WO2025051161A1 - 3cl protease inhibitor for treating or preventing coronavirus infection and use thereof - Google Patents

Abstract

The present application relates to a 3CL protease inhibitor for treating or preventing coronavirus infection and the use thereof. Specifically, the present application relates to a compound of formula (I) or an isotope labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and the use thereof in the preparation of a drug for treating or preventing coronavirus infection, or a disease or symptom caused by a coronavirus.

Description

3CL protease inhibitors for treating or preventing coronavirus infection and uses thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Chinese patent application No. 202311156849.3 filed on September 8, 2023, the entire contents of which are incorporated herein by reference.

Technical Field

The present application relates to the field of biomedicine, and in particular to 3CL protease inhibitors and uses thereof for treating or preventing coronavirus infection.

Background Art

The new coronavirus (SARS-CoV-2) is a positive-strand RNA virus with the largest genome among the currently known RNA viruses. Studies have found that the new coronavirus mainly infects cells through the human respiratory mucosal system. After entering the cell, the viral gene products are cleaved by proteases to begin translation and replication of the required proteins. 3CL proteases recognize specific cleavage sites and cut polyprotein precursors into multiple non-structural proteins. They are essential for the life cycle of the virus and are excellent targets for antiviral drugs. Many marketed antiviral drugs target 3CL proteases such as HIV and HCV. HIV 3CL protease inhibitors lopinavir and ritonavir have certain interactions with the 3CL protease of the new coronavirus in vitro, but have been shown to have no positive effects on patients infected with the new coronavirus in clinical tests. Therefore, strong inhibitors specific for the 3CL protease of the new coronavirus are clinically needed.

Summary of the invention

In the first aspect, the present application provides a compound of formula (I) or an isotope-labeled compound thereof, or a photosensitive isomers, geometric isomers, tautomers or isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof,

in,

One of ^X1 and ^X2 is N, and the other is N or CH;

At most one of ^Y1 and ^Y2 is hydroxy, halogen, cyano, or C1- _C6 alkyl or _C1 - _{C6 alkoxy optionally substituted by hydroxy, halogen or cyano, and the rest are H; or Y2 is hydroxy or carbonyl, and Y1, together with P1 or P3 and the carbon atom or nitrogen atom to which they are attached, forms a C3-C6} ^{cycloalkyl , a three} _{- membered} to _six- membered heterocycloalkyl, a phenyl, or a five-membered to six-membered heteroaryl optionally substituted by halogen or _C1 - _C3 alkyl;

One of ^P1 and ^P3 is ^-L1 - ^Z1- , and the other is selected from H, _C1 - _C6 alkyl or C3- _C6 cycloalkyl optionally substituted by halogen or cyano, or together with ^Y1 and the carbon atom or nitrogen atom to which they are attached, forms _C3 -C6 cycloalkyl optionally substituted by halogen or _C1 - _C3 alkyl, a three-membered _{to six} -membered heterocycloalkyl, a phenyl or a five-membered to six-membered heteroaryl; ^P2 is ^-L2 - ^Z2- ;

^L1 is selected from a bond, _-CH2- , -NH- or -O-; ^L2 is selected from a bond or _-CH2- ;

^Z1 is wherein the ring optionally has 1 or 2 N heteroatoms;

Z ² is selected from a five-membered to ten-membered heteroaryl group, wherein optionally one or more hydrogen atoms in Z ² are each independently substituted by halogen, hydroxyl, cyano, sulfo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ¹ , R ² and R ⁵ are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and optionally one or more hydrogen atoms in R ¹ , R ² and R ⁵ are each independently replaced by halogen. substituted with halogen, hydroxy, amino, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl;

one of R ³ and R ⁴ is H, and the other is selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, amide, carboxyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -O(CH ₂ ) _n1 CR ⁶ R ⁷ R ⁸ , -NH(CH ₂ ) _n1 R ¹⁰ , -O(CH ₂ ) _n1 R ¹¹ , -(CH ₂ ) _n1 NH(CH ₂ ) _n2 R ¹² , -(CH ₂ ) _n1 NHCOR ¹³ , -(CH ₂ ) _n1 NHSO ₂ R ¹⁴ or -(CH ₂ ) _n1 R ¹⁵ , and optionally one or more hydrogen atoms in R ³ and R ⁴ are each independently substituted by halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or a hydroxyl protecting group;

R ⁶ and R ⁷ are selected from hydrogen, or together with the carbon atoms to which they are attached, they form a C ₃ -C ₆ cycloalkyl group or a C ₃ -C ₆ heterocycloalkyl group;

R ⁸ is selected from -NH ₂ , -NHCOR ⁹ or -NHSO ₂ R ⁹ , wherein R ⁹ is selected from C ₁ -C ₆ alkyl or phenyl;

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, three-membered to six-membered heterocycloalkyl, phenyl or five-membered to six-membered heteroaryl;

R ¹⁵ is selected from a three-membered to six-membered heterocycloalkyl group containing at least one nitrogen atom;

_n1 and _n2 are selected from 0, 1, 2 or 3; and

○ is used to indicate that the ring is unsaturated.

In a preferred embodiment of the present invention, when P ¹ is -L ¹ -Z ¹ -, P ³ is selected from H or C ₁ -C ₆ alkyl substituted by cyano, or forms together with Y ¹ and the carbon atom to which they are attached a phenyl group optionally substituted by halogen or C ₁ -C ₃ alkyl; and when P ³ is -L ¹ -Z ¹ -, P ¹ is selected from C ₁ -C ₆ alkyl optionally substituted by halogen or cyano, preferably -CH ₂ CN, -(CH ₂ ) ₂ CN, -CF ₃ or -CH ₂ CF ₃ , or forms together with Y ¹ and the carbon atom or nitrogen atom to which they are attached a pyridyl or hexahydropyridyl group optionally substituted by halogen or C ₁ -C ₃ alkyl.

In another preferred embodiment of the present invention, ^Z2 can be selected from a five-membered to ten-membered heteroaryl group containing 1 to 3 nitrogen atoms, preferably, ^Z2 can be selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazole or quinolyl, wherein optionally one or more hydrogen atoms in ^Z2 can each be optionally substituted by halogen, hydroxyl, cyano, methyl, ethyl, trifluoromethyl or methoxy.

In another preferred embodiment of the present invention, one of ^R3 and ^R4 is H, and the other may be Any one selected from the following groups:

In another preferred embodiment of the present invention, R ¹⁵ may be selected from tetrahydropyrrolyl, hexahydropyridinyl, morpholinyl or thiomorpholinyl.

In another preferred embodiment of the present invention, halogen may be selected from F, Cl or Br; C ₁ -C ₆ alkyl may be selected from methyl, ethyl, propyl or isopropyl; C ₁ -C ₆ haloalkyl may be selected from monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl or trichloromethyl; C ₁ -C ₆ alkoxy may be selected from methoxy, ethoxy or propoxy; C ₁ -C ₆ haloalkoxy may be selected from trifluoromethoxy or trifluoroethoxy; and/or C ₃ -C ₆ cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In another embodiment of the present invention, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite may have the following structure:

For the sake of simplicity, the "compound of formula (I)" or "compound of the present application" mentioned below may also include any isotope-labeled compound of the compound of formula (I), or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites.

The term "optical isomer" means that when a compound has one or more chiral centers, each The amino center can exist in R configuration or S configuration, and the various isomers thus formed are optical isomers. Optical isomers include all diastereomers, enantiomers, mesomers, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatographic columns or by chiral synthesis.

The term "geometric isomer" means that when a double bond exists in a compound, the compound may exist as cis isomers, trans isomers, E isomers and Z isomers. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or a mixture thereof.

The term "tautomer" refers to an isomer that is produced by the rapid movement of an atom in a molecule between two positions. Those skilled in the art will understand that tautomers can transform into each other and may reach an equilibrium state and coexist under a certain state.

Unless otherwise indicated, references herein to "compounds of formula (I)" or "compounds of the present invention" also encompass isotope-labeled compounds in which any atom in the compound is replaced by an isotope atom thereof. The present invention includes all pharmaceutically acceptable isotope-labeled compounds of compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number as the atoms commonly found in nature but with a different atomic mass or mass number.

Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen, such as ² H (D) and ³ H (T), isotopes of carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, isotopes of chlorine, such as ³⁷ Cl, isotopes of fluorine, such as ¹⁸ F, isotopes of iodine, such as ¹²³ I and ¹²⁵ I, isotopes of nitrogen, such as ¹³ N and ¹⁵ N, isotopes of oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, and isotopes of sulfur, such as ³⁵ S.

Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used in an analogous manner to the methods described in the Examples and Preparations appended herein.

The compounds of formula (I) may exist in the form of pharmaceutically acceptable salts, for example, acid addition salts and/or base addition salts of the compounds of formula (I). Unless otherwise indicated, "pharmaceutically acceptable salts" as used herein include acid addition salts or base addition salts that may occur in the compounds of formula (I).

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base addition salts thereof. Acid addition salts are formed from acids that form nontoxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, hexadecanoate, phosphate/hydrogenphosphate/dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemi-salts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, compounds of formula (I) are encompassed within the scope of the present invention regardless of whether they exist in solvated or unsolvated forms.

Certain compounds of the present invention may exist in different crystalline or amorphous forms. Regardless of the form in which they exist, the compounds of formula (I) are included within the scope of the present invention.

To avoid ambiguity, the following definitions are given for the terms used in this article. Unless otherwise specified, the meanings of the terms used in this article are as follows.

The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to humans. Preferably, the term refers to any national regulatory agency certified by regulatory agencies such as CFDA (China), EMEA (Europe), FDA (USA) for use in mammals, preferably humans.

"Prodrug" refers to a drug that reacts with enzymes, gastric acid, etc. under physiological conditions in vivo, for example, by reacting with each other in the enzyme The oxidation, reduction, hydrolysis and other reactions carried out under catalysis are converted into derivatives of the compounds of the present invention.

"Metabolites" refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

As used herein, the term "hydroxyl" refers to -OH; the term "cyano" refers to -CN; the term "amino" refers to -NH ₂ ; and the term "nitro" refers to -NO ₂ . As used herein, the term "hydroxyl protecting group" refers to a protecting group introduced on a hydroxyl group to prevent the hydroxyl group from undergoing side reactions or unwanted chemical changes during reactions. Common hydroxyl protecting groups include, but are not limited to, Boc, Ms, TMS, TBS, and the like.

As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

As used herein, the term "each independently" means that when the number of substituents is more than one, the substituents may be the same or different.

As used herein, the term "optional" or "optionally" means that the event it describes can or cannot occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

As used herein, the term "heteroatom" represents oxygen (O), nitrogen (N), or S(O) _m (wherein m may be 0, 1 or 2, ie, a sulfur atom S, or a sulfoxide group SO, or a sulfonyl group S(O) ₂ ).

As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, the alkyl group has 1-8, or 1-6, or 1-3 carbon atoms. For example, the term "C _1-8 alkyl" refers to a straight or branched atomic group with 1-8 carbon atoms. The term "C _1-8 alkyl" includes the terms "C _1-6 alkyl", "C ₁ -C ₃ alkyl" and "C ₁ -C ₄ alkyl" in its definition. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R) -2-methylbutyl, (S) -2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, etc. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from O, S and N. For example, 5- 7-membered heteroaryl includes, but is not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine. The heteroaryl group may be optionally substituted with one or more suitable substituents.

As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom). For example, the term "C _1-6 haloalkyl" refers to a C _1-6 alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom). As another example, the term "C _1-4 haloalkyl" refers to a C _1-4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom); the term "C _1-3 haloalkyl" refers to a C _1-3 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom); and the term "C _1-2 haloalkyl" refers to a C _1-2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is substituted by a halogen atom). As another example, the term "C ₁ haloalkyl" refers to a methyl group having 1, 2 or 3 halogen substituents. Examples of haloalkyl groups include CF ₃ , C ₂ F ₅ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CH ₂ Cl and the like.

Herein, the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent a list of all integers within the range, and the ranges are only used as a simplified representation. For example, "1-4 substituents" means 1, 2, 3, or 4 substituents; "3-8 ring atoms" means 3, 4, 5, 6, 7, or 8 ring atoms. Therefore, the numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also include any subranges thereof, and each subrange is also deemed to be disclosed herein.

The compounds of the present application can be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those skilled in the art can refer to the synthetic routes of the specific compounds of the specific embodiments of the present application and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain synthetic methods for other compounds.

In a second aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers can be organic or inorganic inert carrier materials, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, mannitol, cellulose, cellulose derivatives, saccharin sodium, glucose, sucrose, magnesium carbonate, saline, glycerol, ethanol, etc. In addition, the pharmaceutical composition may also contain other pharmaceutical additives, such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, disintegrants, lubricants, glidants, etc.

The dosage form of the pharmaceutical composition of the present application can be a liquid dosage form, a solid dosage form or a semisolid dosage form. The liquid dosage form can be a solution (including a true solution and a colloidal solution), an emulsion (including an o/w type, a w/o type and a multiple emulsion), a suspension, an injection (including a water injection, a powder injection and an infusion), an eye drop, a nasal drop, a lotion and an liniment, etc.; the solid dosage form can be a tablet (including a common tablet, an enteric-coated tablet, a lozenge, a dispersible tablet, a chewable tablet, an effervescent tablet, an orally disintegrating tablet), a capsule (including a hard capsule, a soft capsule, an enteric-coated capsule), a granule, a powder, a pill, a suppository, a film, a patch, an aerosol, a spray, etc.; the semisolid dosage form can be an ointment, a gel, a paste, etc. The pharmaceutical composition of the present application can be made into a common preparation, a sustained-release preparation, a controlled-release preparation, a targeted preparation and various microparticle delivery systems.

In some embodiments, the dosage form of the pharmaceutical composition is selected from tablets, granules, powders, syrups, inhalants and injections.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may also include: (a) fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants ( For example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarding agents (e.g., paraffin); (f) absorption accelerators (e.g., quaternary ammonium compounds); (g) wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) adsorbents (e.g., kaolin and bentonite); and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate) or The mixture is mixed.

Preparations suitable for parenteral administration, such as injections, may include aqueous and non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions. The parenteral formulations provided herein are optionally contained in unit dose or multi-dose sealed containers (e.g., ampoules), and can be stored under freeze drying (lyophilization) conditions that require only the addition of a sterile liquid carrier (e.g., water for injection) just before use. Examples of suitable diluents for reconstructing pharmaceutical compositions (e.g., before injection) include antibacterial water for injection, 5% glucose aqueous solution, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.

Sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants, for example chlorofluorocarbons and volatile unsubstituted hydrocarbons, for example butane and propane. Inhalants may contain excipients such as lactose, or aqueous solutions containing, for example, polyethylene oxide-9-lauryl ether, glycocholate and deoxycholate, or oily solutions administered as nasal drops or sprays, or in the form of gels.

The content of the compound of the present application in its pharmaceutical composition can be adjusted according to actual needs (such as dosage form, administration method, administration object, etc.), for example, 0.1-95% by weight, such as 1-95% by weight, 5-90% by weight, 10-80% by weight, etc.

Specifically, the pharmaceutical composition of the present application may specifically contain 0.01-10 g (eg, 0.05 g, 0.1 g, 0.5 g, 1 g or 5 g, etc.) of the compound of the present application.

In a third aspect, the present application provides the use of a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a drug for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus in a subject in need thereof. A compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof can be used to treat or prevent coronavirus infection or a disease or symptom caused by coronavirus in a subject in need thereof.

The term "subject" as used herein refers to any human or non-human organism that can potentially benefit from treatment with a compound of formula (I). Exemplary subjects include humans or mammals of any age. Preferably, the subject is a human.

As used herein, the term "treatment" includes treating a disease or symptom in a mammal, particularly a human, and includes: (a) inhibiting an infection, disease or symptom, i.e., arresting or delaying the development of an infection, disease or symptom; (b) alleviating an infection, disease or symptom, i.e., causing regression of the disease or symptom, and/or (c) curing an infection, disease or symptom.

As used herein, the term "prevention" includes prophylactic therapy in mammals, especially humans, to reduce the likelihood of infection, disease or symptoms. Patients who receive prophylactic therapy can be selected based on their increased risk of infection or disease or symptoms compared to the general population. "Prevention" can include treatment of subjects who have not yet presented with an infection or clinical condition, and prevention of a second occurrence of the same or similar infection or clinical condition.

The inventors of the present application have found that the compounds of the present application can inhibit coronavirus infection, for example, they can act as reversible covalent small molecule inhibitors against the 3CL protease of the new coronavirus (i.e., 3CL protease inhibitors), thereby inhibiting the viral replication of the coronavirus. Therefore, the compounds of the present application can be used to prevent or treat coronavirus infection or diseases or symptoms caused by coronavirus.

In some embodiments, the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV), and coronaviruses with greater than 85% homology to any of the above coronaviruses and with viral activity, including mixed infections caused by more than one coronavirus subtype. In some embodiments, the coronavirus is novel coronavirus (SARS-CoV-2).

In some embodiments, the diseases or symptoms caused by the coronavirus include respiratory infections, acute respiratory syndrome (SARS), pneumonia (including severe pneumonia), gastroenteritis (including acute gastroenteritis), cough, fever, chills, vomiting, headache, chills, shortness of breath, cytokine storm, etc. caused by the virus.

In a fourth aspect, the present application provides a method for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

In some embodiments, the compounds of the present invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, oral mucosa, ocularly, pulmonary, respiratory, vaginally, rectally, intraperitoneally, intralesionally, perilesionally, and the like.

"Therapeutically effective amount" refers to an amount of the compound of the present application that is effective in treating or preventing coronavirus infection or diseases or symptoms caused by coronavirus when administered alone or in combination.

The specific dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors that the attending physician generally considers when determining the individual regimen and dosage level that is most suitable for a particular patient. For example, the daily dose of the compound of the present application can be particularly 0.001-150 mg/kg body weight (e.g., 0.1 mg/kg body weight, 1 mg/kg body weight, 10 mg/kg body weight or 100 mg/kg body weight, etc.).

The specific administration frequency can be determined by technicians in the relevant fields, for example, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, twice a day, three times a day, etc.

Those skilled in the art will appreciate that the definitions and preferences described in one aspect of the present application are equally applicable to other aspects. Those skilled in the art will appreciate that the embodiments of various aspects of the present application can be combined in various ways without departing from the subject matter and ideas of the present application, and these combinations are also included in the scope of the present application.

DETAILED DESCRIPTION

The compounds of formula (I) of the present application can be synthesized by various methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of formula (I), which are well known in the field of synthetic chemistry. Obviously, referring to the exemplary schemes in this patent, those skilled in the art can A person skilled in the art can easily design the synthetic routes of other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions and protecting groups.

The present invention is further described below with reference to the examples; however, these examples do not limit the scope of the present invention. Unless otherwise stated, all reactants used in the examples are obtained from commercial sources; the instruments and equipment used in the synthesis experiments and product analysis and detection are conventional instruments and equipment commonly used in organic synthesis.

Synthetic route of intermediate Int I

1) Synthesis steps of compound 2

Compound 1 (180 g, 1.25 mol, 1 eq) was dissolved in dioxane (1.80 L), and then potassium tert-butoxide (211 g, 1.88 mol, 1.5 eq) and benzyl alcohol (203.4 g, 1.88 mol, 1.5 eq) were added at 25 °C. The mixture was reacted at 100 °C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. Water (1 L) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the target compound 2 (310 g, 1.44 mol, crude product) as a yellow oil. ESI-MS: [M+H] ⁺ , 216.2.

2) Synthesis steps of compound 3

Compound 2 (130 g, 604 mmol, 1 eq) was dissolved in acetonitrile (1.30 L). Then NIS (177 g, 785 mmol, 1.3 eq) and TFA (34.4 g, 302 mmol, 0.5 eq) were added at 25 °C. The mixture was reacted at 45 °C for 16 hours under nitrogen protection. The reaction was completed by LCMS. Water (1 L) was added to the reaction solution, and the mixture was extracted with ethyl acetate (600 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. The mixture was purified by column chromatography (SiO ₂ , PE/EA, 50/1 to 10/1) (TLC, PE/EA, 3/1, R _f = 0.5). The target compound 3 (85.0 g, 249 mmol, 20.6% yield) was obtained as a white solid. ESI-MS: [M+H] ⁺ , 341.9.

3) Synthesis steps of compound 5

Compound 3 (8.9 g, 26.1 mmol, 1 eq) was dissolved in 1,4-dioxane (180 mL). Water (36 mL), compound 4 (6.56 g, 31.3 mmol, 1.5 eq), Na ₂ CO ₃ (6.91 g, 65.2 mmol, 1.3 eq) and tetrakis(triphenylphosphine)palladium (3.01 g, 2.61 mmol, 0.1 eq) were then added in sequence at 25°C. The mixture was reacted at 100°C for 16 hours under nitrogen protection. The reaction was completed by LCMS detection. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. The target compound 5 (4.2 g, 12.3 mmol, 47.0% yield) was obtained as a yellow oil by column chromatography (SiO ₂ , PE/EA, 50/1 to 10/1) purification (TLC, PE:EA, 1/1, R _f = 0.3). ESI-MS: [M+H] ⁺ , 343.1.

4) Synthesis steps of compound Int I

Palladium carbon (10.0 g) was added to methanol (8.0 mL), and then compound 5 (4.0 g, 11.7 mmol, 1 eq) was added at 25 ° C. Under the protection of hydrogen (50 Psi), the reaction was carried out at 50 ° C for 16 hours. TLC detected that the reaction was complete. The reaction solution was filtered through diatomaceous earth and dried under reduced pressure to obtain the target compound Int I (2.3 g, 9.12 mmol, 78.0% yield) as a white solid. ESI-MS: [M+H] ⁺ , 253.1.

¹ H NMR (400MHz, DMSO) δ9.25 (s, 1H), 8.26 (s, 1H), 8.13 (d, J = 7.6Hz, 1H), 7.69-7.58 (m,3H),7.51(d,J＝7.8Hz,1H),6.41(d,J＝7.5Hz,1H),3.68(s,3H),2.50(s,1H).

Example 1: Preparation of compound GDI15-5623

1) Synthesis steps of compound 3

3-Bromo-5-chlorophenol (1 g, 4.82 mmol) and 1,1,1-trifluoro-2-iodo-ethane (2.53 g, 12.05 mmol, 1.18 mL) were dissolved in DMF (15 mL) and K ₂ CO ₃ (2.00 g, 14.46 mmol) was added. The reaction was stirred at 85 °C for 12 hours. After the reaction was completed, it was cooled to room temperature. Water (100 mL) was added, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ , and concentrated by vacuum filtration. Purification by silica gel chromatography gave 1-bromo-3-chloro-5-(2,2,2-trifluoroethoxy)benzene (1.3 g, 4.49 mmol, 93.16% yield) as a yellow oily liquid.

2) Synthesis steps of compound 4

3-(4-Isoquinolyl)-4-methoxy-1-pyridin-2-one (40 mg, 158.56 μmol) and 1-bromo-3-chloro-5-(2,2,2-trifluoroethoxy)benzene (55.08 mg, 190.27 μmol) were dissolved in DMF (1 mL), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (4.51 mg, 31.71 μmol), CuI (3.02 mg, 15.86 μmol) and Cs ₂ CO ₃ (103.32 mg, 317.12 μmol) were added. The reaction was stirred at 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature. Water (10 mL) and ethyl acetate (10 mL*3) were added for extraction, dried over anhydrous Na ₂ SO ₄ , and concentrated by vacuum filtration. The residue was purified by silica gel chromatography to give 1-[3-chloro-5-(2,2,2-trifluoroethoxy)phenyl]-3-(4-isoquinolyl)-4-methoxypyridin-2-one (40 mg, 86.80 μmol, 54.74% yield) as a yellow oily liquid.

3) Synthesis steps of compound GDI15-5623

Dissolve 1-[3-chloro-5-(2,2,2-trifluoroethoxy)phenyl]-3-(4-isoquinolyl)-4-methoxypyridine-2-1 (40 mg, 86.80 μmol) in DMF (2 mL), add LiCl (36.79 mg, 867.99 μmol) and TsOH (149.47 mg, 867.99 μmol), heat the reaction to 140°C, and stir for 16 hours. After the reaction is completed, cool to room temperature, add water (20 mL) and ethyl acetate (20 mL*3) for extraction, dry over anhydrous Na ₂ SO ₄ , and vacuum filter and concentrate. Purify and prepare 1-[3-chloro-5-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxy-3-(4-isoquinolyl)pyridin-2-one (4 mg, 8.59 μmol, 9.90% yield, 96% purity) as an off-white solid by silica gel chromatography.

¹ H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.32 (s, 1H), 8.19-8.09 (m, 2H), 7.67 (dt, J = 16.1, 7.5H z,4H),7.28(d,J＝6.5Hz,2H),7.21(s,1H),6.27(d,J＝7.6Hz,1H),4.87(q,J＝9.0Hz,2H).

Example 2: Preparation of compound GDI15-5431

1) Synthesis steps of compound 7

Compound Int I (330 mg, 1.31 mmol, 1 eq) was dissolved in DMF (3.3 mL), and then compound 3 (410 mg, 1.57 mmol, 1.2 eq), Cs ₂ CO ₃ (1.28 g, 3.92 mmol, 3 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (186 mg, 1.31 mmol, 1 eq) and CuI (124 mg, 654 μmol, 0.5 eq) were added in sequence at 25° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and separated and purified on a silica gel plate (SiO ₂ , PE/EtOAc, 0/1) to obtain the target compound 7 (440 mg, 1.02 mmol, 77.7% yield) as a red oil. ESI-MS: [M+H] ⁺ , 433.2.

2) Synthesis steps of compound GDI15-5431

Compound 7 (200 mg, 462 μmol, 1 eq) was dissolved in DMF (2 mL), and LiCl (97.9 mg, 2.31 mmol, 47.3 μL, 5 eq) and TsOH (397 mg, 2.31 mmol, 5 eq) were added in sequence at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 25%-65%, 8 min) to obtain the target product GDI15-5431 (32.0 mg, 72.4 μmol, 15.7% yield, 94.8% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 419.1.

¹ H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.32 (s, 1H), 8.13 (d, J = 7.9Hz, 1H), 7.73-7.59 (m, 4H), 7.13 (s, 1H), 7.07 (s, 1H), 7.0 2(s,1H),6.25(d,J＝7.6Hz,1H),3.88(d,J＝7.0Hz,2H),1.28-1.17(m,1H),0.57(d,J＝7.7Hz,2H),0.31(d,J＝4.6Hz,2H)

Example 3: Preparation of compound GDI15-6491

1) Synthesis steps of compound 6

Compound 5 (230 mg, 419 μmol, 1 eq) was dissolved in NMP (4.6 mL), and 1-decyl mercaptan (365 mg, 2.10 mmol, 5 eq) and K ₂ CO ₃ (116 mg, 839 μmol, 2 eq) were added in sequence at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was completed by LCMS. Water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (2 mL*3). The product was in the aqueous phase. The aqueous phase was freeze-dried and washed and filtered with (DCM/MeOH, 10/1, 50 mL). The filtrate was concentrated under reduced pressure and purified by silica gel plate to obtain the target product 6 (210 mg, 393 μmol, 93.7% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 478.1.

2) Synthesis steps of compound GDI15-6491

Compound 6 (210 mg, 393 μmol, 1 eq) was dissolved in HCl/dioxane (4 M, 4.2 mL) and stirred at 25°C for 2 hours. The reaction was completed by LCMS. The reaction solution was dried under reduced pressure and purified by HPLC (column: 2_Phenomenex Gemini C18 75*40 mm*3 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-40% B in 8.0 min) to obtain the target compound GDI15-6491 (190 mg, crude, 2HCl) as a white solid. ESI-MS: [M+H] ⁺ , 434.0.

1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.32 (s, 1H), 8.12 (d, J = 7.8Hz, 1H), 7.71-7.63 (m, 4H), 7.14 (t ,J＝1.7Hz,1H),7.09(t,J＝2.0Hz,1H),7.04(s,1H),6.24(d,J＝7.6Hz,1H),3.91(s,2H),0.56(s,4H)

Example 4: Preparation of compound GDI15-6450

1) Synthesis steps of compound 7

Compound 6 (80 mg, 165 μmol, 1 eq) was dissolved in DCM (1.6 mL). Then TEA (50.1 mg, 495 μmol, 69.0 μL, 3 eq) and TFAA (41.6 mg, 198 μmol, 27.6 μL, 1.2 eq) were added in sequence at 0 °C. Under nitrogen protection, the reaction was carried out at 0 °C for 2 hours, and the reaction was completed by LCMS. Water (2 mL) was added to the reaction solution, and it was extracted with DCM (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate separation (PE/EtOAc, 10/1) to obtain the target compound 7 (70 mg, 129 μmol, 77.9% yield) as a white solid. ESI-MS: [M+H] ⁺ , 544.0.

2) Synthesis steps of compound GDI15-6450

Compound 7 (50 mg, 91.9 μmol, 1 eq) was dissolved in DMF (1.0 mL), and then LiCl (19.5 mg, 460 μmol, 9.42 μL, 5 eq) and TsOH (79.2 mg, 460 μmol, 5 eq) were added in sequence at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was decompressed and dried, and purified by preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 20%-50% B in 8 min) to obtain the target product GDI15-6450 (4.5 mg, 8.49 μmol, 9.24% yield) as a white solid. ESI-MS: [M+H] ⁺ , 530.0.

¹ H NMR (400MHz, DMSO) δ11.14-10.43(m,1H),9.90(s,1H),9.24(s,1H),8.32(s,1H),8.13(d,J＝8.0Hz,1H),7. 75-7.57(m,4H),7.17(s,1H),7.04(d,J＝13.1Hz,2H),6.26(d,J＝7.6Hz,1H),4.12(s,2H),0.97-0.86(m,4H)

Example 5: Preparation of compound GDI15-6405

1) Synthesis steps of compound 10

Compound 6 (80 mg, 165 μmol, 1 eq) was dissolved in DCM (1.6 mL). Then TEA (50.1 mg, 496 μmol, 68.9 μL, 3 eq) and compound 9 (30.2 mg, 215 μmol, 1.3 eq) were added at 0°C. Under nitrogen protection, the reaction was carried out at 0°C for 2 hours. The reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, and it was extracted with DCM (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. Purification by silica gel plate (DCM/MeOH, 10/1) gave the target compound 10 (40 mg, 72.5 μmol, 43.9% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 552.2.

2) Synthesis steps of compound GDI15-6405

Compound 10 (40 mg, 72.5 μmol, 1 eq) was dissolved in NMP (1.0 mL). Then K ₂ CO ₃ (20 mg, 144.9 μmol, 2 eq) and 1-decanethiol (63.2 mg, 362.3 μmol, 5 eq) were added at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B, in 8 min) to obtain the target product GDI15-6405 (30.8 mg, 57.3 μmol, 79.0% yield, 100% purity) as a white solid. ESI-MS: [M+H] ⁺ ,538.2.

¹ H NMR (400MHz, DMSO) δ8.19(s,1H),8.03(s,1H),7.74(d,J＝6.6Hz,3H),7.60-7.53(m,2H),7.51-7.45(m,1H),7.42-7.37(m,2 H),7.30(s,2H),7.27(s,1H),7.01(s,2H),6.90(d,J＝1.8Hz,2H),6.24(d,J＝7.6Hz,1H),4.13(s,2H),1.01(d,J＝8.4Hz,4H).

Example 6: Preparation of compound GDI15-6490

1) Synthesis steps of compound 12

Compound GDI15-6491 (150 mg, 318 μmol, 1 eq, HCl) was dissolved in MeCN (2.7 mL) and DMF (0.3 mL), and then compound 8 (88.1 mg, 350 μmol, 1.1 eq), HATU (121 mg, 318 μmol, 1.1 eq) and DIEA (123 mg, 956 μmol, 166 μL, 3 eq). Under nitrogen protection, the reaction was carried out at 25 ° C for 2 hours. LCMS detected that the reaction was complete. Water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate (EtOAc/MeOH, 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.51) to obtain the target compound 12 (100 mg, 149 μmol, 47.0% yield) as a white solid. ESI-MS: [M+H] ⁺ , 667.3.

2) Synthesis steps of compound GDI15-6490

Compound 12 (100 mg, 149 μmol, 1 eq) was dissolved in HCl/dioxane (4 M, 2 mL) and stirred at 25°C for 2 hours. The reaction was completed by LCMS. The reaction solution was dried under reduced pressure and purified by HPLC (column: 2_Phenomenex Gemini C18 75*40 mm*3 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-6490 (14.7 mg, 25.9 μmol, 17.3% yield) as a white solid. ESI-MS: [M+H] ⁺ , 567.0.

¹ H NMR (400MHz, DMSO) δ9.23(s,1H),8.52(s,1H),8.33(s,1H),8.12(d,J＝7.9Hz,1H),7.72-7.63(m,4H),7.32(d,J＝7.2Hz,2H),7.24-7 .13(m,4H),6.97(s,1H),6.93(s,1H),6.23(d,J=7.5Hz,1H),4.29(s,1H),4.10-3.99(m,2H),0.86-0.78(m,2H),0.76-0.64(m,2H).

Example 7: Preparation of compound GDI15-6403

1) Synthesis steps of compound 12

Compound 6 (100 mg, 206 μmol, 1 eq, HCl) was dissolved in MeCN (1.80 mL) and DMF (0.20 mL), and compound 11 (34.5 mg, 227 μmol, 1.1 eq) was added, cooled to 0°C, and HATU (86.3 mg, 227 μmol, 1.1 eq) and DIEA (80.0 mg, 619 μmol, 107.8 μL, 3 eq) were added respectively. Under nitrogen protection, the reaction was stirred at 25°C for 16 hours, and the reaction was completed by LCMS detection. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying. The target compound 12 (80 mg, 137 μmol, 66.5% yield) was obtained as a white solid by column chromatography (PE/EtOAc, 5/1) (TLC, PE/EtOAc, 5/1, R _f = 0.51). ESI-MS: [M+H] ⁺ , 582.1.

2) Synthesis steps of compound GDI15-6403

Compound 12 (80 mg, 137 μmol, 1 eq) was dissolved in NMP (1.6 mL), and 1-decanethiol (119 mg, 687 μmol, 5 eq) and K ₂ CO ₃ (37.9 mg, 274 μmol, 2 eq) were added in sequence at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B, in 8 min) to obtain the target product GDI15-6403 (26.8 mg, 47.1 μmol, 34.3% yield, 100% purity) as a white solid. ESI-MS: [M+H] ⁺ , 568.1.

¹ H NMR (400MHz, DMSO) δ10.84(s,1H),9.28(s,1H),8.35(s,1H),8.29(s,1H),8.20-8.11(m,1H),7.75-7.65(m,4 H),7.34(d,J＝7.7Hz,2H),7.27-7.17(m,3H),7.15(t,J＝1.7Hz,1H),7.01(t,J＝2.0Hz,1H),6.96(s,1H),6.28 (d,J＝7.7Hz,1H),6.03(s,1H),4.84(s,1H),4.09-4.01(m,2H),0.85-0.71(m,4H).

Example 8: Preparation of compound GDI15-6290

The crude product was purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 10%-50%, 8min) to obtain the target product GDI15-6290 (1.10 mg, 2.15μmol, 5.50 yield) as a yellow solid. ESI-MS: [M+H]+, 512.2.

¹ H NMR (400MHz, DMSO) δ9.27(s,1H),8.35(s,1H),8.15(d,J＝8.0Hz,1H),7.81(s,1H),7.73-7.65(m,4H),7.19(s,1H ),7.13-7.07(m,2H),6.29(d,J＝7.7Hz,1H),4.08(s,2H),2.97(s,3H),1.00(t,J＝6.06,2H),0.85(t,J＝5.74,2H).

Example 9: Preparation of compound GDI15-6452

Compound GDI15-5903 (20 mg, 49.0 μmol, 1 eq) was dissolved in DCM (1.0 mL). TEA (9.92 mg, 98.1 μmol, 13.6 μL, 2 eq) and acetic anhydride (5.01 mg, 49.0 μmol, 1 eq) were then added in sequence at 0°C. The mixture was reacted at 0°C for 2 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. The target product GDI15-6452 (14.2 mg, 30.9 μmol, 63.0% yield, 97.9% purity) was obtained as a yellow solid by purification by high performance liquid chromatography (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (FA)-ACN]; gradient: 1%-35% B in 8 min). ESI-MS: [M+H] ⁺ , 450.1.

1H NMR (400MHz, DMSO) δ1.81 (s, 3H) 2.50 (s, 13H) 3.39-3.40 (m, 2H) 4.05 (t, J = 5.57Hz, 2H) 6.26 (d,J＝7.63Hz,1H)7.02-7.18(m,3H)7.62-7.73(m,4H)8.05-8.16(m,2H)8.33(s,1H)9.24(s,1H)

Example 10: Preparation of compound GDI15-5944

1) Synthesis steps of compound GDI15-5944

Compound GDI15-5903 (20.0 mg, 49.0 μmol, 1 eq) was dissolved in DCM (1.0 mL). Then TEA (12.4 mg, 122.6 μmol, 17.1 Μ, 2.5 eq) and Boc ₂ O (13.9 mg, 63.7 μmol, 14.7 μL, 1.3 eq) were added dropwise at 0°C. The mixture was reacted at 25°C for 16 hours, and the reaction was completed by LCMS. Water (5 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. The target product GDI15-5944 (2 mg, 3.94 μmol, 8.0% yield) was obtained as a white solid by purification on a silica gel plate (PE/EtOAc, 0/1). ESI-MS: [M+H] ⁺ , 508.1.

^1H NMR (400MHz, DMSO) δ1.39 (s, 9H) 3.29-3.30 (m, 2H) 4.03 (t, J = 5.26Hz, 2H) 6.04-6.12 (m, 1H) 7.03 (d, J = 11. 61Hz,3H)7.14(s,1H)7.50-7.58(m,1H)7.61-7.73(m,3H)8.10(d,J=8.19Hz,1H)8.32(s,1H)9.18(s,1H).

Example 11: Preparation of compound GDI15-6383

1) Synthesis steps of compound 2

Compound 1 (100 mg, 218 μmol, 1 eq) was dissolved in DCM (2 mL). Then TEA (66.2 mg, 655 μmol, 91.1 μL, 3 eq) and trifluoroacetic anhydride (55.0 mg, 261 μmol, 36.4 μL, 1.2 eq) were added dropwise at 0 °C. The mixture was reacted at 0 °C for 2 hours under nitrogen protection. The reaction was completed by LCMS. The reaction mixture was poured into 5 mL of ice water, and the organic phase was extracted with DCM (2 mL*3). The organic phase was decompressed and dried by spin drying. The target compound 2 (70 mg, 135 μmol, 62.0% yield) was obtained by separation and purification on a silica gel plate (DCM/MeOH, 10/1) (TLC, DCM/MeOH, 10/1, R _f = 0.45, 0.55) as a white solid. ESI-MS: [M+H] ⁺ , 518.1.

2) Synthesis steps of compound GDI15-6383

Compound 2 (25 mg, 48.3 μmol, 1 eq) was dissolved in DMF (1.0 mL). LiCl (10.2 mg, 241 μmol, 4.95 μL, 5 eq) and TsOH (41.6 mg, 241 μmol, 5 eq) were then added at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was dried under reduced pressure and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 15%-55% B, within 8 min) and SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: [CO ₂ -MeOH (0.1% NH ₃ H ₂ O)]; B%: 50%-50%, 9 min) to obtain the target product GDI15-6383 (2.9 mg, 5.76μmol, 9.67% yield) as a white solid. ESI-MS: [M+H] ⁺ , 562.1.

^1H NMR (400MHz, DMSO) δ9.67(t,J＝5.1Hz,1H),9.23(s,1H),8.32(s,1H),8.12(d,J＝7.9Hz,1H),7.79-7.52(m,4H),7.18(t, J＝1.8Hz,1H),7.09(t,J＝2.1Hz,1H),7.06-7.04(m,1H),6.24(d,J＝7.6Hz,1H),4.16(t,J＝5.4Hz,2H),3.59-3.55(m,2H).

Example 12: Preparation of compound GDI15-6337

1) Synthesis steps of compound 5

Compound 4 (50 mg, 95.7 μmol, 1 eq) was dissolved in HCl/dioxane (4 M, 1 mL). The reaction was stirred at 25°C for 1 hour. LCMS detected that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the target compound 5 (43 mg, 93.8 μmol, 97.9% yield, HCl) as a yellow oil. ESI-MS: [M+H] ⁺ , 422.1.

2) Synthesis steps of compound 7

Compound 5 (43 mg, 93.8 μmol, 1 eq, HCl) was dissolved in DCM (0.86 mL), and TEA (28.4 mg, 281 μmol, 39.1 μL, 3 eq) and compound 6 (19.7 mg, 140 μmol, 16.3 μL, 1.5 eq) were added in sequence at 0 °C. The reaction was stirred at 0 °C for 2 hours, and the reaction was completed by LCMS. Ice water (5 mL) was poured into the reaction solution, and it was extracted with ethyl acetate (2 mL*3). The organic phases were combined, and the combined organic phases were washed with 5 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to obtain a crude product. Methanol (1 mL) was added to the crude product to dissolve it, and potassium carbonate (25.9 mg, 188 μmol, 2 eq) was added, and the reaction was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel plate purification method (EtOAc/MeOH, 5/1) to obtain the target compound 7 (25 mg, 47.5 μmol, 50.6% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 526.2.

3) Preparation of compound GDI15-6337

Compound 7 (25 mg, 47.5 μmol, 1 eq) was dissolved in NMP (1 mL), and 1-decyl mercaptan (41.4 mg, 237 μmol, 5 eq) and K ₂ CO ₃ (13.1 mg, 95.0 μmol, 2 eq) were added in sequence at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 26%-56%, 8 min) to obtain the target product GDI15-6337 (8.8 mg, 17.1 μmol, 36.1% yield, 100% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 512.2.

^1H NMR (400MHz, DMSO) δ9.24(s,1H),8.76-8.62(m,1H),8.33(s,1H),8.13(d,J＝7.6Hz,1H),7.85(d,J＝7.1Hz,2H),7.75-7.60(m,4H),7.58-7 .49(m,1H),7.49-7.38(m,2H),7.16(s,1H),7.13(s,1H),7.08(s,1H),6.25(d,J＝7.6Hz,1H),4.20(t,J＝5.1Hz,2H),3.63(d,J＝5.3Hz,2H).

Example 13: Preparation of compound GDI15-6349

1) Synthesis steps of compound 4

Compound 1 (100 mg, 218.2 μmol, 1 eq) was dissolved in DCM (2.0 mL), and then TEA (66.2 mg, 655 μmol, 91.1 μL, 3 eq) and compound 3 (43.9 mg, 284 μmol, 1.3 eq) were added in sequence at 0°C. The mixture was reacted at 0°C for 2 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, and it was extracted with DCM (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying, and separated and purified by silica gel plate (DCM/MeOH, 10/1) (TLC, DCM/MeOH, 10/1, R _f =0.6) to give the target compound 4 (70 mg, 130 μmol, 59.4% yield) as a white solid. ESI-MS: [M+H] ⁺ , 540.2.

2) Preparation of compound GDI15-6349

Compound 4 (70 mg, 130 μmol, 1 eq) was dissolved in NMP (1.0 mL), and then K ₂ CO ₃ (35.8 mg, 259 μmol, 2 eq) and 1-decanethiol (113 mg, 648 μmol, 5 eq) were added at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B, in 8 min) to obtain the target product GDI15-6349 (20.4 mg, 38.8 μmol, 29.2% yield, 97.3% purity) as a white solid. ESI-MS: [M+H] ⁺ , 526.2.

^1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.35-8.27 (m, 2H), 8.13 (d, J = 7.8Hz, 1H), 7.73-7.63 (m, 4H), 7.28-7.16 (m ,6H),7.10-7.01(m,2H),6.26(d,J＝7.7Hz,1H),4.06(t,J＝5.4Hz,2H),3.44-3.40(m,4H),2.52-2.48(m,5H).

Example 14: Preparation of compound GDI15-6335

1) Synthesis steps of compound 2

Compound GDI15-5903 (70 mg, 171 μmol, 1 eq) and compound 1 (47.4 mg, 188 μmol, 1.1 eq) were dissolved in DMF (0.14 mL) and CH ₃ CN (1.26 mL), and then added at 0° C. HATU (71.7 mg, 188 μmol, 1.1 eq) and DIEA (66.5 mg, 514 μmol, 89.6 μL, 3 eq). Under nitrogen protection, the reaction was stirred at 25 °C for 16 hours. The reaction was completed by LCMS. The reaction mixture was poured into 10 mL of ice water and extracted with ethyl acetate (2 mL*3). The target compound 2 (80 mg, 124 μmol, 72.7% yield) was obtained by concentration under reduced pressure as a yellow oil. ESI-MS: [M+H] ⁺ , 641.2.

2) Preparation of compound GDI15-6335

Compound 2 (0.08 g, 124 μmol, 1 eq) was dissolved in HCl/dioxane (4 M, 1.6 mL). The reaction was stirred at 25°C for 1 hour. The reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 25%-55%, 8 min) to obtain the target compound GDI15-6335 (39.9 mg, 73.7 μmol, 59.1% yield, 100% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 541.2.

^1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.38 (t, J = 5.6Hz, 1H), 8.33 (s, 1H), 8.13 (d, J＝7.8Hz,1H),7.73-7.62(m,4H),7.39(d,J＝7.1Hz,2H),7.32-7.25(m,2H),7.2 5-7.20(m,1H),7.19-7.14(m,1H),7.05(t,J＝2.0Hz,1H),6.99(t,J＝1.9Hz,1H) ,6.26(d,J＝7.8Hz,1H),4.45(s,1H),4.06(t,J＝5.4Hz,2H),3.47-3.42(m,2H).

Example 15: Preparation of compound GDI15-6341

1) Preparation of compound GDI15-6341

Compound GDI15-5903 (70 mg, 171 μmol, 1 eq) and TEA (52.1 mg, 514 μmol, 71.6 μL, 3 eq) were dissolved in DCM (1.4 mL), and MsCl (120 mg, 1.05 mmol, 81.0 μL, 6.1 eq) was added under stirring at 0°C. The reaction was stirred at 0°C for 2 hours, and the reaction was completed by LCMS. Ice water (10 mL) was poured into the reaction solution, and it was extracted with ethyl acetate (2 mL*3). The organic phases were combined, and the combined organic phases were washed with 5 mL of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and dried under reduced pressure to obtain a crude product. Methanol (1.4 mL) was added to the crude product to dissolve it, and K ₂ CO ₃ (47.4 mg, 343 μmol, 2 eq) was added, and the reaction was stirred at 25°C for 1 hour. The reaction solution was dried by spin drying and purified by HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 10%-40%, 8min) to obtain the target compound GDI15-6341 (1.8 mg, 3.67μmol, 11.4% yield, 98.9% purity) as a white solid. ESI-MS: [M+H] ⁺ , 486.1.

^1H NMR (400MHz, DMSO) δ10.84(s,1H),9.25(s,1H),8.33(s,1H),8.14(d,J＝9.1Hz,1H),7.76-7.69(m,2H),7.69-7.63(m,2H),7.31(t,J＝ 6.0Hz,1H),7.21-7.16(m,1H),7.10(d,J＝19.0Hz,2H),6.28(d,J＝7.6Hz,1H),4.10(t,J＝5.1Hz,2H),3.33-3.30(m,2H),2.94(s,3H).

Example 16: Preparation of compound GDI15-6348

1) Synthesis steps of compound 2

Compound 1 (100 mg, 218.2 μmol, 1 eq) was dissolved in DCM (2.0 mL). Then TEA (66.2 mg, 655 μmol, 91.1 μL, 3 eq) and TosCl (54.1 mg, 284 μmol, 1.3 eq) were added at 0 °C. The mixture was reacted at 0 °C for 2 hours under nitrogen protection. The reaction was completed by LCMS. Water (2 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried under reduced pressure, and separated and purified by silica gel plate (DCM/MeOH, 10/1) (TLC, DCM/MeOH, 10/1, R _f =0.6) to give the target compound 2 (40 mg, 69.4 μmol, 31.8% yield) as a white solid. ESI-MS: [M+H] ⁺ , 576.1.

2) Preparation of compound GDI15-6348

Compound 2 (40 mg, 69.4 μmol, 1 eq) was dissolved in NMP (1.0 mL), and then K ₂ CO ₃ (19.2 mg, 139 μmol, 2 eq) and 1-decanethiol (60.5 mg, 347 μmol, 5 eq) were added at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B, in 8 min) to obtain the target product GDI15-6348 (17 mg, 30.3 μmol, 43.6% yield, 97.0% purity) as a white solid. ESI-MS: [M+H] ⁺ , 562.1.

^1H NMR (400MHz, DMSO) δ9.25 (s, 1H), 8.33 (s, 1H), 8.19-8.09 (m, 1H), 7.86 (t, J = 5.7Hz, 1H), 7.72-7.64 (m, 6H), 7.35 (d, J = 8.1Hz, 2H), 7. 16(t,J＝1.6Hz,1H),6.94-6.89(m,2H),6.29(d,J＝7.7Hz,1H),3.99(t,J＝5.3Hz,2H),3.13(q,J＝5.3Hz,2H),2.50(s,12H),2.35(s,3H)

Example 17: Preparation of compound GDI15-6351

1) Synthesis steps of compound 3

Compound 1 (1.0 g, 4.82 mmol, 1 eq) was dissolved in DMF (10.0 mL), and then compound 2 (1.19 g, 5.78 mmol, 1.1 eq) and K ₂ CO ₃ (1.67 g, 12.1 mmol, 2.5 eq) were added in sequence at 25°C. The mixture was reacted at 25°C for 16 hours under nitrogen protection. The reaction was completed when detected by LCMS. Add water (10 mL), extract with ethyl acetate (5 mL*3), combine the organic phases, wash with 15 mL saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, filter under reduced pressure and spin dry to obtain the target compound 3 (3 g, 9.04 mmol, crude product) as a colorless oil.

