heteroatoms or heteroatom groups; and, when R ₁ or R _1a is selected from , When , the compound represented by formula (I) is not selected from and .

In some embodiments of the present invention, when R ₈ is selected from BH ₃ ^- , one of R ₄ and R _4a is selected from F, Cl and Br, and the other is selected from F, Cl, Br, OH, OCH ₃ or N ₃ , other variables are as defined in the present invention.

In some aspects of the present invention, the above R are independently selected from H, halogen, OH, NH ₂ , CN, , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylamino, wherein C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} alkylthio and C _1-3 alkylamino are optionally substituted by 1, 2 or 3 R', and other variables are as defined in the present invention.

In some aspects of the present invention, the above R are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, , , , , , and , among which Me, , , , , and Optionally substituted by 1, 2 or 3 R', other variables are as defined in the present invention.

In some aspects of the present invention, the above R are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, , , , , , , and , other variables are as defined in the present invention.

In some solutions of the present invention, the above-mentioned R ₁ and R _1a are independently selected from , , , , , , , , , , , , , , , , , , , and , other variables are as defined in the present invention.

In some solutions of the present invention, the above-mentioned R ₁ and R _1a are independently selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , other variables are as defined in the present invention.

In some solutions of the present invention, the above-mentioned R ₂ , R _2a , R ₃ , R _3a , R ₅ and R _5a , R ₆ and R _6a are independently selected from H, and other variables are as defined in the present invention.

In some aspects of the present invention, the above-mentioned R ₆ and R _6a are independently selected from H and methyl, and other variables are as defined in the present invention.

In some aspects of the present invention, the above-mentioned R ₄ and R _4a are independently selected from F, OH, NH ₂ , N ₃ and , other variables are as defined in the present invention.

In some solutions of the present invention, the above-mentioned R ₇ and R _7a are independently selected from H and CH ₃ , and other variables are as defined in the present invention.

In some solutions of the present invention, the above-mentioned R ₄ and R ₆ are connected together, and the structural unit Selected from , other variables are as defined in the present invention.

In some solutions of the present invention, the above-mentioned R _4a and R _6a are connected together, and the structural unit Selected from , other variables are as defined in the present invention.

In some aspects of the present invention, the above compounds, their optical isomers and their pharmaceutically acceptable salts are selected from Among them, R ₁ and R _1a are independently selected from , , , , , , , , , , , , , , , , , , , , , and ; R ₄ and R _4a are independently selected from H, halogen, OH, NH ₂ , CN, N ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _{1 -6} alkylamino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are any Selected to be substituted by 1, 2 or 3 R; R ₆ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkynyl are optionally replaced by 1, 2 or 3 R substitutions; Alternatively, R ₄ and R ₆ are connected together to form a 5~6-membered heterocycloalkyl group; R ₈ is selected from BH ₃ ^- and -S(R ₉ ); R ₉ is selected from H, CH ₂ OC (=O)R ₁₁ , CH ₂ OC(=O)OR ₁₁ , CH ₂ CH ₂ SC(=O)R ₁₁ and CH ₂ CH ₂ SSCH ₂ R ₁₁ ; R ₁₁ is selected from C _6-10 aryl, 5 ~10-membered heteroaryl, C _1-6 heterocycloalkyl and C ₁ - ₂₀ alkyl, the C ₁ - ₂₀ alkyl is optionally replaced by 1, 2, 3, 4 or 5 C _6-10 aryl , C _3-10 cycloalkyl, OH and F substitution; X ₁ and X _1a are independently selected from -NH-, -O-, -S- and -CH ₂ -; X ₂ and X _2a are independently selected from From -NH-, -O-, -S- and -CH ₂ -; X ₃ and X _3a are independently selected from -O- and -S-; Y and Y _a are independently selected from -O-, - S-, -CH ₂ - and -C(=CH ₂ )-; when R ₈ is selected from BH ₃ ^- , one of R ₄ and R _4a is selected from F, Cl and Br, and the other is selected from F, Cl, Br, OH, OCH ₃ or N ₃ ; When R ₈ is selected from -S (R ₉ ), one of R ₄ and R _4a is selected from F, Cl and Br, and the other is selected from OH, OCH ₃ or N ₃ ; Alternatively, when R ₈ is selected from -S (R ₉ ), and one of R ₄ and R _4a is selected from F, Cl and Br, and the other is not selected from OH, OCH ₃ or N ₃ , R ₄ and R _4a are not Selected from , and R ₄ and R _4a are not simultaneously selected from .

In some aspects of the present invention, the above-mentioned compounds, their optical isomers and pharmaceutically acceptable salts thereof are selected from Among them, R ₁ , R _1a , R _4a , R ₇ , R _7a , R ₈ and R _6a are as defined above.

In some aspects of the present invention, the above compounds, their optical isomers and pharmaceutically acceptable salts thereof are selected from the group consisting of , each of its variables is as defined in the present invention.

In some aspects of the present invention, the above compounds, their optical isomers and their pharmaceutically acceptable salts are selected from , , where R ₁ and R _1a are independently selected from , , , , , , , , , , , , , and ; X ₁ and X _1a are independently selected from -NH- _, -O-, -S- and _{-CH 2} -; _{-CH 2} -; _{X 3 and 2} )-.

In some aspects of the present invention, the above compounds, their optical isomers and their pharmaceutically acceptable salts are selected from , other variables are as defined in the present invention.

In some solutions of the present invention, the above-mentioned R ₁ and R _1a are independently selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , other variables are as defined in the present invention.

The present invention provides compounds represented by formula (I), optical isomers thereof and pharmaceutically acceptable salts thereof, Among them, R ₁ and R _1a are independently selected from , , , , , , and ; T ₁ , T ₂ , _{T 3} , T ₄ , T 5 , T ₆ , T ₇ , T ₈ , T ₉ , T ₁₀ , T ₁₁ , T ₁₂ , and T ₁₃ are each independently selected from -C(R)- and -N-; L ₁ and L ₂ are independently selected from -O-, -N(R)-, -C(RR)- and -C(=O)-; R are independently selected from H, halogen ,OH,NH ₂ ,CN, , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylthio and C _1-6 alkylamino are optionally substituted by 1, 2 or 3 R';R' is selected from F, Cl, Br, I, OH, NH ₂ and CH ₃ ; R ₂ and R _2a respectively Independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkyne group, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are optionally substituted by 1, 2 or 3 R ; R ₃ and R _3a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkyl Amino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are optionally replaced by 1 , 2 or 3 R substituted; R ₄ and R _4a are independently selected from H, halogen, OH, NH ₂ , CN, N ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylthio group, C _1-6 alkylamino group and C _2-6 alkynyl group, wherein C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, C _1-6 alkynyl group and C _2-6 alkynyl is optionally substituted by 1, 2 or 3 R; R ₅ and R _5a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 Alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are optionally substituted by 1, 2 or 3 R; R ₆ and R _6a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino are optionally substituted by 1, 2 or 3 R; R ₇ and R _7a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino is optionally substituted by 1, 2 or 3 R; R ₁₀ and R _10a are independently selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 Alkoxy, C _1-6 alkylthio and C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino are any optionally substituted by 1, 2 or 3 R; alternatively, R ₇ and R ₁₀ are connected together to form a C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl group, the C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl is optionally substituted by 1, 2 or 3 R; R _7a and R _10a are joined together to form a C _3-6 Cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl, the C _3-6 cycloalkyl, C _3-6 cycloalkenyl or C _3-6 cycloalkynyl is optionally replaced by 1, 2 or 3 R substitutions; R ₈ is selected from BH ₃ ^- and -S(R ₉ ); R ₉ is selected from H, CH ₂ OC(=O)R ₁₁ , CH ₂ OC(=O)OR ₁₁ , CH ₂ CH ₂ SC(=O)R ₁₁ and CH ₂ CH ₂ SSCH ₂ R ₁₁ ; R ₁₁ is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heterocycloalkyl and C ₁ - ₂₀ alkyl, the C ₁ - ₂₀ alkyl is optionally substituted by 1, 2, 3, 4 or 5 C _6-10 aryl, C _3-10 cycloalkyl, OH and F; Or, R ₄ and R ₆ or R _4a and R _6a are connected together to form a 5~6-membered heterocycloalkyl group; X ₁ and X _1a are independently selected from -NH-, -O-, -S- and -CH ₂ -; X ₂ and X _2a are independently selected from -NH-, -O-, -S- and -CH ₂ -; X ₃ and X _3a are independently selected from -O- _and -S-; is selected from -O-, -S-, -CH ₂ - and -C(=CH ₂ )-; the 5 to 6-membered heterocycloalkyl, 5 to 10-membered heteroaryl or C _1-6 heterocycle The alkyl group contains 1, 2 or 3 independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, - S(=O) ₂ - and N heteroatoms or heteroatom groups.

In some aspects of the present invention, the above R are independently selected from H, halogen, OH, NH ₂ , CN, , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylamino, wherein C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} alkylthio and C _1-3 alkylamino groups are optionally substituted by 1, 2 or 3 R'.

In some aspects of the present invention, the above R are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, , , , , , and , among which Me, , , , , and Optionally substituted by 1, 2 or 3 R'.

In some aspects of the present invention, the above R are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me, , , , , , , and .

In some solutions of the present invention, the above-mentioned R ₁ and R _1a are independently selected from , , , , , , , , , , , , , , , , , , and .

In some solutions of the present invention, the above-mentioned R ₁ and R _1a are independently selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some aspects of the present invention, the above-mentioned R ₂ , R _2a , R ₃ , R _3a , R ₅ , R _5a , R ₆ and R _6a are each independently selected from H.

In some aspects of the present invention, the above-mentioned R ₄ and R _4a are independently selected from F, OH, NH ₂ , N ₃ and .

In some aspects of the present invention, the above-mentioned R ₇ and R _7a are independently selected from H and CH ₃ .

In some solutions of the present invention, the above-mentioned R ₄ and R ₆ are connected together, and the structural unit Selected from .

In some solutions of the present invention, the above-mentioned R _4a and R _6a are connected together, and the structural unit Selected from .

In some aspects of the present invention, the above-mentioned compounds, their optical isomers and pharmaceutically acceptable salts thereof are selected from Among them, R ₁ , R _1a , R _4a , R ₇ , R _7a , R ₈ and R _6a are as defined above.

The present invention also provides compounds of the following formula, their optical isomers and pharmaceutically acceptable salts thereof, which are selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes amino acids (such as arginine, etc.) salts, as well as salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, ( R )- and ( S )-enantiomers, diastereoisomers isomer, the ( D )-isomer, the ( L )-isomer, and their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to this invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Unless otherwise stated, use wedge-shaped solid line keys ( ) and wedge-shaped dotted keys ( ) represents the absolute configuration of a stereocenter, using a straight solid line key ( ) and straight dotted keys ( ) represents the relative configuration of the three-dimensional center, using a wavy line ( ) represents a wedge-shaped solid line key ( ) or wedge-shaped dotted key ( ), or use a tilde ( ) represents a straight solid line key ( ) and straight dotted keys ( ).

The compounds of the present invention may exist in specific species. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that isomers with different functional groups are in dynamic equilibrium at room temperature and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. structuring. Valence tautomers are interconversions involving the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one, or e.g. and Is a tautomer.

Unless otherwise stated, the terms "enriched in an isomer," "isomerically enriched," "enriched in an enantiomer," or "enantiomerically enriched" refer to one of the isomers or enantiomers. The content is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96 %, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

Unless otherwise stated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

The optically active ( R )- and ( S )-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If it is desired to obtain an enantiomer of a compound of the invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure Enantiomers required. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomeric salts are formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate). The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention. "Optional" or "optionally" means that the subsequently described event or condition may but need not occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not occur.

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

When the listed linking groups do not specify the direction of connection, the direction of connection is arbitrary, for example, The middle linking group L is -MW-. At this time, -MW- can be formed by connecting benzene ring and cyclopentane in the same direction as the reading order from left to right. , it can also be composed by connecting benzene ring and cyclopentane in the opposite direction to the reading order from left to right. . Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the number of atoms in a ring is usually defined as the number of ring members. For example, a "5-6 membered ring" refers to a "ring" with 5-6 atoms arranged around it.

Unless otherwise specified, "5-6 membered ring" means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aromatic group consisting of 5 to 6 ring atoms. base or heteroaryl. The rings include single rings, as well as double ring systems such as spiro rings, parallel rings and bridged rings. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N. The 5-6 membered rings include 5-membered rings, 6-membered rings, etc. "5-6 membered ring" includes, for example, phenyl, pyridyl, piperidinyl and the like; on the other hand, the term "5-6 membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which independently meets the above definition.

Unless otherwise specified, the term "C _1-20 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 20 carbon atoms. The C _1-20 alkyl group includes C _1-10 , C _1-9 , C _1-8 , C _1-6 , C _1-5 , C _1-14 , C _1-3 , C _1-2 , C _2-16 , C _2-4 , C ₁₀ , C ₈ , C ₇ , C ₆ and C ₅ alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine). Examples of C _1-20 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl , s -butyl and t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.

Unless otherwise specified, the term "C _1-6 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl group includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl groups, etc.; it can Is it monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C _1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl , s -butyl and t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl, etc.

Unless otherwise specified, the term "C _1-3 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C _1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), and the like.

The term "heteroalkyl" by itself or in combination with another term refers to a stable linear or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N( H)-. In some embodiments, the heteroalkyl group is C _1-6 heteroalkyl; in other embodiments, the heteroalkyl group is C _1-3 heteroalkyl. A heteroatom or heteroatom group may be located at any internal position of a heteroalkyl group, including the attachment point of the alkyl group to the rest of the molecule, but the terms "alkoxy,""alkylamino," and "alkylthio" (or thioalkyl Oxygen) is a conventional expression for those alkyl groups connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ (CH ₃ ) ₂ , -CH ₂ -CH ₂ -O-CH ₃ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N( CH ₃ )-CH ₃ , -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ - CH ₂ , -S(=O)-CH ₃ , -CH ₂ -CH ₂ -S(=O) ₂ -CH ₃ , and. Up to two heteroatoms can be consecutive, for example _-CH2- NH- _OCH3 .

Unless otherwise specified, the term "C _1-6 alkoxy" means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C _1-6 alkoxy group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. . Examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n -butoxy, isobutyl oxygen group, s -butoxy group and t -butoxy group), pentyloxy group (including n -pentyloxy group, isopentyloxy group and neopentyloxy group), hexyloxy group, etc.

Unless otherwise specified, the term "C _1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy groups, etc. Examples of C _1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, the term "C _1-6 alkylamino" means those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group. The C _1-6 alkylamino group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkylamino group wait. Examples of C _1-6 alkylamino include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -N(CH ₂ CH ₃ )( CH ₂ CH ₃ ), -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ , etc.

Unless otherwise specified, the term "C _1-3 alkylamino" means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. The C _1-3 alkylamino group includes C _1-2 , C ₃ and C ₂ alkylamino groups, etc. Examples of C _1-3 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )CH ₂ CH ₃ , -NHCH ₂ CH ₂ CH ₃ , - NHCH ₂ (CH ₃ ) ₂ etc.

Unless otherwise specified, the term "C _1-6 alkylthio" means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C _1-6 alkylthio group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkane Sulfur group etc. Examples of C _1-6 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , and the like.

Unless otherwise specified, the term "C _1-3 alkylthio" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C _1-3 alkylthio group includes C _1-3 , C _1-2 and C ₃ alkylthio groups, etc. Examples of C _1-3 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , and the like.

Unless otherwise specified, "C _2-6 alkynyl" is used to mean a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, a carbon-carbon triple bond Can be located anywhere on the group. The C _2-6 alkynyl group includes C _2-4 , C _2-3 , C ₄ , C ₃ and C ₂ alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C _2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

Unless otherwise specified, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings. Furthermore, in the case of the "5- to 6-membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 5-6 membered heterocycloalkyl group includes 5-membered and 6-membered heterocycloalkyl groups. Examples of 5-6 membered heterocycloalkyl include but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.) , Tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperidyl base (including 1-piper base and 2-piper base, etc.), morpholin base (including 3-morpholin base and 4-morpholin base, etc.), two Alkyl, dithianyl, iso oxazolidinyl, isothiazolidinyl, 1,2- base, 1,2-thi base, hexahydrogen base, high piperazine base or homopiperidinyl, etc.

