WO2022156678A1

WO2022156678A1 - Macrocyclic tlr7 agonist, and preparation method therefor, pharmaceutical composition thereof and use thereof

Info

Publication number: WO2022156678A1
Application number: PCT/CN2022/072556
Authority: WO
Inventors: 唐国志; 黄孟炜; 马大为
Original assignee: 上海维申医药有限公司
Priority date: 2021-01-20
Filing date: 2022-01-18
Publication date: 2022-07-28
Also published as: CN114805392A; CN115119508A

Abstract

A macrocyclic TLR7 agonist, and a preparation method therefor, a pharmaceutical composition thereof and the use thereof. The macrocyclic TLR7 agonist is a compound as represented by formula I. The compound is new in terms of structure, has relatively good activity and has good application prospects.

Description

Macrocyclic TLR7 agonist, preparation method, pharmaceutical composition and use thereof

This application claims the priority of Chinese patent application 2021100758546 with a filing date of January 20, 2021. This application cites the full text of the above Chinese patent application.

technical field

The present invention relates to a macrocyclic TLR7 agonist, its preparation method, pharmaceutical composition and use thereof.

Background technique

Toll-like receptors (TLRs) are a class of structurally conserved proteins that form the first barrier in the innate immune response. By recognizing various conserved pathogen-associated molecular patterns (PAMPs), TLRs can recognize invasive microorganisms and endogenous molecules released after tissue damage or non-physiological cell death, and activate signaling cascades, resulting in the production of pro-inflammatory cytokines. The inflammatory process is crucial to the occurrence and development of various diseases, such as type I diabetes, sepsis, cancer, viral infectious diseases, etc. Therefore, strategies for manipulating the inflammatory response to treat related diseases through small-molecule TLRs modulators are promising.

There are 10 known members of the human TLRs family, which are type I transmembrane proteins characterized by a leucine-rich extracellular domain and a conserved Toll/interleukin-1 receptor (Toll/interleukin (IL) -1receptor, TIR) domain cytoplasmic tail. In this family, TLR3, TLR7, TLR8 and TLR9 are located in the endosomal compartment. (Vijay K., Int Immunopharmacol., 2018, 59, 391-412)

TLR7 recognizes single-stranded RNA (ssRNA) fragments. TLR7 is mainly expressed in plasmacytoid dendritic cells and B cells. TLR7 stimulation mainly induces the production of type I interferons, including interferon-α (IFN-α), and leads to the transcription of interferon-stimulated genes (ISGs). (Gorden KB., J Immunol., 2005, 174, 1259-1268; Shah M., Expert Opin Investig Drugs, 2016, 25, 437-453) Interferon alpha is one of the main drugs for the treatment of chronic hepatitis B or C. Therefore, the development of TLR7 agonists to treat viral infectious diseases is of great clinical significance.

Studies have also reported treating cancer with TLR7 agonists. WO201772662 reports the treatment of HER2 positive cancers with TLR7 agonist-anti-HER2 conjugates. Yosuke Ota et al. found that intravenous TLR7 agonist DSP-0509 and anti-PD-1 antibodies have synergistic effects on anti-tumor immune responses (AACR 2018 Proceedings: Abstract 4726).

There are currently several related TLR7 agonist patent applications, but there is still a need to continue to develop highly active, safer and therapeutically highly effective TLR7 agonists.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a macrocyclic TLR7 agonist, a preparation method thereof, a pharmaceutical composition and the use thereof, aiming at the defect that the existing TLR7 agonist has a relatively single structure. The compound of the present invention has a novel structure and good activity. .

The present invention provides a compound represented by formula I, its solvate, its prodrug, its metabolite or their (referring to the aforementioned compound represented by formula I, its solvate, its prodrug or its metabolites) product) pharmaceutically acceptable salts:

Wherein, Y is N or CR ^Y ;

R ^Y is C ₁ -C ₄ alkyl substituted by cyano or halogen;

A is O, S, -S(=O) ₂ , -S(=O)(=NH), NR4 or ^CR6R7 ^; R4, ^R6 and ^R7 ^are independently H or _C1 ^- C ₆ alkyl;

B is C ₂ -C ₁₀ alkylene, C ₂ -C ₁₀ unsaturated hydrocarbylene, R ^1-1 substituted C ₂ -C ₁₀ alkylene, R ^1-1 substituted C ₂ -C ₁₀ unsaturated alkylene Hydrocarbyl, -Z ¹ -NH-C(=O)-Z ² -, -Z ³ -NH-C(=O)-Z ⁴ -L ¹ -, -Z ⁵ -L ² -, -Z ⁶ -OZ ⁷ -, -Z ⁸ -OZ ⁹ -L ³ - or -(CH ₂ ) _n -L ⁵ -(CH ₂ ) _r -L ⁴ -;

L ¹ , L ² , L ³ and L ⁴ are independently O, S, S(=O) ₂ , NR ⁸ , and R ⁸ is H or C ₁ -C ₆ alkyl;

-L ⁵ - is C ₃ -C ₆ cycloalkylene, halogen-substituted C ₃ -C ₆ cycloalkylene, "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3 3-6-membered heterocycloalkylene "or halogen-substituted" heteroatoms are selected from one or more of N, O and S, and 3-6-membered heteroatoms with 1-3 heteroatoms Heterocycloalkylene";

n and r are independently 1, 2 or 3;

-Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁶ -, -Z ⁷ -, -Z ⁸ - and -Z ⁹ - are independently C ₁ -C ₆ alkylene , C ₂ -C ₆ unsaturated hydrocarbylene, C ¹ ^-C ₆ alkylene substituted by R ^1-2 or C ₂ -C ₆ unsaturated hydrocarbylene substituted by R 1-2 _;

-Z ⁵ - is a C ₂ -C ₁₀ alkylene group, a C ₂ -C ₁₀ unsaturated hydrocarbylene group, a R ^1-3 substituted C ₂ -C ₁₀ alkylene group, or a R ^1-3 substituted C ₂ -C ₁₀ group Unsaturated hydrocarbylene;

R ^1-1 , R ^1-2 and R ^1-3 are independently OH, CN, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or COOR ^1-1-1 ; R ^1-1-1 is H or C ¹ -C ₃ alkyl _;

R ¹ , R ² and R ³ are independently H, halogen, C ₁ -C ₆ alkyl or halogen-substituted C ₁ -C ₆ alkyl;

Or, "R ¹ and R ² " or "R ² and R ³ " and the carbon atoms to which they are attached together form "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3 4-7-membered heterocycloalkylene group ", R ^1-4 substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3 4-7-membered "Heterocycloalkylene", C ₄ -C ₇ cycloalkylene or C ₄ -C ₇ cycloalkylene substituted by R ^1-5 ; or, "R ¹ and R ² " or "R ² and R ³ " The "heteroatoms selected from one or more of N, O and S, and the 4-7-membered heterocycloalkylene groups with 1-3 heteroatoms" or the above-mentioned "heteroatoms" formed together with the carbon atoms to which they are attached. The "heteroatom is selected from one or more of N, O and S, and the 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" substituted by R ^1-4 . From one or more of N, O, and S, one or two or more arbitrary methylene groups in a 4- to 7-membered heterocycloalkyl group having 1 to 3 heteroatoms are independently replaced by carbonyl or S(=O) ₂ replace;

R ^1-4 and R ^1-5 are independently OH, halogen, CN, C ₁ -C ₆ alkyl, R ^1-6 substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, R ^1-9 substituted C ₁ -C ₆ alkoxy, -S(=O) ₂ R ^1-7 , -C(=O)R ^1-8 , NR ^1-10 R ^1-11 , COOR ^1-12 , SR ^1-13 , C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl substituted by R ^1-19 , "heteroatom selected from one or more of N, O and S, heteroatom 4-7-membered heterocycloalkyl with 1-3 "heteroatoms" and "heteroatoms substituted by R ^1-20 are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 4-7-membered heterocycloalkyl", "heteroatoms selected from one or more of N, O and S, and C ₁ -C ₁₀ heteroaryl groups with 1-4 heteroatoms", R ^{1- 21} -substituted "heteroatoms selected from one or more of N, O and S, C ₁ -C ₁₀ heteroaryl groups with 1 to 4 heteroatoms" or -G(CR ^1-14 R ^{1- 15} ) _u- COOR ^1-16 ; G is O, S, S(=O) ₂ or NH; u is 1, 2 or 3;

R ^1-6 and R ^1-9 are independently halogen, amino, CN, OH, -COOR ^1-17 , -S(=O) ₂ R ^1-31 , -C(=O)NH ₂ , -S( =O) ₂ NH ₂ , C ₁ -C ₃ alkoxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl substituted by COOR ^1-18 , "heteroatom selected from N, O and S One or more of the 4- to 7-membered heterocycloalkyl groups with 1 to 3 heteroatoms", "heteroatoms substituted by R ^1-22 are selected from one or more of N, O and S" , 4- to 7-membered heterocycloalkyl with 1-3 heteroatoms", "heteroatoms are selected from one or more of N, O and S, and C ₁ ~ with 1-4 heteroatoms C ₁₀ Heteroaryl" or R ^1-23 substituted "heteroatom selected from one or more of N, O and S, and C ₁ -C ₁₀ Heteroaryl with 1 to 4 heteroatoms";

R ^1-7 and R ^1-8 are independently C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl substituted by R ^1-24 , "heteroatom selected from N , one or more of O and S, a 4- to 7-membered heterocycloalkyl group with 1 to 3 heteroatoms", "the heteroatom substituted by R ^1-25 is selected from one of N, O and S" One or more, 4-7-membered heterocycloalkyl with 1-3 heteroatoms", "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-4 C ₁ -C ₁₀ heteroaryl", R ^1-26 substituted "heteroatoms are selected from one or more of N, O and S, and C ₁ -C ₁₀ heteroatoms with 1 to 4 heteroatoms Aryl", C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl substituted by R ^1-27 or -NR ^1-28 R ^1-29 ;

R ^1-10 , R ^1-11 , R ^1-12 , R ^1-16 , R ^1-17 , R ^1-18 , R ^1-28 and R ^1-29 are independently H or C ₁ -C ₃ alkanes base; R ^1-31 is C ₁ -C ₃ alkyl;

R ^1-13 is H, C ₁ -C ₆ alkyl or halogen-substituted C ₁ -C ₆ alkyl;

R ^1-14 and R ^1-15 are independently H, C ₁ -C ₆ alkyl or halogen-substituted C ₁ -C ₆ alkyl;

R ^1-19 , R ^1-20 , R ^1-21 , R ^1-22 , R ^1-23 and R ^1-24 are independently OH, halogen, amino, CN or C ₁ -C ₆ alkyl;

R ⁵ is H, CN, halogen, C ₃ -C ₅ cycloalkyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

R ¹³ is H, -CONR ¹⁴ R ¹⁵ , -C(=O)R ¹⁶ or -COOR ¹⁷ , and R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are independently C ₁ -C ₆ alkyl or R ^13- ¹ Substituted C ₁ -C ₆ alkyl; R ^13-1 is CN, halogen, C ₁ -C ₆ alkoxy or -(CH ₂ CH ₂ O) _q -R ^13-2 , R ^13-2 is C ₁ ~C ₆ alkyl, q is an integer from 0 to 460.

In some schemes, in the compound shown in formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts, the definitions of certain groups can be as follows, The remaining groups are defined as described in any of the schemes above (hereafter referred to in this paragraph as "in some schemes"):

A is O;

B is C ₂ -C ₁₀ alkylene, C ₂ -C ₁₀ unsaturated hydrocarbylene, -Z ⁵ -L ² - or -(CH ₂ ) _n -L ⁵ -(CH ₂ ) _r -L ⁴ -;

L ² and L ⁴ are independently O;

-L ⁵ - is C ₃ -C ₆ cycloalkylene;

-Z ⁵ - is C ₂ -C ₁₀ alkylene;

R ¹ , R ² and R ³ are independently H;

Alternatively, R ¹ and R ² together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and 4-7-membered heterocycloalkanes with 1-3 heteroatoms. "R" or R ^1-4 substituted "heteroatom selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms";

R ^1-4 is independently C ₁ -C ₆ alkyl, R ^1-6 substituted C ₁ -C ₆ alkyl, -S(=O) ₂ R ^1-7 , -C(=O)R ^{1- 8.} C ₃ -C ₇ cycloalkyl groups or "4- to 7-membered heterocycloalkyl groups whose heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3";

R ^1-6 is independently "a heteroatom selected from one or more of N, O and S, and a C ₁ -C ₁₀ heteroaryl group with 1 to 4 heteroatoms";

R ^1-7 and R ^1-8 are independently C ₁ -C ₃ alkyl;

R ⁵ is H;

R ¹³ is H, -C(=O)R ¹⁶ or -COOR ¹⁷ , and R ¹⁶ and R ¹⁷ are independently C ₁ -C ₆ alkyl groups.

A is O;

L ² and L ⁴ are independently O;

-L ⁵ - is C ₃ -C ₆ cycloalkylene;

-Z ⁵ - is C ₂ -C ₁₀ alkylene;

R ¹ and R ² together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" Or R ^1-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 3 4- to 7-membered heterocycloalkylene";

R ^1-7 and R ^1-8 are independently C ₁ -C ₃ alkyl;

R ³ is H;

R ⁵ is H;

In some scenarios,

A is O;

L ² and L ⁴ are independently O;

-L ⁵ - is C ₃ -C ₆ cycloalkylene;

-Z ⁵ - is C ₂ -C ₁₀ alkylene;

R ^1-4 is independently C ₁ -C ₆ alkyl, -S(=O) ₂ R ^1-7 , -C(=O)R ^1-8 , C ₃ -C ₇ cycloalkyl or "heteroatom" One or more selected from N, O and S, and a 4- to 7-membered heterocycloalkyl group with 1 to 3 heteroatoms";

R ^1-7 and R ^1-8 are independently C ₁ -C ₃ alkyl;

R ³ is H; R ⁵ is H;

R ¹³ is H.