2) Synthesis steps of compound 4

Compound Int I (100 mg, 396 μmol, 1 eq) was dissolved in DMF (1.0 mL), and then compound 3 (229 mg, 476 μmol, 1.2 eq, 69% purity), Cs ₂ CO ₃ (388 mg, 1.19 mmol, 3 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (56.4 mg, 396 μmol, 1 eq) and CuI (37.8 mg, 198 μmol, 0.5 eq) were added in sequence at 25° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying, and separated and purified by silica gel plate (EtOAc/MeOH, 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.6) to obtain the target compound 4 (80 mg, 159 μmol, 40.1% yield) as a brown oil. ESI-MS: [M+H] ⁺ , 503.1.

3) Preparation of compound GDI15-6351

Compound 4 (80 mg, 159 μmol, 1 eq) was dissolved in NMP (2.0 mL), and then K ₂ CO ₃ (43.9 mg, 318 μmol, 2 eq) and 1-decanethiol (138.5 mg, 795 μmol, 5 eq) were added in sequence at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection. The reaction was completed when LCMS was performed. The reaction solution was filtered at normal pressure and analyzed by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 35%-75% B, in 8 min) to give the target product GDI15-6351 (50.0 mg, 102 μmol, 64.3% yield, 94.0% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 489.1.

^1H NMR (400MHz, DMSO) δ8.72 (s, 1H), 8.64 (s, 1H), 8.54 (d, J = 5.3Hz, 1H), 8.04-7.96 (m, 2 H),7.34(s,1H),7.17(d,J＝7.1Hz,1H),6.53(d,J＝11.8Hz,1H),6.31(d,J＝7.4Hz,1H) ,5.87(d,J＝3.3Hz,1H),5.76(s,2H),4.34(s,1H),4.25(s,1H),2.69(d,J＝7.5Hz,1H) ,2.33(d,J＝2.4Hz,1H),1.43(d,J＝8.0Hz,2H),1.34(s,9H),1.03(s,3H),0.87(s,3H).

Example 18: Preparation of compound GDI15-6352

1) Synthesis steps of compound 3

Compound 1 (1.0 g, 4.82 mmol, 1 eq) was dissolved in DMF (10.0 mL), and then compound 2 (1.09 g, 5.3 mmol, 1.1 eq) and K ₂ CO ₃ (1.67 g, 12.1 mmol, 2.5 eq) were added in sequence at 25°C. The mixture was reacted at 25°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phases were combined and washed with 15 ml of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 3 (2.4 g, 3.61 mmol, crude product) as a colorless oil.

2) Synthesis steps of compound 4

Compound Int I (100 mg, 396 μmol, 1 eq) was dissolved in DMF (2.0 mL), and then compound 3 (157 mg, 475 μmol, 1.2 eq), Cs ₂ CO ₃ (387 g, 1.19 mmol, 3 eq) were added in sequence at 25°C. (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (56.4 mg, 396 μmol, 1 eq) and CuI (37.8 mg, 198 μmol, 0.5 eq). Under nitrogen protection, the mixture was reacted at 100 °C for 16 hours. The reaction was completed by LCMS. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying. The target compound 4 (110 mg, 218 μmol, 55.1% yield) was obtained by separation and purification on a silica gel plate (EtOAc/MeOH, 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.48) as a brown oil. ESI-MS: [M+H] ⁺ , 503.1.

3) Preparation of compound GDI15-6352

Compound 4 (50 mg, 99.3 μmol, 1 eq) (two reactions in parallel) was dissolved in NMP (1.5 mL), and then K ₂ CO ₃ (27.4 mg, 198 μmol, 2 eq) and 1-decanethiol (86.5 mg, 496 μmol, 5 eq) were added in sequence at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B, in 8 min) to obtain the target product GDI15-6352 (50.1 mg, 101 μmol, 50.6% yield, 98.1% purity) as a yellow solid. ESI-MS: [M+H] ⁺ ,489.1.

^1H NMR (400MHz, DMSO) δ9.25 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 7.9Hz, 1H), 7.72-7.63 (m, 4 H),7.54(s,1H),7.43(s,3H),7.22-7.14(m,3H),6.27(d,J＝7.6Hz,1H),5.19(s,2H).

Example 19: Preparation of compound GDI15-5885

1) Synthesis steps of compound 3

Compound 1 (0.2 g, 968 μmol, 1 eq) was dissolved in DMF (2 mL), and then compound 2 (99.2 mg, 581 μmol, 69.0 μL, 0.6 eq) and CS ₂ CO ₃ (315 mg, 969 μmol, 1 eq) were added in sequence at 25°C. Under nitrogen protection, the mixture was reacted at 100°C for 16 hours. LCMS showed that 40% of compound 1 remained and 40% of compound 3 was generated. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 0/1) to obtain the target compound 3 (110 mg, 371 μmol, 38.3% yield) as a red oil. ESI-MS: [M+H]+, 295.2 & 297.9.

2) Synthesis steps of compound 5

Compound Int I (80 mg, 317 μmol, 1 eq) was dissolved in DMF (2.0 mL), and then compound 3 (110 mg, 371 μmol, 1.17 eq), Cs ₂ CO ₃ (310 mg, 951 μmol, 3 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (45.11 mg, 317.12 μmol, 1 eq) and CuI (30.2 mg, 159 μmol, 0.5 eq) were added in sequence at 25° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 3/1) to obtain the target compound 5 (110 mg, 235 μmol, 74.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 468.1.

3) Synthesis steps of compound GDI15-5885

Compound 5 (80 mg, 171 μmol, 1 eq) was dissolved in DMF (2 mL), and LiCl (36.2 mg, 855 μmol, 17.5 μL, 5 eq) and TsOH (147 mg, 855 μmol, 5 eq) were added in sequence at 25 °C. The reaction was stirred at 140 °C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B, in 8 min) to obtain the target product GDI15-5885 (0.022 g, 47.3 μmol, 27.7% yield, 98% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 454.1.

^1H NMR (400MHz, DMSO) δ10.79(s,1H),9.26(s,1H),8.32(s,1H),8.14(d,J＝7.9Hz,1H),7.74-7.65(m,2H),7.62(d,J＝7.7Hz,2H), 7.38-7.30(m,4H),7.28-7.22(m,1H),6.81(t,J＝5.7Hz,1H),6.65-6.57(m,3H),6.24(d,J＝7.6Hz,1H),4.30(d,J＝5.5Hz,2H).

Example 20: Preparation of compound GDI15-5915

1) Synthesis steps of compound 3

Compound 1 (0.3 g, 1.45 mmol, 1 eq) and compound 2 (164.7 mg, 871 μmol, 107 μL, 0.6 eq) were dissolved in DMF (3 ml). Then Cs ₂ CO ₃ (473 mg, 1.45 mmol, 1 eq) was added at 25°C. Under nitrogen protection, the reaction was carried out at 100°C for 16 hours. LCMS showed that 40% of the raw material 1 remained and 40% of the product 3 was generated. The reaction was complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and passed through a silica gel plate. The target compound 3 (160 mg, 508 μmol, 35.0% yield) was obtained by plate purification (PE/EtOAc, 0/1) as a white solid. ESI-MS: [M+H] ⁺ , 313.8.

2) Synthesis steps of compound 5

Compound Int I (153 mg, 610 μmol, 1.2 eq) was dissolved in DMF (3.2 mL), and then compound 3 (0.16 g, 508 μmol, 1 eq), Cs ₂ CO ₃ (497 mg, 1.53 mmol, 3 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (72.3 mg, 508 μmol, 1 eq) and CuI (48.4 mg, 254 μmol, 0.5 eq) were added in sequence at 25° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 0/1) to obtain the target compound 4 (150 mg, 309 μmol, 60.7% yield) as a white oil. ESI-MS: [M+H] ⁺ , 486.1.

3) Synthesis steps of compound GDI15-5915

Compound 5 (170 mg, 349 μmol, 1 eq) was dissolved in DMF (3.4 mL), and TsOH (301 mg, 1.75 mmol, 5 eq) and LiCl (74.1 mg, 1.75 mmol, 35.8 μL, 5 eq) were added. The mixture was reacted at 140 °C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and analyzed by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (FA)-ACN]; gradient: 20%- 45% B, in 8 min) to give the target product GDI15-5915 (33.7 mg, 71.4 μmol, 20.4% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 472.2.

¹ H NMR (400MHz, DMSO) δ9.25 (s, 1H), 8.32 (s, 1H), 8.14 (d, J = 7.5Hz, 1H), 7.76-7.58 (m, 4H), 7.39 (td, J = 7.9, 6.1Hz, 1H), 7.25-7. 14(m,2H),7.07(td,J＝8.7,2.7Hz,1H),6.86(t,J＝6.2Hz,1H),6.72-6.56(m,3H),6.25(d,J＝7.6Hz,1H),4.35(d,J＝6.0Hz,2H).

Example 21: Preparation of compound GDI15-5916

1) Synthesis steps of compound 3

Compound 1 (200 mg, 968 μmol, 1 eq) and compound 2 (119 mg, 581 μmol, 76.0 μL, 0.6 eq) were dissolved in DMF (2 mL), and then Cs ₂ CO ₃ (315 mg, 968 μmol, 1 eq) was added at 25°C. Under nitrogen protection, the reaction was carried out at 25°C for 16 hours. LCMS showed that 50% of the raw material 1 remained and 26% of the product 3 was generated. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 5/1) to obtain the target compound 3 (95 mg, 286 μmol, 29.6% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 331.8.

2) Synthesis steps of compound 5

Compound Int I (65 mg, 257 μmol, 1 eq) was dissolved in DMF (2.0 mL), and then compound 3 (95 mg, 286 μmol, 1.11 eq), Cs ₂ CO ₃ (251 mg, 772 μmol, 3 eq), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (36.6 mg, 257 μmol, 1 eq) and CuI (24.5 mg, 128μmol, 0.5eq). Under nitrogen protection, the reaction was carried out at 100°C for 16 hours. The reaction was completed by LCMS. Water (5mL) was added to the reaction solution, and it was extracted with ethyl acetate (2mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate (EtOAc) to obtain the target compound 5 (90mg, 179μmol, 69.5% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 502.1.

3) Synthesis steps of compound GDI15-5916

Compound 5 (90 mg, 179 μmol, 1 eq) was dissolved in DMF (0.9 mL), and TsOH (154 mg, 895 μmol, 5 eq) and LiCl (37.9 mg, 895 μmol, 18.3 μL, 5 eq) were added. The reaction was carried out at 140 °C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (FA)-ACN]; gradient: 25%-50% B, in 8 min) to obtain the target product GDI15-5916 (5 mg, 10.2 μmol, 5.72% yield) as a white solid. ESI-MS: [M+H] ⁺ , 488.0.

¹ H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.31 (s, 1H), 8.12 (d, J = 8.1Hz, 1H), 7.73-7.54 (m, 4H), 7.44-7. 25(m,4H),6.84(t,J＝6.1Hz,1H),6.69-6.55(m,3H),6.20(d,J＝7.4Hz,1H),4.33(d,J＝6.0Hz,2H).

Example 22: Preparation of compound GDI15-6339

1) Synthesis steps of compound 2

Compound 1 (1 g, 4.62 mmol, 1 eq) was dissolved in THF (20 mL), and BH ₃ .THF (1 M, 11.5 mL, 2.5 eq) was added dropwise at 0°C under nitrogen protection. The reaction was stirred at 65°C for 16 hours. LCMS The reaction was detected to be complete. The reaction solution was cooled, MeOH (10 mL) was added dropwise at 0°C, and then the reaction was stirred at 65°C for 2 hours. H ₂ O (10 mL) and HCl (3N) were then added to the reaction solution in sequence until pH = 2-3. The reaction solution was concentrated under reduced pressure to remove methanol, and then extracted with ethyl acetate (15 mL*2) to remove impurities. Sat.aq.Na ₂ CO ₃ (~6 mL) was added to the aqueous phase until pH = 8-9, extracted with ethyl acetate (15 mL*3), and the combined organic phases were washed with 20 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate and filtered under reduced pressure. HCl/dioxane (5 mL) was added to the filtrate, and the target compound 2 (0.45 g, 1.75 mmol, 37.9% yield, HCl) was obtained as a white solid by spin drying under reduced pressure. ESI-MS: [M+H] ⁺ , 220.0 & 222.0

2) Synthesis steps of compound 3

Compound 2 (153 mg, 595 μmol, 1.5 eq, HCl) and compound Int I (0.1 g, 396 μmol, 1 eq) were dissolved in DMF (3 mL), stirred at 20°C, and CuI (37.8 mg, 198 μmol, 0.5 eq), (1S, 2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (56.4 mg, 396 μmol, 1 eq) and Cs ₂ CO ₃ (517 mg, 1.59 mmol, 4 eq) were added in sequence. The mixture was stirred at 100°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. The reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (5 mL*6), the organic phases were combined and dried over anhydrous magnesium sulfate, dried under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 10%-40%, 10 min) to obtain the target compound 3 (0.056 g, 143μmol, 36.1% yield) as a light yellow solid. ESI-MS: [M+H] ⁺ , 392.1

3) Preparation of compound GDI15-6339

Compound 3 (56 mg, 142.9 μmol, 1 eq) was dissolved in 33% HBr/AcOH solution (2 mL) and stirred at 120°C for 16 hours. The reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 1%-30%, 10 min) to obtain the target compound GDI15-6339 (23.5 mg, 56.5 μmol, 39.5% yield, 90.8% purity) as a white solid. ESI-MS: [M+H] ⁺ , 378.0

¹ H NMR (400MHz, DMSO) δ9.19 (s, 1H), 8.31 (s, 1H), 8.09 (d, J = 7.9Hz, 1H), 7.68-7.65 (m, 2H), 7.64-7.60 (m, 1H), 7. 54(d,J＝7.7Hz,1H),7.45(d,J＝2.1Hz,2H),7.39(s,1H),6.16-6.16(m,1H),6.12(d,J＝7.7Hz,1H),3.82(s,2H).

Example 23: Preparation of compound GDI15-6332

1) Synthesis steps of compound 2

Compound 157-1 (180 mg, 571 μmol, 1.2 eq) and compound Int I (0.12 g, 476 μmol, 1 eq) were dissolved in DMF (1.8 mL), and CuI (45.3 mg, 238 μmol, 0.5 eq), (1S, 2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (67.7 mg, 476 μmol, 1 eq) and Cs ₂ CO ₃ (465 mg, 1.43 mmol, 3 eq) were added in sequence under stirring at 20° C. The mixture was stirred at 100° C. for 16 hours under nitrogen protection, and the reaction was completed after LCMS detection. The reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (5 mL*3), the organic phases were combined and dried over anhydrous magnesium sulfate, dried under reduced pressure, and purified by preparative plate (SiO ₂ , EtOAc/MeOH, 10/1) to obtain the target compound 2 (0.16 g, 329 μmol, 69.2% yield, 95.1% purity) as a white solid. ESI-MS: [M+H] ⁺ , 486.1

2) Synthesis steps of compound GDI15-6332

Compound 2 (0.08 g, 164 μmol, 1 eq, two reactions in parallel) was dissolved in NMP (1.6 mL), stirred at 25°C, and K ₂ CO ₃ (45.5 mg, 329 μmol, 2 eq) and 1-decanethiol (143 mg, 823 μmol, 5 eq) were added in sequence. The reaction was stirred at 140°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 10 min) to obtain the target compound GDI15-6332 (0.072 g, 153 μmol, 46.5% yield, 99% purity) as a white solid. ESI-MS: [M+H] ⁺ , 472.1

¹ H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.33 (s, 1H), 8.18-8.05 (m, 1H), 7.74-7.57 (m, 4H), 7.47 (t, J = 2.0Hz, 1H), 7.46-7.40 (m, 2H), 7.0 6(td,J＝8.1,7.0Hz,1H),6.67(t,J＝6.2Hz,1H),6.46-6.40(m,1H),6.38-6.26(m,2H),6.22(d,J＝7.7Hz,1H),4.33(d,J＝6.2Hz,2H).

Example 24: Preparation of Compound GDI15-6326

1) Synthesis steps of compound 2

Compound 1 (100 mg, 302 μmol, 1 eq) and compound Int I (91.5 mg, 362 μmol, 1.2 eq) were dissolved in DMF (1 mL), and Cs ₂ CO ₃ (295 mg, 906 μmol, 3 eq), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (42.9 mg, 302 μmol, 1 eq) and CuI (28.7 mg, 151μmol, 0.5eq). The reaction was stirred at 100°C for 16 hours. The reaction was completed by LCMS. Ice water (50mL) was poured into the reaction solution, extracted with ethyl acetate (20mL*3), the organic phases were combined, and washed with 50mL saturated sodium chloride. The washed organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate separation (PE/EA, 0/1) to obtain compound 2 (40mg, 79.6μmol, 26.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 503.3.

2) Preparation of compound GDI15-6326

Compound 2 (40 mg, 79.6 μmol, 1 eq) was dissolved in NMP (1 mL), and K ₂ CO ₃ (147 mg, 458 μmol, 1.1 eq) and 1-decanethiol (69.4 mg, 398 μmol, 5 eq) were added in sequence at 25°C. The mixture was stirred at 140°C for 16 hours, and the reaction was complete after LCMS detection. Ice water (5 mL) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (2 mL*3). The organic phases were combined and washed with 5 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate separation (PE/EA, 0/1) and SFC separation (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 36%-66%, 8min) to obtain the target product GDI15-6326 (8.40mg, 16.5μmol, 19.7% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 489.2.

¹ H NMR (400MHz, DMSO) δ10.84(s,1H),9.26(s,1H),8.34(s,1H),8.19-8.12(m,1H),7.77-7.62(m,4H),7.49(t,J＝2.0Hz,1H),7.48-7.40(m,2H), 7.06(t,J＝8.0Hz,2H), 6.66(t,J＝6.3Hz,1H), 6.61(t,J＝2.1Hz,1H), 6.54(dt,J＝8.1,2.6Hz,2H), 6.30(d,J＝7.6Hz,1H), 4.35(d,J＝6.2Hz,2H).

Example 25: Preparation of compound GDI15-5731

1) Synthesis steps of compound 2

At 0°C and _N2 , _BH3 /THF (191.74 mg, 13.86 mmol) was slowly added dropwise to a solution of 3-bromo-5-chlorobenzonitrile (1 g, 4.62 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at 25°C for 16 hours. After the reaction was completed, saturated _NaHCO3 solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL*3), dried over _{anhydrous Na2SO4} , and concentrated by vacuum filtration. Purification by silica gel chromatography gave (3-bromo-5-chloro-phenyl)methylamine (400 mg, 1.81 mmol, 39.27% yield) as an off-white solid.

2) Synthesis steps of compound 4

3-Bromo-5-chlorobenzylamine (380 mg, 1.72 mmol) and DIEA (245.01 mg, 1.90 mmol) were dissolved in DCM (5 mL). Acetyl chloride (148.81 mg, 1.90 mmol, 115.00 μL) was slowly added dropwise at 0 °C under N ₂ conditions. The reaction was stirred at room temperature for 6 hours. After the reaction was completed, saturated NaHCO ₃ solution was added dropwise, extracted with DCM (20 mL*3), dried over anhydrous Na ₂ SO ₄ , and concentrated by vacuum filtration. Purification by silica gel chromatography gave N-[(3-bromo-5-chloro-phenyl)methyl]acetamide (40 mg, 152.36 μmol, 8.84% yield) as a yellow oily liquid.

3) Synthesis steps of compound 5

3-(4-Isoquinolyl)-4-methoxy-1-pyridin-2-one (25 mg, 99.10 μmol) and N-[(3-bromo-5-chlorophenyl)methyl]acetamide (31.22 mg, 118.92 μmol) were dissolved in DMF (1 mL), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (2.82 mg, 19.82 μmol) and CuI (9.44 mg, 49.55 μmol) were added. and Cs ₂ CO ₃ (96.87 mg, 297.30 μmol), the reaction was stirred at 100 ° C for 8 hours. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (15 mL * 3), dried over anhydrous Na ₂ SO ₄ , and vacuum filtered and concentrated. Purification by silica gel chromatography gave N-[[3-chloro-5-[3-(4-isoquinolyl)-4-methoxy-2-oxo-1-pyridyl]phenyl]methyl]acetamide (14 mg, 32.27 μmol, 32.56% yield) as a yellow oily liquid.

4) Synthesis steps of compound GDI15-5731

N-[[3-chloro-5-[3-(4-isoquinolyl)-4-methoxy-2-oxy-1-pyridyl]phenyl]methyl]acetamide (14 mg, 32.27 μmol) was dissolved in DMF (1 mL), LiCl (13.68 mg, 322.67 μmol) and TsOH (16.81 mg, 322.67 μmol) were added, and the reaction was stirred at 140°C for 18 hours. The reaction was cooled to room temperature, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL*3), dried over anhydrous Na ₂ SO ₄ , and concentrated by vacuum filtration. Purify and filtrate the residue by silica gel chromatography to obtain N-[[3-chloro-5-[4-hydroxy-3-(4-isoquinolyl)-2-oxy-1-pyridyl]phenyl]methyl]acetamide (3.5 mg, 8.25 μmol, 25.58% yield, 99% purity) as an off-white solid.

¹ H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 8.12 (d, J = 8.0Hz, 1H), 7.66 (t, J = 8.5Hz, 4H), 7.46 (s, 1H), 7.31 (d, J = 15.4Hz, 2H), 6.25 (d, J = 7.7Hz, 1H), 4.29 (d, J = 5.9Hz, 2H), 1.88 (s, 3H).

Example 29: Preparation of Compound GDI15-5591

1) Synthesis steps of compound GDI15-5591

The crude product from GHDDI was purified by HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 20%-50% B, in 8 min) to obtain the target product GDI15-5591 (0.2 mg, 4.35e ^-1 μmol, 1.11% yield) as a white solid. ESI-MS: [M+H] ⁺ , 460.1.

¹ H NMR (400MHz, DMSO) δ9.18 (s, 1H), 8.32 (s, 1H), 8.09 (d, J = 8.9Hz, 1H), 7.73-7.56 (m, 4H), 7.40 (s, 2H), 7.35 (s, 1H), 3.76 (s, 2H),1.86-1.81(m,2H),1.69-1.64(m,2H),1.53(dt,J＝3.6,5.1Hz,1H),1.26-1.17(m,2H),1.15(s,2H),1.09-1.02(m,2H).

Example 27: Preparation of compound GDI15-6340

1) Synthesis steps of compound 2

Compound 1 (1.5 g, 6.51 mmol, 1 eq) was dissolved in THF (30 mL), and BH ₃ .THF (1 M, 16.3 mL, 2.5 eq) was added dropwise at 0°C under nitrogen protection. The reaction was stirred at 65°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was cooled, and MeOH (16 mL) was added dropwise at 0-5°C, and then stirred at 65°C for 2 hours. H ₂ O (16 mL) and HCl (3N) were added to the reaction solution in sequence until pH = 2-3. The reaction solution was concentrated under reduced pressure to remove methanol, and then extracted with ethyl acetate (20 mL*2) to remove impurities. Sat.aq.Na ₂ CO ₃ (~10 mL) was added to the aqueous phase until pH = 8-9, and extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with 30 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate and filtered under reduced pressure. HCl/dioxane (5 mL) was added to the filtrate, and the mixture was dried under reduced pressure to give the target compound 2 (0.6 g, 2.21 mmol, 34.0% yield, HCl) as a white solid. ESI-MS: [M+H] ⁺ , 234.0 & 236.0

2) Synthesis steps of compound 3

Compound 2 (215 mg, 793 μmol, 2 eq, HCl) and compound Int I (0.1 g, 396 μmol, 1 eq) were dissolved in DMF (4 mL), stirred at 20°C, and CuI (37.8 mg, 198 μmol, 0.5 eq), (1S, 2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (56.4 mg, 396 μmol, 1 eq) and Cs ₂ CO ₃ (517 mg, 1.59 mmol, 4 eq) were added in sequence. The mixture was stirred at 100°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. The reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (5 mL*6), the organic phases were combined and dried over anhydrous magnesium sulfate, dried under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 15%-45%, 10 min) to obtain the target compound 4 (70 mg, 172μmol, 43.5% yield) as a light yellow solid. ESI-MS: [M+H] ⁺ , 406.2.

3) Synthesis steps of compound GDI15-6340

Compound 3 (70 mg, 172 μmol, 1 eq) was dissolved in 33% HBr/AcOH solution (2 mL) and stirred at 120°C for 16 hours. The reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 1%-30%, 10 min) to obtain the target compound GDI15-6340 (24.5 mg, 61.8 μmol, 35.9% yield, 98.9% purity) as a white solid. ESI-MS: [M+H] ⁺ , 392.0.

¹ H NMR (400MHz, DMSO) δ9.14 (s, 1H), 8.30 (s, 1H), 8.06 (d, J = 7.7Hz, 1H), 7.72-7.66 (m, 1H), 7.65 (d, J = 1.3Hz, 2H), 7.48 (d, J = 7.7Hz, 1H), 7.41 (t, J =1.8Hz,1H),7.27(d,J＝14.4Hz,2H),5.99(d,J＝7.7Hz,1H),2.94-2.86(m,2H),2.81-2.71(m,2H).

Example 28: Preparation of compound GDI15-5736

1) Synthesis steps of compound 3C-2

Compound 3C-1 (1.00 g, 4.34 mmol, 1 eq) was dissolved in ethanol (20 mL), and then CoCl ₂ .6H ₂ O (2.06 g, 8.68 mmol, 2 eq) and NaBH ₄ (340 mg, 8.99 mmol, 2.07 eq) were added in sequence at 0°C. The mixture was reacted at 25°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was poured into ice water (50 ml) in batches and extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. Ethyl acetate (10 mL) was added to the crude product, and HCI/EtOAc (3 mL) was added dropwise under stirring, and stirred for 10 minutes. The target compound 3C-2 (1 g, 3.69 mmol, 85.1% yield, HCl) was obtained by filtration as a white solid.

2) Synthesis steps of compound 3C

Compound 3C-2 (400 mg, 1.48 mmol, 1 eq, HCl) was dissolved in methanol (4 mL) and acetic acid (0.4 mL), then paraformaldehyde (177 mg, 5.90 mmol, 162 μL, 4 eq) was added at 25°C, stirred for 1 hour, and then NaBH ₃ CN (250 mg, 3.99 mmol, 2.7 eq) was added. The reaction was carried out at 25°C for 15 hours, and the reaction was completed by LCMS. Water (10 mL) was added to the reaction solution, and extracted with ethyl acetate (5 mL*3). The organic phases were combined and washed with 5 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 3C (300 mg, 1.14 mmol, 77.4% yield) as a yellow oil.

3) Synthesis steps of compound 7

Compound Int I (150 mg, 594 μmol, 1 eq) was dissolved in DMF (3 mL), and then compound 3 (234 mg, 891 μmol, 1.5 eq), Cs ₂ CO ₃ (581 mg, 1.78 mmol, 3 eq), (1S, 2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84.4 mg, 594 μmol, 1 eq) and CuI (56.6 mg, 297 μmol, 0.5 eq) were added in sequence at 25° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (20 mL) was added to the reaction solution, and the mixture was extracted and combined with ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying, and purified by silica gel plate separation (SiO ₂ , PE/EtOAc, 0/1) to obtain the target compound 7 (60.0 mg, 138 μmol, 23.3% yield) as a red oil. ESI-MS: [M+H] ⁺ , 434.1.

4) Synthesis steps of compound GDI15-5736

Compound 7 (60.0 mg, 138 μmol, 1 eq) was dissolved in HBr/AcOH (10 V, 33% purity). The reaction was carried out at 120°C for 16 hours. The reaction was completed by LCMS. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography (column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (FA)-ACN]; B%: 1%-30%, 8 min) to obtain the target compound GDI15-5736 (3.4 mg, 8.10 μmol, 5.86% yield, 100% purity) as a white solid. ESI-MS: [M+H] ⁺ , 420.1.

^1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.32 (s, 1H), 8.13 (d, J = 7.8Hz, 1H), 7.74-7.62 (m, 4H), 7.41 (s, 1H) ),7.38(s,1H),7.31(s,1H),6.27(d,J＝7.6Hz,1H),2.77(t,J＝7.6Hz,2H),2.53(s,2H),2.18(s,6H).

Example 29: Preparation of compound GDI15-5737

1) Synthesis steps of compound 3D

Compound 3C-2 (400 mg, 1.48 mmol, 1 eq, HCl) was dissolved in DCM (1.3 mL) and pyridine (2.6 mL), and then acetyl chloride (79.7 mg, 1.01 mmol, 72.4 μL, 1.1 eq) was added dropwise at 0°C, and reacted at 25°C for 3 hours. The reaction was completed by LCMS. Water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to obtain the target compound 3D (200 mg, 723 μmol, 78.4% yield) as a yellow oil.

2) Synthesis steps of compound 7

Compound Int I (150 mg, 594 μmol, 1 eq) was dissolved in DMF (3 mL), and then compound 3 (328 mg, 1.19 mmol, 2 eq), Cs ₂ CO ₃ (581 mg, 1.78 mmol, 3 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (84.4 mg, 594 μmol, 1 eq) and CuI (56.6 mg, 297 μmol, 0.5 eq) were added in sequence at 25° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying, and purified by silica gel plate separation (SiO ₂ , PE/EtOAc, 0/1) to obtain the target compound 7 (150 mg, 334 μmol, 56.3% yield) as a green solid. ESI-MS: [M+H] ⁺ , 448.1.

3) Synthesis steps of compound GDI15-5737

Compound 7 (60.0 mg, 133 μmol, 1 eq) was dissolved in HBr/AcOH (10 V, 33% purity). The reaction was carried out at 120°C for 16 hours. The reaction was completed by LCMS. The reaction solution was dried under reduced pressure and purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 1%-35%, 8 min) to obtain the target compound GDI15-5737 (13.3 mg, 29.3 μmol, 21.9% yield, 95.6% purity) as a white solid. ESI-MS: [M+H] ⁺ , 420.1.

¹ H NMR (400MHz, DMSO) δ11.54-10.31(m,1H),9.59-8.99(m,1H),8.62-8.21(m,1H),8.14(d,J＝8.1Hz,1H),7.93(t,J＝5.3Hz,1H),7.74-7. 62(m,4H),7.47-7.42(m,1H),7.35(s,1H),7.29(s,1H),6.29(d,J＝7.6Hz,1H),3.29-3.27(m,2H),2.76(t,J＝7.1Hz,2H),1.77(s,3H).

Example 30: Preparation of compound GDI15-6288

1) Synthesis steps of compound 2

Compound 1 (20 g, 92.3 mmol, 1 eq) was dissolved in EtOH (400 mL), and CoCl ₂ .6H ₂ O (43.9 g, 184 mmol, 2 eq) and NaBH ₄ (8.74 g, 230 mmol, 2.5 eq) were added in sequence under stirring at 0°C, and the mixture was stirred at 25°C for 4 hours. The reaction was completed by LCMS. The reaction solution was poured into ice water (1 L), extracted with ethyl acetate (300 mL*3), and the combined organic phase was washed with 1 L saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, and HCL-EtOAc (5 mL) was added during the process of vacuum drying. Solid precipitation was observed, and the solid was filtered, and the filter cake was washed with ethyl acetate. The filter cake was purified by vacuum drying to obtain the desired compound. The target compound 2 (4.8 g, 18.6 mmol, 20.2% yield, HCl) was a white solid. ESI-MS: [M+H] ⁺ , 219.9 & 221.9.

2) Synthesis steps of compound 3

Compound 2 (4.8 g, 18.6 mmol, 1 eq, HCl) was dissolved in DCM (130 mL), and TEA (4.73 g, 46.7 mmol, 6.50 mL, 2.5 eq) and Boc ₂ O (5.30 g, 24.2 mmol, 5.58 mL, 1.3 eq) were added in sequence under stirring, and the mixture was stirred at 25°C for 16 hours. The reaction was completed as detected by LCMS and TLC (PE/EtOAc, 5/1, R _f = 0.57). Ice water (200 mL) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (70 mL*3), and the combined organic phases were washed with 300 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by column chromatography (SiO ₂ , PE/EtOAc, 100/1 to 5/1) to obtain the target compound 3 (2.95 g, 9.20 mmol, 49.2% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 304.9 & 306.9.

3) Synthesis steps of compound 4

Compound 3 (152 mg, 475 μmol, 1.2 eq) and compound Int I (0.1 g, 396 μmol, 1 eq) were dissolved in DMF (1 mL), and CuI (37.7 mg, 198 μmol, 0.5 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (56.3 mg, 396 μmol, 1 eq) and Cs ₂ CO ₃ (387 mg, 1.19 mmol, 3 eq) were added in sequence under stirring at room temperature. The reaction was stirred at 100°C for 16 hours under nitrogen protection. LCMS and TLC (EtOAc/MeOH, 10/1, R _f = 0.51) detected that the reaction was complete. The reaction solution was poured into ice water (5 mL), extracted with ethyl acetate (1 mL*3), and the organic phases were combined and washed with 5 mL of saturated sodium chloride aqueous solution. Washing The organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate purification (SiO ₂ , EtOAc/MeOH, 10/1) to obtain the target compound 4 (47 mg, 95.5 μmol, 12.0% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 492.1.

4) Preparation of compound GDI15-6288

Compound 4 (60 mg, 121 μmol, 1 eq) was dissolved in 33% HBr acetic acid solution (1.2 mL) and stirred at 120°C for 16 hours. The reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 10%-40%, 8 min) to obtain the target compound GDI15-6288 (24 mg, 63.5 μmol, 52.1% yield, 100% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 378.2.

^1H NMR (400MHz, DMSO) δ9.17 (d, J＝8.5Hz, 1H), 8.36 (s, 1H), 8.09 (dd, J＝8.0, 11.1Hz, 1H), 7.74-7.60 (m, 4H), 7.57-7. 52(m,1H),7.52-7.45(m,1H),7.45-7.37(m,1H),6.10(d,J＝7.6Hz,1H),6.05(d,J＝7.5Hz,1H),3.80-3.64(m,2H).

Example 31: Preparation of compound GDI15-6327

1) Preparation of compound GDI15-6327

Compound GDI15-6288 (20 mg, 52.9 μmol, 1 eq) and TEA (16.1 mg, 158 μmol, 22.1 μL, 3 eq) were dissolved in DCM (1 mL), MsCl (10 mg, 87.3 μmol, 6.76 μL, 1.65 eq) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction was completed by LCMS. The reaction solution was poured into ice water. The organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, dissolved in methanol (1 mL), and K ₂ CO ₃ (36.5 mg, 264 μmol, 5 eq) was added. The mixture was stirred at 25°C for 1 hour and the reaction solution was dried. The target compound GDI15-6327 (10 mg, 21.9 μmol, 41.4% yield) was obtained by purification on silica gel plate (EtOAc/MeOH, 2/1) and high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 15%-35%, 8 min) as a white solid. ESI-MS: [M+H] ⁺ , 456.1.

^1H NMR(400MHz, DMSO)δ9.25(d,J＝1.6Hz,1H),8.40-8.30(m,1H),8.14(dd,J＝2.9,6.1Hz,1H),7.79-7.71(m,1H),7.71-7.63(m, 3H),7.62-7.57(m,3H),7.56-7.49(m,2H),6.29(dd,J＝5.4,6.7Hz,1H),4.04(dd,J＝6.2,14.1Hz,2H),2.87(d,J＝2.3Hz,3H).

Example 32: Preparation of compound GDI15-6396

1) Synthesis steps of compound 2

Compound 1 (2 g, 16 mmol), compound 2 (2.49 g, 16 mmol) and K ₂ CO ₃ (4.42 g, 32 mmol) were dissolved in DMF (20 mL) at 60°C and stirred under nitrogen for 3 hours. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, water (200 mL) was added, the precipitate was filtered and washed with water, and the solution was concentrated under reduced pressure to obtain a crude product (2.5 g, 9.6 mmol, 60% yield) as a white solid. ESI-MS: [M+H] ⁺ , 260.60

2) Synthesis steps of compound 4

Compound 5 (2.5 g, 9.6 mmol) and NBS (1.54 g, 8.64 mmol) were dissolved in DMF (25 mL). The reaction was stirred under nitrogen protection at room temperature for 2 hours. LCMS monitoring revealed that the reaction raw materials disappeared and the target product appeared. After the reaction was allowed to rest, water (300 mL) was added to filter the precipitate and wash it with water. The solution was dried under reduced pressure to obtain the crude product 4 (2.3 g, 6.8 mmol, 71% yield) as a white solid. ESI-MS: [M+H] ⁺ , 338.50.

¹ H NMR (400MHz, DMSO) δ8.30 (d, J = 2.4 Hz, 1H), 7.99 (m, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 7.9 Hz, 1H), 4.02 (s, 3H).

3) Synthesis steps of compound 6

Compound 4 (410 mg, 1.2 mmol), compound 5 (276 mg, 1.08 mmol), CsF (547 mg, 3.6 mmol) and Pd(DtBPF)Cl ₂ (77 mg, 0.12 mmol) were dissolved in DMF/H2O (8 mL/2 mL), stirred at 70°C under nitrogen protection for 5 h, and the reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (20 mL) was added to the system. The mixture was extracted with EtOAc (20 mL*3) and dried with Na ₂ SO ₄ , filtered and dried, and further column chromatography with PE:EtOAc (1v:1v to 1v:2v) was performed to obtain compound 6 (170 mg, 0.44 mmol, 36.7% yield) as a yellow solid, ESI-MS: [M+H] ⁺ , 388.00.

4) Synthesis steps of compound 7

Compound 6 (170 mg, 0.44 mmol) and NiCl ₂ .6H ₂ O (157 mg, 0.66 mmol) were dissolved in MeOH (5 mL), stirred and reacted for 5 min at 0°C under nitrogen protection, then sodium borohydride (50 mg, 1.32 mmol) was added three times, and the system was stirred and reacted for 10 min at 0°C. LCMS monitoring showed that the reaction raw materials disappeared and the target product appeared. Then Boc ₂ O (288 mg, 1.32 mmol) was added dropwise, the system gradually warmed to room temperature and reacted at room temperature for 1 h. After the reaction was completed, water (20 mL) was added to the system, and DCM (20 mL*3) was used for extraction. The mixture was dried over Na ₂ SO ₄ , filtered and dried by spin drying, and further purified by column chromatography (PE:EtOAc, 1v:1v to 1v:2v) to give compound 7 (80 mg, 0.17 mmol, 37.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 492.00.

5) Synthesis steps of compound GDI15-6396

Compound 7 (80 mg, 0.16 mmol), decane-1-thiol (65 mg, 0.32 mmol) and NaOH (12.8 mg, 0.32 mmol) were dissolved in DMAc (2 mL) and stirred at 100°C under nitrogen protection for 2 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, the solvent was dried and the residue was further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6396 (4.7 mg, 6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 378.00.

¹ H NMR (400MHz, DMSO) δ11.28(s,1H),9.48(s,1H),8.46(m,1H),8.28(m,1H),8.09(m,3H),7.69(m,5H),7.54(m,1H),6.45(s,1H),3.93(m,2H).

Example 33: Preparation of compound GDI15-6505

1) Synthesis steps of compound 3

Compound 1 (1 g, 8 mmol), compound 2 (1.17 g, 7.6 mmol) and K ₂ CO ₃ (3.32 g, 24 mmol) were dissolved in DMF (20 mL), protected by nitrogen, and reacted at 46° C. for 1 h. LCMS monitored the completion of the reaction, added water (200 mL), filtered and washed with water, and the solution was spin-dried to obtain a crude product, compound 3 (1.05 g, 3.6 mmol, 45.0% yield) as a white solid. ESI-MS: [M+H] ⁺ , 278.8.

2) Synthesis steps of compound 4

Compound 3 (1.05 g, 3.6 mmol) and NBS (510 mg, 2.8 mmol) were dissolved in DMF (13 mL) and reacted at room temperature for 2 h under nitrogen protection. The reaction was completed after LCMS monitoring. Water (100 mL) was added, the solid was filtered and washed with water, and the solvent was dried to obtain compound 4 (1.05 g, 2.9 mmol, 80.56% yield). ESI-MS: [M+H] ⁺ , 356.55.

3) Synthesis steps of compound 6

Compound 4 (1 g, 2.8 mmol), compound 5 (0.93 g, 3.6 mmol), CsF (1.28 g, 8.4 mmol) and Pd(DtBPF)Cl ₂ (270 mg, 4.2 mmol) were dissolved in DMF/H ₂ O (5 mL/1 mL), and reacted at 50°C for 2 h under nitrogen protection. The reaction was completed after LCMS monitoring, and the system solvent was dried by spin drying. Column chromatography (PE/EtOAc, 1v:0v to 10v:1v) gave compound 6 (260 mg, 0.6 mmol, 21.43% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 405.70.

4) Synthesis steps of compound 8

Compound 6 (210 mg, 0.52 mmol) and NiCl ₂ .6H ₂ O (192 mg, 0.78 mmol) were dissolved in MeOH (2 mL) and reacted at 0°C for 10 min under nitrogen protection. NaBH ₄ (78 mg, 2.07 mmol) was then added three times and the system was reacted at 0°C for 10 min. The reaction was completed after LCMS monitoring. Boc ₂ O (451 mg, 2.07 mmol) was added. The system was warmed to room temperature and reacted at room temperature for 1 h. The solvent was spin-dried and column chromatography DCM:MeOH (20:1 to 10:1) was performed to obtain compound 7 (160 mg, 0.25 mmol, 48.5% yield) as a brown oil. ESI-MS: [M+H] ⁺ , 509.85.

4) Synthesis steps of compound GDI15-6505

Compound 8 (130 mg, 0.25 mmol) was dissolved in HBr/HOAc (6 mL) under nitrogen protection and stirred at 100°C for 6 h. The reaction was completed after LCMS monitoring, and the system solvent was dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain GDI15-6505 (3.24 mg, 3.22% yield) as a white solid. ESI-MS: [M+H] ⁺ , 395.70.

1H NMR (400MHz, DMSO) δ11.33(s,1H),9.40(d,J＝6.7Hz,1H),8.46-8.38(m,1H),8.24(dd,J＝13.4,8.3Hz,1H),8 .11-8.06(m,3H),7.96-7.94(m,7.0Hz,1H),7.86-7.68(m,5H),6.43(dd,J＝7.6,1.7Hz,1H),3.91-3.83(m,2H).

Example 34: Preparation of compound GDI15-6590

1) Synthesis steps of compound 3

Compound 1 (2.0 g, 16 mmol) was dissolved in DMF (20 mL), and then K ₂ CO ₃ (6.6 g, 48 mmol) and compound 2 (3.1 g, 18 mmol) were slowly added to the system under nitrogen protection at 0°C. The mixed system was heated to 60°C and reacted for 16 h. It was then extracted with EtOAc (100 mL*3), the organic phases were combined and The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin drying, and further purified by column chromatography (EtOAc/PE, 30% to 40%) to obtain compound 3 (1.2 g, 26.25% yield) as a white solid. ESI-MS: [M+H] ⁺ , 278.80.

¹ H NMR (400MHz, DMSO) δ8.02(dd,J＝9.2,1.8Hz,1H),7.79(s,1H),7.65(d,J＝7.7Hz,1H),6.18(dd,J＝7.7,2.6Hz,1H),5.97(d,J＝2.5Hz,1H),3.82(s,3H).

2) Synthesis steps of compound 3

Compound 3 (1.0 g, 3.59 mmol) and NiCl ₂ .6H ₂ O (1.3 g, 5.38 mmol) were dissolved in MeOH (20 mL) and reacted at 0°C under nitrogen protection for 5 min. Sodium borohydride (406.94 mg, 10.77 mmol) was then added in two batches. The mixed system was reacted at 0°C for 10 min. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. Boc ₂ O (2.3 g, 10.77 mmol) was then added dropwise. The system was slowly warmed to room temperature and reacted at room temperature for 1 h. The system was further purified by column chromatography (EtOAc/PE, 45% to 50%) to obtain compound 4 (700 mg, 50.96% yield) as a white solid. ESI-MS: [M+H] ⁺ , 383.05.

^1H NMR(400MHz, DMSOδ7.60(dd,J＝9.6,1.8Hz,1H),7.43(d,J＝7.6Hz,1H),7.31(s,1H),6.82(s,1H),6 .09(dd,J＝7.6,2.6Hz,1H),5.90(d,J＝2.2Hz,1H),3.93(t,J＝6.1Hz,2H),3.79(s,3H),1.32(s,9H).

3) Synthesis steps of compound 5

Compound 4 (700 mg, 1.82 mmol) and NBS (277 mg, 1.55 mmol) were dissolved in DMF (5 mL) and stirred at room temperature under nitrogen for 3 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the target product. After the reaction was completed, water (50 mL) was added to the system, the solid was filtered and washed with water, and the solution was concentrated and dried to obtain a crude product, compound 5 (400 mg, 47.38% yield) as a white solid. ESI-MS: [M+H] ⁺ , 462.90.

4) Synthesis steps of compound 7

Compound 5 (300 mg, 0.65 mmol), compound 6 (199 mg, 0.78 mmol), CsF (296 mg, 1.95 mmol) and Pd(DtBPF)Cl ₂ (43 mg, 0.0650 mmol) were dissolved in DMF/H ₂ O (1 mL/0.2 mL), stirred at 50°C under nitrogen protection for 5 hours, and the reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (20 mL) was added to the system, the solid residue was filtered and washed with water, the solution was extracted with EtOAc (20 mL*3) and dried with Na ₂ SO ₄ , filtered and dried, and further purified by column chromatography (PE:EtOAc, 20:80 to 0:100) to obtain compound 7 (150 mg, 0.37 mmol, 56.88% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 510.10.

5) Synthesis steps of compound GDI15-6590

Compound 7 (100 mg, 0.20 mmol) was dissolved in AcOH, and HBr in AcOH (5 mL, 33%) solution was added dropwise under nitrogen protection and stirring. The mixed system was reacted at 100°C for 10 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. The reaction system was vacuum-dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O The mixture was purified by centrifugation with 0.1% TFA to give compound GDI15-6590 (6.42 mg, 4.08% yield). ESI-MS: [M+H] ⁺ , 395.75.

^1H NMR (400MHz, DMSO) δ11.49(s,1H),9.43(s,1H),8.52-8.37(m,1H),8.26(t,J＝9.0Hz,1H),8.02-7.98(m,3H ),7.91-7.77(m,5H),7.76-7.70(m,2H),7.66-7.59(m,1H),6.47(dd,J＝7.7,3.3Hz,1H),4.03-3.73(m,2H).

Example 35: Preparation of Compound GDI15-6624

1) Synthesis steps of compound 3

Compound 1 (124 mg, 0.71 mmol), compound 2 (200 mg, 0.79 mmol) and K ₂ CO ₃ (329 mg, 2.38 mmol) were dissolved in DMF (5 mL) and stirred at 60°C under nitrogen protection for 5 hours. LCMS monitoring revealed the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, water (20 mL) was added to the system, the solid residue was filtered and washed with water, and the resulting solution was concentrated and dried to give the crude product compound 3 (250 mg, 0.62 mmol, 87.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 405.70.

2) Synthesis steps of compound 4

Compound 3 (220 mg, 0.54 mmol) and NiCl ₂ .6H ₂ O (193 mg, 0.81 mmol) were dissolved in MeOH (5 mL), stirred at 0°C for 5 min, then sodium borohydride (61 mg, 1.63 mmol) was added in 3 batches, reacted at 0°C for 10 min, LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product, then Boc ₂ O (355 mg, 1.63 mmol) was added dropwise, after the addition was complete, the reaction system gradually warmed to room temperature and reacted at room temperature for 1 h. After the reaction was completed, H ₂ O (20 mL) and DCM (20 mL*3) were added to the system for extraction, dried over Na ₂ SO ₄ , filtered and spin-dried, and column chromatography (PE:EtOAc, 1v:1v to 1v:2v) was performed to obtain compound 4 (110 mg, 0.22 mmol, 39.79% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 510.10.

3) Synthesis steps of compound GDI15-6624

Compound 4 (110 mg, 0.22 mmol, 1 eq) was dissolved in HBr/AcOH (3 mL), and the mixture was stirred at 100 ° C for 5 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, NaHCO ₃ (36.24 mg, 0.43 mmol, 2 eq) was added dropwise to the system, filtered and dried, and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H2O containing 0.1% TFA) to obtain compound GDI15-6624 (31.43 mg, 36.8% yield) as a white solid. ESI-MS: [M+H] ⁺ , 396.05.

^1H NMR (400MHz, DMSO) δ11.63 (s, 1H), 9.50 (m, 1H), 8.49 (d, J = 5.3Hz, 1H), 8.27 (m, 3H), 7.90(m,2H),7.75(m,3H),7.52(d,J＝8.6Hz,1H),6.48(d,J＝7.6Hz,1H),3.96(m,2H).

