Benzothiophene compound as well as pharmaceutical composition, pharmaceutical preparation and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a benzothiophene compound as well as a pharmaceutical composition, a pharmaceutical preparation and application thereof. The benzothiophene compound has a structure as shown in a formula (I), has a very strong excitation effect on an STING-mediated interferon signal channel, can be used as a small-molecule STING agonist, and is used for clinical treatment (especially immunotherapy) of tumors or infectious diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a benzothiophene compound and a pharmaceutical composition, a pharmaceutical preparation and use thereof. Background Art

[0002] Stimulator of interferon gene (STING) is a key adaptor protein involved in the innate immune response to intracellular nucleic acid ligands, and plays a pivotal role in the T cell-mediated tumor immunity process. Intracellular cyclic guanosine monophosphate-adenosine synthetase (cGAS) can be activated by abnormal double-stranded DNA (dsDNA), catalyzing the conversion of ATP and GTP into non-classical 2',3'-cGAMP, activating the STING protein on the endoplasmic reticulum membrane, thereby activating the cGAS-STING pathway and triggering the body's immune response to tumor cells.

[0003] On the one hand, STING agonists can promote the production of type I interferon (IFN-α / β), promote cross-presentation and anti-tumor cytotoxic T lymphocyte responses; on the other hand, they can induce the production of chemokines, help recruit effector T cells, and strengthen their immune effects in the tumor microenvironment. In addition, the immune system activated by STING can also increase the body's sensitivity to radiotherapy and achieve the transformation of "cold" tumors to "hot" tumors. Therefore, STING agonists can enhance the immune effect, activate and enhance the body's innate immune system and adaptive immune function from a broader level, and are expected to be suitable for different populations with various types of cancer.

[0004] So far, the STING agonists that have entered the clinical research stage are mainly cyclic dinucleotide (CDN) compounds, such as MK-1454 (Phase II) developed by Merck, ADU-S100 (Phase II) developed by Aduro, and E-7766 (Phase I) developed by Eisai, most of which need to be administered by intratumoral injection. This type of drug has many disadvantages such as large molecular weight, high difficulty in synthesis, poor physical and chemical properties, and unsatisfactory metabolic stability, which greatly limits the application potential of this type of drug. Most non-CDN STING agonists are in the preclinical research stage, and their activity and drug properties have not yet reached the ideal level.

[0005] Therefore, there is an urgent need to develop new small molecule STING agonists with new structures, better activities and drugability as candidate compounds for tumor immunotherapy. Such STING agonists can be widely used in tumor immunotherapy, or as immune compositions or vaccine adjuvants. Summary of the invention

[0006] Problem that the invention aims to solve

[0007] The present invention aims to provide a benzothiophene compound and a pharmaceutical composition, a pharmaceutical preparation and use thereof. Specifically, the compound is a compound represented by formula (I), which has a strong stimulatory effect on the STING-mediated interferon signaling pathway and can be used as a small molecule STING agonist for the clinical treatment of tumors or infectious diseases (especially immunotherapy).

[0008] Solutions for solving problems

[0009] In a first aspect, the present invention provides a compound represented by formula (I), or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance (e.g., deuterated substance) or prodrug thereof:

[0010]

[0011] in,

[0012] represents a single bond or a double bond; when When it represents a double bond, R3 does not exist;

[0013] X1 and X2 are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group; 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl or C 3-9 Cycloalkyl substitution;

[0014] R1 and R2 are each independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl, 3-9 membered heterocyclyl or -LM; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0015] Alternatively, R1 and R2 are connected to form C 5-8 Cycloalkenyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-8 membered heteroaryl;

[0016] If present, R3 is hydrogen; R4 is hydrogen, hydroxyl, C 1-4 Alkyl or C 1-4 Alkoxy; or, R3 and R4 together form =O;

[0017] R 10 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0018] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0019] Q is -C(=O)- or -NY-;

[0020] When Q is -C(=O)-, Y connected to Q does not exist, and Q and R 4 Connected to each other to form a 5-7 membered heterocyclic group;

[0021] When Q is -NY-, each Y is independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, hydroxy, nitroso, nitro, -S(=O)R Y 、-S(=O)2R Y or -C(=O)R Y ; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl groups are each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0022] If present, each R Y are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl groups are each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted;

[0023] Or, when Q is -NY-, Q and R 4 Connected to each other to form a 5-7 membered heterocyclic group;

[0024] If present, L is -O-(CH2) a -O-, a is 1, 2, 3, 4, 5, 6, 7 or 8;

[0025] If present, M is selected from the structure shown below:

[0026]

[0027] In formula (M1), formula (M2), formula (M3) or formula (M4),

[0028] represents a single bond or a double bond; when When it represents a double bond, R3 does not exist;

[0029] X3, X4, X5, and X6 are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group; 1-6 Alkyl, C 1-6 Alkoxy, C 3-9The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; preferably, X3, X4 are each independently hydrogen; and / or, preferably, X5, X6 are each independently hydrogen or halogen, preferably hydrogen, fluorine or chlorine;

[0030] X7 is -CH2-, -CH(CH3)-, -C(CH3)2-, -NH- or -N(CH)3-;

[0031] R5 and R6 are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group; 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 3-9 Preferably, R5 and R6 are each independently C 1-6 Alkoxy;

[0032] R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; preferably, R7 and R8 are each independently hydrogen;

[0033] R9 is hydrogen, C 1-6 Alkyl, C 6-10 Aryl, C 3-9 cycloalkyl, 5-10 membered heteroaryl or 3-9 membered heterocyclyl; preferably, R9 is hydrogen or C 1-6 Alkyl, preferably hydrogen or methyl;

[0034] b and c are each independently 0, 1, 2, 3, 4 or 5; preferably, b and c are each independently 0 or 1;

[0035] R3, R4, R 10 , Q and Y are as defined in formula (I).

[0036] In this article, "when Q is -NY-, Q and R4 are connected to each other to form a 5-7 membered heterocyclic group" means that Q and the carbon atoms connected thereto, R3 and R4 and the C atoms connected thereto, and the carbon atoms between the carbon atoms together form a 5-7 membered heterocyclic group, including: (1) when R4 is a substituent other than hydrogen as defined above, Q and R 4 or (2) when R4 is hydrogen, Q, the C atom to which R3 and R4 are connected, and the carbon atom between them together form a 5-7 membered heterocyclic group.

[0037] Preferably, the compound of formula (I) is as shown in formula (I-1):

[0038]

[0039] in,

[0040] X1, X2, R1, R2, R 10 , n and Y are as defined in formula (I).

[0041] Alternatively, preferably, the compound of formula (I) is as shown in formula (I-2):

[0042]

[0043] in,

[0044] Z is O or NH;

[0045] n is 0, 1 or 2;

[0046] X1, X2, R1, R2, and R 10 As defined in formula (I).

[0047] Alternatively, preferably, the compound of formula (I) is as shown in formula (I-3):

[0048]

[0049] in,

[0050] X1, X2, R1, R 10 , n, Y and a are as defined in formula (I);

[0051] X3, X4 and R5 are as defined in formula (M1).

[0052] Alternatively, preferably, the compound of formula (I) is as shown in formula (I-4):

[0053]

[0054] in,

[0055] X1, X2, R1, R10 , n, Y and a are as defined in formula (I);

[0056] X5, X6, X7, R6, R7, R8, R9, b and c are as defined in formula (M3).

[0057] Alternatively, preferably, the compound of formula (I) is as shown in formula (I-5):

[0058]

[0059] in,

[0060] n is 1, 2 or 3;

[0061] X1, X2, R1, R3, R 10 , Y and a are as defined in formula (I);

[0062] X5, X6, X7, R6, R7, R8, R9, b and c are as defined in formula (M3).

[0063] Preferably, in the general formula compounds of the present invention, such as the compounds represented by formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) or formula (I-5), X1 and X2 are each independently hydrogen or halogen, preferably hydrogen, fluorine or chlorine, and more preferably hydrogen.

[0064] Preferably, in the compounds of the general formula of the present invention, for example, compounds represented by formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) or formula (I-5), R1 is C 1-6 Alkoxy group, preferably methoxy group.

[0065] Preferably, in the compounds of the general formula of the present invention, such as the compounds represented by formula (I), formula (I-1) or formula (I-2), R2 is hydrogen, halogen, hydroxyl or C 1-6 Alkoxy, preferably C 1-6 Alkoxy; the C 1-6 The alkoxy group is optionally substituted with one or more halogen or C 6-10 Aryl substitution.

[0066] Preferably, in the compounds of the general formula of the present invention, for example, compounds represented by formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) or formula (I-5), R 10 For hydrogen.

[0067] Preferably, in the general formula compounds of the present invention, such as the compounds represented by formula (I), formula (I-1), formula (I-3) or formula (I-4), n is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, and more preferably 1.

[0068] Preferably, in the compounds of the general formula of the present invention, such as the compounds represented by formula (I), Q is -C(=O)-, and Q and R 4 are connected to form a 5-7 membered heterocyclic group, preferably a 5-7 membered oxygen-containing heterocyclic group, more preferably

[0069] Preferably, in the compounds of the general formula of the present invention, such as the compounds represented by formula (I), Q is -NY-, and each Y is independently hydrogen, C 1-6 Alkyl, nitroso, -S(=O)2R Y or -C(=O)R Y , each R Y Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 6-10 Aryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 6-10 The aryl groups are each independently optionally substituted with one or more halogen, C 1-6 Haloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted; preferably each Y is independently hydrogen, C 1-6 Alkyl, nitroso, -S(=O)2R Y or -C(=O)R Y , each R Y Each independently is C 1-6 Alkyl or C 6-10 Aryl; said C 1-6 Alkyl or C 6-10 The aryl groups are each independently optionally substituted with one or more halogen, C 1-6 Haloalkyl, C 1-6 Alkyl or C 1-6 More preferably, one of the Ys is hydrogen.

[0070] Preferably, in the compound of the general formula of the present invention, for example, in the compound represented by formula (I), Q is -NY-, Q and R4 are connected to each other to form a 5-7 membered heterocyclic group, preferably a 5-7 membered nitrogen-containing heterocyclic group, more preferably in represents a single bond or a double bond; n is 1, 2 or 3, preferably 1; Y is hydrogen, C 1-6 Alkyl or -C(=O)C 1-6 Alkyl, preferably hydrogen, methyl or acetyl.

[0071] Preferably, in the general formula compounds of the present invention, such as the compounds represented by formula (I), formula (I-3), formula (I-4) or formula (I-5), a is 1, 2, 3, 4, 5 or 6, preferably 2, 3, 4 or 5.

[0072] In some embodiments, in the compound represented by formula (I), X1 is hydrogen or halogen;

[0073] X2 is hydrogen or halogen;

[0074] represents a single bond, R3 is hydrogen or does not exist, R4 is hydrogen, hydroxyl, C 1-4 alkyl, or R3 and R4 together form =O, Q is -NY- (e.g., represents a single bond, (1) R3 and R4 together form =O, Q is -NY-, and Y is each independently hydrogen, C 1-6 Alkyl, nitroso, nitro, -S(=O)R Y 、-S(=O)2R Y or -C(=O)R Y ; R Y are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, or C 6-10 Aryl, the C 1-6 Alkyl or C 6-10 The aryl groups are each independently optionally substituted with halogen, C 1-6 Haloalkyl, C 1-6 Alkyl or C 1-6 or (2) R3 is hydrogen, R4 is hydrogen, Q is -NY-, and each Y is independently -C(=O)R Y , R Y For hydrogen, C 1-6 Alkyl or C 1-6 or (3) R3 is absent, R4 is hydrogen, Q is -NY-, and Q is in the same group as R3 and R 4 and the carbon atoms connected thereto together form a 5-7 membered heterocyclic group containing 1-3 N atoms, and Y is independently hydrogen, C 1-6 Alkyl or -C(=O)R Y ; R Y is hydrogen or C 1-6 alkyl); or, represents a double bond, R3 does not exist, R4 is a hydroxyl group, Q is -C(=O)-, Y connected to Q does not exist, and Q and R 4 are connected to form a 5-7 membered heterocyclic group containing 1-3 N atoms, or, R3 is absent, R4 is hydrogen, Q is -NY-, and Q and R 4and the carbon atoms to which they are connected together form a 5-7 membered heterocyclic group containing 1-3 N atoms;

[0075] Y is independently hydrogen, nitroso, nitro, C 1-6 Alkyl, -S(=O)R Y 、-S(=O)2R Y or -C(=O)R Y , R Y is hydrogen or C 1-6 alkyl;

[0076] R 10 is hydrogen;

[0077] n is 0, 1, 2 or 3;

[0078] R1 and R2 are each independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or -LM; the C 1-6 alkoxy, each independently optionally substituted with halogen or C 6-10 one or more substitutions in the aryl group;

[0079] L is -O-(CH2) a -O-, a is 1, 2, 3, 4, 5 or 6;

[0080] M is selected from the structure shown below:

[0081]

[0082] In formula (M1), formula (M2), formula (M3) or formula (M4), X3 and X4 are each independently hydrogen; X5 and X6 are each independently hydrogen or halogen; R5 and R6 are each independently hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy; Represents a single bond; R3 and R4 together form =O; R 10 is hydrogen; n is 0, 1 or 2; Q is -NY-, Y is each independently hydrogen or C 1-6 alkyl; X7 is -CH2-, -NH- or -N(CH)3-; R7 and R8 are each independently hydrogen; b and c are each independently 0 or 1; R9 is hydrogen or C 1-6 alkyl.

