CN112898286A - Benzothiophene compound or pharmaceutically acceptable salt and isomer thereof, and preparation method, pharmaceutical composition and application thereof - Google Patents

Abstract

The invention discloses a benzothiophene compound with a structure shown in a general formula I or pharmaceutically acceptable salts and isomers thereof, a preparation method thereof, a pharmaceutical composition and application thereof. The invention overcomes the defects of lack of interferon gene stimulating protein micromolecule excitant, poor drug forming property of nucleotide interferon gene stimulating protein excitant and the like in the prior art, has good excitant activity to the interferon gene stimulating protein, and has good treatment effect to tumors and infectious diseases.

Description

Benzothiophene compounds or their pharmaceutically acceptable salts, isomers and their preparation methods, pharmaceutical compositions and uses

technical field

The present invention relates to the field of chemical medicine, in particular to benzothiophene compounds or their pharmaceutically acceptable salts, isomers and their preparation methods, pharmaceutical compositions and uses.

Background technique

Innate immunity is the first line of defense against invading pathogens and tissue damage. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) from pathogens or damage-associated molecular patterns (DAMPs) from the body itself, initiating a cascade In response, the expression of genes such as interferons (IFNs), chemokines and inflammatory factors is induced. This innate immune response not only suppresses the proliferation and spread of pathogens at an early stage, but also induces an acquired immune response to eventually clear the infection. Additionally, this innate immune response monitors tumor initiation and invasion. At present, a variety of PRRs have been found, such as membrane-bound toll-like receptors (TLRs), C-type lectin receptors (CLRs), unbound intracellular nucleotides Binding oligomerization domain-like receptors (nucleotide-binding oligomerization-domain (NOD)-like receptors, NLRs), retinoic acid-like receptors (retinoic acid-like receptors, RLRs) and cytoplasmic DNA sensors.

Pathogen DNA and DNA leaked from the body's nucleus or mitochondria into the cytoplasm is an immunostimulatory molecule, and there are many DNA sensors in the cytoplasm, such as melanoma deficiency factor 2 (absent in melanoma 2, AIM2), interferon-inducible protein 16 (interferon- inducible protein 16, IFI16), RNA polymerase III and cyclic GMP-AMP synthase (cyclic GMP-AMP synthase, cGAS) and so on. The STimulator of INterferon Genes (STING) located in the cytoplasmic endoplasmic reticulum is the convergence point of these DNA sensors and controls the innate immune response mediated by DNA, an immunostimulatory molecule. Research shows that cGAS recognizes double-stranded DNA in the cytoplasm and catalyzes GTP and ATP to generate 2′3′-cGAMP. As a second messenger, 2′3′-cGAMP binds to interferon gene-stimulating protein, induces interferon gene-stimulating protein to dimerize and transfer from the endoplasmic reticulum membrane to vesicles around the nucleus, recruiting TBK1 and phosphorylating itself, thereby Brings IRF3 close to interferon gene-stimulating protein. TBK1 then phosphorylates IRF3, which translocates to the nucleus to induce the expression of type I interferons (IFNs) and other inflammatory factors. Type I interferons promote the maturation of dendritic cells (DCs), selectively stimulate the cross-presentation of antigens, and recruit CD8 ⁺ T cells, thereby activating the acquired immune system to kill tumor cells or resist pathogen infection. Therefore, interferon gene-stimulating proteins play important roles in innate and acquired immune responses in tumors and pathogen infections.

In view of the key role of interferon gene-stimulating protein in the body's immune response, the application of interferon gene-stimulating protein agonists in the immunotherapy of various diseases has attracted much attention. For example, intratumoral injection of 2′3′-cGAMP resulted in tumor cell regression in mouse models and was able to inhibit the growth of distant tumor cells and induce long-term immune memory. Interferon gene-stimulating protein agonists combined with immune checkpoint inhibitors can increase the efficacy of immune checkpoint inhibitors. In addition, the immune response induced by interferon gene-stimulating protein agonists can effectively control viral infections such as influenza A virus, hepatitis B virus, herpes simplex virus and HIV. Therefore, the research and development of interferon gene-stimulating protein agonists are of great significance for the immunotherapy of cancer and infectious diseases. However, most of the reported interferon gene-stimulating protein agonists are cyclic dinucleotide analogs, but their metabolic instability in vivo, poor membrane permeability, and only intratumoral administration are limited by the defects of interferon gene-stimulating protein. Therefore, the research and development of interferon gene-stimulating protein small molecule agonists are of great significance.

SUMMARY OF THE INVENTION

Purpose of the invention: The purpose of the present invention is to overcome the defect of single structure of the existing interferon gene-stimulating protein small molecule agonists, and provide a benzothiophene compound, its preparation method, pharmaceutical composition and use. The benzothiophene compound of the present invention has good agonistic activity on interferon gene-stimulating protein, and has good therapeutic effect on tumor.

Technical solutions:

In the first aspect of the present invention, a benzothiophene compound having a structure represented by general formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, has the following structure :

wherein, R ¹ and R ² are independently selected from hydrogen, deuterium, halogen, unsubstituted or R ^1-1 substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, - NR ^1-2 R ^1-3 , -(C=O)NR ^1-4 R ^1-5 or -(C=O)OR ^1-6 ;

R ^1-1 is halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy or -NR ^1-1-1 R ^1-1-2 ;

R ^1-1-1 and R ^1-1-2 are independently selected from hydrogen or C _1-4 alkyl;

R ^1-2 to R ^1-6 are independently selected from hydrogen or C _1-4 alkyl;

R ³ and R ⁴ are independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, unsubstituted or R ^3-1 substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy base, C _2-6 alkynyl, C _2-6 alkenyl, C _3-10 cycloalkyl, (C _3-10 cycloalkyl)-oxy, (C _3-10 cycloalkyl)-(C _{1 -6} alkoxy), heterocycloalkyl, heterocycloalkyl-oxy, heterocycloalkyl-(C _1-6 alkoxy), C _6-10 aryl, (C _6-10 aryl) -oxy, (C _6-10 aryl)-(C _1-6 alkoxy), heteroaryl, heteroaryl-oxy, heteroaryl-(C _1-6 alkoxy), -NR ^3-2 R ^3-3 , -(C=O)R ^3-4 , -(C=O)NR ^3-5 R ^3-6 , -(C=O)OR ^3-7 , -S(=O ) ₂ NR ^3-8 R ^3-9 , or R ³ and R ⁴ and the carbon atoms to which they are attached together form a 4-20-membered heterocycloalkoxy group; the heterocycloalkyl group is "heteroatoms selected from N, One or more of O and S, "4- to 10-membered heterocycloalkyl with 1-3 heteroatoms; the heteroaryl group is "heteroatom selected from N, O and S One or more kinds of "5-10-membered heteroaryl groups with 1-3 heteroatoms;

R ^3-1 is halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, or -NR ^3-1-1 R ^{3-1- 2} ;

R ^3-1-1 and R ^3-1-2 are independently selected from hydrogen or C _1-4 alkyl;

R ^3-2 to R ^3-9 are independently selected from hydrogen or C _1-4 alkyl;

R ⁵ is -(C=O)OR ^5-1 , -(C=O)SR ^5-2 , unsubstituted or R ^5-3 substituted "heteroatom selected from one or more of N, O and S Species, "5-10-membered heteroaryl with 1-3 heteroatoms, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 or -(C=O)NR ⁷ R ⁸ ;

R ^5-1 and R ^5-2 are independently selected from hydrogen, C _1-6 alkyl, (C _1-6 alkoxy)-(C _1-6 alkyl)-, C _3-10 cycloalkyl, C _6-10 aryl, "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 5-10-membered heteroaryl groups or "hetero atoms are selected from N, One or more of O and S, "4- to 10-membered heterocycloalkyl with 1-3 heteroatoms;

R ^5-3 is selected from halogen, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, or C _1-4 haloalkoxy;

R ^5-4 and R ^5-5 are independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl or C _3-10 cycloalkyl;

R ⁷ is hydrogen, sulfonic acid group, phosphoryl group, unsubstituted or R ^7-1 substituted C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, (C _3-10 cycloalkane base)-C _1-6 alkyl, heterocycloalkyl, heterocycloalkyl-C _1-6 alkyl, unsubstituted or R ^7-2 substituted C _6-10 aryl, unsubstituted or R ^7-3 Substituted C _6-10 aryl-C _1-6 alkyl, unsubstituted or R ^7-4 substituted heteroaryl-C _1-6 alkyl or unsubstituted or R ^7-5 substituted heteroaryl; The heterocycloalkyl group is a 4- to 10-membered heterocycloalkyl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"; the heteroaryl group is a 5- to 10-membered heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3";

R ^7-1 is halogen, carboxyl, hydroxyl, -NR ^7-1-1 R ^7-1-2 , cyano or C _1-4 alkyl;

R ^7-1-1 and R ^7-1-2 are independently selected from hydrogen or C _1-4 alkyl;

R ^7-2 to R ^7-5 are independently selected from deuterium, halogen, hydroxyl, cyano, nitro, unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, unsubstituted or R ^{7-2 -2-} substituted C _1-4 alkoxy, -NR ^7-2-3 R ^7-2-4 , -(C=O)R ^7-2-5 , -(C=O)NR ^{7-2- 6} R ^7-2-7 , -(C=O)OR ^7-2-8 or -S(=O) ₂ NR ^7-2-9 R ^7-2-10 ;

R ^7-2-1 and R ^7-2-2 are halogen, hydroxyl, cyano or -NR ^7-2-1-1 R ^7-2-1-2 ;

R ^7-2-1-1 and R ^{7-2-1-2 are} independently selected from hydrogen or C _1-4 alkyl;

R ^7-2-3 to R ^{7-2-10 are} independently selected from hydrogen or C _1-4 alkyl;

R ⁸ is hydrogen, cyano, R ^8-1 O-, -NR ^8-2 R ^8-3 , R ^8-4 S-, unsubstituted or R ^8-5 substituted C _1-6 alkyl, C _{2 -6} alkenyl, C _3-10 cycloalkyl, (C _3-10 cycloalkyl)-C _1-6 alkyl, heterocycloalkyl, heterocycloalkyl-C _1-6 alkyl, unsubstituted or R ^8-6 substituted C _6-10 aryl, unsubstituted or R ^8-7 substituted C _6-10 aryl-C _1-6 alkyl, unsubstituted or R ^8-8 substituted heteroaryl, unsubstituted Substituted or R ^8-9 substituted heteroaryl-C _1-6 alkyl; Said heterocycloalkyl is "one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1 -3 "4- to 10-membered heterocycloalkyl groups; the heteroaryl group is "one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-3"5 ~10-membered heteroaryl;

R ^8-1 to R ^8-4 are independently selected from phosphoryl, unsubstituted or R ^8-1-1 substituted C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, ( C _3-10 cycloalkyl)-C _1-6 alkyl, heterocycloalkyl-C _1-6 alkyl, unsubstituted or R ^8-1-2 substituted C _6-10 aryl, unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, unsubstituted or R ^8-1-4 substituted heteroaryl-C _1-6 alkyl, unsubstituted or R ^{8-1 -5} -substituted heteroaryl group, or -(S=O) ₂ OR ^8-1-6 ; the heterocycloalkyl group is "the heteroatom is selected from one or more of N, O and S, the heteroatom is "4-10-membered heterocycloalkyl with 1-3 atoms; the heteroaryl group is "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3 "5-10-membered heteroaryl;

R ^8-1-1 is halogen, hydroxyl, cyano, -NR ^8-1-1-1 R ^8-1-1-2 or C _1-4 alkyl;

R ^8-1-1-1 and R ^{8-1-1-2 are} independently selected from hydrogen or C _1-4 alkyl;

R ^8-1-2 to R ^{8-1-5 are} independently selected from halogen, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 Haloalkoxy, -NR ^8-1-2-1 R ^8-1-2-2 , -(C=O)R ^8-1-2-3 , -(C=O)NR ^{8-1-2- 4} R ^8-1-2-5 , -(C=O)OR ^8-1-2-6 , -S(=O) ₂ NR ^8-1-2-7 R ^8-1-2-8 , or -S(=O) ₂ R ^8-1-2-9 ;

R ^8-1-6 is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl or C _3-10 cycloalkyl;

R ^8-1-2-1 to R ^{8-1-2-9 are} independently selected from hydrogen or C _1-4 alkyl;

R ^8-5 is halogen, carboxyl, hydroxyl, -NR ^8-5-1 R ^8-5-2 , cyano or C _1-4 alkyl;

R ^8-5-1 and R ^8-5-2 are independently selected from hydrogen or C _1-4 alkyl;

R ^8-6 to R ^8-9 are independently selected from deuterium, halogen, hydroxyl, cyano, carboxyl, nitro, unsubstituted or R ^8-6-1 substituted C _1-4 alkyl, unsubstituted or R ^{8 -6-2} substituted C _1-4 alkoxy, -NR ^8-6-3 R ^8-6-4 , -(C=O)R ^8-6-5 , -(C=O)NR ^{8- 6-6} R ^8-6-7 , -(C=O)OR ^8-6-8 , or -S(=O) ₂ NR ^8-6-9 R ^8-6-10 ;

R 8-6-1 and R ^{8-6-2 are} halogen, hydroxyl, cyano or -NR ^8-6-1-1 R ^8-6-1-2 ;

R ^8-6-1-1 and R ^{8-6-1-2 are} independently selected from hydrogen or C _1-4 alkyl;

R ^8-6-3 to R ^{8-6-10 are} independently selected from hydrogen or C _1-4 alkyl;

X is O, C=O, NR ⁹ ,

相连，右端与L相连；The left end of X with

connected, and the right end is connected to L;

R ⁹ to R ¹¹ are independently selected from hydrogen or C _1-6 alkyl;

R ¹² is hydroxyl, cyano, C _1-6 alkoxy, -O(C=O)R ^12-1 , -(S=O) ₂ R ^12-2 , -(S=O)R ^12-3 or -NR ^{12-4 R 12-5 ;}

R ^12-1 to R ^12-3 are independently selected from C _1-6 alkyl;

R ^12-4 and R ^12-5 are independently selected from hydrogen, C _1-6 alkyl or -(C=O)R ^12-4-1 ;

R ^12-4-1 is C _1-6 alkyl;

R ¹³ and R ¹⁴ are independently selected from hydrogen or C _1-6 alkyl;

X and R ^are selected from any combination of the following:

时，R⁵为-(C＝O)NR^5-4(S＝O)₂R^5-5或-(C＝O)NR⁷R⁸；when X is

, R ⁵ is -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 or -(C=O)NR ⁷ R ⁸ ;

When X is C=O, R ⁵ is -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 or unsubstituted or R ^5-3 substituted "heteroatom selected from N, O and One or more of S, "5-10-membered heteroaryl group with 1-3 heteroatoms;

时，R⁵为-(C＝O)OR^5-1、-(C＝O)SR^5-2、未取代或R^5-3取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-3个的”5～10元杂芳基、-(C＝O)NR^5-4(S＝O)₂R^5-5或-(C＝O)NR⁷R⁸；When X is O, NR ⁹ ,

When R ⁵ is -(C=O)OR ^5-1 , -(C=O)SR ^5-2 , unsubstituted or R ^5-3 substituted "heteroatom is selected from one of N, O and S or more, "5-10-membered heteroaryl with 1-3 heteroatoms, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 or -(C=O)NR ^{7R8 ;}

R ⁶ is selected from hydrogen, deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, -(C=O)NR ^6-1 R ^6-2 , -(C=O)OR ^6-3 or -NR ^6-4 R ^6-5 ;

R ^6-1 to R ^6-5 are independently selected from hydrogen or C _1-4 alkyl;

L is (C(R ¹⁵ R ¹⁶ )) _n ;

R ¹⁵ and R ¹⁶ are independently selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 Cycloalkyl, -NR ^15-1 R ^15-2 or R ¹⁵ and R ¹⁶ ring with the carbon atoms to which they are attached to synthesize C _3-10 cycloalkyl;

R ^15-1 and R ^15-2 are independently selected from hydrogen or C _1-4 alkyl;

n is an integer of 1, 2 or 3.

In an embodiment of the present invention, certain groups are defined as follows, and undefined groups are as described in any of the previous embodiments, hereinafter referred to as "in an embodiment of the present invention", when R ¹ and R ² are independently When selected from halogen, the halogen is fluorine, chlorine, bromine or iodine;

^In a certain embodiment of the present invention, when ^R3 and R4 are independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine.

In one embodiment of the present invention, when R ³ and R ⁴ are independently selected from C _1-6 alkoxy, said C _1-6 alkoxy is C _1-4 alkoxy.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from C _1-6 haloalkoxy, said C _1-6 haloalkoxy is C _1-4 haloalkoxy.

In a certain embodiment of the present invention, when ^R3 and R4 are independently selected from _C2-6alkenyl , _{said C2-6alkenyl} is ^C2-4alkenyl .

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from (C _3-10 cycloalkyl)-oxy, said (C _3-10 cycloalkyl)-oxy is ( C _3-6 cycloalkyl)-oxy.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from (C _3-10 cycloalkyl)-(C _1-6 alkoxy), the (C _3-10 cycloalkane) base)-(C _1-6 alkoxy) is (C _3-6 cycloalkyl)-(C _1-4 alkoxy).

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 4-10 In the case of membered heterocycloalkyl-(C _1-6 alkoxy), the 4-10-membered heterocycloalkyl-(C _1-6 alkoxy) is a 4-6 membered heterocycloalkyl-(C _1-4 alkoxy).

In one embodiment of the present invention, when R ³ and R ⁴ are independently selected from (C _6-10 aryl)-oxy, said (C _6-10 aryl)-oxy is phenoxy .

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from (C _6-10 aryl)-(C _1-6 alkoxy), the (C _6-10 aryl) -(C _1-6 alkoxy) is benzene-(C _1-4 alkoxy).

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 5-10 In the case of a heteroaryl-oxy group, the 5-10-membered heteroaryl-oxy group is a 5-6-membered heteroaryl-oxy group.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 5-10 In the case of heteroaryl-(C _1-6 alkoxy), the 5-10-membered heteroaryl-(C _1-6 alkoxy) is a 5-6 membered heteroaryl-(C _1-4 alkoxy).

In a certain embodiment of the present invention, when R ^3-2 to R ^3-9 are C _1-4 alkyl groups, the C _1-4 alkyl groups are methyl, ethyl, propyl, or isopropyl base.

In a certain embodiment of the present invention, when R ³ and R ⁴ together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3""4-20-membered heterocycloalkoxy, the 4-20-membered heterocycloalkyl is a 5-12-membered heterocycloalkoxy.

In a certain embodiment of the present invention, when R ^5-1 is a C _1-6 alkyl group, the C _1-6 alkyl group is a C _1-4 alkyl group.

In a certain embodiment of the present invention, when R ^5-1 is (C _1-6 alkoxy)-(C _1-6 alkyl)-, the (C _1-6 alkoxy)-( C _1-6 alkyl)- is (C _1-4 alkoxy)-(C _1-4 alkyl)-.