Example 36: Preparation of Compound GDI15-6548

1) Synthesis steps of compound 2

Compound 1 (4 g, 16.4 mmol), Zn(CN) ₂ (2.31 g, 19.7 mmol) and Pd(PPh ₃ ) ₄ (1.9 g, 16.4 mmol) were dissolved in DMF (30 mL) and stirred at 100°C under nitrogen protection for 16 h. LCMS monitoring revealed that the starting materials disappeared and the target product appeared. After the reaction, water (200 mL) was added to the system, the solid residue was filtered out, and the solution was concentrated and dried to obtain the crude product compound 2 (2 g, 10.5 mmol, 64.0% yield) as a white solid. ESI-MS: [M+H] ⁺ , 190.00.

2) Synthesis steps of compound 4

Compound 3 (851 mg, 6.8 mmol), compound 2 (1.3 g, 6.8 mmol) and K ₂ CO ₃ (1.88 g, 13.6 mmol) were dissolved in DMF (10 mL) and stirred at 60°C under nitrogen protection for 3 h. LCMS monitoring revealed that the starting materials disappeared and the target product appeared. After the reaction, water (20 mL) was added to the system, the solid residue was filtered out and washed with water, and the filtrate was concentrated and dried to obtain the crude product compound 4 (0.8 g, 2.7 mmol, 39.7% yield) as a white solid.

3) Synthesis steps of compound 5

Compound 4 (800 mg, 2.71 mmol) and NBS (434.22 mg, 2.44 mmol) were dissolved in DMF (8 mL) and stirred under nitrogen protection at room temperature for 2 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, water (30 mL) was added to the system, the solid residue was filtered and washed with water, and the filtrate was concentrated and dried to obtain the crude product compound 5 (520 mg, 1.39 mmol, 51.29% yield) as a white solid. ESI-MS: [M+H] ⁺ , 374.85.

4) Synthesis steps of compound 7

Compound 5 (470 mg, 1.26 mmol), compound 6 (321 mg, 1.26 mmol), CsF (382 mg, 2.51 mmol) and Pd(DtBPF)Cl ₂ (82 mg, 0.13 mmol) were dissolved in DMF/H ₂ O (5 mL/1 mL) and stirred at 70°C under nitrogen protection for 5 h. LCMS monitoring revealed that the starting materials disappeared and the target product appeared. After the reaction was completed, water (20 mL) was added to the system, and extracted with EtOAc (20 mL*3), dried over Na ₂ SO ₄ , filtered and dried by column chromatography (PE:EtOAc, 1v:1v to 1v:2v) to obtain compound 7 (230 mg, 0.5447 mmol, 43.35% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 422.00.

5) Synthesis steps of compound 8

Compound 7 (200 mg, 0.47 mmol) and NiCl ₂ .6H ₂ O (169 mg, 0.71 mmol) were dissolved in MeOH (5 mL) and reacted at 0°C under nitrogen protection for 5 min. Sodium borohydride (54 mg, 1.42 mmol) was then added in three batches. The system continued to react at 0°C for 10 min. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. Boc ₂ O (310 mg, 1.42 mmol) was added dropwise to the system. The system was slowly warmed to room temperature and reacted at room temperature for 1 h. After the reaction was completed, water (20 mL) was added to the system, and extracted with DCM (20 mL*3), dried with Na ₂ SO ₄ , filtered and dried by column chromatography (PE:EtOAc, 1v:1v to 1v:2v) to obtain compound 8 (80 mg, 0.15 mmol, 32.09% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 526.05.

6) Synthesis steps of compound GDI15-6548

Compound 8 (80 mg, 0.15 mmol), decane-1-thiol (40 mg, 0.23 mmol) and NaOH (9.12 mg, 0.23 mmol) were dissolved in DMAc (2 mL) and stirred at 100°C under nitrogen protection for 2 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, the solvent was dried and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain GDI15-6548 (3.12 mg, 7.6 μmol, 4.98% yield) as a white solid. ESI-MS: [M+H] ⁺ , 412.00.

^1H NMR(400MHz,DMSO)δ11.29(s,1H),9.36(s,1H),8.45-8.36(m,1H),8.22(s,1H) ),8.06(m,3H),7.94(m,2H),7.73(m,4H),6.44(d,J=7.7Hz,1H),3.92(m,2H).

Example 37: Preparation of compound GDI15-6623

1) Synthesis steps of compound 2

Compound 1 (10 g, 69.2 mmol) was dissolved in TFA (46 mL), and NIS (17.13 g, 76.1 mmol) was added under nitrogen protection at room temperature. The mixed system continued to react at room temperature for 16 h. After the reaction, the solvent was dried under reduced pressure and EtOAc was added. The mixture was extracted with Na ₂ O ₃ S ₂ (40 mL*5). The organic phases were combined and washed with water (30 mL*2), saturated brine (40 mL*1), dried over anhydrous sodium sulfate, filtered and dried to obtain the crude product Compound 2 (17 g, 91% yield) as a colorless oily liquid.

¹ H NMR (400MHz, DMSO) δ7.76 (d, J = 6.6 Hz, 1H), 7.31 (dd, J = 7.9, 2.2 Hz, 1H), 2.28 (s, 3H).

2) Synthesis steps of compound 3

Compound 2 (5 g, 18.5 mmol) and Zn(CN) ₂ (1.09 g, 9.2 mmol) were dissolved in DMF (50 mL), and Pd(PPh ₃ ) ₄ (2.14 g, 1.8 mmol) was added under nitrogen protection and heated to 90°C for 12 h. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (40 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 10:1) to obtain compound 3 (1 g, 32% yield) as a white solid.

¹ H NMR (400MHz, DMSO) δ7.98 (d, J = 7.1 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 2.32 (s, 3H).

3) Synthesis steps of compound 5

Compound 3 (1.05 g, 6.2 mmol) was dissolved in DMF (13 mL), and compound 4 (0.78 g, 6.2 mmol) and K ₂ CO ₃ (2.57 g, 18.6 mmol) were added at room temperature under nitrogen protection. The system was reacted at 60°C for 3 h. LCMS monitoring revealed that the reaction raw materials disappeared and the target product appeared. After the reaction was completed, water (10 mL) was added to the system, the solid residue was filtered and washed with water, and the solution system was dried under reduced pressure to obtain a crude product, compound 5 (890 mg, 50% yield) as a white solid.

4) Synthesis steps of compound 6

Compound 5 (890 mg, 3.2 mmol) was dissolved in DMF (9 mL), and NBS (461.31 mg, 2.6 mmol) was added under nitrogen protection at room temperature, and then the reaction was continued at room temperature for 3 h. After the reaction was completed, water (10 mL) was added to the system, the residue was filtered and washed with water, and the solution system was spin-dried to obtain the crude product compound 6 (1.0 g, 83% yield) as a white solid. ESI-MS: [M+H] ⁺ , 394.90.

5) Synthesis steps of compound 8

Compound 6 (1 g, 2.8 mmol), compound 7 (0.36 g, 2.52 mmol), CsF (1.28 g, 8.4 mmol) and Pd(dtbpf)Cl ₂ (0.18 g, 0.28 mmol) were dissolved in DMF/H ₂ O (10 mL/2.5 mL) and stirred at 70°C under nitrogen protection for 2 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, water (5 mL) was added to the system and extracted with EtOAc (30 mL*3). The organic phases were combined and saturated with ethanol. The residue was washed with brine, dried over anhydrous sodium sulfate, filtered and dried by spin column chromatography (EtOAc/PE, 1% to 80%) to obtain compound 8 (430 mg, 38.22% yield) as a white solid.

^1H NMR (400MHz, DMSO) δ9.27(s,1H),8.30(s,1H),8.15(d,J＝9.2Hz,1H),8.09(s,1H),8.02(d,J＝7 .9Hz,1H),7.97(s,1H),7.67(s,3H),6.74(d,J＝7.9Hz,1H),3.81(s,3H),3.17(d,J＝4.7Hz,3H).

6) Synthesis steps of compound 9

Compound 8 (430 mg, 1.07 mmol) and NiCl ₂ .6H ₂ O (350.32 mg, 1.61 mmol) were dissolved in methanol MeOH (5 mL), stirred and reacted at 0°C under nitrogen protection for 10 min, then sodium borohydride (121.46 mg, 3.21 mmol) was added in three batches, and the system was reacted at 0°C for 20 min. LCMS monitoring showed that the reaction raw materials disappeared and the target product appeared. Then Boc ₂ O (2.3 g, 10.70 mmol) was added dropwise, and the system was warmed to room temperature for 1 h. After the reaction was completed, the system was purified by concentration column chromatography (EtOAc/PE, 1% to 80%) to obtain compound 9 (450 mg, 74.80% yield) as a green solid. ESI-MS: [M+H] ⁺ , 506.10.

7) Synthesis steps of compound GDI15-6623

Compound 9 (150 mg, 370.5 μmol) was dissolved in HBr in AcOH (2 mL) solution under nitrogen protection at room temperature, and the mixed system was heated to 100°C for 16 h. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. The solvent was concentrated under reduced pressure and dried, and further purified by rep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6623 (3.37 mg, 2.33% yield) as a white solid. ESI-MS: [M+H] ⁺ , 392.10.

1H NMR (400MHz, DMSO) δ11.23 (s, 1H), 9.35 (d, J = 6.5Hz, 1H), 8.45- 8.36(m,1H),8.19(d,J＝7.9Hz,1H),7.97(s,3H),7.75(s,2H),7.69(s,2H), 7.61(d,J＝3.9Hz,1H),6.42(d,J＝8.1Hz,1H),3.77-387(m,2H),2.41(s,3H).

Example 38: Preparation of Compound GDI15-6672

1) Synthesis steps of compound 2

Compound 1 (5 g, 26.8 mmol) was dissolved in 3M H ₂ SO ₄ (22 mL) aqueous solution at 0°C, and then NaNO ₂ (1.85 g, 26.8 mmol) was added, and the mixed system continued to react at 0°C for 1 h. KI (4.45 g, 26.8 mmol) and UREA (0.32 g, 5.3 mmol) were dissolved in water (2 mL), added to the mixed system, and continued to react at 0°C for 1 h, and then gradually warmed to room temperature for 2 h. After the reaction was completed, water (5 mL) was added to quench the reaction, and extracted with EtOAc (30 mL*3), the combined organic phases were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and dried by flash column chromatography to obtain compound 2 (4.2 g) as a white solid.

¹ H NMR (400MHz, DMSO) δ8.26 (s, 1H), 8.06 (s, 1H), 2.44 (s, 3H).

2) Synthesis steps of compound 3

Compound 2 (4.2 g, 14.1 mmol), NBS (2.76 g, 15.5 mmol) and AIBN (0.93 g, 5.6 mmol) were dissolved in DCE (50 mL) under nitrogen protection, and the mixed system was heated at 90 ° C for 4 h. After the reaction was completed, water (50 mL) was added to quench, and DCM (50 mL*3) was extracted. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by flash column chromatography to obtain compound 3 (2 g) as a white solid.

3) Synthesis steps of compound 4

Compound NHBoc ₂ (1.15 g, 5.3 mmol) was dissolved in DMF (20 mL). After the system was cooled to 0 °C, NaH (0.13 g, 5.3 mmol) was added and stirred for 10 min at this temperature. Then, a DMF (10 mL) solution of compound 3 (2 g, 5.3 mmol) was added dropwise to the system. After the addition was completed, the temperature was gradually raised to room temperature. The mixed system was stirred at room temperature for 4 h., water (30 mL) was added to quench, and EtOAc (30 mL*3) was used for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by fast column chromatography to obtain compound 4 (2.5 g) as a colorless oily liquid. ESI-MS: [M+H] ⁺ , 575.9.

4) Synthesis steps of compound 6

Compound 4 (100 mg, 0.20 mmol), compound 5 (42 mg, 0.18 mmol) and CuI (8 mg, 0.009 mmol) were dissolved in DMSO (2 mL), and then K ₂ CO ₃ (81 mg, 0.59 mmol) was added at once, and the system was reacted at 140°C for 1 h. After the reaction was completed, it was cooled to room temperature, and EtOAc (10 mL*3) was added for extraction. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and flash column chromatography (DCM/MeOH, 0% to 10) was performed to obtain compound 6 (18 mg, 0.057 mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 523.00.

5) Synthesis steps of compound GDI-6672

Compound 6 (30 mg, 0.0574 mmol) was dissolved in ethyl acetate (2 mL) solution of HCl and stirred at room temperature for 2 h. After the reaction, the solvent was dried and purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6672 (2.12 mg, 0.005 mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 423.10.

H NMR (400MHz, DMSO) δ11.39(s,1H),9.35(s,1H),8.45-8.35(m,2H),8.24-8.13(m,3H),8.10(d,J＝6 .2Hz,2H),7.87-7.74(m,2H),7.71(d,J＝8.7Hz,1H),6.47(dd,J＝7.6,2.4Hz,1H),3.98-3.92(m,2H).

Example 39: Preparation of Compound GDI15-6591

1) Synthesis steps of compound 3

Compound 1 (1.5 g, 4.4 mmol), compound 2 (0.57 g, 3.9 mmol), CsF (2.01 g, 13.2 mmol) were dissolved in DMF/H ₂ O (20 mL), and Pd-118 (0.29 g, 0.4 mmol) was added under nitrogen protection. The system was heated to 70°C for 4 h under nitrogen protection. After the reaction, water (50 mL) was added to the system and extracted with EtOAc (50 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by flash column chromatography (EtOAc/PE, 10% to 50%) to obtain compound 3 (0.95 g, 54.55% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 388.00.

2) Synthesis steps of compound 4

Compound 3 (200 mg, 0.52 mmol) and K ₂ CO ₃ (143 mg, 1.0 mmol) were dissolved in DMSO (2 mL). H ₂ O ₂ (0.2 mL, 30%) was added under nitrogen protection at 0°C. The mixture was heated to room temperature for 2 hours. h. After the reaction, ice water was added to the system, and extracted with EtOAc (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (PE/EtOAc, 10% to 60%) to obtain compound 4 (160 mg, 76.44% yield) as a white solid. ESI-MS: [M+H] ⁺ , 406.00.

3) Synthesis steps of compound GDI15-6591

Compound 4 (130 mg, 0.32 mmol) was dissolved in DMAC (2 mL), and decane-1-thiol (111.70 mg, 0.64 mmol) and NaOH (25.63 mg, 0.64 mmol) were added at room temperature under nitrogen protection. The system was reacted at 100°C for 3 h, and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6591 (10.17 mg, 8.11% yield) as a white solid. ESI-MS: [M+H] ⁺ , 392.10.

^1H NMR (400MHz, DMSO) δ11.04(s,1H),9.54(s,1H),8.46(s,1H),8.32(d,J＝7.9Hz,1H),8.08- 7.74(m,4H),7.69-7.63(m,2H),7.60(d,J＝7.1Hz,2H),7.46(s,1H),6.27(d,J＝7.7Hz,1H).

Example 40: Preparation of compound GDI15-6564

1) Synthesis steps of compound 2

Compound Int I (400 mg, 1.59 mmol, 1 eq) was dissolved in DMF (8.0 mL), and then compound 1 (417 mg, 2.38 mmol, 1.5 eq) and Cs ₂ CO ₃ (1.03 g, 3.17 mmol, 2 eq) were added in sequence at 25°C. The mixture was reacted at 25°C for 2 hours under nitrogen protection, and the reaction was completed after LCMS detection. Water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (4 mL*3). The organic phases were combined and precipitated with 20 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to give the target compound 2 (440 mg, 1.08 mmol, 68.1% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 408.1.

2) Synthesis steps of compound 3

Compound 2 (0.61 g, 1.50 mmol, 1 eq) was dissolved in EtOH (6 mL) and H ₂ O (1.8 mL), and NH ₄ Cl (480 mg, 8.97 mmol, 6 eq) was added at 25°C. The reaction mixture was then heated to 80°C, and Fe powder (501 mg, 8.97 mmol, 6 eq) was added in batches. The reaction mixture was stirred at 80°C for 3 hours, and the reaction was completed by LCMS. The reaction solution was filtered through diatomaceous earth while hot, and the filter cake was rinsed with hot ethanol. The filtrate was concentrated under reduced pressure to obtain a crude product. Water (50 mL) was poured into the crude product, and extracted with ethyl acetate (20 mL*3). The organic phases were combined, and the combined organic phases were washed with 100 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to give the target compound 3 (480 mg, 1.27 mmol, 84.9% yield) as a yellow solid - MS: [M+H] ⁺ , 378.1.

3) Synthesis steps of compound GDI15-6564

Compound 3 (50 mg, 132 μmol, 1 eq) was dissolved in NMP (2 mL), and 1-decyl mercaptan (115 mg, 661 μmol, 5 eq) and K ₂ CO ₃ (36.5 mg, 264 μmol, 2 eq) were added in sequence at 25°C. The reaction mixture was stirred at 140°C for 16 hours, and the reaction was complete when detected by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 20%-50% B in 8.0 min) to obtain the target product. GDI15-6564 (20.2 mg, 55.5 μmol, 41.9% yield) was a brown solid. ESI-MS: [M+H] ⁺ , 364.0.

^1H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.42-8.28 (m, 1H), 8.15-8.09 (m, 1H), 7.88-7.61 (m, 3H), 7.45 (d, J = 8.0 Hz,1H),7.20-7.11(m,2H),6.81(d,J＝8.4Hz,1H),6.23(dd,J＝3.6,7.3Hz,1H),5.18(s,1H),5.12(s,1H).

Example 41: Preparation of compound GDI15-6579

1) Synthesis steps of compound 4

Compound 3 (90.0 mg, 238 μmol, 1 eq) was dissolved in DCM (2 mL), and TEA (72.3 mg, 715 μmol, 99.5 μL, 3 eq) and acetic anhydride (29.2 mg, 286 μmol, 26.9 μL, 1.2 eq) were added sequentially under stirring at 20 °C. The reaction mixture was reacted at 35 °C for 16 hours, and the reaction was completed by LCMS. Water (3 mL) was added to the reaction solution, and extracted with DCM (3 mL*3). The organic phases were combined, and the combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.62) to obtain a crude product of compound 4 (0.12 g) as a yellow solid.

2) Synthesis steps of compound GDI15-6579

Compound 4 (0.1 g, 238 μmol, 1 eq) was dissolved in HBr/AcOH (2 mL, 33% purity). The reaction mixture was reacted at 120°C for 16 hours. The reaction was completed when LCMS detected that the reaction was complete. The reaction solution was filtered and dried under reduced pressure and analyzed by high performance liquid chromatography (column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 1%-30% B in 8.0 min) was purified to give the target compound GDI15-6579 (16.5 mg, 37.9 μmol, 15.9% yield, 93.3% purity) as a white solid. ESI-MS: [M+H]+, 406.0.

1H NMR(400MHz,DMSO)δ9.60-9.41(m,1H),9.24(s,1H),8.37-8.27(m,1H),8.17-8.0 7(m,1H),7.88-7.62(m,4H),7.60-7.40(m,3H),6.35-6.13(m,1H),2.10-1.85(s,3H).

Example 42: Preparation of Compound GDI15-6576

1) Synthesis steps of compound 3

Compound Int I (150 mg, 595 μmol, 1 eq) was dissolved in HBr/AcOH (2 mL, 33% purity). The reaction mixture was reacted at 120°C for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was filtered and dried under reduced pressure. The target compound 3 (75 mg, 315 μmol, 52.9% yield) was purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 1%-25% B in 8.0 min) to obtain a white solid. ESI-MS: [M+H]+, 293.0.

2) Synthesis steps of compound GDI15-6576

Compound 3 (40 mg, 168 μmol, 1 eq) was dissolved in DMF (2 mL). Compound 1 (54.1 mg, 201 μmol, 1.2 eq), Cs ₂ CO ₃ (164 mg, 505 μmol, 3 eq) were added in sequence at 25°C.

(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (23.9 mg, 168 μmol, 1 eq) and CuI (16.0 mg, 84.0 μmol, 0.5 eq). Under nitrogen protection, the reaction was stirred at 100 °C for 16 hours, and the reaction was monitored by LCMS. Complete. Add ice water (3 mL) to the reaction solution, extract with DCM (2 mL*4), combine the organic phases, concentrate under reduced pressure, and purify by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-50% B in 8.0 min) and silica gel plate separation (EtOAc/MeOH, 8/1) (TLC, EtOAc/MeOH, 8/1, R _f = 0.51) to obtain the target compound GDI15-6576 (8 mg, 21.1 μmol, 12.6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 379.1.

1H NMR (400MHz, DMSO) δ10.92-10.64(m,1H),9.24(s,1H),8.32(s,1H),8.13(d,J＝8.0Hz,1H),7.75-7.70(m,1H),7. 68-7.62(m,2H),7.55(d,J＝7.4Hz,1H),7.52-7.46(m,2H),7.22(d,J＝8.8Hz,1H),6.23(d,J＝7.7Hz,1H),3.82(s,3H).

Example 43: Preparation of Compound GDI15-6592

1) Synthesis steps of compound 7

Compound 6 (550 mg, 1.4 mmol) was dissolved in 4M HCl/MeOH (10 mL) solution, heated to 100°C and maintained at the temperature for 4 h. LCMS monitoring revealed the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, the solvent was dried under reduced pressure to obtain the crude product compound 7 (500 mg, 1.18 mmol, 83.78% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 420.90.

2) Synthesis steps of compound 8

Compound 7 (200 mg, 0.48 mmol) was dissolved in THF (3 mL), and a THF solution of LiAlH4 (0.5 mL, 0.48 mmol) was added dropwise at 0°C under nitrogen protection. The mixed system was stirred at 0°C for 20 min. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, NH ₄ Cl was added to the system, the solvent was removed under reduced pressure, DCM was added, the residue was filtered, and a solution was obtained, which was spin-dried to obtain compound 8 (200 mg, 0.36 mmol, 75.00% yield) as a brown oily liquid. ESI-MS: [M+H] ⁺ , 392.95.

3) Synthesis steps of compound 7

Compound 8 (180 mg, 0.46 mmol) and decane-1-thiol (160 mg, 0.92 mmol) were dissolved in DMAc (2 mL), and NaOH (37 mg, 0.91 mmol) solution was added under nitrogen protection at room temperature. The mixed system was reacted at 100°C for 2 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, the solvent was dried under vacuum and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6592 (3.24 mg, 1.88% yield) as a white solid. ESI-MS: [M+H] ⁺ , 379.00.

1H NMR (400MHz, DMSO) δ11.02(s,1H),9.23(d,J＝2.5Hz,1H),8.31(d,J＝5.5Hz,1H),8.12(t,J＝7.1Hz,1H),7.73-7.58 (m,4H),7.57-7.50(m,2H),7.47(dd,J＝13.8,2.0Hz,1H),6.23(dd,J＝7.6,2.0Hz,1H),5.32(s,1H),4.45-4.01(m,2H).

Example 44: Preparation of Compound GDI15-6706

Compound 3 (10.1 mg, 46.2 μmol, 1.1 eq) and compound 1 (0.01 g, 42.0 μmol, 1 eq) were dissolved in DMSO (0.3 mL), and then CuI (1.6 mg, 8.40 μmol, 0.2 eq) and K ₂ CO ₃ (17.4 mg, 126 μmol, 3 eq) were added in sequence at 20° C. The mixture was reacted at 140° C. for 3 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was slowly added to ice water (2 mL), extracted with EtOAc (2 mL*3), the organic phases were combined, dried under reduced pressure, and chromatographed by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 27%-57% B in 8.0 min) to obtain the target compound GDI15-6706 (3 mg, 7.24 μmol, 17.3% yield, 91% purity) as a light yellow solid. ESI-MS: [M+H] ⁺ , 377.1.

1H NMR (400MHz, DMSO) δ11.32-10.41(m,1H),9.65-8.87(m,1H),8.67-8.22(m,1H),8.14(d,J＝6.5Hz,1H),7.69(dd, J＝8.1,14.2Hz,3H),7.57(d,J＝5.6Hz,1H),7.51-7.39(m,3H),6.26(s,1H),2.48-2.37(m,2H),1.10(q,J＝7.4Hz,3H).

Example 45: Preparation of Compound GDI15-6766

1) Synthesis steps of compound 3

Under nitrogen protection at 0°C, NaH (0.1 g, 3.9 mmol) was added to a DMF (10 mL) solution of compound 1 (1 g, 3.6 mmol). The mixed system was allowed to react for 30 min at 0°C, and then SEMCl (0.78 g, 4.6 mmol) was added dropwise. After the addition was complete, the mixture was reacted at the same temperature for 1.5 h. After the reaction was completed, water (2 mL) was added to the system and extracted with EtOAc (20 mL*3). The organic fractions were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20:1) to obtain compound 2 (1.34 g, 86.11% yield) as an orange-red liquid. ESI-MS: [M+H] ⁺ , 408.75.

2) Synthesis steps of compound 4

Under nitrogen protection at room temperature, DMSO (12 mL) was added to compound 2 (1.18 g, 2.8 mmol), compound 3 (0.35 g, 3.2 mmol), potassium carbonate (1.33 g, 9.6 mmol) and CuI (I) (0.12 g, 0.6 mmol), and the mixture was stirred at 100 ° C for 8 h. After the reaction, water (40 mL) was added to the system and extracted with EtOAc (40 mL * 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product compound 4 (1.2 g, 87.26% yield) as a black oil. ESI-MS: [M+H] ⁺ , 391.85.

3) Synthesis steps of compound 5

DMF (12 mL) was added to a mixture of compound 4 (1.2 g, 3.1 mmol), CH3I (0.44 g, 3.1 mmol) and _K2CO3 (1.267 g, 9.2 mmol), and the _mixture was stirred at room temperature for 3 h. After the reaction, water (20 mL) was added to the mixture and extracted with EtOAc (30 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to give a crude product, compound 5 (1.8 g, 87.10% yield), as a black oil. ESI-MS: [M+H] ⁺ , 405.90.

4) Synthesis steps of compound 6

Add DMF (10 mL) solution to compound 5 (1 g, 2.5 mmol) and NBS (0.36 g, 2.0 mmol), stir and react for 3 h at room temperature under nitrogen protection, add water (20 mL) to the system after the reaction is completed and extract with EtOAc (30 mL*3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry, column chromatography (EtOAc/PE, 50% to 80%) to obtain compound 6 (160 mg, 12% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 485.85.

5) Synthesis steps of compound 8

A mixed solution of DMF/H ₂ O (2 mL/0.5 mL) was added to compound 6 (130 mg, 0.27 mmol), compound 7 (61.44 mg, 0.24 mmol), CsF (121.95 mg, 0.80 mmol) and Pd(dtbpf)Cl2 (17.28 mg, 0.03 mmol), and the mixture was stirred at 70°C for 3 h under nitrogen protection. After the reaction, water (2 mL) was added to the system and extracted with EtOAc (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20:1) to obtain compound 8 (70 mg, 49% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 533.10.

6) Synthesis steps of compound GDI15-6766

Add HBr solution in AcOH (1 mL) to compound 6 (60 mg, 0.11 mmol), and stir the mixture at 100°C for 16 h under nitrogen protection. After the reaction, concentrate the system and purify it by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6766 (20 mg, 46% yield) as a white solid. ESI-MS: [M+H] ⁺ , 389.05.

^1H NMR(400MHz,)δ13.43(s,1H),11.07(s,1H),9.45(s,1H),8.49(s,1H),8.28(d,J＝7.8Hz,1H) ,7.97(s,1H),7.92-7.76(m,4H),7.72(s,1H),7.29(d,J＝1.5Hz,1H),6.36(d,J＝7.7Hz,1H).

Example 46: Preparation of Compound GDI15-6549

1) Synthesis steps of compound 3

Compound 1 (1 g, 8.0 mmol), compound 2 (1.08 g, 8.0 mmol) and potassium carbonate (3.32 g, 24.0 mol) were dissolved in DMF (10 mL) and stirred at 100 ° C for 16 h. LCMS monitoring showed that the starting material disappeared and the target product appeared. After the reaction was completed, water (5 mL) was added to the system, and the solid was filtered out under reduced pressure to obtain a crude product, compound 3 (1.27 g, 66.25% yield) as a white solid.

^1H NMR (400MHz, DMSO) δ7.88(d,J＝7.9Hz,1H),7.59(d,J＝7.6Hz,1H),7.48(d,J＝7.9Hz,1H),7 .42(s,1H),6.11(dd,J＝7.6,2.7Hz,1H),5.93(d,J＝2.6Hz,1H),3.81(s,3H),2.44(s,3H).

2) Synthesis steps of compound 4

Compound 3 (1.27 g, 5.3 mmol) was dissolved in DMF (13 mL), and NBS (0.75 g, 4.2 mmol) was added under nitrogen protection at room temperature, followed by reaction at room temperature for 2 h. LCMS monitoring revealed the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, water (3 mL) was added to the system, and the solid was filtered out under reduced pressure to obtain the crude product compound 4 (850 mg, 50.25% yield) as a brown oily liquid. ESI-MS: [M+H] ⁺ , 320.95.

3) Synthesis steps of compound 6

Compound 4 (790 mg, 2.5 mmol), compound 5 (568.35 mg, 2.2 mmol), CsF (1127.99 mg, 7.4 mmol) and Pd(dtbpf)Cl ₂ (161.33 mg, 0.25 mmol) were dissolved in DMF/H2O (8 mL/2 mL) and stirred at 70°C for 2 h. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (1 mL) was added to the system and extracted with EtOAc (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 10:1) to obtain compound 8 (430 mg, 47.28% yield) as a yellow solid.

¹ H NMR (400MHz, DMSO) δ9.30(s,1H),8.34(s,1H),8.15(s,1H),7.99(d,J＝7.8Hz,1H),7.91(d,J＝7 .9Hz,1H),7.67(d,J＝2.8Hz,3H),7.57(s,1H),7.49(d,J＝7.9Hz,1H),3.81(s,3H),2.46(s,3H).

4) Synthesis steps of compound 8

Compound 6 (430 mg, 1.2 mmol) and NiCl ₂ .6H ₂ O (417.29 mg, 1.8 mmol) were dissolved in MeOH (5 mL) and stirred at 0°C under nitrogen protection for 10 min. Sodium borohydride (398.52 mg, 10.5 mmol) was then added in three batches. The mixed system was reacted at 0°C for 20 min. LCMS monitoring revealed that the reaction raw materials disappeared and the target product appeared. Boc ₂ O (2.55 g, 11.7 mmol) was added dropwise to the system and the temperature was raised to room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (PE/EtOAc, 1% to 80%) to obtain compound 8 (160 mg, 28.99% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 472.00.

5) Synthesis steps of compound GDI15-6549

Compound 8 (160 mg, 0.34 mmol) was dissolved in DMAC (2 mL), and decane-1-thiol (118.31 mg, 0.68 mmol) and sodium hydroxide (27.14 mg, 0.68 mmol) were added at room temperature under nitrogen protection. The reaction system was reacted at 100°C for 3 h. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6549 (9.16 mg, 7.56% yield) as a white solid. ESI-MS: [M+H] ⁺ , 357.75.

¹ H NMR (400MHz, DMSO) δ11.31(s,1H),9.40(s,1H),8.48-8.40(m,1H),7.95(s,3H),7.80-7.67(m,4H),7.51(d,J＝7.9 Hz,1H),7.39(d,J＝7.7Hz,1H),7.32-7.26(m,1H),6.44(d,J＝7.6Hz,1H),3.73-3.89(m,2H),2.39(d,J＝3.7Hz,3H).

Example 47: Preparation of compound GDI15-6550

1) Synthesis steps of compound 3

Compound 1 (2 g, 16 mmol) was dissolved in DMF (20 mL), and compound 2 (3.35 g, 18 mmol) and K ₂ CO ₃ (6.6 g, 48 mmol) were added at 0°C under nitrogen protection. The system was heated to 60°C and the reaction was continued for 16 h at this temperature. After the reaction was completed, water (100 mL) was added to the system and extracted with EtOAc (100 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (EtOAc/PE, 25% to 35%) to obtain compound 3 (1.7 g, 36.25% yield) as a white solid. ESI-MS: [M+H] ⁺ , 294.90.

2) Synthesis steps of compound 4

Compound 3 (1.5 g, 4.6 mmol) was dissolved in DMF (15 mL), NBS (0.8 g, 4.2 mol) was slowly added under nitrogen protection at 0 °C, and then the temperature was raised to room temperature for 2 h. LCMS monitoring revealed that the reaction raw materials disappeared and the target product appeared. After the reaction, water (100 mL) was added to the system, the residue was filtered out and washed with water, and the filtrate was dried to obtain the crude product compound 4 (1.5 g, 4.2 mmol, 89.93% yield) as a white solid. ESI-MS: [M+H] ⁺ , 374.90.

3) Synthesis steps of compound 6

Compound 4 (1.5 g, 4.0 mmol), compound 5 (1.0 g, 4.0 mmol), CsF (1.8 g, 12.0 mmol) and Pd(DtBPF)Cl ₂ (261.30 mg, 0.40 mmol) were dissolved in DMF/H ₂ O (10 mL/2 mL) and heated at 70°C for 4 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, water (200 mL) was added to the system and EtOAc (200 mL*3) was used and dried over anhydrous sodium sulfate. The mixture was filtered and purified by spin column chromatography (EtOAc/PE, 40% to 50%) to obtain compound 6 (500 mg, 1.2 mmol, 44% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 421.90.

4) Synthesis steps of compound 7

Compound 6 (400 mg, 0.95 mmol) and NiCl ₂ ·6H ₂ O (338 mg, 1.42 mmol) were dissolved in MeOH (20 mL) and stirred at 0°C under nitrogen protection for 5 min. Sodium borohydride (107 mg, 2.84 mmol) was then added in three batches. The system continued to react at 0°C for 10 min. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. Boc ₂ O (620 mg, 2.84 mmol) was then slowly added to the system. After the addition was complete, the system was warmed to room temperature and reacted at room temperature for 2 h. After the reaction was completed, the solvent was dried and further column chromatography (EtOAc/PE, 45% to 50%) was performed to obtain compound 7 (300 mg, 60.17% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 526.15.

5) Synthesis steps of compound GDI15-6550

Compound 7 (100 mg, 0.19 mmol), decane-1-thiol (77 mg, 0.38 mmol) and NaOH (15 mg, 0.38 mmol) were dissolved in DMAc (2 mL) and reacted at 100 °C under nitrogen protection for 2 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, the system was spin-dried and purified by column chromatography (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6550 (6.63 mg, 8.48% yield) as a white solid. ESI-MS: [M+H] ⁺ , 411.80.

¹ H NMR (400MHz, DMSO) δ11.28 (s, 1H), 9.38 (d, J = 6.9Hz, 1H), 8.46-8.38 (m, 1H), 8.26-8.10 (m, 4H), 8.05- 7.96(m,2H),7.86(d,J＝7.9Hz,1H),7.83-7.71(m,4H),6.45(dd,J＝7.6,1.7Hz,1H),4.01-3.93(m,2H).

Example 48: Preparation of compound GDI15-6625

1) Synthesis steps of compound 3

Compound 1 (200 mg, 1 mmol) was dissolved in DMF (2 mL), and compound 2 (252.27 mg, 1 mmol) and K ₂ CO ₃ (414.63 mg, 3 mmol) were added at room temperature under nitrogen protection, and the system was heated to 100°C and reacted at this temperature for 16 hours. After the reaction, water was added, and the residue was filtered and washed with water. The filtrate was dried to obtain the crude product compound 3 (334 mg, 61.81% yield) as a white solid. ESI-MS: [M+H] ⁺ , 433.80.

2) Synthesis steps of compound 4

Compound 3 (170 mg, 0.39 mmol) and NiCl ₂ .6H ₂ O (140.23 mg, 0.59 mmol) were dissolved in MeOH (2 mL), stirred at 0°C under nitrogen protection for 10 min, then NaBH ₄ (44.6 mg, 1.18 mmol) was slowly added, and the reaction was continued at 0°C for 20 min. LCMS detected that the reaction raw materials disappeared and the target product Then Boc ₂ O (429.19 mg, 2.00 mmol) was added dropwise, the reaction temperature was raised to room temperature, and stirring was continued for 10 h. The solution was dried under reduced pressure and purified by column chromatography (EtOAc/PE, 80% to 1%) to obtain compound 4 (190 mg, 54.03% yield) as a light yellow solid. ESI-MS: [M+H] ⁺ , 536.10.

3) Synthesis steps of compound GDI15-6625

Compound 4 (150 mg, 0.28 mmol) was dissolved in a solution of HBr in AcOH (2 mL), and the system was heated to 100°C under nitrogen protection for 16 h. The mixed system was concentrated under reduced pressure and column chromatography prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) was used to obtain compound GDI15-6625 (10.36 mg, 8.48% yield) as a white solid. ESI-MS: [M+H] ⁺ , 422.00.

¹ H NMR (400MHz, DMSO) δ11.33(s,1H),9.39(s,1H),8.46-8.39(m,1H),8.28-8.20(m,1H),8.07-8.02(m,3H),7.87-7.81(m ,2H),7.78(s,1H),7.74(dd,J＝7.2,5.6Hz,2H),7.58(dd,J＝8.6,2.4Hz,1H),6.43(d,J＝7.6Hz,1H),3.94-3.77(m,2H).

Example 49: Preparation of compound GDI15-6918

1) Synthesis steps of compound 3

Compound 1 (2 g, 7.9 mmol) and compound 2 (1.41 g, 7.1 mmol) were dissolved in 10 mL DMF. Under nitrogen protection, K ₂ CO ₃ (3.28 g, 23.7 mmol) was added. The system was reacted at 100°C for 3 h. LCMS monitoring revealed that the reaction raw materials disappeared and the target product appeared. After the reaction was completed, water (100 mL) was added to the system and the reaction mixture was stirred for 2 h. DCM (50 mL*2) was used for extraction, and column chromatography (DCM/MeOH, 1v:0v to 10v:1v) was performed to obtain compound 3 (1.3 g, 3 mmol, 37.97% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 431.75.

2) Synthesis steps of compound 4

Compound 3 (200 mg, 0.46 mmol) was dissolved in 6 mL THF, the system was cooled to 0°C, and a THF solution of LiAlH ₄ (0.2 mL, 0.23 mmol) was added dropwise under nitrogen protection, and the reaction was continued at 0°C for 1 h. After the reaction was completed, 0.3 mL NH ₄ Cl solution was added to quench the reaction, and the system was concentrated and purified by column chromatography (DCM/H ₂ O, 1v:0v to 10v:1v) to obtain compound 4 (80 mg, 0.20 mmol, 42.77% yield) as a white solid. ESI-MS: [M+H] ⁺ , 404.05.

3) Synthesis steps of compound 5

Compound 4 (70 mg, 0.17 mmol) was dissolved in 5 mL DCM, and a 1 mL DCM solution of PBr ₃ (70.45 mg, 0.26 mmol) was slowly added under nitrogen protection at 0°C. The reaction system was stirred at room temperature for 0.5 h, then quenched with 10 mL H ₂ O, extracted with DCM, and the organic phase was concentrated and dried to give compound 5 (65 mg, 0.11 mmol, 77.8% yield) as a yellow oily liquid. ESI-MS: [M+H] ⁺ , 466.05.

4) Synthesis steps of compound 6

Add 2 mL of ammonia water to a 2 mL THF solution of compound 5 (55 mg, 0.12 mmol), and react for 3 h at room temperature under nitrogen protection. LCMS monitoring shows that the reaction raw material disappears and the target product appears. After the reaction is completed, the system is concentrated and dried to obtain a crude product, compound 6 (60 mg, 0.32 mmol, 77.8% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 403.15.

5) Synthesis steps of compound 7

Compound 6 (60 mg, 0.15 mmol) was dissolved in 4 mL MeOH solution, and Boc ₂ O (65 mg, 0.30 mmol) was added dropwise under nitrogen protection at room temperature. The reaction was continued under stirring for 16 h at room temperature. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, the system was concentrated and dried and purified on a TLC plate (TLC: DCM: MeOH, 15: 1). Compound 7 (30 mg, 0.054 mmol, 36.02% yield) was obtained as a yellow solid. ESI-MS: [M+H] ⁺ , 403.15.

5) Synthesis steps of compound GDI15-6918

Compound 7 (140 mg, 0.28 mmol) was dissolved in 4 mL HBr/HOAc solution, and the system was stirred at 100 °C for 16 h. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, the solvent was dried in vacuo and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) gave compound GDI15-6918 (0.91 mg, 0.0023 mmol, 0.83% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 389.15.

1H NMR(400MHz,MeOD)δ9.61(d,J＝11.4Hz,1H),8.57-8.45(m,3H),8.41(d,J＝6.6Hz,1H),8.07-7.96(m,3H),7.90 (d,J＝8.7Hz,1H),7.80(dd,J＝7.5,5.2Hz,1H),6.58(dd,J＝7.6,3.6Hz,1H),4.26-4.18(m,1H),4.14-4.08(m,1H).

Example 50: Preparation of compound GDI15-6467

1) Synthesis steps of compound 3

Compound 1 (450 mg, 1.2 mmol), compound 2 (290 mg, 1.3 mmol), CsF (604 mg, 4.0 mmol) and Pd(DtBPF)Cl ₂ (172 mg, 0.26 mmol) were dissolved in DMF/H ₂ O (8 mL/2 mL), stirred at 70°C under nitrogen protection for 5 h, and the target product appeared after the disappearance of the reaction raw materials by LCMS monitoring. After the reaction, water (20 mL) was added, and extracted with EtOAc (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered to dryness on a column layer (PE/EtOAc, 1v:1v to 1v:2v) to obtain compound 3 (300 mg, 0.81 mmol, 61.1% yield) as a black oil. ESI-MS: [M+H] ⁺ , 351.85.

2) Synthesis steps of compound 4

Compound 3 (300 mg, 0.76 mmol) and NiCl ₂ .6H ₂ O (303 mg, 1.28 mmol) were dissolved in MeOH (5 mL) and stirred at 0°C under nitrogen protection for 5 min, and then sodium borohydride was added three times. (97mg, 1.7mmol), the reaction system was continued to react at 0℃ for 10min, LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product, then Boc ₂ O (288mg, 1.32mmol) was added dropwise to the reaction system, the system was warmed to room temperature and reacted at room temperature for 1h. After the reaction was completed, water H ₂ O (10mL) was added to the system and extracted with DCM (20mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20:1 to 10:1) to obtain compound 4 (300mg, 0.65mmol, 85.5% yield) as a black oil. ESI-MS: [M+H] ⁺ , 456.10.

3) Synthesis steps of compound GDI15-6467

Compound 4 (100 mg, 0.22 mmol), decane-1-thiol (53 mg, 0.26 mmol) and NaOH (11 mg, 0.26 mmol) were dissolved in DMAc (2 mL) and stirred at 100°C under nitrogen protection for 2 hours. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, the system was spin-dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6467 (5.11 mg, 4.3% yield) as a white solid. ESI-MS: [M+H] ⁺ , 342.00.

1H NMR(400MHz,DMSO)δ12.02(s,1H),8.22-8.63(m,1H),8.22-8.15(m,4H),7.73-7 .63(m,3H),7.60(d,J＝1.9Hz,1H),6.41(d,J＝7.6Hz,1H),3.83(s,2H),2.44(s,3H).

Example 51: Preparation of compound GDI15-6506

1) Synthesis steps of compound 3

Compound 1 (2g, 16mmol), compound 2 (2.49g, 16mmol) and potassium carbonate (6.63g, 48mmol) were dissolved in DMF (20mL) and stirred at 60℃ under nitrogen protection for 3 hours. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, water (10mL) was added to the system, the solid was filtered out and washed with water, and the filtrate was dried to obtain the crude product compound 3 (2.5g, 9.1mmol, 60% yield) as a white solid. ESI-MS: [M+H] ⁺ , 261.00.

2) Synthesis steps of compound 4

Compound 3 (2.5 g, 9.6 mmol) and NiCl ₂ .6H ₂ O (3.42 g, 14.4 mmol) were dissolved in MeOH (30 mL), stirred and reacted at 0°C under nitrogen protection for 5 min, then sodium borohydride (1.09 g, 28.8 mmol) was added three times, and the reaction continued at 0°C for 10 min. LCMS monitoring showed that the reaction raw materials disappeared and the target product appeared. Boc ₂ O (6.29 g, 28.8 mmol) was added dropwise to the system, and the system was warmed to room temperature and continued to react for 1 h. After the reaction was completed, water (30 mL) was added to the system and extracted with DCM (50 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM: MeOH, 20:1 to 10:1) to obtain compound 4 (460 mg, 1.3 mmol, 13.54% yield) as a yellow solid. ESI-MS: [M+H] ⁺ ,365.00.

3) Synthesis steps of compound 5

Compound 4 (460 mg, 1.26 mmol) and NBS (202 mg, 1.13 mmol) were dissolved in DMF (5 mL) and stirred under nitrogen protection for 2 h at room temperature. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction was completed, water (20 mL) was added to the system and extracted with EtOAc (20 mL*3). The organic phases were combined and The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM:MeOH, 20:1 to 10:1) to obtain compound 5 (260 mg, 0.59 mmol, 46.47% yield) as a yellow solid.

¹ H NMR (400MHz, DMSO) δ7.74(d,J＝7.7Hz,1H),7.58(dd,J＝8.3,2.0Hz,1H),7.46(d,J＝2.1Hz,1H),7.42 -7.39(m,1H),7.32-7.24(m,2H),6.54(d,J＝7.8Hz,1H),4.01-3.96(m,3H),1.37(d,J＝11.1Hz,9H).

4) Synthesis steps of compound 7

Compound 5 (230 mg, 0.52 mmol), compound 6 (107.32 mg, 0.47 mmol), CsF (236.19 mg, 1.56 mmol) and Pd(dtbpf)Cl ₂ (33.78 mg, 0.052 mmol) were dissolved in DMF/H ₂ O (3 mL/0.75 mL), stirred at 50°C under nitrogen protection for 3 hours, and the reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (20 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20:1 to 10:1) to obtain compound 7 (166 mg, 0.45 mmol, 87.32% yield) as a yellow oil.

¹ H NMR (400MHz, CDCl ₃ )δ9.05-8.76(m,1H),8.25-8.17(t,J＝14.5Hz,1H),7.50-7.39(m,2H),7.29-7.04(m,1H),6.39-6.23(m,1H),5.30(s,1H),4.02(s,1H).

4) Synthesis steps of compound GDI15-6506

Compound 7 (140 mg, 0.38 mmol), decane-1-thiol (133.10 mg, 0.76 mmol) and NaOH (30.53 mg, 0.76 mmol) were dissolved in DMAC (5 mL) and stirred at 100°C under nitrogen protection for 2 hours. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, the system solvent was dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6506 (10.08 mg, 7.94% yield) as a white solid. ESI-MS: [M+H] ⁺ , 353.05.

¹ H NMR (400MHz, DMSO) δ7.88(d,J＝7.9Hz,1H),7.59(d,J＝7.6Hz,1H),7.48(d,J＝7.9Hz,1H),7 .42(s,1H),6.11(dd,J＝7.6,2.7Hz,1H),5.93(d,J＝2.6Hz,1H),3.81(s,3H),2.44(s,3H).

Example 52: Preparation of Compound GDI15-6461

1) Synthesis steps of compound 3

Compound GDI15-6288-INT4 (500 mg, 1.47 mmol), compound 2 (327.88 mg, 1.47 mmol), CsF (446.6 mg, 2.94 mmol) and Pd(DtBPF)Cl2 (96.9 mg, 0.15 mmol) were dissolved in DMF/H ₂ O (8 mL/2 mL), stirred at 50°C under nitrogen protection for 2 hours, and the reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction was completed, water (20 mL) was added to the system and extracted with EtOAc (20 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the column layer was filtered and dried. Compound 3 (320 mg, 0.90 mmol, 61.22% yield) was obtained by precipitation (PE/EtOAc, 1v:1v to 1v:2v) as a yellow solid. ESI-MS: [M+H] ⁺ , 355.65.

^1H NMR (400MHz, DMSO) δ8.49(t,J＝1.6Hz,1H),8.46(d,J＝2.8Hz,1H),8.11(d,J＝8.4Hz,1H),7.98(dd, J＝13.2,5.0Hz,2H),7.81(dd,J＝8.4,2.0Hz,1H),7.72(m,1H),6.72(d,J＝8.0Hz,1H),3.93(s,3H).

2) Synthesis steps of compound 4

Compound 3 (320 mg, 0.90 mmol) and NiCl ₂ .6H ₂ O (320.76 mg, 1.35 mmol) were dissolved in MeOH (5 mL) solution and reacted for 5 min under nitrogen protection at 0°C. Sodium borohydride (102.14 mg, 2.7 mmol) was then added in three batches. The mixed system was stirred at 0°C for 10 min. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. Boc ₂ O (589.1 mg, 2.7 mmol) was added dropwise to the mixed system, the reaction system was warmed to room temperature, and reacted at room temperature for 1 h. After the reaction, water (20 mL) and DCM (20 mL*3) were added to the system for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE:EtOAc, 1v:1v to 1v:2v) to obtain compound 4 (180 mg, 0.39 mmol, 43.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ ,459.95.

¹ H NMR (400MHz, CDCl3) δ8.55(s,1H),8.34(d,J＝2.4Hz,1H),7.65(d,J＝9.8Hz,1H),7.41(m,3H),7. 21(d,J＝1.6Hz,1H),6.36(d,J＝7.8Hz,1H),4.32(m,1H),4.11(m,1H),3.89(s,3H),1.42(m,9H).

3) Synthesis steps of compound GDI15-6461

Compound 4 (150 mg, 0.33 mmol), decane-1-thiol (79.23 mg, 0.39 mmol) and NaOH (15.66 mg, 0.39 mmol) were dissolved in DMAc (3 mL) and stirred at 100 ° C under nitrogen protection for 2 hours. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, the system solvent was dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H2O containing 0.1% TFA) to obtain compound GDI15-6461 (11.91 mg, 10.45% yield) as a white solid. ESI-MS: [M+H] ⁺ , 346.05.