In some scenarios,

A is O;

B is C ₂ -C ₁₀ alkylene, C ₂ -C ₁₀ unsaturated hydrocarbylene, -Z ⁵ -L ² - or -(CH ₂ ) _n -L ⁵ -(CH ₂ ) _r -L ⁴ - (eg B is n-pentylene, pentenylene, -O-n-propylidene- or

(

Representation of structural fragments with trans-cyclobutylene fragments, following

the meaning of structural fragments);

L ² and L ⁴ are independently O;

-L ⁵ - is C ₃ -C ₆ cycloalkylene (eg butylene);

-Z ⁵ - is C ₂ -C ₁₀ alkylene (eg n-propylene);

R ¹ and R ² together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" or "4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" substituted by R ^1-4 , C ₄ -C ₇ Cycloalkylene or R ^1-5 substituted C ₄ -C ₇ cycloalkylene (eg R ¹ and R ² and the carbon atoms to which they are attached together form a piperidinyl or substituted piperidinyl);

R ^1-4 is independently C ₁ -C ₆ alkyl, -C(=O)R ^1-8 , C ₃ -C ₇ cycloalkyl or "heteroatom selected from one of N, O and S or A variety of 4-7-membered heterocycloalkyl with 1-3 heteroatoms (for example, R ^1-4 is independently isopropyl, -C(=O)CH ₃ , cyclobutyl or tetrahydropyridine alkyl); when R ^Y is a halogen-substituted C ₁ -C ₄ alkyl group, the R ^1-4 is a C ₁ -C ₆ alkyl group (such as isopropyl);

R ^1-8 is independently C ₁ -C ₃ alkyl (eg methyl);

R ³ is H;

R ¹³ is H;

^R5 is H.

In some aspects, Y is N.

In some schemes, R ^Y is cyano.

In some arrangements, A is O.

In some embodiments, B is C ₂ -C ₁₀ alkylene, C ₂ -C ₁₀ unsaturated hydrocarbylene, -Z ⁵ -L ² -, or -(CH ₂ ) _n -L ⁵ -(CH ₂ ) _r -L ⁴ -, preferably a C ₂ -C ₁₀ alkylene group or a C ₂ -C ₁₀ unsaturated hydrocarbylene group.

In some aspects, L ² and L ⁴ are O.

In some embodiments, -L ⁵ - is C ₃ -C ₆ cycloalkylene.

In some schemes, ^-L5- is cyclobutylene.

In some embodiments, -Z ⁵ - is C ₂ -C ₁₀ alkylene.

In some embodiments, ^-Z5- is n-propylene.

In some arrangements, n and r are one.

In some embodiments, B is n-pentylene, pentenylene (eg

(E.g

)), -n-pentylidene-O- or

(E.g

), preferably B is n-pentylene or pentenylene.

In some schemes, R ¹ and R ² together with the carbon atoms to which they are attached form a "heteroatom selected from one or more of N, O and S, and a 4- to 7-membered subgroup with 1 to 3 heteroatoms. "Heterocycloalkyl" or "heteroatoms substituted by R ^1-4 are selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms".

In some embodiments, R ^1-4 is C ₁ -C ₆ alkyl, R ^1-6 substituted C ₁ -C ₆ alkyl, -S(=O) ₂ R ^1-7 , -C(=O) R ^1-8 , C ₃ -C ₇ cycloalkyl or "4- to 7-membered heterocycloalkyl group whose heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" , preferably C ₁ -C ₆ alkyl, -S(=O) ₂ R ^1-7 , -C(=O)R ^1-8 , C ₃ -C ₇ cycloalkyl or "heteroatom selected from N, O and one or more of S, a 4- to 7-membered heterocycloalkyl group with 1 to 3 heteroatoms", more preferably _{a C1} - _C6 alkyl group or "heteroatoms selected from N, O and S" One or more of 4- to 7-membered heterocycloalkyl groups with 1-3 heteroatoms".

In some schemes, R ^1-6 is "a heteroatom selected from one or more of N, O and S, and a C ₁ -C ₁₀ heteroaryl group with 1 to 4 hetero atoms".

In some embodiments, R ^1-7 and R ^1-8 are C ₁ -C ₃ alkyl.

^In some schemes, R and R ^together with the carbon atoms to which they are attached form

In some schemes, ^R3 is H.

^In some schemes, R5 is H.

In some schemes, R ¹³ is H, -C(=O)R ¹⁶ or -COOR ¹⁷ , preferably H.

In some embodiments, R ¹⁶ and R ¹⁷ are C ₁ -C ₆ alkyl.

In some aspects, R ¹³ is H,

H is preferred.

In some scenarios,

for

In some scenarios,

for

In some schemes, -AB- is

In some embodiments, when B is a C ₂ -C ₁₀ alkylene group or a C ₂ -C ₁₀ alkylene group substituted by R ^1-1 , the C ₂ -C ₁₀ alkylene group and the R ¹ The C ₂ -C ₁₀ alkylene in the ^-1- substituted C ₂ -C ₁₀ alkylene is independently a C ₄ -C ₆ alkylene (eg n-butylene, n-pentylene or n-hexylene), preferably For n-pentylidene.

In some embodiments, when B is a C ₂ -C ₁₀ unsaturated hydrocarbylene group or a C _{2 -C 10 unsaturated hydrocarbylene group substituted by R 1-1, the C 2} _{-C 10} ^unsaturated _{hydrocarbylene} _group and the The C ₂ -C ₁₀ unsaturated alkylene groups in the C ₂ -C ₁₀ unsaturated alkylene groups substituted by R ^1-1 are independently C ₄ -C ₆ alkenyl groups, more preferably C 2 -C 10 unsaturated alkylene groups

(E.g"

(Type E) and

(Z type)”,

).

In some embodiments, when R ⁸ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ alkyl group.

In some embodiments, when -L ⁵ - is C ₃ -C ₆ cycloalkylene or halogen-substituted C ₃ -C ₆ cycloalkylene, the C ₃ -C ₆ cycloalkylene and the The C ₃ -C ₆ cycloalkylene in the halogen-substituted C ₃ -C ₆ cycloalkylene is cyclopropylidene, cyclobutylene, cyclopentylene or cyclohexylene, preferably cyclobutylene (E.g

).

In some aspects, when -Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁶ -, -Z ⁷ -, -Z ⁸ - and -Z ⁹ - are independently C ₁ ～C ₆ alkylene or C _{1-C 6 alkylene substituted by R 1-2, the C 1 ～C 6 alkylene and the C 1} _～ ^C ₆ _alkylene _substituted _by R ^1-2 The C ₁ -C ₆ alkylene group in the alkyl group is independently a C ₁ -C ₃ alkylene group.

In some aspects, when -Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁶ -, -Z ⁷ -, -Z ⁸ - and -Z ⁹ - are independently C ₂ When ～C ₆ unsaturated alkylene group or R ^1-2 substituted C ₂ ～C ₆ unsaturated hydrocarbylene group, the C ₂ ～C ₆ alkylene and R ^1-2 substituted C ₂ ～C ₆ unsaturated The C ₂ -C ₆ unsaturated hydrocarbylene group in the hydrocarbylene group is independently a C ₂ -C ₄ unsaturated hydrocarbylene group.

In some schemes, when -Z ⁵ - is C ₂ -C ₁₀ alkylene or C 2 -C 10 alkylene substituted by R ^1-3 , the C ₂ -C ₁₀ alkylene and the said C ₂ -C ₁₀ alkylene The C ₂ -C ₁₀ alkylene in the C ₂ -C ₁₀ alkylene substituted by R ^1-3 is independently a C ₃ -C ₆ alkylene (eg n-propylene, n-butylene, n-pentylene or n-hexylene), preferably n-butylene.

In some schemes, when -Z ⁵ - is a C ₂ -C ₁₀ unsaturated hydrocarbylene group or a C _{2 -C 10 unsaturated hydrocarbylene group substituted by R 1-3, the C 2} _{-C 10} ^unsaturated _{hydrocarbylene} _group and The C ₂ -C ₁₀ unsaturated hydrocarbylene group in the R ^1-3 substituted C ₂ -C ₁₀ unsaturated hydrocarbylene group is independently a C ₃ -C ₆ unsaturated hydrocarbylene group.

In some scenarios, -Z ⁵ -L ² - is

In some aspects, -(CH ₂ ) _n -L ⁵ -(CH ₂ ) _r -L ⁴ - is

(E.g

).

In some embodiments, when R ^1-1 , R ^1-2 and R ^1-3 are independently halogen, the halogen is independently F, Cl, Br or I.

In some embodiments, when R ^1-1 , R ^1-2 and R ^1-3 are independently C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is independently C ₁ -C ₃ alkyl.

In some schemes, when R ^1-1 , R ^1-2 and R ^1-3 are independently C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is independently C ₁ -C 6 alkoxy C ₃ alkoxy.

In some embodiments, when R ¹ , R ² and R ³ are independently halogen or halogen-substituted C ₁ -C ₆ alkyl, said halogen and said halogen-substituted C ₁ -C ₆ alkyl The halogen of is independently F, Cl, Br or I.

In some embodiments, when R ¹ , R ² and R ³ are independently C ₁ -C ₆ alkyl and halogen-substituted C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl and the In the halogen-substituted C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkane is independently a C ₁ -C ₃ alkyl group.

In some schemes, when "R ¹ and R ² " or "R ² and R ³ " and the carbon atoms to which they are attached together form "the heteroatom is selected from one or more of N, O, and S, the number of heteroatoms 1-3 4-7 membered heterocycloalkylene "or R ^1-4 substituted" heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3 4-7-membered heterocycloalkylene", the "heteroatoms are selected from one or more of N, O and S, and 4-7-membered heterocycloalkanes with 1 to 3 heteroatoms. "Hetero atoms are selected from one or more of N, O and S, and the number of ^heteroatoms is 1 to 3. 4-7-membered heterocycloalkylene" The atom is selected from one or more of N, O and S, and the 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" is independently "the heteroatom is N and the number of heteroatoms is 1. 5-6 membered heterocycloalkylene ", more preferably piperidinylene, such as

In some schemes, when "R ¹ and R ² " or "R ² and R ³ " and the carbon atoms to which they are attached together form an R ^1-4 substituted "heteroatom selected from one of N, O, and S or In the case of a 4- to 7-membered heterocycloalkylene group having 1 to 3 heteroatoms, the R ^1-4 is 1, 2 or 3, preferably 1.

In some schemes, when "R ¹ and R ² " or "R ² and R ³ " and the carbon atoms to which they are attached together form an R ^1-4 substituted "heteroatom selected from one of N, O, and S or When the number of heteroatoms is a 4- to 7-membered heterocycloalkylene group with 1 to 3 heteroatoms, the substitution position of R ^1-4 is located on the heteroatom.

In some embodiments, when R ^1-4 and R ^1-5 are independently halogen, the halogen is F, Cl, Br, or I.

In some embodiments, when R ^1-4 and R ^1-5 are independently C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by R ^1-6 , the C ₁ -C ₆ alkane The C ₁ -C ₆ alkyl group in the C ₁ -C ₆ alkyl group substituted by R ^1-6 is independently a C ₁ -C ₄ alkyl group (such as methyl, ethyl, n-propyl, isopropyl propyl, n-butyl, isobutyl or tert-butyl), more preferably methyl or isopropyl.

In some schemes, when R ^1-4 and R ^1-5 are independently C ₁ -C ₆ alkoxy or R ^1-9 substituted C ₁ -C ₆ alkoxy, the C ₁ -C The C _{1 -C 6 alkoxy group in the 6 alkoxy group and the C 1} _{-C 6} _alkoxy _group _substituted by R ^1-9 is independently a C ₁ -C ₄ alkoxy group.

In some schemes, when R ^1-4 and R ^1-5 are independently C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkyl substituted by R ^1-19 , the C ₃ -C cycloalkyl C ₃ -C ₇ cycloalkyl in ₇ cycloalkyl and R ^1-19 substituted C ₃ -C ₇ cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl , preferably cyclobutyl.

In some schemes, when R ^1-6 and R ^1-9 are independently "heteroatoms are selected from one or more of N, O and S, C ₁ -C ₁₀ with 1-4 heteroatoms "heteroaryl" or R ^1-23 substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4 C ₁ -C ₁₀ heteroaryl", the Said "heteroatoms are selected from one or more of N, O and S, C ₁ -C ₁₀ heteroaryl groups with 1 to 4 heteroatoms" and "heteroatoms substituted by R ^1-21 are selected from One or more of N, O and S, and C ₁ -C ₁₀ heteroaryl with 1 to 4 heteroatoms", "the heteroatom is selected from one or more of N, O and S" , C ₁ -C ₁₀ heteroaryl with 1 to 4 heteroatoms" is independently "a C ₄ -C ₆ heteroaryl with a heteroatom of N and 1 heteroatom", more preferably pyridyl ( E.g

).

In some schemes, when R ^1-4 is a C ₁ -C ₆ alkyl group substituted by R ^1-6 , the number of R ^1-6 is 1, 2 or 3, preferably 1.

In some schemes, when R ^1-4 is C ₁ -C ₆ alkyl substituted by R ^1-6 , the C ₁ -C ₆ alkyl substituted by R ^1-6 is

In some embodiments, when R ^1-13 , R ^1-14 and R ^1-15 are independently C ₁ -C ₆ alkyl or halogen-substituted C ₁ -C ₆ alkyl, the C ₁ -C The C 1 -C ₆ alkyl group in the ₆ alkyl group or the halogen-substituted C ₁ -C ₆ alkyl group is independently _{a C 1} _-C ₃ alkyl group.

In some schemes, when R ^1-13 , R ^1-14 and R ^1-15 are independently halogen-substituted C ₁ -C ₆ alkyl, the halogen-substituted C ₁ -C ₆ alkyl Halogen is independently F, Cl, Br or I.

In some embodiments, when R ^1-19 , R ^1-20 , R ^1-21 , R ^1-22 , R ^1-23 and R ^1-24 are independently halogen, the halogen is independently F, Cl, Br or I.

In some embodiments, when R ^1-19 , R ^1-20 , R ^1-21 , R ^1-22 , R ^1-23 and R ^1-24 are independently C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is independently C ₁ -C ₃ alkyl.

In some schemes, the "heteroatom substituted by R ^1-4 is selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms. "for

In some embodiments, when R ⁵ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ alkyl group.

In some embodiments, when R ⁵ is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is C ₁ -C ₃ alkoxy.

In some embodiments, when R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are independently C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by R ^13-1 , the C ₁ -C ₆ alkyl and the C ₁ -C ₆ alkyl in the C ₁ -C ₆ alkyl substituted by R ^13-1 are independently C ₁ -C ₄ alkyl (such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl or tert-butyl), more preferably n-propyl or n-butyl.

In some embodiments, when R ^13-1 is halogen, the halogen is F, Cl, Br or I.