[0083] In some embodiments, in the compound represented by formula (I), R3 is absent, R4 is hydrogen, represents a single bond or a double bond,

[0084] Q is -NY-, the Y connected to Q does not exist, and Q is connected to R 4and the carbon atoms connected thereto together form a 5-7 membered heterocyclic group containing 1-2 N atoms, wherein Y is hydrogen, C 1-6 Alkyl or -C(=O)R Y , R Y is hydrogen or C 1-6 Alkyl (preferably, Q and R 4 and the carbon atoms connected thereto together form a 5-membered heterocyclic group containing 1 N atom, Y is hydrogen, C 1-5 Alkyl (e.g. C 1-4 Alkyl or C 1-3 alkyl) or -C(=O)R Y , R Y is hydrogen or C 1-5 Alkyl (e.g. C 1-4 Alkyl or C 1-3 More preferably, Q and R 4 and its connected carbon atoms together form represents a single bond or a double bond, Y is hydrogen, C 1-5 Alkyl (e.g. C 1-4 Alkyl or C 1-3 alkyl) or -C(=O)R Y , R Y is hydrogen, methyl, ethyl, propyl, formyl, acetyl or propionyl);

[0085] R 10 is hydrogen;

[0086] n is 1, 2 or 3 (preferably n is 1);

[0087] X1 is hydrogen;

[0088] X2 is hydrogen;

[0089] R1 is C 1-6 Alkoxy (preferably C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy; more preferably methoxy, ethoxy or propoxy);

[0090] R2 is -LM, L is -O-(CH2) a -O-, a is 1, 2, 3, 4 or 5 (preferably a is 2, 3 or 4, for example a is 3);

[0091] M is wherein X5 and X6 are each independently hydrogen or halogen (e.g., X5 is hydrogen and X6 is halogen, or X5 is halogen and X6 is hydrogen); R6 is C 1-6 Alkoxy (preferably C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3alkoxy; more preferably methoxy, ethoxy or propoxy); R3 and R4 together form =O; X7 is -CH2-, -NH- or -N(CH)3-; R7 and R8 are each independently hydrogen; b and c are each independently 0 or 1; R9 is hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl).

[0092] In some embodiments, the compound of formula (I) is as shown in formula (I-5), wherein,

[0093] represents a single bond or a double bond; n is 1; R 10 is hydrogen; R3 is hydrogen; Y is hydrogen, C 1-6 Alkyl or -C(=O)R Y , R Y is hydrogen or C 1-6 Alkyl (preferably, Y is hydrogen, C 1-5 Alkyl (e.g. C 1-4 Alkyl or C 1-3 alkyl) or -C(=O)R Y , R Y is hydrogen or C 1-5 Alkyl (e.g. C 1-4 Alkyl or C 1-3 More preferably, Y is hydrogen, C 1-3 Alkyl (e.g., methyl, ethyl, or propyl) or -C(=O)R Y , R Y is hydrogen, methyl, ethyl, propyl, formyl, acetyl or propionyl);

[0094] X1 is hydrogen; X2 is hydrogen; R1 is C 1-6 Alkoxy (preferably C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy; more preferably methoxy, ethoxy or propoxy); a is (2, 3 or 4, for example a is 3);

[0095] X5 and X6 are each independently hydrogen or halogen (e.g., X5 is hydrogen and X6 is halogen, or X5 is halogen and X6 is hydrogen); R6 is C 1-6 Alkoxy (preferably C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 alkoxy; more preferably methoxy, ethoxy or propoxy); X7 is -CH2-, -NH- or -N(CH)3-; R7 and R8 are each independently hydrogen; b and c are each independently 0 or 1; R9 is hydrogen or C 1-6 Alkyl (e.g. C1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl).

[0096] In a second aspect, the present invention provides the following compounds, or enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts, hydrates, solvates, tautomers, cis-trans isomers, isotope-labeled substances or prodrugs thereof:

[0097]

[0098]

[0099]

[0100]

[0101] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound, or its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts, hydrates, solvates, tautomers, cis-trans isomers, isotope-labeled substances (e.g., deuterated substances) or prodrugs thereof; further, the pharmaceutical composition also comprises at least one pharmaceutically acceptable carrier.

[0102] Preferably, in the above-mentioned pharmaceutical composition, the pharmaceutically acceptable carrier includes at least one of a solvent, a diluent, a dispersant, a suspending aid, a surfactant, an isotonic agent, a thickener, an emulsifier, a preservative, a solid binder, and a lubricant.

[0103] Preferably, the pharmaceutical composition is an immunogenic composition.

[0104] In a fourth aspect, the present invention provides a pharmaceutical preparation, which is made of the above-mentioned compound, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope label (e.g., deuterated substance) or prodrug, or made of the above-mentioned pharmaceutical composition. Alternatively, the present invention provides a pharmaceutical preparation, comprising the above-mentioned compound, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope label (e.g., deuterated substance) or prodrug, or made of the above-mentioned pharmaceutical composition as an active ingredient.

[0105] In a fifth aspect, the present invention provides the above-mentioned compound, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the medical use of the above-mentioned pharmaceutical preparation.

[0106] The present invention provides the above-mentioned compound, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the use of the above-mentioned pharmaceutical preparation in the preparation of a drug for preventing and / or treating STING-dependent type I interferon-related diseases. Alternatively, the present invention provides the above-mentioned compound for preventing and / or treating STING-dependent type I interferon-related diseases, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation.

[0107] Preferably, the drug for preventing and / or treating STING-dependent type I interferon-related diseases is an immune adjuvant.

[0108] The present invention provides a method for preventing and / or treating STING-dependent type I interferon-related diseases, comprising the following steps: administering a preventive and / or therapeutically effective amount of the above-mentioned compound, or its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, cis-trans isomers, isotope labels or prodrugs, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation to an individual in need thereof.

[0109] The present invention provides a method for inducing an individual immune response, comprising the following steps: administering an inducing effective amount of the above-mentioned compound, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation to an individual in need thereof. In the text, a preventive and / or therapeutic effective amount, or an inducing effective amount refers to an amount that can produce a desired response (including preventing or slowing down the occurrence of a disease, reducing the severity of a disease, improving the patient's state, inducing an immune response, delaying or at least slowing down the progression of a disease, or curing) in a patient or individual in need thereof, which can be determined by a person skilled in the art based on the patient's or individual's age, sex, weight, physical condition, family history, risk of disease, etc. in combination with the content of the present invention.

[0110] The above-mentioned compound provided by the present invention, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation can be used to prevent and / or treat STING-dependent type I interferon-related diseases.

[0111] The above-mentioned compound provided by the present invention, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation can be used as a STING agonist.

[0112] Preferably, in the above use, the STING-dependent type I interferon-related disease may be a tumor or an infectious disease.

[0113] More preferably, the tumor includes brain cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer (such as esophageal cancer, rectal cancer, colon cancer), nasopharyngeal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, multiple myeloma, kidney cancer, bladder cancer, bone cancer (such as spinal cancer), malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma (such as pancreatic cancer, lung cancer, thyroid cancer), heart tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline cancer and unknown primary cancer, etc.

[0114] More preferably, the infectious diseases include human immunodeficiency virus infection, herpes simplex virus infection, hepatitis B virus infection, hepatitis C virus infection and the like.

[0115] Effects of the Invention

[0116] The benzothiophene compounds provided by the present invention have a strong stimulatory effect on the STING-mediated interferon signaling pathway, can be used as small molecule STING agonists to promote the production of type I interferon, have a low risk of drug interaction, have good pharmacokinetic properties, have the desired pH stability, and exhibit good drugability, and are used in the clinical treatment of tumors or infectious diseases (especially immunotherapy). DETAILED DESCRIPTION

[0117] [Definition of terms]

[0118] Unless otherwise specified, the following terms have the following meanings. In the absence of a definition, the term shall be interpreted as generally understood by those skilled in the art.

[0119] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is substantially non-toxic to an organism. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting the compound of the present invention with a pharmaceutically acceptable inorganic acid or organic acid, which are also known as acid addition salts. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid (which can form sulfates or acid sulfates), phosphoric acid (which can form phosphates or acid phosphates), etc. Common organic acids include, but are not limited to, trifluoroacetic acid, citric acid (which can form citric acid monosalt, disalt or trisalt), maleic acid (which can form maleic acid monosalt or disalt), fumaric acid (which can form fumaric acid monosalt or disalt), succinic acid (which can form succinic acid monosalt or disalt), tartaric acid (which can form tartaric acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), malonic acid (which can form malonic acid monosalt or disalt), malic acid (which can form malic acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), lactic acid, pyruvic acid, salicylic acid, formic acid, acetic acid, propionic acid, benzoic acid, glycolic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Pharmaceutically acceptable salts may also include salts formed by the compounds of the present invention and pharmaceutically acceptable organic or inorganic bases, which are also called base addition salts. Common base addition salts include, but are not limited to, alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts or N-containing organic bases formed by reacting with N-containing groups. + (C 1-6 Common inorganic or organic bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia water, triethylamine or tetrabutylammonium hydroxide. Pharmaceutically acceptable salts can be synthesized by general chemical methods.

[0120] The term "hydrate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and water through non-covalent intermolecular forces. Common hydrates include but are not limited to hemihydrates, monohydrates, dihydrates, trihydrates, and the like.

[0121] The term "solvate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one solvent molecule through non-covalent intermolecular forces. The term "solvate" includes "hydrate". Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, etc. It should be understood that the present invention encompasses all solvate forms having STING agonist activity.

[0122] The term "isomers" refers to compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0123] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since there are asymmetric centers and other chemical structures that may cause stereoisomerism in the compounds of the present invention, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention and their salts include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, enantiomers and mixtures of diastereomers. Generally, these compounds can be prepared in the form of racemic mixtures. However, if desired, such compounds can be prepared or separated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or single stereoisomer-enriched (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%) mixtures. As described below, a single stereoisomer of a compound is prepared synthetically from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereoisomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with a specific stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0124] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization (e.g. and Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0125] The term "cis-trans isomer" refers to stereoisomers formed by the different positions of atoms (or groups) located on both sides of a double bond or ring system relative to a reference plane; in cis isomers, the atoms (or groups) are located on the same side of the double bond or ring system, and in trans isomers, the atoms (or groups) are located on opposite sides of the double bond or ring system. Unless otherwise indicated, all cis-trans isomeric forms of the compounds of the present invention are within the scope of the present invention.

[0126] The term "isotopically labeled" refers to a compound formed by replacing a specific atom in a structure with an isotope thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 Cl.

[0127] The term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after administration to a patient. Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to a patient (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

[0128] The term "aryl" refers to a monocyclic or condensed polycyclic monovalent group having aromaticity, wherein the ring atoms are all C atoms, for example, 6 to 20, 6 to 14 or 6 to 10 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl and 1,2,3,4-tetrahydronaphthalene. The term "C 6-10 "Aryl" refers to an aromatic group having 6 to 10 carbon atoms, C 6-10 Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalene, and the like.

[0129] The term "heteroaryl" refers to a monocyclic or condensed polycyclic monovalent group having aromaticity, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C atoms, for example, a 5- to 12-membered ring, especially a 5- to 10-membered ring. Non-limiting examples of heteroaryl include, but are not limited to

[0130] The term "5-10 membered heteroaryl" refers to a heteroaryl group having 5 to 10 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P. Non-limiting examples of 5-10 membered heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl and quinolinyl, etc.

[0131] The term "alkyl" refers to a linear or branched monovalent hydrocarbon group containing no unsaturation. 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms, C 1-6 Non-limiting examples of alkyl groups include, but are not limited to, methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), sec-butyl (-CH(CH3)CH2CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), neopentyl (-CH2C(CH3)3), and the like.

[0132] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds, for example, having 2 to 20 carbon atoms. 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms; the term "C 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, butenyl, 2-methyl-2-buten-1-yl, pentenyl, hexenyl, and the like.

[0133] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds, for example, having 2 to 20 carbon atoms. 2-6 "Alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms; the term "C 2-4 "Alkynyl" refers to an alkynyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 1-butynyl, pentynyl, hexynyl, and the like.

[0134] The term "cycloalkyl" refers to a fully saturated monocyclic or polycyclic (eg, spirocyclic, fused or bridged) monovalent cyclic hydrocarbon group, for example, having 3 to 9, 3 to 8 or 3 to 6 ring carbon atoms. 3-9 "Cycloalkyl" refers to a cycloalkyl group having 3 to 9 ring carbon atoms; the term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms; the term "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 ring carbon atoms. 3-9 Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0135] The term "heterocyclyl" refers to a fully saturated or partially unsaturated (but not fully unsaturated, for example, having 1 or 2 double bonds) monocyclic, bridged or spirocyclic monovalent group, at least one (for example, 1, 2, 3 or 4) ring atom of which is a heteroatom selected from N, O, S and P, and the remaining ring atoms are C atoms, for example, it can be a 3- to 9-membered ring, a 3- to 6-membered ring. The term "3- to 9-membered heterocyclyl" refers to a heterocyclyl having 3 to 9 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P; the term "3- to 6-membered heterocyclyl" refers to a heterocyclyl having 3 to 6 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P.

[0136] In the present invention, the "heterocyclic group" includes a "monocyclic heterocyclic group", "heterocyclic alkenyl group", "spiro heterocyclic group", "bridged heterocyclic group" and the like.

[0137] The term "monocyclic heterocyclyl" refers to a fully saturated monocyclic monovalent cyclic group, at least one (e.g., 1, 2, 3 or 4) ring atom of which is a heteroatom selected from N, O, S and P, and the remaining ring atoms are C atoms, for example, it can be a 3- to 9-membered ring, or a 3- to 6-membered ring. The term "3-6-membered monocyclic heterocyclyl" refers to a monocyclic heterocyclyl having 3 to 6 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P. Non-limiting examples of “3-6 membered monocyclic heterocyclyl” include, but are not limited to, oxirane, thioethanethiol, cyclonitroethanethiol, azetidinyl, oxetidinyl, thiatidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, cyclopentylsulfoxide, cyclopentylsulfone, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, 1,4-diphosphaninyl, 1,4-azaphosphaninyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and the like. The term “3-9 membered monocyclic heterocyclyl” refers to a monocyclic heterocyclyl having 3 to 9 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P. Non-limiting examples of "3- to 9-membered monocyclic heterocyclyl" include, but are not limited to, the above-listed "3- to 6-membered monocyclic heterocyclyl", azepanyl, oxepanyl, thiepanyl, and the like.

[0138] The term "heterocycloalkenyl" refers to a monocyclic monovalent cyclic group containing one or two double bonds but no aromaticity, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C atoms, for example, a 3- to 9-membered ring, or a 3- to 6-membered ring. The term "3-9-membered heterocycloalkenyl" refers to a heterocycloalkenyl group having 3 to 9 ring atoms, which may contain 1, 2, 3, or 4 heteroatoms selected from N, O, S, and P. Non-limiting examples of "3- to 9-membered heterocycloalkenyl" include, but are not limited to

[0139] wait.

[0140] The term "heterospirocyclyl" refers to a fully saturated monovalent spirocyclic group, at least one (e.g., 1, 2, 3, or 4) of which ring atoms are heteroatoms selected from N, O, S, and P, and the remaining ring atoms are C atoms, for example, 3 to 9 rings, or 3 to 6 rings. The term "3-9 membered heterospirocyclyl" refers to a heterospirocyclyl having 3 to 9 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S, and P. Non-limiting examples of "3-9 membered heterospirocyclyl" include, but are not limited to, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, and the like.