¹ H NMR (400MHz, DMSO) δ11.74(s,1H),8.57(t,J＝1.7Hz,1H),8.44(d,J＝2.8Hz,1H ),8.06(m,3H),7.80(m,1H),7.66(m,4H),6.38(d,J＝7.6Hz,1H),3.84(m,2H).

Example 53: Preparation of compound GDI15-6651

1) Synthesis steps of compound 2

Compound 1 (5 g, 23.10 mmol) was dissolved in dry THF (50 mL), and BH3-THF (1M in cyclohexane, 69.3 mL, 69.30 mmol) was added dropwise at 20 °C under nitrogen protection. After the addition was complete, the system was reacted at 70 °C for 1 h. After cooling to room temperature, HCl (34.6 mL, 69.30 mmol) was added dropwise to the system, and then the system was heated to 70 °C for 1 h. After the reaction was completed, NaOH (50 mL, 2 mol/L) aqueous solution was added to the system to quench the reaction, and extracted with DCM (200 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to obtain the crude product Compound 2 (4.0 g), which was used directly in the next step without further purification. ESI-MS: [M+H] ⁺ , 221.85.

2) Synthesis steps of compound 3

Compound 2 (500 mg, 2.27 mmol), BOC ₂ O (594 mg, 2.72 mmol) and TEA (574 mg, 5.70 mmol) were dissolved in DCM (5 mL) and stirred at 20°C under nitrogen protection for 2 h. After the reaction, water (100 mL) was added to the system, and extracted with EtOAc (100 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 5% to 25%) to obtain compound 3 (400 mg, 52.27% yield) as a white solid.

¹ H NMR (400MHz, DMSO) δ7.72 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.3 Hz, 1H), 4.13 (d, J = 6.0 Hz, 2H), 1.40 (s, 9H).

3) Synthesis steps of compound 4

Compound 3 (500 mg, 1.56 mmol), bis(pyrinatoyl)diboron (990 mg, 3.90 mmol), potassium acetate (459 mg, 4.68 mmol) and Pd(dppf)Cl ₂ (127 mg, 0.16 mmol) were dissolved in 1,4-dioxane (6 mL) and stirred at 100°C under nitrogen protection for 18 hours. LCMS monitoring revealed that the reaction raw materials disappeared and the target product appeared. After the reaction, H ₂ O (200 mL) was added to the system and extracted with EtOAc (100 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 10:90) to obtain compound 4 (200 mg, 34.88% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 368.1.

4) Synthesis steps of compound 6

Compound 4 (100 mg, 0.27 mmol), compound 5 (45 mg, 0.14 mmol), CsF (124 mg, 0.82 mmol) and Pd(DtBPF)Cl ₂ (18 mg, 0.027 mmol) were dissolved in DMF/H ₂ O (0.5 mL/0.1 mL) and reacted at 50°C under nitrogen protection for 4 hours. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction was completed, water H ₂ O (20 mL) was added to the system and extracted with EtOAc (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 96:4 to 95:5) to obtain compound 6 (50 mg, 37.35% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 492.15.

5) Synthesis steps of compound GDI15-6461

Compound 6 (50 mg, 0.10 mmol) was dissolved in 33% HBr in AcOH (3 mL) solution, stirred at 100°C under nitrogen protection for 16 h, after the reaction, Na ₂ CO ₃ aqueous solution (20 mL) was added to the system to adjust the pH to 6-7, the crude product was further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6651 (3.26 mg, 8.46% yield) as a white solid. ESI-MS: [M+H] ⁺ , 378.1.

¹ H NMR (400MHz, DMSO) δ11.51(s,1H),9.46(s,1H),8.59-8.54(m,1H),8.30(t,J＝7.6Hz,1H),7.98-7.84(m,4H),7.80(t,J＝7. 6Hz,2H),7.64(d,J＝8.1Hz,1H),7.59-7.47(m,3H),7.38(d,J＝2.2Hz,1H),6.45(dd,J＝7.5,2.9Hz,1H),3.99-3.75(m,2H).

Example 54: Preparation of Compound GDI15-6798

1) Synthesis steps of compound 3

Compound 1 (200.00 mg, 0.79 mmol) and K ₂ CO ₃ (328.72 mg, 2.38 mol) were dissolved in DMF (4 mL), bromoacetonitrile (190.20 mg, 1.59 mol) was slowly added under nitrogen protection, and the mixed system was reacted at 50°C for 5 h. After the reaction, water (30 mL) was added to the system, the solid residue was filtered out and washed with water, dried and then spin-dried to obtain the crude product compound 3 (160 mg, 69.28% yield) as an off-white solid. ESI-MS: [M+H] ⁺ , 292.

2) Synthesis steps of compound 4

DMF (1 mL) was added to a mixture of compound 3 (160.00 mg, 0.27 mmol), NBS (97.74 mg, 0.55 mmol) and TFA (0.31 mg, 0.0027 mmol) under nitrogen protection. The mixture was stirred at 20°C for 2 h. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (20 mL) was added to the system and extracted with EtOAc (20 mL*3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 70:30) to obtain compound 4 (80 mg, 74.75% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 372.1.

3) Synthesis steps of compound 6

A mixed solvent of dioxane (8 mL) and H 2 O (1 mL) was added to a system of compound 4 (80.00 mg, 0.22 mmol), compound 5 (33.79 mg, 0.22 mmol), Pd( _dppf )Cl ₂ (31.62 mg, 0.043 mmol) and K ₃ PO ₄ (91.74 mg, 0.43 mmol), and the mixture was refluxed at 60°C for 2 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was extracted with water and ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (MeOH/DCM, 4% to 5%) to obtain compound 6 (40 mg, 46.07% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 402.0.

4) Synthesis steps of compound GDI15-6798

DMAc (2 mL) was added to the system of compound 6 (40 mg, 0.10 mmol), decane-1-thiol (40 mg, 0.20 mmol) and sodium hydroxide (6.37 mg, 0.16 mmol), and the mixture was reacted at 50°C for 1 h under nitrogen protection. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, the system solution was spin-dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6798 (13.36 mg, 16.88% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 492.15.

¹ H NMR (400MHz, DMSO) δ10.44(s,1H),9.63(s,1H),8.55(s,1H),8.39(d,J＝8.0Hz,1H),8.11(s,1H),7 .99-7.92(m,1H),7.87(m,1H),7.77(d,J＝8.4Hz,1H),7.62(s,1H),7.54-7.41(m,3H),5.04(s,2H).

Example 55: Preparation of Compound GDI15-6936

1) Synthesis steps of compound 3

Compound 1 (178.78 mg, 0.49 mmol), compound 2 (150 mg, 0.41 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (28.44 mg, 0.0405 mmol) and K ₃ PO ₄ (172.02 mg, 0.81 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and stirred at 60°C for 1.5 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and column chromatography (MeOH/DCM, 5% to 6%) was performed to obtain compound 3 (100 mg, 46.67% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 531.2.

2) Synthesis steps of compound GDI15-6936

Compound 3 (50 mg, 0.094 mmol) was dissolved in NMP (2 mL), and PPTS (118.36 mg, 0.47 mmol) and LiCl (19.97 mg, 0.47 mmol) were added to the system. After the addition was completed, the system was stirred at 80°C for 16 h. The resulting mixture was further purified by Biotage Isolera One (C18 column, eluent 10% to 90% MeCN/H ₂ O containing 0.1% FA formic acid) to obtain compound GDI15-6936 (16.22 mg, 48.94% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 417.1.

^1H NMR (400MHz, DMSO) δ9.47(d,J＝9.6Hz,1H),8.44(d,J＝17.1Hz,1H),8.35-8.25(m,1H),8.14(d ,3H),7.89(s,1H),7.87-7.75(m,2H),7.70-7.44(m,4H),5.03(s,2H),3.99(d,J=5.2Hz,2H).

Example 56: Preparation of compound GDI15-6845

1) Synthesis steps of compound 3

DMF (2 mL) was added to the system of compound 1 (200 mg, 0.79 mmol), compound 2 (236.52 mg, 1.59 mmol) and K ₂ CO ₃ (328.72 mg, 2.38 mmol), and the mixture was stirred at 75°C for 16 h under nitrogen protection. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (20 mL) was added to the system, the solid residue was filtered out and washed with water, and the filtrate was dried to obtain the crude product compound 3 (150 mg, 0.49 mmol, 61.97% yield) as a white solid. ESI-MS: [M+H] ⁺ , 306.1.

2) Synthesis steps of compound 4

DMF (2 mL) was added to the system of compound 3 (150 mg, 0.49 mmol), NBS (437.21 mg, 2.46 mmol) and TFA (112 mg, 0.98 mmol), and the mixture was stirred under nitrogen protection at room temperature for 1 h. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (30 mL) was added to the system, the solid residue was filtered and washed with water, and the filtrate was concentrated and dried to obtain the crude product compound 4 (130 mg, 0.34 mmol, 68.86% yield) as a white solid. ESI-MS: [M+H] ⁺ , 384.00.

3) Synthesis steps of compound 6

A mixed solvent of DMF/H ₂ O (2 mL) was added to the system of compound 4 (130 mg, 0.34 mmol), compound 5 (53 mg, 0.34 mmol), potassium phosphate (144 mg, 0.68 mmol) and Pd(dtbpf)Cl ₂ (28 mg, 0.034 mmol), and the mixture was stirred at 60°C for 1 h under nitrogen protection. The target product appeared after the disappearance of the reaction raw materials by LCMS monitoring. After the reaction, water (20 mL) was added to the system, and the mixture was extracted with EtOAc (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and further purified by column chromatography (PE/EtOAc, 1v:1v to 1v:2v) to obtain compound 6 (60 mg, 0.14 mmol, 42.65% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 416.05.

4) Synthesis steps of compound GDI15-6845

NMP (3 mL) was added to compound 6 (60 mg, 0.14 mmol, 1 eq), PPTS (181 mg, 0.72 mmol) and LiCl (30.58 mg, 0.72 mmol), and the mixture was stirred at 120°C under nitrogen protection for 1 h. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, the system solution was concentrated, and NaHCO ₃ (24 mg, 0.28 mmol, 2 eq) was added dropwise to the system to quench the reaction, filtered and concentrated, and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% ammonia water) to obtain compound GDI15-6845 (11.04 mg, 19.06% yield) as a white solid. ESI-MS: [M+H] ⁺ , 402.10.

¹ H NMR (400MHz, DMSO) δ9.90(s,1H),9.26(m,1H),8.33(s,1H),8.14(m,1H),7.90(m,1H),7.63(m,5H),7.42(m,2H),4.18(m,2H),2.99(m,2H).

Example 57: Preparation of Compound GDI15-6967

1) Synthesis steps of compound 3

Compound 1 (1.0 g, 3.96 mmol) was dissolved in DMF (10 mL). Compound 2 (1.34 g, 5.94 mmol) and K ₂ CO ₃ (1.64 g, 11.89 mmol) were added to the system under nitrogen protection. The mixed system was stirred at 80°C for 6 h. After the reaction, water (50 mL) was added to the system and extracted with EtOAc (50 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (MeOH/DCM, 3% to 5%) to obtain compound 3 (610 mg, 1.75 mmol, 44.2% yield) as a white solid. ESI-MS: [M+H] ⁺ , 349.1.

2) Synthesis steps of compound 4

Compound 3 (610 mg, 1.75 mmol), NBS (623 mg, 3.5 mmol) and TFA (399 mg, 3.5 mmol) were dissolved in DMF (6 mL) and stirred at room temperature under nitrogen protection for 2 h. LCMS monitored the disappearance of the reaction raw materials and the appearance of the target product. After the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% ammonia water) to obtain compound 4 (320 mg, 0.75 mmol, 42.8% yield) as a white solid. ESI-MS: [M+H] ⁺ , 426.90.

3) Synthesis steps of compound 6

Compound 4 (320 mg, 0.75 mmol), compound 5 (175 mg, 1.12 mmol) and K ₃ PO ₄ (476 mg, 2.24 mmol) were dissolved in 5 mL of dioxane: water (10:1), and xphos-Pd-G2 (117 mg, 0.15 mmol) was added at 60°C under nitrogen protection, and the system continued to react at 60°C for 4 h. After the reaction, water (20 mL) was added to the system and extracted with EtOAc (20 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM: MeOH, 1v:1v to 10v:1v) to obtain compound 6 (58 mg, 0.13 mmol, 16.87% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 459.05.

4) Synthesis steps of compound GDI15-6967

Compound 6 (56 mg, 0.12 mmol, 1 eq), PPTS (153 mg, 0.61 mmol) and LiCl (26 mg, 0.61 mmol) were dissolved in NMP (3 mL) and stirred at 120 °C for 1 h under nitrogen protection. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90%).

MeCN/H ₂ O containing 0.1% ammonia water) to give compound GDI15-6967 (3.09 mg, 5.67% yield) as a white solid. ESI-MS: [M+H] ⁺ , 445.0.

^1H NMR(400MHz,DMSO)δ9.84(m,1H),9.28(m,1H),8.32(m,1H),8.15(m,1H),7.98(m,1 H),7.65(m,3H),7.60(m,1H),7.53(m,1H),7.43(m,2H),4.17(m,2H),2.76(s,2H).

Example 58: Preparation of compound GDI15-7065

1) Synthesis steps of compound 1

DMSO (10 mL) and TEA (211 mg, 2.09 mmol, 1.5 eq) were added to the system of compound GDI15-6547-INT 8 (680 mg, 1.39 mmol, 1.0 eq), PdAMPHOS (99 mg, 0.14 mmol, 0.1 eq) and triethylsilane (485 mg, 4.17 mmol, 3.0 eq), CO was protected, and the mixture was heated to 90°C and stirred for 8 h. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and flash column chromatography (PE/EtOAc, 1:2) was performed to obtain compound 1 (160 mg, 0.41 mmol, 29.42% yield) as a white solid. ESI-MS: [M+H] ⁺ , 391.15.

2) Synthesis steps of compound 2

Potassium tert-butoxide (1M in THF, 1mL, 1mmol) was added to a three-necked round-bottom flask equipped with a stirring bar, a reflux condenser and an addition funnel. The flask was cooled in a dry ice-acetonitrile bath, and a solution of TosMIC (120mg, 0.61mmol) in DME (1.5mL) was added to the system. After the system was stirred for a few minutes, a solution of compound 1 (160mg, 0.41mmol) in DME (1.5mL) was added dropwise. The addition was completed over 30min. After two hours of reaction in an ice bath, the mixture was gradually restored to room temperature, methanol (4 mL) was added to the system, and the reaction was continued at room temperature for 14 h. After the system was concentrated in vacuo, 20 mL of dichloromethane was added, and the mixture was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried by column chromatography (PE/EtOAc, 1v:1v to 1v:2v) to obtain compound 2 (50 mg, 0.12 mmol, 30.39% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 402.05.

3) Synthesis steps of compound GDI15-7065

Compound 2 (50 mg, 0.12 mmol), decane-1-thiol (50 mg, 0.25 mmol) and NaOH (10 mg, 0.25 mmol) were dissolved in DMAc (2 mL) and stirred at 90°C for 2 h under nitrogen protection. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% ammonia water) to obtain compound GDI15-7065 (4.28 mg, 8.84% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 387.95.

^1H NMR (400MHz, DMSO) δ9.02(s,1H),8.28(s,1H),7.99(dd,J＝6.6,2.6Hz,1H),7.72(m,1H),7.52(m,3H),7.43(d,J＝7.9Hz,1H),7.36(m,3H),3.45(s,2H).

Example 59: Preparation of compound GDI15-6920

1) Synthesis steps of compound 3

Bromoacetonitrile (5.8 mg, 47.95 mmol) and K ₂ CO ₃ (16.6 mg, 119.88 mmol) were added to a DMF (20 mL) solution of compound 1 (5.0 g, 39.96 mmol), and the mixture was stirred at 50° C. for 2 h. After the reaction, water (200 mL) was added to the system and extracted with EtOAc (200 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and further purified by column chromatography (MeOH/DCM, 2% to 3%) to obtain compound 3 (4.5 g, 68.60% yield) as a yellow solid.

¹ H NMR (400MHz, DMSO) δ7.65 (d, J＝7.7Hz, 1H), 6.06 (dd, J＝7.7, 2.7Hz, 1H), 5.88 (d, J＝2.7Hz, 1H), 4.92 (s, 2H), 3.75 (s, 3H).

2) Synthesis steps of compound 4

Add DMF (10 mL) to compound 3 (4.50 g, 27.41 mmol) and NBS (4.4 g, 15.57 mmol), stir and react for 2 h at room temperature under nitrogen protection, and monitor the disappearance of the reaction raw materials and the appearance of the target product by LCMS. After the reaction, add water (300 mL) to the system, filter out the solid residue and wash with water, concentrate the filtrate and spin dry to obtain compound 4 (5.1 g, 8.86 mmol, 76.55% yield) as a white solid. ESI-MS: [M+H] ⁺ , 245.0.

3) Synthesis steps of compound 6

DMF/H ₂ O (4 mL/1 mL) was added to the system of compound 4 (400 mg, 1.65 mmol), compound 5 (378.63 mg, 1.65 mmol), CsF (749.95 mg, 4.94 mmol) and Pd(DtBPF)Cl ₂ (106.26 mg, 0.16 mmol), and the mixture was stirred at 70°C for 2 h under nitrogen protection. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, water (100 mL) was added to the system, and the mixture was extracted with EtOAc (100 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 1v:1v to 1v:2v) to obtain compound 6 (500 mg, 1.29 mmol, 58.2% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 266.9.

4) Synthesis steps of compound 7

DMF (5 mL) was added to the system of compound 6 (400 mg, 1.50 mmol) and NBS (267.38 mg, 1.50 mmol), and the reaction was stirred at room temperature for 2 h under nitrogen protection. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction was completed, water (100 mL) was added to the system, the residue was filtered and washed with water, and the filtrate was concentrated and dried to obtain the crude product compound 7 (510 mg, 1.48 mmol, 98.36% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 346.9.

5) Synthesis steps of compound 9

A mixed solution of dioxane (12 mL) and H 2 O (3 mL) was added to the system of compound 7 (300 mg, 0.87 mmol), compound 8 (135.92 mg, 0.87 mmol), Pd( _dppf )Cl ₂ DCM (71.01 mg, 0.087 mmol) and K ₃ PO ₄ (369.01 mg, 1.74 mmol), and the mixture was stirred at 60°C under nitrogen protection for 1 h. After the reaction, water (50 mL) was added to the system and extracted with EtOAc (50 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 50% to 60%) to obtain compound 9 (210 mg, 64.12% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 377.1.

6) Synthesis steps of compound GDI15-6920

DMAc (3 mL) solution was added to a mixture of compound 9 (210 mg, 0.56 mmol), decane-1-thiol (225.60 mg, 1.11 mmol) and NaOH (22.29 mg, 0.56 mmol), and the mixture was stirred at 50°C for 2 h under nitrogen protection. The reaction raw materials disappeared and the target product appeared after LCMS monitoring. After the reaction, the system was concentrated and dried, and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6920 (3.09 mg, 1.47% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 363.1.

¹ H NMR (400MHz, DMSO) δ10.70(s,1H),8.96(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.33 (t,J＝2.0Hz,1H),7.99(s,1H),7.58(d,J＝0.9Hz,1H),7.49-7.42(m,3H),5.01(s,2H).

Example 60: Preparation of compound GDI15-6937

1) Synthesis steps of compound 3

20 mL of DMF:H ₂ O (5:1) mixed solvent was added to the mixed system of compound 1 (1.0 g, 4.11 mmol), compound 2 (991.53 mg, 4.52 mmol) and CsF (2.19 g, 14.4 mmol), Pd-118 (268.15 mg, 0.41 mmol) was added under nitrogen protection at room temperature, and the temperature was raised to 70°C for reaction for 16 h. The reaction was monitored by LCMS. After the reaction, the system was concentrated and dried, and further purified by column chromatography (DCM/MeOH, 1v:0v to 10v:1v) to obtain compound 3 (773 mg, 3.02 mmol, 73.6% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 255.95.

2) Synthesis steps of compound 6

2 mL of a 5:1 1,4-dioxane/water solution was added to a mixture of compound 4 (200 mg, 0.60 mmol), compound 5 (112.31 mg, 0.72 mmol) and K ₃ PO ₄ (381.13 mg, 1.79 mmol), and Pd(dppf)Cl ₂ (65 mg, 0.09 mmol) was added under nitrogen protection. The mixture was stirred at 60°C for 1 h. The reaction was completed after LCMS monitoring. After the reaction was completed, the system was concentrated and purified by thin layer chromatography (DCM:MeOH, 15:1) to obtain a crude product, compound 6 (200 mg, 0.55 mmol, 91.35% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 366.15.

2) Synthesis steps of compound GDI15-6937

Compound 6 (90 mg, 0.25 mmol) and PPTS (309.1 mg, 1.23 mmol) were dissolved in 3 mL of NMP, and LiCl (52.14 mg, 1.23 mmol) was added under nitrogen protection and stirring at room temperature. The mixed system was stirred at 120°C for 2 h, and the reaction was completed by LCMS monitoring. After the reaction was completed, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6937 (50.46 mg, 0.143 mmol, 58.29% yield) as a white solid. ESI-MS: [M+H] ⁺ , 352.10.

1H NMR (400MHz, DMSO) δ8.73(s,1H),8.58(s,1H),8.27(s,1H),7.98(s,1H),7.59(s,1H),7.48-7.42(m,3H),5.00(s,2H),2.46(s,3H).

Example 61: Preparation of compound GDI15-7085

1) Synthesis steps of compound 2

Compound 1 (700 mg, 3.08 mmol, 1 eq) was dissolved in 1,4-dioxane (7 mL), and then hexamethyltin (1.11 g, 3.39 mmol, 703 μL, 1.1 eq) and Pd(PPh ₃ ) ₂ Cl ₂ (649 mg, 925 μmol, 0.3 eq) were added at 25°C. Under nitrogen protection, the reaction mixture was stirred at 100°C for 1 hour, and the reaction was completed by LCMS. Water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 10/1) to obtain the target compound 2 (250 mg, 595 μmol, 19.3% yield) as a white solid. ESI-MS: [M+H] ⁺ , 311.9.

2) Synthesis steps of compound 4

Compound Int L (150 mg, 405 μmol, 1 eq) was dissolved in 1,4-dioxane (4.5 mL), and compound 3 (151 mg, 486 μmol, 1.2 eq), LiCl (51.5 mg, 1.22 mmol, 3 eq), CuI (7.72 mg, 40.5 μmol, 0.1 eq) and Pd(dppf)Cl ₂ (29.7 mg, 40.5 μmol, 0.1 eq) were added in sequence at 20°C. The reaction mixture was stirred at 100°C for 16 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was directly spin-dried and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 4 (30 mg, 31.6 μmol, 7.79% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 438.1.

3) Synthesis steps of compound GDI15-7085

Compound 4 (30 mg, 68.6 μmol, 1 eq) was dissolved in NMP (1 mL). LiCl (14.6 mg, 343 μmol, 5 eq) and PPTS (86.0 mg, 343 μmol, 5 eq) were then added at 20°C. The reaction mixture was stirred at 80°C for 16 hours under nitrogen protection. The reaction was complete after LCMS detection. The reaction solution was filtered and dried, and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B in 8.0 min) to obtain the target product GDI15-7085 (2.2 mg, 5.2 μmol, 3.58% yield) as a white solid. ESI-MS: [M+H] ⁺ , 424.1.

1H NMR(400MHz,DMSO)δ13.68(s,1H),9.48(s,1H),9.39(s,1H),9.35(s,1H ),8.49(s,1H),8.30(d,J＝7.6Hz,1H),7.86-7.71(m,3H),5.36-5.24(m,2H).

Example 62: Preparation of compound GDI15-6973

1) Synthesis steps of compound 3

Compound 1 (2 g, 7.93 mmol, 1 eq) was dissolved in DMF (40 mL), and compound 2 (2.40 g, 31.7 mmol, 2.01 mL, 4 eq) and K ₂ CO ₃ (2.19 g, 15.8 mmol, 2 eq) were added at 20°C, and reacted at 50°C for 2 hours under nitrogen protection. LCMS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (50 mL) and ethyl acetate (20 mL) were added. Insoluble solids were generated in the mixed solution, and the solids were filtered. The filter cake was dried by oil pump to obtain the target compound 3 (1.27 g, 4.38 mmol, 55.2% yield) as a light yellow solid. [M+H] ⁺ , 292.2.

2) Synthesis steps of compound 4

Compound 3 (2 g, 6.87 mmol, 1 eq) was dissolved in MeCN (40 mL), and TFA (235 mg, 2.06 mmol, 0.3 eq) and NBS (1.22 mg, 6.87 mmol, 1 eq) were added at 20 °C. The mixture was reacted at 40 °C for 2 hours under nitrogen protection. The reaction was completed by LCMS. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, filtered under reduced pressure, and dried to obtain the target compound 4 (2.5 g, 5.74 mmol, 83.6% yield) as a brown solid. [M+H] ⁺ , 370.0.

3) Synthesis steps of compound 6

Compound 4 (0.1 g, 270 μmol, 1 eq) and compound 5 (51.0 mg, 324 μmol, 1.2 eq) were dissolved in dioxane (2 mL) and H ₂ O (0.4 mL), and then compound Pd(dppf)Cl ₂ (19.8 mg, 27.0 μmol, 0.1 eq) and K ₃ PO ₄ (143 mg, 675 μmol, 2.5 eq) were added in sequence at 25°C. The reaction mixture was reacted at 100°C for 6 hours, and the reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (PE/EtOAc, 1/1) to obtain the target compound 6 (23 mg, 25.7 μmol, 9.51% yield, 45% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 403.1.

4) Synthesis steps of compound GDI15-6973

Compound 6 (23 mg, 25.7 μmol, 45% purity, 1 eq) was dissolved in NMP (1 mL). PPTS (32.3 mg, 128 μmol, 5 eq) and LiCl (5.45 mg, 128 μmol, 2.63 μL, 5 eq) were then added at 20°C. The reaction mixture was reacted at 80°C for 16 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18150*40mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-50% B in 8.0 min) to obtain the target product GDI15-6973 (1.2 mg, 3.06 μmol, 11.9% yield, 99.2% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 389.0

1H NMR(400MHz,DMSO)δ13.35-12.69(m,1H),9.28(s,1H),8.93-8.73(m,1H),8. 36(s,1H),8.22-7.93(m,3H),7.76-7.58(m,3H),7.56-7.42(m,1H),5.10(s,2H)

Example 63: Preparation of compound GDI15-7004

1) Synthesis steps of compound 3

Compound GDI15-6971 (0.17 g, 449 μmol, 1 eq) and compound 2 (101 mg, 539 μmol, 1.2 eq) were dissolved in toluene (5 mL), and tri-n-butylphosphine (145 mg, 718 μmol, 177μL, 1.6eq) and azodicarbonyl dipiperidine (181mg, 718μmol, 1.6eq). Under nitrogen protection, the reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (0.14g, 166μmol, 37.0% yield, 65% purity) as a yellow solid. [M+H] ⁺ ,548.3

2) Synthesis steps of compound 4

Compound 3 (140 mg, 255 μmol, 1 eq) was dissolved in DCM (1.4 mL) and HCl/dioxane (4 N, 1.4 mL) was added at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction was complete after LCMS detection. The reaction mixture was concentrated under reduced pressure. The crude compound 4 (120 mg, 248 μmol, 97.0% yield, HCl) was obtained as a white solid. ESI-MS: [M+H] ⁺ , 448.2.

3) Synthesis steps of compound 6

Compound 4 (70 mg, 145 μmol, 1 eq, HCl) was dissolved in DCM (3 mL), and TEA (29.2 mg, 289 μmol, 40.2 μL, 2 eq) and compound 5 (20.3 mg, 145 μmol, 16.7 μL, 1 eq) were added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours, and the reaction was complete when detected by LCMS. Ice water (5 mL) was poured into the reaction solution, and extracted with DCM (2 mL*3). The organic phases were combined and concentrated under reduced pressure. The target compound 6 (30 mg, 54.3 μmol, 37.6% yield) was purified by silica gel plate purification method (SiO ₂ , EtoAc/MeOH, 10/1) as a white solid. ESI-MS: [M+H] ⁺ , 552.

4) Synthesis steps of compound GDI15-7004

Compound 6 (30 mg, 54.4 μmol, 1 eq) was dissolved in NMP (1 mL), and then K ₂ CO ₃ (22.5 mg, 163 μmol, 3 eq) and 1-decanethiol (47.4 mg, 272 μmol, 5 eq) were added at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by HPLC column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B in 8.0 min to obtain the target product GDI15-7004 (5.6 mg, 10.4 μmol, 19.2% yield) as a white solid. ESI-MS: [M+H] ⁺ , 538.2.

1H NMR (400MHz, DMSO) δ9.24(s,1H),8.59(s,1H),8.34(s,1H),8.13(d,J＝7.9Hz,1H),7.73-7.57(m,5H),7.53(d,J＝7.6Hz,2H ),7.44(d,J＝5.7Hz,1H),7.33(d,J＝8.2Hz,3H),7.26-7.20(m,1H),6.20(d,J＝7.6Hz,1H),4.42-4.07(m,2H),0.91-0.51(m,4H)

Example 64: Preparation of Compound GDI15-7219

1) Synthesis steps of compound 2

Compound Int I (500 mg, 1.98 mmol, 1 eq) was dissolved in DMF (10 mL), and compound 1 (398 mg, 2.97 mmol, 1.5 eq) and K ₂ CO ₃ (547 mg, 3.96 mmol, 2 eq) were added at 25° C. The reaction mixture was reacted at 50° C. for 2 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure and filtered through a silica gel column. Purification by gelatin plate separation (EtOAc/MeOH, 10/1) gave the target compound 2 (360 mg, 1.18 mmol, 59.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 306.1.

2) Synthesis steps of compound 3

Compound 2 (420 mg, 1.38 mmol, 1 eq) was dissolved in MeCN (8.4 mL), and NBS (244 mg, 1.38 mmol, 1 eq) and TFA (47.1 mg, 412 μmol, 30.6 μL, 0.3 eq) were added at 25 °C. The reaction mixture was reacted at 40 °C for 1 hour. LCMS detected that the reaction was complete. Water (20 mL) was added to the reaction solution, and it was extracted with DCM (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 3 (600 mg, 1.13 mmol, 82.3% yield, 72.5% purity) as a yellow oil. ESI-MS: [M+H] ⁺ , 384.0.

3) Synthesis steps of compound 5

Compound 3 (200 mg, 520 μmol, 1 eq) and compound 4 (240 mg, 780 μmol, 1.5 eq) were dissolved in dioxane (4 mL) and H ₂ O (0.8 mL), and K ₃ PO ₄ (276 mg, 1.30 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (38.1 mg, 52.1 μmol, 0.1 eq) were added at 25°C. Under N ₂ protection, the reaction mixture was reacted at 80°C for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was decompressed and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 5 (50 mg, 102 μmol, 19.7% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 486.1.

4) Synthesis steps of compound GDI15-7219

Compound 5 (50 mg, 102 μmol, 1 eq) was dissolved in NMP (1 mL), and PPTS (129 mg, 514 μmol, 5 eq) and LiCl (21.8 mg, 514 μmol, 10.5 μL, 5 eq) were added at 25°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B in 8.0 min) to obtain the target compound GDI15-7219 (5 mg, 10.5 μmol, 10.3% yield, 100% purity) as a white solid. ESI-MS: [M+H] ⁺ , 472.1.

¹ H NMR(400MHz,DMSO)δ10.09(d,J＝1.9Hz,1H),9.41-9.25(m,1H),8.36(d,J＝10.8Hz,1H) ,8.23-8.09(m,1H),7.97(d,J＝3.5Hz,1H),7.77-7.65(m,2H),7.62-7.55(m,1H),7.20( d,J＝1.4Hz,1H),7.10(s,1H),7.04-6.94(m,1H),5.79(d,J＝7.4Hz,1H),3.88(d,J＝7.1 Hz,2H),1.77(t,J＝6.6Hz,3H),1.25-1.21(m,1H),0.60-0.55(m,2H),0.35-0.30(m,2H)

Example 65: Preparation of Compound GDI15-7278

1) Synthesis steps of compound 3

Compound 2 (4.20 g, 29.3 mmol), Pd(PPh ₃ ) ₄ (1.02 g, 0.8 mol) and CsF (13.35 g, 87.9 mmol) were added to a DMF (50 mL) solution of compound 1 (10 g, 29.3 mmol) under nitrogen protection. The reaction was stirred at 75°C for 1 h. After the reaction, water (30 mL) was added to the system and extracted with EtOAc (30 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 3 (9.5 g, 94.54% yield) as an orange oily compound. ESI-MS: [M+H] ⁺ , 343.05.

2) Synthesis steps of compound 4

NBS (10.39 g, 58.4 mmol) and trifluoroacetic acid (0.17 g, 1.4 mmol) were added to a DMF (30 mL) solution of compound 3 (5 g, 14.6 mmol), and the mixture was stirred at room temperature under nitrogen protection for 16 h. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (5 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 4 (5.14 g, 83.56% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 420.65.

3) Synthesis steps of compound 6

A mixed solution of dioxane/water = 5/1 (25mL/5mL) was added to compound 4 (3g, 7.1mmol), followed by compound 5 (1.11g, 7.1mmol), XPhos Pd G2 (0.56g, 0.7mol) and K ₂ CO ₃ (2.94g, 21.3mmol), and the mixed system was stirred at 100°C for 16h under nitrogen protection. After the reaction, water (20mL) was added to the system and extracted with EtOAc (20mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 6 (1.94g, 60.56% yield) as an orange oily compound. ESI-MS: [M+H] ⁺ , 453.0

4) Synthesis steps of compound 7

A mixed solution of HBr in AcOH (2 mL) was added to compound 6 (300 mg, 0.66 mmol), and the mixture was stirred at room temperature under nitrogen for 16 h. After the reaction, the system was concentrated, and then EtOAc (2 mL) was added. The solid was filtered to obtain compound 7 (180 mg, 74.89% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 362.95.

5) Synthesis steps of compound 9

Compound 8 (56.21 mg, 0.47 mmol) and K ₂ CO ₃ (194.29 mg, 1.41 mmol) were added to a DMF (5 mL) solution of compound 7 (170 mg, 0.47 mmol), and the mixture was stirred at 50°C for 4 h under nitrogen protection. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (5 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 9 (155 mg, 82.31% yield) as a yellow solid.

¹ H NMR (400MHz, DMSO) δ9.36(s,1H),8.47–8.40(m,1H),8.25–8.12(m,2H),7.81–7.60(m,4H),7.54–7.42(m,3H),5.08(s,2H),3.07(s,3H).

6) Synthesis steps of compound 11

Compound 10 (108.24 mg, 0.30 mmol) and DBU (113.68 mg, 0.75 mmol) were added to a solution of compound 9 (100 mg, 0.25 mmol) in DMSO (5 mL). The mixed system was stirred at room temperature for 16 h under nitrogen protection. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (5 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 11 (60 mg, 56.33% yield) as a white solid.

¹ H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.43 (s, 1H), 8.21 (d, J = 7.8Hz, 1H), 8.03 (s, 1H), 7.8 1–7.65(m,5H),7.46(dd,J＝6.3,4.5Hz,2H),3.04(d,J＝1.4Hz,3H),1.86–1.76(m,4H).

7) Synthesis steps of compound GDI15-7278

PPTS (176.16 mg, 0.70 mmol) and LiCl (29.72 mg, 0.70 mmol) were added to a mixture of compound 11 (60 mg, 0.14 mmol) and NMP (3 mL). The mixture was stirred at 140°C for 4 h under nitrogen protection. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (5 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and column chromatography was performed on Biotage Isolera One (C18 column, eluent: 10% to 90% MeCN/H ₂ O containing 0.1% NH ₄ OH) to obtain Compound GDI15-7278 (5.12 mg, 8.84% yield) was a yellow solid. ESI-MS: [M+H] ⁺ , 413.95.

¹ H NMR (400MHz, DMSO) δ10.10 (s, 1H), 9.32 (s, 1H), 8.37 (s, 1H), 8.18 (d, J = 7.6Hz, 1H), 7.90 (s, 1H) ),7.76–7.59(m,4H),7.53(d,J＝7.4Hz,1H),7.49–7.37(m,2H),1.75(dd,J＝21.5,11.6Hz,4H).

Example 66: Preparation of Compound GDI15-7138

1) Synthesis steps of compound 3

Int L (150 mg, 405 μmol, 1 eq) and compound 2 (101 mg, 608 μmol, 1.5 eq) were dissolved in dioxane (3 mL) and water (0.6 mL), and K ₃ PO ₄ (215 mg, 1.01 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (29.7 mg, 40.5 μmol, 0.1 eq) were added in sequence at 25°C. Under nitrogen protection, the reaction was stirred at 80°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (3 mL*3), the organic phases were combined, and washed with 20 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel plate purification method (SiO ₂ , EtOAc/MeOH, 10/1) gave the target compound 3 (120 mg, 291 μmol, 71.8% yield) as a red solid. ESI-MS: [M+H] ⁺ , 413.2.

2) Synthesis steps of compound GDI15-7138

Compound 3 (0.1 g, 242.48 μmol, 1 eq) was dissolved in NMP (2 mL), and PPTS (304.68 mg, 1.21 mmol, 5 eq) and LiCl (51.39 mg, 1.21 mmol, 24.85 μL, 5 eq) were added in sequence at 25°C. The reaction was stirred at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (neutral condition column: Waters Xbridge BEH C18100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-40% B in 8.0 min) to obtain the target product GDI15-7138 (56.5 mg, 139 μmol, 57.2% yield, 97.9% purity) as a white solid. ESI-MS: [M+H] ⁺ ,399.2.

¹ H NMR(400MHz,DMSO)δ9.31(s,1H),8.46(s,1H),8.38(s,1H),8.22-8.11(m,3 H),8.02(d,J＝7.9Hz,1H),7.75-7.62(m,4H),7.34-6.84(m,1H),5.03(s,2H)

Example 67: Preparation of compound GDI15-7139

1) Synthesis steps of compound 6

Compound 2 (82.6 mg, 607 μmol, 1.5 eq) and compound Int L (150 mg, 405 μmol, 1 eq) were dissolved in dioxane (3 mL) and H ₂ O (0.6 mL). K ₃ PO ₄ (215 mg, 1.01 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (29.6 mg, 40.5 μmol, 0.1 eq) were added in sequence at ₂₅ °C. The reaction was stirred at 80°C for 16 hours. The reaction was completed by LCMS. Ice water (10 mL) was added to the reaction solution, extracted with EtOAc (2 mL*3), the organic phases were combined, and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 6 (73 mg, 191 μmol, 47.2% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 382.2.

2) Synthesis steps of compound GDI15-7139

Compound 6 (63 mg, 165 μmol, 1 eq) was dissolved in NMP (1.2 mL), and PPTS (207 mg, 825 μmol, 5 eq) and LiCl (35.0 mg, 825 μmol, 16.9 μL, 5 eq) were added in sequence at 25°C, and the mixture was reacted at 80°C for 16 hours. The reaction was completed after LCMS detection. The reaction solution was filtered, and the filtrate was transferred to a liquid chromatography tube. The target compound GDI15-7139 (23.6 mg, 64.2 μmol, 38.9% yield, 100% purity) was obtained as a white solid by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-45% B in 8.0 min). ESI-MS: [M+H] ⁺ , 368.0.

¹ H NMR (400MHz, DMSO) δ9.95 (s, 1H), 9.32 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 7.4Hz, 1H), 7.92 (s, 1H), 7 .75-7.66(m,2H),7.59(d,J＝8.4Hz,1H),7.35-7.29(m,3H),7.16(s,1H),5.02(s,2H),2.35(s,3H)

Example 68: Preparation of compound GDI15-7142

1) Synthesis steps of compound 2

Compound Int L (150 mg, 405 μmol, 1 eq) was dissolved in dioxane (2.5 mL) and H ₂ O (0.5 mL), and compound 1 (89.3 mg, 608 μmol, 1.5 eq), K ₃ PO ₄ (215 mg, 1.01 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (29.7 mg, 40.5 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 80°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was directly spin-dried and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 2 (100 mg, 306 μmol, 75.5% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 393.1.

2) Synthesis steps of compound GDI15-7142

Compound 2 (0.1 g, 255 μmol, 1 eq) was dissolved in NMP (2 mL), and PPTS (320 mg, 1.27 mmol, 5 eq) and LiCl (54.0 mg, 1.27 mmol, 26.1 μL, 5 eq) were added in sequence at 25°C. The reaction was stirred at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target product GDI15-7142 (47.9 mg, 124 μmol, 48.5% yield, 97.5% purity) as a white solid. ESI-MS: [M+H] ⁺ , 379.2.

¹ H NMR (400MHz, DMSO) δ9.26 (s, 1H), 8.35 (s, 1H), 8.14 (d, J = 7.8Hz, 1H), 8.02 (d, J = 16.0Hz, 2H), 7 .91(d,J＝7.9Hz,1H),7.76(d,J＝7.6Hz,1H),7.71-7.58(m,4H),7.24-6.90(m,1H),4.98(s,2H)

Example 69: Preparation of Compound GDI15-6996

1) Synthesis steps of compound 2

Compound 1 (60 mg, 162 μmol, 1 eq) and compound 2 (100 mg, 324 μmol, 2 eq) were dissolved in dioxane (1 mL) and H ₂ O (0.2 mL), and then compound K ₃ PO ₄ (103 mg, 486 μmol, 126 μL, 3 eq) and Pd(dppf)Cl ₂ (11.9 mg, 16.2 μmol, 0.1 eq) were added in sequence at 20°C. The reaction mixture was reacted at 60°C for 5 hours, and the reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 2 (30 mg, 55.9 μmol, 34.5% yield, 87.9% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 472.2

2) Synthesis steps of compound 2

Compound 2 (30 mg, 63.6 μmol, 1 eq) was dissolved in NMP (1 mL), and 1-decanethiol (55.4 mg, 318 μmol, 5 eq) and K ₂ CO ₃ (17.6 mg, 127 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 100°C for 5 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-65% B in 8.0 min) to obtain the target product GDI15-6996 (12.8 mg, 27.8 μmol, 43.7% yield, 99.3% purity) as a yellow solid. ESI-MS: [M+H] ⁺ ,458.1.

1H NMR(400MHz,DMSO)δ10.27-10.18(m,1H),10.26-9.99(m,1H),9.39-9.21(m,1H) ,8.35(s,1H),8.17(d,J＝8.3Hz,1H),8.01(s,1H),7.79-7.64(m,2H),7.60(d,J＝8.0 Hz,1H),7.19(s,1H),7.13-7.03(m,1H),6.97(s,1H),4.99(s,2H),3.87(d,J＝7.0Hz ,2H),2.18(t,J＝7.9Hz,1H),1.26-1.20(m,1H),0.64-0.51(m,2H),0.39-0.23(m,2H)

Example 70: Preparation of compound GDI15-7082

1) Synthesis steps of compound 3

Compound Int L (1 g, 2.70 mmol, 1 eq) and compound 2 (1.38 g, 5.40 mmol, 2 eq) were dissolved in dioxane (16 mL) and H ₂ O (3.2 mL), and then compound Pd(dppf)Cl ₂ (198 mg, 270 μmol, 0.1 eq) and K ₃ PO ₄ (1.72 g, 8.10 mmol, 3 eq) were added in sequence at 20°C. Under nitrogen atmosphere, the reaction mixture was reacted at 60°C for 16 hours. LCMS showed that 30% of Int L remained and 14% of the product was generated. Pd(dppf)Cl ₂ (198 mg, 270 μmol, 0.1 eq) was added to the reaction solution, and the reaction was continued at 60°C for 5 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by column chromatography (PE/EtOAc, 50/1 to 10/1) to obtain the target compound 3 (600 mg, 8.62 μmol, 53.1% yield, 60% purity) as a light yellow oil. ESI-MS: [M+H] ⁺ , 418.2

2) Synthesis steps of compound 5

Compound 3 (0.3 g, 718 μmol, 1 eq) and compound 1 (202 mg, 1.08 mmol, 1.5 eq) were dissolved in toluene (9 mL), and then compound n-Bu ₃ P (232 mg, 1.15 mmol, 283 μL, 1.6 eq) and 1,1-(azoacetyl)dipiperidine (290 mg, 1.15 mmol, 1.6 eq) were added in sequence at 20°C. Under a nitrogen atmosphere, the reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 5 (0.12 g, 143 μmol, 19.9% yield, 70% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 587.3

3) Synthesis steps of compound GDI15-7082

Compound 5 (70 mg, 53.6 μmol, 70% purity, 1 eq) was dissolved in NMP (1.4 mL), and PPTS (67.3 mg, 268 μmol, 5 eq) and LiCl (11.4 mg, 268 μmol, 5.49 μL, 5 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 80°C for 40 hours, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O(10mM NH4HCO3)-ACN]; gradient: 20%-50% B in 8.0 min) to obtain the target product GDI15-7082 (13.1 mg, 24.9 μmol, 33.2% yield, 90.1% purity) as a yellow solid. ESI-MS: [M+H] ⁺ ,473.1

1H NMR(400MHz,DMSO)δ9.14(s,1H),8.30(s,1H),8.09-8.03(m,1H),7.81(s,1H),7.68-7.53(m ,4H),7.32(d,J＝10.1Hz,2H),6.89(t,J＝1.9Hz,1H),4.92(s,2H),3.99(s,2H),0.80-0.73(m,4H)

Example 71: Preparation of compound GDI15-7126

1) Synthesis steps of compound 9

Compound 3 (0.8 g, 2.12 mmol, 1 eq) was dissolved in DCM (4 mL) and HCl/dioxane (4 M, 4 mL) was added at 25°C. The reaction mixture was reacted at 25°C for 5 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the target compound 9 (0.66 g, 1.77 mmol, 83.3% yield, 83.9% purity, HCl) as a white solid. ESI-MS: [M+H] ⁺ , 276.0 & 278.0.

2) Synthesis steps of compound 10

Compound 9 (300 mg, 958 μmol, 1 eq, HCl) and TEA (290 mg, 2.88 mmol, 400 μL, 3 eq) were dissolved in DCM (6 mL), and compound 7 (202 mg, 1.44 mmol, 166 μL, 1.5 eq) was added dropwise at 0°C. The reaction mixture was reacted at 0°C for 1 hour, and the reaction was completed by LCMS. Ice water (10 mL) was added to the reaction solution, and it was extracted with DCM (2 mL*3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 10 (380 mg, 908 μmol, 94.8% yield, 91% purity) as a yellow oil. ESI-MS: [M+H] ⁺ , 380.0 & 382.0.

3) Synthesis steps of compound 11

Compound 10 (380 mg, 908 μmol, 1 eq) was dissolved in dioxane (7.6 mL), and BPD (276 mg, 1.09 mmol, 1.2 eq), KOAc (267 mg, 2.73 mmol, 3 eq) and Pd(dppf)Cl ₂ (66.4 mg, 90.8 μmol, 0.1 eq) were added in sequence at 25°C. Under N ₂ protection, the reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was purified by silica gel plate separation (PE/EtOAc, 8/1) to obtain the target compound 11 (270 mg, 631 μmol, 69.4% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 428.2.

4) Synthesis steps of compound 12

Compound 11 (195 mg, 456 μmol, 1.3 eq) and compound Int L (130 mg, 351 μmol, 1 eq) were dissolved in dioxane (4 mL) and H ₂ O (0.8 mL), and K ₃ PO ₄ (186 mg, 877 μmol, 2.5 eq) and Pd(dppf)Cl ₂ (25.6 mg, 35.1 μmol, 0.1 eq) were added in sequence at 25°C. Under the protection of N ₂ , the reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS detection. Ice water (10 mL) was added to the reaction solution, and extracted with EtOAc (2 mL*3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 12 (105 mg, 177 μmol, 50.5% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 591.3.

5) Synthesis steps of compound GDI15-7126

Compound 12 (105 mg, 177 μmol, 1 eq) was dissolved in NMP (2.1 mL), and PPTS (223 mg, 888 μmol, 5 eq) and LiCl (37.6 mg, 888 μmol, 18.2 μL, 5 eq) were added in sequence at 25°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered, and the filtrate was transferred to a machine branch tube, and the target compound GDI15-7126 (42.5 mg, 72.1 μmol, 40.6% yield, 97.9% purity) was obtained by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B in 8.0 min) as a white solid was obtained. ESI-MS: [M+H] ⁺ ,577.0.

¹ H NMR (400MHz, DMSO) δ10.24-9.95(m,1H),9.42-9.20(m,1H),8.87(s,1H),8.35( s,1H),8.17(d,J＝7.5Hz,1H),7.99(d,J＝1.9Hz,1H),7.83(d,J＝7.4Hz,2H),7.77 -7.63(m,2H),7.59(d,J＝8.3Hz,1H),7.53-7.47(m,1H),7.47-7.38(m,2H),7.1 7(s,1H),7.10(s,1H),6.97(s,1H),4.99(s,2H),4.21(s,2H),0.96-0.86(m,4H)

Example 72: Preparation of Compound GDI15-6968

1) Synthesis steps of compound 3

DMF (10 mL) and potassium carbonate (1.33 mg, 9.6 mmol) were added to the mixed system of compound 1 (1 g, 4.8 mmol) and compound 2 (1.69 g, 7.2 mmol), and the system was stirred at 50 ° C for 12 h. After the reaction, water was added to the system, and extracted with EtOAc (10 mL*3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 0% to 2%) to obtain compound 3 (900 mg, 2.8 mmol) as a yellow oil.