In some schemes, when R ^13-1 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is C ₁ -C ₃ alkoxy.

In some embodiments, when R ^13-1 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ alkyl group.

In some embodiments, when R ^13-2 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ alkyl group.

In some schemes, the compound shown in formula I is any of the following compounds:

The present invention also provides a compound shown in formula II:

wherein, ^RA and ^RB are independently H or amino protecting groups, and ^RA and ^RB are not H at the same time; Y, A, B, R ¹ , R ² , R ³ and R ⁵ are as defined above .

In some schemes, the compound shown in formula II is any of the following compounds:

The present invention also provides a method for preparing the above-mentioned compound shown in formula I, which is method 1 or method 2:

Method 1 comprises the following steps: subjecting the compound represented by formula II to the deprotection reaction of the following formula to obtain the compound represented by formula I wherein R ¹³ is H;

Wherein, R ^A , R ^B , A, B, Y, R ¹ , R ² , R ³ and R ⁵ are defined as previously described;

Method 2 includes the following steps: performing the acylation reaction of the compound of formula I obtained in method 1, wherein R ¹³ is H, and compound III as shown below, to obtain R ¹³ as -CONR ¹⁴ R ¹⁵ , -C(=O ) R ¹⁶ or -COOR ¹⁷ compound shown in formula I;

Wherein, R ^A , R ^B , A, B, Y, R ¹ , R ² , R ³ and R ⁵ are as defined above.

In method 1, the operation and conditions of the deprotection reaction can be conventional in the art, such as heating in trifluoroacetic acid.

In Method 1, the operation and conditions of the acylation reaction can be conventional in the art, for example, under the action of a base (eg, pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine, or DMAP and DIPEA).

The present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound shown in formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salts, and pharmaceutical excipients.

The present invention also provides the above-mentioned compounds shown in formula I, their solvates, their prodrugs, their metabolites, or their pharmaceutically acceptable salts, or the use of the above-mentioned pharmaceutical compositions in the preparation of medicines. The drugs described are used to treat or prevent tumors or infections caused by viruses.

In some aspects, the virus is preferably one or more of HBV, HCV, HIV, and influenza virus.

The present invention also provides the above-mentioned compounds shown in formula I, their solvates, their prodrugs, their metabolites, or their pharmaceutically acceptable salts, or the use of the above-mentioned pharmaceutical compositions in the preparation of TLR7 agonists .

In the application, the TLR7 agonist can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or preparing according to conventional methods in the art into a kit to provide rapid detection of TLR7 inhibition effect.

The present invention also provides a method for preventing or treating a tumor or infection caused by a virus, comprising administering to a subject a therapeutically effective amount of the above-mentioned compound represented by formula I, its solvate, its prodrug, its Metabolites, their pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions.

In the treatment method, the virus is preferably one or more of HBV, HCV, HIV and influenza virus.

Unless otherwise specified, the terms used in the present invention have the following meanings:

As used herein, linked to an olefinic or alicyclic

Indicates the alkene or alicyclic cis-trans isomer or a mixture of the two. Cis-trans isomers can be named according to cis-trans nomenclature (ie, cis-trans nomenclature) or ZE nomenclature. E.g

express

(Z-configuration olefin) and/or

(E-configuration olefin); another example

express

(trans-cyclobutylene) and/or

(cis-cyclobutylene).

As used herein, terms used may be preceded and/or followed by a single dash "-" or double dash "=" to indicate the bond sequence of the bond between the named substituent and the parent moiety, a single dash for a single bond and a double dash for a double dash. Double bond. In the absence of a single or double dash, a single bond is considered to be formed between a substituent and its parent moiety; further, substituents are read "left to right" or "top to bottom" unless otherwise indicated. For example, "-Z ₅ -L ₂ -" means Z ₅ is connected to A and L ₂ is connected to B.

The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.

The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine. When compounds of the present invention contain relatively basic functional groups, acid additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic 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, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid), amino acids (eg, glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.

The term "prodrug" refers to a derivative of a compound of the present invention, which is converted to a compound of the present invention (drug) when administered to a warm-blooded animal (eg, a human). Typical examples of prodrugs include compounds with biologically labile protecting groups on functional moieties of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to yield the active compound .

The term "metabolite" refers to the degradation product of a compound of the present invention through one or more metabolic processes that exert a desired biological activity.

The terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt" can exist in crystalline or amorphous form. The term "crystal form" means that the ions or molecules in it are arranged strictly periodically in three-dimensional space in a definite manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism. The term "amorphous" means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.

The terms "compound," "solvate," "prodrug," "metabolite," and "pharmaceutically acceptable salt", when stereoisomers exist, may be used as single stereoisomers or as mixtures thereof ( For example, the form of racemate). The term "stereoisomer" refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

The terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt", if tautomers exist, may be expressed as single tautomers or their It exists in the form of a mixture, preferably the more stable tautomer predominates. For example, and are tautomers of each other.

Atoms in the terms "compound," "solvate," "prodrug," "metabolite," and "pharmaceutically acceptable salt" may exist in their natural or unnatural abundance. Taking a hydrogen atom as an example, its natural abundance means that about 99.985% of it is protium and about 0.015% is deuterium; its unnatural abundance means that about 95% of it is deuterium. That is, one or more atoms in the terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may be present in unnatural abundance Atoms that exist in the form.

When any variable (eg R ^1-1 ) appears multiple times in the definition of a compound, the definition that appears at each position of the variable is independent of the definitions appearing at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2 or 3 R ^1-1 groups, that is, the group may be substituted with up to 3 R ^1-1 groups, the definition of R ^1-1 at this position The definitions of the remaining positions R ^1-1 are independent of each other. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms, typically a saturated alkyl group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It resembles an alkyl group.

The term "alkylene" refers to a divalent group of a straight or branched chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms. Two valences can be concentrated on the same atom, such as methylene (-CH ₂ -), ethylene (-CHCH ₃ -), and the two valences can also be attached to two atoms respectively, such as 1,2- Ethylene ( _-CH2CH2- ₎ .

_The term "unsaturated hydrocarbylene" refers to a divalent group having the specified number of carbon atoms, a straight or branched chain aliphatic hydrocarbyl group containing one or more units of unsaturation, eg _-CH2CH2CH = _CHCH2 -.

The term "alkoxy" refers to the group -O-RX, wherein RX is an alkyl group as defined above.

The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, exemplified by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.

The term "cycloalkylene" refers to a divalent group of saturated cyclic alkylene groups, examples of cycloalkylene groups are: cyclopropylidene

Cyclobutylene (e.g.

), cyclopentylene (e.g.

or cyclohexylene, etc.

The term "heterocycloalkyl" refers to a saturated monocyclic group having a heteroatom. Examples of heterocycloalkyl are: tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl , morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and the like.

The term "heterocycloalkylene" refers to a saturated monocyclic divalent group having a heteroatom. Examples of heterocycloalkylenes are: piperidinylene (eg

) tetrahydrofuranylidene, tetrahydropyranylene, tetrahydrothienylene, tetrahydropyridylene, tetrahydropyrrolidene and the like.

The term "aryl" refers to a _C6 - _C10 aryl group such as phenyl or naphthyl.

The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur, When bicyclic, at least one ring is aromatic, such as furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrole base, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, Benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl and the like.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009Sixth Edition)

The term "treatment" refers to therapeutic therapy. In relation to a specific disorder, treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive improvement effect of the present invention is that: the present invention provides a series of macrocyclic compounds with good TLR7 agonistic activity, which can be used to treat or prevent tumors or infections caused by viruses.

Detailed ways

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

The compounds of the present invention are prepared using the following procedures:

Process 1

In Scheme 1, starting compound IIa or IIb or IIc undergoes substitution reaction with compound III to obtain compound IV; compound IV and compound V undergo substitution reaction to generate compound A1; compound A1 undergoes olefin metathesis reaction to obtain macrocyclic compound A2; compound A2 is deprotected The group obtains the target compound Ib or the compound A2 undergoes catalytic hydrogenation to obtain the compound A3, and the compound A3 deprotects the group to obtain the target compound Ia.

Process 2:

In the scheme 2, the starting compound IIa or IIb or IIc undergoes a substitution reaction with compound III to obtain compound IV, and compound IV and compound VI undergo a substitution reaction to generate compound B1; compound B1 undergoes olefin metathesis reaction to obtain macrocyclic compound B2; compound B2 is deprotected The group obtains the target compound Id or the compound B2 undergoes catalytic hydrogenation to obtain the compound B3, and the compound B3 deprotects the group to obtain the target compound Ic.

Process 3:

In the process 3, the starting compound C1 and compound C2 are subjected to substitution reaction to obtain compound compound C3; compound C3 and compound IId are subjected to substitution reaction to obtain compound compound C4; compound C4 is deprotected to obtain compound C5, and compound C5 is subjected to oxidation reaction to obtain compound compound C6; compound C6 is subjected to substitution reaction to obtain macrocyclic compound C7; compound C7 is deprotected to obtain the target compound Ie.

Process 4:

In the scheme 4, starting compound C1 is subjected to substitution reaction to obtain compound compound D1; compound D1 and compound IId are subjected to substitution reaction to obtain compound compound D2; compound D2 is deprotected to obtain compound D3, and compound D3 is subjected to oxidation reaction to obtain compound D4;

Compound D4 is subjected to substitution reaction to obtain macrocyclic compound D5; compound D5 is deprotected to obtain the target compound If.

Process 5:

In Scheme 5, compound I is acylated to obtain compound Ig, and R ¹³ is CONR ¹⁴ R ¹⁵ , C(=O)R ¹⁶ or COOR ¹⁷ ).

In the above Schemes 1 to 5, LG is -OH, halogen, -OS(O) ₂ (C ₁ -C ₄ alkyl), and the definition of each substituent in each compound is as described in any one of the above.

In the following examples, the structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

SHIMADZU LC system (column:

CSH ^™ Prep-C18, 19*150mm, liquid handler LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% trifluoroacetic acid in water).

LC/MS spectra of compounds were obtained using LC/MS (Agilent Technologies 1200 Series). LC/MS conditions were as follows (run time was 10 min):

Acidic conditions: A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoroacetic acid in acetonitrile;

Basic conditions: A: 0.05% NH ₃ ·H ₂ O in water; B: acetonitrile

Neutral conditions: A: 10 mM _NH4OAC in water; B: acetonitrile

Unless otherwise specified, in the following examples, the intermediates and final compounds were purified by silica gel column chromatography, or used

Purification by preparative HPLC on a CSH ^™ Prep-C18 (5 μm, OBD ^™ 19*150 mm) column or on a reverse phase column using XBridge™ Prep Phenyl (5 μm, OBD ^™ 30*100 mm).

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

Thin-layer chromatography (TLC) silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for TLC detection products are 0.15mm to 0.2mm, and the specifications for TLC separation and purification products are 0.4mm～0.5mm.

The known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.

Abbreviations: Ac ₂ O: acetic anhydride; AIBN: azobisisobutyronitrile; BH ₃ : borane; Boc ₂ O: tert-butoxycarbonyl tert-butyl carbonate; CBr ₄ : carbon tetrabromide; CH ₃ I(MeI): iodomethane; _con.H2SO4 : concentrated sulfuric acid; _con.HNO3 : concentrated nitric acid; _Cs2CO3 _: cesium carbonate _; _CH3SNa : sodium methanethiolate; DCM: dichloromethane; DIAD : Diisopropyl azodicarboxylate; DIBAL-H: Diisobutylaluminum hydride; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide ; DMSO: dimethyl sulfoxide; H ₂ SO ₄ : sulfuric acid; HOAc; acetic acid; K ₂ CO ₃ : potassium carbonate; K ₃ PO ₄ : potassium phosphate; LiAlH ₄ : lithium aluminum hydride; LiHMDS: bistrimethylsilicon lithium amide; LiOH: lithium hydroxide; mCPBA: m-chloroperoxybenzoic acid; MeOH: methanol; N,N-diethylaniline: N,N-diethylaniline; NaCNBH ₃ : sodium cyanoborohydride; NaH: Sodium hydride; NaHCO ₃ : sodium bicarbonate; NBS: N-bromosuccinimide; NH ₃ : ammonia; NIS: N-iodosuccinimide; PCy3: tricyclohexylphosphine; Pd(dppf) Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride; Pd(OAc) ₂ : palladium acetate; Pd/C: palladium carbon; Pd ₂ (dba) ₃ : tris (dibenzylideneacetone)dipalladium; POCl ₃ : phosphorus oxychloride; PPh ₃ : triphenylphosphine; SOCl ₂ : thionyl chloride; TBAF: tetrabutylammonium fluoride; TBDPSCl: tert-butyldiphenyl TBSCl: tert-butyldimethylchlorosilane; t-BuOK: potassium tert-butoxide; TEA: triethylamine; TES: triethylsilane; TFA: trifluoroacetic acid; TFAA: trifluoroacetic anhydride; TfOH: trifluoromethanesulfonic acid; THF: tetrahydrofuran; TLC: thin layer chromatography; TMP: trimethyl phosphate; XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene ; Zn: zinc; Zn(CN) ₂ : zinc cyanide

Preparation Example 1 Intermediate A1

Step 1: Preparation of Intermediate A1-2

Intermediate A1-1 (2 g, 5.04 mmol), DIEA (1.95 g, 15.11 mmol) and bis(4-methoxybenzyl)amine (1.56 g, 6.1 mmol) were dissolved in dichloromethane ( 20 mL), the reaction mixture was stirred at 20 degrees for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate A1-2 (2.43 g) as a colorless oil. , 78.0%). MS: 618.8 (M+H) ⁺ .

Step 2: Preparation of Intermediate A1-3

Intermediate A1-2 (2.4 g, 3.9 mol) and potassium tert-butoxide (871.5 mg, 7.7 mmol) were dissolved in 3-buten-1-ol (20 mL) and the reaction was mixed at 90°C and the reaction was stirred 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless oily intermediate A1-3 (2.53 g , 99.6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.17 (d, J=8.6 Hz, 4H), 6.86 (d, J=8.7 Hz, 4H), 6.26 (s, 1H), 5.94-5.79 (m, 1H) ,5.55(s,2H),5.15–4.99(m,2H),4.81(s,4H),4.36(t,J=7.1Hz,2H),3.80(d,J=2.7Hz,6H),3.67– 3.57 (m, 2H), 2.61–2.47 (m, 2H), 0.95–0.89 (m, 2H), 0.02–0.06 (m, 9H).