[0141] The term "heterobridged ring group" refers to a monovalent group obtained by losing a hydrogen atom from a bridged ring compound in which at least one (such as 1, 2, 3 or 4) ring atom is a heteroatom (selected from N, O, S and P). The term "bridged ring compound" refers to a cyclic hydrocarbon in which any two rings in the compound share two carbon atoms that are not directly connected. According to the number of constituent rings, it is divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc.

[0142] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) which are located in Group VII of the Periodic Table of Elements.

[0143] The term "haloalkyl" refers to a linear or branched monovalent group formed by replacing at least one hydrogen atom in an alkyl group with a halogen atom, and does not contain unsaturation. 1-6 "Haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms. 1-6 Non-limiting examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, and the like.

[0144] The term "alkoxy" refers to an alkyl group attached to another moiety through an oxygen atom and contains no unsaturation. 1-6 "Alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms. 1-6 Non-limiting examples of alkoxy groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OC(CH3)3, and the like.

[0145] The term "haloalkoxy" refers to a haloalkyl group attached to another moiety through an oxygen atom and contains no unsaturation. 1-6 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 6 carbon atoms. 1-6 Non-limiting examples of haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, and the like.

[0146] The term "hydroxy" refers to a "-OH" group. The term "amino" refers to a "-NH2" group. The term "nitro" refers to a "-NO2" group. The term "nitroso" refers to a "-NO" group. The term "cyano" refers to a "-CN" group.

[0147] The term "each independently", "independently" or "independently" means that at least two groups (or ring systems) with the same or similar value ranges present in the structure can have the same or different meanings under specific circumstances. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. When substituent X is hydrogen, substituent Y can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl; similarly, when substituent Y is hydrogen, substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.

[0148] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. When a group is referred to as "optionally substituted", it means that the group is substituted or unsubstituted, for example, a heterocyclic group is "optionally" substituted with halogen, which means that the heterocyclic group may be unsubstituted, or may be monosubstituted, polysubstituted or fully substituted with halogen atoms. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0149] The term "room temperature" means that the temperature may be 10-40°C, or 10-30°C, such as 20°C or 25°C.

[0150] In this application, the terms "include", "comprises", and "contains" and their equivalents should be understood as open, non-exclusive meanings, i.e., "including but not limited to", meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included. In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents, and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0151] Unless otherwise specified, in this article, the parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc. should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe the present application, the term "about" indicates the error value that exists, for example, it indicates a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0152] The terms "patient", "individual" and "subject" are used interchangeably and include mammals, such as humans, non-human primates (eg, rhesus monkeys), pigs, cows, horses, sheep, dogs, rabbits, mice, etc.

[0153] For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents.

[0154] In this manual, the abbreviations used and their corresponding full names are shown in the following table:

[0155]

[0156] Example

[0157] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0158] Example 1: Synthesis of Compound W1

[0159]

[0160] Step 1: Dissolve compound 1a (1.0 eq) in DMF, cool to 0°C, add anhydrous potassium carbonate (2.0 eq), then slowly drop methyl thioglycolate (1.5 eq), and heat to 90°C to react overnight. After the reaction is completed, cool to room temperature. Pour the reaction solution into ice water, a large amount of solid precipitates, filter, wash the filter cake with water, and then beat with isopropyl ether. The solid is dried to obtain compound 1b as an off-white solid with a yield of 85%. 1 H NMR (400MHz, DMSO-d6): δ8.03(s,1H),7.60(s,1H),7.49(s,1H),3.85(s,6H),3.82(s,3H).

[0161]

[0162] Step 2: At room temperature, compound 1b (1.0 eq) was dissolved in a mixed solution of MeOH and THF, and 2.5 M aqueous lithium hydroxide solution (5.0 eq) was slowly added dropwise, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated, diluted with water, and 2 M dilute hydrochloric acid was slowly added dropwise to neutralize. A large amount of solid precipitated, which was filtered, and the filter cake was washed with water and dried to obtain compound 1c as a white solid with a yield of 100%.

[0163]

[0164] Step 3: Compound 1c (1.0 eq) was dissolved in NMP, and silver carbonate (1.5 eq) and o-phenanthroline (0.1 eq) were added, and the temperature was raised to 150°C for 1.5 h. After the reaction solution was cooled, it was filtered with diatomaceous earth, the filtrate was diluted with water, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 1d as a white solid with a yield of 98%. 1 H NMR (400MHz, CDCl3): δ7.31 (s, 1H), 7.27 (d, J = 5.4Hz, 1H), 7.24 (s, 1H), 7.20 (dd, J = 5.4, 0.6Hz, 1H), 3.94 (s, 6H).

[0165]

[0166] Step 4: Under argon protection, compound 1d (1.0 eq) was dissolved in ultra-dry tetrahydrofuran, cooled to -78°C, and 1.6 M hexane solution of n-butyl lithium (5.0 eq) was slowly added dropwise. After the addition was completed, the temperature was raised to 0°C and the reaction was continued for 2 h. A suspension of magnesium bromide ether in tetrahydrofuran (1.5 eq) was added in batches. After the addition was completed, the reaction solution was raised to room temperature and the reaction was continued for 1 h until the reaction solution became clear to obtain a solution of compound 1e, which was directly used in the next step without further purification.

[0167]

[0168] Step 5: Under argon protection, 1-(tert-butyloxycarbonyl)-2-pyrrolidone (2.0 eq) was dissolved in ultra-dry tetrahydrofuran, cooled to -78°C, and the solution of compound 1e (1.0 eq) prepared in the first step was slowly added dropwise. The reaction solution was placed at -78°C, reacted for 2 hours, and then slowly warmed to room temperature and reacted overnight. After the reaction was completed, 2M hydrochloric acid was slowly added dropwise to the reaction solution for neutralization, DCM was extracted, the organic phase was concentrated, purified by silica gel column, and slurried with isopropyl ether to obtain compound 1f as a white solid with a yield of 12%. 1 H NMR (400MHz, CDCl3): δ7.86 (s, 1H), 7.27 (d, J = 4.2Hz, 2H), 4.70 (br.s, 1H), 4.00 (s, 3H), 3. 97(s,3H),3.29-3.24(q,2H),3.06-3.02(t,J=5.4Hz,2H),2.07-1.96(m,2H),1.44(s,9H).

[0169]

[0170] Step 6: At room temperature, compound 1f (1.0 eq) was dissolved in EA, and 4.0 M hydrogen chloride dioxane solution (10.0 eq) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and the mixture was filtered, and the filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W1 as a white solid with a yield of 85%. 1 H NMR (400MHz, DMSO-d6): δ8.18(s,1H),8.08(br.s,2H),7.60(s,1H),7.48(s,1H),3.87(s,3H),3.84(s,3H),3.22-3.18(t,J=5.4 Hz,2H),2.92-2.89(m,2H),1.98-1.91(m,2H).

[0171] Example 2: Synthesis of Compound W2

[0172]

[0173] Step 1: At room temperature, compound 2a (1.0 eq) was dissolved in DMF, anhydrous potassium carbonate (1.5 eq) and benzyl bromide (1.2 eq) were added, and the reaction was continued overnight. After the reaction was completed, the mixture was diluted with water, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 2b as a white solid with a yield of 90%. 1 H NMR (400 MHz, CDCl3): δ10.18(s,1H),8.04-7.31(m,6H),7.09(s,1H),5.18(s,2H),3.97(s,3H).

[0174]

[0175] Step 2: Under argon protection, compound 2b (1.0 eq) and ethyl thioglycolate (2.0 eq) were dissolved in DMF, anhydrous potassium carbonate (2.0 eq) and cuprous iodide (0.5 eq) were added, and the temperature was raised to 80°C for 16 h. After the reaction was completed, water was added for dilution, EA was extracted, the organic phase was concentrated to dryness, and isopropyl ether was used for slurrying to obtain compound 2c as a white solid with a yield of 25%. 1 H NMR (400MHz, CDCl3): δ7.89 (s, 1H), 7.51-7.28 (m, 7H), 5.23 (s, 2H), 4.42-4.37 (q, 2H), 4.00 (s, 3H), 1.43-1.40 (t, J = 5.4 Hz, 3H).

[0176]

[0177] Step 3: At room temperature, compound 2c (1.0 eq) was dissolved in a mixed solution of MeOH and THF, and 2.5 M aqueous lithium hydroxide solution (5.0 eq) was slowly added dropwise, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated, diluted with water, and 2 M dilute hydrochloric acid was slowly added dropwise to neutralize. A large amount of solid precipitated, which was filtered, and the filter cake was washed with water and dried to obtain compound 2d as a white solid with a yield of 100%. 1 H NMR (400 MHz, DMSO-d6): δ7.96(s,1H),7.62-7.34(m,7H),5.14(s,2H),3.84(s,3H).

[0178] Step 4: Compound 2d (1.0 eq) was dissolved in N-methylpyrrolidone, and silver carbonate (1.5 eq) and o-phenanthroline (0.1 eq) were added, and the temperature was raised to 150°C for 1.5 h. The reaction solution was cooled and filtered through diatomaceous earth, the filtrate was diluted with water, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 2e as a white solid with a yield of 99%. 1 H NMR (400 MHz, CDCl3): δ7.69-7.17(m,9H),5.24(s,2H),3.98(s,3H).

[0179]

[0180] Step 5: Under argon protection, compound 2e (1.0 eq) was dissolved in ultra-dry tetrahydrofuran, cooled to -78°C, and 1.6 M hexane solution of n-butyl lithium (5.0 eq) was slowly added dropwise. After the addition was completed, the temperature was raised to 0°C and the reaction was continued for 2 h. A suspension of magnesium bromide ether in tetrahydrofuran (1.5 eq) was added in batches. After the addition was completed, the reaction solution was raised to room temperature and reacted for 2 h to obtain a suspension of compound 2f, which was directly used in the next step without further purification.

[0181]

[0182] Step 6: Under argon protection, 1-(tert-butyloxycarbonyl)-2-pyrrolidone (2.0 eq) was dissolved in ultra-dry tetrahydrofuran, cooled to -78°C, and the suspension of compound 2f prepared in the first step (1.0 eq) was slowly added dropwise. The reaction solution was placed at -78°C, reacted for 2h, then slowly warmed to room temperature and reacted overnight. After the reaction was completed, 2M hydrochloric acid was slowly added dropwise to the reaction solution for neutralization, DCM was extracted, the organic phase was concentrated, purified by silica gel column, and compound 2g was obtained as a white solid after slurrying with isopropyl ether, with a yield of 8%. 1H NMR (400MHz, CDCl3): δ7.82(s,1H),7.35(s,1H),7.26(s,1H),5.85(s,1H),4.70(s,1H),4. 00(s,3H),3.28-3.23(q,2H),3.05-3.02(t,J=5.4Hz,2H),2.02-1.95(m,2H),1.45(s,9H).

[0183]

[0184] Step 7: At room temperature, compound 2g (1.0 eq) was dissolved in DMF, anhydrous potassium carbonate (1.5 eq) and iodoethane (2.0 eq) were added, and the reaction was allowed to proceed overnight. The reaction solution was diluted with water, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 2h as an off-white solid with a yield of 81%.

[0185]

[0186] Step 8: At room temperature, compound 2h (1.0 eq) was dissolved in EA, and 4.0 M hydrogen chloride dioxane solution (10.0 eq) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and the mixture was filtered, and the filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W2 as a white solid with a yield of 89%. 1 H NMR (400MHz, DMSO-d6): δ8.28(s,1H),8.06(br.s,2H),7.59(s,1H),7.46(s,1H),4.11-4.05(m,2H),3.8 7(s,3H),3.21-3.17(t,J=5.4Hz,2H),2.90-2.85(m,2H),1.98-1.90(m,2H),1.40-1.36(t,J=5.4Hz,3H).

[0187] Example 3: Synthesis of Compound W3

[0188]

[0189] Step 1: At room temperature, compound 2g (1.0eq) was dissolved in DMF, anhydrous potassium carbonate (1.5eq) and benzyl bromide (2.0eq) were added, and the reaction was allowed to proceed overnight. The reaction solution was diluted with water, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 3a as a colorless oil with a yield of 75%. 1H NMR (400MHz, CDCl3): δ7.80 (s, 1H), 7.49 (d, J = 7.5Hz, 2H), 7.41 (t, J = 7.6Hz, 2H), 7.28 (d, J = 6.7Hz, 3H), 5 .24(s,2H),4.01(s,3H),3.24(t,J=6.6Hz,2H),3.01(t,J=7.2Hz,2H),1.99(q,J=7.0Hz,2H),1.44(s,9H).

[0190]

[0191] Step 2: At room temperature, compound 3a (1.0 eq) was dissolved in EA, and 4.0 M hydrogen chloride dioxane solution (10.0 eq) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and the mixture was filtered, and the filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W3 as a white solid with a yield of 64%. 1 H NMR (400MHz, DMSO-d6): δ8.15(s,1H),8.00(s,2H),7.63(s,1H),7.57(s,1H),7.49(d,J=7.4Hz,2H),7.38(dt, J=25.7,7.3Hz,3H),5.17(s,2H),3.88(s,3H),3.19(t,J=7.2Hz,2H),2.93-2.81(m,2H),1.94(q,J=7.4Hz,2H).

[0192] Example 4: Synthesis of Compound W4

[0193]

[0194] At room temperature, compound 2g (1.0eq) was dissolved in EA, and 4.0M hydrogen chloride dioxane solution (10.0eq) was added to react overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and suction was filtered. The filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W4 as a white solid with a yield of 81%. 1 H NMR (400MHz, DMSO-d6): δ9.46(s,1H),8.13(s,1H),8.02(s,2H),7.54(s,1H),7.34( s,1H),3.87(s,3H),3.17(t,J=7.2Hz,2H),2.92-2.81(m,2H),1.93(p,J=7.3Hz,2H). 13C NMR (100MHz, DMSO-d6): δ193.54,150.93,146.74,140.93,134.95,133.30,130.80,110.23,104.86,56.33,38.82,35.36,22.47.

[0195] Example 5: Synthesis of Compound W5

[0196]

[0197] Compound W1 (1.0 eq) was dissolved in DCM, cooled to 0°C, triethylamine (3.0 eq) was slowly added dropwise, reacted for 10 min, and acetyl chloride (1.5 eq) was slowly added dropwise. The mixture was warmed to room temperature and reacted for 3 h. Water was added to the reaction solution, the liquid was separated, the organic phase was concentrated, and purified by silica gel column to obtain compound W5 as an off-white solid with a yield of 58%. 1 H NMR (400MHz, DMSO-d6): δ8.16(s,1H),7.60(s,1H),7.48(s,1H),3.87(s,3H),3.84(s, 3H), 3.69 (t, J = 7.8Hz, 2H), 3.09 (t, J = 7.0Hz, 2H), 2.36 (s, 3H), 1.87 (q, J = 7.4Hz, 2H).