¹ H NMR (400MHz, DMSO) δ7.21 (t, J = 1.6 Hz, 1H), 7.03-6.99 (m, 1H), 6.90 (t, J = 2.0 Hz, 1H), 4.32 (q, J = 7.9 Hz, 2H).

2) Synthesis steps of compound 4

1,4-Dioxane (9 mL) was added to compound 3 (900 mg, 3.10 mmol), B ₂ Pin ₂ (253 mg, 0.31 mmol), Pd(dppf)Cl ₂ (912 mg, 9.29 mmol) and KOAc (1.57 g, 6.20 mmol), and the mixture was stirred under nitrogen protection at 100°C for 18 h. After the reaction, water was added to the system, and the mixture was extracted with EtOAc (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and column chromatography (PE/EtOAc, 0% to 2%) was performed to obtain compound 4 (400 mg, 1.17 mmol) as a yellow solid.

¹ H NMR (400MHz, DMSO) δ7.46 (s, 1H), 7.21 (d, J = 2.4Hz, 1H), 7.06 (t, J = 2.2Hz, 1H), 4.40-4.36 (m, 2H), 1.29-1.24 (m, 12H).

3) Synthesis steps of compound 6

1,4-dioxane/water = 6:1 (3 mL) was added to the system of compound 4 (180 mg, 0.53 mmol), compound 5 (148 mg, 0.40 mmol), K ₃ PO ₄ (340 mg, 1.60 mmol) and Pd(dppf)Cl ₂ (44 mg, 0.0533 mmol), and the system was stirred at 50°C for 2 h. After the reaction, water was added to the system, and it was extracted with EtOAc (10 mL*3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 0% to 2%) to obtain compound 6 (100 mg, 0.20 mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 500.00.

4) Synthesis steps of compound GDI15-6968

Compound 6 (90 mg, 0.18 mmol) and PPTS (225 mg, 0.90 mmol) were dissolved in NMP (2 mL), and LiCl (38 mg, 0.90 mmol) was added to the system, and then the system was stirred at 120°C for 1 h. After the reaction, the system was filtered and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% NH ₃ H ₂ O) to obtain compound GDI15-6968 (23 mg, 0.047 mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 486.00.

¹ H NMR (400MHz, DMSO) δ10.18(s,1H),9.31(s,1H),8.36(s,1H),8.16(s,1H),8.05(s,1H),7.70(s,2H),7.60(d,J＝8.0Hz,1H),7.33(s,1H),7.21(d,J＝ 17.6Hz,2H),5.00(s,2H),4.85(d,J=8.8Hz,2H).

Example 73: Preparation of compound GDI15-7084

1) Synthesis steps of compound 2

Compound 1 (200 mg, 479 μmol, 1 eq) was dissolved in DMF (4.0 mL), and compound 2 (81.9 mg, 479 μmol, 0.9 eq) and K ₂ CO ₃ (198 mg, 1.44 mmol, 3.0 eq) were added at 20°C. The reaction mixture was reacted at 50°C for 5 hours under nitrogen protection. LCMS showed that there were 14% of the starting material and 12% of the byproducts of the two benzyl groups, and only 24% of the product 2 was generated. Water (5 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 2 (16 mg, 31.5 μmol, 6.7% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 508.1.

2) Synthesis steps of compound GDI15-7084

Compound 2 (16 mg, 31.5 μmol, 1 eq) was dissolved in NMP (1 mL). Then LiCl (6.68 mg, 157 μmol, 5 eq) and PPTS (39.6 mg, 157 μmol, 5 eq) were added in sequence at 20 °C. Under nitrogen protection, the reaction was stirred at 80 °C for 16 hours. The reaction was completed by LCMS detection. The reaction solution was filtered and dried, and then analyzed by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B in 8.0 min) was purified to give the target product GDI15-7084 (2.1 mg, 4.25 μmol, 13.5% yield) as a white solid. ESI-MS: [M+H] ⁺ , 494.1.

¹ H NMR (400MHz, DMSO) δ10.13(s,1H),9.55-9.10(m,1H),8.37(s,1H),8.22-8.15(m,1H),8.07(s,1H),7.78-7.65(m,2H),7.61(d,J＝8.3Hz,1 H),7.48-7.45(m,2H),7.41(t,J＝7.3Hz,2H),7.36(d,J＝7.2Hz,1H),7.20(d,J＝9.0Hz,2H),7.12(d,J＝1.1Hz,1H),5.17(s,2H),5.02(s,2H)

Example 74: Preparation of compound GDI15-7140

1) Synthesis steps of compound 3

Compound 1 (1 g, 4.84 mmol, 1 eq) and compound 2 (513 mg, 4.84 mmol, 489 μL, 1 eq) were dissolved in DCM (20 mL), KOAc (570 mg, 5.81 mmol, 1.2 eq) was added at 25°C, the mixture was reacted at 25°C for 16 hours, NaBH(OAc) ₃ (1.33 g, 6.30 mmol, 1.3 eq) was added to the above reaction solution, the reaction mixture was continued to react at 30°C for 16 hours, and the reaction was completed by LCMS detection. Ice water (80 mL) was added to the reaction solution, and it was extracted with EtOAc (30 mL*3), the organic phases were combined, and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying, and purified by column separation (SiO ₂ , PE/EtOAc, 20/1 to 8/1) to obtain the target compound 3 (1 g, 3.37 mmol, 69.6% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 298.0.

2) Synthesis steps of compound 4

Compound 3 (1 g, 3.37 mmol, 1 eq) was dissolved in dioxane (20 mL), and BPD (1.03 g, 4.05 mmol, 1.2 eq), KOAc (992 mg, 10.1 mmol, 3 eq) and Pd(dppf)Cl ₂ (246 mg, 337 μmol, 0.1 eq) were added in sequence at 25°C. The mixture was reacted at 80°C for 16 hours under N ₂ protection. The reaction was completed after LCMS detection. The reaction solution was purified by silica gel plate separation (PE/EtOAc, 8/1) to obtain the target compound 4 (1 g, 2.91 mmol, 86.3% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 344.1.

3) Synthesis steps of compound 5

Compound 4 (278 mg, 810 μmol, 1.5 eq) and compound Int L (200 mg, 540 μmol, 1 eq) were dissolved in dioxane (4 mL) and H ₂ O (0.8 mL), and K ₃ PO ₄ (286 mg, 1.35 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (39.5 mg, 54.0 μmol, 0.1 eq) were added in sequence at 25°C, and reacted at 80°C for 16 hours under N ₂ protection. The reaction was completed by LCMS detection. Ice water (10 mL) was added to the reaction solution, and extracted with EtOAc (2 mL*3), and the organic phases were combined and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/Methanol, 10/1) to obtain the target compound 5 (210 mg, 414 μmol, 76.7% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 507.2.

4) Synthesis steps of compound GDI15-7140

Compound 5 (190 mg, 374 μmol, 1 eq) was dissolved in NMP (3.8 mL), and PPTS (470 mg, 1.87 mmol, 5 eq) and LiCl (79.4 mg, 1.87 mmol, 38.4 μL, 5 eq) were added in sequence at 25°C, and the mixture was reacted at 80°C for 16 hours. The reaction was completed after LCMS detection. The reaction solution was filtered, and the filtrate was transferred to a machine branch tube and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B in 8.0 min) to obtain the target compound GDI15-7140 (73.6 mg, 147 μmol, 39.4% yield, 98.8% purity) as a white solid. ESI-MS: [M+H] ⁺ ,493.0.

¹ H NMR (400MHz, DMSO) δ9.98(s,1H),9.32(s,1H),8.35(s,1H),8.18(d,J＝7.3Hz,1H),7.93(s,1H),7.75-7.66(m,2H),7.57(d,J＝ 8.1Hz,1H),7.37-7.31(m,4H),7.28-7.21(m,1H),6.76-6.64(m,3H),6.54(t,J＝1.8Hz,1H),5.01(s,2H),4.30(d,J＝6.0Hz,2H)

Example 75: Preparation of Compound GDI15-7125

1) Synthesis steps of compound 13

The compound (290 mg, 1.05 mmol, 1 eq) and TEA (318 mg, 3.15 mmol, 437 μL, 3 eq) were dissolved in DCM (5.8 mL), and MsCl (180 mg, 1.57 mmol, 121 μL, 1.5 eq). The reaction mixture was reacted at 0°C for 1 hour. LCMS detected that the reaction was complete. Ice water (10 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 13 (342 mg, 964 μmol, 91.9% yield) as a yellow oil.

2) Synthesis steps of compound 14

Compound 13 (340 mg, 958 μmol, 1 eq) was dissolved in dioxane (6.8 mL), and BPD (292 mg, 1.15 mmol, 1.2 eq), KOAc (282 mg, 2.88 mmol, 3 eq) and Pd(dppf)Cl ₂ (70.1 mg, 95.8 μmol, 0.1 eq) were added in sequence at 25°C. Under N ₂ protection, the reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was purified by silica gel plate separation (PE/EtOAc, 8/1) to obtain the target compound 14 (250 mg, 622 μmol, 64.9% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 424.1.

3) Synthesis steps of compound 15

Compound 14 (250 mg, 622 μmol, 1.28 eq) and compound Int L (180 mg, 486 μmol, 1 eq) were dissolved in dioxane (5 mL) and H ₂ O (1 mL), and K ₃ PO ₄ (258 mg, 1.22mmol, 2.5eq) and Pd(dppf)Cl ₂ (35.5mg, 48.6μmol, 0.1eq). Under N ₂ protection, the reaction mixture was reacted at 80°C for 16 hours. LCMS detected that the reaction was complete. Ice water (10mL) was added to the reaction solution, and it was extracted with EtOAc (2mL*3). The organic phases were combined and washed with 10mL saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/Methanol, 10/1) to obtain the target compound 15 (170mg, 229μmol, 47.2% yield, 76.4% purity) as a yellow oil. ESI-MS: [M+H] ⁺ , 565.1.

4) Synthesis steps of compound GDI15-7125

Compound 15 (160 mg, 283 μmol, 1 eq) was dissolved in NMP (3.2 mL), and PPTS (355 mg, 1.42 mmol, 5 eq) and LiCl (60.0 mg, 1.42 mmol, 29.0 μL, 5 eq) were added in sequence at 25°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered, and the filtrate was transferred to a machine branch tube, and the target compound GDI15-7125 (41.8 mg, 73.5 μmol, 25.9% yield, 96.9% purity) was obtained by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 20%-50% B in 8.0 min) as a white solid was obtained. ESI-MS: [M+H] ⁺ ,551.2.

¹ H NMR (400MHz, DMSO) δ9.31(s,1H),8.36(s,1H),8.17(d,J＝6.9Hz,1H),8.03(s,1H),7.80(s,1H),7.76-7.64(m,3H),7.60(d,J＝8 .3Hz,1H),7.21(s,1H),7.11(s,1H),7.00(s,1H),5.01(s,2H),4.05(s,2H),2.94(s,3H),1.01-0.96(m,2H),0.86-0.80(m,2H)

Example 76: Preparation of Compound GDI15-7185

1) Synthesis steps of compound 3

Compound 1 (2 g, 9.64 mmol, 1 eq) was dissolved in DMF (40 mL), and compound 2 (4.32 g, 19.3 mmol, 2 eq), K ₂ CO ₃ (2.66 g, 19.3 mmol, 2 eq) and KI (320 mg, 1.93 mmol, 0.2 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 20°C for 16 hours, and the reaction was completed by LCMS. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined and dried under reduced pressure to obtain the target compound 3 (2 g, 5.70 mmol, 59.2% yield) as a colorless oil.

2) Synthesis steps of compound 4

Compound 3 (1 g, 2.85 mmol, 1 eq) was dissolved in DCM (5 mL), and hydrochloric acid/dioxane (4 N, 5 mL) was slowly added dropwise to the reaction solution at 0°C. The mixture was reacted at 20°C for 1 hour, and the reaction was completed by LCMS. The reaction solution was filtered to obtain the target compound 4 (1 g, 2.44 mmol, 85.5% yield, HCl) as a white solid. ESI-MS: [M+H] ⁺ , 249.0.

3) Synthesis steps of compound 5

Compound 4 (1 g, 3.48 mmol, 1 eq) was dissolved in DCM (20 mL), and TEA (705 mg, 4.89 mmol, 2.0 eq) and MsCl (560 mg, 4.89 mmol, 1.5 eq) were added dropwise at 0°C. Under nitrogen protection, the reaction mixture was reacted at 0°C for 1 hour. LCMS detected that the reaction was complete. Water (20 mL), extracted with DCM (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to give the target compound 5 (1 g, 3.04 mmol, 87.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 327.9.

4) Synthesis steps of compound 6

Compound 5 (0.5 g, 1.52 mmol, 1 eq) was dissolved in dioxane (10 mL), and compound BPD (464 mg, 1.83 mmol, 1.2 eq), KOAc (448 mg, 4.56 mmol, 2 eq) and Pd(dppf)Cl ₂ (111 mg, 152 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 80°C for 16 hours. The reaction was completed by LCMS detection, and the reaction solution was directly used for the next step. ESI-MS: [M+H] ⁺ , 376.1.

5) Synthesis steps of compound 7

Compound Int L (240 mg, 648 μmol, 1 eq), K ₃ PO ₄ (344 mg, 1.62 mmol, 2.5 eq), Pd(dppf)Cl ₂ (47.4 mg, 64.8 μmol, 0.1 eq) and H ₂ O (1 mL) were added to the reaction solution of compound 5 in sequence. Under nitrogen protection, the reaction mixture was reacted at 80° C. for 16 hours. After LCMS detection, the reaction was completed. The reaction solution was decompressed and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain The target compound 7 (220 mg, 286 μmol, 44.1% yield) was obtained as a brown solid. ESI-MS: [M+H] ⁺ , 539.1.

6) Synthesis steps of compound GDI15-7185

Compound 7 (200 mg, 371 μmol, 1 eq) was dissolved in NMP (4.0 mL), and LiCl (78.7 mg, 1.86 mmol, 5 eq) and PPTS (466 mg, 1.86 mmol, 5 eq) were added at 20°C. The reaction mixture was reacted at 80°C for 16 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-40% B in 18.0 min) to obtain the target compound GDI15-7185 (80 mg, 152 μmol, 41.1% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 525.1.

1H NMR (400MHz, DMSO) δ10.28-10.03(m,1H),9.31(s,1H),8.36(s,1H),8.17(d,J＝7.8Hz,1H),8.03(s,1H),7.76-7.65(m,2H),7.60(d,J＝8.1Hz,1 H),7.31(t,J=5.9Hz,1H),7.22(s,1H),7.12(s,1H),7.03(s,1H),5.00(s ,2H),4.09(t,J＝5.4Hz,2H),3.38-3.34(m,2H),2.95(s,3H),2.50(s,1H).

Example 77: Preparation of compound GDI15-7083

1) Synthesis steps of compound 3

Compound Int L (0.2 g, 540 μmol, 1 eq) and compound 2 (149 mg, 810 μmol, 1.5 eq) were dissolved in dioxane (2 mL) and H ₂ O (0.4 mL), and then compound Pd(dppf)Cl ₂ (39.5 mg, 54.0 μmol, 0.1 eq) and K ₃ PO ₄ (344 mg, 1.62 mmol, 420 μL, 3 eq) were added in sequence at 20°C. The reaction mixture was reacted at 60°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (50 mg, 73.3 μmol, 13.6% yield, 63% purity) as a light yellow oil. ESI-MS: [M+H] ⁺ , 430.1

2) Synthesis steps of compound 5

Compound 4 (18.7 mg, 174 μmol, 19.0 μL, 1.5 eq) and compound 3 (50 mg, 116 μmol, 1 q) were dissolved in DCM (2.5 mL), and KOAc (13.7 mg, 140 μmol, 1.2 eq) and AcOH (698 μg, 11.6 μmol, 6.66e-1 μL, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (32.1 mg, 151 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction was stirred at 20°C for 16 hours, and the reaction was completed by LCMS detection. The reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 5/1) to obtain the target compound 5 (22 mg, 39.7 μmol, 34.1% yield, 94% purity) as a yellow oil. [M+H] ⁺ ,521.3

3) Synthesis steps of compound GDI15-7083

Compound 5 (30 mg, 57.6 μmol, 1 eq) was dissolved in NMP (1.0 mL), and PPTS (72.4 mg, 288 μmol, 5 eq) and LiCl (12.2 mg, 288 μmol, 5.90 μL, 5 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O(10mM NH4HCO3)-ACN]; gradient: 25%-55% B in 8.0 min) to obtain the target product GDI15-7083 (6.7 g, 12.6 μmol, 21.8% yield, 95% purity) as a yellow solid. ESI-MS: [M+H] ⁺ ,507.1.

1H NMR (400MHz, DMSO) δ9.24(s,1H),8.34(s,1H),8.13(d,J＝6.9Hz,1H),7.91(s,1H),7.71-7.61(m,3H),7.58(d ,J＝10.4Hz,2H),7.40(d,J＝7.9Hz,3H),7.38-7.33(m,1H),7.32-7.26(m,1H),4.98(s,2H),3.88(d,J＝5.6Hz,4H)

Example 78: Preparation of compound GDI15-7053

1) Synthesis steps of compound 3

Compound 1 (1 g, 4.84 mmol, 1 eq) was dissolved in DCM (20 mL), and compound 2 (680 mg, 4.84 mmol, 545 μL, 1 eq) and KOAc (570 mg, 5.81 mmol, 1.2 eq) were added in sequence at 25 °C. After the reaction mixture was reacted at 25 °C for 1 hour, NaBH(OAc) ₃ (1.33 g, 6.30 mmol, 1.3 eq) was added to the reaction solution. The reaction mixture continued to react at 25 °C for 15 hours, and the reaction was completed by LCMS. The reaction solution was added with water (50 mL), extracted with EtOAc (20 mL*3), the organic phases were combined, and washed with 100 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and the reaction solution was purified by silica gel plate separation (PE/EtOAc, 8/1) to obtain the target compound 3 (710 mg, 2.14 mmol, 44.3% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 330.0.

2) Synthesis steps of compound 4

Compound 3 (660 mg, 1.99 mmol, 1 eq) was dissolved in dioxane (13.2 mL), and compound BPD (607 mg, 2.39 mmol, 1.2 eq), KOAc (587 mg, 5.98 mmol, 3 eq) and Pd(dppf)Cl ₂ (145 mg, 199 μmol, 0.1 eq) were added in sequence at 25°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was completed after LCMS detection. The reaction solution was purified by silica gel plate separation (PE/EtOAc, 8/1) to obtain the target compound 4 (510 mg, 1.35 mmol, 67.6% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 378.2.

3) Synthesis steps of compound 5

Compound Int L (120 mg, 324 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H ₂ O (0.5 mL), and compound 4 (183 mg, 486 μmol, 1.5 eq), Pd(dppf)Cl ₂ (23.7 mg, 32.4 μmol, 0.1 eq) and K ₃ PO ₄ (172 mg, 810 μmol, 2.5 eq) were added in sequence at 25°C. The reaction mixture was reacted at 60°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was added with water (10 mL), extracted with EtOAc (2 mL*3), and the organic phases were combined and washed with 20 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain compound 5 (70 mg, 129 μmol, 39.9% yield) as a yellow oil. ESI-MS: [M+H] ⁺ ,541.2.

3) Synthesis steps of compound GDI15-7053

Compound 5 (70 mg, 129 μmol, 1 eq) was dissolved in NMP (1.4 mL), and K ₂ CO ₃ (53.6 mg, 387 μmol, 3 eq) and 1-decanethiol (112 mg, 646 μmol, 5 eq) were added at 25°C. The reaction mixture was reacted at 100°C for 2 hours, and the reaction was completed by LCMS. The reaction solution was filtered, and the filtrate was transferred to a machine branch tube and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-70% B in 8.0 min) to obtain the target compound GDI15-7053 (12.8 mg, 24.2 μmol, 18.7% yield) as a white solid. ESI-MS: [M+H] ⁺ , 527.1.

¹ H NMR (400MHz, DMSO) δ9.99(s,1H),9.32(s,1H),8.34(s,1H),8.18(d,J＝7.4Hz,1H),7.94(s,1H),7.70(t,J＝8.2Hz,2H),7.57(d,J＝8.3Hz,1 H),7.50-7.45(m,1H),7.42(dd,J＝2.2,7.2Hz,1H),7.34-7.27(m,2H),6.77-6.67(m,3H),6.52(s,1H),5.01(s,2H),4.37(d,J＝6.0Hz,2H)

Example 79: Preparation of Compound GDI15-7086

1) Synthesis steps of compound 1

Compound Int I (200 mg, 793 μmol, 1 eq) was dissolved in MeCN (4.0 mL), and TFA (27.1 mg, 238 μmol, 17.7 μL, 0.3 eq) and NBS (141 mg, 793 μmol, 1 eq) were added at 20°C. Under nitrogen protection, the reaction mixture was reacted at 40°C for 2 hours. LCMS detected that the reaction was complete. Water (4 mL) was added to the reaction solution, extracted with EtOAc (5 mL*3), the organic phases were combined, filtered under reduced pressure and dried. EtOAc (5 mL) was added to the residue, stirred at 20°C for 5 minutes, and filtered to obtain the target compound 1 (200 mg, 605 μmol, 76.2% yield) as a white solid. ESI-MS: [M+H] ⁺ , 331.0.

2) Synthesis steps of compound 3

Compound 1 (200 mg, 604 μmol, 1 eq) was dissolved in dioxane (3.5 mL) and H ₂ O (0.7 mL), and compound 2 (142 mg, 906 μmol, 1.2 eq), Na ₂ CO ₃ (160 mg, 1.51 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (44.2 mg, 60.4 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 100°C for 16 hours, and the reaction was completed by LCMS. Water (5 mL) was added to the reaction solution, and extracted with EtOAc (5 mL*3). The organic phases were combined, filtered under reduced pressure, and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (50 mg, 276 μmol, 22.8% yield) as a brown solid. ESI-MS: [M+H] ⁺ ,363.1.

3) Synthesis steps of compound GDI15-7086

Compound 1 (50 mg, 138 μmol, 1 eq) was dissolved in NMP (1 mL), and then K ₂ CO ₃ (57.1 mg, 413 μmol, 3 eq) and 1-decanethiol (120 mg, 689 μmol, 5 eq) were added at 25°C. Under nitrogen protection, the reaction was stirred at 140°C for 16 hours. The reaction was completed by LCMS. The reaction solution was filtered at normal pressure. The filtrate was dried under reduced pressure and purified by HPLC column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min to obtain the target product GDI15-7086 (21.8 mg, 62.5μmol, 45.4% yield) as a white solid. ESI-MS: [M+H] ⁺ , 349.1.

1H NMR(400MHz,DMSO)δ11.73-11.49(m,1H),9.76-9.56(m,1H),9.30(s,1H),8.34(s,1H),8.17(d,J＝7.6Hz,1H), 7.76-7.65(m,2H),7.62(d,J＝8.1Hz,1H),7.57(s,1H),7.51-7.45(m,2H),7.42(t,J＝7.7Hz,1H),7.38-7.34(m,1H)

Example 80: Preparation of compound GDI15-7182

1) Synthesis steps of compound 3

Compound 1 (100 mg, 302 μmol, 1 eq) was dissolved in dioxane (1.6 mL) and H ₂ O (0.4 mL), and compound 2 (121 mg, 393 μmol, 1.3 eq), Na ₂ CO ₃ (62.7 mg, 755 μmol, 2.5 eq) and Pd(dppf)Cl ₂ (22.1 mg, 30.2 μmol, 0.1 eq) were added at 20°C in sequence. Under nitrogen protection, the reaction mixture was reacted at 100°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was directly spin-dried and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (20 mg, 46.2 μmol, 15.3% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 433.1.

2) Synthesis steps of compound GDI15-7182

Compound 3 (20 mg, 46.2 μmol, 1 eq) was dissolved in NMP (1.0 mL), and 1-decanethiol (40.3 mg, 231 μmol, 5 eq) and K ₂ CO ₃ (12.8 mg, 92.4 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-7182 (4 mg, 9.55 μmol, 20.7% yield) as a white solid. ESI-MS: [M+H] ⁺ , 419.1.

¹ H NMR (400MHz, DMSO) δ11.74-11.50(m,1H),9.74-9.49(m,1H),9.30(s,1H),8.34(s,1H),8.17(d,J＝7.9Hz,1H),7.77-7.66(m,2H),7.62(d,J＝8.0Hz ,1H),7.51(d,J＝1.0Hz,1H),7.14(s,1H),7.03(s,1H),6.94(s,1H),3.88 (d,J＝7.0Hz,2H),1.27-1.20(m,1H),0.61-0.55(m,2H),0.35-0.30(m,2H)

Example 81: Preparation of Compound GDI15-7254

1) Synthesis steps of compound 3

Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H ₂ O (0.5 mL). Compound 2 (200 mg, 471 μmol, 1.3 eq), Na ₂ CO ₃ (106 mg, 1.09 mmol, 3 eq), Cata Xium A (13.0 mg, 36.2 μmol, 0.1 eq) and Cata Xium A Pd G ₃ (26.4 mg, 36.2 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was directly concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (100 mg, 180 μmol, 45.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 548.2.

2) Synthesis steps of compound GDI15-7254

Compound 3 (99.3 mg, 181 μmol, 1 eq) was dissolved in NMP (2.0 mL), and LiCl (38.4 mg, 9.06 mmol, 18.6 μL, 5 eq) and PPTS (228 mg, 9.06 mmol, 5 eq) were added at 20°C. The reaction mixture was reacted at 100°C for 2 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*3μm; mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 3%-33% B in 8.0 min) to obtain the target compound GDI15-7254 (12.3 mg, 28.1 μmol, 15.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 434.1.

1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.32 (s, 1H), 8.13 (d, J = 8.2Hz, 1H), 7.76-7.65 (m, 2H), 7.65-7 .60(m,2H),7.44(s,1H),7.18(s,1H),7.10(d,J＝1.8Hz,1H),6.92(s,1H),3.93(s,2H),0.61(s,4H)

Example 82: Preparation of compound GDI15-7223

1) Synthesis steps of compound 3

Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H ₂ O (0.5 mL), and compound 2 (201 mg, 471 μmol, 1.3 eq), Na ₂ CO ₃ (115 mg, 1.09 mmol, 3 eq), CatacXium A (13.0 mg, 36.2 μmol, 0.1 eq) and CatacXium A Pd G ₃ (26.4 mg, 36.2 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was directly spin-dried and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (90 mg, 163 μmol, 45.0% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 552.2.

2) Synthesis steps of compound GDI15-7223

Compound 3 (90 mg, 191 μmol, 1 eq) was dissolved in NMP (1.8 mL), and 1-decanethiol (158 mg, 905 μmol, 5 eq) and K ₂ CO ₃ (75.1 mg, 543 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*3μm; mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 3%-33% B in 8.0 min) to obtain the target compound GDI15-7223 (19.5 mg, 32.5 μmol, 19.6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 538.2.

¹ H NMR (400MHz, DMSO) δ11.73-11.51(m,1H),9.76-9.51(m,1H),9.29(s,1H),8.86(s,1H),8.32(s,1H),8.16(d,J＝7.8Hz,1H),7.83-7.83(m,1 H),7.83(d,J＝7.4Hz,1H),7.69(dd,J＝7.9,10.9Hz,2H),7.60(d,J＝8.4Hz,1H),7.49(d,J＝6.8Hz,1H),7.4 4-7.39(m,2H),7.14-7.01(m,2H),6.92-6.92(m,1H),6.93(s,1H),4.21(s,2H),0.92(s,2H),0.89(s,2H)

Example 83: Preparation of compound GDI15-7222

1) Synthesis steps of compound 3

Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H ₂ O (0.5 mL), and compound 2 (201 mg, 471 μmol, 1.3 eq), Na ₂ CO ₃ (115 mg, 1.09 mmol, 3 eq), CatacXium A (13.0 mg, 36.2 μmol, 0.1 eq) and Cata Xium A Pd G ₃ (26.4 mg, 36.2 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 90°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was directly spin-dried and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (100 mg, 217 μmol, 45.0% yield) as a yellow solid. ESI-MS: [M+H]+, 461.1.

2) Synthesis steps of compound GDI15-7222

Compound 3 (100 mg, 217 μmol, 1 eq) was dissolved in NMP (2.0 mL), and K ₂ CO ₃ (60.0 mg, 434 μmol, 2 eq) and 1-decyl mercaptan (189 mg, 1.08 mmol, 5 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 140°C for 16 hours. LCMS detected that the reaction was complete. Filter and spin dry, and purify by HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: _{[ H2O} (10mM _NH4HCO3 )-ACN]; gradient: 25%-75%B in 8.0min) to obtain the target compound GDI15-7222 (43.2mg, 96.7μmol, 44.6% yield) as a white solid. ESI-MS: [M+H]+, 447.1.

1H NMR(400MHz,DMSO)δ11.71(s,1H),9.70(s,1H),9.31(s,1H),8.35(s,1H),8.18(d,J＝7.6Hz,1 H),7.77-7.66(m,2H),7.65-7.56(m,2H),7.27(s,1H),7.20-7.12(m,2H),4.87(q,J＝8.9Hz,2H).

Example 84: Preparation of Compound GDI15-7207

1) Synthesis steps of compound 3

Compound 1 (250 mg, 755 μmol, 1 eq) was dissolved in dioxane (4 mL) and H ₂ O (1 mL), and compound 2 (338 mg, 981 μmol, 1.3 eq), Na ₂ CO ₃ (200 mg, 1.89 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (55.2 mg, 75.5 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 100°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (27 mg, 57.6 μmol, 7.63% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 469.1.

2) Synthesis steps of compound GDI15-7207

Compound 3 (27 mg, 57.6 μmol, 1 eq) was dissolved in NMP (1.0 mL), and 1-decanethiol (50.2 mg, 288 μmol, 5 eq) and K ₂ CO ₃ (15.9 mg, 115 μmol, 2 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was reacted at 140°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B in 8.0 min) to obtain the target compound GDI15-7207 (8 mg, 17.6 μmol, 30.5% yield) as a white solid. ESI-MS: [M+H] ⁺ , 455.1.

¹ H NMR (400MHz, DMSO) δ11.65(s,1H),9.65(s,1H),9.30(s,1H),8.34(s,1H),8.17(d,J＝7.8Hz,1H),7.76-7.65(m,2H),7.61(d,J＝8.0Hz,1H ),7.52(s,1H),7.48-7.44(m,2H),7.40(t,J＝7.3Hz,2H),7.36-7.30(m,1H),7.15(d,J＝12.9Hz,2H),7.05(t,J＝1.9Hz,1H),5.17(s,2H).

Example 85: Preparation of Compound GDI15-7256

1) Synthesis steps of compound 3

Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and water (0.5 mL), and compound 2 (162 mg, 471 μmol, 1.3 eq), Na ₂ CO ₃ (106 mg, 1.09 mmol, 3 eq), Cata Xium A (13.0 mg, 36.2 μmol, 0.1 eq) and Cata Xium A Pd G ₃ (26.4 mg, 36.2 μmol, 0.1 eq), under nitrogen protection, the reaction mixture was reacted at 90 ° C for 16 hours, and the reaction was completed by LCMS. The reaction solution was directly concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (90 mg, 192 μmol, 53.1% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 468.1.

2) Synthesis steps of compound GDI15-7256

Compound 3 (90 mg, 192 μmol, 1 eq) was dissolved in NMP (1.8 mL), and 1-decanethiol (168 mg, 962 μmol, 5 eq) and K ₂ CO ₃ (53.2 mg, 382 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-7256 (8.0 mg, 17.6 μmol, 9.16% yield) as a white solid. ESI-MS: [M+H] ⁺ , 454.1.

¹ H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.30 (s, 1H), 8.13 (d, J = 8.1Hz, 1H), 7.70-7.58 (m, 3H), 7.38- 7.33(m,3H),7.33-7.21(m,3H),6.69(s,2H),6.56(s,1H),6.47(s,1H),4.29(d,J＝5.9Hz,2H).

Example 86: Preparation of Compound GDI15-7382

1) Synthesis steps of compound 3

Compound 2 (2 g, 6.97 mmol, 1 eq, HCl) was dissolved in DCM (20 mL), and TEA (2.12 g, 20.9 mmol, 2.91 mL, 3 eq) and MsCl (951 g, 7.42 mmol, 574 μL, 1.2 eq) were added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and the reaction was complete by LCMS. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL*3). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the target compound 3 (2 g, 4.87 mmol, 69.9% yield, 80% purity) as a white solid. ESI-MS: [M+H] ⁺ , 326.9.

2) Synthesis steps of compound 4

Compound 3 (500 mg, 1.52 mmol, 1 eq.) was dissolved in dioxane (10 mL), and BPD (463 mg, 1.83 mmol, 1.2 eq), KOAc (448 mg, 4.56 mmol, 3 eq) and Pd(dppf)Cl ₂ (111 mg, 152 μmol, 0.1 eq) were added in sequence at 25°C. Under nitrogen protection, the reaction mixture was stirred at 80°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was used directly in the next step without treatment. ESI-MS: [M+H] ⁺ , 375.1.

3) Synthesis steps of compound 6

Compound 4 (200 mg, 532 μmol, 1 eq) and compound 5 (0.18 g, 543 μmol, 1 eq) were dissolved in dioxane (2 mL) and water (0.4 mL), and Na ₂ CO ₃ (169 mg, 160 mmol, 3 eq), CatacXium A Pd G ₃ (38.8 mg, 53.2 μmol, 0.1 eq) and CatacXium A (19.0 mg, 53.2 μmol, 0.1 eq) were added in sequence at 25°C. Under nitrogen protection, the reaction mixture was stirred at 90°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was poured into ice water (5 mL), extracted with EtOAc (3 mL*3), and the organic phases were combined and washed with 10 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel plate separation (EtOAc/Methanol, 5/1) gave the target compound 6 (50 mg, 90.0 μmol, 18.9% yield, 90% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 500.0.

4) Synthesis steps of compound GDI15-915

Compound 6 (50 mg, 100 μmol, 1 eq) was dissolved in NMP (2 mL), and 1-decanethiol (87.2 mg, 500 μmol, 5 eq) and K ₂ CO ₃ (41.5 mg, 300 μmol, 3 eq) were added in sequence at 25°C. The reaction mixture was stirred at 120°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min) to obtain the target product GDI15-7382 (5.10 mg, 10.4 μmol, 10.4% yield) as a white solid. ESI-MS: [M+H] ⁺ , 486.1.

¹ H NMR (400MHz, DMSO) δ11.76-11.33(m,1H),9.83-9.52(m,1H),9.29(s,1H),8.33(s,1H),8.22-8.11(m,1H),7. 76-7.65(m,2H),7.61(d,J＝8.1Hz,1H),7.56-7.48(m,1H),7.28(t,J＝6.0Hz,1H),7.21-7.12(m,1H),7.06(s, 1H),6.98(s,1H),4.09(t,J＝5.4Hz,2H),3.36-3.34(m,1H),2.95(s,3H),2.94-2.93(m,1H)

Example 87: Preparation of compound GDI15-7141

1) Synthesis steps of compound 2

Compound 1 (300 mg, 906 μmol, 1 eq) was dissolved in DMF (6 mL), and CH ₃ I (103 mg, 725 μmol, 0.8 eq) and K ₂ CO ₃ (250 mg, 1.81 mmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 0°C for 2 hours under nitrogen protection. The reaction was complete after LCMS detection. Water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3). The organic phases were combined, filtered under reduced pressure, and dried to obtain the target compound 2 (250 mg, 724 μmol, 80.0% yield) as a white solid. ESI-MS: [M+H]+, 345.0.

2) Synthesis steps of compound 4

Compound 2 (250 mg, 724 μmol, 1 eq) was dissolved in dioxane (6 mL) and H ₂ O (1.2 mL), and compound 3 (170 mg, 1.09 mmol, 1.2 eq), K ₃ PO ₄ (384 mg, 1.81 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (53.0 mg, 72.4 μmol, 0.1 eq) were added at 20°C. Under nitrogen protection, the reaction mixture was reacted at 80°C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was directly spin-dried. Purification by silica gel plate separation (EtOAc/MeOH, 10/1) gave the target compound 4 (100 mg, 265 μmol, 36.6% yield) as a brown solid. ESI-MS: [M+H]+, 377.1.

3) Synthesis steps of compound GDI15-7141

Compound 4 (100 mg, 265 μmol, 1 eq) was dissolved in NMP (2.0 mL), and 1-decanethiol (231 mg, 1.33 mmol, 5 eq) and K ₂ CO ₃ (73.4 mg, 531 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-7141 (60.8 mg, 168 μmol, 63.2% yield) as a yellow solid. ESI-MS: [M+H]+, 363.1.

1H NMR (400MHz, DMSO) δ9.65(s,1H),9.30(s,1H),8.32(s,1H),8.16(d,J＝7.5Hz,1H),7.94(s,1H),7.74- 7.64(m,2H),7.62-7.57(m,2H),7.51-7.47(m,1H),7.43(t,J＝7.8Hz,1H),7.39-7.35(m,1H),3.47(s,3H).

Example 88: Preparation of compound GDI15-6801

1) Synthesis steps of compound 3

DMAc (145 mL) was added to the system of compound 1 (6 g, 48 mmol), compound 2 (8.7 g, 50.4 mmol) and K ₂ CO ₃ (19.9 g, 144 mmol), and the system was reacted at 100°C for 4 h under nitrogen protection. The reaction was completed by LCMS. After the reaction, the system solution was spin-dried and further purified by column chromatography (DCM:MeOH, 1v:0v to 20v:1v) to obtain compound 3 (1.6 g, 5.8 mmol, 12.08% yield) as a yellow solid. ESI-MS: [M+H]+, 279.90.

2) Synthesis steps of compound 4

MeOH (20 mL) was added to compound 3 (700 mg, 2.5 mmol), and ammonium formate (1.7 g, 27.73 mmol) was added under nitrogen protection at room temperature. The system was stirred at 60 ° C for 1 h, cooled to 0 ° C, (633.6 mg, 10.08 mmol) was added to the system, and reacted at 60 ° C for 18 h. LCMS detected that the reaction was complete. Cooled to 0 ° C, BOC ₂ O (1.38 g, 6.3 mmol) was added to the system and then returned to room temperature for 1 h. LCMS detected that the reaction was complete. After the reaction was completed, the system solvent was dried and further purified by column chromatography (DCM: MeOH, 1v: 0v to 20v: 1v) to obtain compound 4 (400 mg, 1.06 mmol, 41.89% yield) as a green oil. ESI-MS: [M+H] +, 379.10.

3) Synthesis steps of compound 5

DMF (8 mL) was added to a mixture of compound 4 (360 mg, 0.95 mmol) and NBS (135.3 mg, 0.76 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was completed by LCMS monitoring. After the reaction was completed, water (30 mL) was added to the system, the solid was filtered and washed with water, and the filtrate was dried to obtain compound 5 (260 mg, 0.568 mmol, 59.78% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 459.05.

4) Synthesis steps of compound 7

Compound 5 (250 mg, 0.546 mmol), compound 6 (85 mg, 0.49 mmol) and CsF (249 mg, 1.64 mmol) were mixed with DMF:H2O (5:1) 2 mL mixed solvent, and Pd-118 (71 mg, 0.11 mmol) was added under nitrogen protection at room temperature. The system was reacted at 50 ° C for 2 h, and the system was concentrated and further purified by column chromatography (DCM:H2O, 1v:0v to 10v:1v) to obtain pure compound 7 (60 mg, 0.12 mmol, 21.71% yield) as a yellow solid. ESI-MS: [M+H]+, 506.00.

5) Synthesis steps of compound GDI15-6801

Add HBr/HOAc (6 mL) to compound 7 (60 mg, 0.12 mmol), stir and react at 100°C under nitrogen protection for 16 h, and the reaction is complete when detected by LCMS. Further purification by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H2O containing 0.1% TFA) gives compound GDI15-6801 (16.67 mg, 0.042 mmol, 35.8% yield) as a white solid. ESI-MS: [M+H] ⁺ , 392.10.

¹ H NMR (400MHz, DMSO) δ11.41(s,1H),9.42-9.40(m,1H),8.51-8.40(m,1H),8.28-8.22(m,1H),8.18-7.97(m ,3H),7.91-7.77(m,3H),7.76-7.62(m,4H),6.53-6.39(m,1H),4.23-4.16(m,1H),1.47(t,J＝6.2Hz,3H).

Example 89: Preparation of compound GDI15-6919

1) Synthesis steps of compound 3

DMF (5 mL) was added to a mixture of compound 1 (300 mg, 1.89 mmol), compound 2 (477.32 g, 1.89 mmol) and K ₂ CO ₃ (785 mg, 5.68 mmol), and the mixture was stirred at 100° C. for 2 h. The reaction was complete after LCMS detection. After the reaction was completed, water (10 mL) was added to the system, the solid was filtered and washed with water, and the filtrate was concentrated to obtain compound 3 (410 mg, 1.049 mmol, 55.45% yield) as a white solid. ESI-MS: [M+H] ⁺ , 391.00.

2) Synthesis steps of compound 4

Add ammonium acetate solution (280.58 mg, 5.24 mmol, 5 mL) and NaCN (77 mg, 1.57 mmol), ammonia (35% w/w; 5 mL) and ethanol (5 mL) to compound 3 (410 mg, 1.05 mmol), stir under nitrogen at 50°C for 2.5 h, extract with DCM (50 mL*2), wash the combined organic phases with water (50 mL), dry over anhydrous sodium sulfate, filter and spin dry, column chromatography (DCM: MeOH, 20 v: 1 v to 10 v: 1 v) to obtain compound 4 (180 mg, 0.43 mmol, 42.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 417.00.

3) Synthesis steps of compound 5

MeOH (5 mL) was added to the mixed system of compound 4 (180 mg, 0.43 mmol) and NiCl2.6H ₂ O (154 mg, 0.65 mmol), and the mixture was reacted at 0°C for 5 min under nitrogen protection. Then sodium borohydride (49 mg, 1.30 mmol) was added to the system three times, and the mixed system was stirred at 0°C for 10 min. After the reaction, water (20 mL) was added to the system, and the mixture was extracted with DCM (20 mL*3), dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM: MeOH, 10v:1v to 8v:1v) to obtain compound 5 (130 mg, 0.21 mmol, 48.47% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 421.10.

4) Synthesis steps of compound GDI15-6919

HBr/AcOH (5 mL) was added to compound 5 (130 mg, 0.21 mmol, 1 eq), and the mixture was stirred at 100°C for 5 h. The reaction was completed by LCMS. After the reaction was completed, the system was concentrated, and then NaHCO ₃ (35.2 mg, 0.42 mmol, 2 eq) was added dropwise to the system, filtered and concentrated under pressure, and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain GDI15-6919 (12.42 mg, 14.57% yield) as a white solid. ESI-MS: [M+H] ⁺ , 407.05.

¹ H NMR (400MHz, DMSO) δ11.43 (s, 1H), 9.35 (d, J = 13.2Hz, 1H), 8.68 (s, 2H), 8.46-8 .37(m,1H),8.21(m,1H),7.78(m,11H),6.52(m,1H),4.41(s,1H),3.34(s,2H).

Example 90: Preparation of Compound GDI15-6926

1) Synthesis steps of compound 8

Compound 4 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL), and compound 7 (31.3 mg, 246 μmol, 1 eq), KOAc (24.1 mg, 246 μmol, 1.2 eq), TEA (24.8 mg, 246 μmol, 1 eq) and AcOH (14.7 mg, 24.6 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (56.4 mg, 266 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 8 (70 mg, 139 μmol, 68.1% yield) as a white solid. ESI-MS: [M+H] ⁺ , 502.1.

2) Synthesis steps of compound GDI15-6926

Compound 8 (70 mg, 139 μmol, 1 eq) was dissolved in NMP (1.4 mL). Then, 1-decanethiol (121 mg, 697 μmol, 5 eq) and K ₂ CO ₃ (38.5 mg, 279 μmol, 2 eq) were added in sequence at 20°C. Under nitrogen protection, the mixture was reacted at 140°C for 16 hours. The reaction was completed when detected by LCMS. The reaction solution was filtered and dried, and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B in 8.0 min) to obtain the target product. GDI15-6926 (36.3 mg, 74.9 μmol, 53.8% yield) was a white solid. ESI-MS: [M+H]+, 488.1.

1H NMR (400MHz, DMSO) δ9.25(d,J＝2.4Hz,1H),8.33(s,1H),8.13(d,J＝8.2Hz,1H),7.70(t,J＝7.5Hz,2H),7.66-7.60(m,1H),7.59-7.48(m ,3H),7.44-7.37(m,1H),7.01(dt,J＝1.4,8.0Hz,1H),6.57-6.48(m,3H),6.44-6.36(m,1H),6.30(dd,J＝3.1,7.6Hz,1H),4.15-4.07(m,2H)

Example 91: Preparation of compound GDI15-6928

1) Synthesis steps of compound 10

Compound 4 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL), and compound 9 (26.3 mg, 246 μmol, 1 eq), KOAc (24.1 mg, 246 μmol, 1.2 eq), TEA (24.8 mg, 246 μmol, 1 eq) and AcOH (14.7 mg, 24.6 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (56.4 mg, 266 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 1/1) to obtain the target compound 8 (80 mg, 166 μmol, 81.1% yield) as a white solid. [M+H] ⁺ , 482.1.

2) Synthesis steps of compound GDI15-6928

Compound 10 (80 mg, 166 μmol, 1 eq) was dissolved in NMP (1.6 mL). Then, 1-decanethiol (145 mg, 890 μmol, 5 eq) and K ₂ CO ₃ (45.9 mg, 332 μmol, 2 eq) were added in sequence at 20°C. Under nitrogen protection, the mixture was reacted at 140°C for 16 hours. The reaction was completed when detected by LCMS. The reaction solution was filtered and dried, and purified by HPLC (column: Waters Xbridge BEH C ¹⁸ 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 20%-50% B in 8.0 min) to obtain the target product GDI15-6928 (17.7 mg, 37.8 μmol, 22.8% yield) as a white solid. ESI-MS: [M+H]+, 468.1.

¹ H NMR (400MHz, DMSO) δ8.13 (d, J = 3.3Hz, 1H), 7.75-7.43 (m, 8H), 7.33-7.15 (m, 6H), 6.44-5.99 (m, 1H), 3.68-3.45 (m, 4H)

Example 92: Preparation of compound GDI15-6972

1) Synthesis steps of compound 3

Compound 1 (50 mg, 128 μmol, 1 eq) was dissolved in DCM (1.0 mL), and compound 2 (21.7 mg, 154 μmol, 1.2 eq), KOAc (15.1 mg, 154 μmol, 1.2 eq) and AcOH (0.768 mg, 12.8 μmol, 0.1 eq) were added in sequence at 20°C. The reaction mixture was stirred at 20°C under nitrogen protection. After 1 hour, NaBH(OAc) ₃ (35.3 mg, 166 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction was stirred at 20°C for 1 hour. LCMS detected that the reaction was complete. Water (2 mL) was added to the reaction solution, and DCM (2 mL*3) was used for extraction. The organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (40 mg, 77.5 μmol, 60.5% yield) as a white solid. ESI-MS: [M+H] ⁺ , 516.1.

2) Synthesis steps of compound GDI15-6972

Compound 3 (40 mg, 77.5 μmol, 1 eq) was dissolved in NMP (1.0 mL), and 1-decanethiol (67.5 mg, 387 μmol, 5 eq) and K ₂ CO ₃ (21.4 mg, 155 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C ¹⁸ 100*30mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target product GDI15-6972 (17.6 mg, 35.0 μmol, 45.2% yield) as a white solid. ESI-MS: [M+H]+, 502.1.

1H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.31-8.21 (m, 1H), 8.12 (d, J = 7.9Hz, 1H), 7.72-7.60 (m, 4H), 7.59-7 .51(m,2H),7.49-7.37(m,3H),7.30-7.20(m,2H),6.30-6.22(m,1H),3.78-3.69(m,2H),3.61-3.47(m,2H)

Example 93: Preparation of Compound GDI15-6927

1) Synthesis steps of compound 12

Compound 4 (90 mg, 230 μmol, 1 eq) was dissolved in DCM (1.8 mL), and compound 11 (39.1 mg, 276 μmol, 1 eq), KOAc (27.1 mg, 276 μmol, 1.2 eq), TEA (27.8 mg, 276 μmol, 1 eq) and AcOH (16.5 mg, 27.6 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (63.4 mg, 299 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 1/1) to obtain the target compound 12 (90 mg, 174 μmol, 75.7% yield) as a white solid. ESI-MS: [M+H] ⁺ , 516.1.

2) Synthesis steps of compound GDI15-6927

Compound 12 (90 mg, 174 μmol, 1 eq) was dissolved in NMP (1.8 mL). Then, 1-decanethiol (152 mg, 871 μmol, 5 eq) and K ₂ CO ₃ (48.2 mg, 348 μmol, 2 eq) were added in sequence at 20°C. Under nitrogen protection, the mixture was reacted at 140°C for 16 hours. The reaction was completed when detected by LCMS. The reaction solution was filtered and dried, and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 20%-50% B in 8.0 min) to obtain the target product. GDI15-6927 (25.6 mg, 51.0 μmol, 29.2% yield) was a white solid. ESI-MS: [M+H]+, 502.1.