In a certain embodiment of the present invention, when R ^5-1 is a C _3-10 cycloalkyl group, the C _3-10 cycloalkyl group is a C _3-6 cycloalkyl group.

In a certain embodiment of the present invention, when R ⁵ is unsubstituted or R ^5-3 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" In the case of a 5- to 10-membered heteroaryl group, the number of the R ^5-3 is one or more, and when there are multiple R ^5-3 , the R ^5-3 can be the same or different.

In a certain embodiment of the present invention, when R ⁵ is unsubstituted or R ^5-3 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" When a 5- to 10-membered heteroaryl group is used, the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group.

In a certain embodiment of the present invention, when R ^5-4 and R ^5-5 are independently selected from C _1-6 alkyl, said C _1-6 alkyl is C _1-4 alkyl.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-1 substituted C _1-6 alkyl group, the number of said R ^7-1 is one or more, when there are multiple When R ^7-1 , the R ^7-1 may be the same or different.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-1 substituted C _1-6 alkyl group, the C _1-6 alkyl group is a C _1-4 alkyl group.

In one embodiment of the present invention, when R ⁷ is C _2-6 alkenyl, said C _2-6 alkenyl is C _2-4 alkenyl.

In a certain embodiment of the present invention, when R ⁷ is C _3-10 cycloalkyl, said C _3-10 cycloalkyl is C _3-6 cycloalkyl.

In a certain embodiment of the present invention, when R ⁷ is (C _3-10 cycloalkyl)-C _1-6 alkyl, the (C _3-10 cycloalkyl)-C _1-6 alkyl is (C _3-6 cycloalkyl)-C _1-4 alkyl.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-2 substituted C _6-10 aryl group, the number of said R ^7-2 is one or more, when there are multiple When R ^7-2 , the R ^7-2 may be the same or different.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-2 substituted C _6-10 aryl group, the C _6-10 aryl group is phenyl.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl group, the number of said R ^7-3 is one or a Multiple, when multiple R ^7-3s are present, the R ^7-3s may be the same or different.

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl, the C _6-10 aryl-C _1-6 alkyl _6Alkyl is phenyl- _C1-4alkyl .

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" In the case of a 5-10-membered heteroaryl-C _1-6 alkyl group, the number of the R ^7-4 is one or more, and when there are multiple R ^7-4 , the R ^7-4 can be same or different.

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" In the case of a 5-10-membered heteroaryl-C _1-6 alkyl group, the 5-10-membered heteroaryl-C _1-6 alkyl group is a 5-6-membered heteroaryl-C _1-4 alkyl group.

In one embodiment of the present invention, when R ^7-1 is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a certain embodiment of the present invention, when R ^7-1 is C _1-4 alkyl, said C _1-4 alkyl is methyl, ethyl or propyl.

In one embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, the R ^7-2- The number of ¹ is one or more, and when there are multiple R ^7-2-1s , the R ^7-2-1s may be the same or different.

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, the C _1-4 alkane group is methyl, ethyl, propyl or isopropyl.

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from unsubstituted or R ^7-2-2 substituted C _1-4 alkoxy, the R ^7-2 The number of ^-2 is one or more, and when there are multiple R ^7-2-2s , the R ^7-2-2s may be the same or different.

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from unsubstituted or R ^7-2-2 substituted C _1-4 alkoxy, the C _1-4 Alkoxy is methoxy, ethoxy, propoxy or isopropoxy.

In a certain embodiment of the present invention, when R ^7-2-3 to R ^{7-2-10 are} independently selected from C _1-4 alkyl, the C _1-4 alkyl is methyl, ethyl, propyl or isopropyl.

In a certain embodiment of the present invention, when R ^8-1 is an unsubstituted or R ^8-1-1 substituted C _1-6 alkyl group, the number of said R ^8-1-1 is one or more Each, when there are multiple R ^8-1-1s , the R ^8-1-1s may be the same or different.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl .

In a certain embodiment of the present invention, when R ^8-1 is C _2-6 alkenyl, said C _2-6 alkenyl is C _2-4 alkenyl.

In a certain embodiment of the present invention, when R ^8-1 is a C _3-10 cycloalkyl group, the C _3-10 cycloalkyl group is a C _3-6 cycloalkyl group.

In a certain embodiment of the present invention, when R ^8-1 is (C _3-10 cycloalkyl)-C _1-6 alkyl, the (C _3-10 cycloalkyl)-C _1-6 The alkyl group is (C _3-6 cycloalkyl)-C _1-4 alkyl.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, the R ^8-1-3 The number of R 8-1-3 is one or more, and when there are multiple R ^8-1-3 , the R ^8-1-3 can be the same or different.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, the C _6-10 aryl -C _1-6 alkyl is phenyl-C _1-4 alkyl.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-4 substituted "heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1- When there are 3 "5-10-membered heteroaryl-C _1-6 alkyl groups, the number of said R ^8-1-4 is one or more, and when there are multiple R ^8-1-4 , Said R ^8-1-4 may be the same or different.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-4 substituted "heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1- When there are 3 "5-10-membered heteroaryl-C _1-6 alkyl groups, the 5-10-membered heteroaryl-C _1-6 alkyl groups are 5-6-membered heteroaryl-C _1-4 groups. alkyl.

In a certain embodiment of the present invention, when R ^8-1-1 is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In one embodiment of the present invention, when R ^8-1-3 is halogen, said halogen is fluorine, chlorine, bromine or iodine.

In one embodiment of the present invention, when R ^8-1-4 is halogen, the halogen is fluorine, chlorine, bromine or iodine.

In a certain embodiment of the present invention, when R ^8-1-6 is C _1-6 alkyl, said C _1-6 alkyl is C _1-4 alkyl.

In a certain embodiment of the present invention, when R ⁹ to R ¹¹ are independently selected from C _1-6 alkyl groups, the C _1-6 alkyl groups are C _1-4 alkyl groups.

In a certain embodiment of the present invention, when R ¹² is C _1-6 alkoxy, said C _1-6 alkoxy is C _1-4 alkoxy.

In a certain embodiment of the present invention, when R ^12-1 to R ^12-5 are independently selected from C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

对，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸。In one embodiment of the present invention, when X is

Yes, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ .

时，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸。In one embodiment of the present invention, when X is

, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ .

时，R⁵独立地选自-(C＝O)OR^5-1。In one embodiment of the present invention, when X is

, R ⁵ is independently selected from -(C=O)OR ^5-1 .

In one embodiment of the present invention, when R ¹⁵ and R ¹⁶ are independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine.

In a certain embodiment of the present invention, when R ¹⁵ and R ¹⁶ are independently selected from C _1-6 alkyl, said C _1-6 alkyl is C _1-4 alkyl.

In a certain embodiment of the present invention, n is an integer of 1 or 2.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from C _1-6 alkoxy, the C _1-6 alkoxy is methoxy, ethoxy, propoxy , isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

In one embodiment of the present invention, when R ³ and R ⁴ are independently selected from C _1-6 haloalkoxy, said C _1-6 haloalkoxy is trifluoromethoxy.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from C _2-6 alkenyl, said C _2-6 alkenyl is

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from (C _3-10 cycloalkyl)-oxy, said (C _3-10 cycloalkyl)-oxy is a ring Propoxy, cyclobutoxy, cyclopentyloxy or cyclohexyloxy.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from (C _3-10 cycloalkyl)-(C _1-6 alkoxy), the (C _3-10 cycloalkane) base)-(C _1-6 alkoxy) is cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropyloxy, cyclopropylbutoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentyl Methoxy, cyclopentethoxy, cyclohexylmethoxy, or, cyclohexylethoxy.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 4-10 In the case of membered heterocycloalkyl-(C _1-6 alkoxy), the 4-10-membered heterocycloalkyl-(C _1-6 alkoxy) is piperidinylmethyl, piperidinylethyl, piperidine pyridylpropyl, piperidinylbutyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, morpholinobutyl, azetidine methyl, azetidine ethyl, azetidine propyl, azetidinebutyl, piperazinemethyl, piperazineethyl, piperazinepropyl, piperazinebutyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, or , pyrrolidinyl butyl.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from (C _6-10 aryl)-(C _1-6 alkoxy), the (C _6-10 aryl) -(C _1-6 alkoxy) is benzyloxy, phenethyloxy, phenpropyloxy, or, phenbutyloxy.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 5-10 In the case of a heteroaryl-oxy group, the 5- to 10-membered heteroaryl-oxy group is a pyridyloxy group, a pyrimidinyloxy group, a pyrazinyloxy group, a pyridazinoxy group, a pyrrolyloxy group, an imidazolyloxy group or a pyridyloxy group oxazolyl.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 5-10 In the case of heteroaryl-(C _1-6 alkoxy), the 5-10-membered heteroaryl-(C _1-6 alkoxy) is pyridinemethoxy, pyrazoleethoxy, pyrimidine methyl oxy, pyrazinemethoxy, pyridazinemethoxy, pyrrolemethoxy, imidazolemethoxy or pyrazolemethoxy.

In a certain embodiment of the present invention, when R ³ and R ⁴ together with the carbon atoms to which they are attached form a 4-20-membered heterocycloalkoxy group, the 4-20-membered heterocycloalkyl group is dioxopentane 12-crown-4, 15-crown-5, or 18-crown-6.

In a certain embodiment of the present invention, when R ^5-1 is C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ^5-1 is (C _1-6 alkoxy)-(C _1-6 alkyl)-, the (C _1-6 alkoxy)-( C _1-6 alkyl)-is methoxy-methyl-, ethoxy-methyl-, propoxy-methyl-, isopropoxy-methyl-, n-butoxy-methyl- , isobutyloxy-methyl, sec-butoxy-methyl, or, tert-butoxy-methyl-.

In a certain embodiment of the present invention, when R ^5-1 is C _3-10 cycloalkyl, the C _3-10 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain embodiment of the present invention, when R ⁵ is unsubstituted or R ^5-3 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" In the case of a 5- to 10-membered heteroaryl group, the number of the R ^5-3 is 1, 2 or 3.

In a certain embodiment of the present invention, when R ⁵ is unsubstituted or R ^5-3 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" When 5-10-membered heteroaryl, the 5-10-membered heteroaryl is pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-thiadiazolyl, or, 1,2,4-thiadiazolyl.

In a certain embodiment of the present invention, when R ^5-4 and R ^5-5 are independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-1 substituted C _1-6 alkyl group, the number of said R ^7-1 is 1, 2 or 3.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-1 substituted C _1-6 alkyl group, the C _1-6 alkyl group is methyl, ethyl, propyl, iso- propyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ⁷ is C _2-6 alkenyl, said C _2-6 alkenyl is

In a certain embodiment of the present invention, when R ⁷ is C _3-10 cycloalkyl, said C _3-10 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain embodiment of the present invention, when R ⁷ is (C _3-10 cycloalkyl)-C _1-6 alkyl, the (C _3-10 cycloalkyl)-C _1-6 alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-2 substituted C _6-10 aryl group, the number of said R ^7-2 is 1, 2 or 3.

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl group, the number of said R ^7-3 is 1 , 2 or 3.

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl, the C _6-10 aryl-C _1-6 alkyl _6Alkyl is benzyl.

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" In the case of a 5- to 10-membered heteroaryl-C _1-6 alkyl group, the number of the R ^7-4 is 1, 2 or 3.

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" When 5-10-membered heteroaryl-C _1-6 alkyl group, the 5-10-membered heteroaryl-C _1-6 alkyl group is pyridine methyl, pyrimidine methyl, pyrazine methyl, pyridazine methyl group, pyrazolemethyl, pyrrolemethyl, thienylmethyl, furylmethyl, thiazolemethyl or imidazolemethyl.

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, the R ^7-2- The number of ^1s is 1, 2 or 3.

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from unsubstituted or R ^7-2-2 substituted C _1-4 alkoxy, the R ^7-2 The number of ^-2 is 1, 2 or 3.

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from -NR ^7-2-3 R ^7-2-4 , the -NR ^{7-2- 3} R ^{7 -2-4} is -NH ₂ , or,

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from -(C=O)R ^7-2-5 , the -(C=O)R ^{7-2 -5} for

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from -(C=O)NR ^7-2-6 R ^7-2-7 , the -(C= O) NR ^7-2-6 R ^7-2-7 is

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from -(C=O)OR ^7-2-8 , the -(C=O)OR ^{7-2 -8} is -COOH, or,

In a certain embodiment of the present invention, when R ^7-2 to R ^7-4 are independently selected from -S(=O) ₂ NR ^7-2-9 R ^7-2-10 , the -S( =O) ₂ NR ^7-2-9 R ^7-2-10 is

In a certain embodiment of the present invention, when R ^8-1 is an unsubstituted or R ^8-1-1 substituted C _1-6 alkyl group, the number of said R ^8-1-1 is 1, 2 or 3.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ^8-1 is C _2-6 alkenyl, the C _2-6 alkenyl is

In a certain embodiment of the present invention, when R ^8-1 is C _3-10 cycloalkyl, the C _3-10 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In a certain embodiment of the present invention, when R ^8-1 is (C _3-10 cycloalkyl)-C _1-6 alkyl, the (C _3-10 cycloalkyl)-C _1-6 Alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, the R ^8-1-3 The number is 1, 2 or 3.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, the C _6-10 aryl -C _1-6 alkyl is benzyl or phenethyl.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-4 substituted "heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1- When three "5- to 10-membered heteroaryl-C _1-6 alkyl groups are used, the number of said R ^8-1-4 is 1, 2 or 3.

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-4 substituted "heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1- When there are 3 "5-10-membered heteroaryl-C _1-6 alkyl groups, the 5-10-membered heteroaryl-C _1-6 alkyl groups are pyridine methyl, pyrimidine methyl, pyrazine methyl , pyridazine methyl, pyrazole methyl, pyrrole methyl, thienyl methyl, furyl methyl, thiazole methyl or imidazole methyl.

In a certain embodiment of the present invention, when R ^8-1-6 is C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ⁹ to R ¹¹ are independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ¹² is C _1-6 alkoxy, the C _1-6 alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In a certain embodiment of the present invention, when R ^12-1 to R ^12-5 are independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, propyl, iso- propyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ¹⁵ and R ¹⁶ are independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain embodiment of the present invention, when R ³ and R ⁴ are independently selected from "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 4-10 In the case of membered heterocycloalkyl-(C _1-6 alkoxy), the 4-10-membered heterocycloalkyl-(C _1-6 alkoxy) is

In a certain embodiment of the present invention, when R ³ and R ⁴ together with the carbon atoms to which they are attached form "heteroatoms selected from one or more of N, O and S, the number of heteroatoms is 1-3""4-20-membered heterocycloalkyl, the 4-20-membered heterocycloalkyl is

In a certain embodiment of the present invention, when R ⁵ is unsubstituted or R ^5-3 substituted "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" In the case of a 5-10-membered heteroaryl group, the unsubstituted or R ^5-3 substituted heteroaryl group is

In a certain embodiment of the present invention, when R ⁷ is C _1-6 alkyl substituted by R ^7-1 , the C _1-6 alkyl substituted by R ^7-1 is trifluoromethyl, difluoro methyl,

In a certain embodiment of the present invention, when R ⁷ is an unsubstituted or R ^7-2 substituted C _6-10 aryl group, the unsubstituted or R ^7-2 substituted C _6-10 aryl group is

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl, the unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl is

In a certain embodiment of the present invention, when R ⁷ is unsubstituted or R ^7-4 substituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" In the case of a 5-10-membered heteroaryl-C _1-6 alkyl group, the unsubstituted or R ^7-4 substituted heteroaryl-C _1-6 alkyl group is

In a certain embodiment of the present invention, when R ^8-4 is C _1-6 alkyl substituted by R ^8-1-1 , the C _1-6 alkyl substituted by R ^8-1-1 is

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, the unsubstituted or R ^{8- 1-3} substituted C _6-10 aryl-C _1-6 alkyl is

In a certain embodiment of the present invention, when R ^8-1 is unsubstituted or R ^8-1-4 substituted "heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1- 3 "5-10-membered heteroaryl-C _1-6 alkyl, the unsubstituted or R ^8-1-4 substituted heteroaryl-C _1-6 alkyl is

In ^a certain embodiment of the present invention, R1 is hydrogen.

In a certain embodiment of the present invention, R2 is ^hydrogen , or, halogen.

In a certain embodiment of the present invention, R ³ is halogen, C _2-6 alkenyl, C _1-6 alkoxy, or, -NR ^3-2 R ^3-3 .

In a certain embodiment of the present invention, R ⁴ is halogen, C _1-6 alkoxy, C _2-6 alkenyl, heterocycloalkyl-(C _1-6 alkoxy), or, -NR ^{3- 2} R ^3-3 .

In one embodiment of the present invention, R ³ and R ⁴ together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group.

In a certain embodiment of the present invention, R ^3-2 is hydrogen or C _1-4 alkyl.

In a certain embodiment of the invention, R ^3-3 is hydrogen or C _1-4 alkyl.

In a certain embodiment of the present invention, R ⁵ is -(C=O)OR ^5-1 , unsubstituted or R ^5-3 substituted "heteroatom selected from one or more of N, O and S, "5-10-membered heteroaryl group with 1-3 heteroatoms, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ .

In a certain embodiment of the present invention, R ^5-1 is hydrogen, C _1-6 alkyl, (C _1-6 alkoxy)-(C _1-6 alkyl)-, or, C _3-10 ring alkyl.

In a certain embodiment of the present invention, R ^5-4 is hydrogen.

In a certain embodiment of the present invention, R ^5-5 is C _1-6 alkyl.

In a certain embodiment of the present invention, R ⁷ is hydrogen, unsubstituted or R ^7-1 substituted C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, unsubstituted or R ^{7 -2-} substituted C _6-10 aryl, unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl, or, unsubstituted or R ^7-4 substituted heteroaryl-C _1-6 alkyl.

In one embodiment of the present invention, R ^7-1 is halogen, carboxyl, hydroxyl, or, cyano.

In a certain embodiment of the present invention, R ^7-2 is halogen, unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, unsubstituted or R ^7-2-2 substituted C _1-4 alkane oxy, or, -NR ^7-2-3 R ^7-2-4 .

In a certain embodiment of the present invention, R ^7-3 is halogen, cyano, unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, unsubstituted or R ^7-2-2 substituted C _{1 -4alkoxy} , or, -(C=O)NR ^7-2-6 R ^7-2-7 .

In a certain embodiment of the present invention, R ^7-4 is halogen.

In a certain embodiment of the present invention, R ^7-2-1 is halogen.

In a certain embodiment of the present invention, R ^7-2-2 is halogen.

In a certain embodiment of the present invention, R ^7-2-3 is hydrogen.

In a certain embodiment of the present invention, R ^7-2-4 is hydrogen.

In a certain embodiment of the present invention, R ^7-2-6 is hydrogen.