[0198] Example 6: Synthesis of Compound W6

[0199]

[0200] At room temperature, compound W1 (1.0 eq) was dissolved in acetic acid, and 4 M sodium nitrite aqueous solution (5.0 eq) was slowly added dropwise. The reaction was continued for 16 h, and then extracted with DCM. The organic phase was concentrated and purified by silica gel column to obtain compound W6 as a light yellow solid with a yield of 21%. 1 H NMR (400MHz, DMSO-d6): δ8.15(s,1H),7.59(s,1H),7.48(s,1H),4.54(t,J=5.2Hz,1H),3.87( s,3H),3.84(s,3H),3.47(td,J=6.4,5.1Hz,2H),3.04(t,J=7.3Hz,2H),1.80(p,J=6.8Hz,2H).

[0201] Example 7: Synthesis of Compound W7

[0202]

[0203] Except that acetyl chloride was replaced by trifluoroacetic anhydride, other conditions were the same as in Example 5 to obtain compound W7 as a white solid with a yield of 90%. 1 H NMR (400MHz, DMSO-d6): δ9.48(d,J=5.9Hz,1H),8.14(s,1H),7.59(s,1H),7.48(s,1H),3.8 7(s,3H),3.84(s,3H),3.29(q,J=6.6Hz,2H),3.08(t,J=7.1Hz,2H),1.88(p,J=7.1Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ193.70, 156.76 (t, J = 35.9Hz), 151.30, 149.04, 141.2 8,136.18,132.99,130.71,107.10,104.76,56.33,56.10,39.20,35.57,23.64.

[0204] Example 8: Synthesis of Compound W8

[0205]

[0206] Except for replacing acetyl chloride with acryloyl chloride, other conditions were the same as Example 5 to obtain compound W8 as a white solid with a yield of 50%. 1 H NMR (400MHz, DMSO-d6): δ8.15(s,2H),7.59(s,1H),7.48(s,1H),6.21(dd,J=17.1,10.1Hz,1H),6.07(dd,J=17.1,2.3Hz,1H) ,5.58(dd,J=10.0,2.3Hz,1H),3.87(s,3H),3.84(s,3H),3.22(q,J=6.6Hz,2H),3.06(t,J=7.2Hz,2H),1.82(p,J=7.2Hz,2H). 13 CNMR (100MHz, DMSO-d6): δ194.06,165.09,151.28,149.02,141.39,136.19,133. 01,132.28,130.72,125.36,107.11,104.78,56.34,56.10,38.55,35.93,24.63.

[0207] Example 9: Synthesis of Compound W9

[0208]

[0209] Except for replacing acetyl chloride with methanesulfonyl chloride, other conditions were the same as in Example 5 to obtain compound W9 as a white solid with a yield of 72%. 1 H NMR (400MHz, DMSO-d6): δ8.16(s,1H),7.59(s,1H),7.48(s,1H),7.05(t,J=5.8Hz,1H),3 .85(d,J=11.3Hz,6H),3.06(dt,J=28.5,6.9Hz,4H),2.90(s,3H),1.84(p,J=7.2Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ193.99,151.26,149.00,141.35,136.17,132.99,130.79,107.05,104.75,56.33,56.08,42.39,35.55,24.95.

[0210] Example 10: Synthesis of Compound W10

[0211]

[0212] Except for replacing acetyl chloride with ethylsulfonyl chloride, other conditions were the same as in Example 5 to obtain compound W10 as an off-white solid with a yield of 63%. 1 H NMR (400MHz, CDCl3): δ7.89 (s, 1H), 7.27 (s, 2H), 4.46 (t, J = 6.0Hz, 1H), 3.99 (d, J = 10.1Hz, 6H), 3.28 (q, J = 6.6Hz, 2H), 3.19-3.01 (m, 4H), 2.07 (p, J = 6.8Hz, 2H), 1.40 (t, J = 7.4Hz, 3H).

[0213] Example 11: Synthesis of Compound W11

[0214]

[0215] Except that acetyl chloride was replaced by trifluoromethanesulfonyl chloride, other conditions were the same as in Example 5 to obtain compound W11 as an off-white solid with a yield of 55%. 1 H NMR (400MHz, CDCl3): δ7.85(d,J=1.8Hz,1H),7.32-7.25(m,2H),4.17(t,J=7.6Hz,2 H), 3.99 (dd, J=10.6, 1.8Hz, 6H), 3.11 (td, J=6.8, 1.8Hz, 2H), 2.31 (p, J=7.3Hz, 2H).

[0216] Example 12: Synthesis of Compound W12

[0217]

[0218] Except for replacing acetyl chloride with propylsulfonyl chloride, other conditions were the same as in Example 5 to obtain compound W12 as a white solid with a yield of 47%. 1 H NMR (400MHz, CDCl3): δ7.86(s,1H),7.24(s,2H),4.69(t,J=6.2Hz,1H),3.97(d,J=10.2Hz,6H),3.26(q,J=6.5Hz ,2H),3.12(t,J=6.9Hz,2H),3.06-2.96(m,2H),2.05(q,J=6.8Hz,2H),1.92-1.78(m,2H),1.06(t,J=7.4Hz,3H). 13 C NMR (100MHz, CDCl3): δ193.35,151.14,148.92,141.25,136.88,132.67,129. 29,106.00,103.56,56.19,56.07,54.36,42.68,35.60,24.97,17.41,12.96.

[0219] Example 13: Synthesis of Compound W13

[0220]

[0221] Except for replacing acetyl chloride with 4-trifluoromethylbenzoyl chloride, other conditions were the same as in Example 5 to obtain compound W13 as an off-white solid with a yield of 78%. 1 H NMR (400MHz, CDCl3): δ7.94-7.85(m,3H),7.68(d,J=8.1Hz,2H),7.25(s,2H),6.91(s,1H),4 .00(s,3H),3.97(s,3H),3.63(q,J=6.1Hz,2H),3.18(t,J=6.4Hz,2H),2.19(t,J=6.4Hz,2H). 13 C NMR (100MHz, CDCl3): δ194.56,166.16,151.30,149.02,141.12,137.64,137.10,132.61,129.4 9,127.35,125.58,125.54,125.51,105.95,103.54,77.21,56.20,56.07,40.27,36.86,23.62.

[0222] Example 14: Synthesis of Compound W14

[0223]

[0224] Except for replacing acetyl chloride with p-toluenesulfonyl chloride, other conditions were the same as Example 5 to obtain compound W14 as a white solid with a yield of 85%. 1 H NMR (400MHz, DMSO-d6): δ8.08(s,1H),7.67(d,J=8.1Hz,2H),7.58(d,J=4.8Hz,2H),7.47(s,1H),7.37(d,J=8.0 Hz,2H),3.85(d,J=9.4Hz,6H),3.01(t,J=7.1Hz,2H),2.82(q,J=6.7Hz,2H),2.35(s,3H),1.74(p,J=7.1Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ193.81,151.29,149.03,142.99,138.12,136.18,132.97,130 .69,130.07,126.94,107.08,104.77,56.34,56.11,42.44,39.70,35.46,24.51,21.38.

[0225] Example 15: Synthesis of Compound W15

[0226]

[0227] Except for replacing acetyl chloride with 4-methoxybenzenesulfonyl chloride, other conditions were the same as Example 5 to obtain compound W15 as a white solid with a yield of 82%. 1 H NMR (400MHz, CDCl3): δ7.81(d,J=8.6Hz,3H),7.25(s,2H),7.00-6.91(m,2H),4.81(t,J=6.3Hz ,1H),3.98(d,J=8.8Hz,6H),3.83(s,3H),3.07(dt,J=20.8,6.6Hz,4H),1.97(p,J=6.7Hz,2H). 13 C NMR (100MHz, CDCl3): δ193.34,162.84,151.13,148.93,141.28,132.66,131.53,129. 22,129.15,114.25,106.00,103.58,77.21,56.20,56.08,55.54,42.71,35.71,24.10.

[0228] Example 16: Synthesis of Compound W16

[0229]

[0230] Except for replacing acetyl chloride with 4-trifluoromethylbenzenesulfonyl chloride, other conditions were the same as Example 5 to obtain compound W16 as a white solid with a yield of 78%. 1 H NMR (400MHz, DMSO-d6): δ8.09(s,1H),8.07-7.93(m,5H),7.58(s,1H),7.47(s,1H),3.8 5(d,J=10.0Hz,6H), 3.03(t,J=7.1Hz,2H), 2.89(t,J=7.1Hz,2H), 1.76(p,J=7.1Hz,2H).

[0231] Example 17: Synthesis of Compound W17

[0232]

[0233] Except for replacing acetyl chloride with 4-fluorobenzenesulfonyl chloride, other conditions were the same as Example 5 to obtain compound W17 as a white solid with a yield of 60%. 1 H NMR (400MHz, DMSO-d6): δ8.08(s,1H),7.91-7.80(m,2H),7.72(t,J=5.8Hz,1H),7.58(s,1H),7.49-7. 39(m,3H),3.85(d,J=9.6Hz,6H),3.02(t,J=7.2Hz,2H),2.85(q,J=6.7Hz,2H),1.74(p,J=7.1Hz,2H).

[0234] Example 18: Synthesis of Compound W18

[0235]

[0236] Except for replacing acetyl chloride with pentafluorobenzenesulfonyl chloride, other conditions were the same as in Example 5 to obtain compound W18 as a white solid with a yield of 23%. 1 H NMR (400MHz, CDCl3): δ7.87 (s, 1H), 7.27 (s, 2H), 4.26 (t, J = 7.7Hz, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.12 (t, J = 6.9Hz, 2H), 2.34 (p, J = 7.0Hz, 2H).

[0237] Example 19: Synthesis of Compound W19

[0238]

[0239] Step 1: Compound 1f (1.0 eq) was dissolved in dry DCM, protected by argon, cooled to 0°C, 1,3-propanedithiol (3.0 eq) and boron trifluoride ether complex (5.0 eq) were slowly added dropwise, reacted at 0°C for 2 h, moved to room temperature, and reacted for 24 h. The reaction was quenched with saturated sodium bicarbonate solution, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 19a as a colorless oil with a yield of 15%. 1 H NMR (400MHz, CDCl3): δ7.37(s,1H),7.22(s,1H),7.17(s,1H),4.43(s,1H),3.96(d,J=3.0Hz, 6H),3.13-2.97(m,4H),2.81-2.71(m,2H),2.17-2.08(m,2H),1.70-1.60(m,4H),1.42(s,9H).

[0240]

[0241] Step 2: Compound 19a (1.0 eq) was dissolved in DMF, cooled to 0°C, sodium hydride (3.0 eq) was slowly added in batches, reacted for 10 min, iodomethane (5.0 eq) was slowly added dropwise, moved to room temperature, and reacted for 12 h. Water was slowly added to quench the reaction, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 19b as a colorless oil with a yield of 20%.

[0242]

[0243] Step 3: Compound 19b (1.0 eq) was dissolved in a mixed solution of ACE and water, cooled to 0°C, sodium bicarbonate (8.0 eq) and iodine (3.5 eq) were added, and the mixture was reacted for 30 min. The mixture was warmed to room temperature, and a saturated aqueous sodium thiosulfate solution was added to quench the reaction, extracted with EA, and the organic phase was concentrated and purified by silica gel column to obtain compound W19 as a white solid with a yield of 24%. 1 HNMR (400MHz, CDCl3): δ7.86 (s, 1H), 7.27 (d, J = 3.5Hz, 2H), 4.87 (s, 1H), 3.99 (d, J = 10.1Hz, 6H), 3.66(s,3H),3.33(d,J=7.6Hz,2H),3.05(t,J=7.1Hz,2H),2.02(p,J=7.0Hz,2H).LCMS(ESI):m / z 294.1[M+H] + .

[0244] Example 20: Synthesis of Compound W20

[0245]

[0246] Compound W1 (1.0 eq) was dissolved in DCM, cooled to 0°C, DIPEA (3.0 eq) and 4-DMAP (0.1 eq) were added, acetyl chloride (6.0 eq) was slowly added dropwise, the temperature was raised to room temperature, and the reaction was allowed to proceed overnight. Water was added to quench the reaction, the liquids were separated, the organic phase was concentrated, and the mixture was purified by silica gel column to obtain compound W20 as a white solid with a yield of 55%. 1 H NMR (400MHz, DMSO-d6): δ8.16(s,1H),7.60(s,1H),7.48(s,1H),3.87(s,3H),3.84(s, 3H), 3.69 (t, J = 7.8Hz, 2H), 3.09 (t, J = 7.0Hz, 2H), 2.36 (s, 6H), 1.87 (q, J = 7.4Hz, 2H).

[0247] Example 21: Synthesis of Compound W21

[0248]

[0249] Except for replacing 4,5-dimethoxy-2-nitrobenzaldehyde (compound 1a) with 4-methoxy-2-nitrobenzaldehyde (compound 21a), other steps and conditions were the same as Example 1 to obtain the hydrochloride of compound W21 as a white solid with a yield of 84%. 1 HNMR (400MHz, DMSO-d6): δ8.26(s,1H),7.91(d,J=8.8Hz,1H),7.61(d,J=2.3Hz,1H),7.09(dd,J=8.8,2.4Hz,1 H),4.55(s,2H),3.86(s,3H),3.49-3.44(m,2H),3.06(t,J=7.3Hz,2H),1.80(p,J=6.8Hz,2H).LCMS(ESI):m / z 250.1[M+H] + .

[0250] Example 22: Synthesis of Compound W22

[0251]

[0252] Except for replacing 1-(tert-butyloxycarbonyl)-2-pyrrolidone with N-Boc-β-alanine, other steps and conditions were the same as Example 1 to obtain the hydrochloride of compound W22 as a white solid with a yield of 87%. 1H NMR (400MHz, DMSO-d6): δ8.17(s,1H),7.59(s,1H),7.48(s,1H),4.55(s,2H),3.87(s,3H),3.84(s,3H),3.81(d,J=5.6Hz,2H),3.13(t,J=6.2Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ193.49,151.29,149.00,142.05,136.29,133.03,131.14,107.15,104.76,57.65,56.33,56.10,42.17.LCMS(ESI):m / z 266.1[M+H] + .