1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.33-8.21 (m, 1H), 8.12 (d, J = 7.6Hz, 1H), 7.74-7.57 (m, 4H), 7.55-7 .47(m,2H),7.44-7.31(m,2H),7.31-7.20(m,3H),6.31-6.23(m,1H),3.72-3.60(m,2H),3.55-3.43(m,2H)

Example 94: Preparation of compound GDI15-7007

1) Synthesis steps of compound 11

Compound 9 (50 mg, 132 μmol, 1 eq) was dissolved in DCM (2.0 mL), and compound 10 (21.7 mg, 153 μmol, 18.7 μL, 1.2 eq), KOAc (15.1 mg, 153 μmol, 1.2 eq) and AcOH (795 μg, 13.2 μmol, 7.58 e-1 μL, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (35.3 mg, 166 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction was stirred at 20°C for 3 hours, and then the temperature was raised to 40°C and stirred for 3 hours. The reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL*3). The organic phases were combined, concentrated under reduced pressure, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 11 (55 mg, 100 μmol, 78.25% yield, 94% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 516.4.

2) Synthesis steps of compound GDI15-7007

Compound 11 (55 mg, 107 μmol, 1 eq) was dissolved in NMP (1.5 mL), and 1-decanethiol (92.8 mg, 533 μmol, 5 eq) and K ₂ CO ₃ (29.4 mg, 213 μmol, 2 eq) were added at 20° C. Under nitrogen protection, the reaction mixture was reacted at 140° C. for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0min) and silica gel plate purification (EtOAc/MeOH, 3/1) to obtain the target product GDI15-7007 (3.0mg, 5.85μmol, 5.49% yield, 98% purity) as a white solid. ESI-MS: [M+H]+, 502.4.

1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.32-8.21 (m, 1H), 8.13 (d, J = 7.8Hz, 1H), 7.73-7.66 (m, 1H), 7.66 -7.55(m,3H),7.55-7.46(m,2H),7.45-7.15(m,5H),6.33-6.25(m,1H),3.65(s,2H),3.55-3.43(m,2H)

Example 95: Preparation of Compound GDI15-6998

1) Synthesis steps of compound 3

Compound 1 (50 mg, 127 μmol, 1 eq) and compound 2 (19.2 mg, 153 μmol, 17.5 μL, 1.2 eq) were dissolved in DCM (1 mL). Under N ₂ protection, KOAc (15.1 mg, 153 μmol, 17.5 μL, 1.2 eq) was added at 20 °C. μmol, 1.2eq) and AcOH (0.76mg, 12.7μmol, 0.1eq). After the reaction mixture was reacted at 20°C for 1 hour, NaBH(OAc) ₃ (81.3mg, 383μmol, 3eq) was added to the reaction solution. The reaction mixture was continued to react at 20°C for 15 hours, and the reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel plate (EtOAc/MeOH, 1/1) to obtain the target compound 3 (60mg, 120μmol, 93.8% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 500.1.

2) Synthesis steps of compound GDI15-6998

Compound 3 (60 mg, 120 μmol, 1 eq) was dissolved in NMP (1.2 mL), and K ₂ CO ₃ (49.7 mg, 360 μmol, 3 eq) and 1-decanethiol (104 mg, 600 μmol, 5 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours, and the reaction was completed by LCMS. The reaction solution was filtered, and the filtrate was transferred to a machine branch tube and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound GDI15-6998 (20.7 mg, 42.4 μmol, 35.3% yield, 99.6% purity) as a yellow solid. ESI-MS: [M+H] ⁺ ,486.0.

¹ H NMR (400MHz, DMSO) δ9.22 (s, 1H), 8.31-8.20 (m, 1H), 8.11 (d, J = 7.6Hz, 1H), 7.73-7.58 (m, 4H), 7.57-7.50 (m, 2H), 7.47-7.4 0(m,1H),7.28(s,1H),7.11(d,J＝8.7Hz,2H),7.06-6.97(m,1H),6.26-6.19(m,1H),3.69-3.64(m,2H),3.49(d,J＝7.2Hz,2H)

Example 96: Preparation of Compound GDI15-6999

1) Synthesis steps of compound 5

Compound 1 (50 mg, 127 μmol, 1 eq) and compound 4 (19.2 mg, 153 μmol, 17.5 μL, 1.2 eq) were dissolved in DCM (1 mL). Under N ₂ protection, KOAc (15.1 mg, 153 μmol, 1.2 eq) and AcOH (0.76 mg, 12.7 μmol, 0.1 eq) were added in sequence at 20°C. After reacting at 20°C for 1 hour, NaBH(OAc) ₃ (81.3 mg, 383 μmol, 3 eq) was added to the reaction solution. The reaction mixture was continued to react at 20°C for 15 hours, and the reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 1/1) to obtain the target compound 5 (58 mg, 116 μmol, 90.6% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 500.1.

2) Synthesis steps of compound GDI15-6999

Compound 5 (58 mg, 116 μmol, 1 eq) was dissolved in NMP (1.2 mL). Under N ₂ protection, K ₂ CO ₃ (48.1 mg, 348 μmol, 3 eq) and 1-decanethiol (101 mg, 580 μmol, 5 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours. The reaction was completed by LCMS. The reaction solution was filtered and the filtrate was transferred to a machine branch tube. The target compound GDI15-6999 (20.5 mg, 42.1 μmol, 36.2% yield, 99.7% purity) was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) was obtained as a yellow solid. ESI-MS: [M+H] ⁺ ,486.0.

¹ H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.31-8.21 (m, 1H), 8.12 (d, J = 7.7Hz, 1H), 7.71-7.59 (m, 4H), 7.58-7.43 (m, 3H) ,7.38(t,J＝7.3Hz,1H),7.21(s,1H),7.12(s,2H),6.24(t,J＝6.6Hz,1H),3.73-3.63(m,2H),3.52(d,J＝6.0Hz,2H)

Example 97: Preparation of compound GDI15-7002

1) Synthesis steps of compound 7

Compound 1 (50 mg, 127 μmol, 1 eq) and compound 6 (19.2 mg, 153 μmol, 17.5 μL, 1.2 eq) were dissolved in DCM (1 mL). KOAc (15.1 mg, 153 μmol, 1.2 eq) and AcOH (0.76 mg, 12.7 μmol, 0.1 eq) were added at 20 °C under N ₂ protection. After reacting at 20 °C for 1 hour, NaBH(OAc) ₃ (81.3 mg, 383 μmol, 3 eq) was added to the reaction solution. The reaction mixture continued to react at 20 °C for 15 hours, and the reaction was completed by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel plate separation (EtOAc/MeOH, 1/1) to obtain the target compound 7 (55 mg, 110 μmol, 85.9% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 500.1.

2) Synthesis steps of compound GDI15-7002

Compound 7 (55 mg, 110 μmol, 1 eq) was dissolved in NMP (1.1 mL). Under N ₂ protection, K ₂ CO ₃ (45.6 mg, 330 μmol, 3 eq) and 1-decanethiol (95.9 mg, 550 μmol, 5 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours. The reaction was completed by LCMS. The reaction solution was filtered and the filtrate was transferred to a machine branch tube. The target compound GDI15-7002 (11.2 mg, 23.1 μmol, 20.9% yield, 100% purity) was purified by high performance liquid chromatography (column: Phenomenex Gemini-NX 80*40 mm*3 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) was obtained as a yellow solid. ESI-MS: [M+H] ⁺ ,486.0.

1H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.31-8.19 (m, 1H), 8.12 (d, J = 7.7Hz, 1H), 7.73-7.56 (m, 4H), 7.55 -7.44(m,2H),7.42-7.27(m,2H),7.04(s,2H),6.30-6.20(m,1H),3.70-3.56(m,2H),3.54-3.42(m,2H)

Example 98: Preparation of compound GDI15-7000

1) Synthesis steps of compound 3

Compound 1 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (2.0 mL), and compound 2 (22.8 mg, 205 μmol, 1.2 eq), KOAc (24.1 mg, 246 μmol, 1.2 eq) and AcOH (1.23 mg, 20.5 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (56.4 mg, 266 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction was stirred at 20°C for 1 hour, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL*3). The organic phases were combined, concentrated under reduced pressure, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (70 mg, 144 μmol, 70.4% yield) as a white solid. [M+H] ⁺ , 486.2.

2) Synthesis steps of compound GDI15-7000

Compound 3 (70 mg, 144 μmol, 1 eq) was dissolved in NMP (1.4 mL), and 1-decanethiol (126 mg, 720 μmol, 5 eq) and K ₂ CO ₃ (39.8 mg, 288 μmol, 2 eq) were added at 20° C. The reaction mixture was reacted at 140° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 1%-30% B in 8.0 min)-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target product GDI15-7000 (36 mg, 76.3 μmol, 53.0% yield) as a white solid. ESI-MS: [M+H]+, 472.1.

1H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.29 (d, J = 10.0Hz, 1H), 8.12 (d, J = 6.0Hz, 1H), 7.71-7.58 (m, 4H), 7.5 2(s,2H),7.51-7.43(m,2H),6.23(t,J＝6.4Hz,1H),6.10-6.04(m,1H),3.78-3.73(m,3H),3.60-3.49(m,4H)

Example 99: Preparation of compound GDI15-7005

1) Synthesis steps of compound 3

Compound 1 (50 mg, 128 μmol, 1 eq) was dissolved in DCM (1.0 mL), and compound 2 (17.1 mg, 154 μmol, 1.2 eq), KOAc (15.1 mg, 154 μmol, 1.2 eq) and AcOH (0.76 mg, 20.5 μmol, 0.1 eq) were added in sequence at 20°C. The reaction mixture was stirred at 20°C under nitrogen protection. After 1 hour, NaBH(OAc) ₃ (35.3 mg, 166 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction was stirred at 20°C for 1 hour. LCMS detected that the reaction was complete. Water (2 mL) was added to the reaction solution, and DCM (2 mL*3) was used for extraction. The organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (40 mg, 82.3 μmol, 64.3% yield) as a white solid. ESI-MS: [M+H] ⁺ , 486.2.

2) Synthesis steps of compound GDI15-7005

Compound 3 (40 mg, 82.3 μmol, 1 eq) was dissolved in NMP (1.0 mL), and 1-decanethiol (71.8 mg, 412 μmol, 5 eq) and K ₂ CO ₃ (22.8 mg, 165 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 5%-35% B in 8.0 min) to obtain the target product GDI15-7005 (6 mg, 12.7 μmol, 15.5% yield) as a white solid. ESI-MS: [M+H]+, 472.1.

1H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.29 (d, J = 5.1Hz, 1H), 8.18-8.07 (m, 1H), 7.70-7.59 (m, 4H), 7.57-7 .48(m,3H),7.48-7.43(m,1H),7.28-7.19(m,1H),6.28-6.14(m,1H),3.75(s,3H),3.51(d,J＝10.4Hz,4H)

Example 100: Preparation of Compound GDI15-6997

1) Synthesis steps of compound 4

Compound 3 (50 mg, 132 μmol, 1 eq) was dissolved in DCM (2.0 mL), and compound 4 (23.9 mg, 199 μmol, 15.5 μL, 1.5 eq), KOAc (15.6 mg, 159 μmol, 1.2 eq) and AcOH (795 μg, 13.2 μmol, 7.58 e-1 μL, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (36.5 mg, 172 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction was stirred at 20°C for 16 hours, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, concentrated under reduced pressure, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 4 (34 mg, 61.4 μmol, 46.4% yield, 87% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 482.1.

2) Synthesis steps of compound GDI15-6997

Compound 4 (34 mg, 70.5 μmol, 1 eq) was dissolved in NMP (1 mL), and 1-decyl mercaptan (61.5 mg, 353 μmol, 5 eq) and K ₂ CO ₃ (19.5 mg, 141 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 20%-55% B in 8.0 min) to obtain the target product. GDI15-6997 (9.4 mg, 19.4 μmol, 27.5% yield, 96.4% purity) was a yellow solid. ESI-MS: [M+H] ⁺ , 468.0.

1H NMR (400MHz, DMSO) δ10.96-10.46(m,1H),9.24(s,1H),8.39(s,1H),8.31(s,1H),8.13(d,J＝7.4Hz,1H),7.84-7.64(m,3H),7.43-7.37(m ,1H),7.29-7.16(m,7H),6.85(dd,J＝3.6,8.7Hz,1H),6.25(t,J＝8.8Hz,1H),5.16-4.99(m,1H),3.29(s,2H),2.82-2.76(m,2H),1.24(s,1H)

Example 101: Preparation of Compound GDI15-7068

1) Synthesis steps of compound 3

Compound 1 (100 mg, 0.26 mmol) and triethylamine (40.18 mg, 0.40 mmol) were dissolved in MeOH (2 mL), stirred and reacted for 30 min at room temperature under nitrogen protection, compound 2 (37.21 mg, 0.26 mmol) and acetic acid (0.05 mL) were added to the system, and the system continued to react at room temperature for 1 h, then NaBH3CN (33.27 mg, 0.53 mmol) was added dropwise to the system, and stirred and reacted for 1.5 h at room temperature after the addition was complete. After the reaction was completed, water (5 mL) was added to the system and extracted with EtOAc (15 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM: MeOH, 20:1 to 10:1) to obtain compound 3 (55 mg, 40.23% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 392.05.

2) Synthesis steps of compound GDI15-7068

Compound 3 (40 mg, 0.0775 mmol), decane-1-thiol (31.97 mg, 0.155 mmol) and NaOH (6.2 mg, 0.155 mmol) were dissolved in DMAC (1 mL) and stirred at 100°C for 8 h under nitrogen protection. After the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H2O containing 0.1% ammonia water) to obtain compound GDI15-7068 (7 mg, 17.94% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 502.05.

¹ H NMR (400MHz, DMSO) δ9.22(s,1H),8.32(s,1H),8.12(d,J＝8.1Hz,1H),7.70-7.62(m,4H),7.46-7.26(m,8H),6.22(d,J＝7.4Hz,1H),3.72-3.67(m,4H).

Example 102: Preparation of Compound GDI15-6995

1) Synthesis steps of compound 3

Compound 1 (50 mg, 128 μmol, 1 eq) was dissolved in DCM (1.0 mL), and compound 2 (16.6 mg, 154 μmol, 1.2 eq), KOAc (15.1 mg, 154 μmol, 1.2 eq) and AcOH (0.768 mg, 12.8 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (35.3 mg, 166 μmol, 1.3 eq) was added to the reaction solution. Nitrogen protection Under protection, the reaction was stirred at 20°C for 1 hour. The reaction was completed by LCMS. Water (2 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, concentrated under reduced pressure, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (30 mg, 62.1 μmol, 48.6% yield) as a white solid. ESI-MS: [M+H]+, 483.2.

2) Synthesis steps of compound GDI15-6995

Compound 3 (30 mg, 62.1 μmol, 1 eq) was dissolved in NMP (1.0 mL), and 1-decanethiol (54.2 mg, 311 μmol, 5 eq) and K ₂ CO ₃ (17.2 mg, 124 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-45% B in 8.0 min) to obtain the target product GDI15-6995 (19.1 mg, 40.7 μmol, 65.6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 469.1.

1H NMR (400MHz, DMSO) δ9.21 (s, 1H), 8.47 (t, J = 4.4Hz, 1H), 8.31-8.22 (m, 1H), 8.10 (d, J = 7.8Hz, 1H), 7.72-7.60 (m, 4H), 7.6 0-7.48(m,3H),7.47-7.34(m,2H),7.21(td,J＝6.4,12.6Hz,1H),6.30-6.10(m,1H),3.76(d,J＝11.1Hz,2H),3.58-3.51(m,2H)

Example 103: Preparation of Compound GDI15-7003

1) Synthesis steps of compound 3

Compound 1 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL), and compound 2 (22.1 mg, 205 μmol, 1.2 eq), KOAc (24.1 mg, 246 μmol, 1.2 eq) and AcOH (1.23 mg, 20.5 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (56.4 mg, 266 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, concentrated under reduced pressure, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (70 mg, 145 μmol, 70.8% yield) as a white solid. ESI-MS: [M+H] ⁺ , 483.2.

2) Synthesis steps of compound GDI15-7003

Compound 3 (70 mg, 145 μmol, 1 eq) was dissolved in NMP (1.4 mL), and 1-decyl mercaptan (126 mg, 725 μmol, 5 eq) and K ₂ CO ₃ (40.1 mg, 290 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and the target compound was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-45% B in 8.0 min) The product GDI15-7003 (34.6 mg, 74.8 μmol, 50.9% yield) was a white solid. ESI-MS: [M+H] ⁺ , 469.1.

1H NMR (400MHz, DMSO) δ9.22(s,1H),8.47(s,1H),8.41(ddd,J＝1.3,4.8,13.3Hz,1H),8.27(d,J＝17.3Hz,1H),8.13-8.09(m,1H),7.70-7.59( m,5H),7.57-7.50(m,2H),7.48-7.41(m,1H),7.26(ddd,J＝4.9,7.7,17.2Hz,1H),6.22(t,J＝7.5Hz,1H),3.69-3.62(m,2H),3.54-3.45(m,2H)

Example 104: Preparation of Compound GDI15-7001

1) Synthesis steps of compound 3

Compound 1 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL), and compound 2 (22.1 mg, 205 μmol, 1.2 eq), KOAc (24.1 mg, 246 μmol, 1.2 eq) and AcOH (1.23 mg, 20.5 μmol, 0.1 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 20°C for 1 hour, and NaBH(OAc) ₃ (56.4 mg, 266 μmol, 1.3 eq) was added to the reaction solution. Under nitrogen protection, the reaction was stirred at 20°C for 1 hour, and the reaction was completed by LCMS detection. Water (2 mL) was added to the reaction solution, extracted with DCM (2 mL*3), the organic phases were combined, concentrated under reduced pressure, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (70 mg, 145 μmol, 70.8% yield) as a white solid. ESI-MS: [M+H]+, 483.2.

2) Synthesis steps of compound GDI15-7001

Compound 3 (70 mg, 145 μmol, 1 eq) was dissolved in NMP (1.4 mL), and 1-decanethiol (126 mg, 725 μmol, 5 eq) and K ₂ CO ₃ (40.1 mg, 290 μmol, 2 eq) were added at 20°C. The reaction mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 5%-35% B in 8.0 min) to obtain the target product GDI15-7001 (33.8 mg, 72.1 μmol, 49.7% yield) as a white solid. ESI-MS: [M+H]+, 469.1.

1H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.44 (dd, J = 5.9, 12.1Hz, 2H), 8.33-8.18 (m, 1H), 8.12 (d, J = 8.1Hz, 1H), 7. 73-7.56(m,5H),7.55-7.47(m,2H),7.37-7.28(m,2H),6.32-6.21(m,1H),3.72-3.64(m,2H),3.53-3.43(m,2H)

Example 105: Preparation of Compound GDI15-6988

1) Synthesis steps of compound 3

DMF (10 mL) was added to a mixture of compound 1 (700 mg, 4 mmol), compound 2 (1 g, 4 mmol) and K ₂ CO ₃ (1.66 g, 12 mmol), and the mixture was stirred at 60° C. for 3 h under nitrogen protection. LCMS The reaction was detected to be complete. After the reaction was completed, water (20 mL) was added to the system, the system was filtered, and washed with water. The filtrate was spin-dried to obtain the crude product compound 3 (850 mg, 2.08 mmol, 52.21% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 407.95

2) Synthesis steps of compound 4

A mixed solution of EtOH (10 mL)/H ₂ O (2 mL) was added to compound 3 (850 mg, 2.08 mmol), Fe (349 mg, 6.25 mmol) and NH ₄ Cl (557 mg, 10.42 mmol), and the mixture was reacted at 50°C under nitrogen protection for 6 hours. The reaction was completed after LCMS detection. The reaction solution was filtered, concentrated and dried by column chromatography (DCM/MeOH, 20/1 to 10/1) to obtain compound 4 (610 mg, 1.61 mmol, 77.46% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 378.05

3) Synthesis steps of compound GDI15-6988

NMP (5 mL) was added to compound 4 (110 mg, 0.29 mmol), PPTS (366 mg, 1.46 mmol) and LiCl (62 mg, 1.46 mmol), and the mixture was stirred at 150°C under nitrogen protection for 2 h. The reaction was complete after LCMS detection. After the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% NH ₃ /H ₂ O) to obtain compound GDI15-6988 (41.99 mg, 39.64% yield) as a white solid. ESI-MS: [M+H] ⁺ , 364.00.

¹ H NMR (400MHz, DMSO) δ9.13(s,1H),8.28(s,1H),8.06(d,J＝7.6Hz,1H),7.62(m,3H),7.36(d,J＝7.6Hz,1H),7. 23(d,J＝2.3Hz,1H),7.03(dd,J＝8.6,2.4Hz,1H),6.81(d,J＝8.6Hz,1H),5.93(d,J＝7.5Hz,1H),5.45(s,2H).

Example 106: Preparation of Compound GDI15-7800

1) Synthesis steps of compound 2

MeOH (4 mL) was added to the mixed system of compound 1 (200 mg, 0.52 mmol) and NiCl ₂ .6H ₂ O (294.18 mg, 1.24 mmol), and the mixture was reacted at 0°C for 10 min under nitrogen protection. Then NaBH ₄ (93.57 mg, 2.48 mmol) was slowly added, and the reaction was continued at 0°C for 20 min. Boc ₂ O (900.39 mg, 4.13 mmol) was added dropwise to the system, and the system was slowly warmed to room temperature and reacted at room temperature for 1 h. The system was concentrated and further purified by column chromatography (EtOAc/PE, 50% to 80%). A solution of HCL in MeOH (4M) (4 mL) was added to the obtained compound, and the mixture was reacted at room temperature for 30 min under nitrogen protection. The system was concentrated and dried to obtain compound 2 (100 mg, 30.93% yield) as a gray-green solid. ESI-MS: [M+H] ⁺ , 491.95.

2) Synthesis steps of compound 3

MeOH (2 mL) was added to compound 2 (100 mg, 0.25 mmol), paraformaldehyde (229.88 mg, 2.5 mmol) and sodium cyanoborohydride (48.12 mg, 0.76 mmol), and the mixture was stirred at room temperature under nitrogen protection for 16 h. After the reaction, water (2 mL) was added to the system and extracted with EtOAc (10 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 10:1) to obtain compound 3 (22 mg, 20.54% yield) as a white solid. ESI-MS: [M+H] ⁺ , 420.10.

3) Synthesis steps of compound GDI15-7800

A solution of HBr in AcOH (1 mL) was added to compound 3 (20 mg, 0.0476 mmol), and the mixture was stirred at 100°C for 16 h under nitrogen protection. After the reaction, the mixture was concentrated in vacuo and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-7800 (2 mg, 10.29%) as a white solid. ESI-MS: [M+H] ⁺ , 406.10.

¹ H NMR (400MHz, DMSO) δ11.31(s,1H),9.42(d,J＝36.2Hz,2H),8.42(d,J＝56.1Hz,1H),8.10(d, J＝96.0Hz,1H),7.75(d,J＝11.3Hz,6H),6.45(s,1H),4.40-4.09(m,2H),2.84-2.65(m,6H).

Example 107: Preparation of Compound GDI15-6799

1) Synthesis steps of compound 2

A mixed solution of HCl/MeOH (10 mL) was added to compound 1 (500 mg, 1.29 mmol, 1 eq), and the mixture was stirred at 100°C for 5 h under nitrogen protection. The reaction was completed by LCMS. After the reaction, the system was concentrated, and NaHCO ₃ (217 mg, 2.58 mmol, 2 eq) was slowly added dropwise to the organic phase to quench the reaction. The system was further spin-dried and purified by column chromatography (PE: EtOAc, 1v:1v to 1v:2v) to obtain compound 2 (420 mg, 1.0 mmol, 77.5% yield) as a yellow solid. ESI-MS: [M+H]+, 421.05.

2) Synthesis steps of compound 3

Add THF (4 mL) to compound 2 (420 mg, 1.0 mmol), stir and react for 5 min at 0°C under nitrogen protection, then add iAlH4/THF (1N, 0.5 mL, 0.50 mmol) in three batches, and continue to react for 55 min at 0°C. LCMS detection shows that the reaction is complete. After the reaction is completed, pour the system into NH ₄ Cl/H ₂ O (5 mL) to quench, extract, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry, column chromatography (DCM/MeOH, 20:1 to 10:1) to obtain compound 3 (230 mg, 0.59 mmol, 58.67% yield) as a yellow solid. ESI-MS: [M+H]+, 393.10.

3) Synthesis steps of compound 4

DCM (4 mL) was added to compound 3 (230 mg, 0.59 mmol), stirred for 5 min under nitrogen protection at 0°C, then PBr3 (158.5 mg, 0.59 mmol) was added three times, and the system continued to react at 0°C for 25 min. LCMS detected that the reaction was complete. After the reaction, water (10 mL) was added to the system, and extracted with DCM (20 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to obtain compound 4 (190 mg, 0.42 mmol, 71.2% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 457.05.

4) Synthesis steps of compound 5

DCM (2 mL) was added to compound 4 (60 mg, 0.13 mmol) and pyrrole (28 mg, 0.40 mmol) and stirred at room temperature for 1 h. The reaction was completed after LCMS detection. Water (10 mL) was then added to the system and extracted with DCM (20 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 15:1) to obtain compound 6 (30 mg, 0.067 mmol, 51.10% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 446.10.

5) Synthesis steps of compound GDI15-6799

Add HBr/AcOH (2 mL) mixed solution to compound 6 (30 mg, 0.067 mmol, 1 eq), stir and react for 16 h at 110 °C under nitrogen protection, and the reaction is complete when LCMS is detected. After the reaction is completed, the system is concentrated, and NaHCO3 (11 mg, 0.13 mmol, 2 eq) is gradually added dropwise to the organic phase to quench the reaction, filter and concentrate, and further purify by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-6799 (4.18 mg, 14.41% yield) as a white solid. ESI-MS: [M+H] ⁺ , 432.15.

¹ H NMR (400MHz, DMSO) δ11.19(d,J＝7.6Hz,1H),9.70(s,1H),9.34(d,J＝6.0Hz,1H),8.47-8.37(m,1H),8.20(t ,J＝9.1Hz,1H),7.91(s,1H),7.71(m,4H),7.54(m,1H),6.43(m,1H),4.28(m,2H),3.09(m,4H),1.90(m,4H).

Example 108: Preparation of Compound GDI15-6675

DMSO (2 mL) was added to compound 1 (338 mg, 1.0 mmol), compound 2 (200 mg, 0.84 mmol), CuI (32 mg, 0.17 mmol) and K2CO3 (232 mg, 1.68 mmol), and the mixture was stirred at 140°C for 2 h under nitrogen protection. The reaction was completed by LCMS. Water (10 mL) was then added to the system and extracted with EtOAc (10 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to obtain compound GDI15-6675 (10.20 mg, 22.9 μmol, 2.29% yield) as a white solid. ESI-MS: [M+H] ⁺ , 446.05.

¹ H NMR (400MHz, DMSO) δ10.79(s,1H),8.18(s,1H),7.73-7.53(m,9H),6.29(s,1H),3.41(s,2H),2.33(s,4H),1.45-1.38(m,6H).

Example 109: Preparation of Compound GDI15-6780

1) Synthesis steps of compound 3

Compound 1 (10 g, 79.9 mmol, 1 eq) and compound 2 (12.4 g, 79.9 mmol, 1 eq) were dissolved in DMF (100 mL), and K ₂ CO ₃ (22.1 g, 160 mmol, 2 eq) was added at 20°C. Under nitrogen protection, the reaction mixture was stirred at 60°C for 5 hours, and the reaction was completed by LCMS. Water (200 mL) was added to the reaction solution, and it was extracted with EtOAc (100 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by column separation (SiO ₂ , PE/EtOAc, 50/1 to 10/1) to obtain the target compound 3 (17 g, 65.2 mmol, 81.6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 261.0.

2) Synthesis steps of compound 4

Compound 3 (17 g, 65.2 mmol, 1 eq) was dissolved in MeCN (170 mL), and NBS (10.4 g, 58.7 mmol, 0.9 eq) was added at 20 °C. Under nitrogen protection, the reaction mixture was stirred at 20 °C for 3 hours, and the reaction was completed by LCMS. Water (80 mL) was added to the reaction solution, and it was extracted with EtOAc (50 mL*3). The organic phases were combined, filtered under reduced pressure and dried. EtOAc (30 mL) was added to the residue, stirred at room temperature for 15 min, and the filter cake was filtered and dried to obtain the target compound 4 (20 g, 58.9 mmol, 90.3% yield) as a white solid. ESI-MS: [M+H] ⁺ , 338.9.

3) Synthesis steps of compound 6

Compound 4 (10 g, 29.4 mmol, 1 eq) was dissolved in dioxane (200 mL) and H ₂ O (40 mL). Compound 5 (9.25 g, 44.2 mmol, 1.5 eq), Na ₂ CO ₃ (7.8 g, 73.3 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (2.15 g, 2.94 mmol, 0.1 eq) were then added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 100°C for 16 hours. LCMS detected that the reaction was complete. Water (300 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (50 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by column separation (SiO ₂ , PE/EtOAc, 50/1 to 10/1) to obtain the target compound 6 (7.4 g, 19.1 mmol, 32.4% yield) as a brown solid. [M+H] ⁺ ,388.1.

4) Synthesis steps of compound 7

Compound 6 (1 g, 2.58 mmol, 1 eq) was dissolved in MeOH (50 mL). NiCl.6H ₂ O (6.13 g, 25.8 mmol, 10 eq) was then added at 0°C and stirred for 5 min. LiBH ₄ /THF solution (12.9 mL, 25.8 mmol, 10 eq, 2 M) was then slowly added dropwise at 0°C. Under nitrogen protection, the reaction mixture was stirred at 0°C for 16 hours. LCMS showed that the starting material was completely consumed. Boc ₂ O (1.69 g, 7.74 mmol, 10 eq, 1.78 mL) was then added to the reaction solution and reacted at 20°C for 1 hour. LCMS showed that the reaction was complete. Water (50 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (30 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 0/1) to obtain the target compound 7 (0.44 g, 894 μmol, 34.7% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 492.2.

5) Synthesis steps of compound 8

Compound 7 (0.44 g, 894 μmol, 1 eq) was dissolved in DCM (2 mL). Then HCl/dioxane (2 mL, 4 M) was added at 20°C. The reaction mixture was stirred at 20°C for 1 hour, and the reaction was complete after LCMS detection. The reaction solution was decompressed and dried to obtain the target compound 8 (0.31 g, 667 μmol, 74.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 392.1.

6) Synthesis steps of compound 9

Compound 8 (70 mg, 151 μmol, 1 eq) was dissolved in DCM (1.4 mL). Then TEA (45.7 mg, 452 μmol, 3 eq) and trifluoroacetic anhydride (41.1 mg, 196 μmol, 1.3 eq) were added in sequence at 0°C. Under nitrogen protection, the reaction mixture was stirred at 0°C for 1 hour. LCMS detected that the reaction was complete. Water (2 mL) was added to the reaction solution, and it was extracted with DCM (2 mL*3). The organic phases were combined, filtered under reduced pressure, and dried. Purification by silica gel plate (EtOAc/MeOH, 10/1) gave the target compound 9 (45 mg, 92.2 μmol, 61.2% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 488.1.

7) Synthesis steps of compound GDI15-6780

Compound 9 (30 mg, 61.5 μmol, 1 eq) was dissolved in NMP (3 mL). Then, 1-decanethiol (53.6 mg, 307 μmol, 5 eq) and K ₂ CO ₃ (17 mg, 123 μmol, 2 eq) were added in sequence at 20°C. Under nitrogen protection, the reaction mixture was stirred at 140°C for 16 hours. The reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-55% B in 8.0 min) to obtain the target product GDI15-6780 (11.7 mg, 24.7 μmol, 40.2% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 474.1.

1H NMR (400MHz, DMSO) δ11.01-10.72(m,1H),9.84(d,J＝4.0Hz,1H),9.25(s,1H),8.40-8.28(m,1H),8.16-8.10(m,1H),7.80-7.54( m,6H),7.42(dd,J＝6.1,8.1Hz,1H),6.30(dd,J＝2.1,7.6Hz,1H),4.44-4.30(m,1H),4.17(ddd,J＝4.6,11.4,15.6Hz,1H),2.50(s,1H)

Example 110: Preparation of Compound GDI15-6745

1) Synthesis steps of compound 3

Compound 1 (10 g, 79.9 mmol, 1 eq) and compound 2 (12.4 g, 79.9 mmol, 1 eq) were dissolved in DMF (100 mL), and K ₂ CO ₃ (22.1 g, 160 mmol, 2 eq) was added in batches at 20°C. Under nitrogen protection, the reaction was stirred at 60°C for 5 hours. The reaction was completed by LCMS. Water was added to the reaction solution. (200 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, filtered under reduced pressure and dried, and purified by column chromatography (SiO ₂ , PE/EtOAc, 50/1 to 10/1) (TLC, PE/EtOAc, 0/1, R _f = 0.69) to obtain the target compound 3 (17 g, 65.2 mmol, 81.6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 261.0.

2) Synthesis steps of compound 4

Compound 3 (17 g, 65.2 mmol, 1 eq) was dissolved in MeCN (170 mL), and NBS (10.4 g, 58.7 mmol, 0.9 eq) was added at 20 °C. Under nitrogen protection, the reaction was stirred at 20 °C for 3 hours. LCMS detected that the reaction was complete. Water (80 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL*3). The organic phases were combined, filtered and dried under reduced pressure, and then a mixed solvent of MTBE/EtOAc (MTBE/EtOAc, 5/1, 15 mL) was added at 20 °C, stirred for 15 min, and then filtered. The filter cake was dried under reduced pressure to obtain the target compound 4 (20 g, 58.9 mmol, 90.3% yield) as a white solid. ESI-MS: [M+H]+, 338.9.

3) Synthesis steps of compound 6

Compound 4 (10 g, 29.4 mmol, 1 eq) was dissolved in dioxane (200 mL) and H ₂ O (40 mL). Compound 5 (9.25 g, 44.2 mmol, 1.5 eq), Na ₂ CO ₃ (7.8 g, 73.3 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (2.15 g, 2.94 mmol, 0.1 eq) were then added in sequence at 20° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection. The reaction was completed by LCMS detection. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, filtered and dried under reduced pressure, and purified by column chromatography (SiO ₂ , PE/EtOAc, 50/1 to 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.45) to obtain the target compound 6 (7.4 g, 19.1 mmol, 32.4% yield) as a brown solid. ESI-MS: [M+H]+, 388.1

4) Synthesis steps of compound 6

Compound 6 (1 g, 2.58 mmol, 1 eq) was dissolved in MeOH (50 mL). NiCl.6H ₂ O (6.13 g, 25.8 mmol, 10 eq) was then added at 0°C and stirred for 5 min. LiBH ₄ /THF solution (12.9 mL, 25.8 mmol, 10 eq, 2 M) was then slowly added dropwise at 0°C. Under nitrogen protection, the mixture was reacted at 0°C for 16 hours, and the reaction was completed by LCMS. Boc ₂ O (1.69 g, 7.74 mmol, 3 eq, 1.78 mL) was then added to the reaction solution, and the mixture was reacted at 20°C for 1 hour, and the reaction was completed by LCMS. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 0/1) to obtain the target compound 7 (0.44 g, 894 μmol, 34.7% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 492.2.

5) Synthesis steps of compound 8

Compound 7 (0.44 g, 894 μmol, 1 eq) was dissolved in DCM (2 mL). Then HCl/dioxane (2 mL, 4 M) was added at 20°C. The reaction was allowed to proceed for 1 hour at 20°C. The reaction was completed after LCMS detection. The reaction solution was decompressed and dried to obtain the target compound 8 (0.31 g, 667 μmol, 74.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 392.1.

6) Synthesis steps of compound 10

Compound 8 (50 mg, 117 μmol, 1 eq) was dissolved in DCM (1 mL). TEA (35.4 mg, 350 μmol, 3 eq) and compound 9 (21.3 mg, 152 μmol. 1.3 eq) were then added sequentially at 0°C. Nitrogen Under protection, the mixture was reacted at 0°C for 1 hour. The reaction was completed by LCMS. Water (3 mL) was added to the reaction solution, and extracted with DCM (3 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 10 (20 mg, 40.3 μmol, 34.5% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 496.1.

7) Synthesis steps of compound GDI15-6745

Compound 10 (20 mg, 40.3 μmol, 1 eq) was dissolved in NMP (1 mL). Then, 1-decanethiol (35.2 mg, 202 μmol, 5 eq) and K ₂ CO ₃ (11.2 mg, 80.7 μmol, 2 eq) were added in sequence at 20°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection. The reaction was completed by LCMS. The reaction solution was filtered and dried, and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-55% B in 8.0 min) to obtain the target product GDI15-6745 (7.8 mg, 16.2 μmol, 40.1% yield) as a white solid. ESI-MS: [M+H] ⁺ ,482.1.

1H NMR (400MHz, DMSO) δ9.24(d,J＝2.0Hz,1H),8.90(q,J＝6.2Hz,1H),8.33(d,J＝6.4Hz,1H),8.19-8.07(m,1H),7.88-7.78(m,2H),7. 75-7.61(m,4H),7.57-7.48(m,3H),7.48-7.39(m,3H),6.29(dd,J＝2.0,7.6Hz,1H),4.55-4.37(m,1H),4.26-4.13(m,1H),2.50(s,1H)

Example 111: Preparation of Compound GDI15-6831

1) Synthesis steps of compound 11

Compound 10 (100 mg, 233 μmol, 1 eq, HCl) and compound 12 (42.6 mg, 280 μmol, 1.2 eq) were dissolved in MeCN (1.8 mL) and DMF (0.2 mL), and HATU (97.7 mg, 257 μmol, 1.1 eq) and DIEA (90.5 mg, 700 μmol, 122 μL, 3 eq) were added in sequence under stirring at 0°C, and reacted at 25°C for 2 hours. LCMS detected that the reaction was complete. Water (5 mL) was added to the reaction solution, and extracted with EtOAc (2 mL*3). The organic phases were combined and washed with 5 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.60) to obtain the target compound 11 (35 mg, 36.6 μmol, 15.7% yield, 82% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 525.2.

2) Synthesis steps of compound GDI15-6831

Compound 11 (35 mg, 57.0 μmol, 1 eq) was dissolved in NMP (1 mL), and then K ₂ CO ₃ (15.8 mg, 114 μmol, 2 eq) and 1-decanethiol (49.7 mg, 285 μmol, 5 eq) were added in sequence at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*3μm; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 10%-40% B in 8.0 min) to obtain the target product GDI15-6831 (5 mg, 9.38 μmol, 26.7% yield, 97.5% purity) as a white solid. ESI-MS: [M+H]+, 511.1.

¹ H NMR (400MHz, DMSO) δ9.24 (s, 1H), 8.55-8.45 (m, 1H), 8.37-8.25 (m, 1H), 8.12 (d, J = 7.1Hz, 1H), 7.74-7.59 (m, 3H), 7 .59-7.37(m,5H),7.36-7.24(m,4H),6.30-6.15(m,2H),4.94(t,J＝4.6Hz,1H),4.35-4.12(m,1H),4.09-3.86(m,1H)

Example 112: Preparation of Compound GDI15-6779

1) Synthesis steps of compound 11

Compound 10 (60.0 mg, 140 μmol, 1 eq, HCl) and compound 12 (42.2 mg, 168 μmol, 1.2 eq) were dissolved in MeCN (1.6 mL) and DMF (0.4 mL), and HATU (58.6 mg, 154 μmol, 1.1 eq) and DIEA (54.3 mg, 420 μmol, 73.2 μL, 3 eq) were added in sequence under stirring at 0°C, and reacted at 25°C for 1 hour. The reaction was completed by LCMS detection. Water (5 mL) was added to the reaction solution, and extracted with EtOAc (2 mL*3), the organic phases were combined, and washed with 5 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.60) to obtain the target compound 11 (60 mg, 96.0 μmol, 68.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 625.2.

2) Synthesis steps of compound GDI15-6779

Compound 11 (50 mg, 78.0 μmol, 1 eq) was dissolved in AcOH (1 mL), and then HBr (0.5 mL, 33% acetic acid solution) was added. The reaction mixture was reacted at 120°C for 5 hours. The reaction was completed by LCMS. The reaction liquid was filtered and dried under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C ¹⁸ 150*40mm*10μm; mobile phase: [H ₂ O(10mM NH ₄ HCO ₃ )-ACN]; gradient: 15%-55% B in 8.0 min) to obtain the target compound GDI15-6779 (10.3 mg, 19.8 μmol, 24.7% yield, 98% purity) as a white solid. ESI-MS: [M+H] ⁺ , 511.1.

¹ H NMR (400MHz, DMSO) δ9.23 (s, 1H), 8.64-8.49 (m, 1H), 8.34-8.30 (m, 1H), 8.12 (d, J = 7.1Hz, 1H), 7.72-7.61 (m, 3H), 7.55-7.4 7(m,2H),7.46-7.36(m,3H),7.35-7.19(m,4H),6.28-6.18(m,1H),4.44-4.37(m,1H),4.28-4.11(m,1H),4.05-3.94(m,1H)

Example 113: Preparation of Compound GDI15-6784

1) Synthesis steps of compound 11

Compound 1 (70 mg, 163.4 μmol, 1 eq, HCl) was dissolved in DCM (2 mL), and TEA (49.6 mg, 490 μmol, 68.2 μL, 3 eq) and compound 2 (62.3 mg, 327 μmol, 2 eq) were added in sequence under stirring at 0°C. The reaction was carried out at 0°C for 2 hours, and the reaction was completed after LCMS detection. Ice water (10 mL) was poured into the reaction solution, and it was extracted with EtOAc (5 mL*3). The organic phases were combined and washed with 20 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target compound 3 (57 mg, 95.2 μmol, 58.3% yield, 100% purity) was purified by silica gel plate purification method (SiO ₂ , EtOAc/MeOH, 0/1) as a white solid. ESI-MS: [M+H] ⁺ , 546.1

2) Synthesis steps of compound GDI15-6784

Compound 3 (52 mg, 95.2 μmol, 1 eq) was dissolved in NMP (1 mL), and then K ₂ CO ₃ (39.5 mg, 285 μmol, 3 eq) and 1-decanethiol (83.0 mg, 476 μmol, 5 eq) were added at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by high performance liquid chromatography (column: Phenomenex Gemini-NX 100*30 mm*3 μm; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 8%-38% B in 8.0 min) to obtain the target product GDI15-6784 (5.3 mg, 9.66 μmol, 10.2% yield, 97% purity) as a white solid. ESI-MS: [M+H]+, 532.1.

1H NMR (400MHz, DMSO) δ9.13(d,J＝5.3Hz,1H),8.27-8.11(m,1H),8.06(d,J＝8.3Hz,1H),7.67-7.56(m,4H),7.47-7.38(m, 5H),7.33(d,J＝8.0Hz,1H),7.25-7.23(m,1H),6.15-6.05(m,1H),5.96-5.88(m,1H),3.82-3.74(m,2H),2.41-2.34(m,3H)

Example 114: Preparation of Compound GDI15-6987

1) Synthesis steps of compound 3

Under nitrogen protection at room temperature, compound 2 (3.91 g, 24.7 mmol) and KOH (4.63 g, 82.5 mmol) were added to a DMSO (15 mL) solution of compound 1 (2.5 g, 16.5 mmol), and the mixed system was reacted at 60 ° C for 2 h. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (10 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 3 (3.3 g, 87.27% yield) as an orange solid.

¹ H NMR (400MHz, DMSO) δ8.61 (d, J = 4.1Hz, 1H), 7.86 (td, J = 7.7, 1.7Hz, 1H), 7.59-7.32 (m, 6H), 5.98 (s, 1H).

2) Synthesis steps of compound 4

Under nitrogen protection at room temperature, sodium hydroxide (1.82 g, 45.6 mmol) was slowly added to a MeOH (10 mL) solution of compound 3 (1.3 g, 5.7 mmol), and the mixed system was reacted at 80°C for 16 h. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (5 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 4 (1.17 g, 82.46% yield) as a white solid. ESI-MS: [M+H] ⁺ , 247.90.

3) Synthesis steps of compound 6

Under nitrogen protection at room temperature, slowly add compound 5 (69.86 mg, 0.48 mmol), HATU (307.07 mg, 0.81 mmol) and DIPEA (156.27 mg, 1.21 mmol) to a DMF (5 mL) solution of compound 4 (100 mg, 0.40 mmol), and the mixed system continues to react for 2 h at room temperature. After the reaction, add water (5 mL) to the system and extract with EtOAc (5 mL*3), combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 6 (106 mg, 70.21% yield) as an orange solid. ESI-MS: [M+H] ⁺ , 374.0.

4) Synthesis steps of compound GDI15-6987

CDI (32.52 mg, 0.20 mmol) was slowly added to a toluene (5 mL) solution of compound 6 (50 mg, 0.13 mmol), and the mixed system was reacted at 100 ° C for 16 h. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (5 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% NH ₄ OH) to obtain compound GDI15-6987 (13.15 mg, 24.61% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 400.0.

¹ H NMR (400MHz, DMSO) δ9.43(s,1H),8.57(s,1H),8.29(dd,J＝19.4,7.6Hz,2H),7.96(d,J＝8.3Hz,1H),7 .83-7.74(m,2H),7.54-7.38(m,3H),7.36-7.26(m,2H),6.95(d,J＝9.4Hz,1H),6.67(t,J＝6.6Hz,1H).

Example 115: Preparation of Compound GDI15-7312

1) Synthesis steps of compound 3

Under nitrogen protection at room temperature, compound 2 (2.50 g, 0.02 mol) and K ₂ CO ₃ (7.66 g, 0.06 mol) were added to a DMF (50 mL) solution of compound 1 (4.7 g, 0.02 mol), and the mixed system was reacted at 50°C for 3 h. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (30 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and column chromatography (PE/EtOAc, 10:1) was performed to obtain compound 3 (5 g, 78.92% yield) as a colorless oily compound.

¹ H NMR (400MHz, DMSO) δ7.35 (s, 1H), 7.27 (s, 1H), 7.05 (s, 1H), 3.83 (d, J = 7.0Hz, 2H), 1.15 (s, 1H), 0.61-0.47 (m, 2H), 0.30 (d, J = 4.9Hz, 2H).

2) Synthesis steps of compound 3

Under nitrogen protection at room temperature, compound 4 (765.77 mg, 6.48 mmol), potassium tert-butoxide (2.2 g, 19.45 mmol), Pd(OAc) 2 (145.53 mg, 0.65 mmol), and Pd(PPh ₃ ) ₄ (749.05 mg, 0.65 mmol) were added to a solution of compound ₃ (2 g, 6.48 mmol) in dioxane (20 mL), and the mixed system was reacted at 100°C for 16 h. After the reaction, water (20 mL) was added to the system and extracted with EtOAc (40 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 10:1) to obtain compound 5 (1.4 g, 88.96% yield) as a brown oily compound. ESI-MS: [M+H] ⁺ , 299.10.

3) Synthesis steps of compound 6

Under nitrogen protection at room temperature, NaOH (1.41 g, 40 mmol) was added to a mixed solution of compound 5 (1.3 g, 4.3 mmol) in MeOH/H ₂ O = 1:1 (70 mL), and the mixed system was reacted at 80°C for 8 h, filtered, and further purified by reverse column to obtain compound 6 (1 g, 63.64% yield) as a white solid. ESI-MS: [M+H] ⁺ , 317.95.

4) Synthesis steps of compound 8

Under nitrogen protection at room temperature, compound 7 (148.5 mg, 1.03 mmol), HATU (587.57 mg, 1.55 mmol), and DIPEA (399.4 mg, 3.10 mmol) were added to a DMF (4 mL) solution of compound 6 (350 mg, 1.03 mmol), and the mixed system was allowed to react for 3 h at room temperature. After the reaction, water (5 mL) was added to the system and extracted with EtOAc (15 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (DCM: MeOH, 20:1 to 10:1) to obtain compound 8 (300 mg, 65.60% yield) as a colorless oily compound. ESI-MS: [M+H] ⁺ , 444.00.

4) Synthesis steps of compound GDI15-7312

Under nitrogen protection at room temperature, CDI (262.96 mg, 1.62 mmol) was added to a toluene (1.5 mL) solution of compound 8 (120 mg, 0.27 mmol), and the mixture was reacted at 110°C for 2 h. Further purification by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent 30% to 90% MeCN/H ₂ O containing 0.1% ammonia water) gave compound GDI15-7312 (31 mg, 24.42% yield) as a light yellow solid. ESI-MS: [M+H] ⁺ , 470.00.

¹ H NMR (400MHz, DMSO) δ9.43(s,1H),8.56(s,1H),8.29(dd,J＝14.4,7.6Hz,2H),7.94(d,J＝8.2Hz,1H),7.79(dt,J＝14.8,6.9Hz,2H),7.29(dd,J＝9.4,6. 4Hz,1H),7.06-6.90(m,3H),6.87(s,1H),6.67(t,J＝6.9Hz,1H),3.85(d,J ＝7.0Hz,2H),1.26-1.17(m,1H),0.64-0.49(m,2H),0.32(q,J＝4.9Hz,2H).

Example 116: Preparation of Compound GDI15-7314

1) Synthesis steps of compound 3

PtO ₂ (26.77 mg, 96.6 mol) was added to a MeOH (2 mL) solution of compound GDI15-7242 (20 mg, 48.3 mol), hydrogen (0.1 MPa) was introduced into the mixture, and the mixture was stirred at room temperature for 3 h. After the reaction, the system was filtered, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and further purified by prep-HPLC (column: Gemini 5μm C18 column, 150*21.2 mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-7314 (5.04 mg, 25.05% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 418.1.