Unless otherwise specified, the terms "C _6-10 aromatic ring" and "C _6-10 aryl" in the present invention can be used interchangeably, and the term "C _6-10 aromatic ring" or "C _6-10 aryl" means a group composed of 6 A cyclic hydrocarbon group composed of up to 10 carbon atoms with a conjugated π electron system. It can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It can be monovalent, divalent or multivalent, and C _6-10 aryl groups include C _6-9 , C ₉ , C ₁₀ and C ₆ aryl groups, etc. Examples of C _6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).

Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" can be used interchangeably in the present invention. The term "5-10 membered heteroaryl" means a ring consisting of 5 to 10 ring atoms. It is a cyclic group with a conjugated π electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. The nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). A 5- to 10-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5- to 10-membered heteroaryl groups include 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 5- to 6-membered heteroaryl groups, and the like. Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl). azolyl group, etc.), imidazolyl group (including N -imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, etc.), Azole group (including 2- Azolyl, 4- Azolyl and 5- azolyl, etc.), triazolyl (1 H -1,2,3-triazolyl, 2 H -1,2,3-triazolyl, 1 H -1,2,4-triazolyl and 4 H -1,2,4-triazolyl, etc.), tetrazolyl, iso Azolyl (3-iso Azolyl, 4-iso Azolyl and 5-iso azolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyridyl Base, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.) , benzo Azolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoline Phyllinyl (including 2-quinoline linyl and 5-quino quinolyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any specific case of n to n+m carbons, for example, C _1-6 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ , also includes any range from n to n+m, for example, C _1-6 includes C _1-3 , C _1-6 , C _1-4 , C _3-6 , C _3-5 , C _2-5 and C _1-5 , etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m. For example, a 5-6-membered ring includes a 5-membered ring and a 6-membered ring.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternative, preferred embodiments include, but are not limited to, examples of the present invention.

The HPLC detection conditions of the present invention are mainly as follows: Chromatographic column: YMC-Pack ODS-A 150*4.6mm, 5μm, mobile phase: water (0.06875% trifluoroacetic acid)-acetonitrile (0.0625% trifluoroacetic acid); flow rate: 1.0 mL/ min; detection wavelength: UV 220 nm & 215 nm & 254 nm; column temperature: 40 ℃.

The present invention adopts the following abbreviations: aq represents water; CDCl ₃ represents deuterated chloroform; CD ₃ OD represents deuterated methanol; DMSO- d ₆ represents deuterated dimethyl sulfoxide; DMF represents N, N-dimethylmethane Amide; Bz represents benzyl; TBS represents tertiary butyldimethylsilyl; DMTr represents 4,4'-bismethoxytrityl; CE represents cyanoethyl; i -Pr represents isopropyl base; DMTrCl represents 4,4'-bismethoxytrityl chloride; DDTT represents (E)-N,N-dimethyl-N'-(3-thio-3H-1,2,4- Disulfazol-5-yl)formamidine; DCA represents 2,2-dichloroacetic acid; BSA represents N,O-bistrimethylsilylacetamide, and ug or μg represents micrograms.

In order to make the above and other objects, features and advantages of the present invention more clearly understood, embodiments are given below and described in detail with reference to the accompanying drawings.

The present application is described in detail below through examples, but does not mean that there are any adverse limitations to the present application. The present application has been described in detail, and its specific embodiments have also been disclosed. For those skilled in the art, various changes and improvements can be made to the specific implementations of the present application without departing from the spirit and scope of the present application. is obvious.

Example 1: Preparation of Compounds 1A, 1B, 1C and 1D

Step 1: Preparation of Compound 1-2 Under nitrogen protection, trimethylsilyl chloride (1.61 g, 14.86 mmol, 1.89 mL) was added dropwise to a solution of compound 1-1 (1 g, 3.71 mmol) in pyridine (20 mL), and the reaction was carried out at 0 °C for 30 min. Benzyl chloride (605 mg, 4.30 mmol, 500.00 μL) was added to the reaction system, and the temperature was raised to 15 °C for 3 h. Stop the reaction, cool to 0°C, add water (10 mL) and ammonia (5 mL) in sequence to quench the reaction, stir for 10 min, extract the reaction mixture with ethyl acetate (25 mL x 3), combine the organic phases, and add anhydrous sodium sulfate Dry, filter, and the filtrate is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 9/1) to obtain compound 1-2.

MS (ESI) m/z (M+H) ⁺ = 374.1.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.26 (br s, 1H), 8.77 (s, 1H), 8.71 (s, 1H), 8.05 (d, J =7.3 Hz, 2H), 7.66 (t, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 2H), 6.39 (dd, J =2.3, 17.3 Hz, 1H), 5.77 (d, J =6.3 Hz, 1H), 5.64 - 5.39 ( m, 1H), 5.18 (t, J =5.4 Hz, 1H), 4.63 - 4.45 (m, 1H), 4.08 - 3.93 (m, 1H), 3.81 - 3.76 (m, 1H), 3.64 - 3.58 (m, 1H).

Step 2: Preparation of Compounds 1-3 Compound 1-2 (1.5 g, 4.02 mmol) was dissolved in pyridine (15 mL), and silver nitrate (2.73 g, 16.07 mmol) and tertiary butyldimethylsilyl chloride (636 mg, 4.22 mmol, 517.07 μL) were added successively. ), the reaction system was stirred at room temperature for 4 h. The reaction was quenched by adding water (50 mL), extracted with ethyl acetate (40 mL v/v) = 4/1), get compound 1-3.

MS (ESI) m/z (M+H) ⁺ = 488.1.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.29 (br s, 1H), 8.73 (br s, 1H), 8.58 (s, 1H), 8.01 (br d, J =7.3 Hz, 2H), 7.66 - 7.36 (m, 3H), 6.39 (br d, J =18.6 Hz, 1H), 5.82 (d, J =6.6 Hz, 1H), 5.66 - 5.39 (m, 1H), 4.73 - 4.50 (m, 1H), 4.08 - 4.02 (m, 1H), 4.00 - 3.94 (m, 1H), 3.85 - 3.80 (m, 1H), 0.83 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H).

Step 3: Preparation of Compounds 1-4 Compound 1-3 (1.8 g, 3.69 mmol) was dissolved in dichloromethane (20 mL), and 2, 4, 6-trimethylpyridine (3.30 g, 27.24 mmol, 3.60 mL), 4, 4' were added successively. -Bismethoxytrityl chloride (3.75 g, 11.07 mmol), the reaction system was stirred at room temperature for 16 h. The reaction was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL (v/v) = 7/3), compound 1-4 was obtained.

MS (ESI) m/z (M+H) ⁺ = 790.4.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.04 (s, 1H), 8.82 (s, 1H), 8.19 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.72 - 7.62 (m, 1H ), 7.59 - 7.54 (m, 4H), 7.49 - 7.43 (m, 4H), 7.35 - 7.31 (m, 2H), 7.29 - 7.24 (m, 1H), 6.86 - 6.83 (m, 4H), 6.37 (dd , J =2.9, 15.2 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.54 - 4.40 (m, 1H), 4.14 (br s, 1H), 3.81 (s, 3H), 3.80 (s, 3H) , 3.79 - 3.70 (m, 1H), 3.49 (dd, J =3.2, 11.7 Hz, 1H), 0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).

Step 4: Preparation of Compounds 1-5 At 0°C, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 3.06 mL) was added to a solution of compound 1-4 (2.2 g, 2.78 mmol) in tetrahydrofuran (20 mL). After the addition was completed, the reaction was heated to room temperature. The reaction was carried out with warm stirring for 3 h. The reaction system was poured into a mixed system composed of ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with water (50 mL x 3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 9/1) to obtain compound 1-5.

MS (ESI) m/z (M+H) ⁺ = 676.2.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.09 (s, 1H), 8.73 (s, 1H), 8.16 (s, 1H), 7.65 - 7.58 (m, 1H), 7.56 - 7.50 (m, 4H), 7.47 - 7.39 (m, 4H), 7.34 - 7.29 (m, 2H), 7.26 - 7.21 (m, 1H), 6.85 (d, J =8.3 Hz, 4H), 6.31 (dd, J =7.0, 11.4 Hz, 1H ), 5.72 - 5.51 (m, 1H), 5.46 - 5.34 (m, 1H), 4.69 (br d, J =5.1 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H),3.53 - 3.44 (m, 1H), 3.37 (s, 1H), 3.03 (br t, J =12.1 Hz, 1H).

Step 5: Preparation of Compounds 1-6 Under nitrogen protection, 2-cyanoethyl-N,N-diisopropylphosphoramidite chloride (525 mg, 2.22 mmol) was added dropwise to compound 1-5 (1 g, 1.48 mmol) and diisopropyl Add ethylamine (742.00 mg, 5.74 mmol, 1.00 mL) to a solution of acetonitrile (10 mL), and stir the reaction system at room temperature for 2 h. Stop the reaction, add ethyl acetate (100 mL) to dilute, wash with saturated sodium bicarbonate solution (50 mL x 3), wash the organic phase with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrated, compounds 1-6.

MS (ESI) m/z = 793.4.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.04 (br d, J =12.0 Hz, 1H), 8.76 (d, J =4.6 Hz, 1H), 8.23 (d, J =16.9 Hz, 1H), 8.01 (br d, J =7.3 Hz, 2H), 7.65 - 7.56 (m, 1H), 7.55 - 7.48 (m, 4H), 7.44 - 7.37 (m, 4H), 7.31 - 7.26 (m, 2H), 7.24 - 7.20 ( m, 1H), 6.83 - 6.77 (m, 4H), 6.44 - 6.19 (m, 1H), 4.64 - 4.50 (m, 1H), 4.31 - 4.00 (m, 2H), 3.76 (dd, J =3.7, 8.1 Hz, 6H), 3.65 - 3.29 (m, 5H), 2.80 - 2.71 (m, 1H), 2.67 - 2.59 (m, 1H), 2.53 (t, J =6.5 Hz, 1H), 1.13 (dd, J = 3.4, 6.6 Hz, 6H), 1.05 (d, J =6.8 Hz, 3H), 0.99 (d, J =6.8 Hz, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 148.91, 148.74.

Step 6: Preparation of Compounds 1-8 Dissolve compound 1-7 (10 g, 26.93 mmol) in pyridine (150 mL), add 4,4'-bismethoxytrityl chloride (11.86 g, 35.01 mmol) dropwise, and react at room temperature for 16 h. . The reaction was quenched by adding water (100 mL), dichloromethane (200 mL) was added to the system, the solid was filtered off, the organic phase was separated, washed with water (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain The solid was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 20/1 ~ 10/1; dichloromethane/methanol (v/v) = 1/0 ~ 10/1 ) to obtain a crude product. The crude product was dissolved in dichloromethane (50 mL), and then the solution was added dropwise to methyl tertiary butyl ether (200 mL). The solid was filtered out and dried under vacuum to obtain compound 1-8.

MS (ESI) m/z (M+H) ⁺ = 674.3.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.25 (s, 1H), 8.69 (s, 1H), 8.60 (s, 1H), 8.04 (d, J =7.6 Hz, 2H), 7.69 - 7.59 (m , 1H), 7.59 - 7.51 (m, 2H), 7.36 (d, J =7.6 Hz, 2H), 7.28 - 7.15 (m, 7H), 6.88 - 6.76 (m, 4H), 6.07 (d, J = 4.8 Hz, 1H), 5.76 (s, 1H), 5.67 (d, J =5.6 Hz, 1H), 5.31 (d, J =5.6 Hz, 1H), 4.84 - 4.72 (m,1H), 4.40 - 4.47 (m ,1H), 3.71 (d, J = 1.2 Hz, 6H), 3.23 (d, J = 4.8 Hz, 2H).

Step 7: Preparation of Compound 1-9B Under nitrogen protection, compound 1-8 (15 g, 22.26 mmol) and imidazole (4.55 g, 66.79 mmol) were dissolved in pyridine (60 mL), and tertiary butyldimethylsilyl chloride (5.03 g, 33.40 mmol, 4.09 mL), and the reaction system was stirred at room temperature for 4 h. Add ethyl acetate (200 mL) to the system to dilute, filter out the white solid, concentrate the solution to dryness, redissolve in ethyl acetate (200 mL), wash with saturated brine (100 mL x 4), and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 ~ 5/3) to obtain compound 1-9A (6.00 g, yield: 29.3% , the third peak), compound 1-9B (4.00 g, yield: 22.3 %, second peak), compound 1-9C (5.60 g, yield: 31.4 %, first peak).

Compound 1-9A: MS (ESI) m/z (M+H) ⁺ = 788.4. ¹ H NMR (400MHz, CDCl ₃ ) δ9.03 (br s, 1H), 8.76 (s, 1H), 8.25 (s , 1H), 8.01 (br d, J =7.3 Hz, 2H), 7.63 - 7.55 (m, 1H), 7.55 - 7.47 (m, 2H),7.37 (br d, J =7.1 Hz, 2H), 7.30 - 7.16 (m, 8H), 7.20 - 7.11 (m, 1H), 6.78 (br d, J =8.8 Hz, 4H), 6.06 (d, J =4.9 Hz, 1H), 4.78 - 4.74 (m, 1H), 4.62 - 4.55 (m,1H), 4.18 (br d, J =3.9 Hz, 1H), 3.76 (s, 6H), 3.51 (dd, J =3.3, 10.6 Hz, 1H), 3.29 - 3.16 (m, 2H ), 0.88 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H).

Compound 1-9B: MS (ESI) m/z (M+H) ⁺ = 788.4. ¹ H NMR (400MHz, CDCl ₃ ) δ9.23 (s, 1H), 8.88 (s, 1H), 8.38 (s, 1H), 8.17 (br d, J =7.3 Hz, 2H), 7.79 - 7.70 (m, 1H), 7.67 (t, J =7.6 Hz, 2H), 7.59 (br d, J =7.6 Hz, 2H), 7.48 (br d, J =8.6 Hz, 4H), 7.44 - 7.30 (m, 4H), 6.96 (br d, J =8.8 Hz, 4H), 6.25 (d, J =5.1 Hz, 1H), 5.19 - 5.11 (m, 1H), 4.55 - 4.47(m, 1H), 4.40 - 4.45 (m, 1H), 3.92 (s, 6H), 3.73 - 3.64 (m, 1H), 3.52-3.55 (m, 1H), 2.87 (d, J =3.9 Hz, 1H), 0.98 (s, 9H), 0.14 (s, 3H), 0.00(s, 3H).

Step 8: Preparation of Compounds 1-10 Under nitrogen protection, a solution of compound 1-6 (1.3 g, 1.48 mmol) in acetonitrile (5 mL) was added dropwise to compound 1-9B (1.16 g, 1.47 mmol) and tetrazole (0.45 M acetonitrile solution, 32.98 mL). and 4Å molecular sieve (2 g) in acetonitrile (20 mL) solution at room temperature. After 4 h, add ( E )-N,N-dimethyl-N'-(3-thio-3H-1, 2,4-Dithiazol-5-yl)formamidine (1 g, 4.87 mmol), continue stirring for 1 h. The reaction system was filtered, the filtrate was diluted with ethyl acetate (100 mL), the organic phase was washed with saturated sodium bicarbonate solution (50 mL x 3), saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure, and the crude product is purified by silica gel column chromatography (dichloromethane/ethyl acetate (v/v) = 9/1) to obtain compound 1-10.

MS (ESI) m/z (M/2+H) ⁺ = 798.4.

Step 9: Preparation of Compounds 1-11 Compound 1-10 (2.1 g, 1.32 mmol) was dissolved in dichloromethane (10 mL), and dichloroacetic acid (24.04 g, 5.27 mmol, 18 mL, 5% dichloromethane solution) and triethyl were added dropwise. Silane (10.92 g, 93.91 mmol, 15 mL), the reaction system was stirred at room temperature for 1.5 h. Dichloromethane (100 mL) was added to the reaction system, washed with water (100 mL), saturated sodium bicarbonate (100 mL x 2), and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain compound 1-11.