[0253] Example 23: Synthesis of Compound W23

[0254]

[0255] Except for replacing 1-(tert-butyloxycarbonyl)-2-pyrrolidone with 1-Boc-2-piperidone, other steps and conditions were the same as Example 1 to obtain the hydrochloride of compound W23 as a white solid with a yield of 84%. 1 H NMR (400MHz, DMSO-d6): δ8.21(s,1H),7.99(s,2H),7.59(s,1H),7.46(s,1H),3.85(d,J= 11.0Hz, 6H), 3.07 (t, J=6.8Hz, 2H), 2.82 (q, J=6.5Hz, 2H), 1.67 (td, J=12.7, 6.6Hz, 4H). 13 C NMR (100MHz, DMSO-d6): δ194.23,151.31,149.04,141.44,136.24,133.02, 130.96,107.07,104.80,56.36,56.12,39.69,39.00,37.84,27.03,21.66.

[0256] Example 24: Synthesis of Compound W24

[0257]

[0258] Compound W1 (1.0 eq) was dissolved in DCM, cooled to 0°C, triethylamine (3.0 eq) was added, Boc anhydride (2.0 eq) was slowly added dropwise, the temperature was raised to room temperature, and the reaction was continued for 2 h. Water was added to quench the reaction, EA was extracted, concentrated to dryness, and purified by silica gel column to obtain compound W24 as a white solid with a yield of 95%. 1H NMR (400MHz, CDCl3): δ7.86(s,1H),7.27(s,1H),7.26(s,1H),4.70(s,1H),3.99(d,J=10. 7Hz, 6H), 3.26 (q, J = 6.6Hz, 2H), 3.04 (t, J = 7.2Hz, 2H), 2.00 (p, J = 7.0Hz, 2H), 1.44 (s, 9H).

[0259] Example 25: Synthesis of Compound W25

[0260]

[0261] Step 1: Under argon protection, compound 25a (1.0 eq) was dissolved in DCM, cooled to 0°C, and a DCM solution of titanium tetrachloride (1.8 eq) was slowly added dropwise, reacted for 20 min, and a DCM solution of 1,1-dichloromethyl ether (1.2 eq) was slowly added dropwise, reacted for 30 min, warmed to room temperature, and reacted for 5 h. Water was added to quench the reaction, EA was extracted, the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 25b as a colorless oil with a yield of 100%. 1 H NMR (400MHz, CDCl3): δ7.98-7.93(m,1H),7.27(s,1H),7.26(s,1H),3.97(s,3H),3.95(s,3H).

[0262]

[0263] Step 2: Compound 25b (1.0 eq) was dissolved in toluene, rhodanine (1.1 eq) and ammonium acetate (2.0 eq) were added, and the mixture was reacted at 160°C for 20 min in a sealed tube, and cooled to room temperature, where a large amount of solid precipitated. A small amount of ethanol was added, the solid was filtered, washed with water, washed with a small amount of ethanol, and dried to obtain compound 25c as a yellowish solid with a yield of 20%. 1 H NMR (400MHz, DMSO-d6): δ13.85(s,1H),7.52(s,1H),7.22(t,J=8.5Hz,1H),7.10(dd,J=9.0,1.5Hz,1H),3.92(s,3H),3.83(s,3H).

[0264]

[0265] Step 3: Compound 25c (1.0 eq) was dissolved in 2.5 M sodium hydroxide solution (10.0 eq), reacted at 75°C for 30 min, the reaction solution gradually became clear, a small amount of activated carbon was added, stirred at 75°C for 15 min, and filtered while hot. The reaction was moved to an ice bath, and 6 M dilute hydrochloric acid was slowly added dropwise to neutralize, a large amount of solid precipitated, filtered, and dried to obtain compound 25d as a white solid.

[0266]

[0267] Step 4: Compound 25d (1.0 eq) was dissolved in 1,4-dioxane, iodine (1.5 eq) was added, the mixture was reacted at 150°C overnight in a sealed tube, cooled to room temperature, the reaction solution was poured into ice water, saturated sodium bicarbonate solution was slowly added dropwise for decolorization, EA was extracted, the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 25e as a white solid with a yield of 25%. LCMS (ESI): m / z 257.0 [M+H] + .

[0268]

[0269] Step 5: Compound 25e (1.0 eq) was dissolved in N-methylpyrrolidone, and silver carbonate (1.2 eq) and o-phenanthroline (0.1 eq) were added, and the mixture was reacted at 150°C for 1.5 h. Water and EA were added to the reaction solution, filtered through diatomaceous earth, extracted with EA, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 25f as a colorless oil with a yield of 100%. LCMS (ESI): m / z 213.0 [M+H] + .

[0270]

[0271] Step 6-8: Except for replacing compound 1d with compound 25f, the other steps and conditions were the same as Example 1 to obtain the hydrochloride of compound W25 as a white solid with a yield of 88%. LCMS (ESI): m / z 298.1 [M+H] + .

[0272] Example 26: Synthesis of Compound W26

[0273]

[0274] Step 1: Compound 25e (1.0 eq) was dissolved in DMF, anhydrous potassium carbonate (2.5 eq) was added, and the mixture was stirred at room temperature for 10 min. Methyl iodide (5.0 eq) was slowly added dropwise, and the mixture was reacted at room temperature for 20 min. The mixture was diluted with water, extracted with EA, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 26a as a white solid with a yield of 98%. 1H NMR (400MHz, CDCl3): δ8.07 (s, 1H), 7.10 (d, J = 1.2Hz, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.96 (s, 3H).

[0275]

[0276] Step 2: Compound 26a (1.0 eq) was dissolved in DMF, NCS (1.1 eq) was slowly added in batches at room temperature, and the reaction was allowed to proceed overnight. The mixture was diluted with water, extracted with EA, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 26b as a white solid with a yield of 70%. 1 H NMR (400MHz, CDCl3): δ8.11(s,1H),4.05(s,3H),4.03(s,3H),3.98(s,3H).

[0277]

[0278] Step 3: Compound 26b (1.0 eq) was dissolved in THF, and 2.5 M aqueous lithium hydroxide solution (10.0 eq) was added, and the reaction was allowed to react at room temperature overnight. The reaction solution was concentrated to a small volume, and 3 M dilute hydrochloric acid was slowly added dropwise to neutralize it. A large amount of solid precipitated, which was filtered, washed with water, and dried to obtain compound 26c as a white solid with a yield of 65%. 1 H NMR (400MHz, DMSO-d6): δ13.83(br.s,1H),8.05(s,1H),3.99(d,J=1.1Hz,3H),3.97(s,3H).

[0279]

[0280] Step 4: Compound 26c (1.0 eq) was dissolved in N-methylpyrrolidone, and silver carbonate (1.2 eq) and o-phenanthroline (0.1 eq) were added, and the mixture was reacted at 150°C for 2 h. Water and EA were added to the reaction solution, filtered through diatomaceous earth, extracted with EA, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 26d as a white solid with a yield of 99%. 1 H NMR (400MHz, CDCl3): δ7.41 (q, J=5.5Hz, 2H), 4.04 (d, J=1.1Hz, 3H), 4.00 (s, 3H).

[0281]

[0282] Step 5-7: Except for replacing compound 1d with compound 26d, the other steps and conditions were the same as in Example 1 to obtain the hydrochloride of compound W26 as a white solid with a yield of 84%. LCMS (ESI): m / z 332.0 [M+H] + .

[0283] Example 27: Synthesis of Compound W27

[0284]

[0285] Step 1: Dissolve compound 2g (1.0 eq) and 1,3-dibromopropane (1.2 eq) in acetonitrile, add anhydrous cesium carbonate (3.0 eq), and heat to 70°C under argon protection, reflux for 1 h. Cool to room temperature, extract with EA, combine the organic phases, concentrate, and purify with a silica gel column to obtain compound 27a as a white solid with a yield of 66%. 1 H NMR (400MHz, CDCl3): δ7.85(s,1H),7.31(s,1H),7.28(s,1H),4.24(t,J=5.9Hz,2H),3.99(d,J=7.3Hz,3H),3.69(t,J=6 .3Hz,2H),3.26(t,J=6.6Hz,2H),3.04(td,J=7.2,2.3Hz,2H),2.45(p,J=6.1Hz,2H),2.00(p,J=7.0Hz,2H),1.45(s,9H).

[0286]

[0287] Step 2: At room temperature, compound 27a (1.0 eq) was dissolved in EA, and 4.0 M hydrogen chloride dioxane solution (10.0 eq) was added to react overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and the filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W27 as a white solid with a yield of 90%. 1 H NMR (400MHz, DMSO-d6): δ8.15(s,1H),8.02(s,1H),7.58(s,2H),7.44(s,1H),4.15(dt,J=9.2,4.4Hz,2H),3.86-3.8 4(m,5H),3.70(t,J=6.5Hz,2H),3.53(q,J=6.1Hz,2H),3.01(q,J=6.4,6.0Hz,2H),2.33-2.16(m,2H).LCMS(ESI):m / z 386.0[M+H] + .

[0288] Example 28: Synthesis of Compound W28

[0289]

[0290] Step 1: Under argon protection, compound 25f (1.0 eq) was dissolved in 1,2-dichloroethane, cooled to -10°C, succinic anhydride (2.0 eq) was added, and anhydrous aluminum chloride (1.5 eq) was slowly added in batches, reacted for 10 min, raised to 45°C, and reacted for 5 h. The reaction solution was cooled to room temperature, 1M hydrochloric acid was added, and a large amount of solid precipitated. The filter cake was washed with water and a small amount of DCM, and dried to obtain compound 28a as a white solid with a yield of 15%. 1 H NMR (400MHz, DMSO-d6): δ12.20(s,1H),8.32(s,1H),7.59(s,1H),3.93(s,3H),3.86(s,3H),3.34(t,J=6.3Hz,2H),2.60(t,J=6.3Hz,2H).

[0291]

[0292] Step 2: Compound 28a (1.0 eq) was dissolved in DMF, anhydrous potassium carbonate (3.0 eq) was added, stirred at room temperature for 10 min, iodomethane (5.0 eq) was slowly added dropwise, the temperature was raised to 60°C, and the reaction was continued for 2 h. After the reaction was completed, water was added for dilution, EA was extracted, the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 28b as a white solid with a yield of 90%. 1 H NMR (400MHz, CDCl3): δ8.02(s,1H),7.11(s,1H),4.07-3.93(m,6H),3.74(s,3H),3.36(t,J=6.8Hz,2H),2.82(t,J=6.7Hz,2H).

[0293]

[0294] Step 3: Dissolve compound 28b (1.0 eq) in anhydrous DCM, cool to 0°C, slowly add anhydrous aluminum chloride (2.0 eq) in batches, and warm to room temperature. React overnight. Dilute the reaction solution with water, extract with DCM, combine the organic phases, concentrate, and purify on a silica gel column to obtain compound 28c as a white solid with a yield of 77%. 1 H NMR (400MHz, DMSO-d6): δ9.54(s,1H),8.25(s,1H),7.47(s,1H),3.92(s,3H),3.61(s,3H),3.40(t,J=6.3Hz,2H),2.67(t,J=6.3Hz,2H).

[0295]

[0296] Step 4: Under argon protection, compound 28c (1.0 eq) and compound 27a (1.0 eq) were dissolved in acetonitrile, anhydrous cesium carbonate (3.0 eq) was added, and the mixture was reacted at 70°C for 2 h. After the reaction was completed, the reaction solution was diluted with water, extracted with DCM, and the organic phases were combined, concentrated, purified by silica gel column, and slurried with isopropyl ether to obtain compound 28d as a white solid with a yield of 34%.

[0297]

[0298] Step 5: At room temperature, compound 28d (1.0 eq) was dissolved in EA, and 4.0 M hydrogen chloride dioxane solution (10.0 eq) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and the mixture was filtered, and the filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W28 as a white solid with a yield of 55%. 1 H NMR (400MHz, DMSO-d6): δ8.28(s,1H),8.17(s,1H),8.03(s,2H),7.59(s,1 H),7.57(s,1H),7.52(s,1H),4.26(td,J=6.1,3.6Hz,4H),3.86(d,J=7.4H z, 6H), 3.61 (s, 3H), 3.37 (d, J = 6.3Hz, 2H), 3.20 (t, J = 7.2Hz, 2H), 2.95-2. 82(m,2H),2.68(t,J=6.4Hz,2H),2.20(q,J=6.1Hz,2H),2.01-1.89(m,2H). 13 C NMR (100MHz, DMSO-d6): δ192.99,173.09,151.58,148.30,141.84,141.14,136.37,132.97,130.91,125.6 0,108.37,104.96,101.93,71.14,65.62,57.13,56.40,51.91,38.81,35.39,33.58,29.90,28.08,22.38.

[0299] Example 29: Synthesis of Compound W29

[0300]

[0301] Step 1: At room temperature, compound 28d (1.0 eq) was dissolved in THF, and 2.5 M aqueous lithium hydroxide solution (10.0 eq) was added to react overnight. The reaction solution was concentrated to a small volume, and 1 M hydrochloric acid was slowly added dropwise to neutralize. A large amount of solid precipitated, which was filtered, washed with water, and dried to obtain compound 29a as a white solid with a yield of 75%. 1 H NMR (400MHz, DMSO-d6): δ8.14(s,1H),7.57(d,J=8.5Hz,2H),7.51(s,1H),6.87(d,J=7.0Hz,1H),4.26(td,J=6.2,2.7Hz,4H),3.86(d,J=8 .1Hz, 6H), 3.28 (s, 2H), 3.01 (q, J = 6.7Hz, 4H), 2.56 (t, J = 6.4Hz, 2H), 2.19 (t, J = 6.2Hz, 2H), 1.75 (q, J = 7.1Hz, 2H), 1.37 (d, J = 3.2Hz, 9H).

[0302]

[0303] Step 2: Compound 29a (1.0 eq) was dissolved in EA at room temperature, and 4.0 M hydrogen chloride dioxane solution (10.0 eq) was added to react overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and the mixture was filtered. The filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W29 as a white solid with a yield of 60%. 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),8.17(s,1H),8.06(s,2H),7.64-7.48(m,3H),4.26(td,J=6.1,3.7Hz,4H),3.86(dd,J=7.6,5.4Hz,6H ), 3.29 (d, J = 6.4Hz, 2H), 3.20 (t, J = 7.1Hz, 2H), 2.88 (q, J = 6.7Hz, 2H), 2.60 (t, J = 6.3Hz, 2H), 2.19 (p, J = 6.4Hz, 2H), 1.94 (q, J = 7.3Hz, 2H). 13 CNMR (100MHz, DMSO-d6): δ193.48,193.21,174.00,151.57,148.30,142.06,141.14,136.37,132.97,130.9 2,125.40,108.38,104.96,101.92,71.12,65.63,57.12,56.40,38.80,35.41,33.65,29.90,28.39,22.38.