¹ H NMR(400MHz,MeOD)δ9.57(s,1H),8.60(s,1H),8.39(d,J＝8.0Hz,1H),8.06-7.95(m,2H), 7.93-7.86(m,1H),7.45-7.35(m,3H),7.26(dd,J＝7.3,1.6Hz,1H),4.19(ddd,J＝13.8,9.5 ,4.9Hz,1H),3.87-3.76(m,1H),2.80-2.68(m,1H),2.43-2.33(m,1H),2.19-2.10(m,1H) ,1.99(d,J＝4.0Hz,1H), 1.61(ddd,J＝13.7,12.5,6.9Hz,1H), 1.06(dd,J＝6.6,3.8Hz,3H).

Example 117: Preparation of Compound GDI15-7281

1) Synthesis steps of compound 3

Compound 2 (3.41 g, 0.02 mol) was added to a solution of compound 1 (3.0 g, 0.02 mol) in DMF (30 mL). 0.02mol), sodium p-toluenesulfonate (11.65g, 0.06mol), then stirred at 0℃ for 30 minutes, then NaH (1.67g, 0.04mol, 60%wt) was added to the system, then stirred at 0℃ for 30 minutes, slowly heated to 80℃ and stirred for 5h. After the reaction, water (10mL) was added to the system and extracted with EtOAc (30mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 10% to 20%) to obtain compound 3 (1.0g, 20.71% yield) as a colorless oily compound. ESI-MS: [M+H] ⁺ , 242.95.

2) Synthesis steps of compound 4

To a solution of compound 3 (900 mg, 3.71 mmol) in MeOH/H ₂ O = 1:1 (60 mL) was added NaOH (1.2 g, 29.67 mmol), and then the temperature was raised to 80°C and stirred for 2 h. After the reaction, the system was filtered, and the filter cake was further purified by biotage isolera one column (C18 column, eluent 10% to 90% MeOH/H ₂ O) to obtain compound 4 (400 mg, 38.02% yield) as a white solid. ESI-MS: [M+H] ⁺ , 261.90.

3) Synthesis steps of compound 6

Compound 5 (177.88 mg, 1.23 mmol), HATU (938.26 mg, 2.47 mmol) and DIPEA (478.37 mg, 3.70 mmol) were added to a DMF (4 mL) solution of compound 4 (350 mg, 1.23 mmol). The mixture was stirred at room temperature for 3 h. After the reaction, H ₂ O (5 mL) was added to the system and extracted with EtOAc (15 mL*3). The mixture was dried over anhydrous sodium sulfate, filtered and dried by column chromatography. (DCM/MeOH, 20:1) to give compound 6 (220 mg, 41.38% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 388.15.

4) Synthesis steps of compound GDI15-7281

CDI (476.59 mg, 2.94 mmol) was added to a toluene (2 mL) solution of compound 6 (190 mg, 0.49 mmol), and the mixture was heated to 110°C and stirred for 3 h. After the reaction, the system was concentrated and further purified by prep-HPLC (column: Gemini 5μm C18 column, 150*21.2 mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% NH ₄ OH) to obtain compound GDI15-7281 (65 mg, 32.07% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 414.0.

¹ H NMR (400MHz, DMSO) δ9.37(s,1H),8.45(s,1H),8.23(d,J＝8.2Hz,1H),7.95(d,J＝8.2Hz,1H),7.84(t,J＝7.5Hz,1H),7.75(t,J＝7.2Hz,1H ),7.25(s,1H),7.15(dd,J＝5.9,1.8Hz,2H),4.85(q,J＝8.8Hz,2H),4.13(dd,J＝10.4,5.8Hz,2H),3.25-3.21(m,1H),3.11-3.04(m,1H).

Example 118: Preparation of Compound GDI15-7242

1) Synthesis steps of compound 3

To a mixture of compound 1 (8 g, 52.77 mmol) and compound 2 (19.7 g, 110.82 mmol) was added dry THF (200 mL), and stirring was continued while adding NaH (2.66 g, 110.82mmol), the mixed system was stirred at 80℃ for 3h. After the reaction, saturated NH ₄ Cl solution was added to the system, and extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 10% to 15%) to obtain compound 3 (4.7g, 36.70% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 243.25.

2) Synthesis steps of compound 4

To a solution of compound 3 (4.7 g, 19.37 mmol) in MeOH (150 mL) was added NaOH solution (154.9 mL, 154.92 mmol, 1 mol/L) and the mixture was stirred at 80°C for 16 h. After the reaction, the system was concentrated and further purified by Biotage Isolera One (C18 column, eluent 10% to 90% MeOH/H ₂ O) to obtain compound 4 (4 g, 72.81% yield) as a white solid.

¹ H NMR (400MHz, D ₂ O)δ8.30(d,J＝5.1Hz,1H),7.41-7.34(m,2H),7.33(s,1H),7.26(d,J＝6.6Hz,1H),7.21-7.16(m,2H),5.11(s,1H),2.35(s,3H).

3) Synthesis steps of compound 6

Compound 5 (300 mg, 2.1 mmol), HATU (2.37 g, 6.2 mmol) and DIPEA (537.85 mg, 4.2 mmol) were added to a DMF (4 mL) solution of compound 4 (885.44 mg, 3.1 mmol), and the mixture was stirred at room temperature under nitrogen protection for 1 h. After the reaction, water (200 mL) was added to the system and extracted with EtOAc (200 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. Spin column chromatography (MeOH/DCM, 4% to 5%) gave compound 6 (500 mg, 61.95% yield) as a white solid. ESI-MS: [M+H] ⁺ , 387.75.

4) Synthesis steps of compound GDI15-7242

CDI was added to a toluene (5 mL) solution of compound 6 (500 mg, 1.29 mmol), and the mixture was stirred at 110°C for 2 h. After the reaction, water (100 mL) was added to the system and extracted with DCM (100 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (MeOH/DCM, 5% to 10%) to obtain compound GDI15-7281 (400 mg, 67.48% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 414.10.

¹ H NMR (400MHz, DMSO) δ9.42(s,1H),8.56(s,1H),8.27(dd,J＝7.7,3.0Hz,2H),7.93(d,J＝8.1Hz,1H),7.83-7.74(m,2H),7 .49(t,J＝7.8Hz,1H),7.44-7.38(m,2H),7.33(d,J＝7.5Hz,1H),6.72(s,1H),6.56(dd,J＝7.6,1.6Hz,1H),2.19(s,3H).

Example 119: Preparation of Compound GDI15-7244

1) Synthesis steps of compound 3

THF (80 mL) was added to a mixture of compound 1 (3 g, 19.8 mmol), compound 2 (3.41 g, 19.8 mmol) and sodium 4-methylbenzenesulfonate (7.06 g, 39.6 mmol), and NaH (1.58 g, 39.6 mmol) was added under nitrogen protection at 0°C with stirring. The temperature of the system was slowly raised to 75°C and stirred for 3 h. The reaction was completed after LCMS monitoring, and then water (100 mL) was added to the system, and the mixture was extracted with EtOAc (100 mL*3), filtered and vortexed. Dry column chromatography (PE/EtOAc, 1v:0v to 10v:1v) gave compound 3 (1.1 g, 3.4 mmol, 17.17% yield) as a brown oil. ESI-MS: [M+H] ⁺ , 243.20.

2) Synthesis steps of compound 4

1M NaOH (33 mL) was added to a MeOH (33 mL) solution of compound 3 (1 g, 4.1 mmol), and then the system temperature was raised to 80°C and stirred for 10 h. After the reaction, EtOAc (30 mL) was added to the system and extracted with water (30 mL*2). The aqueous phases were combined and purified with a C18 c column (H ₂ O/MeOH, 20/1 to 3/1) to obtain compound 4 (1 g, 3.5 mmol, 85.37% yield) as a white solid. ESI-MS: [M+H] ⁺ , 216.60.

3) Synthesis steps of compound 6

DMF (5 mL) was added to the mixture of compound 4 (450 mg, 1.58 mmol) and DIPEA (613.9 mg, 4.76 mmol), and HATU (1.2 g, 3.17 mmol) was added under nitrogen protection. The mixture was stirred at room temperature for 10 min, and then compound 5 (274.44 mg, 1.90 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The reaction was completed after LCMS monitoring. The system was concentrated and then further purified by column chromatography (DCM/MeOH, 1v:0v to 20v:1v) to obtain compound 6 (140 mg, 0.36 mmol, 22.76% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 388.20.

3) Synthesis steps of compound GDI15-7244

CDI (351 mg, 2.166 mmol) was added to a toluene solution (2 mL) of compound 6 (140 mg, 0.36 mmol), and the mixture was stirred at 110°C for 5 h. The reaction was completed by LCMS. The system was concentrated, purified by slurrying (DCM/MeOH, 1v:0v to 20v:1v) and Pre-TLC DCM:MeOH (20v:1v), and then further purified by prep-HPLC (column: Gemini 5μm C18 column, 150*21.2mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-7244 (50 mg, 0.120 mmol, 33.13% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 414.10

¹ H NMR (400MHz, DMSO) δ9.43(s,1H),8.56(s,1H),8.27(d,J＝7.9Hz,1H),8.15(s,1H),7.92(d,J＝8.1Hz,1H),7.78(dt,J＝16.1,7.1Hz,2 H),7.48(d,J＝7.8Hz,1H),7.43(d,J＝10.1Hz,2H),7.34(d,J＝7.6Hz,1H),7.21(d,J＝9.4Hz,1H),6.95(d,J＝9.5Hz,1H),2.16(s,3H).

Example 120: Preparation of Compound GDI15-7243

1) Synthesis steps of compound 3

Compound 1 (3 g, 19.8 mmol), compound 2 (3.41 g, 19.8 mmol) and sodium 4-methylbenzenesulfonate (7.77 g, 39.6 mmol) were added to a THF (50 mL) solution under nitrogen protection at 0°C. The system was stirred at 70°C for 3 h. The reaction was completed by LCMS. Then water (100 mL) was added to the system to quench, and the mixture was extracted with EtOAc (100 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 1v:0v to 10v:1v) to obtain compound 3 (2 g, 8.2 mmol, 41.41% yield) as a brown oily compound. ESI-MS: [M+H] ⁺ , 243.2.

2) Synthesis steps of compound 4

To a solution of compound 3 (1 g, 4.1 mmol) in MeOH (33 mL) was added a solution of NaOH (1.31 g, 32.8 mmol, 33 mL), and the system was slowly heated to 80 °C for 5 h at 0 °C. The reaction was complete after LCMS detection. The system was concentrated and further purified by prep-HPLC (column: Gemini 5 μm C18 column, 150*21.2 mm, eluent: 30% to 90% MeOH/H ₂ O containing ammonia water) to obtain compound 4 (210 mg, 0.7 mmol, 17.07% yield) as a white solid. ESI-MS: [M+H] ⁺ , 262.0.

3) Synthesis steps of compound 6

DMF (4 mL) was added to a mixture of compound 4 (210 mg, 0.74 mmol), compound 5 (107 mg, 0.74 mmol), HATU (422.23 mg, 1.11 mmol) and DIPEA (287 mg, 2.22 mmol), and the mixture was stirred at room temperature for 2 h under nitrogen protection. The reaction was completed by LCMS. Water (20 mL) was then added to the system and extracted with EtOAc (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/TEA, 200 v:1 v) to obtain compound 6 (140 mg, 0.36 mmol, 48.76% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 388.0.

3) Synthesis steps of compound GDI15-7243

Toluene (5 mL) was added to the mixed system of compound 6 (140 mg, 0.36 mmol) and CDI (293 mg, 1.80 mmol), and the system was stirred at 110°C for 5 hours under nitrogen protection. The reaction was completed by LCMS. Then water (20 mL) was added to the system and extracted with EtOAc (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 50 v: 1 v to 20 v: 1 v) to obtain compound GDI15-7243 (35.26 mg, 0.0852 mmol, 23.60% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 414.15.

¹ H NMR (400MHz, DMSO) δ9.41(s,1H),8.56(s,1H),8.26(d,J＝8.0Hz,1H),7.98(d,J＝8.3Hz,1H),7.78(dt,J＝24.4,7.0Hz,2H),7.4 9(t,J＝7.8Hz,1H),7.42(m,2H),7.31(d,J＝7.5Hz,1H),7.05(m,1H),6.73(d,J＝9.3Hz,1H),6.43(d,J＝6.6Hz,1H),2.63(s,3H).

Example 121: Preparation of Compound GDI15-7315

1) Synthesis steps of compound 3

Compound 2 (1.5 g, 0.01 mmol) and KOH (0.69 g, 0.01 mmol) were added to a DMSO (20 mL) solution of compound 1 (2.0 g, 0.01 mmol), and the mixture was stirred at 55 °C for 3 h under nitrogen protection. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (30 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 10:1) to obtain compound 3 (1.4 g, 56.76% yield) as a colorless oily compound. ESI-MS: [M+H] ⁺ , 247.05.

2) Synthesis steps of compound 4

1M NaOH (65 mL) was added to a solution of compound 3 (2 g, 8.1 mmol) in MeOH (65 mL), and the mixture was stirred at 80°C for 10 h. After the reaction, EtOAc (30 mL) was added to the mixture, and the mixture was extracted with water (50 mL*2). The aqueous phases were combined, concentrated, and purified by C18 column chromatography (eluent H ₂ O/MeOH, 20/1 to 3/1) to obtain compound 4 (0.7 g, 2.4 mmol, 29.63% yield) as a white solid. ESI-MS: [M+H] ⁺ , 247.05.

3) Synthesis steps of compound 6

DMF (5 mL) was added to compound 4 (450 mg, 1.58 mmol) and DIPEA (613.9 mg, 4.76 mmol). HATU (1.2 g, 3.17 mmol) was added to the system under nitrogen protection. The mixed system was stirred for ten minutes and then compound 5 (274.44 mg, 1.90 mmol) was added. The reaction was continued at room temperature for 30 minutes. The reaction was completed by LCMS. After the reaction was completed, the system was concentrated and purified by column chromatography (DCM: MeOH, 1V: 0V to 20V: 1V) to obtain compound 6 (140 mg, 0.36 mmol, 22.76% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 387.95.

4) Synthesis steps of compound GDI15-7315

CDI (645 mg, 3.98 mmol) was added to a toluene solution (2 mL) of compound 6 (260 mg, 0.66 mmol), and the mixture was stirred at 110°C for 5 h under nitrogen protection. The reaction was completed by LCMS. After the reaction, the system was concentrated and purified by slurrying (DCM/MeOH, 1v:0v to 20v:1v) and Pre-TLC (DCM/MeOH, 20v:1v), and further purified by prep-HPLC (column: Gemini 5μm C18 column, 150*21.2mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-7315 (150 mg, 0.355 mmol, 53.56% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 418.05.

1H NMR (400MHz, DMSO) δ9.48(s,1H),8.59(s,1H),8.30(d,J＝8.1Hz,1H),8.23(d,J＝7.5Hz,1H),8.0 3(d,J＝8.3Hz,1H),7.86(m,1H),7.79(t,J＝7.5Hz,1H),7.42-7.24(m,4H),7.21(m,1H),6.62(m,1H).

Example 122: Preparation of Compound GDI15-7316

1) Synthesis steps of compound 3

Compound 2 (1.5 g, 0.01 mmol) and KOH (0.69 g, 0.01 mmol) were added to a DMSO (20 mL) solution of compound 1 (2.0 g, 0.01 mmol), and the mixture was stirred at 55 °C for 3 h under nitrogen protection. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (30 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (PE/EtOAc, 10:1) to obtain compound 3. (1.4 g, 56.76% yield) is a colorless oily compound. ESI-MS: [M+H] ⁺ , 247.05.

2) Synthesis steps of compound 3

To a mixed solution of compound 3 (1.3 g, 0.01 mol) in MeOH/H ₂ O=1:1 (84 mL) was added NaOH (1.70 g, 0.04 mol), and the mixed system was reacted at 80°C under nitrogen protection for 6 h. After the reaction, the system was filtered and further separated by column biotage isolera one (C18 column, eluent 10% to 90% MeCN/H ₂ O containing 0.1% formic acid) to obtain compound 4 (1.0 g, 58.49% yield) as a white solid.

¹ H NMR (400MHz, D ₂ O) δ8.34 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 2.9 Hz, 1H), 7.40-7.28 (m, 4H), 7.25-7.21 (m, 1H), 5.13 (s, 1H).

3) Synthesis steps of compound 6

Add (190.47 mg, 1.32 mmol), HATU (753.48 mg, 1.99 mmol) and DIPEA (512.22 mg, 3.96 mmol) to the THF (4 mL) solution of compound 4 (380 mg, 1.32 mmol), and stir the reaction at room temperature for 2 hours under nitrogen protection. After the reaction, add water (5 mL) and EtOAc (15 mL*3) to the system, wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry, and column chromatography (DCM/MeOH, 20:1 to 10:1) to obtain compound 6 (370 mg, 64.33% yield) as a yellow oily compound. ESI-MS: [M+H] ⁺ , 391.9.

4) Synthesis steps of compound GDI15-7316

CDI (372.40 mg, 2.30 mmol) was added to a toluene (2 mL) solution of compound 6 (150 mg, 0.38 mmol), and the mixture was stirred at 110°C for 2 h under nitrogen protection. After the reaction, prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% ammonia water) was used to obtain compound GDI15-7316 (45 mg, 27.85% yield) as a light yellow solid. ESI-MS: [M+H] ⁺ , 417.95.

^1H NMR (400MHz, DMSO) δ9.44 (s, 1H), 8.56 (s, 1H), 8.35 (m, 1H), 8.27 (d, J = 8.2Hz, 1H), 7 .96(d,J＝8.2Hz,1H),7.79(m,2H),7.47(m,4H),7.34(d,J＝7.4Hz,1H),7.03(m,1H).

Example 123: Preparation of Compound GDI15-6986

1) Synthesis steps of compound 3

Add DMSO (50 mL) to compound 1 (5.00 g, 28.50 mmol), compound 2 (8.16 g, 34.20 mmol), copper (I) iodide (1.09 g, 5.70 mmol) and potassium carbonate (11.82 g, 85.50 mmol), and stir the mixture under nitrogen protection at 110°C for 16 h. After the reaction, filter the system, add water to the filtrate and extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry, and column chromatography (EtOAc/PE, 45% to 50%) to obtain compound 3 (1.2 g, 15.79% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 286.0.

2) Synthesis steps of compound 4

NBS (249.16 mg, 1.40 mmol) was added to a DMF (2.5 mL) solution of compound 3 (500 mg, 1.75 mmol), and the mixture was stirred at room temperature for half an hour. After the reaction, water (50 mL) was added to the system and extracted with EtOAc (50 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 5% to 6%) to obtain compound 4 (360 mg, 56.42% yield) as a yellow solid.

^1H NMR (400MHz, DMSO) δ7.94 (d, J = 8.0Hz, 1H), 7.70-7.64 (m, 2H), 7.60 (s, 1H), 7.57-7.51 (m, 1H) ,7.40(ddd,J＝9.7,5.3,3.2Hz,1H),7.35(d,J＝8.0Hz,1H),6.61(d,J＝8.5Hz,1H),4.08(s,3H).

3) Synthesis steps of compound 6

A mixture of dioxane (5 mL) and H 2 O (3 mL) was added to a mixture of compound 4 ( ₁₅₀ mg, 0.41 mmol), compound 5 (125.95 mg, 0.494 mmol), XPhos-Pd-G2 (32.34 mg, 0.041 mmol) and K ₂ CO ₃ (170.57 mg, 1.23 mmol), and the mixture was stirred at 80°C for 2 h under nitrogen protection. After the reaction, the system was returned to room temperature and filtered. Water was then added to the filtrate and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (EtOAc/PE, 45% to 50%) to obtain compound 6 (50 mg, 29.44% yield) as a white solid. ESI-MS: [M+H] ⁺ , 413.15.

4) Synthesis steps of compound GDI15-6986

PPTS (152.16 mg, 0.61 mmol) and LiCl (25.66 mg, 0.61 mmol) were added to a solution of compound 6 (50 mg, 0.12 mmol) in NMP (2 mL), and the mixture was heated to 100°C and stirred for 2 h under nitrogen protection. After the reaction, the system was concentrated and purified by Biotage Isolera One (C18 column, eluent: 10% to 90% MeCN/H ₂ O containing 0.1% formic acid) to obtain compound GDI15-6986 (21.16 mg, 43.85% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 399.1.

^1H NMR (400MHz, DMSO) δ10.81(s,1H),9.59(d,J＝4.3Hz,1H),8.55(d,J＝6.4Hz,1H),8.36(d,J＝7.5Hz,1H),8.13(d,J＝7.8Hz,1 H),7.96-7.81(m,3H),7.68-7.52(m,4H),7.47(d,J＝7.3Hz,1H),7.35(dd,J＝16.0,8.3Hz,1H),6.66(dd,J＝8.4,4.2Hz,1H).

Example 124: Preparation of Compound GDI15-8128

1) Synthesis steps of compound 3

To a THF (120 mL) solution of compound 1 (10 g, 59.0 mmol), compound 2 (10.15 g, 59.0 mmol) and sodium p-toluenesulfonate (21.03 g, 118 mmol) was slowly added NaH (2.83 g, 118 mmol) at 0°C, and then stirred at 70°C for 3 h. The reaction was completed by LCMS. After the reaction was completed, H ₂ O (100 mL) was added to the system and extracted with EtOAc (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 1v:0v to 10v:1v) to obtain compound 3 (8 g, 30.7 mmol, 52.03% yield) as a brown oily compound. ESI-MS: [M+H] ⁺ , 261.0.

2) Synthesis steps of compound 4

To a solution of compound 3 (8 g, 30.7 mmol) in MeOH (100 mL), NaOH (6.14 g, 153.5 mmol) in H ₂ O (150 mL) was added at 0°C, and the mixture was stirred at 70°C for 16 h. The reaction was completed by LCMS. The system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent: 10% to 20% ACN/H ₂ O containing) to obtain compound 4 (4.1 g, 13.6 mmol, 44.30% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 280.0.

3) Synthesis steps of compound 6

Add THF (20 mL) to a mixture of compound 4 (2.1 g, 7 mmol), compound 5 (1.01 g, 7 mmol), T4P (3.78 g, 10.5 mmol) and DIPEA (2.71 g, 21 mmol) and stir at room temperature for 2 h. The reaction is complete after LCMS detection. Then add water H ₂ O (50 mL) to the system and extract with EtOAc (50 mL*3), dry with anhydrous sodium sulfate, filter and spin dry column chromatography (DCM/MeOH, 20v:1v) to obtain compound 6 (350 mg, 0.9 mmol, 12.86% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 406.1.

4) Synthesis steps of compound GDI15-8128

Toluene solution (10 mL) was added to the mixed system of compound 6 (350 mg, 0.86 mmol) and CDI (839 mg, 5.17 mmol), and the mixture was stirred at 100°C for 5 h under nitrogen protection. The reaction was completed by LCMS. Then, water H ₂ O (20 mL) was added to the system and extracted with DCM (20 mL*3), dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20 v: 1 v to 10 v: 1 v) to obtain compound GDI15-8128 (168.64 mg, 0.39 mmol, 45.28% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 432.05.

1H NMR (400MHz, DMSO) δ9.43(s,1H),8.55(s,1H),8.28(m,2H),7.93(d,J＝8.2Hz,1H),7.78(m ,2H),7.44(m,1H),7.26(s,1H),7.19(d,J＝9.5Hz,1H),6.80(s,1H),6.59(m,1H),2.22(s,3H).

Example 125: Preparation of Compound GDI15-7956

1) Synthesis steps of compound 2

Add chlorpyrifos and phenyl ester (43.46 g, 277.6 mmol, 4.0 eq.) to a DCM (500 mL) solution of compound 1 (10 g, 69.4 mmol, 1.0 eq.) and pyridine (16.47 g, 208.2 mmol, 3.0 eq.) at 0°C, and then warm the system to room temperature for 4 h. After the reaction, concentrate the system, add EtOAc (500 mL) for recrystallization, and filter to obtain compound 2 (22 g, 57.2 mmol, 82.42% yield). ESI-MS: [M+H] ⁺ , 385.05.

2) Synthesis steps of compound 4

To a DMF (100 mL) solution of compound 2 (10 g, 26 mmol) and compound 3 (3.29 g, 28.6 mmol) was added NaH (1.25 g, 52 mmol), and the mixture was stirred at room temperature for 16 h. The reaction was complete when detected by LCMS. After the reaction, water (100 mL) was added to the system, and after filtration, the mixture was further purified by prep-HPLC (column: Gemini 5 μm C18 column, 150*21.2 mm, eluent: 8% to 14% MeCN/H ₂ O containing 0.1% ammonia water) to obtain compound 4 (1.4 g, 21.15% yield) as a white solid. ESI-MS: [M+H] ⁺ , 254.05.

3) Synthesis steps of compound 5

DMF (5 mL) was added to a mixture of compound 4 (500 mg, 1.97 mmol), K ₂ CO ₃ (819 mg, 5.92 mmol), and CH ₃ I (140.12 mg, 0.99 mmol), and then stirred at room temperature under nitrogen for 2 h. The reaction was complete after LCMS detection. After the reaction, water (20 mL) was added to the system and extracted with EtOAc (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (DCM/MeOH, 20 v: 1 v) to obtain compound 5 (206 mg, 0.36 mmol, 39.04% yield) as a white solid. ESI-MS: [M+H] ⁺ , 268.0.

3) Synthesis steps of compound 6

DMF (3 mL) was added to the mixture of compound 5 (100 mg, 0.3741 mmol) and NBS (333 mg, 1.87 mmol), and the mixture was stirred at room temperature for 2 h under nitrogen protection. The reaction was completed by LCMS. After the reaction, H ₂ O (20 mL) was added to the mixture and extracted with (20 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20 v:1 v) to obtain compound 6 (60 mg, 0.1733 mmol, 46.32% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 345.95.

4) Synthesis steps of compound GDI15-7956

A mixed solution of dioxane/water (4mL/1mL) was added to compound 6 (53mg, 0.15mmol), compound 7 (44mg, 0.23mmol), potassium phosphate (97mg, 0.46mmol) and XPhos Pd G2 (24mg, 0.03mmol), and the mixture was stirred at 80℃ for 2h under nitrogen protection. The reaction was completed by LCMS. After the reaction, the system was concentrated and further analyzed by prep-HPLC (column: Gemini 5μm C18 column, 150*21.2mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% TFA) to obtain compound GDI15-7956 (2mg, 3.2% yield) as a white solid. ESI-MS: [M+H] ⁺ , 412.00.

¹ H NMR (400MHz, DMSO) δ9.42(d,J＝2.6Hz,1H),8.46(d,J＝2.3Hz,1H),8.27(d,J＝8.4H z,1H),7.81(m,3H),7.62(s,1H),7.37(d,J=1.5Hz,2H),3.48(s,3H),2.29(s,3H).

Example 126: Preparation of Compound GDI15-8019

1) Synthesis steps of compound 2

Add DMF (5 mL) to compound 1 (500 mg, 1.97 mmol), DIPEA (764 mg, 5.92 mmol) and SEMCl (494 mg, 2.96 mmol), stir and react for 16 h under nitrogen protection, and the reaction is complete by LCMS. After the reaction, add water (20 mL) to the system, extract with EtOAc (20 mL*3), dry with anhydrous sodium sulfate, filter and spin dry column chromatography (PE/EtOAc, 1v:1v to 1v:2v) to obtain compound 2 (230 mg, 0.60 mmol, 30.29% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 384.15.

2) Synthesis steps of compound 3

Add DMF (5 mL) to compound 2 (230 mg, 0.60 mmol) and NBS (319 mg, 1.79 mmol), stir and react for 2 h at room temperature under nitrogen protection, and the reaction is complete when detected by LCMS. After the reaction, add water (20 mL) to the system and extract with EtOAc (20 mL*3), dry with anhydrous sodium sulfate, filter and spin dry, column chromatography (DCM/TEA, 200 v: 1 v) to obtain compound 3 (140 mg, 0.19 mmol, 32.47% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 464.0.

2) Synthesis steps of compound 4

A mixture of dioxane/water (4mL/1mL) was added to compound 3 (90mg, 0.19mmol), compound 4 (56mg, 0.29mmol), K ₃ PO ₄ (124mg, 0.58mmol) and XPhos Pd G2 (76mg, 0.097mmol), and the mixture was stirred at 80°C under nitrogen for 6 hours. The reaction was complete by LCMS. After the reaction, water (20mL) was added to the system and extracted with EtOAc (20mL*3), dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20v:1v) to obtain compound 5 (63mg, 0.12mmol, 61.28% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 528.10.

2) Synthesis steps of compound GDI15-8019

To a solution of compound 5 (63 mg, 0.119 mmol) in DCM (1.5 mL), TFA (1.5 mL) was added under nitrogen protection at 0°C, and the mixture was stirred at room temperature for 4 hours. The reaction was completed by LCMS. After the reaction was completed, the system was concentrated and further purified by prep-HPLC (column: Gemini 5μm C18 column, 150*21.2mm, eluent: 30% to 90% MeOH/H ₂ O containing 0.1% TFA) to obtain compound GDI15-8019 (3.06 mg, 0.0077 mmol, 6.47% yield) as a white solid. ESI-MS: [M+H] ⁺ , 398.05.

¹ H NMR (400MHz, DMSO) δ11.76(s,1H),9.42(s,1H),8.48(s,1H),8.27(d,J＝8.1Hz ,1H),7.81(m,3H),7.58(t,J＝1.9Hz,1H),7.41(d,J＝1.9Hz,2H),2.14(s,3H).

Example 127: Preparation of Compound GDI15-7810

1) Synthesis steps of compound 3

Compound 2 (0.62 g, 6.30 mol) and KOH (0.89 g, 15.80 mmol) were added to a DMSO (12 mL) solution of compound 1 (1.2 g, 7.90 mmol), and the mixture was stirred at 55 °C for 3 h under nitrogen protection. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (30 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 10:1) to obtain compound 3 (1.0 g, 55.70% yield) as a colorless oily compound. ESI-MS: [M+H] ⁺ , 230.95.

2) Synthesis steps of compound 4

To a mixed solution of compound 3 (1.0 g, 4.40 mmol) in MeOH/H ₂ O＝1:1 (90 mL) was added NaOH (1.41 g, 35.20 mmol), and the mixture was stirred at 80°C for 6 h. The system was concentrated and filtered, and further purified by biotage isolera one (C18 column, eluent: 10% to 90% MeCN/H ₂ O containing 0.1% formic acid) to obtain compound 4 (900 mg, 75.00% yield) as a white solid.

3) Synthesis steps of compound 6

Compound 5 (255.69 mg, 1.77 mmol) and NMI (424.69 mg, 5.17 mmol) were added to a DCM (4 mL) solution of compound 4 (400 mg, 1.48 mmol) under nitrogen protection. The system was stirred at 0°C for 30 minutes, and TCFH (497.62 mg, 1.77 mmol) was added dropwise to the system. The temperature was raised to room temperature and the reaction was continued for 2 hours. After the reaction was completed, water (10 mL) was added to the system and extracted with EtOAc (10 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 6 (220 mg, 39.71% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 375.00.

4) Synthesis steps of compound GDI15-7810

CDI (216.29 mg, 1.33 mmol) was added to a toluene solution (1 mL) of compound 6 (100 mg, 0.27 mmol), and the system was then reacted at 100°C for 2 h. After the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% FA) to obtain compound GDI15-7810 (3.10 mg, 2.89% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 401.0.

^1H NMR (400MHz, DMSO) δ9.45(s,1H),8.56(s,1H),8.44(d,J＝1.2Hz,1H),8.28(d,J＝7 .8Hz,1H),8.03-7.96(m,2H),7.85-7.75(m,2H),7.57-7.47(m,4H),7.42(m,1H).

Example 128: Preparation of Compound GDI15-7811

1) Synthesis steps of compound 3

Compound 1 (2g, 13.21mmol) and compound 2 (3.15g, 19.81mmol) were dissolved in DMSO (20mL), and then KOH (3.70g, 66mmol) was added to the system. The mixed system was stirred at 60°C for 4h. After the reaction, water was added to the system and extracted with EtOAc (30mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 30%) to obtain compound 3 (2g, 8.70mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 229.95.

2) Synthesis steps of compound 4

Compound 3 (2 g, 8.70 mmol) and NaOH (2.78 g, 69.60 mmol) were dissolved in a mixed solution of MeOH (70 mL) and H ₂ O (70 mL), then heated to 80°C and reacted at this temperature for 12 h. After the reaction, the system was concentrated at 60°C and purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H ₂ O) to obtain compound 4 (2.10 g, 7.80 mmol) as a white solid. ESI-MS: [M+H] ⁺ , 248.95.

3) Synthesis steps of compound 6

DMF (10 mL) was added to a mixture of compound 4 (1 g, 3.70 mmol), compound 5 (430 mg, 2.90 mmol) and HATU (2.81 g, 7.40 mmol), followed by DIPEA (1.43 g, 11.10mmol), the mixed system was stirred at room temperature for 2h. After the reaction, water was added to the system and extracted with EtOAc (50mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 5%) to obtain compound 6 (350mg, 0.90mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 374.95.

3) Synthesis steps of compound GDI15-7811

Toluene (4 mL) was added to the system of compound 6 (300 mg, 0.80 mmol) and CDI (779 mg, 4.80 mmol), and the mixed system was stirred at 110°C for 2 h. After the reaction, water was added to the system and EtOAc (10 mL*3) was added. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 0% to 5%) to obtain compound GDI15-7811 (90 mg, 0.22 mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 401.00.

^1H NMR (400MHz, DMSO) δ9.43 (s, 1H), 8.57 (s, 1H), 8.30-8.22 (m, 2H), 7.99 (d, J = 8.5Hz, 1H), 7.84-7.74 (m, 2H),7.48(tt,J＝4.7,3.5Hz,2H),7.42(t,J＝1.6Hz,1H),7.39-7.30(m,2H),7.07(dd,J＝9.6,3.9Hz,1H).

Example 129: Preparation of Compound GDI15-7959

1) Synthesis steps of compound 3

Add DMSO (35 mL) to compound 1 (3.3 g, 21.8 mmol), then continue to add compound 2 (3.08 g, 23.90 mmol) and KOH (2.44 g, 43.5 mmol), and continue stirring the mixed system at 60 ° C for 4 h under nitrogen protection. After the reaction is completed, add water (35 mL) to the system and extract with EtOAc (50 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (EtOAc/PE, 20% to 30%) to obtain compound 3 (3 g, 56.42% yield) as a white solid. ESI-MS: [M+H] ⁺ , 401.00.

2) Synthesis steps of compound 4

Add MeOH/H ₂ O＝1:1 (200mL) mixed solution to compound 3 (3g, 12.3mmol), then continue to add NaOH (3.94g, 98.4mmol) at room temperature, and heat to 80℃ under nitrogen protection for 12h. After the reaction is completed, filter and further purify the remaining part by biotage isolera one (C18 column, eluting with 10％to 90％MeCN/H ₂ O) to obtain compound 4 (3.5g, 95.12％yield) as a white solid. ESI-MS: [M+H] ⁺ ,262.95.

3) Synthesis steps of compound 6

Add MeCN (5mL) to compound 4 (500mg, 1.76mmol) and then add compound 5 (303.87mg, 2.11mmol) to the system. Add NMI (504.70mg, 6.15mmol) slowly at 0℃ under nitrogen protection, then continue to stir and react at 0℃ for 1h, add TCFH (591.37mg, 2.11mmol) dropwise to the system, slowly warm to room temperature and continue to react at room temperature for 15h. After the reaction, add water (10mL) to the system and extract with EtOAc (10mL*3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry column chromatography (EtOAc/PE, 0% to 50%) to obtain compound 6 (200mg, 29.13% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 389.00.

4) Synthesis steps of compound GDI15-7959

Toluene (5 mL) was added to compound 6 (200 mg, 0.51 mmol), and then CDI (416.94 mg, 2.57 mmol) was added to the system. The mixture was stirred at 100°C for 4 h under nitrogen protection. After the reaction, the system was concentrated, and the remaining portion was purified by prep-HPLC (Gemini 5um C18 column, 150*21.2mm, eluting with 30% to 90% MeCN/H ₂ O containing 0.1% NH ₄ OH) to obtain compound GDI15-7959 (73.10 mg, 33.91% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 389.00.

^1H NMR (400MHz, DMSO) δ9.43(s,1H),8.55(s,1H),8.27(d,J＝8.0Hz,1H),7.94(d,J＝8.3Hz,1H),7 .79(m,2H),7.54-7.44(m,2H),7.42(m,1H),7.34(m,2H),7.03(d,J=9.7Hz,1H),2.37(s,3H).

Example 130: Preparation of Compound GDI15-7990

1) Synthesis steps of compound 3

Add DMSO (20 mL) solution to compound 1 (2 g, 13.21 mmol) and compound 2 (1.87 g, 14.52 mmol), then continue to add KOH (3.70 g, 66.00 mmol), heat the system to 60 ° C and react for 4 hours. After the reaction, add water to the system and extract with EtOAc (30 mL * 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 30%) to obtain compound 3 (2.20 g, 9.00 mmol) as a yellow solid. ESI-MS: [M+H] ⁺ , 244.00.

2) Synthesis steps of compound 4

A mixed solution of MeOH (66 mL) and H ₂ O (66 mL) was added to compound 3 (2.00 g, 8.20 mmol), and then NaOH (2.62 g, 65.60 mmol) was added to the system. The temperature was slowly raised to 80°C and reacted for 12 h. After the reaction, the mixture was concentrated by rotary evaporation at 60°C. The remaining part was further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluting with 0% to 30% MeCN/H ₂ O) to obtain compound 4 (2.30 g, 8.10 mmol) as a white solid. ESI-MS: [M+H] ⁺ , 262.95.

3) Synthesis steps of compound 6

THF (20 mL) was added to a mixture of compound 4 (2.1 g, 7.4 mmol), compound 5 (960 mg, 6.6 mmol), T ₃ P (3.53 g, 11.1 mmol) and DIPEA (2.86 g, 22.2 mmol), followed by reaction at room temperature for 16 h. The reaction was complete when detected by LCMS. After the reaction, water (20 mL) was added to the system and extracted with EtOAc (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM: MeOH, 20 v: 1 v) to obtain compound 6 (220 mg, 0.6 mmol, 8.11% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 389.10.

4) Synthesis steps of compound 6

Toluene (5 mL) was added to compound 6 (220 mg, 0.57 mmol), and then CDI (917.4 mg, 5.66 mmol) was added to the system. The temperature was raised to 100°C for 2 h. The reaction was completed by LCMS. The system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluting with 75% to 95% MeCN/H ₂ O containing 0.1% FA) to obtain compound GDI15-7990 (53.76 mg, 22.91% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 414.90.

^1H NMR (400MHz, DMSO) δ9.43(s,1H),8.55(d,J＝3.7Hz,1H),8.27(d,J＝8.3Hz,1H),8.16(d,J＝4.1Hz,1H),7.95(d,J＝8.3Hz,1 H),7.83(d,J＝7.6Hz,1H),7.78(d,J＝8.3Hz,1H),7.43(m,3H),7.32(t,J＝7.2Hz,1H),6.96(d,J＝2.9Hz,1H),1.65(s,3H).

Example 131: Preparation of Compound GDI15-7989

1) Synthesis steps of compound 3

Under nitrogen protection at 0℃, DMSO (30mL) was added to compound 1 (2.5g, 14.7mmol), compound 2 (3.51g, 22.0mmol) and KOH (3.3g, 58.8mmol), and the system was heated to 60℃ for 4h. LCMS detected that the reaction was complete, 100mL of water was added to the system to quench the reaction, and 100mL of EtOAc was used for extraction. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (PE/EtOAc, 1v:0v to 10v:1v) to obtain compound 3 (2.3g, 9.3mmol, 63.27% yield) as a brown oil. ESI-MS: [M+H] ⁺ , 247.95.

2) Synthesis steps of compound 4

MeOH (70 mL) was added to compound 3 (2.3 g, 9.3 mmol), and a H ₂ O solution (70 mL) of NaOH (2.98 g, 74.4 mmol) was slowly added under nitrogen protection at 0°C. The system was stirred at 70°C for 12 h. The reaction was completed by LCMS. After the reaction, the system was concentrated, and the remaining part was further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2mm, eluting with 10% to 15% ACN/H ₂ O) to obtain compound 4 (1.3 g, 4.5 mmol, 48.39% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 266.95.

3) Synthesis steps of compound 6

Add THF (10 mL) to compound 4 (1.1 g, 3.8 mmol), compound 5 (490 mg, 3.4 mmol), T ₃ P (1.81 g, 5.7 mmol) and DIPEA (1.47 g, 11.4 mmol), stir and react for 4 h at room temperature under nitrogen protection, and the reaction is complete when LCMS is detected. After the reaction is completed, add water (20 mL) to the system and extract with EtOAc (20 mL*3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry, column chromatography (DCM:TEA, 200 v:1 v) to obtain compound 6 (60 mg, 0.2 mmol, 5.26% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 393.00.

4) Synthesis steps of compound GDI15-7989

Toluene (5 mL) was added to compound 6 (65 mg, 0.17 mmol), followed by CDI (268 mg, 1.66 mmol), and the temperature was raised to 110°C for 2 h. The reaction was complete as detected by LCMS. The system was then concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150*21.2 mm, eluting with 75% to 95% MeCN/H ₂ O containing 0.1% FA) to obtain compound GDI15-7989 (30.47 mg, 43.99% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 419.00.

¹ H NMR (400MHz, DMSO) δ9.44(s,1H),8.56(s,1H),8.28(m,2H),7.97(d,J＝8.2Hz,1H),7.83(t,J＝7 .1Hz,1H),7.77(t,J＝7.0Hz,1H),7.48(m,2H),7.29(s,1H),7.21(d,J＝8.9Hz,1H),7.10(m,1H).

Example 132: Preparation of Compound GDI15-8160

1) Synthesis steps of compound 3

Add DMSO (80 mL) to compound 1 (8.5 g, 50.1 mol), compound 2 (6.76 g, 52.6 mmol) and KOH (14.06 g, 250.5 mmol), stir and react for 4 h at 60 ° C under nitrogen protection. LCMS detection shows that the reaction is complete. Then add water (200 mL) to the system and extract with EtOAc (200 mL*3). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry column chromatography (DCM: MeOH, 50v:1v to 20v:1v) to obtain compound 3 (8.2 g, 31.3 mmol, 62.48% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 262.05.

2) Synthesis steps of compound 4

MeOH (45 mL) was added to compound 3 (4 g, 15.3 mmol), and a solution of NaOH (1.84 g, 45.8 mmol) in H2O (45 mL) was slowly added under nitrogen protection at 0°C. The system was reacted for 16 h at 60°C. The reaction was completed after LCMS detection. The system was then concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150*21.2 mm, eluting with 10% to 20% ACN/H ₂ O containing) to obtain compound 4 (2.6 g, 8.6 mmol, 56.21% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 236.95.

3) Synthesis steps of compound 6

Compound 4 (2.6 g, 8.6 mmol), compound 5 (1.24 g, 8.6 mmol), DIPEA (3.33 g, 25.8 mmol) and T4P (4.65 g, 12.9 mmol) were dissolved in THF (30 mL), stirred at room temperature under nitrogen protection for 2 h, and the reaction was completed by LCMS. After the reaction, water (50 mL) was added to the system and extracted with EtOAc (50 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM: MeOH, 20 v: 1 v) to obtain compound 6 (500 mg, 1.2 mmol, 13.95% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 407.10.

4) Synthesis steps of compound GDI15-8160

Toluene (10 mL) was added to compound 6 (500 mg, 1.23 mmol) and CDI (996 mg, 5.15 mmol), and the mixture was stirred at 100 °C for 5 h under nitrogen protection. The reaction was completed by LCMS. After the reaction, water (20 mL) was added to the system and extracted with DCM (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20 v: 1 v to 10 v: 1 v) to obtain compound GDI15-8160 (33.63 mg, 0.078 mmol, 6.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 433.30.

1H NMR (400MHz, DMSO) δ9.44(s,1H),8.54(s,1H),8.28(d,J＝7.9Hz,1H),7.94(d,J＝8.3Hz,1H),7 .79(m,2H),7.47(m,2H),7.29(s,1H),7.22(d,J＝9.2Hz,1H),7.07(d,J＝9.7Hz,1H),2.38(s,3H).

Example 133: Preparation of Compound GDI15-8161

1) Synthesis steps of compound 3

DMF (8 mL) was added to compound 1 (360 mg, 2.5 mmol), compound 2 (360 mg, 2.5 mmol), TCFH (1.4 g, 5.0 mmol) and NMI (616 mg, 7.5 mmol), and the mixture was stirred at room temperature for 4 h under nitrogen protection. The reaction was completed by LCMS detection. Water (20 mL) was then added to the system and extracted with EtOAc (20 mL*3), dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20 v: 1 v) to obtain compound 3 (140 mg, 0.53 mmol, 21.20% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 265.05.

2) Synthesis steps of compound 4

CDI (429 mg, 2.65 mmol) was added to a toluene solution (5 mL) of compound 3 (140 mg, 0.53 mmol), and the mixture was stirred at 110°C for 2 h. The reaction was completed after LCMS detection. The system was then concentrated and further purified by column chromatography (MeOH/DCM, 5% to 10%) to obtain compound 4 (80 mg, 52.03% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 291.15.

3) Synthesis steps of compound 5

Add NBS (98.10 mg, 0.55 mmol) to a DMF (2 mL) solution of compound 4 (80 mg, 0.28 mmol) and stir at room temperature for 2 h. After the reaction, add water (10 mL) to the system and extract with EtOAc (30 mL*3). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry, column chromatography (MeOH/DCM, 2% to 3%) to obtain compound 5 (62 mg, 60.92% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 368.90.

4) Synthesis steps of compound 8

B ₂ Pin ₂ (670 mg, 2.64 mmol), potassium carbonate (518 mg, 5.28 mmol) and Pd(dppf)Cl ₂ .DCM (143 mg, 0.18 mmol) were added to a solution of compound 6 (400 mg, 1.76 mmol) in dioxane (10 mL), and then the nitrogen was replaced and stirred at 90°C for 16 h under nitrogen protection. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (30 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by column chromatography (DCM/MeOH, 20:1) to obtain compound 8 (220 mg, 45.57% yield) as a yellow oily compound.

5) Synthesis steps of compound GDI15-8161

Compound 8 (32 mg, 0.087 mmol), potassium carbonate (36 mg, 0.26 mmol) and Pd-PEPPSI-IPent (7.3 mg, 0.0086 mmol) were added to a mixed solution of compound 5 (35.70 mg, 0.13 mmol) in dioxane/water = 4:1 (5 mL), and the mixed system was stirred at 85°C for 2 h. After the reaction, water (10 mL) was added to the system and extracted with EtOAc (30 mL*3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and purified by prep-HPLC (column: Gemini 5μm C18 column, 150*21.2 mm, eluent: 30% to 90% MeCN/H ₂ O containing 0.1% ammonia water) to obtain GDI15-8161 (0.43 mg, 33.83% yield) as a yellow solid. ESI-MS: [M+H] ⁺ ,437.0.

1H NMR (400MHz, DMSO) δ9.44(s,1H),8.55(s,1H),8.28(d,J＝8.5Hz,2H),7.96(d,J＝ 8.2Hz,1H),7.80(m,2H),7.51(d,J＝9.5Hz,1H),7.43(d,J＝8.5Hz,2H),7.10(m,1H).

Examples 134-141 were synthesized by a similar route to Example 130.

Example 142: Preparation of Compound GDI15-5416

1) Synthesis steps of compound 5

Compound 4 (8.3 g, 35.0 mmol, 1 eq) and compound 2 (8.80 g, 42.0 mmol, 1.2 eq, HCl) were dissolved in dioxane (8.3 mL) and H ₂ O (1.7 mL). At 20°C, Na ₂ CO ₃ (11.1 g, 105 mmol, 3 eq) and Pd(PPh ₃ ) ₄ (4.05 g, 3.50 mmol, 0.1 eq) were added. Under N ₂ atmosphere, the reaction mixture was reacted at 100°C for 16 hours. LCMS detected that the reaction was complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL*3). The organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried. The target compound 5 (5 g, 21.2 mmol, 60.4% yield) was obtained by separation and purification on a silica gel column (SiO ₂ , PE/EtOAc, 20/1 to 3/1) as a yellow solid. ESI-MS: [M+H] ⁺ , 237.0.

2) Synthesis steps of compound GDI15-495

Compound 5 (4.5 g, 19.1 mmol, 1 eq) was dissolved in DMF (45 mL), and compound P-TsOH (16.4 g, 95.23 mmol, 5 eq) and LiCl (4.04 g, 95.2 mmol, 1.95 mL, 5 eq) were added at 20 ° C. The reaction mixture was reacted at 120 ° C for 2 hours, and the reaction was completed by LCMS. Ice water (100 mL) was added to the reaction solution, and it was extracted with DCM (20 mL * 2). The pH of the aqueous phase was adjusted to 8 with saturated NaHCO ₃ aqueous solution, and the solid was filtered and dried to obtain the target compound GDI15-495 (3 g, 13.5 mmol, 70.9% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 223.0.

3) Synthesis steps of compound GDI15-5416

Compound GDI15-495 (200 mg, 900 μmol, 1 eq) was dissolved in DMF (4 mL) and H ₂ O (0.2 mL). Compound 3 (417 mg, 1.35 mmol, 1.5 eq) and Cu-TMEDA (125 mg, 270 μmol, 0.3 eq) were added at 20°C. The reaction mixture was reacted at 45°C for 16 hours under an O ₂ atmosphere. The reaction was completed by LCMS. Water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (5 mL*3). The organic phases were combined, washed with saturated sodium chloride (3 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried. Purification by HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 25%-60% B in 8 min) gave the target compound GDI15-5416 (30 mg, 74.5 μmol, 8.27% yield) as a white solid. ESI-MS: [M+H] ⁺ , 403.1.