MS (ESI) m/z (M+H) ⁺ = 990.3.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.24 (br s, 1H), 8.84 - 8.74 (m, 2H), 8.32 - 8.19 (m, 2H), 8.07 - 7.99 (m, 3H), 7.89 - 7.84 (m , 1H), 7.66 - 7.47 (m, 6H), 7.44 - 7.37 (m, 1H), 6.39 - 6.26 (m, 1H), 5.98 (d, J =7.6 Hz, 0.5H), 5.79 (d, J = 7.8 Hz, 0.5H), 5.73 (t, J =5.3 Hz, 0.5H), 5.60 (t, J =5.3 Hz, 0.5H), 5.25 - 4.94 (m, 3H), 4.63 - 4.21 (m, 6H) , 4.03 - 3.92 (m, 1H), 3.83 - 3.72 (m, 1H), 3.70 - 3.62 (m, 1H), 2.84 - 2.73 (m, 3H), 0.69 (d, J =2.4 Hz, 9H), - 0.11 - -0.21 (m, 3H), -0.32 - -0.45 (m, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 68.00, 67.97.

Step 10: Preparation of Compounds 1-12 Under nitrogen protection, compound 1-11 (1 g, 1.01 mmol), 4Å molecular sieve (2 g) and tetrazole (0.45 M acetonitrile solution, 58 mL) were mixed with acetonitrile (15 mL), and 2 was added dropwise to the reaction system. -A solution of cyanoethyl N,N,N',N'-tetraisopropylphosphitediamine (431.36 mg, 1.43 mmol, 454.55 μL) in acetonitrile (10 mL), added in 30 minutes, and the reaction system was at room temperature Stir the reaction for 1 h. Stop the reaction, filter, add ethyl acetate (150 mL) to the filtrate to dilute, wash the organic phase with saturated sodium bicarbonate solution (100 mL x 3), saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and filtrate Concentrate under reduced pressure, and the solid obtained is purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/3) to obtain compound 1-12.

MS (ESI) m/z (M/2+H) ⁺ = 545.6.

Step 11: Preparation of Compounds 1-13 Under nitrogen protection and 0 °C, borane dimethyl sulfide (2 M dichloromethane solution, 1.00 mL) was added dropwise to compound 1-12 (500 mg, 459.11 μmol) and 4Å molecular sieve (500 mg) dichloromethane. After adding methane (15 mL) solution, raise the temperature to 15 °C and react for 20 min. Stop the reaction, add water (5 mL) to quench the reaction, dilute with dichloromethane (40 mL), filter, wash the filtrate with water (30 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 1-13 , was used directly in the next reaction without further purification.

Step 12: Preparation of Compounds 1-14 Compound 1-13 (480 mg, 435.22 μmol) was dissolved in 30% methylamine ethanol solution (15 mL), and the reaction was stirred at room temperature for 12 h. The reaction system was concentrated under reduced pressure, and the solid obtained was dissolved in water (20 mL), extracted with ethyl acetate (10 mL), and the aqueous phase was freeze-dried to obtain compound 1-14.

Step 13: Preparation of Compounds 1-14A, 1-14B, 1-14C and 1-14D The crude compound 1-14 was dissolved in water (10 mL) and subjected to high-efficiency preparative liquid phase separation (separation conditions: chromatographic column: Xbridge 150*30 mm*10 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile] ; Acetonitrile%: 12%-32%, flow rate: 25 mL/min, 7 min). Compound 1-14A (HPLC retention time 3.283 min); Compound 1-14B (HPLC retention time 3.654 min); Compound 1-14C (HPLC retention time 4.282 min); Compound 1-14D (HPLC retention time 4.866 min).

Compound 1-14A: MS (ESI) m/z (M+H) ⁺ = 789.2. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.64 (s, 1H), 8.52 (s, 1H), 8.24 (s , 1H), 8.22 (s, 1H), 8.11 - 7.41 (m, 4H), 6.37 - 6.27 (m, 1H), 5.96 (s, 1H), 5.25 - 5.02 (m, 1H), 4.98 - 4.62 (m , 3H), 4.41 - 4.18 (m, 4H), 3.98 - 3.80 (m, 2H), 0.94 (m, 9H), 0.51 - -0.16 (m, 9H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 92.31-89.90, 52.80. ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -201.02.

Compound 1-14B: MS (ESI) m/z (M+H) ⁺ = 789.3. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.62 - 8.50 (m, 1H), 8.44 - 8.33 (m, 1H) , 8.24 (br s, 1H), 8.19 (s, 1H), 8.13 - 7.38 (m, 4H), 6.38 - 6.23 (m, 1H), 5.96 (s, 1H), 5.47 - 5.14 (m, 1H), 4.91 - 4.68 (m, 2H), 4.51 - 4.17 (m, 5H), 3.87 - 3.69 (m, 2H), 0.95 (s, 9H), 0.25 (s, 3H), 0.24 (s, 3H), 0.13 - -0.44 (m, 3H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 91.24 - 90.10, 53.03. ¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -201.36.

Compound 1-14C: MS (ESI) m/z 775.5. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.98 (br s, 1H), 8.78 (br s, 1H), 8.59 - 8.39 (m, 1H) , 8.29 - 8.05 (m, 2H), 7.82 (br s, 2H), 6.34 (br d, J =12.8 Hz, 1H), 6.13 - 5.89 (m, 1H), 5.58 - 5.32 (m, 1H), 5.17 (br s, 1H), 5.05 - 4.64 (m, 3H), 4.45 - 4.22 (m, 3H), 3.84 - 3.74 (m, 2H), 1.00 (s, 9H), 0.76 - -0.11 (m, 9H) . ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 92.51 - 90.91, 50.69. ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -201.87.

Compound 1-14D: MS (ESI) m/z 775.3. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.26 (s, 1H), 8.97 (s, 1H), 8.82 - 8.37 (m, 4H), 8.29 (s, 1H), 7.82 (s, 1H), 6.46 - 6.31 (m, 1H), 6.16 (s, 1H), 6.11 - 5.99 (m, 1H), 5.77 - 5.57 (m, 1H), 5.13 - 5.01 (m, 2H), 4.64 (br d, J = 11.5 Hz, 1H), 4.55 - 4.37 (m, 2H), 3.93 - 3.79 (m, 2H), 1.14 (s, 9H), 0.95 (m, 6H) , 0.74 (br s, 3H). ³¹ P NMR (162MHz, DMSO- d ₆ ) δ 91.98 - 90.66, 52.69. ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -201.92.

Step 14: Preparation of Compound 1A The photoactive isomer compound 1-14A (20 mg, 24.31 μmol) was dissolved in pyridine (2 mL), and triethylamine (290.80 mg, 2.87 mmol, 0.4 mL) and triethylamine trihydrofuride were added in sequence. (197.80 mg, 1.23 mmol, 0.2 mL), the reaction system was heated to 50 °C and stirred for 14 h. Cool to room temperature, add isopropoxytrimethylsilane (745 mg, 5.63 mmol, 1 mL), and continue the reaction at room temperature for 4 h. The reaction was concentrated under reduced pressure, and the concentrated residue was dissolved in water (2 mL), back-extracted with ethyl acetate (3 mL), and the aqueous phase was separated by high-performance liquid phase preparation (separation conditions: chromatographic column: Xbridge 150*30 mm*10 μm; Mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 0%-20%, flow rate: 25 mL/min, 7min), to obtain compound 1A (HPLC retention time 1.386 min).

MS (ESI) m/z (M+H) ⁺ = 674.8.

¹ H NMR (400MHz, D ₂ O) δ 8.42 (br s, 2H), 8.18 (br s, 1H), 8.06 (br s, 1H), 6.37 (br d, J =15.8 Hz, 1H), 6.13 ( s, 1H), 5.62 - 5.36 (m, 1H), 5.05 (br s, 1H), 4.95 - 4.77 (m, 2H), 4.46 (br t, J =7.3 Hz, 2H), 4.40 - 4.26 (m, 2H), 4.08 - 3.93 (m, 2H), 0.10 (br s, 3H).

³¹ P NMR (162 MHz, D ₂ O) δ 93.99 - 91.82, 54.64.

¹⁹ F NMR (376 MHz, D ₂ O) δ -202.66.

Step 15: Preparation of Compounds 1B, 1C, 1D Other photoactive pure isomers 1B, 1C, and 1D can be prepared from compounds 1-14B, 1-14C, and 1-14D respectively by referring to the preparation method of compound 1A.

Compound 1B: MS (ESI) m/z (MH) ^- = 672.9. ¹ H NMR (400MHz, D ₂ O)δ 8.10 (br s, 1H), 8.06 (br s, 1H), 7.95 (br s,1H), 7.66 (br s, 1H), 6.34 - 6.16 (m, 1H), 5.91 (br d, J =5.9 Hz, 1H), 5.54 - 5.25 (m, 1H), 4.55 - 4.34 (m, 5H), 4.29 (br d, J =7.3 Hz, 1H), 4.18 (br d, J =12.2 Hz, 1H), 3.92 - 3.80 (m, 2H), 0.08 (br s, 3H). ³¹ P NMR (162 MHz, D ₂ O ) δ 93.84 - 92.90, 53.89. ¹⁹ F NMR (376 MHz, D ₂ O) δ -203.40.

Compound 1C: MS (ESI) m/z (MH) ^- = 672.9. ¹ H NMR (400MHz, D ₂ O) 8.30 - 7.95 (m, 3H), 7.75 (br s, 1H), 6.24 (d, J =13.8 Hz, 1H), 6.08 (s, 1H), 5.35 - 5.06 (m, 1H), 4.97 (br d, J =3.3 Hz, 1H), 4.57 - 4.28 (m, 6H), 4.02 - 3.87 (m, 2H), 0.32 (br s, 3H). ³¹ P NMR (162 MHz, D ₂ O) δ 95.59 - 93.68, 53.85. ¹⁹ F NMR (376 MHz, D ₂ O) δ -202.82.

Compound 1D: MS (ESI) m/z (MH) ^- = 672.9. ¹ H NMR (400MHz, D ₂ O)δ7.97 (br s, 1H), 7.83 - 7.75 (m, 3H), 6.23 (br d, J = ³¹ P NMR (162 MHz, D ₂ O) δ 94.34 - 93.26, 53.47. ¹⁹ F NMR (376 MHz, D ₂ O) δ -203.12.

Example 2: Preparation of Compounds 2A and 2B

Step 1: Preparation of compound 2-2 Under argon protection, compound 1-5 (1.8 g, 2.66 mmol), 4Å molecular sieve (2 g) and tetrazole (0.45 M acetonitrile solution, 88.80 mL) were dispersed in acetonitrile (10 mL). After stirring at room temperature for 10 minutes, a solution of compound 2-1 (2.33 g, 2.66 mmol) in acetonitrile (10 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution (40 mL x 3) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, concentrated in vacuo and spun to dryness to obtain compound 2-2. MS (ESI) m/z (M/2+H) ⁺ = 725.8.

Step 2: Preparation of Compound 2-3 BH ₃ -Me ₂ S (2 M in THF, 3.31 mL) was slowly added to compound 2-2 (3.2 g, 2.21 mmol), 4Å molecular sieve (3 g), and dichloromethane ( 35 mL) mixed solution. The reaction was stirred at room temperature for 40 min and then filtered. The filter cake was washed with ethyl acetate (50 mL). Water (20 mL) was added to the filtrate, then extracted with ethyl acetate (20 mL x3). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain compound 2-3. The crude product was directly used in the next reaction.

Step 3: Preparation of Compound 2-4 Compound 2-3 (3.2 g, 2.19 mmol) was dissolved in a mixed solution of acetonitrile (9 mL) and acetic acid (80% aqueous solution, 27 mL), and the reaction solution was stirred at room temperature for 18 hours. After adding ethyl acetate (20 mL) to dilute, wash with saturated sodium bicarbonate (10 mL x 3) and saturated brine (5 mL). The organic phase was dried over sodium sulfate, filtered, the filtrate was concentrated in vacuum, and the residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate = 0~100%, then methylene chloride/methanol = 0~10%) and purified. Compound 2-4 was obtained.

MS (ESI) m/z (M+H) ⁺ = 860.3.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.25 (s , H), 11.23 (s , 1H), 8.73 - 8.66 (m, 2H), 8.57 (s , 1H), 8.56 (s , 1H), 8.08 - 7.96 (m, 4H), 7.72 - 7.43 (m, 6H), 6.50 - 6.32 (m, 2H), 6.06-5.77 (m, 2H), 5.70 - 5.23 (m, 3H), 4.90 - 4.66 (m , 1H), 4.52 - 4.30 (m, 2H), 4.26 - 4.06 (m, 4H), 3.73 - 3.52 (m, 2H), 2.99 - 2.79 (m, 2H), 0.68 - 0.15 (br, 3H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 114.2 - 115.2

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ -201.38 - -201.75, -204.16 - -204.3

Step 4: Preparation of Compounds 2-5 Under argon protection, 4 Å molecular sieve (0.5 g) was added to a solution of compound 2-4 (200 mg, 232.68 μmol) in acetonitrile (1 mL), and tetrazole (0.45 M acetonitrile solution, 7.76) was added at room temperature. mL). The mixture was stirred at room temperature for 15 min, and then 2-cyanoethyl N,N,N',N'-tetraisopropylphosphitediamine (105.20 mg, 349.02 μmol) was added in portions. The reaction solution was stirred at room temperature for 1 hour. The molecular sieve was removed by filtration, and the filter cake was washed three times with ethyl acetate (5 mL). The filtrate was washed with saturated sodium bicarbonate solution (5 mL x 3) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated in vacuo and spun to dryness to obtain compound 2-5. The product was used directly in the next reaction without purification. MS (ESI) m/z (M+H) ⁺ = 959.4.

Step 5: Preparation of Compound 2-6 Borane dimethyl sulfide (2 M in tetrahydrofuran, 344.26 μL) was added dropwise to a solution of compound 2-5 (220 mg, 229.51 μmol) in dichloromethane (6 mL) at 0 °C. The reaction solution was stirred at 0°C for 20 minutes, and water (2 mL) was added to quench. Continue stirring for 10 minutes and extract with dichloromethane (5 mL x 3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and spin-dried under vacuum to obtain compound 2-6. The product was used directly in the next reaction without purification.

Step 6: Preparation of Compounds 2A, 2B and 2C Compound 2-6 (0.5 g, 0.502 mol) was dissolved in 30% methylamine ethanol solution (20 mL), and the reaction was stirred at 35°C for 72 h. The reaction system was concentrated under reduced pressure, and the solid obtained was separated by high-efficiency preparative liquid phase (separation conditions: chromatographic column: Waters Xbridge Prep OBD C18 150*30 mm*10 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; Acetonitrile%: 20% - 90%, flow rate: 25 mL/min, 20 min).