In a certain embodiment of the present invention, R ^7-2-7 is hydrogen.

In a certain embodiment of the present invention, R ⁸ is hydrogen, cyano, R ^8-1 O-, or, -NR ^8-2 R ^8-3 .

In a certain embodiment of the invention, R ^8-1 is hydrogen, unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, unsubstituted or R ^8-1-4 Substituted heteroaryl-C _1-6 alkyl, or, -(S=O) ₂ OR ^8-1-6 .

In a certain embodiment of the present invention, R ^8-1-1 is hydroxy.

In a certain embodiment of the present invention, R ^8-1-3 is halogen.

In a certain embodiment of the present invention, R ^8-1-4 is halogen.

In a certain embodiment of the present invention, R ^8-1-6 is hydrogen or C _1-6 alkyl.

In a certain embodiment of the present invention, R ^8-2 is hydrogen or C _1-6 alkyl.

In a certain embodiment of the invention, R ^8-3 is hydrogen or C _1-6 alkyl.

其中，X的左端与

相连，右端与L相连。In an embodiment of the present invention, X is C=O,

where the left end of X is the same as

connected, and the right end is connected to L.

^In a certain embodiment of the present invention, R10 is hydrogen.

^In a certain embodiment of the present invention, R11 is hydrogen.

In a certain embodiment of the invention, R ¹² is hydroxy, cyano, C _1-6 alkoxy, -O(C=O)R ^12-1 , -(S=O) ₂ R ^12-2 , or , -NR ^12-4 R ^12-5 .

In a certain embodiment of the present invention, R ^12-1 is C _1-6 alkyl.

In a certain embodiment of the present invention, R ^12-2 is C _1-6 alkyl.

In a certain embodiment of the present invention, R ^12-4 is hydrogen.

In a certain embodiment of the present invention, R ^12-5 is hydrogen.

In a certain embodiment of the present invention, ^R13 is hydrogen.

In a certain embodiment of the present invention, ^R14 is hydrogen.

对，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸。In one embodiment of the present invention, when X is

Yes, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ .

时，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸。In one embodiment of the present invention, when X is

, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ .

时，R⁵独立地选自-(C＝O)OR^5-1。In one embodiment of the present invention, when X is

, R ⁵ is independently selected from -(C=O)OR ^5-1 .

^In a certain embodiment of the present invention, R6 is hydrogen.

In a certain embodiment of the present invention, R ¹⁵ is hydrogen, halogen, or, C _1-6 alkyl.

In a certain embodiment of the present invention, R ¹⁶ is hydrogen, halogen, or, C _1-6 alkyl.

In one embodiment of the present invention,

R ¹ is hydrogen;

R ² is hydrogen, or, halogen;

R ³ is halogen, C _2-6 alkenyl, C _1-6 alkoxy, or, -NR ^3-2 R ^3-3 ;

R ⁴ is halogen, C _1-6 alkoxy, C _2-6 alkenyl, heterocycloalkyl-(C _1-6 alkoxy), -NR ^3-2 R ^3-3 , or, R ³ and R ⁴ and the carbon atoms to which they are attached together form a 4-20-membered heterocycloalkoxy group;

R ^3-2 is hydrogen or C _1-4 alkyl;

R ^3-3 is hydrogen or C _1-4 alkyl;

R ⁵ is -(C=O)OR ^5-1 , unsubstituted or R ^5-3 substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3. "5-10-membered heteroaryl, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

R ^5-1 is hydrogen, C _1-6 alkyl, (C _1-6 alkoxy)-(C _1-6 alkyl)-, or, C _3-10 cycloalkyl;

R ^5-3 is C _1-4 alkyl;

R ^5-4 is hydrogen;

R ^5-5 is C _1-6 alkyl;

R ⁷ is hydrogen, unsubstituted or R ^7-1 substituted C _1-6 alkyl, C _2-6 alkenyl, C _3-10 cycloalkyl, unsubstituted or R ^7-2 substituted C _6-10 aryl base, unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl, or, unsubstituted or R ^7-4 substituted heteroaryl-C _1-6 alkyl;

R ^7-1 is halogen, carboxyl, hydroxyl, or, cyano;

R ^7-2 is halogen, unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, unsubstituted or R ^7-2-2 substituted C _1-4 alkoxy, or, -NR ^{7- 2-3} R ^7-2-4 ;

R ^7-3 is halogen, cyano, unsubstituted or R ^7-2-1 substituted C _1-4 alkyl, unsubstituted or R ^7-2-2 substituted C _1-4 alkoxy, or, - (C=O)NR ^7-2-6 R ^7-2-7 ;

R ^7-4 is halogen;

R ^7-2-1 is halogen;

R ^7-2-2 is halogen;

R ^7-2-3 is hydrogen;

R ^7-2-4 is hydrogen;

R ^7-2-6 is hydrogen;

R ^7-2-7 is hydrogen;

R ⁸ is hydrogen, cyano, R ^8-1 O-, or, -NR ^8-2 R ^8-3 ;

R ^8-1 is hydrogen, unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, unsubstituted or R ^8-1-4 substituted heteroaryl-C _{1- 6} alkyl, or, -(S=O) ₂ OR ^8-1-6 ;

R ^8-1-1 is hydroxyl;

R ^8-1-3 is halogen;

R ^8-1-4 is halogen;

R ^8-1-6 is hydrogen or C _1-6 alkyl;

R ^8-1-2-3 is C _1-4 alkyl;

R ^8-1-2-4 is hydrogen;

R ^8-1-2-5 is hydrogen;

R ^8-2 is hydrogen or C _1-6 alkyl;

R ^8-3 is hydrogen or C _1-6 alkyl;

其中，X的左端与

相连，右端与L相连；X is C=O,

where the left end of X is the same as

connected, and the right end is connected to L;

R ¹⁰ is hydrogen;

R ¹¹ is hydrogen;

R ¹² is hydroxy, cyano, C _1-6 alkoxy, -O(C=O)R ^12-1 , -(S=O) ₂ R ^12-2 , or, -NR ^12-4 R ^{12- 5} ;

R ^12-1 is C _1-6 alkyl;

R ^12-2 is C _1-6 alkyl;

R ^12-4 is hydrogen;

R ^12-5 is hydrogen;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

X and R ^are selected from any combination of the following:

时，R⁵为-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸；when X is

, R ⁵ is -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

When X is C=O, R ⁵ is -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, unsubstituted or R ^5-3 substituted "heteroatom is selected from N, One or more of O and S, "5-10-membered heteroaryl group with 1-3 heteroatoms;

时，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸；when X is

, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

时，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸；when X is

, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

时，R⁵独立地选自-(C＝O)OR^5-1；when X is

, R ⁵ is independently selected from -(C=O)OR ^5-1 ;

R ⁶ is hydrogen;

R ¹⁵ is hydrogen, halogen, or, C _1-6 alkyl;

R ¹⁶ is hydrogen, halogen, or, C _1-6 alkyl.

In one embodiment of the present invention,

R ¹ is hydrogen;

R ² is hydrogen, or, halogen;

R ³ is C _1-6 alkoxy;

R ⁴ is C _1-6 alkoxy, heterocycloalkyl-(C _1-6 alkoxy), or, R ³ and R ⁴ together with the carbon atoms to which they are attached form a 4-20-membered heterocycloalkoxy group ;

R ⁵ is -(C=O)OR ^5-1 , unsubstituted or R ^5-3 substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3. "5-10-membered heteroaryl, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

R ^5-1 is hydrogen, C _1-6 alkyl, (C _1-6 alkoxy)-(C _1-6 alkyl)-, or, C _3-10 cycloalkyl;

R ^5-3 is C _1-4 alkyl;

R ^5-4 is hydrogen;

R ^5-5 is C _1-6 alkyl;

R ⁷ is hydrogen, unsubstituted or R ^7-1 substituted C _1-6 alkyl, C _3-10 cycloalkyl, unsubstituted or R ^7-3 substituted C _6-10 aryl-C _1-6 alkyl base, or, unsubstituted or R ^7-4 substituted heteroaryl-C _1-6 alkyl;

R ^7-1 is halogen, hydroxyl, or, cyano;

R ^7-3 is halogen, cyano, or, unsubstituted or R ^7-2-1 substituted C _1-4 alkyl

R ^7-4 is halogen;

R ^7-2-1 is halogen;

R ⁸ is hydrogen, cyano, R ^8-1 O-, or, -NR ^8-2 R ^8-3 ;

R ^8-1 is hydrogen, unsubstituted or R ^8-1-3 substituted C _6-10 aryl-C _1-6 alkyl, or, unsubstituted or R ^8-1-4 substituted heteroaryl-C _1-6 alkyl;

R ^8-1-1 is hydroxyl;

R ^8-1-3 is halogen;

R ^8-1-4 is halogen;

其中，X的左端与

相连，右端与L相连；X is C=O,

where the left end of X is the same as

connected, and the right end is connected to L;

R ¹⁰ is hydrogen;

R ¹¹ is hydrogen;

R ¹² is hydroxy, cyano, C _1-6 alkoxy, -O(C=O)R ^12-1 , -(S=O) ₂ R ^12-2 , or, -NR ^12-4 R ^{12- 5} ;

R ^12-1 is C _1-6 alkyl;

R ^12-2 is C _1-6 alkyl;

R ^12-4 is hydrogen;

R ^12-5 is hydrogen;

R ¹³ is hydrogen;

R ¹⁴ is hydrogen;

X and R ^are selected from any combination of the following:

时，R⁵为-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸；when X is

, R ⁵ is -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

When X is C=O, R ⁵ is -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, unsubstituted or R ^5-3 substituted "heteroatom is selected from N, One or more of O and S, "5-10-membered heteroaryl group with 1-3 heteroatoms;

时，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸；when X is

, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

时，R⁵为-(C＝O)OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸；when X is

, R ⁵ is -(C=O)OR ^5-1 , -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ;

时，R⁵独立地选自-(C＝O)OR^5-1；when X is

, R ⁵ is independently selected from -(C=O)OR ^5-1 ;

R ⁶ is hydrogen;

R ¹⁵ is hydrogen, halogen, or, C _1-6 alkyl;

R ¹⁶ is hydrogen, halogen, or, C _1-6 alkyl.

In a certain embodiment of the present invention, the compound shown in the described formula I can be any of the following structures:

The second aspect of the present invention provides a preparation method of the compound described in the first aspect of the present invention, which comprises the following steps:

时，R⁵为-(C＝O)NR⁷R⁸、或、-(C＝O)NR^5-4(S＝O)₂R^5-5时，(1) When X is

When R ⁵ is -(C=O)NR ⁷ R ⁸ , or, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 ,

in,

R ₁₇ is hydrogen or C _1-6 alkyl;

R ¹⁸ is R ⁷ and R ¹⁹ is R ⁸ ; alternatively, R ¹⁸ is R ^5-4 and R ¹⁹ is R ^5-5 ;

Definitions of R ¹ , R ² , R ³ , R ⁴ , R ^5-4 , R ^5-5 , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and L as defined in the first aspect of the present invention;

Step a: in a solvent, compound II-1 and compound III-1 react to generate IV;

Step b: in a solvent, compound IV and compound V react to generate compound I-1;

Method two, including steps:

R⁵为-(C＝O)OR^5-1、-(C＝O)SR^5-2、未取代或R^5-3取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-3个的”5～10元杂芳基、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸时，(2) When X is

R ⁵ is -(C=O)OR ^5-1 , -(C=O)SR ^5-2 , unsubstituted or R ^5-3 substituted "heteroatom selected from one or more of N, O and S Species, "5-10-membered heteroaryl with 1-3 heteroatoms, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ,

in,

Y is -NHR ¹¹ , or, -NHR ¹³ ;

R ¹⁸ is R ⁷ and R ¹⁹ is R ⁸ ; alternatively, R ¹⁸ is R ^5-4 and R ¹⁹ is R ^5-5 ;

R ²⁰ is -COOH, or, -NHR ¹⁴ ;

X ^a is

R ^5a is -(C=O)OR ^5-1 , -(C=O)SR ^5-2 , or, unsubstituted or R ^5-3 substituted "heteroatom selected from one of N, O and S" or more, "5-10-membered heteroaryl group with 1-3 heteroatoms;

R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-5 , R ⁷ , R ⁸ , R ¹¹ , R ¹³ , R ¹⁴ and L are as defined in the first aspect of the present invention;

Step c: in a solvent, compound II-2 and compound III-2 react to form compound I-2;

Step d: in a solvent, compound I-2 reacts with compound V to generate compound I-3;

R⁵为-(C＝O)OR^5-1、-(C＝O)SR^5-2、未取代或R^5-3取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-3个的”5～10元杂芳基、-(C＝O)NR^5-4(S＝O)₂R^5-5、或、-(C＝O)NR⁷R⁸时，(3) When X is

R ⁵ is -(C=O)OR ^5-1 , -(C=O)SR ^5-2 , unsubstituted or R ^5-3 substituted "heteroatom selected from one or more of N, O and S Species, "5-10-membered heteroaryl with 1-3 heteroatoms, -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 , or, -(C=O)NR ⁷ R ⁸ ,

Wherein, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹² and L are as defined in the first aspect of the present invention;

Step e: in a solvent, compound II-3 is reacted with compound VI to generate compound I-4;

(4) When X is C=O, and R ⁵ is -(C=O)NR ^5-4 (S=O) ₂ R ^5-5 ,

Wherein, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^5-4 , R ^5-5 and L are as defined in the first aspect of the present invention;

Step f: In a solvent, compound II-4 is reacted with compound VII to generate compound I-5.

The third aspect of the present invention provides a pharmaceutical composition, which contains the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or Hydrate, and pharmaceutical excipients or carriers.

Further, in the above pharmaceutical composition, the amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is therapeutically effective quantity.

Further, in the above-mentioned pharmaceutical composition, one or more second therapeutic agents are also included, and the second therapeutic agents are drugs for preventing and/or treating tumors.

Further, the second therapeutic agent is a traditional cytotoxic chemotherapeutic drug, a DNA-damaging agent or other anti-tumor immune drug.

The fourth aspect of the present invention provides a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or, the present invention Use of the pharmaceutical composition described in the third aspect in the preparation of a medicament.

Further, the medicament is a medicament for preventing and/or treating tumors or infectious diseases.

The fifth aspect of the present invention provides a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or, the present invention Use of the pharmaceutical composition described in the third aspect in the preparation of a vaccine adjuvant.

Further, the vaccine adjuvant is a vaccine adjuvant for treating tumors or infectious diseases.

The sixth aspect of the present invention provides a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or, the present invention Use of the pharmaceutical composition described in the third aspect in the preparation of an interferon gene-stimulating protein agonist.

The seventh aspect of the present invention provides a pharmaceutical combination comprising: the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or Hydrate and, immune checkpoint inhibitors or DNA damaging agents. The immune checkpoint inhibitor is LAG-3 inhibitor, TIM3 inhibitor, PD-1/PD-L1 inhibitor, IDO1 inhibitor, CTLA-4 inhibitor, TIGIT inhibitor or VISTA inhibitor, preferably PD- 1/PD-L1 inhibitor, IDO1 inhibitor, or CTLA-4 inhibitor. The DNA damaging agent is a PARP inhibitor. The compounds described in the first aspect of the present invention, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and immune checkpoint inhibitors can be administered simultaneously or separately; The compound of the first aspect of the invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and the DNA damaging agent may be administered simultaneously or separately.

The eighth aspect of the present invention provides a use of the pharmaceutical combination according to the sixth aspect of the present invention in a medicament for treating tumors.

The ninth aspect of the present invention provides the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for treating tumors In the application in the first aspect of the present invention, the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, is used in combination with an immune checkpoint inhibitor. The compounds described in the first aspect of the present invention, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and immune checkpoint inhibitors can be administered simultaneously or separately.

The tenth aspect of the present invention provides a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, used in the preparation of treating tumors For use in medicine, the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, is used in combination with a DNA damage-causing agent. The compounds described in the first aspect of the present invention, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and the DNA damaging agent may be administered simultaneously or separately.

In the present invention, the tumors include but are not limited to non-small cell lung cancer, liver cancer, gastric cancer, leukemia, melanoma, colon cancer, glioma, kidney cancer, ovarian cancer, pancreatic cancer, breast cancer, head and neck cancer, prostate cancer cancer, multiple myeloma, or cervical cancer.

The term "immune checkpoint inhibitor" refers to a substance that inhibits the activity of co-inhibitory receptors, blocks negative regulatory signals, and restores the activity of T cells, thereby enhancing the immune response.

The term "LAG-3 inhibitor" refers to a substance that inhibits the activity of LAG-3 and restores the activity of T cells, thereby enhancing the immune response.

The term "TIM3 inhibitor" refers to a substance that inhibits the activity of TIM3 and restores the activity of T cells, thereby enhancing the immune response.

The term "PD-1/PD-L1 inhibitor" refers to a substance that can block the binding of PD-1 to PD-L1, block negative regulatory signals, and restore the activity of T cells, thereby enhancing the immune response.

The term "IDO1 inhibitor" refers to a substance that inhibits the activity of IDO1 and restores the activity of T cells, thereby enhancing the immune response.

The term "CTLA-4 inhibitor" refers to a substance that blocks the negative regulatory signals mediated by CTLA-4 and restores the activity of T cells, thereby enhancing the immune response.

The term "VISTA inhibitor" refers to a substance that inhibits the activity of VISTA and restores the activity of T cells, thereby enhancing the immune response.

The term "TIGIT inhibitor" refers to a substance that inhibits the activity of TIGIT and restores the activity of T cells, thereby enhancing the immune response.

The term "DNA-damaging agent" refers to a substance that induces DNA damage.

The term "simultaneous administration" refers to administration at the same time point, for example, administration of a benzothiophene compound having the structure shown in general formula I, or a pharmaceutically acceptable salt, isomer, metabolite, or prodrug thereof at the same time , a solvate or a hydrate, and a separate pharmaceutical composition of an immune checkpoint inhibitor; or, at the same time point, administer "a benzothiophene compound having the structure shown in general formula I, or a pharmaceutically acceptable compound thereof. Separate pharmaceutical compositions of accepted salts, isomers, metabolites, prodrugs, solvates or hydrates" and "separate pharmaceutical compositions comprising immune checkpoint inhibitors".

The term "separate administration" refers to administration at different time points, for example, administration at different time points "comprising a benzothiophene compound having the structure shown in general formula I, or a pharmaceutically acceptable salt or isomer thereof. , metabolite, prodrug, solvate or hydrate pharmaceutical composition" and "a separate pharmaceutical composition comprising an immune checkpoint inhibitor"; A single pharmaceutical composition of a thiophene compound, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof" and "a single pharmaceutical combination comprising an immune checkpoint inhibitor" one of the substances" and then the other. Separate administration can be close in time or at a long interval, but it is necessary to ensure that the benzothiophenes having the structure shown in general formula I, or their pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates, etc. Compounds or hydrates, and immune checkpoint inhibitors can work together to provide the desired therapeutic effect. For example, prior to administration of an immune checkpoint inhibitor (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to administration, or after administration of an immune checkpoint inhibitor (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or after 12 weeks) administration of a benzothiophene compound having the structure shown in formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof.

The pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed. The pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.

The pharmaceutical compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical or parenteral (infusion, injection, implant Intradermal, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in controlled release or delayed release dosage forms (eg, liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, softgels, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges agent.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonate or bicarbonate), phosphoric acid (forming phosphate, monophosphate Hydrogen salts, dihydrogen phosphates, sulfuric acid (to form sulfate or hydrogen sulfate), hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid , malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like Organic acid salts also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, which can be used by Converted to any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is isolated, thereby regenerating the free form of the compound. The free form of the compound and its various salt forms The difference lies in certain physical properties, such as solubility in polar solvents.

"Pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid groups or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

The term "isomer" refers to compounds having the same chemical formula but different arrangements of atoms.

The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of formula I or a salt thereof. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, and the like, of the administered compound. Accordingly, the present invention includes metabolites of compounds of the present invention, including compounds produced by methods of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain its metabolites.

Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention, and parenterally administering them to animals, eg, rats, mice, guinea pigs, monkeys, at detectable doses (eg, greater than about 0.5 mg/kg) , or humans, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolation of its transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding epitopes present in the metabolite). Metabolite structures are determined in a conventional manner, eg, by MS, LC/MS or NMR analysis. In general, analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the present invention. The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Any compound that can be transformed in vivo to provide a biologically active substance (ie, a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, a compound containing a carboxyl group can form a physiologically hydrolyzable ester, which acts as a prodrug by hydrolysis in vivo to yield the compound of formula I itself. The prodrugs are preferably administered orally, since hydrolysis in many cases occurs primarily under the influence of digestive enzymes. Parenteral administration can be used when the ester itself is active or hydrolysis occurs in the blood.

The terms "active ingredient," "therapeutic agent," or "active substance" refer to a chemical entity that is effective in treating the target disorder, disease, or condition.

When the exemplified linking group does not indicate its direction of attachment, the direction of attachment is in the same direction as read from left to right.

是指，相应的基团通过该位点与式I所示化合物中的其它片段、基团进行连接。It can be understood by those skilled in the art that, according to the conventions used in the art, the formula used in the structural formula of the group described in this application

It means that the corresponding group is connected with other fragments and groups in the compound represented by formula I through this site.

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.

Beneficial effects: the benzothiophene compound of the present invention overcomes the defects of the existing small molecule agonists of interferon gene-stimulating protein and the poor drugability of nucleotide-type interferon gene-stimulating protein agonists. The pyrimido five-membered heterocyclic compound of the present invention has good agonistic activity on interferon gene-stimulating protein, and has good therapeutic effect on tumors and infectious diseases.

Detailed ways

Example 1: Synthesis of Compound S7

Step 1: Synthesis of Compound 2

Under nitrogen protection, compound 1 (10 g, 39.2 mmol) was combined with Na ₂ S ₂ O ₃ .5H ₂ O (48.6 g, 196.1 mmol), Pd(dppf)Cl ₂ (2.9 g, 3.92 mmol), dppf (3.3 g, 5.88 mmol), Cs ₂ CO ₃ (38.3 g, 117.6 mmol) were dissolved in DMF (300 mL) and ethylene glycol (16 mL), warmed to 140° C., and reacted overnight. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added to dilute the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography. Purification gave compound 2 (2.9 g, 35%). ¹ H NMR (500MHz, Chloroform-d) δ 7.07(s, 1H), 6.93(s, 1H), 6.22(s, 1H), 3.90(s, 3H), 3.89(s, 3H), 3.88(s , 2H).

Step 2: Synthesis of Compound S7

Compound 2 (100 mg, 0.48 mmol) and succinic anhydride (96 mg, 0.96 mmol) were dissolved in anhydrous THF (3 ml), triethylamine was added, and the reaction was stirred at room temperature for 6 h. After the reaction was completed, the solvent was evaporated under reduced pressure. Water (3 ml) was added to the reaction residue, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S7 (118 mg, 80%). ¹ H NMR (500 MHz, (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.41-7.34 (m, 2H) , 3.89(d, J=17.6Hz, 6H), 2.70-2.62(m, 2H), 2.59-2.51(m, 2H).

For the synthesis of compounds S8 to S15 in the following Examples 2 to 9, reference can be made to the synthesis method of Example 1, and only the corresponding raw materials need to be replaced.

Example 2: Synthesis of Compound S8

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.37-7.30 (m, 2H), 3.91 ( s, 3H), 3.87 (s, 3H), 3.45 (s, 2H).

Example 3: Synthesis of Compound S9

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.79 (d, J=2.2Hz, 1H), 7.53 (d, J=2.2Hz, 1H) , 7.24(s, 1H), 3.94(s, 3H), 3.44(s, 2H).

Example 4: Synthesis of Compound S10

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.81 (d, J=2.3Hz, 1H), 7.50 (d, J=2.2Hz, 1H) , 7.28(s, 1H), 6.84(t, J=9.3Hz, 1H), 5.70(dd, J=9.3, 1.8Hz, 1H), 5.47(dd, J=9.2, 1.9Hz, 1H), 3.87( s, 3H), 3.45(s, 2H).

Example 5: Synthesis of Compound S11

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.69 (d, J=2.2Hz, 1H), 7.39-7.35 (m, 2H), 4.14 ( q, J=7.0Hz, 2H), 3.89 (d, J=17.6Hz, 5H), 3.54 (s, 2H), 1.26 (t, J=6.9Hz, 3H).

Example 6: Synthesis of Compound S12

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.37-7.30 (m, 2H), 3.91 ( s, 3H), 3.87(s, 3H), 2.84(s, 2H), 1.39(s, 3H), 1.37(s, 3H).

Example 7: Synthesis of Compound S13

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.71 (d, J=2.3Hz, 1H), 7.37 (d, J=2.1Hz, 1H) , 7.24(s, 1H), 4.27(t, J=6.5Hz, 2H), 3.90(s, 3H), 3.68-3.57(m, 4H), 3.39(s, 2H), 2.73(t, J=6.4 Hz, 2H), 2.58-2.44(m, 4H).

Example 8: Synthesis of Compound S14

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.70 (s, 1H), 7.26-7.20 (m, 2H), 6.00 (s, 2H), 3.45(s, 2H).

Example 9: Synthesis of Compound S15

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.8 (br, 1H), 10.98 (s, 1H), 7.79 (s, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 4.30- 4.21(m, 4H), 3.45(s, 2H).

Example 10: Synthesis of Compound S16

Compound S8 (100 mg, 0.34 mmol) and hydrazine hydrochloride (24 mg, 0.34 mmol) were dissolved in dry DMF (5 mL), HATU (193.2 mg, 0.51 mmol) and DIPEA (132 mg, 1.02 mmol) were added to the above solution ) and reacted overnight at room temperature. After the reaction was completed, the reaction solution was poured into ice water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S16 ( 86 mg, 82%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.78 (s, 1H), 9.06 (t, J=3.7Hz, 1H), 7.69 (d, J=2.1Hz, 1H), 7.40-7.34 (m, 2H), 4.01(d, J=3.7Hz, 2H), 3.89(s, 3H), 3.76(s, 3H), 3.34(s, 2H).

For the synthesis of compounds S17 to S35 in the following Examples 11 to 29, reference can be made to the synthesis method of Example 10, and only the corresponding raw materials need to be replaced.

Example 11: Synthesis of Compound S17

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.78(s, 1H), 9.86(s, 1H), 8.73(s, 1H), 7.69(s, 1H), 7.39-7.33(m, 1H), 4.35(m, 2H), 3.89(s, 3H), 3.80(s, 3H), 3.33(s, 3H), 2.56(m, 1H).

Example 12: Synthesis of Compound S18

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 10.78 (s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.40-7.33 (m, 2H), 3.89 ( d, J=17.6Hz, 6H), 3.43 (s, 2H), 3.12 (s, 3H).

Example 13: Synthesis of Compound S19

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.86 (s, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.41-7.34 (m, 2H), 3.89 ( d, J=17.6Hz, 6H), 3.41(s, 2H).

Example 14: Synthesis of Compound S20

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.86(s, 1H), 10.50(s, 1H), 7.69(s, 1H), 7.51(s, 1H), 7.39(s, 1H), 7.12( s, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.37 (s, 2H).

Example 15: Synthesis of Compound S21

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.39-7.33 (m, 2H), 3.91 (s, 3H), 3.87 ( s, 3H), 3.63 (s, 3H), 3.36 (s, 2H), 3.18 (s, 3H).

Example 16: Synthesis of Compound S22

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.37-7.30 (m, 2H), 7.21 (s, 1H), 7.09 ( s, 1H), 3.89 (d, J=17.6Hz, 5H), 3.46 (s, 2H).

Example 17: Synthesis of Compound S23

1H NMR (500MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 7.70 (d, J=2.1Hz, 1H), 7.34 (s, 1H), 7.28 (d, J=2.2Hz, 1H), 6.73(s, 1H), 4.10(s, 2H), 3.89(d, J=17.6Hz, 6H), 3.42(s, 2H).

Example 18: Synthesis of Compound S24

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.37-7.33 (m, 2H), 7.09 (s, 1H), 6.33 ( s, 2H), 5.89 (tt, J=13.8, 5.5Hz, 1H), 5.21 (dt, J=13.9, 1.0Hz, 2H), 3.93-3.85 (m, 6H), 3.40 (s, 2H).

Example 19: Synthesis of Compound S25

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.34 (s, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J=2.0Hz, 1H), 7.09(s, 1H), 3.89(d, J=17.6Hz, 5H), 3.60(t, J=5.5Hz, 2H), 3.43(s, 2H), 2.80(t, J=5.5Hz, 2H).

Example 20: Synthesis of Compound S26

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.40-7.30 (m, 2H), 7.09 (s, 1H), 4.80 ( d, J=6.8Hz, 1H), 4.13 (t, J=7.0Hz, 1H), 3.99-3.90 (m, 1H), 3.88 (d, J=15.9Hz, 6H), 3.77-3.67 (m, 2H) ), 3.51-3.41(m, 2H), 3.37-3.29(m, 2H).

Example 21: Synthesis of Compound S27

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.16 (s, 1H), 7.72-7.64 (m, 3H), 7.44-7.36 (m, 4H), 7.18 (tt, J =7.2, 1.5Hz, 1H), 3.89(d, J=16.7Hz, 6H), 3.55(s, 2H).

Example 22: Synthesis of Compound S28

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.16 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.60-7.54 (m, 2H), 7.44- 7.39(m, 2H), 7.17-7.10(m, 2H), 3.89(d, J=17.6Hz, 6H), 3.55(s, 2H), 2.33(s, 3H).

Example 23: Synthesis of Compound S29

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.27 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.68-7.61 (m, 2H), 7.44- 7.39(m, 2H), 7.19-7.11(m, 2H), 3.89(d, J=17.6Hz, 6H), 3.56(s, 2H).

Example 24: Synthesis of Compound S30

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.45-7.40 (m, 2H), 7.39-7.29 (m, 3H), 7.33-7.23(m, 3H), 6.04(s, 1H), 4.63(t, J=1.0Hz, 2H), 3.89(d, J=17.6Hz, 6H), 3.42(s, 2H).

Example 25: Synthesis of Compound S31

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.73 (t, J=1.7Hz, 1H), 8.47-8.40 (m, 1H), 7.70 (dt, J=9.9, 2.1 Hz, 2H), 7.40-7.35(m, 2H), 7.25(dd, J=7.9, 3.5Hz, 1H), 7.06(s, 1H), 4.67(s, 2H), 3.89(d, J=17.6Hz , 6H), 3.46(s, 2H).

Example 26: Synthesis of Compound S32

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.19 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.40-7.27 (m, 7H), 4.66 ( t, J=1.0Hz, 2H), 3.89 (d, J=17.6Hz, 6H), 3.35 (s, 2H).

Example 27: Synthesis of Compound S33

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.33 (s, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J=2.2Hz, 1H), 4.08-4.01 (m, 1H), 3.89 (d, J=17.6Hz, 6H), 3.81-3.72 (m, 4H), 3.33 (s, 2H).

Example 28: Synthesis of Compound S34

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.52 (s, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.39-7.32 (m, 2H), 3.88 ( d, J=15.4Hz, 6H), 3.36(s, 2H).

Example 29: Synthesis of Compound S35

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.40-7.37 (m, 1H), 7.34 (s, 1H), 7.32 ( d, J=7.7Hz, 1H), 7.20 (d, J=7.7Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.25 (s, 2H).

Example 30: Synthesis of Compound S36

Step 1: Synthesis of Compound 5

Under nitrogen protection, compound 3 (10 g, 47.4 mmol) was dissolved in anhydrous DMF, anhydrous potassium carbonate (13 g, 94.8 mmol) was added, and at 0 °C, compound 4 (6.9 g, 57.8 mmol) was added dropwise to The above suspension was stirred at 0 °C for 30 min. Then, the temperature was raised to 80°C, and the reaction was carried out overnight. After the reaction was completed, it was cooled to room temperature, DMF was evaporated under reduced pressure, water was added, extracted with DCM (100 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain Compound 5 (9.1 g, 72%).

Step 2: Generation of Compound 6

Compound 5 was dissolved in THF, 2M NaOH aqueous solution was added at 0° C., the mixture was transferred to room temperature, and the reaction was stirred for 2 h. After the reaction was completed, 2M dilute hydrochloric acid was added to adjust the pH to 2-3, a white precipitate was precipitated, suction filtered, the filter cake was washed with THF, the filter cake was collected and dried to obtain compound 6, which was directly put into the next reaction.

Step 3: Generation of Compound 8

Compound 6 (5 g, 21 mmol) was dissolved in dry DMF (20 mL), HATU (12 g, 31.5 mmol), DIPEA (8.1 g, 63 mmol) and compound 7 (2.8 g, 21 mmol) were added sequentially. React overnight at room temperature. After the reaction was completed, DMF was evaporated under reduced pressure. Water (10 mL) was added to the reaction residue, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 8 (6.3 g, 85%). ¹ H NMR (500MHz, Chloroform-d) δ 8.28-8.18 (m, 2H), 7.51 (d, J=2.1Hz, 1H), 7.46 (s, 1H), 4.09 (d, J=5.7Hz, 2H) ), 3.89(d, J=14.6Hz, 6H), 1.42(s, 9H).

Step 4: Synthesis of Compound S36

Compound 8 (600 mg, 1.7 mmol) was dissolved in DCM (5 mL), placed at 0 °C, and _CF3COOH (1 mL) was added. Transfer to room temperature and stir the reaction for 2h. After the reaction was completed, the solvent and excess CF ₃ COOH were evaporated under reduced pressure. The resulting product was then dissolved in dry DMF (5 mL), followed by addition of hydroxylamine hydrochloride (120 mg, 1.7 mmol), HATU (970 mg, 2.6 mmol) and DIPEA (1.1 g, 8.5 mmol). The reaction was stirred at room temperature for 6 h. After the reaction was completed, the DMF was evaporated under reduced pressure. Water (20 mL) was added to the reaction residue, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S36 (421 mg, 80 %). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.50 (d, J=4.8 Hz, 1H), 8.25 (t, J=5.8 Hz, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.73 (d, J=2.2Hz, 1H), 7.57 (d, J=2.1Hz, 1H), 7.42 (s, 1H), 3.96-3.86 (m, 8H).

For the synthesis of compounds S37 to S70 in the following Examples 31 to 64, reference can be made to the synthesis method of Example 30, and only the corresponding raw materials need to be replaced.

Example 31: Synthesis of Compound S37

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.83 (d, J=4.8 Hz, 1H), 8.28 (d, J=2.1 Hz, 1H), 8.07 (t, J=4.4 Hz, 1H), 8.01 (d, J=4.9Hz, 1H), 7.53 (d, J=2.0Hz, 1H), 7.44 (s, 1H), 3.90 (d, J=12.8Hz, 6H), 3.37 (td, J=6.2, 4.4Hz, 2H), 2.74(t, J=6.2Hz, 2H).

Example 32: Synthesis of Compound S38

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.28 (d, J=2.1 Hz, 1H), 8.18-8.10 (m, 2H), 7.65 (t, J=5.3 Hz, 1H), 7.54 (d, J=2.1Hz, 1H), 7.44(s, 1H), 3.89(d, J=14.6Hz, 6H), 3.59(d, J=5.3Hz, 2H), 1.20(s, 6H).

Example 33: Synthesis of Compound S39

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.15 (t, J=5.8 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.32 (s, 1H), 4.01 (d, J=5.7Hz, 2H), 3.89 (d, J=14.6Hz, 6H), 3.58 (s, 3H), 3.15 (s, 3H).

Example 34: Synthesis of Compound S40

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.24 (d, J=2.0 Hz, 1H), 8.18 (t, J=5.8 Hz, 1H), 7.46-7.39 (m, 2H), 7.16 (s, 1H), 4.06-3.95 (m, 2H), 3.97-3.80 (m, 7H), 1.24 (d, J=6.6Hz, 6H).

Example 35: Synthesis of Compound S41

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.22 (d, J=2.2 Hz, 1H), 8.16 (t, J=5.8 Hz, 1H), 7.41 (d, J=3.6 Hz, 2H), 7.35 (d, J=2.2Hz, 1H), 4.57 (t, J=7.3Hz, 1H), 4.04 (d, J=5.9Hz, 2H), 3.93-3.83 (m, 8H), 3.42 (t, J= 6.8Hz, 2H).

Example 36: Synthesis of Compound S42

¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.25-8.15 (m, 1H), 7.48-7.41 (m, 1H), 7.38 (s, 1H), 7.20 (s, 1H), 7.09 (s, 1H) ), 6.09(s, 1H), 4.09(d, J=5.7Hz, 2H), 3.89(d, J=13.7Hz, 6H).

Example 37: Synthesis of Compound S43

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.24 (d, J=2.0 Hz, 1H), 8.18 (t, J=5.8 Hz, 1H), 7.49 (d, J=2.1 Hz, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 4.09-3.94 (m, 2H), 3.89 (d, J=14.8Hz, 6H), 2.39 (p, J=5.8Hz, 1H), 1.41 (ddd, J=10.4, 9.7, 5.7Hz, 2H), 1.04 (ddd, J=10.7, 9.7, 5.6Hz, 2H).

Example 38: Synthesis of Compound S44

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.1 Hz, 1H), 8.15 (t, J=5.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.47 (s, 1H), 7.41 (ddt, J=7.5, 2.6, 1.1Hz, 2H), 7.34-7.22 (m, 3H), 4.64 (t, J=1.0Hz, 2H), 4.08 (d, J=5.9Hz, 2H) ), 3.89(d, J=14.3Hz, 6H).