Step 3: Preparation of Intermediate A1-4

Intermediate A1-3 (2.5 g, 3.9 mmol), zinc cyanide (637 mg, 7 mmol), zinc dust (455 mg, 7 mmol) and palladium acetate (156 mg, 0.7 mmol) were dissolved in In DMF (10 mL), the reaction mixture was stirred at 100 degrees for 8 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate A1-4 (1.8 g, 78%) as a colorless oil. MS: 600.5 (M+H) ⁺ .

Step 4: Preparation of Intermediate A1

Intermediate A1-4 (1.7 g, 2.8 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (20 mL) and the reaction was mixed and stirred at 25 degrees for 5 hours. The reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain white solid Intermediate A1 (1.28 g, 98%). MS: 469.9 (M+H) ⁺ .

Preparation Example 2 Intermediate A2

Step 1: Preparation of Intermediate A2-2

Intermediate A2-1 (2.0 g, 10.6 mmol), TEA (1.6 g, 15.9 mmol) and bis(4-methoxybenzyl)amine (4.06 g, 12.7 mmol) were dissolved in dichloromethane ( 20 mL), the reaction mixture was stirred at 20 degrees for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine respectively, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oily intermediate A2-2 (4.0 g, 92%). MS: 410.2 (M+H) ⁺ .

Step 2: Preparation of Intermediate A2

Intermediate A2-2 (4 g, 9.8 mmol) and sodium methanethiolate (2.05 g, 29.3 mmol) were dissolved in DMF (30 mL) and the reaction was mixed at 110 degrees and stirred for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid Intermediate A2 (2.8 g, 68%). MS: 422.2 (M+H) ⁺ .

Preparation Example 3 Intermediate A3

Intermediate A2-2 (2.0 g, 4.9 mmol) and potassium tert-butoxide (5.5 g, 48.8 mmol) were dissolved in 3-buten-1-ol (20 mL) and the reaction was mixed at 90 degrees with stirring The reaction was carried out for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain yellow solid Intermediate A3 (1.5 g, 69%). MS: 446.3 (M+H) ⁺ .

Preparation Example 4 Intermediate A4

Step 1: Preparation of Intermediate A4-2

Intermediate A4-1 (11.3 g, 60 mmol) was dissolved in dichloromethane (240 mL), _CF3SO3Na (28.2 g, 180 mmol) and water (96 mL ₎ were added with stirring at 0°C , and the reaction was stirred at 0°C for 10 minutes. t-BuOOH (42 mL) was added to the above reaction solution with stirring at 0 degrees, and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless oily intermediate A4-2 (1.9 g, 13%). MS: 256.1 (M+H) ⁺ .

Step 2: Preparation of Intermediate A4-3

Intermediate A4-2 (1.9 g, 7.5 mmol) and bis(4-methoxybenzyl)amine (1.9 g, 7.5 mmol) and DIEA (1.9 g, 14.9 mmol) were dissolved in isopropanol ( 20 mL), the reaction mixture was stirred at 130 degrees for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine respectively, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oily intermediate A4-3 (900 mg, 25%). MS: 477.0 (M+H) ⁺ .

Step 3: Preparation of Intermediate A4-4

Intermediate A4-3 (0.9 g, 1.8 mol) and sodium hydrogen (117 mg, 2.9 mmol) were dissolved in tetrahydrofuran (10 mL) and the reaction was mixed at 0 degrees and stirred for 0.5 h. SEMCl (366 mg, 2.2 mmol) was then added to the above reaction mixture and the reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a colorless oily intermediate A4-4 (600 mg) , 67%). MS: 608.0 (M+H) ⁺ .

Step 4: Preparation of Intermediate A4-5

Intermediate A4-4 (500 mg, 0.82 mmol) and potassium tert-butoxide (185 mg, 1.6 mmol) were dissolved in 3-buten-1-ol (10 mL) and the reaction was mixed at 110 °C with stirring The reaction was carried out for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain a colorless oily intermediate A4-5 (300 mg , 57%).

Step 5: Preparation of Intermediate A4

Intermediate A4-5 (300 mg, 0.46 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) and the reaction was mixed and stirred at 25 degrees for 15 hours. The reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain intermediate A4 (230 mg) as a white solid. MS: 513.1 (M+H) ⁺ .

Preparation Example 5 Intermediate B1

Step 1: Preparation of Intermediate B1-2

Intermediate B1-1 (3.3 g, 14.5 mmol) was dissolved in 15 mL of dichloromethane, and trifluoroacetic anhydride (6.1 g, 29.0 mmol) was added dropwise to the reaction mixture with stirring at 0°C. The reaction mixture was then warmed to room temperature and stirring was continued for 3 hours. The reaction mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate B1-2 (4.0 g, yield 96%) as a colorless oil. MS: 288.1 (M+H) ⁺ .

Step 2: Preparation of Intermediate B1-3

Intermediate B1-2 (5.0 g, 17.4 mmol) was dissolved in trifluoroacetic acid (40 mL), NIS (7.8 g, 34.8 mmol) and concentrated H ₂ SO ₄ (0.37 g) were added successively with stirring at 0°C , 3.8 mmol). The reaction mixture was warmed to room temperature and stirring was continued for 12 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain intermediate B1-3 (3.7 g, yield 51%) as a white solid. MS: 414.5 (M+H) ⁺ .

Step 3: Preparation of Intermediate B1-4

Intermediate B1-3 (1.7 g, 4.1 mmol) was suspended in 20 mL of methanol, and an aqueous potassium carbonate solution (1.14 g in 2.5 mL of water) was added to the mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, and the crude product Intermediate B1-4 was directly used in the next reaction without purification.

Step 4: Preparation of Intermediate B1-5

Intermediate B1-4 (1.3 g, 4.1 mmol) was dissolved in ethyl acetate (20 mL) and water (20 mL), followed by the addition of di-tert-butyl dicarbonate (1.1 g, 4.9 mmol) and carbonic acid Sodium hydrogen (464 mg, 5.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a colorless oil. Intermediate B1-5 (1.5 g, 87% yield).

Step 5: Preparation of Intermediate B1-6

Under nitrogen protection, intermediate B1-5 (1.0 g, 2.4 mmol), allylboronic acid pinacol ester (4.0 g, 24 mmol), tris(dibenzylideneacetone)dipalladium (0.44 g , 0.48 mmol), tricyclohexylphosphine (0.13 g, 0.48 mmol) and potassium phosphate (1.5 g, 7.3 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at 80°C for 2 hours and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate B1-6 (700 mg, yield 88%) as a yellow oil.

Step 6: Preparation of Intermediate B1

Under nitrogen protection, intermediate B1-6 (600 mg, 1.8 mmol) was dissolved in THF (15 mL), and a 1.5 M solution of DIBAL-H in toluene (3.6 mL, 5.4 mmol) was added with stirring at 0°C. . The reaction mixture was then stirred at 0°C for 2 hours, quenched by the addition of methanol, and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate B1 (130 mg, yield 24%) as a yellow oil.

Preparation Example 6 Intermediate B2

Step 1: Preparation of Intermediate B2-2

Intermediate B2-1 (5.0 g, 22 mmol) was dissolved in dichloromethane (120 mL), trifluoroacetic anhydride (6.1 mL, 43.9 mmol) was added dropwise at 0°C, and the reaction mixture was warmed to room temperature And the reaction was stirred for 12 hours. The reaction mixture was concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain intermediate B2-2 (5.9 g, yield 93%) as a white solid. MS: 288.1 (M+H) ⁺ . ¹ H NMR (CDCl ₃ , 400MHz) δ 7.91-7.86(m, 2H), 7.24-7.19(m, 1H), 4.82(d, J=20Hz, 2H), 3.92(s, 3H), 3.87(t , J=6.0Hz, 2H), 3.03-2.99 (m, 2H).

Step 2: Preparation of Intermediate B2-3

Intermediate B2-2 (5.9 g, 20.5 mmol) was dissolved in trifluoroacetic acid (40 mL), and NIS (7.8 g, 34.8 mmol) and concentrated sulfuric acid (4 mL) were added successively with stirring at 0°C. The reaction mixture was warmed to room temperature and reacted for 12 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate B2-3 (7.0 g, yield 83%) as a white solid. ¹ H NMR (CDCl ₃ , 400MHz) δ 8.39(s, 1H), 7.83(s, 1H), 4.69-4.68(m, 2H), 3.92(s, 3H), 3.90-3.82(m, 2H), 3.01-2.95 (m, 2H).

Step 3: Preparation of Intermediate B2-4

Intermediate B2-3 (7.0 g, 16.9 mmol) was suspended in methanol (20 mL) and potassium carbonate solution (4.7 g in 10 mL water) was added. The reaction mixture was stirred at room temperature for 3 hours, then the reaction mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product Intermediate B2-4 was directly used in the next reaction without purification. MS: 318.1 (M+H) ⁺ .

Step 4: Preparation of Intermediate B2-5

Intermediate B2-4 (5.4 g, 16.9 mmol) was dissolved in ethyl acetate (60 mL) and water (60 mL), sodium bicarbonate (1.7 g, 20 mmol) and dicarbonic acid were added at 0°C Di-tert-butyl ester (4.5 g, 20.3 mmol) in ethyl acetate (20 mL). The reaction mixture was warmed to room temperature and stirring was continued for 12 hours. The reaction mixture was then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate B2-5 (5.8 g, yield 82%) as a colorless oil. MS: 403.1(M-55+41) ⁺ . ¹ H NMR (CDCl ₃ , 400MHz) δ 8.34(s, 1H) 7.79(s, 1H), 4.47(s, 2H), 3.91(s, 3H), 3.63(t, J=5.6Hz, 2H), 2.85(t, J=5.6Hz, 2H), 1.50(s, 9H).

Step 5: Preparation of Intermediate B2-6

Under nitrogen protection, intermediate B2-5 (1.0 g, 2.4 mmol), allylboronic acid pinacol ester (4.0 g, 24 mmol), tris(dibenzylideneacetone)dipalladium (0.44 g , 0.48 mmol), tricyclohexylphosphine (0.13 g, 0.48 mmol) and potassium phosphate (1.5 g, 7.3 mmol) were dissolved in DMF (15 mL) and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oily intermediate B2-6 (608 mg, yield 77%). MS: 317.2(M-55+41) ⁺ .

Step 6: Preparation of Intermediate B2

Under nitrogen protection, intermediate B2-6 (1.1 g, 3.2 mmol) was dissolved in 40 mL of dry THF, and a 1.5 M solution of DIBAL-H in toluene (6.4 mL, 9.6 mmol) was added with stirring at 0°C, The reaction was continued to stir for 30 minutes, then quenched by addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate B2 (480 mg, yield 49%) as a colorless oil. ¹ H NMR (CDCl ₃ , 400MHz) δ7.03(s, 2H), 5.97-5.87(m, 1H), 5.11-5.03(m, 2H), 4.63(s, 2H), 4.53(s, 2H), 3.61 (t, J=5.6 Hz, 2H), 3.33 (d, J=5.6 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H), 1.48 (s, 9H).

Preparation Example 7 Intermediate B3

Step 1: Preparation of Intermediate B3-1

Intermediate B1-5 (10 g, 27.0 mmol) and pinacol diboronate (13.7 g, 54.0 mmol) were dissolved in 1,4-dioxane (200 mL) followed by the addition of PdCl ₂ ( dppf) (2 g, 2.7 mmol), potassium acetate (8 g, 81 mmol), the reaction mixture was stirred at 80° C. for 2 hours. Then water was added to quench the reaction, and extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried, filtered, and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography to obtain yellow solid intermediate B3 -1 (10.5 g, 93% yield). MS: 418.3 (M+H) ⁺ .

Step 2: Preparation of Intermediate B3

Intermediate B3-1 (10.5 g, 25.2 mmol) was dissolved in ethanol (50 mL) and water (25 mL) and m-chloroperbenzoic acid (5.2 g, 30.2 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and the reaction was continued to stir for 1 hour, then quenched by the addition of ice water and extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered and concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain intermediate B3 (7.5 g, yield 97%) as a white solid. MS: 308.2 (M+H) ⁺ .

Preparation Example 8 Intermediate B4

Step 1: Preparation of Intermediate B4-2

Intermediate B4-1 (trans configuration, 5.0 g, 4.7 mmol) was dissolved in THF (50 mL), and a 2.5M solution of lithium aluminum tetrahydride in THF (69.2 mL, 173 mmol) was added dropwise with stirring at 0 °C. ). The reaction mixture was warmed to room temperature and reacted for 12 hours. The reaction was then quenched by dropwise addition of ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate B4-2 (2.0 g, yield) as a colorless oil. 50%).

Step 2: Preparation of Intermediate B4-3

Intermediate B4-2 (2.0 g) was dissolved in THF (15 mL) and sodium hydrogen (124 mg, 5.2 mmol) was added at 0°C. After the reaction mixture was stirred at room temperature for 30 minutes, diphenyl-tert-butylchlorosilane (1.2 g, 4.3 mmol) was added and stirring was continued at room temperature for 1 hour. The reaction was then quenched by addition of ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate B4-3 (110 mg, yield) as a colorless oil. 72%).

Step 3: Preparation of Intermediate B4-4

Intermediate B4-3 (3 g, 8.5 mmol) was dissolved in dichloromethane (50 mL), then triphenylphosphine (3.3 g, 12.7 mmol) and carbon tetrabromide (4.2 g, 12.7 mmol) were added mol), the reaction mixture was reacted at room temperature for 2 hours. Then ice water was added to quench the reaction, and it was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Colorless oil Intermediate B4-4 (3.2 g, 91% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J=6.9 Hz, 4H), 7.41 (dd, J=10.7, 7.0 Hz, 6H), 3.60-3.70 (m, 2H), 3.49 (dd, J=9.7, 6.5Hz, 1H), 3.38(t, J=8.8Hz, 1H), 2.56(h, J=8.0Hz, 1H), 2.25(d, J=7.0Hz, 1H), 2.03(q, J=11.1, 9.9Hz, 1H), 1.85 (q, J=10.0, 9.2Hz, 1H), 1.60-1.80 (m,, 2H), 1.06 (s, 9H).