Compound 2A (HPLC retention time: t = 9.2 min). MS (ESI) m/z (MH) ^- = 657.3. ¹ H NMR (400MHz, D ₂ O) δ 8.21 (s, 2H), 7.88 (s, 2H), 6.26 (s, 1H), 6.22 (s, 1H), 5.50 (s, 1H), 5.37 (s, 1H), 4.89 - 4.73 (m, 2H), 4.38-4.35 (m, 2H), 4.18-4.15 (m, 2H), 3.92-3.85 (m, 2H), 0.45- -0.2 (br, 6 H). ³¹ P NMR (162MHz, D ₂ O) δ 93.43-92.29 ¹⁹ F NMR (376MHz, D ₂ O) δ -203.09,

Compound 2B (HPLC retention time: t = 11.1 min). MS (ESI) m/z (M+H) ⁺ = 659.2. ¹ H NMR (400MHz, D ₂ O)δ 8.16 (s, 1H), 8.03 (s, 2H), 7.62-7.75 (m, 1H), 6.35-6.30 (m, 1H), 6.18-6.14 (m, 2H), 5.42-5.25 (m, 2H), 5.19-5.07 (m,. 2H), 4.48-4.35 (m, 2H), 4.36 - 4.26 ( m, 2H), 4.26-4.17 (m, 2H), 3.85-3.81 (m, 2H), 0.55- -0.15 (br, 6 H) ³¹ P NMR (162 MHz, D ₂ O) δ 92.77-90.51 ¹⁹ F NMR (376 MHz, D ₂ O) δ -202.63

Compound 2C (HPLC retention time: t = 17.0 min). MS (ESI) m/z (M+H) ⁺ = 659.4. ¹ H NMR (400 MHz, D ₂ O)δ 8.12 (s, 2H), 7.84 (s, 2H), 6.15 (s, 1H), 6.11 (s, 1H), 5.42-5.26 (m, 2H), 5.09-5.03 (m, 2H), 4.35-4.28 (m, 4H), 3.89-3.84 (m, 2H), 0.55- -0.1 (br, 6 H) ³¹ P NMR (162 MHz, D ₂ O) δ 95.02-92.41 ¹⁹ F NMR (376 MHz, D ₂ O) δ -201.85

Step 7: Preparation of Compound 2D Dowex-50W ion exchange resin (20 g) was placed in a beaker, washed with deionized water (10 mL), then added sulfuric acid (15% deionized water solution), stirred for 5 min, poured out the liquid, and transferred the resin to the chromatograph In the column, rinse with sulfuric acid (15% deionized water solution, 4 CV) and deionized water until pH = 7.0. Move the treated resin into a beaker, add sodium hydroxide (15% deionized water solution), stir for 5 minutes, pour out the liquid, transfer the resin to the chromatographic column, and use sodium hydroxide (15% deionized water solution) and water in sequence. Rinse to pH =7.0. Compound 2B (140 mg, 202.28 umol, 2NH ₄ ) was dissolved in water (2 mL), and purified by the above obtained chromatography column to obtain compound 2D. MS (ESI) m/z (M+H) ⁺ = 659.3. ¹ H NMR (400MHz, D ₂ O)δ 8.27 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.78 ( s, 1H), 6.33-6.25 (m, 2H), 5.55-5.42 (m, 2H), 5.05-4.90 (m, 2H), 4.44-4.36 (m, 3H), 4.29-4.25 (m, 1H), 4.02-3.96 (m, 2H), 0.55- -0.2 (br, 6 H). ³¹ P NMR (162 MHz, D ₂ O) δ 93.43-92.29 ¹⁹ F NMR (376 MHz, D ₂ O) δ -203.09

Example 3: Preparation of Compounds 3A, 3B, 3C, and 3D

Step 1: Preparation of compound 3-2 Under argon protection, compound 4-chloro-5-fluoro-7H-pyrrolo[2,3-D]-pyrimidine (1.03 g, 6.0 mmol) was dissolved in acetonitrile (40 mL) solution, and BSA (1.76 mL, 7.2 mmol), the reaction system was stirred for 5 min, and then 3-1 (3.0 g, 6.0 mmol) and trimethylsilyl triflate (1.32 mL, 7.2 mmol) were added in sequence. The reaction was carried out at 25°C for 30 min and then the temperature was raised to 80°C for 3 h. Add water (100 mL) to quench the reaction, extract with ethyl acetate (100 mL Purification by chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) gave compound 3-2. MS (ESI) m/z (M+H) ⁺ = 616.1 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 8.11 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.65-7.38 (m, 9H), 7.18 (s, 1H), 6.69 (d, J = 8 Hz, 1H), 6.15-6.07 (m, 2H), 4.91-4.66 (m, 3H).

Step 2: Preparation of compound 3-3 Under argon protection, compound 3-2 (200 mg, 0.32 mmol) was added to the methanol solution of sodium methoxide (4 mL, 0.5 mol/L, 1.92 mmol). React at 25°C for 1 hour. Acetic acid was added to the reaction system to adjust the pH to 7.0, and the crude product was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to obtain compound 3-3. MS (ESI) m/z (M+H) ⁺ = 300.1 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (s, 1H), 7.66 (s, 1H), 6.18 (d, J = 4.0 Hz , 1H), 5.35 (d, J = 4.0 Hz, 1H), 5.16 (d, J = 4.0 Hz, 1H), 5.10-5.06 (m, 1H), 4.35-4.31 (m, 1H), 4.11-4.09 ( m, 1H), 4.07 (s, 3H), 3.92-3.88 (m, 1H), 3.65-3.51 (m, 2H).

Step 3: Preparation of Compound 3-4 Under argon protection, compound 3-3 (100 mg, 0.34 mmol) was dissolved in acetonitrile (10 mL), and sodium iodide (250 mg, 1.68 mmol) and trimethylsilyl iodide (0.2 mL, 1.56 mmol) were added successively. . The reaction was stirred at 25°C for 3 h, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 8/1) to obtain compound 3-4. MS (ESI) m/z (M+H) ⁺ = 286.0 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.1 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.35 (d , J = 3.2 Hz, 1H), 6.06 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 5.35-5.02 (m, 3H), 4.23 (s, 1H), 4.06-4.04 (m, 1H), 3.88 -3.86 (m, 1H), 3.62-3.51 (m, 2H).

Step 4: Preparation of Compounds 3-5 Under nitrogen protection, DMTrCl (2.57 g, 7.57 mmol) was slowly added to the solution of compound 3-4 (1.8 g, 6.31 mmol) in pyridine (10 mL), and the reaction system was stirred at 25°C for 12 h. Concentrate to dryness under reduced pressure, redissolve in ethyl acetate (50 mL), wash the organic phase with saturated brine (20 mL x 5), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is subjected to silica gel column chromatography. Purification (dichloromethane/methanol (v/v) = 20/1) gave compound 3-5. MS (ESI) m/z (M+H) ⁺ = 588.3. ¹ H NMR (400MHz, DMSO- d ₆ )12.15 (br s, 1H), 7.93 (d, J =2.9 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.32 - 7.14 (m, 8H), 6.86 (dd, J =2.0, 8.8 Hz, 4H), 6.08 (d, J =3.7 Hz, 1H), 5.50 (d, J =5.9 Hz, 1H), 5.19 (d, J =5.6 Hz, 1H), 4.34 - 4.25 (m, 1H), 4.12 (q, J =5.1 Hz, 2H), 3.99 (q, J =4.5 Hz, 1H), 3.73 ( s, 6H).

Step 5: Preparation of Compounds 3-6 Under nitrogen protection, compound 3-5 (0.85 g, 1.45 mmol) was dissolved in pyridine (8 mL), and imidazole (200 mg, 2.94 mmol) and tertiary butyldimethylsilyl chloride (265 mg, 1.76 mmol) were added successively. ), the reaction system was stirred at 25°C for 12 h. Most of the solvent was removed under reduced pressure, and the reaction solution was poured into ethyl acetate (30 mL). The organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was passed through a silica gel column. Purification by chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) gave compound 3-6. MS (ESI) m/z (M+H) ⁺ = 702.3. ¹ H NMR (400MHz, DMSO- d ₆ )12.14 (br s, 1H), 7.92 (br s, 1H), 7.39 (br s, 2H) , 7.33 - 7.21 (m, 7H), 7.13 (br s, 1H), 6.88 (br s, 4H), 6.11 (br s, 1H), 5.10 (br s, 1H), 4.40 (br d, J =4.4 Hz, 1H), 4.16 - 3.94 (m, 3H), 3.78 - 3.68 (m, 6H), 3.23 (br d, J =9.3 Hz, 1H), 0.79 - 0.70 (m, 9H), -0.03 (br d , J =2.2 Hz, 3H), -0.10 - -0.17 (m, 3H).

Step 6: Preparation of Compounds 3-7 Compound 1-6 (0.7 g, 997.36 μmol) was dissolved in tetrahydrofuran (4 mL), and 4Å molecular sieve (1 g) and tetrazole (0.45 M acetonitrile solution, 33.25 mL) were added successively, and then placed under argon protection conditions at 25 °C. Then, a solution of compound 3-6 (1.05 g, 1.20 mmol) in acetonitrile (6 mL) was added dropwise to the reaction system, and the reaction was stirred for 1 h. The reaction solution was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution (50 mL x 3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (dichloromethane/methanol (v/v) = 10/1) to obtain compound 3-7. ³¹ P NMR (162MHz, CDCl ₃ ) δ 138.84, 138.40. ¹⁹ F NMR (376MHz, CDCl ₃ ) δ -163.24, -196.85 - -198.69.

Step 7: Preparation of Compounds 3-8 At 0 °C, under argon protection, compound 3-7 (1.8 g, 1.22 mmol) was dissolved in dichloromethane (30 mL), and 4Å molecular sieve (2 g) and borane dimethyl sulfide complex (2 M in tetrahydrofuran, 2.44 mL), raise the temperature to 20 °C and stir for 30 min. The reaction was quenched with water (5 mL), diluted with dichloromethane (40 mL), filtered, the filtrate was washed with water (30 mL x 3), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 3-8 , was used directly in the next reaction without further purification.

Step 8: Preparation of Compounds 3-9 Compound 3-8 (1.6 g, 1.07 mmol) was dissolved in dichloromethane (20 mL), and 2, 2-dichloroacetic acid (1.23 g, 5.37 mmol, 5% dichloromethane solution) and triethyl were added successively Silane (14.56 g, 125.22 mmol, 20 mL) was added, and the reaction system was stirred at 25 °C for 1 h. The reaction was diluted with dichloromethane (50 mL), and the organic phase was washed with water (50 mL), saturated sodium bicarbonate solution (50 mL x 2) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to Concentrate under pressure, and the crude product is purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 9/1), and high-efficiency preparative liquid phase separation (separation conditions: Chromatographic column: Xbridge Prep OBD C18 150*30 mm 5 μm ; Mobile phase: [Water (10 mM ammonium bicarbonate)-acetonitrile]; Acetonitrile%: 45%-45%, flow rate: 25 mL/min, 8 min) to obtain compound 3-9 (HPLC retention time 3.488 min). MS (ESI) m/z (M+H) ⁺ =886.2

Step 8: Preparation of Compounds 3-10 Compound 3-9 (180 mg, 203.23 μmol) was dissolved in acetonitrile (2 mL) at 20 °C under argon protection, and 4Å molecular sieve (0.5 g) and 1H-tetrazole in acetonitrile solution (0.45 M, 0.45 M, 9.03 mL), 2-cyanoethyl N,N,N',N'-tetraisopropylphosphitediamine (91.88 mg, 304.85 μmol, 96.82 μL) was added dropwise, and the reaction system was stirred for 1 h. Filter, dilute the filtrate with ethyl acetate (30 mL), wash the organic phase with saturated sodium bicarbonate solution (20 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane/ Methanol (v/v) = 15/1) to obtain compound 3-10. ³¹ P NMR (162MHz, CD ₃ CN) δ 139.33, 138.84, 137.41, 136.85. ¹⁹ F NMR (376MHz, CD ₃ CN) δ -165.95, 166.02, -199.48 - -201.40.

Step 9: Preparation of Compound 3-11 At 0°C, under argon protection, borane dimethyl sulfide complex (2 M tetrahydrofuran solution, 243.72 μL) was added dropwise to compound 3-10 (160 mg, 162.48 μmol) and 4 A molecular sieve (200 mg). Dichloromethane (5 mL) solution was added, and the reaction system was stirred at 15 °C for 30 min. Add water (5 mL) to quench the reaction, add dichloromethane (40 mL) to dilute, filter, and wash the filtrate with water (30 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain crude product 3-11. Further purification was used directly in the next reaction.

Step 10: Preparation of compounds 3-12A, 3-12B, 3-12C, 3-12D Compound 3-11 (140 mg, 140.20 μmol) was dissolved in 30% methylamine ethanol solution (5 mL), and the reaction was stirred at 20 °C for 72 h. The reaction system was concentrated under reduced pressure, and the resulting residue was dissolved in water (10 mL), back-extracted with ethyl acetate (10 mL), and the aqueous phase was freeze-dried. The crude product was subjected to high-efficiency preparative liquid phase separation (separation conditions: chromatography column: Xbridge Prep OBD C18 150*30 mm 5 μm; mobile phase: [water (0.04% ammonia + 10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 5%-45%, flow rate: 25 mL/min, 7 min). Obtained: compound 3-12A (HPLC retention time 2.143 min); a mixture of compounds 3-12B and 3-12C (HPLC retention time 2.304 min); compound 3-12D (HPLC retention time 2.596 min).

Compound 3-12A: MS (ESI) m/z (M+H) ⁺ =789.3. ¹ H NMR (400MHz, CD ₃ OD) δ 8.74 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.59 (s, 1H), 6.40 (d, J = 15.4 Hz, 1H), 6.21 (s, 1H), 5.62 - 5.40 (m, 1H), 5.31 - 5.08 (m, 1H ), 4.55 - 4.24 (m, 6H), 4.03 - 3.97 (m, 2H), 0.99 (s, 9H), 0.83 - -0.35 (m, 12H). ³¹ P NMR (162MHz, DMSO- d ₆ ) δ 93.38 -90.01. ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -165.43, -200.43 - -200.57.

Mixture of compounds 3-12B and 3-12C: MS (ESI) m/z (M+H) ⁺ =789.3. ³¹ P NMR (162MHz, DMSO- d ₆ ) δ 93.82-90.37. ¹⁹ F NMR (376MHz, DMSO - d ₆ ) δ -164.75, -165.44, -199.67- -200.85.

Compound 3-12D: MS (ESI) m/z (M+H) ⁺ =789.3. ¹ H NMR (400MHz, CD ₃ OD) δ 8.62 (br s, 1H), 8.21 (br s, 1H), 7.86 - 7.61 (m, 1H), 7.42 (br s, 1H), 6.37 (br d, J = 16.6 Hz, 1H), 6.07 (br s, 1H), 5.58 - 5.32 (m, 1H), 5.28 - 5.08 (m , 1H), 4.59 - 4.26 (m, 6H), 4.02 - 3.80 (m, 2H), 1.07 - 0.85 (m, 9H), 0.73 - 0.05 (m, 12H). ³¹ P NMR (162MHz, DMSO- d ₆ ) δ 94.76-91.59. ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -165.15, -200.66 - -200.94.

Step 11: Preparation of Compound 3A Compound 3-12A (10 mg, 12.69 μmol) was dissolved in pyridine (1 mL), and triethylamine (73.83 mg, 729.59 μmol, 101.55 μL) and triethylamine trihydrogen fluoride salt (49.01 mg, 304.00 μmol, 49.55) were added successively. μL), the reaction temperature was raised to 50 °C and the reaction was stirred for 48 h. The system was cooled to 25 °C, then isopropoxytrimethylsilane (193.01 mg, 1.46 mmol, 259.08 μL) was added, and the reaction system was stirred at 25 °C for 4 h. Concentrate under reduced pressure, dissolve the residue in water (3 mL), back-extract with ethyl acetate (3 mL), collect the aqueous phase, and perform high-efficiency preparative liquid phase separation (separation conditions: Chromatographic column: Xbridge Prep OBD C18 150*30 mm 5 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 0 % - 30 %, flow rate: 25 mL/min, 7 min). Compound 3A was obtained. MS (ESI) m/z (MH) ⁺ =672.8. ¹ H NMR (400MHz, D ₂ O) δ 8.23 (br s, 1H), 7.95 (br s, 1H), 7.77 (br s, 1H), 7.08 (br s, 1H), 6.23 (br d, J = 16.1 Hz, 1H), 6.05 (br s, 1H), 5.64 - 5.36 (m, 1H), 5.01 - 4.74 (m, 1H), 4.57 (br s , 1H), 4.44 - 4.30 (m, 2H), 4.20 (br d, J = 8.8 Hz, 1H), 4.15 - 4.03 (m, 2H), 3.84 (t, J = 12.2 Hz, 2H), 0.02 (br s, 6H). ³¹ P NMR (162MHz, D ₂ O) δ 94.63-92.15. ¹⁹ F NMR (376MHz, D ₂ O) δ -165.60, -203.17 - -203.42.

Step 12: Preparation of Compounds 3B and 3C The mixture of compounds 3-12B and 3-12C (20 mg, 24.32 μmol, 2NH ₄ ⁺ ) was dissolved in pyridine (1 mL), and triethylamine (147.65 mg, 1.46 mmol, 203.10 μL) and triethylamine triethylamine were added successively. Hydrogen fluoride salt (117.62 mg, 729.59 μmol, 118.92 μL) was heated to 50 °C and stirred for 48 h. The system was cooled to 25 °C, then isopropoxytrimethylsilane (386.03 mg, 2.92 mmol, 518.16 μL) was added, and the reaction system was stirred at 25 °C for 4 h. Concentrate under reduced pressure, dissolve the residue in water (3 mL), back-extract with ethyl acetate (3 mL), collect the aqueous phase, and perform high-efficiency preparative liquid phase separation (separation conditions: Chromatographic column: Xbridge Prep OBD C18 150*30 mm 5 μm; mobile phase: [water (0.04% ammonia + 10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 0% - 30%, flow rate: 25 mL/min, 7 min). Compound 3B (HPLC retention time 6.24 min) and compound 3C (HPLC retention time 6.27 min) were obtained.