Example 39: Synthesis of Compound S45

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.2 Hz, 1H), 8.10 (t, J=5.8 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.46 (s, 1H), 7.17 (dtt, J=8.0, 4.9, 1.0Hz, 1H), 7.11 (s, 1H), 6.97 (td, J=8.1, 5.0Hz, 1H), 4.69 (d, J=1.1 Hz, 2H), 4.10 (d, J=5.9Hz, 2H), 3.88 (d, J=15.6Hz, 6H).

Example 40: Synthesis of Compound S46

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.1 Hz, 1H), 8.14 (t, J=5.8 Hz, 1H), 7.69-7.63 (m, 2H), 7.57-7.48 ( m, 4H), 7.45 (s, 1H), 4.65 (t, J=1.0Hz, 2H), 4.10 (d, J=5.7Hz, 2H), 3.89 (d, J=15.0Hz, 6H).

Example 41: Synthesis of Compound S47

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.3 Hz, 1H), 8.14 (t, J=5.8 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.43 (s, 1H), 7.32 (dt, J=8.4, 1.0Hz, 2H), 7.15 (s, 1H), 6.85-6.78 (m, 2H), 4.63 (t, J=1.0Hz, 2H), 4.05 ( d, J=5.9Hz, 2H), 3.89 (d, J=15.2Hz, 6H), 3.78 (s, 3H).

Example 42: Synthesis of Compound S48

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.3 Hz, 1H), 8.10 (t, J=5.8 Hz, 1H), 7.66 (s, 1H), 7.62-7.54 (m, 3H), 7.48-7.40 (m, 3H), 4.65 (t, J=1.0Hz, 2H), 4.12 (d, J=5.9Hz, 2H), 3.88 (d, J=13.6Hz, 6H).

Example 43: Synthesis of Compound S49

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (d, J=2.2 Hz, 1H), 8.10 (t, J=5.8 Hz, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.46 (s, 1H), 7.40-7.33 (m, 3H), 7.15-7.09 (m, 2H), 4.63 (t, J=1.0Hz, 2H), 4.04 (d, J=5.9Hz, 2H), 3.88 ( d, J=11.4Hz, 6H).

Example 44: Synthesis of Compound S50

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, J=2.3 Hz, 1H), 8.10 (t, J=5.8 Hz, 1H), 7.85-7.79 (m, 2H), 7.59 (s, 1H), 7.53(d, J=2.2Hz, 1H), 7.47-7.38(m, 3H), 6.99(s, 2H), 4.65(t, J=1.0Hz, 2H), 4.12(d, J=5.9 Hz, 2H), 3.89 (d, J=12.6Hz, 6H).

Example 45: Synthesis of Compound S51

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (d, J=2.3 Hz, 1H), 8.14 (t, J=5.8 Hz, 1H), 7.59-7.53 (m, 2H), 7.47 (s, 1H), 7.32 (dt, J=8.4, 1.1Hz, 2H), 7.11 (dp, J=8.2, 0.9Hz, 2H), 4.65 (t, J=1.0Hz, 2H), 4.09 (d, J=5.9 Hz, 2H), 3.89 (d, J=15.2Hz, 6H), 2.33 (d, J=0.8Hz, 3H).

Example 46: Synthesis of Compound S52

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 8.23 (t, J=5.8 Hz, 1H), 7.51 (ddt, J= 8.3, 4.9, 1.0Hz, 2H), 7.25 (s, 1H), 7.20-7.12 (m, 2H), 4.67 (t, J=1.0Hz, 2H), 3.94 (d, J=5.9Hz, 2H), 3.89(d, J=10.6Hz, 6H).

Example 47: Synthesis of Compound S53

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.40 (dd, J=8.0, 1.5 Hz, 1H), 8.35 (s, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.18-8.10 ( m, 2H), 7.57 (d, J=2.1Hz, 1H), 7.49-7.40 (m, 2H), 4.80 (s, 2H), 3.94 (d, J=5.7Hz, 2H), 3.89 (d, J =15.2Hz, 6H).

Example 48: Synthesis of Compound S54

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.30 (d, J=2.3 Hz, 1H), 8.15 (t, J=5.8 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 6.91 (t, J=9.2Hz, 1H), 5.71 (dd, J=9.3, 1.8Hz, 1H), 5.49 (dd, J=9.3, 2.0Hz, 1H), 3.99 (d, J=5.9Hz, 2H), 3.90 (s, 3H), 3.87 (p, J=6.5Hz, 1H), 1.24 (d, J=6.6Hz, 6H).

Example 49: Synthesis of Compound S55

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.15 (t, J=5.8 Hz, 1H), 8.00 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.44 (d, J= 2.3Hz, 1H), 6.43(s, 1H), 4.06-3.92(m, 2H), 3.92-3.80(m, 4H), 1.23(d, J=6.6Hz, 6H).

Example 50: Synthesis of Compound S56

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.31 (d, J=2.1 Hz, 1H), 8.12 (t, J=5.8 Hz, 1H), 8.06-8.00 (m, 2H), 7.14 (s, 1H), 3.99 (d, J=5.9Hz, 2H), 3.86 (p, J=6.5Hz, 1H), 1.24 (d, J=6.6Hz, 6H).

Example 51: Synthesis of Compound S57

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.25 (d, J=2.1 Hz, 1H), 8.15 (t, J=5.8 Hz, 1H), 7.33 (s, 1H), 7.20 (d, J= 2.2Hz, 1H), 7.13 (s, 1H), 6.18 (q, J=4.6Hz, 1H), 3.99 (d, J=5.9Hz, 2H), 3.86 (s, 3H), 3.86 (p, J= 6.5Hz, 1H), 2.97 (d, J=4.6Hz, 3H), 1.24 (d, J=6.4Hz, 6H).

Example 52: Synthesis of Compound S58

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.15 (t, J=5.8 Hz, 1H), 7.97 (s, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.29 (d, J= 2.1Hz, 1H), 7.12 (s, 1H), 6.87 (t, J=13.5Hz, 1H), 5.69 (dd, J=13.5, 1.9Hz, 1H), 5.47 (dd, J=13.5, 1.9Hz, 1H), 3.98 (d, J=5.7Hz, 2H), 3.90 (s, 3H), 3.87 (p, J=6.5Hz, 1H), 1.24 (d, J=6.4Hz, 6H).

Example 53: Synthesis of Compound S59

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.29-8.19 (m, 2H), 7.56-7.49 (m, 3H), 7.44-7.36 (m, 3H), 7.33 (s, 1H), 7.18 (tt , J=7.3, 1.5Hz, 1H), 4.14 (d, J=5.7Hz, 2H), 3.89 (d, J=12.1Hz, 6H).

Example 54: Synthesis of Compound S60

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.23 (t, J=5.8 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.60-7.53 (m, 3H), 7.50 (s, 1H), 7.20-7.14(m, 2H), 5.67(s, 1H), 4.15(d, J=5.9Hz, 2H), 3.89(d, J=14.3Hz, 6H), 2.33(d, J=0.9 Hz, 3H).

Example 55: Synthesis of Compound S61

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.29 (d, J=2.0 Hz, 1H), 8.23 (t, J=5.8 Hz, 1H), 8.15 (s, 1H), 7.57 (d, J= 2.1Hz, 1H), 7.49-7.42 (m, 3H), 7.21-7.13 (m, 2H), 4.12 (d, J=5.9Hz, 2H), 3.89 (d, J=13.6Hz, 6H).

Example 56: Synthesis of Compound S62

¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.31-8.24(m, 2H), 8.03(s, 1H), 7.74-7.68(m, 2H), 7.54-7.47(m, 3H), 7.38(s) , 1H), 4.16 (d, J=5.9Hz, 2H), 3.88 (d, J=15.6Hz, 6H).

Example 57: Synthesis of Compound S63

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.29-8.20 (m, 2H), 8.11 (s, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.43-7.37 (m, 3H), 6.99-6.93(m, 2H), 4.15(d, J=5.9Hz, 2H), 3.89(d, J=15.2Hz, 6H), 3.81(s, 3H).

Example 58: Synthesis of Compound S64

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27-8.19 (m, 2H), 7.72 (s, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.38 (s, 1H), 7.25- 7.18(m, 2H), 6.79-6.73(m, 2H), 5.01(s, 2H), 4.15(d, J=5.9Hz, 2H), 3.89(d, J=13.5Hz, 6H).

Example 59: Synthesis of Compound S65

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.31-8.22 (m, 1H), 8.12 (s, 1H), 7.46-7.39 (m, 4H), 7.23-7.16 (m, 3H), 4.19 (d , J=5.7Hz, 2H), 3.88(d, J=13.6Hz, 6H).

Example 60: Synthesis of Compound S66

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 8.27-8.20 (m, 2H), 7.46 (d, J=2.1 Hz, 1H), 7.41 (s, 1H), 3.96 ( d, J=5.7Hz, 2H), 3.89 (d, J=12.6Hz, 6H).

Example 61: Synthesis of compound S67

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.27-8.18 (m, 2H), 7.45-7.38 (m, 2H), 4.00-3.94 (m, 5H), 3.89 (d , J=9.5Hz, 6H).

Example 62: Synthesis of Compound S68

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.20 (t, J=5.8 Hz, 1H), 7.43-7.35 (m, 2H), 3.99(d, J=5.7Hz, 2H), 3.89(d, J=13.7Hz, 6H), 3.11(s, 3H).

Example 63: Synthesis of Compound S69

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.31-8.22 (m, 2H), 8.13 (s, 1H), 7.48-7.40 (m, 2H), 3.99 (d, J=5.7Hz, 2H), 3.90(d, J=12.8Hz, 6H).

Example 64: Synthesis of Compound S70

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.43 (d, J=5.0 Hz, 1H), 8.26 (t, J=5.8 Hz, 1H), 8.06 (s, 1H), 7.21 (s, 1H) , 3.99(d, J=5.9Hz, 2H), 3.93(s, 3H), 3.88(s, 3H).

Example 65: Synthesis of Compounds S71 and S72

Step 1: Synthesis of Compound 10

Compound 6 (10 g, 42 mmol) was dissolved in dry DMF (80 mL), and compound 9 (4.9 g, 50.4 mmol), EDCI (13.7 g, 71.4 mmol) and TEA (29 mL, 210 mmol) were added sequentially. The reaction was carried out overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the reaction residue, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 10 (10 g, 87 %).

Step 2: Synthesis of Compound 11

Under nitrogen protection, compound 10 (10 g, 35.1 mmol) was dissolved in anhydrous THF (80 mL), and at 0 °C, a solution of methylmagnesium bromide in tetrahydrofuran (1 M, 36 mL, 35.1 mmol) was slowly added dropwise to In the above solution, after the dropwise addition was completed, it was transferred to room temperature, and the reaction was stirred for 4h. After the reaction was completed, place it at 0°C and slowly add dilute hydrochloric acid dropwise until no bubbles were generated. The solvent was evaporated under reduced pressure, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 11 (7.3 g, 88%).

Step 3: Synthesis of Compound 12

Under nitrogen protection, compound 11 (7 g, 30 mmol) was dissolved in anhydrous THF (100 mL), HMPA (3.2 mL, 18 mmol) was added, cooled at -78 °C, and then LDA in THF was slowly added dropwise to the above solution. The solution (1M, 36 mL, 36 mmol) was kept at this temperature for 30 min. Then, ethyl bromoacetate was slowly added dropwise to the above solution. After the dropwise addition was completed, the solution was transferred to room temperature and reacted overnight. After the reaction was completed, put it at 0 °C, and slowly add saturated ammonium chloride solution dropwise until no bubbles were generated. The solvent was removed under reduced pressure, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 12 (6.8 g, 70%).

Step 4: Synthesis of Compound S71

A mixed solution (1:1, 60 mL) of hydroxylamine hydrochloride (13 g, 186 mmol) in ethanol/water was stirred at room temperature. After it was completely dissolved, raw material 12 (6 g, 18.6 mmol) was added to the above solution, and heated to reflux. , overnight reaction. After the reaction was completed, ethanol and water were evaporated under reduced pressure, and the compound S71 (6.3 g, 45%) was obtained by column chromatography for separation and purification. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.52 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.85(s, 3H), 3.83(s, 3H), 3.00(t, J=7.9, Hz, 2H), 2.60(t, J=7.9Hz, 2H), 1.19(t, J=7.1Hz) , 3H).

Step 5: Synthesis of Compound S72

Compound S71 (100 mg, 0.3 mmol) was dissolved in THF (2 mL), placed at 0 °C, slowly added dropwise with aqueous sodium hydroxide solution (1 M, 0.6 mL, 0.6 mmol), transferred to room temperature, and reacted for 2 h. After the reaction was completed, it was transferred to 0° C., diluted hydrochloric acid (1 M) was added, the pH was adjusted to neutrality, and the compound S72 (93 mg, 95%) was obtained by lyophilization. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.52 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 3.85 (s, 3H), 3.83 ( s, 3H), 3.00 (t, J=7.9, Hz, 2H), 2.60 (t, J=7.9 Hz, 2H).

Example 66: Synthesis of Compound S73

The raw material S72 (100 mg, 0.32 mmol) was dissolved in THF (5 mL), chloromethyl acetate (139 mg, 1.28 mmol) KI (212 mg, 1.28 mmol) and cesium carbonate (209 mg, 0.64 mmol) were added to the above reaction solution, The reaction was carried out for 5h at room temperature. After the reaction was completed, suction filtered, concentrated the filtrate, added water (2 mL), extracted with ethyl acetate (5 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography Compound S73 is obtained. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.52 (s, 1H), 7.44-7.35 (m, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 5.96 (s, 2H), 3.89(s, 3H), 3.83(s, 3H), 3.12(t, J=8.4Hz, 2H), 2.60(t, J=8.5Hz, 2H), 2.10(s, 3H).

Example 67: Synthesis of Compound S5

Step 1: Synthesis of Compound 13

Compound 12 (200 mg, 0.62 mmol) was dissolved in methanol (2 mL), placed at 0 °C, NaOH aqueous solution (1 M, 1.2 mL, 1.2 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was placed at 0° C., and diluted hydrochloric acid was added to adjust the pH to 2 to 3. The solution was precipitated, filtered with suction, and the filter cake was washed with methanol. The filter cake was collected and dried to obtain compound 13 (164 mg, 90%), which was directly put into one-step reaction.

Step 2: Synthesis of Compound S5

Compound 13 (100 mg, 0.34 mmol) was dissolved in dry DMF (5 mL) and HATU (194 mg, 0.51 mmol), DIPEA (219 mg, 1.7 mmol) and methanesulfonamide (36 mg, 0.37 mmol) were added sequentially. Stir at room temperature and react overnight. After the reaction was complete, spin off DMF under reduced pressure, add water (1 mL), extract with ethyl acetate (5 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography to obtain compound S5 ( 71 mg, 56%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.08 (d, J=2.3 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.45 (s, 1H), 4.36 (s, 1H) , 3.89(d, J=11.9Hz, 6H), 3.54(t, J=8.4Hz, 2H), 3.14(s, 3H), 2.62(t, J=8.5Hz, 2H).

Example 68: Synthesis of Compound S6

The synthesis refers to the synthesis method of Example 67, and only needs to replace the corresponding raw materials.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.08 (d, J=2.0 Hz, 2H), 7.48 (d, J=2.2 Hz, 1H), 7.43 (s, 1H), 3.89 (d, J= 11.0Hz, 6H), 3.55 (t, J=8.4Hz, 2H), 3.22-3.03 (m, 2H), 2.62 (t, J=8.4Hz, 2H), 1.35 (t, J=6.9Hz, 3H) .

Example 69: Synthesis of Compound S1

Compound 13 (200 mg, 0.68 mmol) and N-methylmorpholine (0.22 mL, 2.04 mmol) were dissolved in dry THF (5 mL), placed at -78 °C, and chloromethyl isobutyl ester (97 μL, 0.75 mmol) was added dropwise to the above solution, and the reaction was stirred at this temperature for 15 min. Then, formic hydrazide (41 mg, 0.68 mmol) was added to the above solution, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, the solvent was evaporated under reduced pressure, and extracted with ethyl acetate (5 mL×3).

The reaction residue obtained in the previous step was dissolved in DCM, TEA (0.29 mL, 2.04 mmol) was added, p-toluenesulfonyl chloride (195 mg, 1.02 mmol) was added to the above solution, and the reaction was stirred at room temperature for 12 h. After the reaction was complete, water was added to quench the reaction, extracted with DCM (5 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound S1 (97 mg, 45%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.08 (d, J=2.2 Hz, 2H), 7.44-7.36 (m, 2H), 3.90 (d, J=12.1 Hz, 6H), 3.54 (t, J=7.8Hz, 2H), 3.19(t, J=7.8Hz, 2H).

Example 70: Synthesis of Compound S2

Compound 13 (200 mg, 0.68 mmol) and N-methylmorpholine (0.22 mL, 2.04 mmol) were dissolved in dry THF (5 mL), placed at -78 °C, and chloromethyl isobutyl ester (97 μL, 0.75 mmol) was added dropwise to the above solution, and the reaction was stirred at this temperature for 15 min. Then compound 14 (51 mg, 0.68 mmol) was added to the above solution, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, the solvent was evaporated under reduced pressure, and extracted with ethyl acetate (5 mL×3).

The above reaction residue was dissolved in pyridine, heated to reflux, and reacted overnight. After the reaction was completed, it was cooled to room temperature, and water was added to quench the reaction. The solvent was evaporated under reduced pressure, extracted with ethyl acetate (5 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound S2 (90 mg, 40%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.3 Hz, 1H), 7.52-7.46 (m, 2H), 3.89 (d, J=14.1 Hz, 6H), 3.62-3.54 ( m, 3H), 3.44-3.37 (m, 2H), 2.39 (s, 2H).

Example 71: Synthesis of Compound S3

Step 1: Synthesis of Compound 14

Under nitrogen protection, compound 11 (2 g, 8.5 mmol) was dissolved in anhydrous THF (10 mL), HMPA (0.9 mL, 5.0 mmol) was added, cooled at -78 °C, and then LDA was slowly added dropwise to the above solution. solution in THF (1 M, 9.5 mL, 9.4 mmol), and the reaction was maintained at this temperature for 30 min. Then, bromoacetonitrile was slowly added dropwise to the above solution, the dropwise addition was completed, and the solution was transferred to room temperature and reacted overnight. After the reaction was completed, put it at 0 °C, and slowly add saturated ammonium chloride solution dropwise until no bubbles were generated. The solvent was removed under reduced pressure, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 14 (1.1 g, 50%).

Step 2: Synthesis of Compound 15

Compound 14 (1 g, 3.83 mmol) was dissolved in ethanol (10 mL), potassium carbonate (1.6 g, 11.5 mmol) and hydroxylamine hydrochloride (798 mg, 11.5 mmol) were added, heated to reflux, and reacted overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, water was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 15 (943 mg, 80%).