Step 4: Preparation of Intermediate B4-5

Intermediate B3 (1 g, 3.25 mmol) and Intermediate B4-4 (1.4 g, 3.3 mmol) were dissolved in DMF (10 mL) followed by the addition of cesium carbonate (2.1 g, 6.5 mmol). The reaction mixture was reacted at 100°C for 1 hour. The reaction was then quenched by addition of ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate B4-5 (1.4 g, yield) as a colorless oil. rate 67%). MS: 644.4 (M+H) ⁺ .

Step 5: Preparation of Intermediate B4-6

Intermediate B4-5 (1.4 g, 2.2 mmol) was dissolved in tetrahydrofuran (20 mL) and a solution of lithium tetrahydroaluminum in THF (2.5 M in THF, 0.87 mL, 2.2 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0° C. for 30 minutes, followed by dropwise addition of ice water to quench the reaction, and extraction with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate B4-6 (trans configuration) as a colorless oil. , 1.1 g, yield 82%). MS: 616.4 (M+H) ⁺ .

Step 6: Preparation of Intermediate B4

Intermediate B4-6 (615 mg, 1.0 mmol) was dissolved in dichloromethane (20 mL), triphenylphosphine (526 mg, 2.0 mmol) and carbon tetrabromide (915 mL) were added dropwise at 20°C mg, 2.8 mmol), then the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give crude product, which was purified by silica gel column chromatography to give Intermediate B4 (550 mg) as a colorless oil. , 81%).

Preparation Example 9 Intermediate B5

Step 1: Preparation of Intermediate B5-1

4-Bromo-1-butanol (5 g, 32.3 mmol) was dissolved in DMF (80 mL) and NaH (1.6 g, 39.5 mmol) was added at 0°C. The reaction mixture was then brought back to room temperature and stirred for 30 minutes, then diphenyl-tert-butylchlorosilane (10.9 g, 39.5 mmol) was added and the reaction was stirred for 2 hours at room temperature. The reaction was then quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate B5-1 (3.0 g, yield) as a colorless oil. rate 22%).

Step 2: Preparation of Intermediate B5-2

Intermediate B3 (1 g, 3.3 mmol) and Intermediate B5-1 (1.2 g, 3.3 mmol) were dissolved in DMF (10 mL) followed by the addition of cesium carbonate (2.1 g, 6.5 mmol). The reaction mixture was stirred at 100°C for 1 hour. After cooling, the reaction was then quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate B5-2 (1.5 g, yield) as a colorless oil. rate 75%). MS: 618.4 (M+H) ⁺ .

Step 3: Preparation of Intermediate B5-3

Intermediate B5-2 (0.7 g, 1.2 mmol) was dissolved in tetrahydrofuran (20 mL), and a solution of lithium tetrahydroaluminum in THF (2.5 M in THF, 0.46 mL, 2.3 mmol) was added dropwise at 0°C, The reaction was stirred at 0°C for 30 minutes, quenched by dropwise addition of ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine and water, respectively, dried, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain Intermediate B5-3 (0.55 g, yield) as a colorless oil. rate 82%). MS: 590.4 (M+H) ⁺ .

Step 4: Preparation of Intermediate B5

Intermediate B5-3 (1.1 g, 1.8 mmol) was dissolved in dichloromethane (20 mL), triphenylphosphine (740 mg, 2.8 mmol) and carbon tetrabromide (915 mmol) were added dropwise at 20 °C mg, 2.8 mmol), then the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give Intermediate B5 (850 mg) as a colorless oil. , 71%).

Preparation Example 10 Intermediate B6

Step 1: Preparation of Intermediate B6-1

Synthesis of intermediate B6-1 Referring to intermediate B2, intermediate B6-1 was prepared by using methyl 3-bromobenzoate in place of intermediate B2-5.

Step 2: Preparation of Intermediate B6

The synthesis of intermediate B6 Referring to intermediate B5, intermediate B6 was prepared by using intermediate B6-1 ester instead of intermediate B5-3.

Example 1

Compound I-1

Step 1: Preparation of Intermediate I-1-1

Intermediate I-12-1 (411 mg, 1.1 mmol), Intermediate A1 (500 mg, 1.1 mmol) and cesium carbonate (548 mg, 1.7 mmol) were dissolved in DMF (10 mL), followed by The reaction mixture was stirred at 25°C for 15 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid intermediate I-1-1( 490 mg, 60%). MS: 731.4 (M+H) ⁺ .

Step 2: Preparation of Intermediate I-1-2

Under nitrogen protection, intermediate I-1-1 (490 mg, 0.67 mmol) was dissolved in dichloromethane (200 mL), followed by the addition of Grubbs second-generation catalyst (114 mg, 0.13 mmol) with stirring at room temperature , and then the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain yellow solid Intermediate I-1-2 (120 mg, 26%). MS: 703.4 (M+H) ⁺ .

Step 3: Preparation of Intermediate I-1

Intermediate I-1-2 (40 mg, 0.057 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 110° C. for 1 hour. The reaction was cooled, the reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain the crude product. The crude product was prepared by Liquid chromatography gave compound I-1 (10 mg, 37%) as a white solid. MS: 363.2 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(s, 2H), 8.08(s, 1H), 7.91(s, 1H), 7.08(s, 1H), 5.81-5.76(m, 1H), 5.50-5.40(m, 1H), 5.29(s, 2H), 4.88-4.85(m, 2H), 4.22-4.18(m, 2H), 3.72-3.69(m, 2H), 3.37-3.28(m, 2H) ), 3.07(d, J=7.2Hz, 2H), 2.79-2.75(m, 2H).

Example 2

Compound I-2

Step 1: Preparation of Intermediate I-2-1

Under nitrogen protection, intermediate I-1-2 (40 mg, 0.057 mmol) was dissolved in ethyl acetate (10 mL), followed by addition of palladium on carbon (20 mg) with stirring at room temperature, followed by hydrogen The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and concentrated to yield intermediate I-2-1 as a yellow solid (40 mg, 100%). MS: 705.2 (M+H) ⁺ .

Step 2: Preparation of Intermediate I-2

Intermediate I-2-1 (40 mg, 0.057 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 110° C. for 1 hour. The reaction was cooled, the reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain the crude product. The crude product was prepared by Liquid chromatography gave compound I-2 as a white solid (15 mg, 55%). MS: 365.2 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.87(s, 2H), 7.91(s, 1H), 7.69(s, 1H), 6.86(s, 1H), 5.32(s, 2H), 4.43- 4.36(m,2H),4.18-4.12(m,2H),3.36-3.30(m,2H),2.85-2.80(m,2H),2.65-2.59(m,2H),1.75-1.68(m,2H) ), 1.49-1.42 (m, 2H), 1.37-1.28 (m, 2H).

Example 3

Compound I-3

Step 1: Preparation of Intermediate I-3-1

Intermediate A2 (350 mg, 0.83 mmol), Intermediate B5 (676 mg, 1 mmol) and cesium carbonate (406 mg, 1.2 mmol) were dissolved in DMF (10 mL), and the reaction mixture was heated at 25 The reaction was stirred at °C for 2 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oily intermediate I-3-1 (550 mg, 65%). MS: 993.5 (M+H) ⁺ .

Step 2: Preparation of Intermediate I-3-2

Intermediate I-3-1 (120 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 mL) and a 1M solution of TBAF in tetrahydrofuran (0.2 mL, 0.2 mmol), then the reaction mixture was stirred at 25 °C for reaction 12 Hour. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid intermediate I-3-2( 80 mg, 80%). MS: 755.4 (M+H) ⁺ .

Step 3: Preparation of Intermediate I-3-3

Intermediate 1-3-2 (350 mg, 0.45 mmol) was dissolved in dichloromethane (10 mL) and m-chloroperoxybenzoic acid (93 mg, 0.54 mmol) was added to the reaction with stirring at 0°C The reaction mixture was then stirred at 25°C for 2 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid intermediate I-3-3( 340 mg, 95%). MS: 771.4 (M+H) ⁺ .

Step 4: Preparation of Intermediate I-3-4

A solution of intermediate 1-3-3 (340 mg, 0.43 mmol) and potassium tert-butoxide (96 mg, 0.85 mmol) in tetrahydrofuran (10 mL) was stirred at 25 °C for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain a yellow solid intermediate Body I-3-4 (200 mg, 64%). MS: 707.4 (M+H) ⁺ .

Step 5: Preparation of Intermediate I-3

Synthesis of compound 1-3 Referring to compound 1-2, white solid compound 1-3 was prepared by using intermediate 1-3-4 instead of intermediate 1-2-1. MS: 367.2 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ8.86(s, 2H), 7.95(s, 1H), 7.89-7.87(m, 1H), 7.56(s, 1H), 6.77(s, 1H), 5.30(s, 2H), 4.72-4.65(m, 2H), 4.40-4.32(m, 2H), 4.18-4.12(m, 2H), 3.32-3.28(m, 2H), 2.74-2.70(m, 2H) ), 1.65-1.57 (m, 4H).

Example 4

Compound I-4

Synthesis of compound I-4 Referring to compound I-2, white solid compound I-4 was prepared by using intermediate B6 instead of intermediate I-12-1. MS: 310.2 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.97(s,1H),7.65(s,1H),7.16-7.10(m,1H),7.05-7.10(m,1H),6.90-6.87(m , 1H), 5.36(s, 2H), 4.36-4.28(m, 2H), 2.68-2.62(m, 2H), 1.75-1.67(m, 2H), 1.35-1.28(m, 4H).

Example 5

Compound I-5

Synthesis of compound 1-5 Referring to compound 1-3, white solid compound 1-5 was prepared by using intermediate B4 instead of intermediate B5. MS: 393.3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.91(s, 1H), 8.81(s, 1H), 7.86(d, J=2.2Hz, 1H), 7.62(s, 1H), 6.73(s, 1H), 5.30-5.27(m, 2H), 4.17-4.13(m, 4H), 3.75-3.71(m, 2H), 3.35-3.31(m, 2H), 2.78-2.74(m, 2H), 2.42- 2.36 (m, 2H), 1.90-1.85 (m, 1H), 1.84-1.75 (m, 1H), 1.73-1.68 (m, 2H).

Example 6

Compound I-6

Step 1: Preparation of Intermediate I-6-1

Intermediate 1-5-4 (732 mg, 1 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain a colorless oily intermediate Intermediate Intermediate 1-6-1 (588 mg, 93%). MS: 632.2 (M+H) ⁺ .

Step 2: Preparation of Intermediate I-6-2

Intermediate 1-6-1 (88.5 mg, 140 μmol) was dissolved in methanol (5 mL), then acetone (40.6 mg, 699.8 μmol) and acetic acid (8.4 mg, 140 μmol) were added to the above reaction The mixture was stirred at room temperature for 1 hour. NaCNBH ₃ (44.1 mg, 699.8 μmol) was added to the above reaction mixture, and the reaction mixture was stirred at 60 degrees for 3 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was filtered through a silica gel column. Analytical purification afforded intermediate 1-6-2 as a yellow solid (48 mg, 51%). MS: 675.1 (M+H) ⁺ .

Step 3: Preparation of Compound 1-6

Intermediate I-6-2 (48 mg, 71.2 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 110° C. for 1 hour. The reaction was cooled, the reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain the crude product. The crude product was prepared by Liquid chromatography gave compound I-6 as a white solid (11 mg, 36%). MS: 435.3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.87(d, J=1.9Hz, 1H), 7.63(s, 1H), 6.74(s, 1H), 5.30(s, 2H), 4.62-4.58( m,1H),4.30-4.25(m,2H),3.75-3.70(m,2H),3.45-3.38(m,1H),3.23-3.18(m,1H),2.95-2.90(m,1H), 2.85-2.78(m, 1H), 2.48-2.34(m, 3H), 1.92-1.87(m, 1H), 1.82-1.78(m, 1H), 1.70-1.64(m, 2H), 1.27(dd, J =6.6,4.8Hz,6H).

Example 7

Compound I-7

Synthesis of compound 1-7 Referring to compound 1-6, white solid compound 1-7 was prepared by using cyclobutanone instead of acetone. MS: 447.3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.86(s,1H), 7.64(s,1H), 6.75(s,1H), 5.29(s,2H), 4.57-4.52(m,1H), 4.38-4.27(m, 1H), 4.09-4.04(m, 2H), 3.76-3.72(m, 1H), 3.09-3.05(m, 1H), 2.91(d, J=18.7Hz, 1H), 2.82- 2.76 (m, 1H), 2.44-2.38 (m, 2H), 2.29-2.11 (m, 5H), 1.92-1.65 (s, 7H).

Example 8

Compound I-8

Synthesis of compound 1-8 Referring to compound 1-6, white solid compound 1-8 was prepared by using intermediate 1-3-4 instead of intermediate 1-5-4. MS: 409.3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.42(s,1H),7.96(d,J=1.4Hz,1H),7.86(s,1H),6.77(d,J=1.2Hz,1H) ,5.32(s,2H),4.68(s,2H),4.38(t,J＝6.5Hz,2H),4.28(d,J＝4.9Hz,2H),3.60-3.55(m,2H),3.24- 3.15(m,1H), 2.91-2.87(m,1H), 2.77-2.74(m,1H), 1.63-1.58(m,4H), 1.29-1.25(m,6H).

Example 9

Compound I-9

Synthesis of compound 1-9 Referring to compound 1-6, compound 1-9 was prepared as a white solid by using intermediate 1-3-4 instead of intermediate 1-5-4 and cyclobutanone instead of acetone. MS: 421.3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.81(s,1H), 7.98(s,1H), 7.86(s,1H), 6.78(s,1H), 5.31(s,2H), 4.70- 6.64(m, 2H), 4.40-4.33(m, 2H), 4.06-4.01(m, 1H), 3.75-3.70(m, 2H), 3.07(s, 1H), 2.90-2.68(m, 2H), 2.22-2.05 (m, 4H), 1.77-1.53 (m, 7H).

Example 10

Compound I-10

Step 1: Preparation of Intermediate I-10-3

Synthesis of Intermediate I-10-3 Referring to Compound I-2, Intermediate I-10-3 was prepared as a white solid by using Intermediate I-11-1 instead of Intermediate I-12-1. MS: 705.3 (M+H) ⁺ .