[0304] Example 30: Synthesis of Compound W30

[0305]

[0306] Step 1: Compound 2d (1.0 eq) was dissolved in DMF at room temperature, and dimethylhydroxylamine hydrochloride (1.2 eq), EDCI (1.1 eq) and triethylamine (5.0 eq) were added and reacted for 16 h. The mixture was diluted with water, extracted with EA, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 30a as a colorless oil with a yield of 96%. 1 H NMR (400MHz, CDCl3): δ8.08-8.03(m,1H),7.50(d,J=7.1Hz,2H),7.45-7.38(m,2H),7.37-7 .33(m,1H),7.31(s,1H),7.29(s,1H),5.24(s,2H),4.00(s,3H),3.83(s,3H),3.42(s,3H).

[0307]

[0308] Step 2: Under argon protection, 3-chloro-1-propanol (4 mL) was dissolved in THF (100 mL), cooled to -20 ° C, and isopropylmagnesium chloride-lithium chloride (1.3M in THF, 40 mL) was slowly added dropwise, reacted for 10 min, magnesium chips (2.0 g) and DCE (2 mL) were added, warmed to room temperature, reacted for 20 min, and then warmed to 70 ° C and reacted for 2 h. The reaction was cooled to 0 ° C, and a THF solution of compound 30a (3.5 g) was slowly added dropwise, warmed to room temperature, and reacted for 1 h. Saturated ammonium chloride solution was slowly added dropwise to quench the reaction, extracted with EA, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 30b as a white solid with a yield of 57%. 1 H NMR (400MHz, CDCl3): δ7.83 (s, 1H), 7.49 (d, J = 7.2Hz, 2H), 7.45-7.38 (m, 2H), 7.38-7.34 (m, 1H), 7.30(s,2H),5.24(s,2H),4.01(s,3H),3.78(s,2H),3.13(t,J=7.0Hz,2H),2.06(p,J=6.6Hz,2H).

[0309]

[0310] Step 3: Dissolve chromium trioxide (2.0 eq) in water, cool to 0°C, and drop concentrated sulfuric acid (5.0 eq). Dissolve compound 30b (1.0 eq) in acetone, cool to 0°C, and slowly drop the above aqueous solution of chromium trioxide. React at 0°C for 1 h, warm to room temperature, and react for 2 h. Dilute with ice water, a large amount of solid precipitates, filter, wash with water, and dry to obtain compound 30c as a white solid with a yield of 24%.

[0311]

[0312] Step 4: Compound 30c (1.0 eq) was dissolved in methanol, concentrated sulfuric acid (2.0 eq) was added, the temperature was raised to 80°C, and the reaction was continued for 3 h. The reaction solution was cooled to room temperature, concentrated to a small volume, and diluted with water. A large amount of solid precipitated, which was filtered, washed with water, and dried to obtain compound 30d as a white solid with a yield of 100%. 1 H NMR (400MHz, CDCl3): δ7.49(d,J=7.6Hz,2H),7.42(t,J=7.4Hz,2H),7.36(d,J=7.1Hz,1H),7.3 0(s,3H),5.24(s,2H),4.01(s,3H),3.73(s,3H),3.33(t,J=6.8Hz,2H),2.81(t,J=6.8Hz,2H).

[0313]

[0314] Step 5: Compound 30d (1.0 eq) was dissolved in a mixed solution of methanol and THF, 5% palladium on carbon (0.5 eq) was added, and the mixture was reacted for 24 h under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered with diatomaceous earth, the filtrate was concentrated to dryness, and slurried with isopropyl ether to obtain compound 30e as a white solid with a yield of 42%. 1 H NMR (400MHz, DMSO-d6): δ9.38(s,1H),8.17(s,1H),7.54(s,1H),7.33(s,1H),3.88(s,3H),3.61(s,3H),3.29(s,2H),2.68(t,J=6.4Hz,2H).

[0315]

[0316] Step 6-7: Except for replacing compound 28c with compound 30e, other steps and conditions were the same as Example 28 to obtain the hydrochloride of compound W30 as an off-white solid with a yield of 94%. 1H NMR (400MHz, DMSO-d6): δ8.16 (dd, J=19.4, 3.9Hz, 2H), 7.93 (s, 2H), 7.62 (d, J= 3.7Hz,2H),7.55(d,J=3.8Hz,2H),4.24(t,J=6.0Hz,4H),3.88(d,J=3.9Hz,6H), 3.61(s,3H),3.31(m,2H),3.18(t,J=5.4Hz,2H),2.95-2.82(m,2H),2.69(t,J=6 .3Hz,2H),2.35-2.24(m,2H),1.93(p,J=7.5Hz,2H).LCMS(ESI):m / z600.2[M+H] + .

[0317] Example 31: Synthesis of Compound W31

[0318]

[0319] Step 1: Compound 31a (1.0 eq) and potassium nitrate (3.0 eq) were dissolved in acetic acid, cooled to 0°C, trifluoroacetic acid (3.0 eq) was slowly added dropwise, warmed to room temperature, and reacted overnight. The reaction solution was poured into ice water, and saturated sodium bicarbonate solution was slowly added dropwise to neutralize. A large amount of solid precipitated, which was filtered and dried to obtain compound 31b as a white solid with a yield of 44%. 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),7.81(s,1H),4.01(s,3H),3.89(s,3H).

[0320]

[0321] Step 2-4: Except for replacing compound 1a with compound 31b, other steps and conditions were the same as step 1-3 in Example 1 (synthesis of compound 1d) to obtain compound 31e as a white solid with a yield of 94%. 1 H NMR (400MHz, CDCl3): δ7.40 (dd, J=5.6, 0.7Hz, 1H), 7.35 (d, J=5.5Hz, 1H), 7.30-7.28 (m, 1H), 3.96 (s, 3H), 3.94 (s, 3H).

[0322]

[0323] Step 5-9: Except for replacing compound 25f with compound 31e, other steps and conditions were the same as Example 28 to obtain the hydrochloride of compound W31 as an off-white solid with a yield of 89%. 1H NMR (400MHz, DMSO-d6): δ8.19(d,J=5.2Hz,2H),8.02(d,J=7.0Hz,2H),7.74(s,1 H),7.61(s,1H),7.53(s,1H),4.31(t,J=6.0Hz,2H),4.22(t,J=5.9Hz,2H),3.86( s,6H),3.61(s,3H),3.39(d,J=6.2Hz,2H),3.20(t,J=7.1Hz,2H),2.88(q,J=6.6 Hz,2H),2.68(q,J=6.4,5.3Hz,2H),2.24(p,J=6.1Hz,2H),1.95(p,J=7.2Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ193.47,193.04,173.09,154.82,151.58,148.36,143.86,142.24,141.13,138.92,132.99,131.55,130. 95,128.25,108.29,105.02,104.99,70.52,65.67,57.02,56.44,51.91,38.82,35.38,33.62,30.04,28.09,22.39.LCMS(ESI):m / z 634.1[M+H] + .

[0324] Example 32: Synthesis of Compound W32

[0325]

[0326] Step 1: Except for replacing 1,3-dibromopropane with 1,2-dibromoethane, the other steps and conditions were the same as Step 1 of Example 27 (Synthesis of Compound 27a) to obtain Compound 32a as a white solid with a yield of 74%. LCMS (ESI): m / z 472.1 [M+H] + .

[0327]

[0328] Step 2-3: Except for replacing compound 27a with compound 32a, the other steps and conditions were the same as steps 4-5 of Example 28 (synthesis of compound W28) to obtain the hydrochloride of compound W32 as a white solid with a yield of 91%. LCMS (ESI): m / z 604.1 [M+H] + .

[0329] Example 33: Synthesis of Compound W33

[0330]

[0331] Except that 1,5-dibromopentane was used to replace 1,2-dibromoethane, the other steps and conditions were the same as those in Example 32 to obtain the hydrochloride of compound W33 as a white solid with a yield of 85%. LCMS (ESI): m / z 646.2 [M+H] + .

[0332] Example 34: Synthesis of Compound W34

[0333]

[0334] Except for replacing succinic anhydride with glutaric anhydride, other steps and conditions were the same as Example 28 to obtain the hydrochloride salt of compound W34 as a white solid with a yield of 88%. 1 H NMR (400MHz, DMSO-d6): δ8.21(s,1H),8.17(s,1H),7.98(s,2H),7.59(s,1H),7.56( s,1H),7.51(s,1H),4.26(q,J=5.6Hz,4H),3.85(d,J=7.0Hz,6H),3.60(s,3H),3.19 (t,J=7.1Hz,2H),3.10(t,J=7.2Hz,2H),2.88(q,J=6.6Hz,2H),2.40(q,J=8.5,8.0H z,2H),2.24-2.14(m,2H),1.90(dq,J=21.8,7.3Hz,4H).LCMS(ESI):m / z632.2[M+H] + .

[0335] Example 35: Synthesis of Compound W35

[0336]

[0337] At room temperature, compound W34 (1.0 eq) was dissolved in DCM, triethylamine (3.0 eq) was added, acetyl chloride (1.5 eq) was slowly added dropwise, and the reaction was continued for 30 min. Water was added to separate the mixture, the organic phase was concentrated, and purified by silica gel column to obtain compound W35 as an off-white solid with a yield of 66%. 1H NMR (400MHz, CDCl3): δ7.92(s,1H),7.84(s,1H),7.33(s,1H),7.29(s,1H),7.08 (s,1H),5.86(s,1H),4.38(q,J=6.5Hz,4H),3.92(d,J=20.0Hz,6H),3.71(s,3H), 3.39(t,J=6.6Hz,2H),3.07(q,J=6.4Hz,4H),2.48(q,J=7.4Hz,2H),2.43-2.30( m,2H),2.12(t,J=7.1Hz,2H),2.04(q,J=6.7Hz,2H),1.98(s,3H).LCMS(ESI):m / z 674.2[M+H] + .

[0338] Example 36: Synthesis of Compound W36

[0339]

[0340] Step 1: Under argon protection, compound 2g (1.0 eq) and compound 27a (1.0 eq) were dissolved in acetonitrile, anhydrous cesium carbonate (3.0 eq) was added, and the mixture was reacted at 70°C for 16 h. After the reaction was completed, the reaction solution was diluted with water, extracted with DCM, and the organic phases were combined, concentrated, purified by silica gel column, and slurried with isopropyl ether to obtain compound 36a as an off-white solid with a yield of 28%. LCMS (ESI): m / z 771.3 [M+H] + .

[0341]

[0342] Step 2: At room temperature, compound 36a (1.0 eq) was dissolved in EA, and a 4.0 M solution of hydrogen chloride in dioxane (10.0 eq) was added, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was concentrated to a small volume at low temperature, a small amount of n-hexane was added, and the mixture was filtered. The filter cake was washed with isopropyl ether and dried to obtain the hydrochloride of compound W36 as a white solid with a yield of 84%. LCMS (ESI): m / z 571.2 [M+H] + .

[0343] Example 37: Synthesis of Compound W37

[0344]

[0345] Except that 1-Boc-2-piperidone was used to replace 1-(tert-butyloxycarbonyl)-2-pyrrolidone, the other steps and conditions were the same as step 6 in Example 2 (synthesis of compound 2g) to obtain compound 37a as a white solid with a yield of 10%. LCMS (ESI): m / z 380.1 [M+H] + .

[0346]

[0347] Except for replacing compound 2g with compound 37a, the other steps and conditions were the same as Example 36 to obtain the hydrochloride of compound W37 as a white solid with a yield of 85%. LCMS (ESI): m / z 585.2 [M+H] + .

[0348] Example 38: Synthesis of Compound W38

[0349]

[0350] Step 1: Dissolve compound 2g (1.0eq) in ultra-dry DCM, cool to 0°C under argon protection, slowly drop 1,3-propanedithiol (2.0eq) and boron trifluoride ether complex (5.0eq), and react for 15min. Slowly drop saturated sodium bicarbonate solution to quench the reaction, extract with EA, concentrate the organic phase, and purify on a silica gel column to obtain compound 38a as a colorless oil with a yield of 33%. LCMS (ESI): m / z 456.1 [M+H] + .

[0351]

[0352] Step 2: Compound 28c (1.0 eq) was dissolved in ultra-dry THF, and 1,3-propanedithiol (5.0 eq) and boron trifluoride ether complex (20.0 eq) were slowly added dropwise under argon protection, and the temperature was slowly raised to 50°C for overnight reaction. Saturated sodium bicarbonate solution was slowly added dropwise to quench the reaction, EA was extracted, the organic phase was concentrated, and purified by silica gel column to obtain compound 38b as a white solid with a yield of 95%. 1 H NMR (400MHz, CDCl3): δ7.49(s,1H),7.02(s,1H),5.44(s,1H),4.00(s,3H),3.61( s,3H),3.01(t,J=12.5Hz,2H),2.85-2.74(m,2H),2.54-2.48(m,4H),2.05(s,2H).

[0353]

[0354] Step 3: Compound 38b (1.0 eq) was dissolved in acetonitrile, cesium carbonate (3.5 eq) and 1,3-dibromopropane (2.5 eq) were added, and the mixture was reacted at 70°C for 1 h under argon protection. The reaction solution was cooled to room temperature, concentrated and purified by silica gel column to obtain compound 38c as a white solid with a yield of 57%. LCMS (ESI): m / z 523.0 [M+H] + .

[0355]

[0356] Step 4: Compound 38a (1.0 eq) and compound 38c (1.1 eq) were dissolved in acetonitrile, cesium carbonate (5.0 eq) was added, and the mixture was reacted at 70°C for 5 h under argon protection. The reaction solution was cooled to room temperature, concentrated, and purified by silica gel column to obtain compound 38d as a light yellow oil with a yield of 42%. 1 H NMR (400MHz, CDCl3): δ7.47(s,1H),7.36(s,1H),7.28(s,1H),7.22(s,1H ),7.03(s,1H),4.36(dt,J=19.0,6.2Hz,6H),3.93(s,3H),3.89(s,3H),3. 61(s,3H),3.02(q,J=13.2,11.9Hz,8H),2.78(t,J=14.5Hz,4H),2.50(d, J=7.2Hz,4H),2.38(q,J=6.1Hz,2H),1.95(d,J=13.1Hz,4H),1.42(s,9H).