Step 3: Synthesis of Compound S3

Compound 15 (200 mg, 0.65 mmol) was added to triethyl orthoformate (5 mL), a catalytic amount of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 10 min, then heated to 60° C. and stirred for 30 min. After the reaction was completed, cooled to room temperature, concentrated under reduced pressure, added water, extracted with ethyl acetate (10 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain Compound S3 (103 mg, 50%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J=2.2 Hz, 1H) , 3.90(d, J=12.1Hz, 6H), 3.41(t, J=7.8Hz, 2H), 2.96(t, J=7.8Hz, 2H).

Example 72: Synthesis of Compound S4

Compound 13 (200 mg, 0.68 mmol) and N-methylmorpholine (0.22 mL, 2.04 mmol) were dissolved in dry THF (5 mL), placed at -78 °C, and chloromethyl isobutyl ester (97 μL, 0.75 mmol) was added dropwise to the above solution, and the reaction was stirred at this temperature for 15 min. Then, formic hydrazide (41 mg, 0.68 mmol) was added to the above solution, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, the solvent was evaporated under reduced pressure, and extracted with ethyl acetate (5 mL×3).

The above reaction residue was dissolved in toluene (5 mL), Lawson's reagent (412 mg, 1.02 mmol) was added, and the mixture was heated to reflux and reacted overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the compound S4 (73 mg, 32%) was obtained by separation and purification by column chromatography. ¹ HNMR (500MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.10 (d, J=2.3Hz, 1H), 7.57-7.51 (m, 2H), 3.90 (d, J=11.5Hz, 6H) ), 3.45 (dd, J=8.2, 7.5Hz, 2H), 3.30-3.23 (m, 2H).

The synthesis of compounds S74 to S90 in the following Examples 73 to 89 refers to the synthesis method of Example 65, and only needs to replace the corresponding raw materials.

Example 73: Synthesis of Compound S74

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 11.52 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=4.9 Hz, 1H), 3.94 (s, 3H), 3.87(s, 3H), 3.11(t, J=8.5Hz, 2H), 2.56(t, J=8.5Hz, 2H).

Example 74: Synthesis of Compound S75

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 11.52 (s, 1H), 7.65 (s, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.28 (s, 1H), 3.92(s, 3H), 3.09(t, J=8.5Hz, 2H), 2.57(t, J=8.5Hz, 2H).

Example 75: Synthesis of Compound S76

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 11.52 (s, 1H), 8.28 (s, 2H), 7.30-7.24 (m, 1H), 6.02 (s, 2H), 3.07(t, J=8.4Hz, 2H), 2.56(t, J=8.4Hz, 2H).

Example 76: Synthesis of Compound S77

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 11.52 (s, 1H), 7.93 (d, J=2.1Hz, 1H), 7.40 (d, J=2.1Hz, 1H) , 7.27(s, 1H), 6.86(t, J=9.2Hz, 1H), 5.68(dd, J=9.3, 2.0Hz, 1H), 5.46(dd, J=9.3, 1.8Hz, 1H), 3.87( s, 3H), 3.17 (t, J=8-5Hz, 2H), 2.57 (t, J=8.4Hz, 2H).

Example 77: Synthesis of Compound S78

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 11.52 (s, 1H), 7.92 (d, J=2.1Hz, 1H), 7.40 (d, J=2.1Hz, 1H) , 7.27(s, 1H), 6.86(t, J=9.2Hz, 1H), 5.68(dd, J=9.3, 2.0Hz, 1H), 5.46(dd, J=9.3, 1.8Hz, 1H), 3.87( s, 3H), 3.17 (t, J=8.5Hz, 2H), 2.57 (t, J=8.4Hz, 2H).

Example 78: Synthesis of Compound S79

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 8.26 (s, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.18 (s, 1H), 7.09 (d, J=2.2Hz, 1H), 6.11 (q, J=4.5Hz, 1H), 3.86 (s, 3H), 3.16 (t, J=8.5Hz, 2H), 2.97 (d, J=4.6Hz, 3H) , 2.57(t, J=8.4Hz, 2H).

Example 79: Synthesis of Compound S80

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 11.26 (s, 1H), 7.78 (s, 1H), 7.44-7.37 (m, 2H), 3.89 (d, J=7.5 Hz, 6H), 3.15(s, 2H), 1.31(s, 6H).

Example 80: Synthesis of Compound S81

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 10.65 (s, 1H), 7.46-7.40 (m, 2H), 7.37 (d, J=2.2Hz, 1H), 3.89 ( d, J=9.7Hz, 6H), 3.37-3.29 (m, 1H).

Example 81: Synthesis of Compound S82

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 3.85 (s, 3H), 3.83 ( s, 3H), 3.66 (s, 3H), 3.00 (t, J=7.9, Hz, 2H), 2.60 (t, J=7.9 Hz, 2H).

Example 82: Synthesis of Compound S83

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 7.46-7.38 (m, 2H), 7.32 (d, J=2.2Hz, 1H), 3.89 (d, J=9.9Hz, 6H), 3.21(t, J=8.4Hz, 2H), 2.59(t, J=8.4Hz, 2H), 2.13(s, 2H).

Example 83: Synthesis of Compound S84

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.38 (s, 1H), 7.28 (d, J=2.0 Hz, 1H) , 3.89(d, J=5.3Hz, 6H), 3.04(t, J=8.5Hz, 2H), 2.57(t, J=8.4Hz, 2H).

Example 84: Synthesis of Compound S85

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 7.52 (d, J=5.0 Hz, 1H), 7.18 (s, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.06(t, J=8.4Hz, 2H), 2.60(t, J=8.5Hz, 2H).

Example 85: Synthesis of Compound S86

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.48 (d, J=2.0 Hz, 1H), 7.44-7.38 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.89 (d, J=9.0Hz, 6H), 3.04 (t, J=8.5Hz, 2H), 2.61 (t, J=8.5Hz, 2H), 1.26 (t, J=7.0Hz, 3H).

Example 86: Synthesis of Compound S87

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.49 (d, J=2.1 Hz, 1H), 7.46-7.40 (m, 2H), 3.89 (d, J=8.2 Hz, 6H), 3.65 (p, J=5.5Hz, 1H), 3.01 (t, J=8.4Hz, 2H), 2.59 (t, J=8.4Hz, 2H), 1.60 (dd, J=5.5, 2.3Hz, 4H).

Example 87: Synthesis of Compound S88

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 7.89 (d, J=2.3Hz, 1H), 7.52 (d, J=2.1Hz, 1H), 7.29 (s, 1H) , 3.92(s, 3H), 3.05(t, J=8.5Hz, 2H), 2.55(t, J=8.4Hz, 2H).

Example 88: Synthesis of Compound S89

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.33-7.27 (m, 2H), 6.01 (s, 2H), 3.04 ( t, J=8.4Hz, 2H), 2.59 (t, J=8.4Hz, 2H).

Example 89: Synthesis of Compound S90

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 7.42-7.37 (m, 2H), 7.34 (d, J=2.2Hz, 1H), 5.26 (s, 2H), 3.89 ( d, J=5.3Hz, 6H), 3.06 (t, J=8.5Hz, 2H), 2.53 (t, J=8.4Hz, 2H).

Example 90: Synthesis of Compound S91

Compound S84 (100 mg, 0.31 mmol) was dissolved in anhydrous DMF (5 mL), HATU (179 mg, 0.47 mmol), methanesulfonamide (32 mg, 0.33 mol) and DIPEA (120 mg, 0.93 mmol) were added in sequence, and stirred at room temperature The reaction was carried out for 5 hours. After the reaction was completed, water was added to quench the reaction, DMF was evaporated under reduced pressure, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography Compound S91 was obtained (55 mg, 45%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ 7.58(s, 1H), 7.49(s, 1H), 7.37(s, 1H), 7.10(s, 1H), 3.89(s, 3H), 3.74( s, 3H), 3.14 (s, 3H), 2.95 (t, J=8.5Hz, 2H), 2.57 (t, J=8.4Hz, 2H).

For the synthesis of S92 to S94 in the following Examples 91 to 93, reference can be made to the synthesis method in Example 90, and only the corresponding raw materials need to be replaced.

Example 91: Synthesis of Compound S92

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.52 (s, 1H), 8.10 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 3.85 ( s, 3H), 3.83 (s, 3H), 3.00 (t, J=7.9, Hz, 2H), 2.99 (s, 3H), 2.60 (t, J=7.9Hz, 2H).

Example 92: Synthesis of Compound S93

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.52 (s, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 7.39-7.32 (m, 2H), 3.89 (d, J=8.2 Hz, 6H), 3.63 (s, 3H), 3.06 (t, J=8.5Hz, 2H), 2.48 (t, J=8.5Hz, 2H).

Example 93: Synthesis of Compound S94

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.01 (s, 1H), 7.65 (s, 1H), 7.49 (dd, J=17.4, 2.0 Hz, 1H), 7.42 (s, 1H), 3.89 ( d, J=9.0Hz, 6H), 3.63 (s, 3H), 2.99 (t, J=8.5Hz, 2H), 2.43 (t, J=8.5Hz, 2H).

Example 94: Synthesis of Compounds S95 and S96

Step 1: Synthesis of compound S95

Compound 2 (200 mg, 0.96 mmol) was dissolved in anhydrous THF (2 mL), placed at 0 °C, and a solution of triphosgene (142 mg, 0.48 mmol) in anhydrous THF (2 mL) was slowly added dropwise to the above solution. Then triethylamine (0.2 mL, 1.5 mmol) was added, heated to reflux, and reacted overnight. After the reaction was completed, it was cooled to room temperature, filtered with suction, the filter cake was washed with anhydrous THF, and the filtrate was concentrated and dried. The dried residue was redissolved in 2 mL of anhydrous THF, placed at 0 °C, and the solution of compound 13 in anhydrous THF (2 mL) was slowly added dropwise to the above solution. After the dropwise addition, the reaction was heated under reflux for 4 h. After the reaction was completed, it was cooled to room temperature, the solvent was evaporated under reduced pressure, water (2 mL) was added, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography gave compound S95 (169 mg, 52%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.43-7.35 (m, 2H), 6.71 (t, J=5.8 Hz, 1H), 4.16 (q, J=7.0Hz, 2H), 3.98-3.89 (m, 6H), 3.87 (s, 2H), 1.24 (t, J=6.9Hz, 3H).

Step 2: Synthesis of Compound S96

Compound S95 (100 mg, 0.30 mmol) was dissolved in methanol (2 mL), NaOH aqueous solution (1 M, 0.6 mL, 0.6 mmol) was added dropwise to the above solution, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the pH was adjusted to 2-3 with dilute hydrochloric acid, precipitated out, filtered with suction, washed the filter cake with methanol, collected the filter cake, and dried to obtain compound S96 (84 mg, 90%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 9.60 (s, 1H), 7.69 (d, J=2.1Hz, 1H), 7.32-7.24 (m, 2H), 7.15 ( t, J=5.8Hz, 1H), 4.00 (d, J=5.7Hz, 2H), 3.89 (d, J=17.9Hz, 6H).

Example 95: Synthesis of Compound S97

The synthesis refers to the synthesis method in Example 90, and only needs to replace the corresponding raw materials.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (br, 1H), 9.60 (s, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.41-7.36 (m, 2H), 7.08 ( t, J=4.3Hz, 1H), 3.89 (d, J=17.9Hz, 6H), 3.47 (td, J=6.2, 4.4Hz, 2H), 2.62 (t, J=6.2Hz, 2H).

Example 96: Test of compound binding ability to human interferon gene-stimulating protein

The specific steps of the interferon gene-stimulated protein competitive binding test experiment are based on the kit from CISBIO. Basic principle: a specific Anti 6His-Tb ³⁺ antibody is used as a donor, which binds to the 6His-labeled h interferon gene-stimulating protein protein, and the d2-labeled interferon gene-stimulating protein ligand is used as a receptor (CISBIO, catalogue no. 64BDSTGPEG ), the compound was dissolved in DMSO to set 10 concentration points, incubated with the above-mentioned ligands and receptors, and the IC ₅₀ of the compound to be tested that competed with the ligand in the system to bind to the interferon gene-stimulating protein was detected.

The specific experimental steps are as follows

① Set up negative control wells, standard wells, and compound wells in the experiment, and add 5 μL of negative control, standard cGAMP of different concentrations, and samples to be tested in different concentrations to the negative control wells, standard wells, and compound wells respectively;

②Add 5μL of 1X detection buffer to the negative control wells, and add 5μL of 1X 6His-labeled h-interferon gene-stimulating protein to the standard and compound wells;

③Add 10μL of 1X IFN-gene-stimulating protein ligand-d2 and 1X Anti 6His-Tb ³⁺ mixed working solution to all wells;

④ Seal the plate with membrane and incubate at room temperature for 4 hours;

⑤Tear off the film, and use the HTRF compatible reader to read the absorbance values at 616nm and 665nm respectively.

⑥ Calculate the ratio of the signal emitted by the acceptor and the donor: Ratio=Signal 665nm/Signal 616nm X 10 ⁴

⑦ Calculate the IC ₅₀ value using the Ratio value, and then convert the IC ₅₀ value of the compound by the standard cGAMP.

The experimental results are shown in Table 1 below, C: IC ₅₀ >100 nM; B: IC ₅₀ =100 nM-10 nM; A: IC ₅₀ <10 nM;

Table 1 Binding ability of compounds to be tested to human interferon gene-stimulating protein

Example 97: Measurement of the amount of IFNβ released

Experimental operation steps: THP-1 cells were plated (1×10 ⁵ cells/well), the next day, after the cells were changed, the compounds to be tested with different concentrations were incubated with THP-1 cells for 24 hours, and then the medium supernatant was collected , and the IFN-β content was detected by ELISA according to the following steps.

①Standard addition: Set standard wells and sample wells, and add 50 μL of standard with different concentrations (0, 25, 50, 100, 200, 400pg/ml) to each standard well.

② Sample addition: set up blank wells (the blank control wells do not add samples and enzyme labeling reagents, and the operations in other steps are the same) and the wells for the samples to be tested. First add 40 μL of sample diluent to the well of the sample to be tested on the enzyme-labeled coated plate, and then add 10 μL of the sample to be tested (the final dilution of the sample is 5 times). Add the sample to the bottom of the well of the microtiter plate, try not to touch the wall of the well, and shake gently to mix.

③ Add enzyme: Add 100 μL of enzyme labeling reagent to each well, except for blank wells.

④ Incubation: Seal the plate with a sealing film and incubate at 37°C for 60 minutes.

⑤ Dosing: Dilute the 20-fold concentrated washing solution with distilled water 20-fold for later use.

⑥Washing: Carefully peel off the sealing film, discard the liquid, spin dry, fill each well with washing solution, let it stand for 30 seconds, then discard, repeat 5 times, and pat dry.

⑦ Color development: first add 50 μl of color developer A to each well, then add 50 μl of color developer B, gently shake and mix, and develop color at 37°C for 15 minutes in the dark.

⑧ Stop: Add 50 μL of stop solution to each well to stop the reaction (the blue turns to yellow at this time).

⑨Determination: Zero the blank well, and measure the absorbance (OD value) of each well in sequence at a wavelength of 450 nm. The measurement should be carried out within 15 minutes after adding the stop solution.

⑩Calculation: Calculate the IFN-β content in each sample after the standard curve is obtained from the standard substance, and calculate the EC ₅₀ value according to the IFN-β content induced by the test compound at different concentrations.

After the activation of the interferon gene-stimulating protein protein, the expression of IFNβ is induced to exert anti-tumor or anti-infection effects. The production of IFNβ is an important indicator of the activation of interferon gene-stimulated protein. In this experiment, the method of ELISA was used to detect the production of IFNβ after co-incubation of different concentrations of the compounds to be tested with THP-1 cells. The results are shown in Table 2 below. C: EC ₅₀ >10 μM; B: EC ₅₀ =10 μM-1 μM; A: EC ₅₀ <1 μM.

Table 2 The production of IFNβ after co-incubation of test compounds with different concentrations of THP-1 cells

Compound number IC₅₀(μM) Compound number IC₅₀(μM) S1 B S37 A S2 B S38 A S3 B S39 A S5 B S45 B S6 A S53 A S7 A S68 A S8 A S69 A S12 A S70 A S13 B S71 A S14 A S72 A S16 B S73 A S18 A S74 A S19 A S76 A S20 A S80 A S21 A S81 A S22 B S82 B S26 B S83 A S30 A S84 A S31 B S85 A S32 B S86 A S33 A S89 A S35 A S92 B S36 A cGAMP A

Claims (13)

1. Benzothiophene compounds with a structure shown in a general formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, wherein the structure is as follows:

wherein R is¹And R²Independently selected from hydrogen, deuterium, halogen, unsubstituted or R^1-1Substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, -NR^1-2R^1-3、-(C＝O)NR^1-4R^1-5OR- (C ═ O) OR^1-6；

R^1-1Is halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy or-NR^1-1-1R^1-1-2

R^1-1-1And R^1-1-2Independently selected from hydrogen or C_1-4An alkyl group;

R^1-2～R^1-6independently selected from hydrogen or C_1-4An alkyl group;

R³and R⁴Independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, unsubstituted or R^3-1Substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-10Cycloalkyl group, (C)_3-10Cycloalkyl) -oxy, (C)_3-10Cycloalkyl) - (C)_1-6Alkoxy), heterocycloalkyl-oxy, heterocycloalkyl- (C)_1-6Alkoxy group), C_6-10Aryl group, (C)_6-10Aryl) -oxy, (C)_6-10Aryl group) - (C_1-6Alkoxy), heteroaryl-oxy, heteroaryl- (C)_1-6Alkoxy), -NR^3-2R^3-3、-(C＝O)R^3-4、-(C＝O)NR^3-5R^3-6、-(C＝O)OR^3-7、-S(＝O)₂NR^3-8R^3-9Or R³And R⁴Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;

R^3-1is halogen, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, or-NR^3-1-1R^3-1-2；

R^3-1-1And R^3-1-2Independently selected from hydrogen or C_1-4An alkyl group;

R^3-2～R^3-9independently selected from hydrogen or C_1-4An alkyl group;

R⁵is- (C ═ O) OR^5-1、-(C＝O)SR^5-2Unsubstituted or R^5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

R^5-1And R^5-2Independently selected from hydrogen, C_1-6Alkyl, (C)_1-6Alkoxy group) - (C_1-6Alkyl) -, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, or 4-10 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;

R^5-3selected from halogen, hydroxy, amino, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, or C_1-4A haloalkoxy group;

R^5-4and R^5-5Is independently selected fromHydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-10A cycloalkyl group;

R⁷is hydrogen, sulfonic group, phosphoryl group, unsubstituted or R^7-1Substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-10Cycloalkyl group, (C)_3-10Cycloalkyl) -C_1-6Alkyl, heterocycloalkyl-C_1-6Alkyl, unsubstituted or R^7-2Substituted C_6-10Aryl, unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6Alkyl, unsubstituted or R^7-4Substituted heteroaryl-C_1-6Alkyl or unsubstituted or R^7-5Substituted heteroaryl; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;