Compound 3B: MS (ESI) m/z (MH) ^- =672.9. ¹ H NMR (400MHz, D ₂ O) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.25 (d, J = 16.6 Hz, 1H), 6.07 (s, 1H), 5.42 - 5.17 (m, 1H), 5.14 - 4.97 (m, 1H), 4.64 - 4.58 (m, 1H), 4.36 - 4.26 (m, 2H), 4.13 (br d, J = 10.0 Hz, 3H), 3.86 (dd, J = 5.3, 12.0 Hz, 1H), 3.78 (br dd, J = 5.1, 11.2 Hz, 1H), 0.00 (br s, 3H), -0.17 (br s, 3H). ³¹ P NMR (162MHz, D ₂ O) δ 94.34-93.23. ¹⁹ F NMR (376MHz, D ₂ O) δ -164.48, -201.40.

Compound 3C: MS (ESI) m/z (MH) ^- =672.9. ¹ H NMR (400MHz, D ₂ O) δ 8.30 (br s, 1H), 8.05 (br s, 1H), 7.77 (br s, 1H ), 7.12 (br s, 1H), 6.27 (br d, J = 15.4 Hz, 1H), 6.09 (br s, 1H), 5.62 - 5.23 (m, 1H), 4.92 - 4.69 (m, 3H), 4.40 - 4.23 (m, 3H), 4.18 (br d, J = 9.0 Hz, 1H), 4.07 (br d, J = 11.7 Hz, 1H), 3.86 (br d, J = 8.3 Hz, 2H), 0.06 (br s, 6H). ³¹ P NMR (162MHz, D ₂ O) δ 93.82-89.83. ¹⁹ F NMR (376MHz, D ₂ O) δ -165.87, -202.61 - -203.31.

Step 13: Preparation of Compound 3D Compound 3-12D (10 mg, 12.16 μmol, 2NH ₄ ⁺ ) was dissolved in pyridine (1 mL), and triethylamine (73.83 mg, 729.59 μmol, 101.55 μL) and triethylamine trifluoride salt (49.01 mg, 304.00 μmol, 49.55 μL), the reaction temperature was raised to 50 °C and the reaction was stirred for 48 h. The system was cooled to 25 °C, then isopropoxytrimethylsilane (193.01 mg, 1.46 mmol, 259.08 μL) was added, and the reaction system was stirred at 25 °C for 4 h. Concentrate under reduced pressure, dissolve the residue in water (3 mL), back-extract with ethyl acetate (3 mL), collect the aqueous phase, and perform high-efficiency preparative liquid phase separation (separation conditions: Chromatographic column: Xbridge Prep OBD C18 150*30 mm 5 μm; mobile phase: [water (0.04% ammonia + 10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 0% - 30%, flow rate: 25 mL/min, 7 min). Obtain compound 3D. MS (ESI) m/z (MH) ^- =672.8. ¹ H NMR (400MHz, D ₂ O) δ 8.30 (br s, 1H), 8.12 (br s, 1H), 7.69 (br s, 1H), 7.15 (br s, 1H), 6.29 (br dd, J = 3.3, 16.1 Hz, 1H), 6.04 (br d, J = 7.0 Hz, 1H), 5.76 - 5.50 (m, 1H), 5.24 - 5.09 (m, 1H), 4.97 - 4.92 (m, 1H), 4.49 - 4.43 (m, 2H), 4.40 (br d, J = 12.0 Hz, 1H), 4.31 (br d, J = 8.0 Hz, 2H), 4.02 - 3.85 (m, 2H), 0.29 (br s, 6H). ³¹ P NMR (162MHz, D ₂ O) δ 94.73-93.43. ¹⁹ F NMR (376MHz, D ₂ O) δ -164.94, -201.79.

Example 4: Preparation of Compounds 4A, 4B, 4C, and 4D

Step 1: Preparation of compound 4-1 Under argon protection, compound 2-2 (2.3 g, 1.59 mmol) was dissolved in pyridine at 15 °C, then DDTT (976.77 mg, 4.76 mmol) was added, and the reaction system was stirred for 2 h. The obtained brown reaction liquid was diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate solution (50 x 3 mL) and saturated brine in sequence, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 ~ 1/4) to obtain compound 4-1. MS (ESI) m/z (M/2+H) ⁺ =742.1

Step 2: Preparation of compound 4-2 Compound 4-1 (2 g, 1.21 mmol) was added to a mixed solution of 80% acetic acid (36 mL) and acetonitrile (10 mL), and the reaction was stirred for 20 h at 40 °C. The reaction solution was added with ethyl acetate (300 mL). Dilute, carefully add saturated sodium bicarbonate solution to adjust the pH to 9.0, separate the organic phase, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is slurried with ethyl acetate (10 mL) and filtered. , the filter cake was washed with ethyl acetate (2 x 2mL), and dried under vacuum to obtain compound 4-2. MS (ESI) m/z (M+H) ⁺ =878.3. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.74-8.25 (m, 4H), 8.08-8.02 (m, 5H), 7.57-7.48 ( m, 7H), 6.44-6.37 (m, 2H), 5.82-5.69 (m, 1H), 5.56-5.51 (m, 2H), 5.05-4.95 (m, 1H), 4.55-4.43 (m, 2H), 4.35-4.25 (m, 4H), 3.84-3.64 (m, 2H), 2.88-2.84 (m, 2H). ³¹ P NMR (162MHz, DMSO- d ₆ ) δ 69.59- 67.63 ¹⁹ F NMR (376MHz, DMSO- d ₆ ) δ -203 - -207

Step 3: Preparation of compound 4-3 Compound 4-2 (400 mg, 455.70 μmol) was dissolved in acetonitrile (2 mL), 4 A molecular sieve (0.3 g) and tetrazole (0.45 M acetonitrile solution, 10.13 mL) were added successively, and the resulting reaction mixture was purged with argon gas. Bubble for 4 min, then add dropwise 2-cyanoethyl N,N,N',N'-tetraisopropylphosphitediamine (206.03 mg, 683.55 μmol), and stir the reaction system for 1 h. Dilute with ethyl acetate (60 mL) and filter, wash the organic phase with saturated sodium bicarbonate (20 mL 3. MS (ESI) m/z (M+H) ⁺ =977.2.

Step 4: Preparation of compound 4-4 Compound 4-3 (0.43 g, 440.21 μmol) was dissolved in dichloromethane (30 mL). The resulting mixture was bubbled with argon gas for 4 min, stirred at 15 °C for 10 min, then cooled to 0 °C, and borane dimethyl sulfide was added dropwise. After the ether complex (2 M tetrahydrofuran solution, 660.32 μL) was added, the reaction system was heated to 15 °C and stirred for 30 min. Add water (20 mL) to quench the reaction, add dichloromethane (50 mL) to dilute, stir at room temperature for 30 min, and separate the liquids. Wash the organic phase with saturated brine (10 mL), dry over anhydrous magnesium sulfate, filter, and decompress the filtrate. Concentrate to obtain crude product 4-4, which is directly used in the next reaction without further purification.

Step 5: Preparation of Compound 4-5 Compound 4-4 (420 mg, 423.97 μmol) was dissolved in a mixed solution of ethanol (3 mL) and acetonitrile (3 mL), tertiary butylamine (6 mL) was added, and the reaction was stirred at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain crude product 4-5, which was directly used in the next reaction without further purification.

Step 6: Preparation of Compounds 4A, 4B, 4C and 4D Compound 4-5 (350 mg, 395.70 μmol) was dissolved in 30% methylamine ethanol solution (40 mL), and the reaction was stirred at room temperature for 24 h. The reaction system was concentrated under reduced pressure, the residue was dissolved in water (10 mL), and back-extracted with ethyl acetate (5 mL 150*30 mm 10 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 0% - 30%, flow rate: 25 mL/min, 20 min). Obtain: Compound 4A (HPLC retention time 5.4 min); Compound 4B (HPLC retention time 5.9 min); Compound 4C (HPLC retention time 6.7 min); Compound 4D (HPLC retention time 7.4 min).

Compound 4A: MS (ESI) m/z (M+H) ⁺ =677.2. ¹ H NMR (400 MHz, D ₂ O) δ 8.36 (s, 1H), 8.27 (s, 1H), 7.96 (s, 1H ), 7.91 (s, 1H), 6.29-6.23 (m, 2H), 5.80 (d, J = 51.2 Hz, 1H), 5.45 (d, J = 51.2 Hz,1H), 4.85-4.72 (m, 2H) , 4.38-4.32 (m, 2H), 4.24-4.15 (m, 1H), 3.91-3.87 (m, 2H), 0.50- -0.20 (br, 3H). ³¹ P NMR (162MHz, D ₂ O) δ 96.2 -91.9, 54.5. ¹⁹ F NMR (376MHz, D ₂ O) δ -202.7- -203.0.

Compound 4B: MS (ESI) m/z (M+H) ⁺ =677.2. ¹ H NMR (400 MHz, D ₂ O) δ 8.01 (s, 1H), 7.98 (s, 1H), 7.86 (br s, 1H), 7.46 (br s, 1H), 6.37 (d, J = 13.6 Hz, 1H), 6.16 (d, J = 14.0 Hz, 1H), 5.38-5.07 (m, 2H), 4.42-4.32 (m, 2H), 4.32-4.25 (m, 1H), 4.25 -4.18 (m, 1H), 3.87-3.79 (m, 2H), 0.25- -0.30 (br, 3H). ³¹ P NMR (162MHz, D ₂ O) δ 94.7 - 91.5, 54.062. ¹⁹ F NMR (376MHz, D ₂ O) δ -202.5- -204.1.

Compound 4C: MS (ESI) m/z (M+H) ⁺ =677.2. ¹ H NMR (400 MHz, D ₂ O) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H ), 7.75 (s, 1H), 6.16-6.08 (m, 2H), 5.81 (d, J = 50.8 Hz, 1H), 5.40 (d, J = 51.2 Hz, 1H), 5.03-4.81 (m, 2H) , 4.38-4.28 (m, 4H), 3.96-3.88 (m, 2H), 0.50- -0.20 (br, 3H). ³¹ P NMR (162MHz, D ₂ O) δ 94.3 - 91.1, 54.033. ¹⁹ F NMR ( 376MHz, D ₂ O) δ -201.377- -202.447.

Compound 4D: MS (ESI) m/z (M+H) ⁺ =677.1. ¹ H NMR (400 MHz, D ₂ O) δ 8.01 (s, 1H), 7.92 (s, 2H), 7.77 (s, 2H ), 6.19-6.16 (m, 2H), 5.31-5.18 (m, 2H), 4.81-4.72 (m, 2H), 4.38-4.27 (m, 4H), 3.85-3.77 (m, 2H), 0.50- - 0.10 (br, 3H). ³¹ P NMR (162MHz, D ₂ O) δ 94.8 - 91.5, 54.011. ¹⁹ F NMR (376MHz, D ₂ O) δ -202.724- -202.889.

Example 5: Preparation of compounds 5A, 5B, 5C, 5D

Step 1: Preparation of compound 5-2 Compound 5-1 (20 g, 76.84 mmol) was dissolved in acetonitrile (300 mL) at 0 °C, sodium hydride (4.61 g, 115.26 mmol, 60%) was added, and after stirring for 0.5 h, benzyl bromide (13.14 g, 76.84 mmol), raised the temperature to 20 °C and stirred for 3 h. Methanol was added to quench the reaction, and water (100 mL) and ethyl acetate (150 mL) were added simultaneously. The organic phase was separated, dried over anhydrous sodium sulfate, the solid was filtered off, the filtrate was concentrated, and the crude product was slurried with petroleum ether, and the solid was separated to obtain Compound 5-2. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.41 - 7.30 (m, 5H), 5.74 (d, J = 3.8 Hz, 1H), 4.76 (d, J = 11.8 Hz, 1H), 4.60 - 4.55 (m, 2H ), 4.35 (dt, J = 3.2, 7.0 Hz, 1H), 4.13 (dd, J = 3.2, 8.8 Hz, 1H), 4.02 - 3.92 (m, 2H), 3.87 (dd, J = 4.6, 8.8 Hz, 1H), 1.58 (s, 3H), 1.37 (s, 3H), 1.35 (d, J = 4.4 Hz, 6H).

Step 2: Preparation of compound 5-3 Compound 5-2 (51 g, 145.55 mmol) was dissolved in water (42 mL) and acetic acid (179.55 g, 2.99 mol, 171 mL), and the reaction was stirred at 20 °C for 72 h. The reaction solution was neutralized with 1.0 M sodium hydroxide solution, extracted with ethyl acetate (300 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was concentrated to obtain crude product 5-3 without further purification. used directly for the next reaction. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.40 - 7.32 (m, 5H), 5.74 (d, J = 3.8 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.59 (t, J = 4.0 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H), 4.14 - 4.06 (m, 2H), 3.91 (dd, J = 8.8, 4.4 Hz, 1H), 3.72 - 3.61 (m, 2H), 2.56 (br s, 2H), 1.57 (s, 3H), 1.34 (s, 3H).

Step 3: Preparation of compound 5-4 A solution of compound 5-3 (20 g, 64.45 mmol) in water (200 mL) was added to a solution of sodium periodate (15.99 g, 74.76 mmol) in water (100 mL), and the reaction was stirred at 0 °C for 1 h. Then add ethylene glycol (2.60 g, 41.89 mmol, 2.34 mL) and continue stirring for 20 min. The reaction solution was extracted with ethyl acetate (170 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated. The crude product 5-4 was obtained, which was directly used in the next reaction without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 9.60 (d, J = 1.8 Hz, 1H), 7.35 - 7.32 (m, 5H), 5.80 (d, J = 3.6 Hz, 1H), 4.76 - 4.70 (m, 1H ), 4.65 - 4.60 (m, 1H), 4.58 (t, J = 3.8 Hz, 1H), 4.47 (dd, J = 9.0, 1.6 Hz, 1H), 3.83 (dd, J = 9.4, 4.4Hz, 1H) , 1.59 (s, 3H), 1.36 (s, 3H).

Step 4: Preparation of Compound 5-5 Compound 5-4 (17.94 g, 64.46 mmol) was dissolved in dioxane (45 mL) and water (40 mL) at 0 °C, and formalin (36 mL, 483.54 mmol, 37% aqueous solution) and Sodium hydroxide (1 M aqueous solution, 176 mL) was heated to 20 °C and stirred for 48 h. The reaction solution was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solid was filtered off, and the filtrate was concentrated to obtain crude product 5-5, which was used directly in the next reaction without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.38 - 7.31 (m, 5H), 5.78 - 5.72 (m, 1H), 4.83 - 4.76 (m, 1H), 4.66 - 4.61 (m, 1H), 4.55 (d, J = 11.7 Hz, 1H), 4.22 - 4.16 (m, 1H), 3.95 - 3.85 (m, 2H), 3.80 - 3.74 (m, 1H), 3.62 - 3.50 (m, 1H), 2.37 (t, J = 6.9 Hz, 1H), 1.88 (dd, J = 3.7, 9.6 Hz, 1H), 1.62 (s, 3H), 1.32 (s, 3H).

Step 5: Preparation of Compounds 5-6 Compound 5-5 (19 g, 61.22 mmol) was dissolved in diisopropyl ether (350 mL), lipase Novozyme-435 (1.5 g, 61.22 mmol) and vinyl acetate (5.27 g, 61.22 mmol, 5.67 mL) were added , the reaction was heated to 50°C and stirred for 16 h. The reaction mixture was extracted with ethyl acetate (200 mL = 1/0 ~ 0/1), compound 5-6 is obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.34 (m, 5H), 5.75 (d, J = 4.0 Hz, 1H), 4.80 (d, J = 11.8 Hz, 1H), 4.65 (t, J = 4.6 Hz, 1H), 4.51 (d, J = 11.8 Hz, 1H), 4.25 (d, J = 11.8 Hz, 1H), 4.12 - 4.06 (m, 1H), 4.00 (d, J = 5.4 Hz, 1H), 3.93 ( br d, J = 6.8 Hz, 2H), 2.36 (t, J = 6.8 Hz, 1H), 2.01 - 1.97 (m, 3H), 1.62 (s, 3H), 1.33 (s, 3H).