Step 2: Preparation of Compound 1-10

Synthesis of compound 1-10 Referring to compound 1-6, white solid compound 1-10 was prepared by using intermediate 1-10-3 instead of intermediate 1-5-4. MS: 407.3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.49(s,1H),7.91(s,1H),7.70(s,1H),6.92(s,1H),5.34(d,J=1.7Hz, 2H), 4.49-4.46(m, 1H), 4.42-4.38(m, 1H), 4.26-4.23(m, 2H), 3.65-3.52(m, 2H), 3.16-3.00(m, 2H), 2.96- 2.92 (m, 1H), 2.65-2.60 (m, 2H), 1.76-1.73 (m, 2H), 1.53-1.49 (m, 2H), 1.30 (dd, J=6.6, 3.7 Hz, 8H).

Example 11

Compound I-11

Step 1: Preparation of Intermediate I-11-1

Intermediate B2 (0.4 g, 1.3 mmol) was dissolved in dichloromethane (10 mL), and triphenylphosphine (785.9 mg, 3.0 mmol) and carbon tetrabromide (991.8 mg, 3.0 mmol) were added dropwise at 20 °C. 3.0 mmol), then the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a colorless oily intermediate I-11- 1 (0.23 g, 31%). MS: 309.9[M+H-56] ⁺ .

Step 2: Preparation of Intermediate I-11-2

Intermediate I-11-1 (0.23 g, 619.7 μmol), Intermediate B1 (320.1 mg, 681.7 μmol) and cesium carbonate (403.8 mg, 1.2 mmol) were dissolved in DMF (4 mL), followed by The reaction mixture was stirred at 90°C for 5 hours. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid intermediate I-11-2( 0.4 g, 86%). MS: 755.2 (M+H) ⁺ .

Step 3: Preparation of Intermediate I-11-3

Under nitrogen protection, intermediate I-11-2 (0.4 g, 529.9 μmol) was dissolved in dichloromethane (200 mL), followed by the addition of Grubbs second-generation catalyst (20 mg, 529.9 μmol) with stirring at room temperature , and then the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to obtain crude product, which was purified by silica gel column chromatography to obtain yellow solid Intermediate I-11-3 (0.20 g, 51%). MS: 727.2 (M+H) ⁺ .

Step 4: Preparation of Intermediate I-11-4

Under nitrogen protection, intermediate 1-11-3 (0.12 g, 165.1 μmol) was dissolved in ethyl acetate (10 mL), followed by addition of palladium on carbon (60 mg) with stirring at room temperature, followed by hydrogen The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and concentrated to yield intermediate I-11-4 as a yellow solid (0.12 g, 99.7%). MS: 729.2 (M+H) ⁺ .

Step 5: Preparation of Intermediate I-11-5

Intermediate 1-11-4 (0.12 g, 164.6 μmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL), and the reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain a colorless oily intermediate Intermediate Intermediate 1-11-5 (88 mg, 85%). MS: 629.2 (M+H) ⁺ .

Step 6: Preparation of Intermediate I-11-6

Intermediate I-11-5 (88 mg, 140 μmol) was dissolved in methanol (5 mL), then acetone (40.6 mg, 699.8 μmol) and acetic acid (8.4 mg, 140 μmol) were added to the above reaction The mixture was stirred at room temperature for 1 hour. NaCNBH ₃ (44.1 mg, 699.8 μmol) was added to the above reaction mixture, and the reaction mixture was stirred at 60 degrees for 3 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was filtered through a silica gel column. Analytical purification afforded intermediate I-11-6 as a yellow solid (44 mg, 47%). MS: 671.1 (M+H) ⁺ .

Step 7: Preparation of Compound 1-11

Intermediate I-11-6 (44 mg, 65.6 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 110° C. for 1 hour. The reaction was cooled, the reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain the crude product. The crude product was prepared by Liquid chromatography gave compound I-11 as a white solid (6.25 mg, 22%). MS: 431.0 (M+H) ⁺ . ¹ H NMR(400MHz,DMSO)δ7.70(s,1H),7.50(br,2H),7.37(s,1H),6.87(s,1H),5.20(s,2H),4.42(s,2H) ), 4.25(s, 2H), 3.65(dd, J=28.1, 21.5Hz, 2H), 3.01(s, 3H), 2.63(s, 2H), 1.74(s, 2H), 1.55–1.40(m, 2H), 1.33–1.28 (m, 8H).

Example 12

Compound I-12

Step 1: Preparation of Intermediate I-12-1

Synthesis of Intermediate I-12-1 With reference to Intermediate I-11-1, Intermediate I-12-1 was prepared by using Intermediate B1 instead of Intermediate B2. MS: 309.9[M+H-56] ⁺ .

Step 2: Preparation of Intermediate I-12-3

Synthesis of Intermediate 1-12-3 With reference to Intermediate 1-11-3, Intermediate 1-12-3 was prepared by using Intermediate 1-12-1 in place of Intermediate 1-11-1. MS: 727.2 (M+H) ⁺ .

Step 3: Preparation of Compound 1-12

Intermediate I-12-3 (100 mg, 137.6 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 110° C. for 1 hour. The reaction was cooled, the reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain the crude product. The crude product was prepared by Compound 1-12 (4.91 mg, 8.4%) was isolated as a white solid by liquid chromatography. MS: 387.1 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO) δ8.15(s, 1H), 7.55(br, 2H), 7.29(s, 1H), 7.04(s, 1H), 5.74(dd, J=14.7, 7.8Hz, 1H ), 5.44(dd, J=15.3, 7.8Hz, 1H), 5.19(s, 2H), 4.83(s, 2H), 4.27(s, 2H), 3.36(s, 2H), 3.08(d, J= 6.9Hz, 2H), 2.78(s, 2H), 2.49–2.44(m, 2H), 2.40(s, 1H).

Example 13

Compound I-13 and Compound I-14

Step 1: Preparation of Intermediate I-13-1

Intermediate I-11-3 (100 mg, 137.6 μmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL), and the reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain a colorless oily intermediate Intermediates Intermediate I-13-1 (80 mg, 93%). MS: 627.2 (M+H) ⁺ .

Step 2: Preparation of Intermediate I-13-2

Intermediate I-13-1 (88 mg, 127.6 μmol) was dissolved in methanol (5 mL), then acetone (40.6 mg, 699.8 μmol) and acetic acid (8.4 mg, 140 μmol) were added to the above reaction The mixture was stirred at room temperature for 1 hour. NaCNBH ₃ (40.2 mg, 638.2 μmol) was added to the above reaction mixture, and the reaction mixture was stirred at 60 degrees for 3 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain the crude product, which was filtered through a silica gel column. Analytical purification afforded Intermediate I-13-2 as a yellow oil (45 mg, 53%). MS: 669.1 (M+H) ⁺ .

Step 3: Preparation of Compound 1-13 and Compound 1-14

Intermediate I-13-2 (18.4 mg, 27.5 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 110° C. for 1 hour. The reaction was cooled, the reaction mixture was concentrated and evaporated to dryness, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain the crude product. The crude product was prepared by Liquid chromatography obtained compound I-13 and compound I-14 as white solids.

Compound 1-13 (2.8 mg). MS: 429.0 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO) δ7.99(s,1H), 7.50(br,2H), 7.28(s,1H), 6.93(s,1H), 5.83–5.68(m,1H), 5.41(dt , J＝15.3, 7.5Hz, 1H), 5.14(s, 2H), 4.83(s, 2H), 3.48(s, 2H), 3.01(d, J＝6.7Hz, 2H), 2.91–2.82(m, 1H), 2.75 (s, 2H), 2.62 (d, J=5.2 Hz, 2H), 2.47 (d, J=6.3 Hz, 2H), 1.02 (t, J=8.1 Hz, 6H).

Compound 1-14 (2.8 mg). MS: 429.0 (M+H) ⁺ . ¹ H NMR(400MHz, DMSO)δ7.68(s,1H),7.54(br,2H),7.31(s,1H),6.89(s,1H),5.70(t,J=8.3Hz,1H), 5.66-5.56(m, 1H), 5.12(s, 2H), 4.61-4.50(m, 2H), 3.55(s, 2H), 3.15(d, J=7.4Hz, 2H), 2.92-2.83(m, 1H), 2.74 (s, 2H), 2.61 (d, J=5.0 Hz, 2H), 2.34 (s, 2H), 1.04 (d, J=6.5 Hz, 6H).

Example 14

Compound I-15

Step 1: Preparation of Intermediate I-15-2

Synthesis of Intermediate 1-15-2 With reference to Intermediate 1-11-5, Intermediate 1-15-2 was prepared by using Intermediate 1-12-3 in place of Intermediate 1-11-3. MS: 629.2 (M+H) ⁺ .

Step 2: Preparation of Intermediate I-15-3

Intermediate I-15-2 (39 mg, 0.06 mmol) and TEA (35 mg, 0.34 mmol) were dissolved in tetrahydrofuran (5 mL), and acetyl chloride (10 mL) was added to the reaction mixture with stirring at 0°C. mg, 0.13 mmol) and stirring was continued for 2 h at room temperature. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give Intermediate I-15-3 (11 mg, 15%) as a colorless oil. MS: 671.2 (M+H) ⁺ .

Step 3: Preparation of Compound 1-15

Synthesis of compound I-15 Referring to intermediate I-2, compound I-15 was prepared as a white solid by using intermediate I-15-3 instead of intermediate I-12-3. MS: 431.2 (M+H) ⁺ . ¹ H NMR(400MHz,DMSO)δ7.61(s,1H),7.50(br,2H),7.36(s,1H),6.80(s,1H),5.17(s,2H),4.56(s,1H) ),4.49(s,1H),4.39-4.36(m,2H),3.61-3.58(m,2H),2.72-2.61(m,4H),2.03(s,3H),1.70(br,2H), 1.45(br,2H), 1.31(br,2H).

Example 15

Compound I-16

Synthesis of compound I-16 Reference compound I-11, prepared by using intermediate I-15-2 instead of intermediate I-11-5 and tetrahydro-4H-pyran-4-one instead of acetone to give compound I- 16. MS: 473.2 (M+H) ⁺ . ¹ H NMR(400MHz, DMSO)δ7.53(s,1H),7.50(br,2H),7.35(s,1H),6.65(s,1H),5.13(s,2H),4.39-4.36(m ,2H),3.87-3.86(m,2H),3.57(s,2H),3.32-3.24(m,2H),2.71-2.62(m,6H),1.74-1.71(m,4H),1.45-1.24 (m, 7H).

Example 16

Compound I-17

Synthesis of compound 1-17 Referring to compound 1-15, white solid compound 1-17 was prepared by using 4-(bromomethyl)pyridine instead of acetyl chloride. MS: 480.1 (M+H) ⁺ . ¹ H NMR(400MHz,DMSO)δ8.50(s,2H),7.58(s,1H),7.50(br,2H),7.34-7.33(m,3H),6.62(s,1H),5.13(s ,2H),4.42-4.39(m,2H),3.61(s,2H),3.48(s,2H),2.70-2.55(m,6H),1.70(br,2H),1.47-1.44(m,2H) ), 1.31-1.24 (m, 2H).

Example 17

Compound I-18

Synthesis of compound 1-18 Referring to compound 1-11, white solid compound 1-18 was prepared by using intermediate 1-15-2 instead of intermediate 1-11-5. MS: 431.1 (M+H) ⁺ . ¹ H NMR(400MHz,DMSO)δ7.57-7.41(m,3H),7.36(s,1H),6.68(s,1H),5.15(s,2H),4.37(t,J=6.5Hz,2H ), 3.68(s, 2H), 2.94(s, 1H), 2.80(s, 2H), 2.68(s, 2H), 2.59(s, 2H), 1.69(s, 2H), 1.41(d, J= 6.2Hz, 2H), 1.34 (d, J=6.2Hz, 2H), 1.06 (d, J=6.3Hz, 6H).

Example 18

Compound I-19

Synthesis of compound 1-19 Referring to compound 1-11, compound 1-19 was prepared as a white solid by using intermediate 1-15-2 instead of intermediate 1-11-5 and cyclobutanone instead of acetone. MS: 443.0 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO) δ7.54(br,3H), 7.35(s,1H), 6.64(s,1H), 5.14(s,2H), 4.38(s,2H), 3.29(s,2H) ), 2.76(s, 1H), 2.60(s, 4H), 2.45(s, 2H), 2.00(d, J=7.1Hz, 2H), 1.80(s, 2H), 1.68(s, 4H), 1.42 -1.38(m, 2H), 1.33-1.28(m, 2H).

Example 19

Compound I-20

Compound I-19 (15 mg, 33.9 μmol), TEA (10.3 mg, 101.7 μmol) and butyryl chloride (7.2 mg, 67.8 μmol) were dissolved in dichloromethane (5 mL), and the reaction mixture was dissolved at 40 The reaction was stirred for 16 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was separated by preparative liquid chromatography to obtain compound I-20 (2.9 mg, 17%) as a white solid. MS: 513.3 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 10.97(s, 1H), 7.64(s, 1H), 7.54(s, 1H), 6.64(s, 1H), 5.24(s, 2H), 4.45(s, 2H), 2.75(s, 1H), 2.62(s, 4H), 2.46(d, J=7.2Hz, 4H), 2.00(d, J=7.5Hz, 3H), 1.80(s, 2H), 1.72– 1.53 (m, 6H), 1.39-1.28 (m, 5H), 0.90 (t, J=7.4Hz, 3H).

Example 20

Compound I-21

Compound 1-19 (15 mg, 33.9 μmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydrogen (4.1 mg, 101.7 μmol) was added to the reaction solution under stirring at 0 degrees, and the stirring was continued for reaction 1 Hour. Then, chlorobutyl carbonate (23.2 mg, 169.5 μmol) was added to the above reaction solution at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was separated by preparative liquid chromatography to obtain compound I-21 (4 mg, 22%) as a white solid. MS: 543.3 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO) δ10.81(s,1H), 8.38(s,1H), 7.65(s,1H), 7.55(s,1H), 6.64(s,1H), 5.23(s,2H) ), 4.45(t, J＝6.6Hz, 2H), 4.14(t, J＝6.6Hz, 2H), 3.28(s, 2H), 2.81–2.70(m, 1H), 2.61(d, J＝4.6Hz ,4H),2.44(t,J＝5.7Hz,2H),1.99(d,J＝3.8Hz,2H),1.78–1.71(m,2H),1.69(s,2H),1.66–1.55(m, 4H), 1.39–1.21m, 6H), 0.91 (t, J=7.4Hz, 3H).