R^7-1is halogen, carboxyl, hydroxyl, -NR^7-1-1R^7-1-2Cyano or C_1-4An alkyl group;

R^7-1-1and R^7-1-2Independently selected from hydrogen or C_1-4An alkyl group;

R^7-2～R^7-5independently selected from deuterium, halogen, hydroxy, cyano, nitro, unsubstituted or R^7-2-1Substituted C_1-4Alkyl, unsubstituted or R^7-2-2Substituted C_1-4Alkoxy, -NR^7-2-3R^7-2-4、-(C＝O)R^7-2-5、-(C＝O)NR^7-2-6R^7-2-7、-(C＝O)OR^7-2-8or-S (═ O)₂NR^7-2-9R^7-2-10；

R^7-2-1And R^7-2-2Is halogen, hydroxy, cyano or-NR^7-2-1-1R^7-2-1-2

R^7-2-1-1And R^7-2-1-2Independently selected from hydrogen or C_1-4An alkyl group;

R^7-2-3R^7-2-10independently selected from hydrogen or C_1-4An alkyl group;

R⁸is hydrogen, cyano、R^8-1O-、-NR^8-2R^8-3、R⁸⁴S-, unsubstituted or R^8-5Substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-10Cycloalkyl group, (C)_3-10Cycloalkyl) -C_1-6Alkyl, heterocycloalkyl-C_1-6Alkyl, unsubstituted or R^8-6Substituted C_6-10Aryl, unsubstituted or R^8-7Substituted C_6-10aryl-C_1-6Alkyl, unsubstituted or R^8-8Substituted heteroaryl, unsubstituted or R^8-9Substituted heteroaryl-C_1-6An alkyl group; the heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;

R^8-1～R^8-4independently selected from phosphoryl, unsubstituted or R^8-1-1Substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-10Cycloalkyl group, (C)_3-10Cycloalkyl) -C_1-6Alkyl, heterocycloalkyl-C_1-6Alkyl, unsubstituted or R^8-1-2Substituted C_6-10Aryl, unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6Alkyl, unsubstituted or R^8-1-4Substituted heteroaryl-C_1-6Alkyl, unsubstituted or R^8-1-5Substituted heteroaryl, or- (S ═ O)₂OR^8-1-6(ii) a The heterocycloalkyl is a 4-to 10-membered heterocycloalkyl of which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3; the heteroaryl is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S;

R^8-1-1is halogen, hydroxy, -cyano, -NR^8-1-1-1R^8-1-1-2Or C_1-4An alkyl group;

R^8-1-1-1and R^8-1-1-2Independently selected from hydrogen or C_1-4An alkyl group;

R^8-1-2R^8-1-5independently selected from halogen, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, -NR^8-1-2-1R^8-1-2-2、-(C＝O)R^8-1-2-3、-(C＝O)NR^8-1-2-4R^8-1-2-5、-(C＝O)OR^8-1-2-6、-S(＝O)₂NR^8-1-2-7R^8-1-2-8or-S (═ O)₂R^8-1-2-9；

R^8-1-6Is hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl or C_3-10A cycloalkyl group;

R^8-1-2-1R^8-1-2-9independently selected from hydrogen or C_1-4An alkyl group;

R^8-5is halogen, carboxyl, hydroxyl, -NR^8-5-1R^8-5-2Cyano or C_1-4An alkyl group;

R^8-5-1and R^8-5-2Independently selected from hydrogen or C_1-4An alkyl group;

R^8-6～R^8-9independently selected from deuterium, halogen, hydroxy, cyano, carboxy, nitro, unsubstituted or R^8-6-1Substituted C_1-4Alkyl, unsubstituted or R^8-6-2Substituted C_1-4Alkoxy, -NR^8-6-3R^8-6-4、-(C＝O)R^8-6-5、-(C＝O)NR^8-6-6R^8-6-7、-(C＝O)OR^8-6-8or-S (═ O)₂NR^8-6-9R^8-6-10

R^8-6-1And R^8-6-2Is halogen, hydroxy, cyano or-NR^8-6-1-1R^8-6-1-2；

R^8-6-1-1And R^8-6-1-2Independently selected from hydrogen or C_1-4An alkyl group;

R^8-6-3R^8-6-10independently selected from hydrogen or C_1-4An alkyl group;

x is O, C ═ O, NR⁹、

Left end of X and

the right end of the L-shaped connecting rod is connected with the L;

R⁹～R¹¹independently selected from hydrogen or C_1-6An alkyl group;

R¹²is hydroxy, cyano, C_1-6Alkoxy, -O (C ═ O) R^12-1、-(S＝O)₂R^12-2、-(S＝O)R^12-3or-NR¹²⁴R^12-5；

R^12-1～R^12-3Independently selected from C_1-6An alkyl group;

R^12-4and R^12-5Independently selected from hydrogen, C_1-6Alkyl or- (C ═ O) R^12-4-1；

R^12-4-1Is C_1-6An alkyl group;

R¹³and R¹⁴Independently selected from hydrogen or C_1-6An alkyl group;

x and R⁵Selected from any combination of:

when X is

When R is⁵Is- (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

When X is C ═ O, R⁵Is- (C ═ O) NR^5-4(S＝O)₂R^5-5Or is unsubstituted or R^5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;

when X is O, NR⁹、

To, R⁵Is- (C ═ O) OR^5-1、-(C＝O)SR^5-2Unsubstituted or R^5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

R⁶Selected from hydrogen, deuterium, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, - (C ═ O) NR^{6- 1}R^6-2、-(C＝O)OR^6-3or-NR^6-4R^6-5；

R^6-1～R^6-5Independently selected from hydrogen or C_1-4An alkyl group;

l is (C (R)¹⁵R¹⁶))_n；

R¹⁵And R¹⁶Independently selected from hydrogen, halogen, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_3-6Cycloalkyl, -NR^15-1R^15-2Or R¹⁵And R¹⁶Ring synthesis of C with the carbon atom to which they are attached_3-10A cycloalkyl group;

R^15-1and R^15-2Independently selected from hydrogen or C_1-4An alkyl group;

n is an integer of 1, 2 or 3.

2. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I: when R is¹And R²Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or when R³And R⁴Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or when R³And R⁴Independently selected from C_1-6At alkoxy, said C_1-6Alkoxy is C_1-4An alkoxy group;

and/or when R³And R⁴Independently selected from C_1-6When halogenated alkoxy, said C_1-6Haloalkoxy is C_1-4A haloalkoxy group;

and/or when R³And R⁴Independently selected from C_2-6When alkenyl, said C_2-6Alkenyl is C_2-4An alkenyl group;

and/or when R³And R⁴Independently selected from (C)_3-10Cycloalkyl) -oxy, said (C)_3-10Cycloalkyl) -oxy is (C)_3-6Cycloalkyl) -oxy;

and/or when R³And R⁴Independently selected from (C)_3-10Cycloalkyl) - (C)_1-6Alkoxy group), said (C)_3-10Cycloalkyl) - (C)_1-6Alkoxy) is (C)_3-6Cycloalkyl) - (C)_1-4Alkoxy groups);

and/or when R³And R⁴Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl_1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)_1-6Alkoxy) is 4-to 6-membered heterocycloalkyl- (C_1-4Alkoxy groups);

and/or when R³And R⁴Independently selected from (C)_6-10Aryl) -oxy, said (C)_6-10Aryl) -oxy is phenoxy;

and/or when R³And R⁴Independently selected from (C)_6-10Aryl group) - (C_1-6Alkoxy group), said (C)_6-10Aryl group) - (C_1-6Alkoxy) is benzene- (C)_1-4Alkoxy groups);

and/or when R³And R⁴Independently selected from one or more of N, O and S as heteroatoms, and when the number of the heteroatoms is 1-3 and the 5-10 membered heteroaryl-oxy is 5-10 membered heteroaryl-oxy, the 5-10 membered heteroaryl-oxy is 5-6 membered heteroaryl-oxy;

and/or when R³And R⁴Independently selected from one or more of N, O and S as heteroatoms, 1-3 of the heteroatoms, and 5-10-membered heteroaryl- (C)_1-6Alkoxy), said 5-to 10-membered heteroaryl- (C)_1-6Alkoxy) is 5-6 membered heteroaryl- (C)_1-4Alkoxy groups);

and/or when R^3-2And R^3-3Independently selected from C_1-4When alkyl, said C_1-4Alkyl is methyl, ethyl, propyl or isopropyl;

and/or when R³And R⁴Form one or more of "heteroatom is selected from N, O and S together with the carbon atom to which they are attached, and when the number of heteroatoms is 1-3," 4-20 membered heterocycloalkoxy group, the 4-20 membered heterocycloalkyl group is 5-12 membered heterocycloalkoxy group;

and/or when R^5-1Is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^5-1Is (C)_1-6Alkoxy group) - (C_1-6Alkyl) -said (C)_1-6Alkoxy group) - (C_1-6Alkyl) -is (C)_1-4Alkoxy group) - (C_1-4Alkyl) -;

and/or when R^5-1Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl being C_3-6A cycloalkyl group;

and/or when R⁵Is unsubstituted or R^5-3When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is^5-3The number is one or more, when there are more than one R^5-3When R is said^5-3May be the same or different;

and/or when R⁵Is unsubstituted or R^5-3The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the 5-10 membered heteroaryl is 5-6 membered heteroaryl;

and/or when R^5-4And R^5-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R⁷Is unsubstituted or R^7-1Substituted C_1-6When it is alkyl, said R^7-1Is one or more, when there are more than one R^7-1When R is said^7-1May be the same or different;

and/or when R⁷Is unsubstituted or R^7-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R⁷Is C_2-6When alkenyl, said C_2-6Alkenyl is C_2-4An alkenyl group;

and/or when R⁷Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl being C_3-6A cycloalkyl group;

and/or when R⁷Is (C)_3-10Cycloalkyl) -C_1-6When alkyl is present, said (C)_3-10Cycloalkyl) -C_1-6Alkyl is (C)_3-6Cycloalkyl) -C_1-4An alkyl group;

and/or when R⁷Is unsubstituted or R^7-2Substituted C_6-10When aryl is said to R^7-2Is one or more, when there are more than one R^7-2When R is said^7-2May be the same or different;

and/or when R⁷Is unsubstituted or R^7-2Substituted C_6-10When aryl, said C_6-10Aryl is phenyl;

and/or when R⁷Is unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6When it is alkyl, said R^7-3Is one or more, when there are more than one R^7-3When R is said^7-3May be the same or different;

and/or when R⁷Is unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6When alkyl, said C_6-10aryl-C_1-6Alkyl is phenyl-C_1-4An alkyl group;

and/or when R⁷Is unsubstituted or R^7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C_1-6When it is alkyl, said R^7-4Is one or more, when there are more than one R^7-4When R is said^7-4May be the same or different;

and/or when R⁷Is unsubstituted or R^7-4The substituted heteroatom is selected from N, O and SOr more than one kind of 5-10 membered heteroaryl-C with 1-3 hetero atoms_1-6When alkyl, said 5-to 10-membered heteroaryl-C_1-6Alkyl is 5-to 6-membered heteroaryl-C_1-4An alkyl group;

and/or when R^7-1When the halogen is fluorine, chlorine, bromine or iodine;

and/or when R^7-1Is C_1-4When alkyl, said C_1-4Alkyl is methyl, ethyl or propyl;

and/or when R^7-2～R^7-4Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or when R^7-2～R^7-4Independently selected from unsubstituted or R^7-2-1Substituted C_1-4When it is alkyl, said R^7-2-1Is one or more, when there are more than one R^7-2-1When R is said^7-2-1May be the same or different;

and/or when R^7-2～R^7-4Independently selected from unsubstituted or R^7-2-1Substituted C_1-4When alkyl, said C_1-4Alkyl is methyl, ethyl, propyl or isopropyl;

and/or when R^7-2～R^7-4Independently selected from unsubstituted or R^7-2-2Substituted C_1-4At alkoxy, said R^7-2-2Is one or more, when there are more than one R^7-2-2When R is said^7-2-2May be the same or different;

and/or when R^7-2～R^7-4Independently selected from unsubstituted or R^7-2-2Substituted C_1-4At alkoxy, said C_1-4Alkoxy is methoxy, ethoxy, propoxy or isopropoxy;

and/or when R^7-2-3R^7-2-10Independently selected from C_1-4Alkyl radical, said C_1-4Alkyl is methyl, ethyl, propyl or isopropyl;

and/or when R^8-1Independently selected from unsubstituted or R^8-1-1Substituted C_1-6When it is alkyl, said R^8-1-1Is one or more, when there are more than one R^8-1-1When R is said^8-1-1May be the same or different;

and/or when R^8-1Is unsubstituted or R^8-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^8-1Is C_2-6When alkenyl, said C_2-6Alkenyl is C₂₄An alkenyl group;

and/or when R^8-1Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl being C_3-6A cycloalkyl group;

and/or when R^8-1Is (C)_3-10Cycloalkyl) -C_1-6When alkyl is present, said (C)_3-10Cycloalkyl) -C_1-6Alkyl is (C)_3-6Cycloalkyl) -C_1-4An alkyl group;

and/or when R^8-1Is unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6When it is alkyl, said R^8-1-3Is one or more, when there are more than one R^8-1-3When R is said^8-1-3May be the same or different;

and/or when R^8-1Is unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6When alkyl, said C_6-10aryl-C_1-6Alkyl is phenyl-C_1-4An alkyl group;

and/or when R^8-1Is unsubstituted or R^8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C_1-6When it is alkyl, said R^8-1-4Is one or more, when there are more than one R^8-1-4When R is said^8-1-4May be the same or different;

and/or when R^8-1Is unsubstituted or R^8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C_1-6When alkyl, said 5-to 10-membered heteroaryl-C_1-6Alkyl is 5-to 6-membered heteroaryl-C_1-4An alkyl group;

and/or when R^8-1-1When the halogen is fluorine, chlorine, bromine or iodine;

and/or when R^8-1-3When the halogen is fluorine, chlorine, bromine or iodine;

and/or when R^8-1-4When the halogen is fluorine, chlorine, bromine or iodine;

and/or when R^8-1-6Is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^8-1-3When the halogen is fluorine, chlorine, bromine or iodine;

and/or when R^8-1-4When the halogen is fluorine, chlorine, bromine or iodine;

and/or when R⁹～R¹¹Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R¹²Is C_1-6At alkoxy, said C_1-6Alkoxy is C_1-4An alkoxy group;

and/or when R^12-1～R^12-5Is independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

Or, when X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

Or, when X is

When R is⁵Independently selected from- (C ═ O) OR^5-1；

And/or when R¹⁵And R¹⁶Independently selected from halogen, said halogen is fluorine, chlorine, bromine or iodine;

and/or when R¹⁵And R¹⁶Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or n is an integer of 1 or 2.

3. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I: when R is³And R⁴Independently selected from C_1-6At alkoxy, said C_1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy;

and/or when R³And R⁴Independently selected from C_1-6When halogenated alkoxy, said C_1-6Haloalkoxy is trifluoromethoxy;

and/or when R³And R⁴Independently selected from C_2-6When alkenyl, said C_2-6Alkenyl is

And/or when R³And R⁴Independently selected from (C)_3-10Cycloalkyl) -oxy, said (C)_3-10Cycloalkyl) -oxy is cyclopropoxy, cyclobutoxy, cyclopentyloxy or cyclohexyloxy;

and/or when R³And R⁴Independently selected from (C)_3-10Cycloalkyl) - (C)_1-6Alkoxy group), said (C)_3-10Cycloalkyl) - (C)_1-6Alkoxy) is cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropoxy, cyclopropylbutoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy or cyclohexylethoxy;

and/or when R³And R⁴Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl_1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)_1-6Alkoxy) is piperidinemethyl, piperidinylethyl, piperidinopropyl, piperidinobutyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, morpholinobutyl, azetidinemethyl, azetidinoethyl, azetidinopropyl, azetidinobutyl, piperazinemethyl, piperazineethyl, piperazinopropyl, piperazinobutyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, or pyrrolidinylbutyl;

and/or when R³And R⁴Independently selected from (C)_6-10Aryl group) - (C_1-6Alkoxy group), said (C)_6-10Aryl group) - (C_1-6Alkoxy) is benzyloxy, phenethyloxy, phenylpropyloxy or phenylbutyloxy;

and/or when R³And R⁴Independently selected from one or more of N, O and S as heteroatoms, and 1-3 heteroatoms, when the number of the heteroatoms is' 5-10 membered heteroaryl-oxy, the 5-10 membered heteroaryl-oxy is pyridyloxy, pyrimidyloxy, pyrazinyloxy, pyridazinyloxy, pyrrolyloxy, imidazolyloxy or pyrazolyloxy;

and/or when R³And R⁴Independently selected from one or more of N, O and S as heteroatoms, 1-3 of the heteroatoms, and 5-10-membered heteroaryl- (C)_1-6Alkoxy), said 5-to 10-membered heteroaryl- (C)_1-6Alkoxy) is pyridylmethoxy, pyrazolylethoxy, pyrimidylmethoxy, pyrazinylmethoxy, pyridazinylmethoxy, pyrrolylmethoxy, imidazolylmethoxy or pyrazolylmethoxy;

and/or when R³And R⁴When the compounds and the carbon atoms connected with the compounds form 4-20-membered heterocyclic alkoxy, the 4-20-membered heterocyclic alkyl is dioxolane, dioxahexane alkyl, 12-crown-4, 15-crown-5 or 18-crown-6;

and/or when R^5-1Is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R^5-1Is (C)_1-6Alkoxy group) - (C_1-6Alkyl) -said (C)_1-6Alkoxy group) - (C_1-6Alkyl) -is methoxy-methyl-, ethoxy-methyl-, propoxy-methyl-, isopropoxy-methyl-, n-butoxy-methyl-, isobutoxy-methyl, sec-butoxy-methyl or tert-butoxy-methyl-;

and/or when R^5-1Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R⁵Is unsubstituted or R^5-3When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is^5-3The number of (a) is 1, 2 or 3;

and/or when R⁵Is unsubstituted or R^5-3When the substituted heteroatom is selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroaryl group has 5-10 members, the heteroaryl group having 5-10 members is pyrazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-thiadiazolyl or 1, 2, 4-thiadiazolyl;

and/or when R^5-4And R^5-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R⁷Is unsubstituted or R^7-1Substituted C_1-6When it is alkyl, said R^7-1The number of (a) is 1, 2 or 3;

and/or when R⁷Is unsubstituted or R^7-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R⁷Is C_2-6When alkenyl, said C_2-6Alkenyl is