Step 6: Preparation of Compounds 5-7 Compound 5-6 (5 g, 14.19 mmol) was dissolved in pyridine (21 mL) and dichloromethane (83 mL), p-toluenesulfonyl chloride (2.98 g, 15.61 mmol) was added, and the reaction was stirred at 15 °C for 24 h. . The reaction solution was quenched with 10% hydrochloric acid solution, extracted with dichloromethane (40 mL Ethyl acetate (v/v) = 1/0 ~ 1/1) to obtain compound 5-7. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.79 (br d, J = 7.9 Hz, 2H), 7.37 - 7.30 (m, 7H), 5.68 (d, J = 3.6 Hz, 1H), 4.69 (br d, J = 12.1 Hz, 1H), 4.56 (br t, J = 4.2 Hz, 1H), 4.54 - 4.45 (m, 2H), 4.33 (d, J = 10.6 Hz, 1H), 4.16 (d, J = 11.8 Hz, 1H), 4.12 - 4.08 (m, 1H), 4.00 - 3.93 (m, 2H), 2.41 (s, 3H), 1.89 (s, 3H), 1.34 (s,3H), 1.26 (s, 3H).

Step 7: Preparation of Compounds 5-8 Compound 5-7 (20 g, 40.61 mmol) was dissolved in acetic acid (200 mL) at 0 °C, acetic anhydride (38.03 mL, 406.06 mmol) and sulfuric acid (216.44 μL, 4.06 mmol) were added, and the reaction was heated to 20 °C. Stir the reaction for 6 h. The reaction solution was poured into water (600 mL), neutralized with sodium hydroxide solution to pH = 7, extracted with ethyl acetate (200 mL x 3), combined organic phases, washed with saturated brine (200 mL), and anhydrous sodium sulfate Dry, filter out the solid, and concentrate the filtrate to obtain crude product 5-8, which is directly used in the next step of reaction without further purification.

Step 8: Preparation of Compounds 5-9 Compound N-(5H-purin-6-yl)benzamide (5.87 g, 24.52 mmol) was dissolved in dichloroethane (200 mL), and N,O-bistrimethylsilylacetamide (16.16 mL, 65.39 mmol), raise the temperature to 80 ℃ and stir for 0.5 h, cool to 0 ℃, then add compound 5-8 (9.0 g, 16.35 mmol) and trimethylsilyl triflate (4.73 mL, 26.15 mmol), and raise the temperature Stir the reaction at 80°C for 1 hour. The reaction solution was cooled to room temperature, poured into saturated sodium bicarbonate solution (200 mL), extracted with ethyl acetate (200 mL x 2), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 ~ 0/1) to obtain compound 5-9. MS (ESI) m/z (M+H) ⁺ =730.3.

Step 9: Preparation of Compounds 5-10 Compound 5-9 (11 g, 10.85 mmol) was dissolved in water (24 mL) and dioxane (24 mL), and ammonia (33.44 mL, 217.06 mmol, 25-28%) and 2.0 M sodium hydroxide aqueous solution ( 31.68 mL), and the reaction was stirred at 25 °C for 18 h. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (40 mL Analytical purification (dichloromethane/methanol (v/v) = 1/0 ~ 10/1) gave compound 5-10. MS (ESI) m/z (M+H) ⁺ =474.1.

Step 10: Preparation of Compound 5-11 Compound 5-10 (1.68 g, 3.38 mmol) was dissolved in ammonia water (19.31 mL), and the reaction was stirred at 30 °C for 24 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/0 ~ 10/1) to obtain compound 5-11. MS (ESI) m/z (M+H) ⁺ =370.2

Step 11: Preparation of Compounds 5-12 Compound 5-11 (1.4 g, 3.79 mmol) was dissolved in methanol (140 mL), palladium hydroxide/carbon (0.45 g, 640.84 μmol, 20% moisture) was added, and the reaction was stirred for 2 h under a hydrogen atmosphere at 60 °C. Then ammonium formate (1.91 g, 30.32 mmol) was added, and the reaction was continued to stir for 15 h. The reaction liquid was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to obtain crude product 5-12. It was used directly in the next reaction without further purification. ¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.22 (s, 1H), 8.14 (s, 1H), 7.32 (s, 2H), 5.89 (s, 1H), 4.55 (s, 1H), 4.40 (s , 1H), 4.25 (s, 1H), 3.93– 3.91 (m, 1H), 3.81 - 3.74 (m, 4H)

Step 12: Preparation of Compound 5-13 At 0°C, under nitrogen protection, compound 5-12 (1 g, 3.58 mmol) was dissolved in pyridine (20 mL) and N, N-dimethylformamide (10 mL), and trimethylsilyl chloride (1.97 g was added , 18.12 mmol, 2.3 mL), stir for 30 min, add benzyl chloride (968.00 mg, 6.89 mmol, 0.8 mL), and stir the reaction at 20 °C for 3 h. The reaction solution was quenched with water (10 mL) and ammonia (10 mL), stirred for 30 min, and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was filtered through silica gel Purification by column chromatography (ethyl acetate/methanol (v/v) = 20/3) gave compound 5-13. MS (ESI) m/z (M+H) ⁺ =384.0 ¹ H NMR (400MHz, CDCl ₃ ) δ 9.24 (br s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 7.99 (br d, J = 7.5 Hz, 2H), 7.65 - 7.59 (m, 1H), 7.52 (t, J = 7.5 Hz, 2H), 6.12 (s, 1H), 4.68 - 4.62 (m, 2H), 4.09 - 4.05 (m, 1H), 3.99 (s, 2H), 3.89 (d, J = 8.0 Hz, 1H).

Step 13: Preparation of Compounds 5-14 Under argon protection at 20°C, compound 5-13 (500 mg, 1.30 mmol) was dissolved in pyridine (10 mL), DMTrCl (530 mg, 1.56 mmol) was added, stirred for 16 h, and the reaction solution was added with methanol (10 mL) Quench and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1 ~ 10/1) to obtain compound 5-14. MS (ESI) m/z (M+H) ⁺ =686.2

Step 14: Preparation of Compounds 5-15 Under argon protection at 20°C, compound 5-14 (500 mg, 729.16 μmol), tetrazole (0.45 M acetonitrile solution, 25.00 mL) and 4Å molecular sieve were dispersed in acetonitrile (4 mL), and compound 1- was added 6 (836.68 mg, 955.20 μmol) in acetonitrile (2 mL). The reaction was stirred for 1 h. The reaction solution was filtered off with molecular sieves and diluted with ethyl acetate (50 mL). The organic phase was sequentially diluted with saturated sodium bicarbonate aqueous solution (50 mL x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 100/3) to obtain Compounds 5-15. MS (ESI) m/z (M/2+H) ⁺ =731.0.

Step 15: Preparation of Compounds 5-16 At 0°C, under argon protection, compound 5-15 (1.3 g, 890.13 μmol) and 4Å molecular sieve (300 mg) were dispersed in dichloromethane (30 mL), and borane dimethyl sulfide (2 M) was added dropwise. Tetrahydrofuran solution, 1.34 mL), and the reaction was stirred at 0°C for 15 min. The reaction solution was diluted with dichloromethane (50 mL), and the molecular sieve was filtered off. The filtrate was washed with water (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was passed through a silica gel column. Analysis and purification (dichloromethane/ethyl acetate (v/v) = 1/1) gave compound 5-16.

Step 16: Preparation of Compound 5-17 Compound 5-16 (850 mg, 576.55 μmol) was dissolved in dichloromethane (10 mL), 2, 2-dichloroacetic acid in dichloromethane (10.53 g, 2.31 mmol, 2 mL, 5%) was added, and the reaction was stirred 0.5 h, add dichloromethane (50 mL) to dilute, wash the organic phase with saturated sodium bicarbonate solution (20 mL /methanol (v/v) = 10/1) was separated and purified to obtain compound 5-17. MS (ESI) m/z (M-14+H) ⁺ =856.4.

Step 17: Preparation of Compound 5-18 Compound 5-17 (400 mg, 467.44 μmol), 4Å molecular sieve (1 g) and tetrazole (0.45 M acetonitrile solution, 16 mL) were dispersed in acetonitrile (2 mL) and tetrahydrofuran under argon protection at 20 °C. (3 mL), add dropwise a solution of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphitediamine (189.80 mg, 629.71 μmol, 0.2 mL) in acetonitrile (0.5 mL), Stir the reaction for 1 h. The reaction solution was filtered off the molecular sieve, the filtrate was diluted with ethyl acetate (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to Concentrate under pressure, and the crude product is separated and purified by thin layer chromatography (dichloromethane/methanol (v/v) = 15/1) to obtain compound 5-18.

Step 18: Preparation of Compound 5-19 At 0°C, under argon protection, compound 5-18 (230 mg, 237.46 μmol) and 4Å molecular sieve (100 mg) were dispersed in tetrahydrofuran (3 mL) and dichloromethane (2 mL), and borane dimethyl was added dropwise. thioether (2 M solution in tetrahydrofuran, 460.00 μL), the reaction was heated to 15°C and stirred for 10 min. The reaction solution was diluted with dichloromethane (20 mL) and filtered. The filtrate was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product 5-19, which was used directly in the next reaction without further purification.

Step 19: Preparation of Compounds 5A, 5B, 5C and 5D Compound 5-19 (200 mg, 203.58 μmol) was dissolved in an aqueous solution of methylamine (10 mL, 33%), stirred at 20°C for 24 h, the reaction solution was extracted with ethyl acetate (30 mL), and the aqueous phase was lyophilized to obtain the crude product After high-efficiency preparative liquid phase separation (separation conditions: chromatographic column: Xbridge Prep OBD C18 150*40 mm10 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 0% - 20%, flow rate: 25 mL/min, 25 min). Obtain: Compound 5A (HPLC retention time 5.59 min); Compound 5B (HPLC retention time 5.87 min); Compound 5C (HPLC retention time 6.16 min); Compound 5D (HPLC retention time 7.44 min).

Compound 5A: MS (ESI) m/z (MH) ^- =666.8 ¹ H NMR (400MHz, D ₂ O) δ 8.11 (s, 2H), 8.02 (s, 1H), 7.99 (s, 1H), 6.27 ( d, J = 16.1 Hz, 1H), 6.01 (s, 1H), 5.58 - 5.42 (m, 1H), 4.84 - 4.72 (m, 1H), 4.67 (br s, 1H), 4.46 (br d, J = 10.5 Hz, 1H), 4.35 (br d, J = 9.0 Hz, 1H), 4.20 - 4.10 (m, 2H), 4.07 - 3.88 (m, 4H), 0.52 - -0.57 (m, 6H). ¹⁹ F NMR (376MHz, D ₂ O) -202.51 - -202.65. ³¹ P NMR (162MHz, D ₂ O) δ 94.12 - 90.98.

Compound 5B: MS (ESI) m/z (MH) ^- =667.1 ¹ H NMR (400MHz, D ₂ O) δ 8.26 (s, 1H), 8.15 - 8.09 (m, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 6.30 (d, J = 16.4 Hz, 1H), 6.05 (s, 1H), 5.48 - 5.42 (m, 0.5H), 5.33 (br s, 0.5H), 5.02 - 4.86 (m , 1H), 4.75 (s, 1H), 4.51 (br d, J = 10.5 Hz, 1H), 4.33 (br d, J = 9.0 Hz, 1H), 4.23 (br d, J = 12.0 Hz, 1H), 4.15 (br d, J = 12.2 Hz, 1H), 4.04 (br d, J = 5.4 Hz, 1H), 3.95 - 4.02 (m, 2H), 3.91 (d, J = 8.1 Hz, 1H), 0.46 - - 0.33 (m, 6H). ¹⁹ F NMR (376MHz, D ₂ O) -201.02 - -201.20. ³¹ P NMR (162MHz, D ₂ O) δ 94.86 - 93.72.

Compound 5C: MS (ESI) m/z (MH) ^- =666.8. ¹ H NMR (400MHz, D ₂ O) δ 8.40 (s, 1H), 7.89 (s, 1H), 7.82 (br s, 1H), 7.75 (br s, 1H), 6.29 (br d, J = 13.7 Hz, 1H), 6.02 (s, 1H), 5.59 - 5.23 (m, 1H), 4.73 (br s, 1H), 4.71 - 4.68 (m , 2H), 4.39 - 4.28 (m, 2H), 4.21 - 4.08 (m, 1H), 4.07 - 3.90 (m, 3H), 3.88 (br d, J = 7.3 Hz, 1H), 0.18 (br s, 6H ). ¹⁹ F NMR (376MHz, D ₂ O) -204.17 - -204.48. ³¹ P NMR (162MHz, D ₂ O) δ 96.82 - 89.33.

Compound 5D: MS (ESI) m/z (MH) ^- =666.8. ¹ H NMR (400MHz, D ₂ O) δ 8.45 (s, 1H), 8.32 (s, 1H), 8.07 (br s, 1H), 8.05 (br s, 1H), 6.46 (d, J = 14.7 Hz, 1H), 6.17 (s, 1H), 5.64 - 5.39 (m, 1H), 5.18 - 5.05 (m, 1H), 4.98 (br d, J = 8.8 Hz, 1H), 4.90 (s, 1H), 4.53 - 4.36 (m, 3H), 4.19 - 4.14 (m, 2H), 4.10 (br dd, J = 5.6, 12.0 Hz, 1H), 4.02 ( br d, J = 8.1 Hz, 1H), 0.61 - 0.11 (m, 6H). ¹⁹ F NMR (376MHz, D ₂ O) -201.73 - -202.52. ³¹ P NMR (162MHz, D ₂ O) δ 95.28 - 93.68 .

Example 6: Preparation of compounds 6A, 6B, 6C, 6D

Step 1: Preparation of compound 6-1 At 20°C, compound D -arabinose (25 g, 166.5 mmol) was dissolved in DMF (250 mL), imidazole (17 g, 249.8 mmol) and tertiary butyldiphenylchlorosilane (45.8 g, 166.5 mmol) and stir for 2 h. The solution was poured into water (2.5 L), extracted with ethyl acetate (1000 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 6-1, which was used directly in the next reaction without further purification. MS (ESI) m/z (M+Na) ⁺ = 411.2.

Step 2: Preparation of compound 6-2 Compound 6-1 (17.5 g, 45.0 mmol) was dissolved in anhydrous acetone (150 mL, 2.04 mol), anhydrous copper sulfate (20 g, 125.3 mmol) and sulfuric acid (0.8 mL, 98%) were added successively, and the reaction mixture was stirred at 20 °C and stirred for 17 h. Filtration, the filtrate was neutralized with calcium hydroxide, filtered again, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 ~ 7/3) to obtain compound 6 -2. MS (ESI) m/z (M+Na) ⁺ = 451.2. ¹ H NMR (400MHz, CDCl ₃ )7.70 - 7.65 (m, 4H), 7.45 - 7.37 (m, 6H), 5.89 (d, J =4.2 Hz, 1H), 4.56 (d, J =4.2 Hz, 1H), 4.45-4.44 (m, 1H), 4.09 - 4.04 (m, 1H), 3.85 - 3.81 (m, 2H), 1.33 (s, 3H) , 1.30 (s, 3H), 1.07 (s, 9H).

Step 3: Preparation of compound 6-3 Under nitrogen protection, compound 6-2 (27 g, 63.0 mmol) was dissolved in tetrahydrofuran (300 mL), benzyl bromide (44 mL, 370.8 mmol) and potassium hydroxide (31.8 g, 565.9 mmol) were added successively, and the reaction mixture was Heat to 70°C and stir for 17 h. Cool to room temperature, filter, wash the filter residue with tetrahydrofuran (20mL ), compound 6-3 was obtained. MS (ESI) m/z (M+Na) ⁺ = 393.1. ¹ H NMR (400MHz, CDCl ₃ )7.38 - 7.28 (m, 10H), 5.92 (d, J =3.9 Hz, 1H), 4.66 (d, J =4.2 Hz, 1H), 4.62 - 4.55 (m, 4H), 4.29-4.28 (m, 1H), 4.04 (d, J =2.9 Hz, 1H), 3.65 (d, J =6.1 Hz, 2H), 1.45 (s, 3H), 1.33 (s, 3H).