Example 21

Compound I-22

Synthesis of compound 1-22 Referring to compound 1-15, white solid compound 1-22 was prepared by using methanesulfonyl chloride instead of acetyl chloride. MS: 467.1 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO) 7.63(s, 1H), 7.50(br, 2H), 7.36(s, 1H), 6.78(s, 1H), 5.17(s, 2H), 4.40-4.36(m, 2H) ),4.26(s,2H),3.38-3.35(m,2H),2.88(s,3H),2.76(br,2H),2.62(br,2H),1.70(br,2H),1.45(br, 2H), 1.33 (br, 2H).

Example 22

Compound I-23

Synthesis of compound 1-23 Referring to compound 1-11, white solid compound 1-23 was prepared by using intermediate A4 instead of intermediate A1. MS: 474.1 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO)δ7.46(s,1H), 7.34(br,2H), 7.13(s,1H), 6.64(s,1H), 5.13(s,2H), 4.29(br,2H) ),3.53(s,2H),2.91-2.82(m,1H),2.65(br,2H),2.56(br,4H),1.66(br,2H),1.36(br,4H),1.03(d, J=8Hz, 6H).

Example 23

Compound I-24

Synthesis of compound 1-24 Referring to compound 1-19, white solid compound 1-24 was prepared by using intermediate A4 instead of intermediate A1. MS: 486.1 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO)δ7.46(s,1H), 7.35(br,2H), 7.13(s,1H), 6.57(s,1H), 5.13(s,2H), 4.25(br,2H) ),3.25(s,2H),2.77-2.73(m,1H),2.62(br,4H),2.49-2.43(m,2H),1.99(br,2H),1.85-1.70(m,2H), 1.64(br,4H), 1.34(br,4H).

Test Example 1: Cell-level drug efficacy evaluation

Test Example 1. Determination of the agonistic activity of the compounds of the present invention on human TLR7

The agonistic activity of the compounds of the present invention to TLR7 in the HEK-Blue ^™ hTLR7 stably expressing human TLR7 cell line was tested by the following method:

1. Weigh the compounds to be tested and prepare them with DMSO (Sigma) to a concentration of 10 mM. The compounds to be tested were serially diluted by 3.16 times in DMSO, with a total of 10 concentration gradients, and the highest concentration was 1 mM.

2. The compounds to be tested and the DMSO control were diluted 10-fold with DPBS buffer (Gibco), and then added in a volume of 20 μL to a 96-well cell culture plate (Corning).

3. HEK-Blue ^™ hTLR7 cells (Invivogen) were digested with cell separation solution (Gibco) and counted (TC-20 cell counter, Bio-rad). Cells were diluted to 4.4E5/ml using DMEM cell medium (Gibco). Add 180 μL to a 96-well cell culture plate. Incubate for 16-22 h in a 37 °C, 5% _CO incubator.

4. Prepare QUANTI-Blue detection reagent (Invivogen) and add 180 μL to a new 96-well plate. Remove 20μL of cell culture supernatant from the cell culture plate and add it to a 96-well plate, incubate at 37°C for 1-3 hours.

5. The Neo2 multifunctional microplate reader (Bio-tek) measures the light absorption at 630 nm, and uses GraphPad Prism to calculate the half effective concentration of the drug EC ₅₀ .

Table 1. EC ₅₀ values of compounds of the invention for agonistic effect of human TLR7

化合物compound	EC ₅₀(nM) _EC50 (nM)	化合物compound	EC ₅₀(nM) _EC50 (nM)
化合物I-1Compound I-1	5151	化合物I-2Compound I-2	8585
化合物I-3Compound I-3	368368	化合物I-5Compound I-5	279279
化合物I-6Compound I-6	367367	化合物I-7Compound I-7	237237
化合物I-8Compound I-8	136136	化合物I-9Compound I-9	148148
化合物I-10Compound I-10	7777	化合物I-11Compound I-11	1414
化合物I-12Compound I-12	77	化合物I-13Compound I-13	99
化合物I-14Compound I-14	55	化合物I-15Compound I-15	503503
化合物I-16Compound I-16	7676	化合物I-17Compound I-17	16951695
化合物I-18Compound I-18	7272	化合物I-19Compound I-19	100100
化合物I-22Compound I-22	974974	化合物I-23Compound I-23	6969
化合物I-24Compound I-24	778778

Claims

A compound shown in formula I, its solvate, its prodrug, its metabolite or their pharmaceutically acceptable salt:

Wherein, Y is N or CR Y ;

R Y is C 1 -C 4 alkyl substituted by cyano or halogen;

A is O, S, -S(=O) 2 , -S(=O)(=NH), NR4 or CR6R7 ; R4, R6 and R7 are independently H or C1 - C 6 alkyl;

B is C 2 -C 10 alkylene, C 2 -C 10 unsaturated hydrocarbylene, R 1-1 substituted C 2 -C 10 alkylene, R 1-1 substituted C 2 -C 10 unsaturated alkylene Hydrocarbyl, -Z 1 -NH-C(=O)-Z 2 -, -Z 3 -NH-C(=O)-Z 4 -L 1 -, -Z 5 -L 2 -, -Z 6 -OZ 7 -, -Z 8 -OZ 9 -L 3 - or -(CH 2 ) n -L 5 -(CH 2 ) r -L 4 -;

L 1 , L 2 , L 3 and L 4 are independently O, S, S(=O) 2 , NR 8 , and R 8 is H or C 1 -C 6 alkyl;

-L 5 - is C 3 -C 6 cycloalkylene, halogen-substituted C 3 -C 6 cycloalkylene, "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3 3-6-membered heterocycloalkylene "or halogen-substituted" heteroatoms are selected from one or more of N, O and S, and 3-6-membered heteroatoms with 1-3 heteroatoms Heterocycloalkylene";

n and r are independently 1, 2 or 3;

-Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 6 -, -Z 7 -, -Z 8 - and -Z 9 - are independently C 1 -C 6 alkylene , C 2 -C 6 unsaturated hydrocarbylene, C 1 -C 6 alkylene substituted by R 1-2 or C 2 -C 6 unsaturated hydrocarbylene substituted by R 1-2 ;

-Z 5 - is a C 2 -C 10 alkylene group, a C 2 -C 10 unsaturated hydrocarbylene group, a R 1-3 substituted C 2 -C 10 alkylene group, or a R 1-3 substituted C 2 -C 10 group Unsaturated hydrocarbylene;

R 1-1 , R 1-2 and R 1-3 are independently OH, CN, NH 2 , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or COOR 1-1-1 ; R 1-1-1 is H or C 1 -C 3 alkyl ;

R 1 , R 2 and R 3 are independently H, halogen, C 1 -C 6 alkyl or halogen-substituted C 1 -C 6 alkyl;

Or, "R 1 and R 2 " or "R 2 and R 3 " and the carbon atoms to which they are attached together form "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3 4-7-membered heterocycloalkylene group ", R 1-4 substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3 4-7-membered "Heterocycloalkylene", C 4 -C 7 cycloalkylene or C 4 -C 7 cycloalkylene substituted by R 1-5 ; or, "R 1 and R 2 " or "R 2 and R 3 " The "heteroatoms selected from one or more of N, O and S, and the 4-7-membered heterocycloalkylene groups with 1-3 heteroatoms" or the above-mentioned "heteroatoms" formed together with the carbon atoms to which they are attached. The "heteroatom is selected from one or more of N, O and S, and the 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" substituted by R 1-4 . From one or more of N, O, and S, one or two or more arbitrary methylene groups in a 4- to 7-membered heterocycloalkyl group having 1 to 3 heteroatoms are independently replaced by carbonyl or S(=O) 2 replace;

R 1-4 and R 1-5 are independently OH, halogen, CN, C 1 -C 6 alkyl, R 1-6 substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, R 1-9 substituted C 1 -C 6 alkoxy, -S(=O) 2 R 1-7 , -C(=O)R 1-8 , NR 1-10 R 1-11 , COOR 1-12 , SR 1-13 , C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted by R 1-19 , "heteroatom selected from one or more of N, O and S, heteroatom 4-7-membered heterocycloalkyl with 1-3 "heteroatoms" and "heteroatoms substituted by R 1-20 are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 4-7-membered heterocycloalkyl", "heteroatoms selected from one or more of N, O and S, and C 1 -C 10 heteroaryl groups with 1-4 heteroatoms", R 1- 21 -substituted "heteroatoms selected from one or more of N, O and S, C 1 -C 10 heteroaryl groups with 1 to 4 heteroatoms" or -G(CR 1-14 R 1- 15 ) u- COOR 1-16 ; G is O, S, S(=O) 2 or NH; u is 1, 2 or 3;

R 1-6 and R 1-9 are independently halogen, amino, CN, OH, -COOR 1-17 , -S(=O) 2 R 1-31 , -C(=O)NH 2 , -S( =O) 2 NH 2 , C 1 -C 3 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted by COOR 1-18 , "heteroatom selected from N, O and S One or more of the 4- to 7-membered heterocycloalkyl groups with 1 to 3 heteroatoms", "heteroatoms substituted by R 1-22 are selected from one or more of N, O and S" , 4- to 7-membered heterocycloalkyl with 1-3 heteroatoms", "heteroatoms are selected from one or more of N, O and S, and C 1 ~ with 1-4 heteroatoms C 10 Heteroaryl" or R 1-23 substituted "heteroatom selected from one or more of N, O and S, and C 1 -C 10 Heteroaryl with 1 to 4 heteroatoms";

R 1-7 and R 1-8 are independently C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted by R 1-24 , "heteroatom selected from N , one or more of O and S, a 4- to 7-membered heterocycloalkyl group with 1 to 3 heteroatoms", "the heteroatom substituted by R 1-25 is selected from one of N, O and S" One or more, 4-7-membered heterocycloalkyl with 1-3 heteroatoms", "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-4 C 1 -C 10 heteroaryl", R 1-26 substituted "heteroatoms are selected from one or more of N, O and S, and C 1 -C 10 heteroatoms with 1 to 4 heteroatoms Aryl", C 6 -C 10 aryl, C 6 -C 10 aryl substituted by R 1-27 or -NR 1-28 R 1-29 ;

R 1-10 , R 1-11 , R 1-12 , R 1-16 , R 1-17 , R 1-18 , R 1-28 and R 1-29 are independently H or C 1 -C 3 alkanes base; R 1-31 is C 1 -C 3 alkyl;

R 1-13 is H, C 1 -C 6 alkyl or halogen-substituted C 1 -C 6 alkyl;

R 1-14 and R 1-15 are independently H, C 1 -C 6 alkyl or halogen-substituted C 1 -C 6 alkyl;

R 1-19 , R 1-20 , R 1-21 , R 1-22 , R 1-23 and R 1-24 are independently OH, halogen, amino, CN or C 1 -C 6 alkyl;

R 5 is H, CN, halogen, C 3 -C 5 cycloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

R 13 is H, -CONR 14 R 15 , -C(=O)R 16 or -COOR 17 , and R 14 , R 15 , R 16 and R 17 are independently C 1 -C 6 alkyl or R 13- 1 Substituted C 1 -C 6 alkyl; R 13-1 is CN, halogen, C 1 -C 6 alkoxy or -(CH 2 CH 2 O) q -R 13-2 , R 13-2 is C 1 ~C 6 alkyl, q is an integer from 0 to 460.
The compound shown in formula I as claimed in claim 1, its solvate, its prodrug, its metabolite or their pharmaceutically acceptable salt, is characterized in that, it is any of the following schemes:

plan 1:

A is O;

B is C 2 -C 10 alkylene, C 2 -C 10 unsaturated hydrocarbylene, -Z 5 -L 2 - or -(CH 2 ) n -L 5 -(CH 2 ) r -L 4 -;

L 2 and L 4 are independently O;

-L 5 - is C 3 -C 6 cycloalkylene;

-Z 5 - is C 2 -C 10 alkylene;

R 1 , R 2 and R 3 are independently H;

Alternatively, R 1 and R 2 together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and 4-7-membered heterocycloalkanes with 1-3 heteroatoms. "R" or R 1-4 substituted "heteroatom selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms";

R 1-4 is independently C 1 -C 6 alkyl, R 1-6 substituted C 1 -C 6 alkyl, -S(=O) 2 R 1-7 , -C(=O)R 1- 8. C 3 -C 7 cycloalkyl groups or "4- to 7-membered heterocycloalkyl groups whose heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3";

R 1-6 is independently "a heteroatom selected from one or more of N, O and S, and a C 1 -C 10 heteroaryl group with 1 to 4 heteroatoms";

R 1-7 and R 1-8 are independently C 1 -C 3 alkyl;

R 5 is H;

R 13 is H, -C(=O)R 16 or -COOR 17 , and R 16 and R 17 are independently C 1 -C 6 alkyl;

Scenario 2:

A is O;

B is C 2 -C 10 alkylene, C 2 -C 10 unsaturated hydrocarbylene, -Z 5 -L 2 - or -(CH 2 ) n -L 5 -(CH 2 ) r -L 4 -;

L 2 and L 4 are independently O;

-L 5 - is C 3 -C 6 cycloalkylene;

-Z 5 - is C 2 -C 10 alkylene;

R 1 and R 2 together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" Or R 1-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 3 4- to 7-membered heterocycloalkylene";

R 1-4 is independently C 1 -C 6 alkyl, R 1-6 substituted C 1 -C 6 alkyl, -S(=O) 2 R 1-7 , -C(=O)R 1- 8. C 3 -C 7 cycloalkyl groups or "4- to 7-membered heterocycloalkyl groups whose heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3";

R 1-6 is independently "a heteroatom selected from one or more of N, O and S, and a C 1 -C 10 heteroaryl group with 1 to 4 heteroatoms";

R 1-7 and R 1-8 are independently C 1 -C 3 alkyl;

R 3 is H;

R 5 is H;

R 13 is H, -C(=O)R 16 or -COOR 17 , and R 16 and R 17 are independently C 1 -C 6 alkyl

Scenario 3:

A is O;

B is C 2 -C 10 alkylene, C 2 -C 10 unsaturated hydrocarbylene, -Z 5 -L 2 - or -(CH 2 ) n -L 5 -(CH 2 ) r -L 4 -;

L 2 and L 4 are independently O;

-L 5 - is C 3 -C 6 cycloalkylene;

-Z 5 - is C 2 -C 10 alkylene;

R 1 and R 2 together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" Or R 1-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 3 4- to 7-membered heterocycloalkylene";