And/or when R⁷Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R⁷Is (C)_3-10Cycloalkyl) -C_1-6When alkyl is present, said (C)_3-10Cycloalkyl) -C_1-6The alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl;

and/or when R⁷Is unsubstituted or R^7-2Substituted C_6-10When aryl is said to R^7-2The number of (a) is 1, 2 or 3;

and/or when R⁷Is unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6When it is alkyl, said R^7-3The number of (a) is 1, 2 or 3;

and/or when R⁷Is unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6When alkyl, said C_6-10aryl-C_1-6Alkyl is benzyl;

and/or when R⁷Is unsubstituted or R^7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C_1-6When it is alkyl, said R^7-4The number of (a) is 1, 2 or 3;

and/or when R⁷Is unsubstituted or R^7-4Substituted "hetero atoms selected from one or more of N, O and S, the number of hetero atoms being 1-3"5-to 10-membered heteroaryl-C_1-6When alkyl, said 5-to 10-membered heteroaryl-C_1-6The alkyl is pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl, pyridazinmethyl, pyrazolylmethyl, pyrrolylmethyl, thienylmethyl, furylmethyl, thiazolylmethyl or imidazolylmethyl;

and/or when R^7-2～R^7-4Independently selected from unsubstituted or R^7-2-1Substituted C_1-4When it is alkyl, said R^7-2-1The number of (a) is 1, 2 or 3;

and/or when R^7-2～R^7-4Independently selected from unsubstituted or R^7-2-2Substituted C_1-4At alkoxy, said R^7-2-2The number of (a) is 1, 2 or 3;

and/or when R^7-2～R^7-4Independently selected from-NR^7-2-3R^7-2-4When said is-NR^7-2-3R^7-2-4is-NH₂Or

And/or when R^7-2～R^7-4Independently selected from- (C ═ O) R^7-2-5When said- (C ═ O) R^7-2-5Is composed of

And/or when R^7-2～R^7-4Independently selected from- (C ═ O) NR^7-2-6R^7-2-7When said- (C ═ O) NR^7-2-6R^7-2-7Is composed of

And/or when R^7-2R^7-4Independently selected from- (C ═ O) OR^7-2-8When said- (C ═ O) OR^7-2-8is-COOH or

And &Or, when R is^7-2～R^7-4Independently selected from-S (═ O)₂NR^7-2-9R^7-2-10When the formula is-S (═ O)₂NR^7-2-9R^7-2-10Is composed of

And/or when R^8-1Is unsubstituted or R^8-1-1Substituted C_1-6When it is alkyl, said R^8-1-1The number of (a) is 1, 2 or 3;

and/or when R^8-1Is unsubstituted or R^8-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R^8-1Is C_2-6When alkenyl, said C_2-6Alkenyl is

And/or when R^8-1Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R^8-1Is (C)_3-10Cycloalkyl) -C_1-6When alkyl is present, said (C)_3-10Cycloalkyl) -C_1-6The alkyl is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl;

and/or when R^8-1Is unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6When it is alkyl, said R^8-1-3The number of (a) is 1, 2 or 3;

and/or when R^8-1Is unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6When alkyl, said C_6-10aryl-C_1-6Alkyl is benzyl or phenethyl;

and/or when R^8-1Is unsubstituted or R^8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C_1-6When it is alkyl, said R^8-1-4The number of (a) is 1, 2 or 3;

and/or when R^8-1Is unsubstituted or R^8-1-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C_1-6When alkyl, said 5-to 10-membered heteroaryl-C_1-6The alkyl is pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl, pyridazinmethyl, pyrazolylmethyl, pyrrolylmethyl, thienylmethyl, furylmethyl, thiazolylmethyl or imidazolylmethyl;

and/or when R^8-1-6Is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R⁹～R¹¹Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R¹²Is C_1-6At alkoxy, said C_1-6Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

and/or when R^12-1～R^12-5Is independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R¹⁵And R¹⁶Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

4. Benzothiophenes of claim 1, having the structure of formula IA compound, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, wherein when R is³And R⁴Independently selected from one or more of N, O and S as heteroatoms, 1-3 of heteroatom (S)' 4-10 membered heterocycloalkyl_1-6Alkoxy), said 4-to 10-membered heterocycloalkyl group- (C)_1-6Alkoxy) is

And/or when R³And R⁴Together with the carbon atom to which they are attached form "one or more heteroatoms selected from N, O and S, and when the number of heteroatoms is 1-3," 4-20 membered heterocycloalkyl group, said 4-20 membered heterocycloalkyl group is

And/or when R⁵Is unsubstituted or R^5-3The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the substituent is unsubstituted or R^5-3Substituted heteroaryl is

And/or when R⁷Is R^7-1Substituted C_1-6When it is alkyl, said R^7-1Substituted C_1-6The alkyl is trifluoromethyl, difluoromethyl,

And/or when R⁷Is unsubstituted or R^7-2Substituted C_6-10When aryl, said is unsubstituted or R^7-2Substituted C_6-10Aryl is

And/or when R⁷Is unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6When alkyl, said is unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6Alkyl is

And/or when R⁷Is unsubstituted or R^7-4The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3 and the substituted heteroaryl is 5-10-membered heteroaryl-C_1-6When alkyl, said is unsubstituted or R^7-4Substituted heteroaryl-C_1-6Alkyl is

And/or when R^8-1Is R^8-1-1Substituted C_1-6When it is alkyl, said R^8-1-1Substituted C_1-6Alkyl is

And/or when R^8-1Is unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6When alkyl, said is unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6Alkyl is

And/or when R^8-1Is unsubstituted or R^8-1-4Substituted "hetero atomsOne or more selected from N, O and S, and 1-3 hetero atoms of 5-10 membered heteroaryl-C_1-6When alkyl, said is unsubstituted or R^8-1-4Substituted heteroaryl-C_1-6Alkyl is

5. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I:

R¹is hydrogen;

and/or, R²Is hydrogen, or halogen;

and/or, R³Is halogen, C_2-6Alkenyl radical, C_1-6Alkoxy, or-NR^3-2R^3-3；

And/or, R⁴Is halogen, C_1-6Alkoxy radical, C_2-6Alkenyl, heterocycloalkyl- (C)_1-6Alkoxy), -NR^3-2R^3-3Or R³And R⁴Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;

and/or, R^3-2Is hydrogen or C_1-4An alkyl group;

and/or, R^3-3Is hydrogen or C_1-4An alkyl group;

and/or, R⁵Is- (C ═ O) OR^5-1Unsubstituted or R^5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

And/or, R^5-1Is hydrogen, C_1-6Alkyl, (C)_1-6Alkoxy group) - (C_1-6Alkyl) -, or C_3-10A cycloalkyl group;

and/or, R^5-4Is hydrogen;

and/or, R^5-5Is C_1-6An alkyl group;

and/or, R⁷Is hydrogen, unsubstituted or R^7-1Substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-10Cycloalkyl, unsubstituted or R^7-2Substituted C_6-10Aryl, unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6Alkyl, or unsubstituted or R^7-4Substituted heteroaryl-C_1-6An alkyl group;

and/or, R^7-1Is halogen, carboxyl, hydroxyl or cyano;

and/or, R^7-2Is halogen, unsubstituted or R^7-2-1Substituted C_1-4Alkyl, unsubstituted or R^7-2-2Substituted C_1-4Alkoxy, or-NR^7-2-3R^7-2-4；

And/or, R^7-3Is halogen, cyano, unsubstituted or R^7-2-1Substituted C_1-4Alkyl, unsubstituted or R^7-2-2Substituted C_1-4Alkoxy, or- (C ═ O) NR^7-2-6R^7-2-7；

And/or, R^7-4Is halogen;

and/or, R^7-2-1Is halogen;

and/or, R^7-2-2Is halogen;

and/or, R^7-2-3Is hydrogen;

and/or, R^7-2-4Is hydrogen;

and/or, R^7-2-6Is hydrogen;

and/or, R^7-2-7Is hydrogen;

and/or, R⁸Is hydrogen, cyano, R^8-1O-, or, -NR^8-2R^8-3；

And/or, R^8-1Is hydrogen, unsubstituted or R^8-1-1Substituted C_1-6Alkyl, unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6Alkyl, unsubstituted or R^8-1-4Substituted heteroaryl-C_1-6Alkyl, or- (S ═ O)₂OR^8-1-6；

And/or, R^8-1-1Is a hydroxyl group;

and/or, R^8-1-3Is halogen;

and/or, R^8-1-4Is halogen;

and/or, R^8-1-6Is hydrogen or C_1-6An alkyl group;

and/or, R^8-2Is hydrogen or C_1-6An alkyl group;

and/or, R^8-3Is hydrogen or C_1-6An alkyl group;

and/or X is C ═ O,

Wherein, the left end of X is connected with

The right end of the L-shaped connecting rod is connected with the L;

and/or, R¹⁰Is hydrogen;

and/or, R¹¹Is hydrogen;

and/or, R¹²Is hydroxy, cyano, C_1-6Alkoxy, -O (C ═ O) R^12-1、-(S＝O)₂R^12-2or-NR^12-4R^12-5；

And/or, R^12-1Is C_1-6An alkyl group;

and/or, R^12-2Is C_1-6An alkyl group;

and/or, R^12-4Is hydrogen;

and/or, R^12-5Is hydrogen;

and/or, R¹³Is hydrogen;

and/or, R¹⁴Is hydrogen;

and/or, when X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

Or, when X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

Or, when X is

To, R⁵Independently selected from- (C ═ O) OR^5-1；

And/or, R⁶Is hydrogen;

and/or, R¹⁵Is hydrogen, halogen, or, C_1-6An alkyl group;

and/or, R¹⁶Is hydrogen, halogen, or, C_1-6An alkyl group.

6. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I:

R¹is hydrogen;

R²is hydrogen, or halogen;

R³is halogen, C_2-6Alkenyl radical, C_1-6Alkoxy, or-NR^3-2R^3-3；

R⁴Is halogen, C_1-6Alkoxy radical, C_2-6Alkenyl, heterocycloalkyl- (C)_1-6Alkoxy), -NR^3-2R^3-3Or R³And R⁴Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;

R^3-2is hydrogen or C_1-4An alkyl group;

R^3-3is hydrogen or C_1-4An alkyl group;

R⁵is- (C ═ O) OR^5-1Unsubstituted or R^5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

R^5-1Is hydrogen, C_1-6Alkyl, (C)_1-6Alkoxy group) - (C_1-6Alkyl) -or C_3-10A cycloalkyl group;

R^5-3is C_1-4An alkyl group;

R^5-4is hydrogen;

R^5-5is C_1-6An alkyl group;

R⁷is hydrogen, unsubstituted or R^7-1Substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-10Cycloalkyl, unsubstituted or R^7-2Substituted C_6-10Aryl, unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6Alkyl or unsubstituted or R7^-4Substituted heteroaryl-C_1-6An alkyl group;

R^7-1is halogen, carboxyl, hydroxyl or cyano;

R^7-2is halogen, unsubstituted or R^7-2-1Substituted C_1-4Alkyl, unsubstituted or R^7-2-2Substituted C_1-4Alkoxy or-NR^{7-2- 3}R^7-2-4；

R^7-3Is halogen, cyano, unsubstituted or R^7-2-1Substituted C_1-4Alkyl, unsubstituted or R^7-2-2Substituted C_1-4Alkoxy, or- (C ═ O) NR^7-2-6R^7-2-7

R^7-4Is halogen;

R^7-2-1is halogen;

R^7-2-2is halogen;

R^7-2-3is hydrogen;

R^7-2-4is hydrogen;

R^7-2-6is hydrogen;

R^7-2-7is hydrogen;

R⁸is hydrogen, cyano, R^8-1O-, or, -NR^8-2R^8-3；

R^8-1Is hydrogen, unsubstituted or R^8-1-1Substituted C_1-6Alkyl radical, aminoSubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6Alkyl, unsubstituted or R^8-1-4Substituted heteroaryl-C_1-6Alkyl or- (S ═ O)₂OR^8-1-6；

R^8-1-1Is a hydroxyl group;

R^8-1-6is hydrogen or C_1-6An alkyl group;

R^8-1-2-3is C_1-4Alkyl radical

R^8-1-2-4Is hydrogen;

R^8-1-2-5is hydrogen;

R^8-1-3is halogen;

R^8-1-4is halogen;

R^8-2is hydrogen or C_1-6An alkyl group;

R^8-3is hydrogen or C_1-6An alkyl group;

x is C ═ O,

Wherein, the left end of X is connected with

The right end of the L-shaped connecting rod is connected with the L;

R¹⁰is hydrogen;

R¹¹is hydrogen;

R¹²is hydroxy, cyano, C_1-6Alkoxy, -O (C ═ O) R^12-1、-(S＝O)₂R^12-2or-NR^12-4R^12-5；

R^12-1Is C_1-6An alkyl group;

R^12-2is C_1-6An alkyl group;

R^12-4is hydrogen;

R^12-5is hydrogen;

R¹³is hydrogen;

R¹⁴is hydrogen;

x and R⁵Selected from any combination of:

when X is

When R is⁵Is- (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

When X is C ═ O, R⁵Is- (C ═ O) NR^5-4(S＝O)₂R^5-5Or is unsubstituted or R^5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;

when X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

When X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

When X is

When R is⁵Independently selected from- (C ═ O) OR^5-1；

R⁶Is hydrogen;

R¹⁵is hydrogen, halogen or C_1-6An alkyl group;

R¹⁶is hydrogen, halogen or C_1-6An alkyl group.

7. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I:

R¹is hydrogen;

R²is hydrogen or halogen;

R³is C_1-6An alkoxy group;

R⁴is C_1-6Alkoxy, heterocycloalkyl- (C)_1-6Alkoxy) or R³And R⁴Together with the carbon atoms to which they are attached form a 4-20 membered heterocycloalkoxy group;

R⁵is- (C ═ O) OR^5-1Unsubstituted or R^5-3The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3, 5-10 membered heteroaryl, - (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

R^5-1Is hydrogen, C_1-6Alkyl, (C)_1-6Alkoxy group) - (C_1-6Alkyl) -or C_3-10A cycloalkyl group;

R^5-3is C_1-4An alkyl group;

R^5-4is hydrogen;

R^5-5is C_1-6An alkyl group;

R⁷is hydrogen, unsubstituted or R^7-1Substituted C_1-6Alkyl radical, C_3-10Cycloalkyl, unsubstituted or R^7-3Substituted C_6-10aryl-C_1-6Alkyl or unsubstituted or R^7-4Substituted heteroaryl-C_1-6An alkyl group;

R^7-1is halogen, hydroxy or cyano;

R^7-3is halogen, cyano or unsubstituted or R^7-2-1Substituted C_1-4Alkyl radical

R^7-4Is halogen;

R^7-2-1is halogen;

R⁸is hydrogen, cyano, R^8-1O-, or, -NR^8-2R^8-3；

R^8-1Is hydrogen, unsubstituted or R^8-1-1Substituted C_1-6Alkyl, unsubstituted or R^8-1-3Substituted C_6-10aryl-C_1-6Alkyl, or, unsubstituted or R^8-1-4Substituted heteroaryl-C_1-6An alkyl group;

R^8-1-1is a hydroxyl group;

R^8-1-3is halogen;

R^8-1-4is halogen;

x is C ═ O,

Wherein, the left end of X is connected with

The right end of the L-shaped connecting rod is connected with the L;

R¹⁰is hydrogen;

R¹¹is hydrogen;

R¹²is hydroxy, cyano, C_1-6Alkoxy, -O (C ═ O) R^12-1、-(S＝O)₂R^12-2or-NR^12-4R^12-5；

R^12-1Is C_1-6An alkyl group;

R^12-2is C_1-6An alkyl group;

R^12-4is hydrogen;

R^12-5is hydrogen;

R¹³is hydrogen;

R¹⁴is hydrogen;

x and R⁵Selected from any combination of:

when X is

When R is⁵Is- (C ═ O) NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

When X is C ═ O, R⁵Is- (C ═ O) NR^5-4(S＝O)₂R^5-5Or is unsubstituted or R^5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;

when X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

When X is

When R is⁵Is- (C ═ O) OR^5-1、-(C＝O)NR^5-4(S＝O)₂R^5-5Or- (C ═ O) NR⁷R⁸；

When X is

When R is⁵Independently selected from- (C ═ O) OR^5-1；

R⁶Is hydrogen;

R¹⁵is hydrogen, halogen or C_1-6An alkyl group;

R¹⁶is hydrogen, halogen or C_1-6An alkyl group.

8. The benzothiophene compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having a structure represented by formula I: the compound shown in the formula I is any one of the following compounds:

9. the method for preparing benzothiophenes having the structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, as claimed in claim 1, wherein: the method comprises the following steps:

the method one comprises the following steps:

wherein,

R₁₇is hydrogen or C_1-6An alkyl group;

R¹⁸is R⁷，R¹⁹Is R⁸(ii) a Or, R¹⁸Is R^5-4，R¹⁹Is R^5-5；

R¹、R²、R³、R⁴、R^5-4、R^5-5、R⁶、R⁷、R⁸、R¹⁰And L is as defined in claim 1;

step a: in a solvent, reacting the compound II-1 with the compound III-1 to generate IV;

step b: in a solvent, reacting the compound IV with the compound V to generate a compound I-1;

the second method comprises the following steps:

wherein,

y is-NHR¹¹or-NHR¹³；

R¹⁸Is R⁷，R¹⁹Is R⁸(ii) a Or, R¹⁸Is R^5-4，R¹⁹Is R^5-5；

R²⁰is-COOH, or-NHR¹⁴；

X^aIs composed of

R^5aIs- (C ═ O) OR^5-1、-(C＝O)SR^5-2Or, unsubstituted or R^5-3The substituted heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-3, namely 5-10-membered heteroaryl;

R¹、R²、R³、R⁴、R⁶、R^5-1、R^5-2、R^5-3、R^5-4、R^5-5、R⁷、R⁸、R¹¹、R¹³、R¹⁴and L is as defined in claim 1;

step c: in a solvent, the compound II-2 and the compound III-2 react to generate a compound I-2;

step d: reacting the compound I-2 with the compound V in a solvent to generate a compound I-3;

the third method comprises the following steps:

wherein R is¹、R²、R³、R⁴、R⁶、R⁵、R¹²And L is as defined in claim 1;

step e: in a solvent, reacting a compound II-3 with a compound VI to generate a compound I-4;

the method IV comprises the following steps:

wherein R is¹、R²、R³、R⁴、R^5-4、R^5-5、R⁶And L is as defined in claim 1;

step f: in a solvent, the compound II-4 reacts with the compound VII to generate the compound I-5.

10. A pharmaceutical composition, which comprises a therapeutically effective amount of one or more benzothiophenes having a structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, as claimed in any one of claims 1 to 8, and a pharmaceutically acceptable adjuvant or carrier.

11. Use of the benzothiophene compound having a structure represented by formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, as defined in any one of claims 1 to 8, or a pharmaceutical composition thereof as defined in claim 10, in the preparation of a medicament for the prevention and/or treatment of tumors or infectious diseases.

12. Use of the benzothiophene compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or the pharmaceutical composition of claim 10, for the preparation of a vaccine adjuvant for the prevention and/or treatment of tumors or infectious diseases.

13. Use of the benzothiophene compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having the structure represented by formula I, or the pharmaceutical composition of claim 10, for the preparation of an interferon gene stimulating protein agonist.