[0357]

[0358] Step 5: At room temperature, compound 38d (1.0 eq) was dissolved in DMF, sodium hydride (3.0 eq) was slowly added in batches, reacted for 10 min, iodomethane (5.0 eq) was slowly added dropwise, and reacted for 2 h. The reaction solution was slowly quenched with water, extracted with EA, the organic phase was concentrated, and purified by silica gel column to obtain compound 38e as an off-white solid with a yield of 84%. LCMS (ESI): m / z 912.2 [M+H] + .

[0359]

[0360] Step 6: Compound 38e (1.0 eq) was dissolved in a mixed solution of ACE and water, cooled to 0°C, sodium bicarbonate (8.0 eq) and iodine (3.5 eq) were added, and the mixture was reacted for 30 min. The mixture was warmed to room temperature, and a saturated aqueous sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with EA, and the organic phase was concentrated and purified by silica gel column to obtain compound W38 as an off-white solid with a yield of 78%. LCMS (ESI): m / z 632.2 [M+H] + .

[0361] Example 39: Synthesis of Compound W39

[0362]

[0363] Step 1: Under argon protection, compound 1d (1.0 eq) was dissolved in ultra-dry DCM, cooled to -10°C, succinic anhydride (2.0 eq) was slowly added dropwise, anhydrous aluminum chloride (1.5 eq) was slowly added in batches, reacted for 10 min, slowly warmed to room temperature, and reacted for 72 h. After the reaction was completed, 1 M hydrochloric acid was added, and a large amount of solid precipitated. The filter cake was washed with water and a small amount of DCM, and dried to obtain compound 39a as a white solid with a yield of 22%. LCMS (ESI): m / z 295.1 [M+H] + .

[0364] Step 2: Compound 39a was dissolved in a mixed solution of acetic acid / acetic anhydride, p-toluenesulfonic acid (0.1 eq) was added, and the mixture was heated to 55°C for 10 min. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined, concentrated, and purified by silica gel column chromatography to obtain compound W39 as a white solid with a yield of 24%. LCMS (ESI): m / z 277.0 [M+H] + .

[0365] Example 40: Synthesis of Compound W40

[0366]

[0367]

[0368] Compound 40d was synthesized according to steps and conditions substantially similar to those of Example 1 (steps 1-3). Except for replacing compound 1d with compound 40d, the other steps and conditions were the same as those of Example 39 to obtain compound W40 as a white solid with a yield of 88%. LCMS (ESI): m / z 325.0 [M+H] + .

[0369] Example 41: Synthesis of Compound W41

[0370]

[0371] Except that 5-chloro-2-fluoro-4-methoxybenzaldehyde (compound 41a) was used to replace 5-bromo-2-fluoro-4-methoxybenzaldehyde (compound 40a), the other steps and conditions were the same as those in Example 40 to obtain compound W41 with a yield of 89%. LCMS (ESI): m / z 281.0 [M+H] + .

[0372] Example 42: Synthesis of Compound W42

[0373]

[0374] Except for replacing compound 39a with compound 28a, the other steps and conditions were the same as Example 39 to obtain compound W42 as a white solid with a yield of 84%. LCMS (ESI): m / z 295.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ7.61(s,1H),7.58(s,1H),6.17(t,J=4.2Hz,1H),3.91(s,3H),3.85(s,3H),3.61(d,J=4.2Hz,2H).

[0375] Example 43: Synthesis of Compound W43

[0376]

[0377] Compound W28 (1.0 eq) was dissolved in DMSO, triethylamine (3.0 eq) was added, and the mixture was reacted at room temperature for 2 h. Water was added to quench the reaction, and the mixture was extracted with EA, concentrated to dryness, and purified by silica gel column to obtain compound W43 as a white solid with a yield of 64%. LCMS (ESI): m / z 600.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.60(s,1H),7.57(s,1H),7.51(s,1H),7.42(s,1H),4.25(q,J=5.9Hz,4H),3.92(t,J=7.2Hz,2H),3.87 (s,3H),3.82(s,3H),3.65(s,3H),3.31-3.28(m,2H),2.97(t,J=8.0Hz,2H),2.59(t,J=6.4Hz,2H),2.21-2.15(m,2H),1.99(t,J=7.7Hz,2H).

[0378] Example 44: Synthesis of Compound W44

[0379]

[0380] Compound W43 (1.0 eq) was dissolved in ultra-dry dichloromethane, sodium borohydride (2.0 eq) was added, and the mixture was reacted at room temperature for 2 h. Water was added to quench the reaction, and the mixture was extracted with EA, concentrated to dryness, and purified by silica gel column to obtain compound W44 with a yield of 69%. LCMS (ESI): m / z 602.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.60(s,1H),7.57(s,1H),7.51(s,1H),7.42(s,1H),4.25(q,J=5.9Hz,4H),4.03-3.95(m,3H),3.87( s,3H),3.82(s,3H),3.65(s,3H),3.31-3.28(m,2H),2.97(t,J=8.0Hz,2H),2.59(t,J=6.4Hz,2H),2.21-2.15(m,2H),1.99(t,J=7.7Hz,2H).

[0381] Example 45: Synthesis of Compound W45

[0382]

[0383] At room temperature, compound W44 (1.0 eq) was dissolved in DCM, triethylamine (3.0 eq) was added, and acetyl chloride (1.5 eq) was slowly added dropwise, and the reaction was continued for 30 min. Water was added to separate the mixture, the organic phase was concentrated, and purified by silica gel column to obtain compound W45 with a yield of 90%. LCMS (ESI): m / z 644.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.60(s,1H),7.57(s,1H),7.51(s,1H),7.42(s,1H),4.25(q,J=5.9Hz,4H),4.03-3.95(m,3H),3.87(s,3H), 3.82(s,3H),3.65(s,3H),3.31-3.28(m,2H),2.97(t,J=8.0Hz,2H),2.59 (t,J=6.4Hz,2H),2.35(s,3H),2.21-2.15(m,2H),1.99(t,J=7.7Hz,2H).

[0384] Example 46: Synthesis of Compound W46

[0385]

[0386] Compound W28 (1.0 eq) was dissolved in a 1 / 1 THF / H2O mixed solvent, and lithium hydroxide (3.0 eq) was added. The reaction was allowed to react at room temperature for 3 h. The reaction solution was concentrated to a small volume, and 1 M hydrochloric acid was slowly added dropwise to neutralize. A large amount of solid precipitated, which was filtered, washed with water, and dried to obtain compound W46 as a light yellow solid with a yield of 50%. LCMS (ESI): m / z 586.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.18(s,1H),8.27(s,1H),7.60(s,1H),7.57(s,1H),7.51(s,1H),7.42(s,1H),4.25(q,J=5.9Hz,4H),3.92(t,J=7. 2Hz,2H),3.87(s,3H),3.82(s,3H),3.31-3.28(m,2H),2.97(t,J=8.0Hz,2H),2.59(t,J=6.4Hz,2H),2.21-2.15(m,2H),1.99(t,J=7.7Hz,2H).

[0387] Example 47: Synthesis of Compound W47

[0388]

[0389] At room temperature, compound W44 (1.0 eq) was dissolved in DCM, triethylamine (3.0 eq) was added, iodomethane (1.5 eq) was slowly added dropwise, and the reaction was continued for 30 min. Water was added to separate the mixture, the organic phase was concentrated, and purified by silica gel column to obtain compound W47 with a yield of 91%. LCMS (ESI): m / z 616.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.60(s,1H),7.57(s,1H),7.51(s,1H),7.42(s,1H),4.25(q,J=5.9Hz,4H),4.03-3.95(m,3H),3.87( s,3H),3.82(s,3H),3.65(s,3H),3.31-3.28(m,2H),2.97(t,J=8.0Hz,2H),2.59(t,J=6.4Hz,2H),2.27-2.18(m,5H),1.99(t,J=7.7Hz,2H).

[0390] Example 48: Synthesis of Compound W48

[0391]

[0392] Compound 25e (1.0 eq) and methyl 3-(methylamino)propionate (1.1 eq) were dissolved in THF, HATU (2.0 eq) and DIPEA (3.0 eq) were added, and the temperature was raised to 60°C for 5 hours. The reaction solution was poured into water, extracted with EA three times, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 48a with a yield of 65%. LCMS (ESI): m / z 355.9 [M+H] + .

[0393] Compound 48a (1.0 eq) was dissolved in anhydrous DCM, cooled to 0°C, and anhydrous aluminum chloride (2.0 eq) was slowly added in batches and warmed to room temperature. The reaction was allowed to react overnight. The reaction solution was diluted with water, extracted with DCM, and the organic phases were combined, concentrated, and purified by silica gel column to obtain compound 48b with a yield of 54%. LCMS (ESI): m / z 342.0 [M+H] + .

[0394]

[0395] Except that 28c was replaced by 48b, the conditions were the same as step 4 in Example 28 to obtain compound 48c; except that 28d was replaced by 48c, the conditions were the same as step 5 in Example 28 to obtain compound 48d; except that W28 was replaced by 48d, the conditions were the same as Example 43 to obtain compound W48 with a yield of 48%. LCMS (ESI): m / z 629.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.60(s,1H),7.57(s,1H),7.51(s,1H),7.42(s,1H),4.25(q,J=5.9Hz,4H),3.87(s,3H),3.82(s,3H),3 .65(s,3H),3.42(t,J=7.2Hz,2H),3.31-3.28(m,5H),2.97(t,J=8.0Hz,2H),2.67(t,J=6.4Hz,2H),2.21-2.15(m,2H),1.99(t,J=7.7Hz,2H).

[0396] Example 49: Synthesis of Compound W49

[0397]

[0398] Compound W48 (1.0 eq) was dissolved in a THF / H2O = 1 / 1 mixed solvent, and lithium hydroxide (3.0 eq) was added and reacted at room temperature for 3 h. The reaction solution was concentrated to a small volume, and 1 M hydrochloric acid was slowly added dropwise to neutralize it. A large amount of solid precipitated, which was filtered, washed with water, and dried to obtain compound W49 with a yield of 94%. LCMS (ESI): m / z 615.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ12.15(s,1H),8.27(s,1H),7.60(s,1H),7.57(s,1H),7.51(s,1H),7.42(s,1H),4.25(q,J=5.9Hz,4H),3.87(s,3H), 3.82(s,3H),3.42(t,J=7.2Hz,2H),3.31-3.28(m,5H),2.97(t,J=8.0Hz,2H),2.67(t,J=6.4Hz,2H),2.21-2.15(m,2H),1.99(t,J=7.7Hz,2H).

[0399] Experimental Example 1: Activation of the STING-mediated interferon (IFN) signaling pathway by compounds

[0400] In this experiment, the activity of SEAP (secreted embryonic alkaline phosphastase) reporter gene regulated by IFN regulatory factor (interferon regulatory factor) was monitored in THP1-Blue-ISG cells to evaluate the agonistic effect of the test compound on STING-mediated IFN signaling pathway at the cellular level.

[0401] The THP1-Blue-ISG cells in the logarithmic growth phase were centrifuged and resuspended in cell culture medium RPMI-1640 to a density of 2×10 6 / mL, inoculated into 96-well cell culture plates at 50μL / well. Use cell culture medium to gradiently dilute the mother solution of the test compound into 2× working concentration dilution (the test compound is gradiently diluted 10 times, and the concentrations after dilution are: 20, 10, 1, 0.1, 0.01 and 0.001μM), add 50μL / well compound × working concentration dilution to the 96-well plate (50μL of culture medium containing 2% DMSO is added to the negative control well; MSA-2 is added to the positive control well), and the culture plate is placed in a cell culture incubator and incubated for 16h. After the cell incubation is completed, 10μL of cell culture supernatant is transferred to a 96-well plate, 90μL / well of QUANTI-Blue solution is added, and incubated at 37℃ for 3h, and the absorbance value at 620nm is read using an enzyme reader. EC 50 The experimental results are shown in Table 1.

[0402] Table 1 Agonistic effect of test compounds on STING-mediated IFN signaling reporter gene

[0403] Compound No. <![CDATA[EC 50 (nM)]]> Excitation rate W1 / 94.4%@20μM W28 5.14 / W29 29 98.8%@1μM W30 18 / W31 / 129.5%@1μM W42 / 98.8%@10μM W43 48 88.91%@1μM W46 28 90.55%@1μM MSA-2(Yang Shen) / 0.0%@1μM

[0404] Note: The “@” in Table 1 refers to the activation rate of the test compound on the STING-mediated IFN signal reporter gene in THP1-Blue-ISG cells at the corresponding concentration.

[0405] The structure of MSA-2 is as follows:

[0406] The results show that the compound prepared in the example of the present invention has a strong agonistic effect on the STING-mediated interferon signaling pathway in THP1-Blue-ISG cells, which is better than the positive control molecule MSA-2.

[0407] Experimental Example 2: Comparison of the stability of compounds at different pH

[0408] Compound 28 (10 mg) was placed in 200 μL of PBS buffer at pH 7.4, spotted by TLC thin layer chromatography, and then observed under ultraviolet light; after shaking reaction at 25°C for 10 min, TLC monitoring showed that about 10% of compound 28 was converted into compound 43, after shaking reaction at 25°C for 30 min, TLC monitoring showed that about 35% of compound 28 was converted into compound 43, after shaking reaction at 25°C for 2 h, TLC monitoring showed that about 65% of compound 28 was converted into compound 43. From the above experimental results, it can be seen that compound 28 is unstable in weakly alkaline (pH 7.4) PBS and is easily converted into compound 43.

[0409] Compound 43 (10 mg) was placed in acetic acid / sodium acetate buffer at pH 3, acetic acid / sodium acetate buffer at pH 5.2, and PBS buffer at pH 7.4, respectively, and incubated with shaking at 25°C. Samples were taken at 1 h and 24 h, respectively, and the changes of compound 43 were monitored by liquid chromatography-mass spectrometry. According to the chromatographic results, the chromatographic purity of compound 43 at three different pH values ​​(pH 3, pH 5.2, pH 7.4) after incubation for 1 h and 24 h was above 95%, and no instability or deterioration was observed.

[0410] By comparing the stability differences between compound 28 and compound 43 at different pH values, it can be seen that compound 28 exhibits insufficient stability under weakly alkaline conditions (pH 7.4); while compound 43 exhibits good stability results at all three tested pH values.

[0411] Compounds 44 to 49 have similar structures to Compound 43, and it is expected that Compounds 44 to 49 can exhibit substantially equivalent stability to Compound 43 at the above pH.