R 1-4 is independently C 1 -C 6 alkyl , -S(=O) 2 R 1-7 , -C(=O)R 1-8 , C 3 -C 7 cycloalkyl or "heteroatom" One or more selected from N, O and S, and a 4- to 7-membered heterocycloalkyl group with 1 to 3 heteroatoms";

R 1-7 and R 1-8 are independently C 1 -C 3 alkyl;

R 3 is H; R 5 is H;

R 13 is H;

Scenario 4:

A is O;

B is C 2 -C 10 alkylene, C 2 -C 10 unsaturated hydrocarbylene, -Z 5 -L 2 - or -(CH 2 ) n -L 5 -(CH 2 ) r -L 4 -;

L 2 and L 4 are independently O;

-L 5 - is C 3 -C 6 cycloalkylene;

-Z 5 - is C 2 -C 10 alkylene;

R 1 and R 2 together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" or "4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" substituted by R 1-4 , C 4 -C 7 Cycloalkylene or C 4 -C 7 cycloalkylene substituted by R 1-5 ;

R 3 is H;

R 1-4 is independently C 1 -C 6 alkyl, -C(=O)R 1-8 , C 3 -C 7 cycloalkyl or "heteroatom selected from one of N, O and S or A variety of 4-7-membered heterocycloalkyl groups with 1-3 heteroatoms"; when R Y is a halogen-substituted C 1 -C 4 alkyl group, the R 1-4 is C 1 -C 6 alkyl (eg isopropyl);

R 1-8 is independently C 1 -C 3 alkyl;

R 3 is H;

R 13 is H;

R5 is H.
The compound of formula I, its solvate, its prodrug, its metabolite or their pharmaceutically acceptable salts according to claim 1, wherein Y is N;

and/or, R Y is cyano;

and/or, A is O;

And/or, B is a C 2 -C 10 alkylene group, a C 2 -C 10 unsaturated hydrocarbylene group, -Z 5 -L 2 -, or -(CH 2 ) n -L 5 -(CH 2 ) r - L 4 -, preferably C 2 -C 10 alkylene or C 2 -C 10 unsaturated hydrocarbylene;

and/or, L 2 and L 4 are O;

And/or, -L 5 - is C 3 -C 6 cycloalkylene;

And/or, -Z 5 - is C 2 -C 10 alkylene;

and/or, n and r are 1;

And/or, R 1 and R 2 together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and 4-7-membered heteroatoms with 1-3 heteroatoms. Cycloalkyl" or R 1-4 substituted "heteroatom selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms";

And/or, R 1-4 is C 1 -C 6 alkyl, R 1-6 substituted C 1 -C 6 alkyl, -S(=O) 2 R 1-7 , -C(=O)R 1-8 , C 3 -C 7 cycloalkyl or "4- to 7-membered heterocycloalkyl whose heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3", Preferably C 1 -C 6 alkyl, -S(=O) 2 R 1-7 , -C(=O)R 1-8 , C 3 -C 7 cycloalkyl or "heteroatom is selected from N, O and One or more of S, a 4- to 7-membered heterocycloalkyl group with 1 to 3 heteroatoms", more preferably a C 1 -C 6 alkyl group or "a heteroatom selected from N, O and S One or more 4- to 7-membered heterocycloalkyl groups with 1-3 heteroatoms";

And/or, R 1-6 is "a heteroatom selected from one or more of N, O and S, and a C 1 -C 10 heteroaryl group with 1 to 4 hetero atoms";

And/or, R 1-7 and R 1-8 are C 1 -C 3 alkyl;

and/or, R is H;

and/or, R 5 is H;

and/or, R 13 is H, -C(=O)R 16 or -COOR 17 , preferably H;

And/or, R 16 and R 17 are C 1 -C 6 alkyl groups.
The compound represented by formula I, its solvate, its prodrug, its metabolite or their pharmaceutically acceptable salts as claimed in claim 1, wherein,
for

and / or,
for

and/or, -AB- for
The compound of formula I, its solvate, its prodrug, its metabolite or its pharmaceutically acceptable salt according to claim 1, wherein when B is C 2 -C 10 alkylene C 2 -C 10 alkylene group or C 2 -C 10 alkylene group substituted with R 1-1 , C in the C 2 -C 10 alkylene group and the C 2 -C 10 alkylene group substituted with R 1-1 2 - C10 alkylene is independently C4 - C6 alkylene, preferably n-pentylene

And/or, when B is a C 2 -C 10 unsaturated hydrocarbylene group or a C 2 -C 10 unsaturated hydrocarbylene group substituted by R 1-1, the C 2 -C 10 unsaturated hydrocarbylene group and the The C 2 -C 10 unsaturated hydrocarbylene group in the C 2 -C 10 unsaturated hydrocarbylene group substituted by R 1-1 is independently a C 4 -C 6 alkenyl group, preferably

And/or, when R 8 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group;

And/or, when -L 5 - is a C 3 -C 6 cycloalkylene or a halogen-substituted C 3 -C 6 cycloalkylene, the C 3 -C 6 cycloalkylene and the The C 3 -C 6 cycloalkylene group in the halogen-substituted C 3 -C 6 cycloalkylene group is a cyclopropylene group, a cyclobutylene group, a cyclopentylene group or a cyclohexylene group, preferably a cyclobutylene group;

and/or, when -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 6 -, -Z 7 -, -Z 8 - and -Z 9 - are independently C 1 - In the case of a C 6 alkylene group or a C 1 -C 6 alkylene group substituted with R 1-2 , the C 1 -C 6 alkylene group and the C 1 -C 6 alkylene group substituted with R 1-2 C 1 -C 6 alkylene in the group is independently C 1 -C 3 alkylene;

and/or, when -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 6 -, -Z 7 -, -Z 8 - and -Z 9 - are independently C 2 - When C 6 unsaturated alkylene group or R 1-2 substituted C 2 -C 6 unsaturated hydrocarbylene group, the C 2 -C 6 alkylene group and R 1-2 substituted C 2 -C 6 unsaturated alkylene group The C 2 -C 6 unsaturated hydrocarbylene group in the hydrocarbon group is independently a C 2 -C 4 unsaturated hydrocarbylene group;

And/or, when -Z 5 - is a C 2 -C 10 alkylene or a C 2 -C 10 alkylene substituted by R 1-3 , the C 2 -C 10 alkylene and the R The C 2 -C 10 alkylene in the 1-3 substituted C 2 -C 10 alkylene is independently a C 3 -C 6 alkylene, preferably n-butylene;

And/or, when -Z 5 - is a C 2 -C 10 unsaturated hydrocarbylene group or a C 2 -C 10 unsaturated hydrocarbylene group substituted by R 1-3, the C 2 -C 10 unsaturated hydrocarbylene group and the The C 2 -C 10 unsaturated hydrocarbylene groups in the C 2 -C 10 unsaturated hydrocarbylene groups substituted by R 1-3 are independently C 3 -C 6 unsaturated hydrocarbylene groups;

and/or, when R 1-1 , R 1-2 and R 1-3 are independently halogen, the halogen is independently F, Cl, Br or I;

And/or, when R 1-1 , R 1-2 and R 1-3 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is independently C 1 -C 3 alkane base;

And/or, when R 1-1 , R 1-2 and R 1-3 are independently C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is independently C 1 -C 3 alkoxy;

And/or, when R 1 , R 2 and R 3 are independently halogen or halogen-substituted C 1 -C 6 alkyl, said halogen and said halogen-substituted C 1 -C 6 alkyl halogen is independently F, Cl, Br or I;

And/or, when R 1 , R 2 and R 3 are independently C 1 -C 6 alkyl and halogen-substituted C 1 -C 6 alkyl, the C 1 -C 6 alkyl and the Among the halogen-substituted C 1 -C 6 alkyl groups, C 1 -C 6 alkanes are independently C 1 -C 3 alkyl groups;

And/or, when "R 1 and R 2 " or "R 2 and R 3 " and the carbon atoms to which they are attached together form "the heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1-3 4-7-membered heterocycloalkylene "or R 1-4 substituted" heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3. ~7-membered heterocycloalkylene", the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 3. 4-7 membered heterocycloalkylene " and R 1-4 substituted "heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1 to 3 4-7 membered heterocycloalkylene" in "heteroatom" One or more selected from N, O and S, and a 4- to 7-membered heterocycloalkylene group with 1 to 3 heteroatoms" is independently "a 5-membered heteroatom with N and 1 heteroatom. -6-membered heterocycloalkylene", more preferably piperidinylene, such as

And/or, when "R 1 and R 2 " or "R 2 and R 3 " and the carbon atoms to which they are attached together form R 1-4 substituted "heteroatoms selected from one or more of N, O and S" When the number of heteroatoms is 4-7 membered heterocycloalkylene with 1-3 heteroatoms, the R 1-4 is 1, 2 or 3, preferably 1;

And/or, when "R 1 and R 2 " or "R 2 and R 3 " and the carbon atoms to which they are attached together form R 1-4 substituted "heteroatoms selected from one or more of N, O and S" When the number of heteroatoms is 4-7-membered heterocycloalkylene with 1-3 heteroatoms, the substitution position of R 1-4 is located on the heteroatom;

and/or, when R 1-4 and R 1-5 are independently halogen, said halogen is F, Cl, Br or I;

And/or, when R 1-4 and R 1-5 are independently C 1 -C 6 alkyl or C 1-C 6 alkyl substituted by R 1-6, the C 1 - C 6 alkyl and The C 1 -C 6 alkyl groups in the C 1 -C 6 alkyl groups substituted by R 1-6 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or isopropyl;

And/or, when R 1-4 and R 1-5 are independently C 1 -C 6 alkoxy or C 1 -C 6 alkoxy substituted by R 1-9 , the C 1 -C 6 C 1 -C 6 alkoxy in alkoxy and R 1-9 substituted C 1 -C 6 alkoxy is independently C 1 -C 4 alkoxy;

And/or, when R 1-4 and R 1-5 are independently C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl substituted by R 1-19 , the C 3 -C 7 C 3 -C 7 cycloalkyl in cycloalkyl and R 1-19 substituted C 3 -C 7 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, Cyclobutyl is preferred;

And/or, when R 1-6 and R 1-9 are independently "heteroatoms are selected from one or more of N, O and S, C 1 -C 10 heteroatoms with 1-4 heteroatoms Aryl" or R 1-23 substituted "heteroatoms are selected from one or more of N, O and S, and C 1 -C 10 heteroaryl groups with 1 to 4 heteroatoms", the The "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is C 1 -C 10 heteroaryl with 1 to 4" and R 1-21 substituted "heteroatom is selected from N , one or more of O and S, and the "heteroatom is selected from one or more of N, O and S" in the C 1 -C 10 heteroaryl group with 1 to 4 heteroatoms, C 1 -C 10 heteroaryl with 1 to 4 heteroatoms" is independently "C 4 -C 6 heteroaryl with 1 heteroatom and 1 heteroatom", preferably pyridyl, for example

And/or, when R 1-4 is a C 1 -C 6 alkyl group substituted by R 1-6 , the number of R 1-6 is 1, 2 or 3, preferably 1;

And/or, when R 1-13 , R 1-14 and R 1-15 are independently C 1 -C 6 alkyl or halogen-substituted C 1 -C 6 alkyl, the C 1 -C 6 The C 1 -C 6 alkyl group in the alkyl or halogen-substituted C 1 -C 6 alkyl group is independently a C 1 -C 3 alkyl group;

And/or, when R 1-13 , R 1-14 and R 1-15 are independently halogen-substituted C 1 -C 6 alkyl, the halogen in the halogen-substituted C 1 -C 6 alkyl independently F, Cl, Br or I;

And/or, when R 1-19 , R 1-20 , R 1-21 , R 1-22 , R 1-23 and R 1-24 are independently halogen, the halogen is independently F, Cl , Br or I;

And/or, when R 1-19 , R 1-20 , R 1-21 , R 1-22 , R 1-23 and R 1-24 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is independently C 1 -C 3 alkyl;

And/or, when R 5 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group;

And/or, when R 5 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy;

And/or, when R 14 , R 15 , R 16 and R 17 are independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by R 13-1 , the C 1 -C 6 The alkyl group and the C 1 -C 6 alkyl group in the C 1 -C 6 alkyl group substituted by R 13-1 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl or tert-butyl, preferably n-propyl or n-butyl;

And/or, when R 13-1 is halogen, the halogen is F, Cl, Br or I;

And/or, when R 13-1 is C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy;

And/or, when R 13-1 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group;

And/or, when R 13-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 3 alkyl group.
The compound of formula I, its solvate, its prodrug, its metabolite or its pharmaceutically acceptable salt according to claim 5, wherein -Z 5 -L 2 - is

and/or, -(CH 2 ) n -L 5 -(CH 2 ) r -L 4 - is
E.g

And/or, when R 1-4 is C 1 -C 6 alkyl substituted by R 1-6 , the C 1 -C 6 alkyl substituted by R 1-6 is

And/or, said R 1-4 substituted "heteroatom selected from one or more of N, O and S, and a 4- to 7-membered heterocycloalkylene with 1 to 3 heteroatoms" for
The compound represented by formula I, its solvate, its prodrug, its metabolite or their pharmaceutically acceptable salt according to claim 1, wherein said compound represented by formula I is any of the following compounds:
A compound of formula II:

Wherein, RA and RB are independently H or amino protecting group, and RA and RB are not H at the same time; Y, A, B, R 1 , R 2 , R 3 and R 5 are as defined in claim 1 Any of -6.
The compound of formula II according to claim 8, wherein the compound of formula II is any of the following compounds:
A pharmaceutical composition comprising the compound shown in the formula I as described in any one of claims 1-7, its solvate, its prodrug, its metabolite or their pharmaceutically acceptable salt, and medical supplements.
The compound of formula I according to any one of claims 1-7, its solvate, its prodrug, its metabolite, their pharmaceutically acceptable salt or the pharmaceutical combination according to claim 10 The application of the drug in the preparation of a drug or a TLR7 agonist for the treatment or prevention of tumors or infections caused by viruses;

Preferably, the virus is one or more of HBV, HCV, HIV and influenza virus;

Preferably, the TLR7 agonist is used in a mammalian organism or in vitro.
A kind of method for preventing or treating tumor or infection caused by virus, it comprises administering the compound shown in formula I, its solvate, Its prodrugs, its metabolites, their pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions;

In the treatment method, the virus is preferably one or more of HBV, HCV, HIV and influenza virus.