Step 4: Preparation of compound 6-4 Compound 6-3 (33.5 g, 90.4 mmol) was dissolved in methanol (250 mL), D -camphorsulfonic acid (0.1 g, 399.5 μmol) was added, and the reaction mixture was heated to 70°C and stirred for 12 h. Cool to room temperature, add 30 drops of triethylamine, and concentrate the reaction solution under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 ~ 7/3) to obtain the compound 6-4. MS (ESI) m/z (M+Na) ⁺ = 367.0. ¹ H NMR (400MHz, CDCl ₃ )7.39 - 7.23 (m, 10H), 4.92 (s, 0.6H), 4.87 (d, J = 4.6 Hz , 0.4H), 4.79 - 4.44 (m, 4H), 4.28 (q, J = 2.2 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.89 - 3.82 (m, 1H), 3.66-3.65 (m, 0.6H), 3.54 (d, J = 5.6 Hz, 0.7H), 3.45-3.44 (m,0.4H), 3.44 - 3.41 (s, 3H), 3.37-3.36 (m, 0.6H), 2.61 - 2.59 ( m, 0.3H).

Step 5: Preparation of compound 6-5 Compound 6-4 (1.24 g, 3.6 mmol) was dissolved in dichloromethane (40 mL) at 0°C, and pyridine (2.7 mL 33.5 mmol) and trifluoromethanesulfonic anhydride (0.8 mL, 4.9 mmol) were added successively, 20 After 1 min, add water (10 mL) to quench the reaction, separate the liquids, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. Dissolve the crude product in tetrahydrofuran (25 mL), cool to 0°C, and add tetrabutyl to the system. Ammonium fluoride (1 M solution in tetrahydrofuran, 18 mL), heated to 20°C and stirred for 12 h, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/ 0 ~ 9/1), compound 6-5 was obtained. MS (ESI) m/z (M+Na) ⁺ = 369.2. ¹ H NMR (400MHz, CDCl ₃ )7.40 - 7.28 (m, 10H), 5.05 - 4.99 (m, 1H), 4.74 - 4.47 (m, 5H ), 4.32 (m, 1H), 4.16 - 4.04 (m, 1H), 3.69 - 3.63 (m, 1H), 3.58 - 3.51 (m, 1H), 3.34 (s, 3H). ¹⁹ F NMR (376MHz, CDCl ₃ ) -209.4.

Step 6: Preparation of compound 6-6 Compound 6-5 (8.4 g, 24.2 mmol) was dissolved in trifluoroacetic acid (90 mL, 1.2 mol) and water (10 mL, 555.1 mmol) at 20°C. After stirring for 12 h, water (150 mL) and Dichloromethane (200 mL) was added to the solution. The aqueous phase was adjusted to pH = 7.0 with 10 M sodium hydroxide. The organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined and washed with Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 ~ 7/3) to obtain compound 6-6. MS (ESI) m/z (M+Na) ⁺ = 355.0. ¹⁹ F NMR (376MHz, CDCl ₃ ) -206.8.

Step 7: Preparation of Compounds 6-7 - 50°C, under argon protection, compound 6-6 (5.9 g, 17.8 mmol) and carbon tetrachloride (7.7 mL 80.3 mmol) were dissolved in toluene (70 mL), and tris(dimethylamino) was added dropwise A solution of phosphine (3.49 g, 21.41 mmol, 3.89 mL) in toluene (5 mL) was heated to 0°C and stirred for 3 h, then cooled to -20°C, cold toluene (30 mL) was added to dilute, and cold saturated solution was added dropwise. The reaction was quenched with brine (30 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 6-7, which was used directly in the next reaction without further purification. MS (ESI) m/z (M+NH ₄ ) ⁺ = 369.1. ¹ H NMR (400MHz, CDCl ₃ )7.27-7.26 (m, 10H), 6.30- 6.29 (m, 1H), 5.16 - 4.95 (m, 1H), 4.89- 4.85 (m, 1H), 4.72- 4.43 (m, 4H), 4.12- 4.11 (m, 1H), 3.80 - 3.50 (m, 2H). ¹⁹ F NMR (376MHz, CDCl ₃ ) -200.5 - -200.6.

Step 8: Preparation of Compounds 6-8 At 20°C, under argon protection, compound 6-7 (6.5 g, 18.5 mmol) and 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (3.2 g, 18.5 mmol) were dissolved in To acetonitrile (100 mL), potassium hydroxide (3.1 g, 55.6 mmol) and tris(3, 6-dioxaheptyl)amine (599.3 mg, 1.9 mmol) were added in sequence. After stirring for 12 h, the reaction solution was concentrated. , the crude product was dissolved in ethyl acetate (150 mL) and water (60 mL), separated, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Concentrate, and the crude product is purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1/0 ~ 4/1) to obtain compound 6-8. MS (ESI) m/z (M+H) ⁺ = 486.1. ¹ H NMR (400MHz, CDCl ₃ )8.61 (s, 1H), 7.41 - 7.30 (m, 11H), 6.67- 6.60 (m, 1H), 4.81 - 4.74 (m, 1H), 4.65 - 4.50 (m, 4H), 4.43 - 4.33 (m, 2H), 3.92 - 3.84 (m, 1H), 3.68- 3.65 (m, 1H). ¹⁹ F NMR (376MHz , CDCl ₃ ) -165.8- -165.9, -203.8- -204.5.

Step 9: Preparation of Compounds 6-9 - 70°C, under nitrogen protection, compound 6-8 (0.1 g, 179.1 μmol) was dissolved in dichloromethane (5 mL), and boron trichloride (1 M n-heptane solution, 0.9 mL) was added dropwise. The reaction was stirred at this temperature for 1 h. Methanol (15 mL) was slowly added to quench the reaction, raised to room temperature, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/0 ~ 20/1) to obtain the compound. 6-9. ¹ H NMR (400MHz, DMSO- d ₆ )8.73 (s, 1H), 8.03 (d, J =1.5 Hz, 1H), 6.52 (d, J =15.4 Hz, 1H), 5.76 (d, J =6.1 Hz , 1H), 5.35 - 5.16 (m, 2H), 4.44 - 4.30 (m, 1H), 4.01 - 3.93 (m, 1H), 3.80 - 3.55 (m, 2H). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) -169.15, -204.15 - -204.64.

Step 10: Preparation of Compounds 6-10 Compound 6-9 (0.33 g, 1.1 mmol) was dissolved in a methanol solution of sodium methoxide (0.5 M, 16.5 mL) at 10°C, and the reaction was stirred at this temperature for 12 h. The solvent was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/0 ~ 20/1) to obtain compound 6-10. MS (ESI) m/z (M+H) ⁺ = 302.0. ¹ H NMR (400MHz, DMSO- d ₆ )8.48 (s, 1H), 7.67 (d, J =2.0 Hz, 1H), 6.50 - 6.43 ( m, 1H), 5.73 (d, J =6.0 Hz, 1H), 5.32 - 5.28 (m, 0.5H), 5.17 (t, J =5.3 Hz, 1.5H), 4.41 - 4.30 (m, 1H), 4.10 - 4.04 (m, 3H), 3.95- 3.94 (m, 1H), 3.72 - 3.70 (m, 1H), 3.60 - 3.55 (m, 1H). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) -166.9, - 204.8.

Step 11: Preparation of Compound 6-11 Under argon protection at 20°C, compound 6-10 (0.22 g, 730.3 μmol) was dissolved in acetonitrile (20 mL), and sodium iodide (547.3 mg, 3.6 mmol) and trimethylsilyl chloride (463 μL) were added successively. 3.6 mmol), and the reaction was stirred for 3 h at this temperature. Cool to 0°C, add methanol (3 mL) to quench the reaction, stir the reaction for 5 minutes, concentrate under reduced pressure to remove the solvent, and the crude product is purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/0 ~ 10/1), compound 6-11 was obtained. MS (ESI) m/z (M+H) ⁺ = 288.0. ¹ H NMR (400MHz, DMSO- d ₆ )12.19 (s, 1H), 7.96 (s, 1H), 7.35 (s, 1H), 6.34- 6.31 (m, 1H), 5.70 (br s, 1H), 5.25 - 5.18 (m, 1H), 5.11 - 5.05 (m, 1H), 4.34- 4.28 (m, 1H), 3.92 (s, 1H), 3.75 - 3.53 (m, 2H). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) -165.3, -204.8- - 205.0.

Step 12: Preparation of Compound 6-12 Under argon protection at 20°C, compound 6-11 (0.36 g, 1.25 mmol) was dissolved in pyridine (8 mL), DMTrCl (0.26 g, 767.4 μmol) was added, and the reaction was stirred at this temperature for 4 h. Methanol (3 mL) was added to quench the reaction. After stirring for 5 min, the solvent was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (60 mL). The organic phase was washed with saturated brine (15 mL x 3) and anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/0 ~ 20/1) to obtain compound 6-12. MS (ESI) m/z (M+H) ⁺ = 592.2. ¹ H NMR (400MHz, DMSO- d ₆ )12.23 (s, 1H), 7.98 (s, 1H), 7.39 - 7.18 (m, 10H), 6.86- 6.83 (m, 4H), 6.37– 6.32 (m, 1H), 5.70 (d, J =6.8 Hz, 1H), 5.36 - 5.17 (m, 1H), 4.52 - 4.40 (m, 1H), 4.09 - 4.02 (m, 1H), 3.73 (s, 6H), 3.29 - 3.19 (m, 2H). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) -165.4, -201.9.

Step 13: Preparation of Compound 6-13 Under argon protection at 20°C, compound 6-12 (0.25 g, 424.0 μmol) was dissolved in acetonitrile (5 mL), and tetrazole (0.45 M acetonitrile solution, 10 mL) and 4Å molecular sieve (0.6 g) were added successively. ), stir for 10 min, add 1-6 (0.65 g, 742.1 μmol) acetonitrile solution, continue stirring for 50 min, pour the mixture into ethyl acetate (30 mL), filter, and the filtrate is washed with saturated sodium bicarbonate in turn. Aqueous solution (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 1/0 ~ 20/1), compound 6-13 was obtained.

Step 14: Preparation of Compound 6-14 Under argon protection, compound 6-13 (0.68 g, 498.4 μmol) was dissolved in dichloromethane (5 mL) at 25 °C, 4Å molecular sieve (0.6 g) was added, and after stirring for 30 min, borane dichloride was added dropwise to the system. Methyl sulfide complex (2 M tetrahydrofuran solution, 747.63 μL) was added to the reaction system and stirred at 25 °C for 20 min. The reaction solution was diluted with dichloromethane (40 mL) and filtered. The filtrate was washed with water (10 mL) and saturated brine (10 mL) in sequence, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product 6-14. After further purification, it was directly used in the next reaction.

Step 15: Preparation of Compound 6-15 Compound 6-14 (0.73 g, 529.7 μmol) was dissolved in dichloromethane (5 mL), 2,2-dichloroacetic acid (5 mL, 2.6 mmol, 5% dichloromethane solution) was added, and the mixture was heated at 20 °C. The reaction was stirred for 30 min, triethylsilane (5 mL, 31.3 mmol) was added to the system, and the reaction was continued for 30 min. The reaction solution was poured into dichloromethane (60 mL), then washed with saturated sodium bicarbonate solution (10 mL x 2), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product Silica gel column chromatography purified (dichloromethane/methanol (v/v) = 1/0 ~ 20/1) to obtain compound 6-15. MS (ESI) m/z (M+H) ⁺ = 774.3. ¹ H NMR (400MHz, DMSO- d ₆ ) 12.26 (s, 1H), 11.25 (s, 1H), 8.76 (s, 1H), 8.58 - 8.57 (m, 1H), 8.03– 8.02 (m, 2H), 7.95– 7.94 (m, 1H), 7.69 - 7.62 (m, 1H), 7.59 - 7.51 (m, 2H), 7.35 - 7.34 (m, 1H ), 6.49 - 6.31 (m, 2H), 6.01 (d, J = 6.5 Hz, 1H), 5.67- 5.66 (m, 1H), 5.61 - 5.52 (m, 1H), 5.45– 5.44 (m, 1H), 5.36– 5.35 (m, 1H), 5.09– 5.08 (m, 1H), 4.85 - 4.69 (m, 1H), 4.51 - 4.40 (m, 1H), 4.39 - 4.31 (m, 1H), 4.27 - 4.10 (m , 4H), 3.56– 3.55 (m, 2H), 2.89- 2.88 (m, 2H). ¹⁹ F NMR (376MHz, DMSO- d ₆ ) -164.8, -201.3, -206.9. ³¹ P NMR (162MHz, DMSO- d ₆ ) δ 115.0 - 115.1.

Step 16: Preparation of Compound 6-16 Under argon protection, compound 6-15 (0.22 g, 284.5 μmol), 4Å molecular sieve (1 g) and tetrazole (0.45 M acetonitrile solution, 10 mL, 4.5 mmol) were dispersed in acetonitrile (2 mL) at 20 °C. ) and tetrahydrofuran (5 mL), 2-cyanoethyl N,N,N',N'-tetraisopropylphosphite diamine (120 μL, 377.8 μmol) in acetonitrile (0.5 mL) was added dropwise ) solution, the reaction system was stirred for 1 h. The reaction solution was diluted with ethyl acetate (50 mL) and filtered. The filtrate was washed with water (20 mL (v/v) = 10/1) was separated and purified to obtain compound 6-16.

Step 17: Preparation of Compound 6-17 Under argon protection, at 0 °C, borane dimethyl sulfide complex (2 M tetrahydrofuran solution, 0.2 mL, 0.4 mmol) was added dropwise to compound 6-16 (0.1 g, 114.6 μmol) and 4Å molecular sieve (0.5 g ) in tetrahydrofuran (5 mL), add the reaction system and stir for 30 min at 15°C. Add ethyl acetate (40 mL) to dilute and filter. The filtrate was washed with water (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 6-17, which was used directly in the next reaction without further purification. MS (ESI) m/z (M+H) ⁺ = 887.2

Step 18: Preparation of Compounds 6A, 6B, 6C and 6D Compound 6-17 (0.11 g, 124.1 μmol) was dissolved in 33% methylamine ethanol solution (3 mL), and the reaction was stirred at 15 °C for 18 h. The reaction system was concentrated under reduced pressure, and the residue was dissolved in water (10 mL), back-extracted with ethyl acetate (30 mL), and the aqueous phase was freeze-dried. The crude product was subjected to high-efficiency preparative liquid phase separation (separation conditions: chromatography column: Xbridge Prep OBD C18 150*40 mm10 μm; mobile phase: [water (0.05% ammonium hydroxide)-acetonitrile]; acetonitrile%: 0% - 30%, flow rate: 25 mL/min, 20 min). Obtain: Compound 6A (HPLC retention time 6.05 min); Compound 6B (HPLC retention time 6.47 min); Compound 6C (HPLC retention time 6.39 min); Compound 6D (HPLC retention time 7.47 min).

Compound 6A: MS (ESI) m/z (MH) ^- = 674.7 ¹ H NMR (400MHz, D ₂ O) δ8.43 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.24 (s, 1H), 6.49 - 6.38 (m, 2H), 5.87 - 5.70 (m, 1H), 5.38 - 5.19 (m, 1H), 5.19 - 5.03 (m, 1H), 4.86 - 4.81 (m, 1H) , 4.55 - 4.37 (m, 2H), 4.32 - 4.18 (m, 2H), 4.07 - 3.94 (m, 2H), 0.62 - -0.39 (m, 6H). ¹⁹ F NMR (376MHz, D ₂ O) -165.05 , -201.16 - -201.51, -203.00 - -203.35. ³¹ P NMR (162MHz, D ₂ O) δ95.50 - 90.45.

Compound 6B: MS (ESI) m/z (MH) ^- = 674.8 ¹ H NMR (400MHz, D ₂ O) δ8.50 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.20 (s, 1H), 6.56 - 6.37 (m, 2H), 5.63 - 5.40 (m, 1H), 5.39 - 5.14 (m, 2H), 4.53 - 4.35 (m, 3H), 4.35 - 4.23 (m, 2H) , 4.10 - 3.91 (m, 2H), 0.28 (br s, 6H). ¹⁹ F NMR (376MHz, D ₂ O) -164.19, -199.92 - -200.68, -201.18 - -202.10. ³¹ P NMR (162MHz, D ₂ O) δ95.93 - 91.70.

Compound 6C : MS (ESI) m/z (MH) ^- = 674.7 ¹ H NMR (400MHz, D ₂ O) δ8.39 (s, 1H), 8.15 (s, 1H), 7.93 - 7.83 (m, 1H) , 7.20 (s, 1H), 6.53 - 6.35 (m, 2H), 5.71 - 5.49 (m, 1H), 5.37 - 5.16 (m, 1H), 5.13 - 4.90 (m, 2H), 4.55 - 4.36 (m, 3H), 4.31 - 4.18 (m, 1H), 4.10 - 3.96 (m, 2H), 0.36 (brs., 6H). ¹⁹ F NMR (376MHz, D ₂ O) -165.35, -199.73 - -200.19, -202.31 - -202.91. ³¹ P NMR (162MHz, D ₂ O) δ96.82 - 90.33.