[0412] Experimental Example 3: Inhibitory effects of compounds on cytochrome P450 enzymes CYP3A4, CYP2B6 and CYP1A2

[0413] 1. Experimental Materials

[0414] Human liver microsomes, catalog number 452117, were purchased from Corning; NADPH, catalog number BD11658, were purchased from Bidler.

[0415] 2. Experimental Methods

[0416] 1 μL of 2 mM test compound or quality control inhibitor (ketoconazole for CYP3A4 and CYP2B6 inhibitors, furafylline for CYP1A2 inhibitor) was added, and the final concentration of the test compound or quality control inhibitor was 10 μM. DMSO was used as a solvent control, and all experiments were performed in duplicate.

[0417] A mixed solution system containing phosphate buffered saline, ultrapure water, MgCl2 and human liver microsomes was prepared according to the table below.

[0418] Reagents Stock solution concentration volume Final concentration <![CDATA[MgCl2 stock solution]]> 50mM 20μL 5mM Phosphate buffered saline 200mM 100μL 100mM Ultrapure water -- 56μL -- Human liver microsomes 20mg / mL 2μL 0.2mg / mL Test compound or quality control inhibitor 2mM 1μL 10μM

[0419] Take 1 μL of the substrate stock solution and add it to the above mixed solution.

[0420] CYP enzyme subtypes Substrate Stock solution concentration Final concentration Incubation time CYP3A4 Midazolam 1mM 5μM 5min CYP2B6 Bupropion 10mM 50μM 20min CYP1A2 Phenacetin 8mM 40μM 20min

[0421] The obtained reaction system was preheated in a 37°C water bath for 5 min, and then 20 μL of 10 mM NADPH solution was added to start the reaction, with a final NADPH concentration of 1 mM, and incubated at 37°C for the incubation time shown in the table above.

[0422] After the incubation, the reaction was terminated with 400 μL cold methanol (internal standard, 500 nM Labetalol, 100 nM Alprazolam and 2 μM Ketoprofen). The sample was centrifuged at 3220 g for 60 min to precipitate the protein. 100 μL of the supernatant was diluted with 100 μL ultrapure water (according to the peak shape and signal intensity of LC-MS / MS) and analyzed by LC-MS / MS.

[0423] 3. Conclusion

[0424] The results showed that the inhibition rate of the compounds of the examples of the present invention on each CYP enzyme subtype at 10 μM was less than 50%, and the risk of DDI (drug-drug interaction) was low.

[0425]

[0426] Experimental Example 4: Plasma kinetic study of compounds in CD-1 mice

[0427] 1. Experimental Animals

[0428] CD-1 mice, SPF grade, male, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.

[0429] 2. Experimental Methods

[0430] The compounds were tested for pharmacokinetic properties in rodents following oral and intravenous administration using standard protocols.

[0431] In the experiment, the candidate compound was prepared into a clear solution and given to mice orally and intravenously once. The solvent was 5% DMSO + 45% PEG400 + 50% pH 4.5 acetate buffer. Six mice were used for oral and intravenous administration of each compound. The oral dosage was 10 mg / kg (the concentration of the drug solution was 1 mg / mL and the administration volume was 10 μL / g); the intravenous dosage was 3 mg / kg (the concentration of the drug solution was 0.3 mg / mL and the administration volume was 10 μL / g).

[0432] Sampling was performed at 0.0833h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration. Whole blood samples were immediately placed on ice and centrifuged at 4℃ and 2000g for 5min within 0.5h after collection to separate plasma. The upper layer of samples was collected into sample tubes, frozen in a -10 to -30℃ refrigerator within 0.5h, and transferred to a -60 to -90℃ refrigerator within 24h.

[0433] 3. Data Analysis

[0434] The concentration of each compound in the plasma samples at each time point was detected by LC-MS / MS, and the plasma clearance rate (CL), peak time (T max ), half-life (t 1 / 2 ), peak concentration (C max ), area under the drug-time curve (AUC 0-t ), tissue distribution volume (Vd), mean residence time (MRT 0-t ) and bioavailability (F) and other PK parameters.

[0435] 4. Experimental Results

[0436] The pharmacokinetic test results of the compounds of the present invention are shown in the following table.

[0437] Table 2. Pharmacokinetic test results of the compounds of the present invention

[0438]

[0439] As can be seen from Table 2, the compounds of the embodiments of the present invention have the characteristics of good plasma exposure, high bioavailability, etc., and have good pharmacokinetic properties, and can be used as oral STING agonists for clinical development in the future.

[0440] It should be noted that although the technical solutions of the present invention are described with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto. The various embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Without departing from the scope and spirit of the described embodiments, many modifications and changes are obvious to those of ordinary skill in the art. The choice of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A compound of formula (I), or an enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance, or prodrug thereof, in, represents a single bond or a double bond; when When it represents a double bond, R3 does not exist; X1 and X2 are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group; 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl or C 3-9 Cycloalkyl substitution; R1 and R2 are each independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl, 3-9 membered heterocyclyl or -LM; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; Alternatively, R1 and R2 are connected to form C 5-8 Cycloalkenyl, 5-8 membered heterocyclic group, C 6-8 Aryl or 5-8 membered heteroaryl; If present, R3 is hydrogen; R4 is hydrogen, hydroxyl, C 1-4 Alkyl or C 1-4 Alkoxy; or, R3 and R4 together form =O; R 10 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Q is -C(=O)- or -NY-; When Q is -C(=O)-, Y connected to Q does not exist, and Q and R 4 Connected to each other to form a 5-7 membered heterocyclic group; When Q is -NY-, each Y is independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, hydroxy, nitroso, nitro, -S(=O)R Y 、-S(=O)2R Y or -C(=O)R Y ; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl groups are each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; If present, each R Y are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl groups are each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; Or, when Q is -NY-, Q and R 4 Connected to each other to form a 5-7 membered heterocyclic group; If present, L is -O-(CH2) a -O-, a is 1, 2, 3, 4, 5, 6, 7 or 8; If present, M is selected from the structure shown below: In formula (M1), formula (M2), formula (M3) or formula (M4), represents a single bond or a double bond; when When it represents a double bond, R3 does not exist; X3, X4, X5, and X6 are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group; 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl substituted; preferably, X3, X4 are each independently hydrogen; and / or, preferably, X5, X6 are each independently hydrogen or halogen, preferably hydrogen, fluorine or chlorine; X7 is -CH2-, -CH(CH3)-, -C(CH3)2-, -NH- or -N(CH)3-; R5 and R6 are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group; 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is each independently optionally substituted with one or more halogen, cyano, amino, hydroxyl, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 3-9 Preferably, R5 and R6 are each independently C 1-6 Alkoxy; R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; preferably, R7 and R8 are each independently hydrogen; R9 is hydrogen, C 1-6 Alkyl, C 6-10 Aryl, C 3-9 cycloalkyl, 5-10 membered heteroaryl or 3-9 membered heterocyclyl; preferably, R9 is hydrogen or C 1-6 Alkyl, preferably hydrogen or methyl; b and c are each independently 0, 1, 2, 3, 4 or 5; preferably, b and c are each independently 0 or 1; R3, R4, R 10 , Q and Y are as defined in formula (I).

2. The compound according to claim 1, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, wherein: The compound is shown in formula (I-1): in, X1, X2, R1, R2, R 10 , n and Y as defined in claim 1; Alternatively, the compound is as shown in formula (I-2): in, Z is O or NH; n is 0, 1 or 2; X1, X2, R1, R2, and R 10 As defined in claim 1; Alternatively, the compound is as shown in formula (I-3): in, X1, X2, R1, R 10 , n, Y and a as defined in claim 1; X3, X4 and R5 are as defined in claim 1; Alternatively, the compound is as shown in formula (I-4): in, X1, X2, R1, R 10 , n, Y and a as defined in claim 1; X5, X6, X7, R6, R7, R8, R9, b and c are as defined in claim 1; Alternatively, the compound is as shown in formula (I-5): in, n is 1, 2 or 3; X1, X2, R1, R3, R 10 , Y and a as defined in claim 1; X5, X6, X7, R6, R7, R8, R9, b and c are as defined in claim 1.

3. The compound according to claim 1 or 2, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, wherein: X1 and X2 are each independently hydrogen or halogen, preferably hydrogen, fluorine or chlorine, more preferably hydrogen.

4. A compound according to any one of claims 1 to 3, or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R1 is C 1-6 Alkoxy group, preferably methoxy group.

5. A compound according to any one of claims 1 to 4, or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R2 is hydrogen, halogen, hydroxyl or C 1-6 Alkoxy, preferably C 1-6 Alkoxy; the C 1-6 The alkoxy group is optionally substituted with one or more halogen or C 6-10 Aryl substitution.

6. A compound according to any one of claims 1 to 5, or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R 10 For hydrogen.

7. A compound according to any one of claims 1 to 6, or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: n is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 1.

8. A compound according to any one of claims 1 to 7, or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Q is -C(=O)-, Q and R 4 are connected to form a 5-7 membered heterocyclic group, preferably a 5-7 membered oxygen-containing heterocyclic group, more preferably Alternatively, Q is -NY-, each Y is independently hydrogen, C 1-6 Alkyl, nitroso, -S(=O)2R Y or -C(=O)R Y , each R Y Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 6-10 Aryl; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 6-10 The aryl groups are each independently optionally substituted with one or more halogen, C 1-6 Haloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted; preferably each Y is independently hydrogen, C 1-6 Alkyl, nitroso, -S(=O)2R Y or -C(=O)R Y , each R Y Each independently is C 1-6 Alkyl or C 6-10 Aryl; said C 1-6 Alkyl or C 6-10 The aryl groups are each independently optionally substituted with one or more halogen, C 1-6 Haloalkyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted; more preferably one of the Y is hydrogen; Alternatively, Q is -NY-, Q and R4 are connected to each other to form a 5-7 membered heterocyclic group, preferably a 5-7 membered nitrogen-containing heterocyclic group, more preferably in represents a single bond or a double bond; n is 1, 2 or 3, preferably 1; Y is hydrogen, C 1-6 Alkyl or -C(=O)C 1-6 Alkyl, preferably hydrogen, methyl or acetyl.

9. A compound according to any one of claims 1 to 8, or an enantiomer, diastereomer, racemate and mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: a is 1, 2, 3, 4, 5 or 6, preferably 2, 3, 4 or 5.

10. The compound according to claim 1 or 2, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, wherein: X1 is hydrogen or halogen; X2 is hydrogen or halogen; represents a single bond, R3 is hydrogen or does not exist, R4 is hydrogen, hydroxyl, C 1-4 alkyl, or R3 and R4 together form =O, Q is -NY-; or, represents a double bond, R3 does not exist, R4 is a hydroxyl group, Q is -C(=O)-, Y connected to Q does not exist, and Q and R 4 are connected to form a 5-7 membered heterocyclic group containing 1-3 N atoms, or, R3 is absent, R4 is hydrogen, Q is -NY-, and Q and R 4 and the carbon atoms to which they are connected together form a 5-7 membered heterocyclic group containing 1-3 N atoms; Y is independently hydrogen, nitroso, nitro, C 1-6 Alkyl, -S(=O)R Y 、-S(=O)2R Y or -C(=O)R Y , R Y is hydrogen or C 1-6 alkyl; R 10 is hydrogen; n is 0, 1, 2 or 3; R1 and R2 are each independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or -LM; the C 1-6 alkoxy, each independently optionally substituted with halogen or C 6-10 one or more substitutions in the aryl group; L is -O-(CH2) a -O-, a is 1, 2, 3, 4, 5 or 6; M is selected from the structure shown below: In formula (M1), formula (M2), formula (M3) or formula (M4), X3 and X4 are each independently hydrogen; X5 and X6 are each independently hydrogen or halogen; R5 and R6 are each independently hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy; Represents a single bond; R3 and R4 together form =O; R 10 is hydrogen; n is 0, 1 or 2; Q is -NY-, Y is each independently hydrogen or C 1-6 alkyl; X7 is -CH2-, -NH- or -N(CH)3-; R7 and R8 are each independently hydrogen; b and c are each independently 0 or 1; R9 is hydrogen or C 1-6 alkyl.

11. The compound according to claim 10, or its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, cis-trans isomers, isotope-labeled substances or prodrugs, wherein: R3 does not exist, R4 is hydrogen, represents a single bond or a double bond, Q is -NY-, the Y connected to Q does not exist, and Q is connected to R 4 and the carbon atoms connected thereto together form a 5-7 membered heterocyclic group containing 1-2 N atoms, Y is hydrogen, C 1-6 Alkyl or -C(=O)R Y , R Y is hydrogen or C 1-6 alkyl; R 10 is hydrogen; n is 1, 2 or 3; X1 is hydrogen; X2 is hydrogen; R1 is C 1-6 Alkoxy; R2 is -LM, L is -O-(CH2) a -O-, a is 1, 2, 3, 4 or 5; M is Wherein, X5 and X6 are each independently hydrogen or halogen; R6 is C 1-6 Alkoxy; R3 and R4 together form =O; X7 is -CH2-, -NH- or -N(CH)3-; R7 and R8 are each independently hydrogen; b and c are each independently 0 or 1; R9 is hydrogen or C 1-6 alkyl.

12. A compound, or an enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance, or prodrug thereof, wherein the compound is selected from the following compounds:

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or an enantiomer, diastereomer, racemate and a mixture thereof, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier; and / or, Preferably, the pharmaceutical composition is an immunogenic composition.

14. A pharmaceutical preparation, which is made from the compound according to any one of claims 1 to 12, or its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts, hydrates, solvates, tautomers, cis-trans isomers, isotope-labeled substances or prodrugs thereof, or is made from the pharmaceutical composition according to claim 13.

15. Use of the compound according to any one of claims 1 to 12, or its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts, hydrates, solvates, tautomers, cis-trans isomers, isotope-labeled substances or prodrugs, or the pharmaceutical composition according to claim 13, or the pharmaceutical preparation according to claim 14 in the preparation of a medicament for preventing and / or treating STING-dependent type I interferon-related diseases; Preferably, the STING-dependent type I interferon-related disease is a tumor or an infectious disease; and / or, Preferably, the drug for preventing and / or treating STING-dependent type I interferon-related diseases is an immune adjuvant.

16. Use of the compound according to any one of claims 1 to 12, or its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, hydrate, solvate, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the pharmaceutical composition according to claim 13, or the pharmaceutical preparation according to claim 14 in the preparation of a STING agonist.

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