Compound 6D : MS (ESI) m/z (MH) ^- = 674.7 ¹ H NMR (400MHz, D ₂ O) δ8.25 (s, 1H), 8.06 (s, 1H), 7.66 (s, 1H), 7.05 (s, 1H), 6.29 - 6.15 (m, 2H), 5.75 - 5.56 (m, 1H), 5.42 - 5.23 (m, 1H), 5.23 - 5.01 (m, 2H), 4.52 - 4.35 (m, 4H) , 4.04 - 3.93 (m, 2H), 0.34 (br s, 6H). ¹⁹ F NMR (376MHz, D ₂ O) -164.82, -200.86, -202.28. ³¹ P NMR (162MHz, D ₂ O) δ96.94 - 91.91.

Bioactivity testing experiments

Experimental Example 1: STING in vitro binding test experiment

Fluorescence polarization assay (FP assay) was used to detect the affinity of compounds to human STING protein. There are a certain amount of luciferin-labeled c-di-GMP and different concentrations of test compounds in the reaction system. When the C-terminal protein of recombinant human STING is added, the two small molecules competitively bind to the protein. The bound luciferin-labeled c-di-GMP rotates slowly in the liquid phase, and the degree of fluorescence polarization detected at this time is also higher. The degree of fluorescence polarization is inversely proportional to the concentration and affinity of the compound to be tested. By detecting the size of polarized light in the reaction system, we can accurately know the affinity of the test compound for human STING.

The soluble human STING protein sequence used in the experiment was intercepted from the C-terminal part of the human wild-type endoplasmic reticulum-binding protein STING, from amino acids 140 to 379. The human STING protein has multiple alleles with sequence differences, and different alleles have different affinities for CDN (Yi, et. al., "Single Nucleotide Polymorphisms of Human STING can affect innate immune response to cyclic dinucleotides" PLOS ONE. 2013, 8 (10), e77846). Wild-type STING sequences (G230, R232, R293) accounted for approximately 57.9% of the total. The N-terminal of the recombinant STING protein is a 6His-SUMO sequence to facilitate correct folding and purification of the protein. It is cleaved by protease, and the C-terminal STING is used for FP testing.

The FP test uses a 384-well plate, and a 10 μl reaction system in each well is added with a final concentration of 30 nM luciferin-labeled c-di-GMP, 10 μM human STING protein, and different concentrations of reference compounds or test compounds. Centrifuge at 1000g for 1 minute, incubate at room temperature in the dark for 30 minutes, and read the plate with Envision.

The experimental results of the STING in vitro binding assay as described above are shown in Table 1. Table 1 Compound number FP affinity test IC ₅₀ (μM) 2',3'-cGAMP 6.66 1A 13.96 1B 3.21 1C 3.73 1D 5.61 2A 3.58 2B 2.00 3A 5.91 3B 4.35 3C 2.93 3D 2.70 4A 2.76 4B 2.26 4C 1.44 4D 2.86 5A 2.81 5B 5.47 5C 4.97 5D 5.14 6A 2.39 6B 1.76 6C 2.40 6D 2.53

Conclusion: In the FP affinity test, the compounds of the present invention showed higher affinity for human wild-type STING protein than endogenous 2'3'-cGAMP.

Experimental Example 2: THP1-dual reporter gene activity test experiment

The THP1-Dual™ cells used in the test (InvivoGen catalog code: thpd-nfis) were constructed by stably integrating two inducible reporter genes in the human monocytic cell line THP1. The promoter sequence of the secreted embryonic alkaline phosphatase (SEAP) reporter gene includes a basic promoter of IFN-β and five upstream copies of the NF-κB consensus transcriptional response element. and 3 copies of c-Rel binding sites. The secretory luciferase (Lucia) reporter gene is driven by five interferon (IFN)-stimulated response elements and an ISG54 basic promoter. This makes it possible to simultaneously study two major downstream signaling pathways of STING: the NF κB pathway by detecting SEAP activity: and the IRF pathway by assessing Lucia luciferase activity.

Dilute the compound in PB buffer (50 mM HEPES, 100 mM KCl, 3 mM MgCl2, 0.1 mM DTT, 85 mM Sucrose, 1 mM ATP, 0.1 mM GTP, 0.2%BSA). Add 20 μL of reference or test compound to each well of a 96-well plate, followed by 180 μL of THP1-Dual cells suspended in PB buffer (approximately 100,000 cells/well). After incubating the plate for 30 minutes at 37°C and 5% _CO2 , centrifuge at 1000 rpm for 10 minutes, discard the supernatant, wash twice with 200 μL/well RPMI-1640, add 200 μL of RPMI-1640 per well, and culture for 18 hours. The supernatant was collected and activation of the IRF3 pathway was quantified using QUANTI-Luc ^™ according to the manufacturer's instructions.

The results of the THP1-dual in vitro binding assay as described above are shown in Table 2. Table 2 Compound number EC ₅₀ (μM) 2',3'-cGAMP 20.19 ADU-S100 23.39 1A 74.69 1B 7.38 1C 16.76 1D 7.48 2A 1.75 2B 3.39 3B 42.21 3C 47.17 3D 26.13 4A 3.06 4B 3.68 4C 10.18 4D 48.20 5A 6.20 5B 11.42 5C 5.13 5D 12.6 6A 1.36 6B 9.31 6C 2.31 6D 12.30

Conclusion: In human monocyte cell line THP-1, the compound of the present invention has a strong ability to promote beta interferon activation.

Experimental Example 3: Raw-Dual Reporter Gene Activity Test Experiment

The RAW-Dual™ cells used in the test (InvivoGen catalog code: rawd-ismip) were constructed by stably integrating two inducible reporter genes in the mouse macrophage cell line RAW264.7: the NF-KB pathway was studied by detecting SEAP activity. and studying the IRF3 pathway by assessing the activity of Lucia luciferase. Add 200 μL of cell suspension (50,000 cells per well) to a 96-well plate (Corning 3599 flat-bottom plate) and culture it in a 37°C incubator for 18 to 24 hours. The next day, discard the culture medium, add 200 μL of compound solution pre-prepared with culture medium to each well, and incubate at room temperature for 30 minutes. Aspirate off the treatment liquid, wash twice with serum-free culture medium, and then add 200 μL of culture medium to each well. , culture in a 37°C incubator for 18 to 24 hours. On the third day, 20 μL of supernatant was taken from each well, and QUANTI-LucTM was used to quantify the activation of the IRF3 pathway according to the manufacturer's instructions.

The results of the RAW cell viability assay as described above are shown in Table 3 Table 3 Compound number Raw, EC50 (μM) ADU-S100 47.08 1B 15.8 1C 41.4 1D 24.4 2A 23.4 2B 2.1 3C 9.4 3D 10.0 4B 2.6 4C 6.3 4D 21.0 5B 54.8 5C 28.2 5D 31.6 6B 5.4 6C 1.1 6D 9.5

Conclusion: In the test, it was found that the compound of the present invention has a strong ability to activate STING in the mouse macrophage cell line RAW reporter gene test experiment.

Experimental Example 4: In vivo drug efficacy experiment 1

This experiment uses the 4T1 breast cancer syngeneic mouse model to evaluate the efficacy of the compounds. 1E5 4T1 breast cancer cells (Shanghai Institute of Cell Studies, Chinese Academy of Sciences) were inoculated subcutaneously into 6-8 week old Balb/C mice (Vital Lever). When the tumor volume reached 100mm3, they were randomly divided into groups of 8 mice in each group. Intratumoral administration was performed sequentially on the 1st, 4th, and 8th days after grouping. The single intratumoral administration (IT) was performed on the first day after grouping. ADU-S100 dosage groups are 100ug per mouse (single dose) and 30ug per mouse (three times). Compound 2B dosage groups are 30ug per mouse (single dose), 100ug per mouse (single dose) and 30ug per mouse (three times). Tumor volume measurements were performed after the start of dosing and twice a week. The calculation formula of tumor volume is: V = 0.5 a × b ² , where a and b represent the long and short diameters of the tumor respectively. Each point is the mean and standard error (SEM) of tumor volume. Differences between groups were statistically analyzed using two-way ANOVA (statistical differences on day 25 are shown in the figure, Prism7, **** p<0.0001). The tumor volume in the drug treatment group was significantly smaller than that in the control group. All tumors in Compound 2B 100ug (single) and 30ug (three times) groups disappeared, and the tumor inhibitory effect was better than that of ADU-100 at the same dose. The results are shown in Figure 1.

Experimental Example 5: In vivo drug efficacy experiment 2

In this experiment, the CT-26 colon cancer syngeneic mouse model was used to evaluate the efficacy of the compounds. 3E5 CT-26 colon cancer cells (ATCC-CRL-2638) were inoculated subcutaneously into 6-8 week old Balb/C mice (Shanghai Lingchang Biology). When the tumor volume reached 100mm3, they were randomly divided into groups, with 8 mice in each group. . Intratumoral administration was performed sequentially on the 1st, 4th, and 8th days after grouping, for a total of three times. The dosage of compound 2B in each group was 1ug per mouse, 3ug per mouse, 9ug per mouse, and 18 μg per mouse. Compound ADU-S100 was administered at a dose of 125 μg per mouse. Tumor volume was measured three times a week after the start of dosing. The calculation formula of tumor volume is: V = 0.5 a × b ² , where a and b represent the long and short diameters of the tumor respectively. Each point is the mean and standard error (SEM) of tumor volume. The differences between the control group and the treatment group were statistically analyzed using two-way ANOVA (the statistical difference on day 11 is shown in the figure, Prism7, **** p<0.0001).

Compared with the control group, the tumor growth rate of mice in the drug treatment group was significantly slower. The inhibitory effect of compound 2B on mouse tumor growth was dose-dependent. Compound 2B 18 μg per mouse produced comparable tumor inhibitory effects to compound ADU-S100 125 μg per mouse. The results are shown in Figure 2.

Experimental Example 6: In vivo drug efficacy experiment 3

In this experiment, the MC38 colon cancer syngeneic mouse model was used to evaluate the efficacy of the compounds. 3E5 MC38 colon cancer cells (Nanjing Kebai) were inoculated subcutaneously into 6-8 week old C57BL/6 mice (Shanghai Bikai). When the tumor volume reached about 100mm3, they were randomly divided into groups, with 5-6 mice in each group. Intratumoral administration was performed sequentially on the 1st, 4th, and 8th days after grouping. A single intratumoral administration was administered on the first day after grouping. ADU-S100 dosage group is 100ug per mouse (single dose). Compound 2B dosage groups were 100ug per mouse (single), 30ug per mouse (three times) and 10ug per mouse (three times). The compound 6C dose group was 30ug per mouse (three times). Tumor volume measurements were performed after the start of dosing and twice a week. The calculation formula of tumor volume is: V = 0.5 a × b ² , where a and b represent the long and short diameters of the tumor respectively. Each point is the mean and standard error (SEM) of tumor volume. The differences between the control group and the treatment group were statistically analyzed using two-way ANOVA (the statistical difference on day 28 is shown in the figure, Prism7, **** p<0.0001).

Compared with the control group, the tumor growth of mice in the administration group was significantly inhibited. All the tumors of mice in the groups of compound 2B 30ug (three times) and 10ug (three times) and compound 6C 30ug (three times) disappeared. The results are shown in Figure 3.

Although the present invention has been disclosed above through embodiments, they are not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention belongs can make some modifications and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be determined by the appended patent application scope.

without

Figure 1: Results of drug efficacy experiments in the 4T1 breast cancer syngeneic mouse model; Figure 2: Results of drug efficacy experiments on CT-26 colon cancer syngeneic mouse model; Figure 3: Results of drug efficacy experiments on the MC38 colon cancer syngeneic mouse model.

Claims (13)

Compounds represented by formula (I), their optical isomers and pharmaceutically acceptable salts thereof,

Among them, R ₁ and R _1a are independently selected from

,

,

,

,

,

and

; L ₂ is independently selected from -O-, -N(R)-, -C(RR)- and -C(=O)-; R is independently selected from H, halogen, OH, NH ₂ , CN ,

, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino, wherein C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylthio and C _1-6 alkylamino are optionally substituted by 1, 2 or 3 R';R' is selected from F, Cl, Br, I, OH, NH ₂ and CH ₃ ; R ₄ and R _4a are respectively Independently selected from H, halogen, OH, NH ₂ , CN, N ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _{2 -6} alkynyl, wherein C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl are optionally replaced by 1, 2 or 3 R is substituted; R ₆ is selected from H, halogen, OH, NH ₂ , CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino and C _2-6 alkynyl, in which C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio and C _1-6 alkylamino are optionally substituted by 1, 2 or 3 R; R ₈ Selected from BH ₃ ^- and -S(R ₉ ); R ₉ is selected from H, CH ₂ OC(=O)R ₁₁ , CH ₂ OC(=O)OR ₁₁ , CH ₂ CH ₂ SC(=O)R ₁₁ and CH ₂ CH ₂ SSCH ₂ R ₁₁ ; R ₁₁ is selected from C _6-10 aryl, 5-10 membered heteroaryl, C _1-6 heterocycloalkyl and C ₁ - ₂₀ alkyl, the C ₁ - ₂₀ alkyl is optionally substituted by 1, 2, 3, 4 or 5 C _6-10 aryl, C _3-10 cycloalkyl, OH and F; X ₁ and X _1a are selected from -O-; X ₂ , ^X _{2a is selected from -O- ; _ _} Cl and Br, the other is selected from F, Cl, Br, OH, OCH ₃ or N ₃ ; when R ₈ is selected from -S (R ₉ ), one of R ₄ and R _4a is selected from F, Cl and Br, The other is selected from OH, OCH ₃ or N ₃ ; Or, when R ₈ is selected from -S (R ₉ ), and one of R ₄ and R _4a is selected from F, Cl and Br, the other is not selected from OH, OCH ₃ or N ₃ , R ₁ and R _1a are not selected from

, and R ₁ and R _1a are not simultaneously selected from

; The 5 to 10-membered heteroaryl or C _1-6 heterocycloalkyl group contains 1, 2 or 3 independently selected from -O-, -NH-, -S-, -C(=O)-, - C(=O)O-, -S(=O)-, -S(=O) ₂ - and N heteroatoms or heteroatom groups. The compound according to claim 1, its optical isomer and its pharmaceutically acceptable salt, wherein R are independently selected from H, halogen, OH, NH ₂ , CN,

, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylamino, wherein C _1-3 alkyl, C _1-3 alkoxy, C _{1- 3} alkylthio and C _1-3 alkylamino groups are optionally substituted by 1, 2 or 3 R'. The compound according to claim 2, its optical isomers and pharmaceutically acceptable salts thereof, wherein R are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me,

,

,

,

,

,

and

, among which Me,

,

,

,

,

and

Optionally substituted by 1, 2 or 3 R'. The compound according to claim 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein R are independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, Me,

,

,

,

,

,

,

and

. The compound according to claim 1, its optical isomer and its pharmaceutically acceptable salt, wherein R ₁ and R _1a are each independently selected from

,

,

,

,

,

,

,

,

,

,

,

and

; or R ₆ is selected from H and methyl. The compound according to any one of claims 1 to 4, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₂ , R _2a , R ₃ , R _3a , R ₅ and R _5a , R ₆ is selected from H. The compound according to any one of claims 1 to 4, its optical isomer and its pharmaceutically acceptable salt, wherein R ₄ and R _4a are independently selected from F, OH, NH ₂ and N ₃ and

. The compound according to any one of claims 1 to 5, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from

Among them, R ₁ and R _1a are as defined in claim items 1 to 5; R _4a is as defined in claim item 1 or 7 respectively; R ₇ , R _7a and R _6a are selected from H; R ₈ is as defined in claim item 1. The compound according to claim 8, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from

The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from

Among them, R ₁ and R _1a are independently selected from

,

,

,

,

,

,

and

; X ₁ and X _1a are selected from -O- _; X ₂ and _{X 2a are} selected from -O-; The compound according to claim 10, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from

The compound according to any one of claims 8 to 11, its optical isomers and pharmaceutically acceptable salts thereof, wherein R ₁ and R _1a are each independently selected from

,

,

and

. The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from

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