¹ H NMR(400MHz, DMSO)δ0.28-0.36(m,2H)0.52-0.62(m,2H)1.19-1.28(m,1H)3.90(d,J＝7.00Hz,2H)6.51(t,J＝6.82Hz,1H)7.04-7.21(m,1H)7.12( s,1H)7.12(s,1H)7.24(t,J＝1.63Hz,1H)7.62-7.81(m,1H)7.70(ddd,J＝ 6.19,4.32,2.13Hz,1H)7.73-7.76(m,1H)7.77-7.80(m,1H)7.84(dd,J＝ 6.82,1.81Hz,1H)8.17(d,J＝8.00Hz,1H)8.28-8.81(m,1H)8.96-9.64(m,1H)

Example 143: Preparation of Compound GDI15-5229

1) Synthesis steps of compound 3

Compound 1 (0.5 g, 5.26 mmol, 1 eq) and compound 2 (1.65 g, 7.89 mmol, 1.5 eq, HCl)) were dissolved in DMF (10 mL) and H ₂ O (0.5 mL). CU-TMEDA (244 mg, 526 μmol, 0.1 eq) and TEA (1.60 g, 15.8 mmol, 2.20 mL, 3 eq) were added at 20°. The reaction mixture was reacted at 45°C for 16 hours under an oxygen atmosphere. The reaction was completed by LCMS detection. The reaction solution was slowly poured into water (30 mL), extracted with EtOAc (20 mL*3), and the organic phases were combined and washed with 20 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (60 mg, 203 μmol, 3.86% yield, 75.2% purity) as a yellow oil. ESI-MS: [M+H] ⁺ , 223.1

2) Synthesis steps of compound 4

Compound 3 (60 mg, 270 μmol, 1 eq) was dissolved in DMF (1.8 mL), and NBS (38.4 mg, 216 μmol, 0.8 eq) was added at 20°C. The reaction mixture was reacted at 20°C for 4 hours, and the reaction was complete after LCMS detection. The reaction solution was added to water (5 mL), extracted with EtOAc (5 mL*3), and the organic phases were combined. The product was filtered and dried under reduced pressure, and purified by silica gel plate separation (PE/EtOAc, 0/1) to obtain the target compound 4 (0.03 g, 18.9 μmol, 7.01% yield, 19% purity) as a white solid. ESI-MS: [M+H] ⁺ , 301.0 & 303.0.

3) Synthesis steps of compound GDI15-5229

Compound 4 (22 mg, 55.5 μmol, 1 eq) was dissolved in DMF (2 mL), and compound 6 (25.7 mg, 83.3 μmol, 1.5 eq), Pd(PPh ₃ ) ₄ (6.42 mg, 5.55 μmol, 0.1 eq) and Cs ₂ CO ₃ (45.2 mg, 139 μmol, 2.5 eq) were added in sequence at 20°C. The reaction mixture was reacted at 100°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was added to water (10 mL), extracted with EtOAc (5 mL*3), the organic phases were combined, washed with saturated sodium chloride (5 mL), and dried under reduced pressure. Purification by high performance liquid chromatography (column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 40%-60% B in 8 min) gave the target compound GDI15-5229 (2.10 mg, 5.00μmol, 9.01% yield, 96% purity) as a white solid. ESI-MS: [M+H] ⁺ , 403.1

H NMR (400MHz, DMSO) δ9.58-9.35(m,1H),8.61(s,1H),8.32(d,J＝8.1Hz,1H),7.98(d,J＝6.3Hz,1H),7.93-7.70(m,3H),7.51(d,J＝8.1Hz,1H),7 .41(s,1H),7.30(s,1H),6.98(s,1H),6.56(t,J＝6.9Hz,1H),3.86(d,J＝ 6.9Hz,2H),1.27-1.13(m,1H),0.63-0.48(m,2H),0.31(d,J＝4.5Hz,2H)

Example 144: Preparation of Compound GDI15-5249

1) Synthesis steps of compound 3

Compound 1 (1 g, 5.75 mmol, 1 eq) was dissolved in dioxane (10 mL) and H ₂ O (2 mL), and compound 2 (2.13 g, 6.90 mmol, 1.2 eq), Pd(PPh ₃ ) ₄ (664 mg, 575 μmol, 0.1 eq) and NaHCO ₃ (1.21 g, 14.4 mmol, 559 μL, 2.5 eq) were added in sequence at 20°C. Under nitrogen atmosphere, the reaction mixture was reacted at 100°C for 16 hours, and the reaction was completed after LCMS detection. The reaction solution was decompressed and dried. The target compound 3 (0.56 g, 2.03 mmol, 35.3% yield) was obtained by purification on a silica gel column (SiO ₂ , PE/EtOAc, 1/1 to 0/1) as a yellow solid. ESI-MS: [M+H] ⁺ , 276.0.

2) Synthesis steps of compound GDI15-5249

Compound 3 (0.1 g, 363 μmol, 1 eq) and compound 4 (89.2 mg, 725 μmol, 2 eq) were dissolved in DMF (2 mL) and H ₂ O (0.1 mL), and CU-TMEDA (16.8 mg, 36.3 μmol, 0.1 eq) was added at 20°C. The reaction mixture was reacted at 45°C for 16 hours under an oxygen atmosphere, and the reaction was completed by LCMS. The reaction solution was slowly poured into water (10 mL), extracted with EtOAc (5 mL*3), the organic phases were combined, concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [water (FA)-ACN]; gradient: 20%-60% B in 8 min) to obtain GDI15-5249 (30 mg, 84.2 μmol, 23.2% yield, 99% purity) as a white solid. ESI-MS: [M+H] ⁺ , 353.0.

1H NMR(400MHz,DMSO)δ8.70(d,J＝2.4Hz,1H),8.66(dd,J＝1.3,4.8Hz,1H),8.01-7.95 (m,1H),7.85(dd,J＝2.0,7.0Hz,1H),7.80(dd,J＝2.0,6.7Hz,1H),7.59(dd,J＝4.8,8.1H z,1H),7.38(t,J＝1.6Hz,1H),7.28-7.23(m,1H),6.97(t,J＝2.1Hz,1H),6.48(t,J＝7.0 Hz,1H),3.86(d,J＝7.0Hz,2H),1.28-1.15(m,1H),0.61-0.53(m,2H),0.36-0.30(m,2H)

Example 145: Preparation of Compound GDI15-5359

1) Synthesis steps of compound 3

Compound 1 (160 mg, 580 μmol, 1 eq) was dissolved in DMF (3.2 mL) and H ₂ O (0.16 mL). Compound 2 (190 mg, 870 μmol, 1.5 eq) and Cu-TMEDA (6.74 mg, 14.51 μmol, 0.1 eq) were added at 20°C. The reaction mixture was reacted at 45°C for 16 hours under an oxygen atmosphere. The reaction was completed by LCMS. Water (5 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 mL*3). The organic phases were combined, washed with saturated sodium chloride (3 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried. Purification by HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: _[ water ( _NH4HCO3 )-ACN]; gradient: 50%-85% B in 8 min) gave the target compound GDI15-5359 (29.6 mg, 80.7μmol, 13.9% yield) as a white solid. ESI-MS: [M+H] ⁺ , 367.1.

^1H NMR(400MHz,DMSO)δ8.55(d,J＝4.9Hz,1H),8.48(s,1H),7.89(dd,J＝2.0,7.1Hz,1H), 7.70(dd,J＝1.9,6.7Hz,1H),7.48(d,J＝5.0Hz,1H),7.39(t,J＝1.6Hz,1H),7.27(dd,J＝ 1.5,2.1Hz,1H),6.97(t,J＝2.1Hz,1H),6.49(t,J＝6.9Hz,1H),3.87(d,J＝7.0Hz,2H), 2.13(s,3H),1.22(dtd,J＝2.8,7.6,12.1Hz,1H),0.60-0.54(m,2H),0.35-0.30(m,2H)

Example 146: Preparation of Compound GDI15-5356

Compound 1 (40 mg, 145.07 μmol, 1 eq) was dissolved in DMF (0.8 mL) and H ₂ O (0.04 mL). Compound 2 (36.7 mg, 160 μmol, 1.1 eq) and Cu-TMEDA (6.74 mg, 14.51 μmol, 0.1 eq) were added at 20°C. The reaction mixture was reacted at 45°C for 16 hours under an O ₂ atmosphere. The reaction was complete after LCMS detection. Water (2 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (1 mL*3). The organic phases were combined, washed with saturated sodium chloride (3 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried. Purification by HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 35%-70% B in 8 min) gave the target compound GDI15-5356 (2 mg, 52.9 μmol, 36.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 378.0.

¹ H NMR (400MHz, DMSO) δ9.14-9.05(m,2H),8.68-8.63(m,1H),7.89-7.85(m,2H),7.41-7.25(m,2H),6.99( s,1H),6.57-6.50(m,1H),3.87(d,J＝7.0Hz,2H),1.23(d,J＝7.0Hz,1H),0.59-0.55(m,2H),0.32(s,2H)

Example 147: Preparation of Compound GDI15-5589

1) Synthesis steps of compound 7

Compound 6 (200 mg, 520 μmol, 1 eq) was dissolved in dioxane (2 mL) and H ₂ O (0.4 mL), and then compound 3 (117 mg, 743 μmol, 1.3 eq), Na ₂ CO ₃ (121 mg, 1.14 mmol, 2 eq) and Pd(PPh ₃ ) ₄ (60.1 mg, 52.0 μmol, 0.1 eq) were added in sequence at 25°C. The mixture was reacted at 100°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. Water (5 mL) was added to the reaction mixture. Solid precipitated, the reaction solution was filtered, and the filter cake was collected. Ethyl acetate (2 mL) was added to the filter cake, stirred at 20°C for 5 minutes, and filtered to obtain the target compound 7 (110 mg, 263 μmol, 46.1% yield) as a white solid. ESI-MS: [M+H] ⁺ , 417.0.

2) Synthesis steps of compound GDI-5589

Compound 7 (100 mg, 240 μmol, 1 eq) was dissolved in DMF (2 mL), and LiCl (50.8 mg, 1.20 mmol, 24.5 μL, 5 eq) and TsOH (206 mg, 1.20 mmol, 5 eq) were added in sequence at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was complete as determined by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 20%-55% B, in 8 min) to obtain the target product GDI15-5589 (38 mg, 92.2 μmol, 38.4% yield, 97.8% purity) as a white solid. ESI-MS: [M+H] ⁺ , 403.0.

¹ H NMR (400MHz, DMSO-d ₆ )δ＝8.62(d,J＝1.6Hz,1H),8.44(d,J＝2.3Hz,1H),7.97(t,J＝2.0Hz,1H),7.61(d,J＝7.7Hz,1H),7.15-7.05(m,2H),6.98( t,J＝2.0Hz,1H),6.19(d,J＝7.7Hz,1H),3.87(d,J＝7.1Hz,2H),1.26-1.18(m,1H),0.60-0.54(m,2H),0.34-0.29(m,2H).

Example 148: Preparation of Compound GDI15-5572

1) Synthesis steps of compound 7

Compound 6 (200 mg, 520 μmol, 1 eq) was dissolved in dioxane (2 mL) and H ₂ O (0.4 mL), and then compound 3 (92.3 mg, 623 μmol, 1.2 eq), Na ₂ CO ₃ (121 mg, 1.14mmol, 2eq) and Pd(PPh ₃ ) ₄ (60.1mg, 52.0μmol, 0.1eq). Under nitrogen protection, the reaction was carried out at 100°C for 16 hours. The reaction was completed by LCMS. Water (5mL) was added to the reaction solution, and it was extracted with ethyl acetate (2mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 7 (60mg, 147μmol, 28.5% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 408.3.

2) Synthesis steps of compound GDI-5572

Compound 7 (40 mg, 147 μmol, 1 eq) was dissolved in DMF (0.8 mL), and LiCl (20.8 mg, 490 μmol, 10.0 μL, 5 eq) and TsOH (84.4 mg, 490 μmol, 5 eq) were added in sequence at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 25%-50% B in 8 min) to obtain the target product GDI15-5572 (16.5 mg, 41.9 μmol, 42.7% yield, 100% purity) as a yellow solid. ESI-MS: [M+H]+, 394.1.

1H NMR (400MHz, DMSO) δ13.05(s,1H),9.97(d,J＝4.6Hz,1H),9.30(s,1H),8.35(s,1H),8.19-8.13(m,2H),8.11(d,J＝1.1H z,1H),7.75-7.65(m,3H),7.62-7.55(m,2H),7.51-7.37(m,3H),7.33(d,J＝6.9Hz,1H),7.12(t,J＝7.5Hz,1H),5.46(s,2H)

Example 149: Preparation of Compound GDI15-5477

1) Synthesis steps of compound 3

Compound 1 (500 mg, 1.47 mmol, 1 eq) was dissolved in dioxane (10 mL) and H ₂ O (2 mL), and then compound 2 (20 mg, 1.47 mmol, 1 eq), Na ₂ CO ₃ (388 mg, 3.66 mmol, 2.5 eq) and Pd(PPh ₃ ) ₄ (169 mg, 146 μmol, 0.1 eq) were added in sequence at 25° C. The mixture was reacted at 100° C. for 16 hours under nitrogen protection, and the reaction was completed by LCMS detection. Water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying. The target compound 3 (0.43 g, 1.39 mmol, 95.5% yield) was obtained as a brown oil by column chromatography (PE/EtOAc, 3/1) (TLC, PE/EtOAc, 3/1, R _f = 0.55). ESI-MS: [M+H] ⁺ , 307.1.

2) Synthesis steps of compound 5

Pd/C (0.43 g) was added to MeOH (8.6 mL), and then compound 3 (0.43 g, 1.39 mmol, 1 eq) was added at 25°C. The mixture was reacted at 50°C for 16 hours under the protection of hydrogen (50 Psi). The reaction was completed by LCMS. The reaction solution was filtered through diatomaceous earth, and the filtrate was dried under reduced pressure to obtain the target compound 5 (240 mg, 1.11 mmol, 79.6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 217.1.

3) Synthesis steps of compound 7

Compound 5 (0.1 g, 462 μmol, 1 eq) was dissolved in DMF (2.0 mL), and then compound 6 (181 mg, 693 μmol, 1.5 eq), Cs ₂ CO ₃ (452 mg, 1.39 mmol, 3 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (65.7 mg, 462 μmol, 1 eq) and CuI (44.0 mg, 231 μmol, 0.5 eq) were added in sequence at 25°C. Under nitrogen protection, the mixture was reacted at 80°C for 16 hours. The reaction was completed after LCMS detection. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 mL*3). The organic phases were combined and precipitated with anhydrous sulfur. The product was dried over sodium bicarbonate, filtered under reduced pressure and dried by spin drying, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) (TLC, EtOAc/MeOH, 10/1, R _f = 0.60) to obtain the target compound 7 (80 mg, 201 μmol, 43.5% yield) as a white solid. ESI-MS: [M+H] ⁺ , 397.1.

4) Synthesis steps of compound GDI15-5477

Compound 7 (70 mg, 176 μmol, 1 eq) was dissolved in DMF (1.4 mL), and then TsOH (151 mg, 881 μmol, 5 eq) and LiCl (37.3 mg, 881 μmol, 18.0 μL, 5 eq) were added in sequence at 25°C, and the mixture was reacted at 140°C for 16 hours. The reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 25%-45% B, in 8 min) to obtain the target product GDI15-5477 (10.8 mg, 28.2 μmol, 15.9% yield) as a white solid. ESI-MS: [M+H] ⁺ , 383.1.

¹ H NMR (400MHz, DMSO) δ8.37(s,1H),8.21(s,1H),7.60(s,1H),7.55(d,J＝7.8Hz,1H),7.08-7.03(m,2H),6.95(t,J＝2.12Hz,1H) ,6.16(d,J＝7.6Hz,1H),3.85(d,J＝7.0Hz,2H),2.27(s,3H),1.13-1.26(m,1H),0.56(d,J＝7.0Hz,2H),0.30(d,J＝5.0Hz,2H).

Example 150: Preparation of Compound GDI15-5688

1) Synthesis steps of compound 8

Compound 6 (0.1 g, 286 μmol, 1 eq) and compound 7 (74.2 mg, 429 μmol, 1.5 eq) were dissolved in dioxane (2 mL) and water (0.4 mL), and Na ₂ CO ₃ (91.0 mg, 858 μmol, 3eq) and Pd(dppf)Cl ₂ (20.9mg, 28.6μmol, 0.1eq). Under nitrogen protection, the reaction was stirred at 80°C for 16 hours. The reaction was completed by LCMS. Ice water (5mL) was poured into the reaction solution, extracted with ethyl acetate (5mL*3), the organic phases were combined, and washed with 10mL saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target compound 8 (0.06g, 151μmol, 52.7% yield) was purified by silica gel plate purification method (SiO ₂ , PE/EtOAc, 1/1) (TLC, PE/EtOAc, 1/1, R _f = 0.5) as a yellow solid. ESI-MS: [M+H] ⁺ , 401.2.

2) Preparation of compound GDI15-5688

Compound 8 (0.06 g, 151 μmol, 1 eq) was dissolved in DMF (1.2 mL), and then LiCl (32.0 mg, 754 μmol, 15.4 μL, 5 eq) and TsOH (130 mg, 754 μmol, 5 eq) were added in sequence at 25°C. The mixture was reacted at 140°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was filtered at normal pressure and purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 45%-85% B, in 8 min) to obtain the target product GDI15-5688 (0.02 g, 52.1 μmol, 34.6% yield, 100% purity) as a yellow solid. ESI-MS: [M+H]+, 384.1.

¹ H NMR (400MHz, DMSO) δ9.91(s,1H),8.54(s,1H),7.76(d,J＝7.5Hz,1H),7.12(td,J＝1.9,5.7Hz,2H),7.02(t,J＝2.0Hz,1H ), 6.18 (d, J = 7.5Hz, 1H), 3.89 (d, J = 7.0Hz, 2H), 2.57 (s, 3H), 1.30-1.15 (m, 1H), 0.62-0.53 (m, 2H), 0.37-0.28 (m, 2H).

Example 151: Preparation of Compound GDI15-5784

1) Synthesis steps of compound 4

Compound 4_1 (1 g, 4.82 mmol, 1 eq) was dissolved in DMF (20 mL), and K ₂ CO ₃ (1.33 g, 9.64 mmol, 2 eq) and compound 2 (1.52 g, 7.23 mmol, 709 μL, 1.5 eq) were added in sequence under stirring. The reaction was stirred at 80°C for 1 hour, and the reaction was completed as detected by TLC (PE/EtOAc, 5/1, Rf=0.71). Ice water (50 mL) was poured into the reaction solution, and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with 50 mL of saturated sodium chloride aqueous solution. The washed organic phases were dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by column chromatography (SiO ₂ , PE/EtOAc, 50/1 to 10/1) to obtain the target compound 4 (200 mg, 691 μmol, 14.3% yield) as a colorless oil.

2) Synthesis steps of compound 2

Compound 1 (25.0 g, 174 mmol, 19.8 mL, 1 eq) was dissolved in dioxane (250 mL) at room temperature, and BnOH (28.3 g, 261 mmol, 27.2 mL, 1.5 eq) and t-BμOK (29.3 g, 261 mmol, 1.5 eq) were added in sequence under stirring. The reaction was stirred at 100 ° C for 16 hours, and the reaction was completed by LCMS detection. Ice water (300 mL) was poured into the reaction solution, and extracted with ethyl acetate (80 mL*3), and the organic phases were combined and washed with 100 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by column chromatography (SiO ₂ , PE/EtOAc, 20/1 to 5/1) (TLC, PE/EtOAc, 3/1, R _f = 0.61) to obtain the target compound 2 (35 g, 163 mmol, 93.4% yield) as a yellow oil. ESI-MS: [M+H] ⁺ , 216.1

3) Synthesis steps of compound 3

Pd/C (2.00 g, 10% purity) was dissolved in MeOH (100 mL) at room temperature, and compound 2 (4.00 g, 18.6 mmol, 1 eq) was added under stirring. The mixture was stirred at 25°C under a hydrogen balloon atmosphere for 16 hours. The reaction was complete after LCMS detection. The reaction mixture was filtered and dried to obtain the target product, compound 3 (2.2 g, 17.6 mmol, 94.6% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 126.1.

4) Synthesis steps of compound 4

Compound 3 (0.125 g, 999 μmol, 1 eq) and compound 4 (0.2 g, 691 μmol, 0.69 eq) were dissolved in DMF (2.5 mL). CuI (95.1 mg, 500 μmol, 0.5 eq), (1S, 2S)-(+)-N, N-dimethylcyclohexane-1, 2-diamine (142 mg, 999 μmol, 1 eq) and Cs ₂ CO ₃ (976 mg, 3.00 mmol, 3 eq) were added in sequence under stirring at room temperature. The reaction was stirred at 100 ° C for 16 hours under nitrogen protection. LCMS detected that the reaction was complete. The reaction solution was poured into ice water (5 mL), extracted with ethyl acetate (2 mL*3), and the organic phases were combined and washed with 5 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate purification (SiO ₂ , PE/EtOAc, 0/1) to obtain the target compound 4 (0.09 g, 270 μmol, 27.0% yield) as a brown solid. ESI-MS: [M+H] ⁺ , 334.2.

5) Synthesis steps of compound 5

Compound 4 (0.09 g, 270 μmol, 1 eq) was dissolved in DMF (4.5 mL), and NBS (43.2 mg, 243 μmol, 0.9 eq) was added under stirring. The reaction was stirred at 20 °C for 16 hours, and the reaction was completed by LCMS. The reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (3 mL*3), and the organic phases were combined and washed with 5 mL of saturated sodium chloride aqueous solution. The washed organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate purification method (SiO ₂ , PE/EtOAc, 0/1) to obtain the target compound 5 (0.09 g, 218 μmol, 80.9% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 411.9 & 413.9.

6) Synthesis steps of compound 7

Compound 5 (0.08 g, 194 μmol, 1 eq) and compound 6 (28.7 mg, 194 μmol, 1 eq) were dissolved in dioxane (1.6 mL) and H ₂ O (0.32 mL), and Na ₂ CO ₃ (41.1 mg, 388 μmol, 2 eq) and Pd(dppf)Cl ₂ (14.2 mg, 19.4 μmol, 0.1 eq) were added in sequence under stirring. Under nitrogen protection, the reaction was stirred at 100°C for 16 hours, and the reaction was completed by LCMS. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL*3). The organic phases were combined, concentrated under reduced pressure, and purified by silica gel plate purification method (SiO ₂ , PE/EtOAc, 1/1) to obtain the target product 7 (0.07 g, 161 μmol, 82.8% yield) as a brown solid. ESI-MS: [M+H] ⁺ ,436.2.

7) Preparation of compound GDI15-5784

Compound 7 (0.04 g, 91.8 μmol, 1 eq) was dissolved in DMF (2.0 mL). Then, LiCl (10.2 mg, 241 μmol, 4.95 μL, 5 eq) and TsOH (79.0 mg, 459 μmol, 5 eq) were added in sequence at 25°C. Under nitrogen protection, the reaction was carried out at 140°C for 16 hours. The reaction was completed by LCMS. The reaction solution was decompressed and dried, and purified by preparative high performance liquid chromatography column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 25%-60% B, and the target product GDI15-5784 (0.025 g, 52.6 μmol, 57.3% yield, 89.4% purity) was obtained in 8 min as a yellow solid.

¹ H NMR (400MHz, DMSO) δ9.01-9.08(m,1H),8.78(d,J＝1.50Hz,1H),8.42(t,J＝1.94Hz,1H),7.57(d,J＝7.75Hz, 1H), 7.26 (dt, J = 8.60, 1.83Hz, 2H), 7.16 (t, J = 2.00Hz, 1H), 6.13 (d, J = 7.63Hz, 1H), 4.87 (q, J = 8.84Hz, 2H).

Example 152: Preparation of Compound GDI15-5243

1) Synthesis steps of compound 3

Compound 1 (200 mg, 1.06 mmol, 1 eq) and compound 2 (328 mg, 1.06 mmol, 1 eq) were dissolved in DMF (4 mL), and Cs ₂ CO ₃ (866 mg, 2.66 mmol, 2.5 eq) and Pd(PPh ₃ ) ₄ (123 mg, 106 μmol, 0.1 eq) were added in sequence at 20°C. The reaction mixture was stirred at 120°C for 16 hours, and the reaction was completed by LCMS. Water (20 mL) was added to the reaction solution, and extracted with EtOAc (5 mL*3). The organic phases were combined and washed with 5 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (SiO ₂ , PE/EtOAc, 10/1) to obtain the target compound 3 (190 mg, 656 μmol, 61.7% yield) as a white solid. ESI-MS: [M+H] ⁺ , 290.1.

2) Synthesis steps of compound 4

Compound 3 (190 mg, 656 μmol, 1 eq) was dissolved in DMF (4 mL), and LiCl (139 mg, 3.28 mmol, 5 eq) and p-TsOH (565 mg, 3.28 mmol, 5 eq) were added in sequence at 20 °C. The reaction mixture was stirred at 120 °C for 2 hours, and the reaction was completed when LCMS was detected. Water (20 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3). The organic phases were combined and washed with 5 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and separated by silica gel plate (SiO ₂ , PE/EtOAc, 10/1) was purified to obtain the target compound 4 (140 mg, 508 μmol, 77.4% yield) as a white solid. ESI-MS: [M+H] ⁺ , 276.0.

3) Synthesis steps of compound GDI15-5243

Compound 4 (50 mg, 181 μmol, 1 eq) and compound 5 (43.7 mg, 199 μmol, 1.1 eq) were dissolved in DMF (1 mL) and water (50 μL), and the catalyst Cu-TMEAD (8.42 mg, 18.1 μmol, 0.1 eq) was added at 20 °C. The reaction mixture was reacted at 45 °C under oxygen conditions for 16 hours, and the reaction was completed by LCMS detection. The reaction solution was poured into water (4 mL), extracted with EtOAc (2 mL*3), the organic phases were combined, and washed with 3 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 45%-75% B in 7 min) to obtain the target compound GDI15-5243 (40.2 mg, 109μmol, 59.9% yield, 99.1% purity) as a light yellow solid. ESI-MS: [M+H] ⁺ , 367.2.

^1H NMR (400MHz, DMSO) δ8.56-8.50(m,2H),8.18(d,J＝2.63Hz,1H),8.02(dd,J＝9.66,2.76Hz,1H),7.83(s,1H),7.33(t,J＝1.57Hz,1H),7.19(t,J＝1.82 Hz,1H),6.94(t,J＝2.01Hz,1H),6.61(d,J＝9.54Hz,1H),3.90(d,J＝7.15Hz ,2H),2.40(s,3H),1.27-1.17(m,1H),0.61-0.55(m,2H)0.30-0.36(m,2H)

Example 153: Preparation of Compound GDI15-5239

1) Synthesis steps of compound 3

Compound 1 (250 mg, 2.63 mmol, 1 eq) and compound 2 (789 mg, 2.89 mmol, 1.1 eq) were dissolved in DMF (5 mL) and water (0.25 mL), and compound Cu-TMEDA (122 mg, 263 μmol, 0.1 eq) was added at 20 °C. Under nitrogen protection, the reaction mixture was reacted at 50 °C for 16 hours, and the reaction was completed by LCMS. Ice water (20 mL) was added to the reaction solution, and it was extracted with EtOAc (10 mL*3), and the organic phases were combined. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EtOAc, 100/1 to 0/1) to obtain the target compound 3 (130 mg, 541 μmol, 20.6% yield) as a black oil. ESI-MS: [M+H] ⁺ , 241.0.

2) Synthesis steps of compounds 4 & 4A

Compound 3 (130 mg, 541 μmol, 1 eq) was dissolved in DMF (1.3 mL), and NBS (77.0 mg, 433 μmol, 0.8 eq) was added at 25 °C. The reaction mixture was reacted at 25 °C for 3 hours, and a small amount of raw materials remained when detected by LCMS. Ice water (5 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3), and the organic phases were combined. The organic phase was concentrated under reduced pressure and purified by silica gel plate separation (PE/EtOAc, 1/1) to obtain a mixture of target compounds 4 & 4A (140 mg, 438 μmol, 81.1% yield) as a green solid. ESI-MS: [M+H] ⁺ , 319.0 & 320.9.

3) Synthesis steps of compound GDI15-5239

The mixture of compound 4 & 4A (140 mg, 438 μmol, 1 eq) was dissolved in DMF (2.8 mL), and compound 5 (203 mg, 658 μmol, 1.5 eq), Cs ₂ CO ₃ (357 mg, 1.10 mmol, 2.5 eq) and Pd(PPh ₃ ) ₄ (50.7 mg, 43.8 μmol, 0.1 eq) were added at 25°C. Under nitrogen atmosphere, the reaction mixture was reacted at 120°C for 16 hours. LCMS detected that the reaction of the raw materials was complete. Ice water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3), and the organic phases were combined. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C ₁₈ 150*40mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 45%-65%, 8min) to obtain the target compound GDI15-5239 (40.0 mg, 93.0μmol, 21.2% yield, 97.9% purity) as a white solid. ESI-MS: [M+H] ⁺ , 421.0&421.0.

1H NMR (400MHz, DMSO) δ9.08(s,2H),8.56(s,1H),8.29(d,J＝2.6Hz,1H),8.05(dd,J＝2.8,9.6Hz,1H),7.33(t,J＝1.5Hz,1H),7.20(t,J＝ 1.7Hz,1H),6.95(t,J＝1.9Hz,1H),6.64(d,J＝9.6Hz,1H),3.89(d,J＝7.1Hz,2H),1.29-1.14(m,1H),0.62-0.51(m,2H),0.38-0.26(m,2H)

Example 154: Preparation of Compound GDI15-5228

1) Synthesis steps of compound 3

Compound 1 (0.5 g, 5.26 mmol, 1 eq) and compound 2 (1.65 g, 7.89 mmol, 1.5 eq, HCl)) were dissolved in DMF (10 mL) and H ₂ O (0.5 mL). CU-TMEDA (244 mg, 526 μmol, 0.1 eq) and TEA (1.60 g, 15.8 mmol, 2.20 mL, 3 eq) were added at 20°. The reaction mixture was reacted at 45°C for 16 hours under an oxygen atmosphere. The reaction was completed by LCMS detection. The reaction solution was slowly poured into water (30 mL), extracted with EtOAc (20 mL*3), and the organic phases were combined and washed with 20 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (EtOAc/MeOH, 10/1) to obtain the target compound 3 (60 mg, 203 μmol, 3.86% yield, 75.2% purity) as a yellow oil. ESI-MS: [M+H] ⁺ , 223.1

2) Synthesis steps of compound 4 & compound 4A

Compound 3 (60 mg, 270 μmol, 1 eq) was dissolved in DMF (1.8 mL), and NBS (38.4 mg, 216 μmol, 0.8 eq) was added at 20 °C. The reaction mixture was reacted at 20 °C for 4 hours, and the reaction was completed by LCMS. The reaction solution was added to water (5 mL), extracted with EtOAc (5 mL*3), the organic phases were combined, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 0/1) to obtain the target compound 4 (0.03 g, 18.9 μmol, 7.01% yield, 19% purity) and compound 4A (0.03 g, 75.9 μmol, 28.1% yield, 76.2% purity) as white solids. ESI-MS: [M+H]+, 301.0 & 303.0.

3) Synthesis steps of compound GDI15-432 & compound GDI15-432A

The mixture of compound 4 and compound 4A (22 mg, 55.5 μmol, 1 eq) was dissolved in DMF (2 mL), and compound 6 (25.7 mg, 83.3 μmol, 1.5 eq), Pd(PPh ₃ ) ₄ (6.42 mg, 5.55 μmol, 0.1 eq) and Cs ₂ CO ₃ (45.2 mg, 139 μmol, 2.5 eq) were added in sequence at 20°C. The reaction mixture was reacted at 100°C for 16 hours under nitrogen protection, and the reaction was completed by LCMS. The reaction solution was added to water (10 mL), extracted with EtOAc (5 mL*3), the organic phases were combined, washed with saturated sodium chloride (5 mL), and dried under reduced pressure. The target compound GDI15-5228 (10.9 mg, 26.5 μmol, 47.8% yield, 98% purity) was obtained as a white solid by purification by HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 40%-60% B in 8 min). ESI-MS: [M+H]+, 403.1

1H NMR(400MHz,DMSO)δ9.49(s,1H),8.62(s,1H),8.36-8.24(m,2H),8.16 (dd,J＝2.8,9.8Hz,1H),7.90-7.67(m,2H),7.50(d,J＝8.3Hz,1H),7.33(s,1 H),7.19(d,J＝1.8Hz,1H),6.92(t,J＝1.9Hz,1H),6.68(d,J＝9.6Hz,1H),3.8 7(d,J＝7.1Hz,2H),1.26-1.13(m,1H),0.62-0.52(m,2H),0.33-0.25(m,2H)

Example 155: Preparation of Compound GDI15-5471

Compound Int I (150 mg, 594 μmol, 1 eq) and compound 3 (186 mg, 713 μmol, 1.2 eq) were dissolved in DMF (3 mL), and Cs ₂ CO ₃ (581 mg, 1.78 mmol, 3 eq), (1S, 2S)-N1, N2-dimethylcyclohexane-1, 2-diamine (84.5 mg, 594 μmol, 1 eq) and CuI (56.6 mg, 297 μmol, 0.5 eq) were added under an oxygen atmosphere. Under a nitrogen atmosphere, the reaction mixture was reacted at 100 ° C for 16 hours, and the reaction was completed by LCMS. The reaction solution was slowly poured into water (10 mL), extracted with EtOAc (4 mL*3), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate and reduced pressure. Filter and spin dry. Purify on silica gel plate (PE/EtOAc, 0/1) to obtain the target compound GDI15-5471 (20.0 mg, 43.8 μmol, 21.2% yield, 95% purity) as a yellow solid. ESI-MS: [M+H] ⁺ , 433.3.

^1H NMR (400MHz, DMSO) δ9.78-8.92(m,1H),8.79-8.24(m,1H),8.16(d,J＝8.0Hz ,1H),7.95(d,J＝7.9Hz,1H),7.78-7.61(m,3H),7.17(t,J＝1.8Hz,1H),7.12 -7.08(m,1H),7.05(t,J＝2.0Hz,1H),6.63(d,J＝8.0Hz,1H),3.89(d,J＝7.0H z,2H),3.77(s,3H),1.27-1.17(m,1H),0.61-0.53(m,2H),0.35-0.28(m,2H)

Example 156: Preparation of Compound GDI15-5472

1) Synthesis steps of compound 3

Compound 1 (0.6 g, 1.76 mmol, 1 eq) and compound 2 (324 mg, 2.64 mmol, 1.5 eq) were dissolved in dioxane (6 mL) and water (1.2 mL). Compound Cs ₂ CO ₃ (1.15 g, 3.52 mmol, 2 eq) and Pd(PPh ₃ ) ₄ (203 mg, 176 μmol, 0.1 eq) were added to the reaction at 20°C. Under N ₂ atmosphere, the reaction mixture was reacted at 45°C for 16 hours. LCMS detected that the reaction was complete. Water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (8 mL*3). The organic phases were combined, washed with saturated sodium chloride (3 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried. The target compound 3 (0.46 g, 1.57 mmol, 89.5% yield) was obtained by column separation and purification (SiO ₂ , PE/EtOAc, 20/1 to 2/1) as a yellow solid. ESI-MS: [M+H] ⁺ , 293.1.

2) Synthesis steps of compound 5

Compound Pd/C (0.45 g, 10%) was dissolved in MeOH (45 mL), and compound 3 (0.45 g, 1.53 mmol, 1 eq) was added to the reaction under nitrogen atmosphere. The reaction mixture was reacted at 50°C for 4 hours under H ₂ (50 psi) atmosphere, and the reaction was complete when detected by LCMS. The reaction solution was filtered, the filter cake was rinsed with methanol, the filtrate was dried over anhydrous sodium sulfate, and filtered under reduced pressure and dried to obtain the target compound 4 (0.28 g, 1.38 mmol, 90.6% yield) as a white solid. ESI-MS: [M+H] ⁺ , 203.0.

3) Synthesis steps of compound GDI15-5472

Compound 4 (0.38 g, 1.88 mmol, 1 eq) and compound 5 (590 mg, 2.26 mmol, 1.2 eq) were dissolved in DMF (7.5 mL). Compound Cs ₂ CO ₃ (1.84 g, 5.64 mmol, 3 eq), (1S, 2S)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (53.5 mg, 376 μmol, 0.2 eq) and CuI (178 mg, 940 μmol, 0.5 eq) were added to the reaction at 20°C. Under N ₂ atmosphere, the reaction mixture was reacted at 100°C for 16 hours. LCMS detected that the reaction was complete. Water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (5 mL*3). The organic phases were combined, washed with saturated sodium chloride (3 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried. Purification by silica gel plate (SiO ₂ , EtOAc/Methanol, 10/1) gave the target compound GDI15-5472 (0.23 g, 601 mmol, 32.0% yield) as a white solid. ESI-MS: [M+H] ⁺ , 383.1.

^1H NMR (400MHz, DMSO) δ0.30-0.35(m,2H)0.59(s,2H)1.20-1.27(m,1H)3.85(s,3H)3.89(d,J＝7.09Hz,2H)6.56(d,J＝7.95Hz,1H)7.00(t,J＝1.96Hz, 1H)7.11(dt,J＝6.42,1.86Hz,2H)7.37(dd,J＝7.40,4.71Hz,1H)7.76(d, J＝7.95Hz,1H)7.82(d,J＝7.82Hz,1H)8.37-8.47(m,1H)8.51-8.58(m,1H)

Example 157: Preparation of Compound GDI15-5428

1) Synthesis steps of compound 3

Compound GDI15-5399 (45 mg, 113 μmol, 1 eq) and TEA (22.9 mg, 226 μmol, 31.5 μL, 2 eq) were dissolved in DCM (0.5 mL), and MsCl (40.0 mg, 349 μmol, 27.0 μL, 3.1 eq) was added at 0°C. The reaction mixture was reacted at 25°C for 1 hour, and the reaction was completed by LCMS. Water (5 mL) was added to the reaction solution, and it was extracted with EtOAc (1 mL*3). The organic phases were combined, washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel plate separation (PE/EtOAc, 0/1) to obtain the target compound 7 (23 mg, 55.3 μmol, 48.8% yield) as a yellow solid. ESI-MS: [M+H] ⁺ , 415.2.

2) Synthesis steps of compound GDI15-5428

Compound 7 (15 mg, 36.1 μmol, 1 eq) was dissolved in DMF (1 mL), KCN (21.2 mg, 0.325 mmol, 13.9 μL, 9 eq) was added at 0°C, and the reaction mixture was reacted at 25°C for 1 hour. The reaction was completed by LCMS. The reaction solution was added with water (10 mL), extracted with EtOAc (3 mL*3), and the organic phases were combined and washed with 5 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 45%-65% B in 8 min) to obtain the target compound GDI15-5428 (2.1 mg, 5.17 μmol, 14.3% yield) as a yellow solid. ESI-MS: [M+H] ⁺ ,406.2.

¹ H NMR (400MHz, DMSO) δ8.56(d,J＝1.7Hz,1H),8.37(d,J＝1.8Hz,1H),7.90(d,J＝7.3Hz,1H),7.70(s,1H),7.36(s,1H),7.24(s,1H),6.99-6.97(m, 1H),6.61(d,J＝6.8Hz,1H),3.85(d,J＝6.8Hz,2H),3.82(s,2H),2.38(s,3H),1.23(s,1H),0.56(d,J＝6.0Hz,2H),0.32(d,J＝4.9Hz,2H)

Example 158: Preparation of Compound GDI15-5399

1) Synthesis steps of compound 3

Compound 1 (2 g, 13.1 mmol, 1 eq) was dissolved in DMF (40 mL) and H ₂ O (2 mL). Compound 2 (4.29 g, 19.5 mmol, 1.5 eq) and Cu-TMEDA (606 mg, 1.31 mmol, 0.1 eq) were added in sequence at 25°C under an O ₂ atmosphere. The reaction mixture was reacted at 90°C for 16 hours. The reaction was completed by LCMS. Ice water (100 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (40 mL*3). The organic phases were combined and washed with 200 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure and dried by spin drying, and purified by HPLC (column: Welch Xtimate C18 250*70mm#10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 5%-32% B in 17 min) to obtain the target compound 3 (118 mg, 483μmol, 3.70% yield) as a white solid. ESI-MS: [M+H] ⁺ , 245.1.

2) Synthesis steps of compound 4

Compound 3 (110 mg, 450 μmol, 1 eq) was dissolved in DMF (1.1 mL), and NBS (240 mg, 1.35 mmol, 3 eq) was added at 25 °C. The reaction mixture was reacted at 25 °C for 16 hours, and the reaction was completed by TLC. Ice water (10 mL) was added to the reaction solution, and it was extracted with EtOAc (2 mL*3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried. Purification by silica gel plate (PE/EtOAc, 0/1) gave the target compound 4 (90 mg, 278 μmol, 61.8% yield, 100% purity) as a white solid. ESI-MS: [M+H] ⁺ , 323.1.

3) Synthesis steps of compound 6

Compound 4 (70 mg, 216 μmol, 1 eq) was dissolved in dioxane (1.4 mL) and H ₂ O ₍ 0.28 mL), and compound 5 (80.2 mg, 259 μmol, 1.2 eq), Na ₂ CO ₃ (68.8 mg, 649 μmol, 3 eq) and Pd(PPh ₃ ) ₄ (25.0 mg, 21.6 μmol, 0.1 eq) were added in sequence under N 2 protection at 25° C. The reaction mixture was reacted at 100° C. for 16 hours, and the reaction was completed by LCMS detection. Water (10 mL) was added to the reaction solution, and impurities were removed by extraction with EtOAc (2 mL). The pH of the aqueous phase was adjusted to 3 with 2M HCl at 0°C, and extracted with EtOAc (2 mL*3). The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to obtain the target compound 6 (25 mg, 60.8 μmol, 28.1% yield) as a white solid. ESI-MS: [M+H] ⁺ , 411.1.

4) Synthesis steps of compound GDI15-5399

Compound 6 (10 mg, 24.3 μmol, 1 eq) was dissolved in THF (0.5 mL). Under N ₂ protection, BH ₃ .THF (1 M, 60.8 μL, 2.5 eq) was added at 25°C. The reaction mixture was reacted at 25°C for 4 hours. LCMS detected that the reaction was complete. The reaction solution was added dropwise to MeOH (2 mL). The mixture was heated The mixture was stirred at 40°C for 1 h, and purified by HPLC (column: Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (FA)-ACN]; gradient: 15%-55% B in 8 min) to obtain the target compound GDI15-5399 (4.4 mg, 10.4μmol, 42.8% yield, 94% purity) as a white solid. ESI-MS: [M+H] ⁺ , 397.2.

¹ H NMR (400MHz, CDCl ₃ )δ8.57(s,1H),8.36(s,1H),7.66(d,J＝7.3Hz,1H),7.50(s,1H),7.30(d,J＝1.5Hz,1H),7.26-7.24(m,1H),6.89(t,J＝2.1Hz,1H),6.5 7(d,J＝7.3Hz,1H),4.21(d,J＝15.3Hz,2H),3.81(d,J＝7.0Hz,2H),2.44(s,3H),1.26(s,1H),0.66-0.59(m,2H),0.33(d,J＝5.8Hz,2H)

Test Example 1: Activity determination of compounds

SARS-CoV-2/Hela-ACE Test

Compounds were transferred to 384-well plates (Greiner, Part. No. 781090-2B) and then added to Hela-ACE cells (cell density 5000 cells/20 μl MEM with 2% FBS). Plates with cells were transferred to the BSL3 laboratory. SARS-CoV-2 (USA-WA1/2020 Vero E6 cells) was diluted to an MOI of 0.75 to 1 to achieve ~30–60% cell infection. After incubation of the test plates at 37°C 5% CO2 for 48 hours, formaldehyde was added to a final concentration of 4% to fix the cells. Human polyclonal serum antibodies were used as primary antibodies, and goat anti-human H+L conjugated Alexa 488 (Thermo Fisher Scientific A11013) was used as secondary antibodies. DAPI (Thermo Fisher Scientific D1306) DNA staining was performed.

Uninfected cell toxicity assay

The compounds were transferred to a 1536-well plate (Corning No.9006BC) and then added to Hela-ACE cells (cell density 600 cells/5 μL MEM with 2% FBS). After incubation at 37°C 5% CO2 for 48 hours, the cell activity was tested. 2 μL 50% Cell-Titer Glo (Promega No G7573) water was diluted and added to the cell test plate, and the values were read using EnVision Plate Reader (Perkin Elmer).

Enzyme activity test

Inhibition assays were performed using 200 nM recombinant SARS-CoV-2 main protease and 15 μM fluorogenic substrate (Dabcyl-TSAVL QSGFRK-Glu (EDANS); Genscript). The assay buffer consisted of 50mM Tris-HCl, pH 7.3, 1mM EDTA. SARS-CoV-2 3CLpro was dissolved in 25μL assay buffer and mixed with different concentrations of compounds. The mixture was incubated at 37°C for 30 minutes. Substrate dissolved in 25μL assay buffer was then added to start the reaction. The M5 multi-mode microplate reader immediately measured the fluorescence signal at 350nm (excitation)/490nm (emission) every 1 minute at 37°C for 10 minutes. The RFU at the 6th minute of the reaction with different concentrations of the compound was used to generate the IC ₅₀ curve compared to the reaction with the lowest concentration. For each compound, the IC ₅₀ value for SARS-CoV-2 3CLpro was measured at 12 concentrations. The experimental data were analyzed by GraphPad Prism software.

The activity results of the exemplary compounds are shown in Tables 1 and 2 below.

Table 1: Activity results of exemplary compounds

Table 2: Activity results of exemplary compounds

Claims (12)

A compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,
in, One of ^X1 and ^X2 is N, and the other is N or CH; At most one of ^Y1 and ^Y2 is hydroxy, halogen, cyano, or C1- _C6 alkyl or _C1 - _{C6 alkoxy optionally substituted by hydroxy, halogen or cyano, and the rest are H; or Y2 is hydroxy or carbonyl, and Y1, together with P1 or P3 and the carbon atom or nitrogen atom to which they are attached, forms a C3-C6} ^{cycloalkyl , a three} _{- membered} to _six- membered heterocycloalkyl, a phenyl, or a five-membered to six-membered heteroaryl optionally substituted by halogen or _C1 - _C3 alkyl; One of ^P1 and ^P3 is ^-L1 - ^Z1- , and the other is selected from H, _C1 - _C6 alkyl or C3- _C6 cycloalkyl optionally substituted by halogen or cyano, or together with ^Y1 and the carbon atom or nitrogen atom to which they are attached, forms _C3 -C6 cycloalkyl optionally substituted by halogen or _C1 - _C3 alkyl, a three-membered _{to six} -membered heterocycloalkyl, a phenyl or a five-membered to six-membered heteroaryl; P ² is -L ² -Z ² -; L ¹ is selected from a bond, -CH ₂ -, -NH- or -O-; L ² is selected from a bond or -CH ₂ -; ^Z1 is wherein the ring optionally has 1 or 2 N heteroatoms; Z ² is selected from a five-membered to ten-membered heteroaryl group, wherein optionally one or more hydrogen atoms in Z ² are each independently substituted by halogen, hydroxyl, cyano, sulfo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy; R ¹ , R ² and R ⁵ are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and optionally one or more hydrogen atoms in R ¹ , R ² and R ⁵ are each independently substituted by halogen, hydroxyl, amino, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; one of R ³ and R ⁴ is H, and the other is selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, amide, carboxyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -O(CH ₂ ) _n1 CR ⁶ R ⁷ R ⁸ , -NH(CH ₂ ) _n1 R ¹⁰ , -O(CH ₂ ) _n1 R ¹¹ , -(CH ₂ ) _n1 NH(CH ₂ ) _n2 R ¹² , -(CH ₂ ) _n1 NHCOR ¹³ , -(CH ₂ ) _n1 NHSO ₂ R ¹⁴ or -(CH ₂ ) _n1 R ¹⁵ , and optionally one or more hydrogen atoms in R ³ and R ⁴ are each independently substituted by halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or a hydroxyl protecting group; R ⁶ and R ⁷ are selected from hydrogen, or together with the carbon atoms to which they are attached, they form a C ₃ -C ₆ cycloalkyl group or a C ₃ -C ₆ heterocycloalkyl group; R ⁸ is selected from -NH ₂ , -NHCOR ⁹ or -NHSO ₂ R ⁹ , wherein R ⁹ is selected from C ₁ -C ₆ alkyl or phenyl; R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, three-membered to six-membered heterocycloalkyl, phenyl or five-membered to six-membered heteroaryl; R ¹⁵ is selected from a three-membered to six-membered heterocycloalkyl group containing at least one nitrogen atom; _n1 and _n2 are selected from 0, 1, 2 or 3; and ○ is used to indicate that the ring is unsaturated. The compound of formula (I) according to claim 1 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or a prodrug thereof, or a metabolite thereof, wherein When ^P1 is -L1- ^Z1- , ^P3 is selected from H or _C1 - _C6 alkyl substituted by cyano, or together with ^Y1 and the carbon atom to which they are attached, forms a phenyl group optionally substituted by halogen or C1- _{C3 alkyl} ; ^and When ^P3 is -L1- ^Z1- , ^P1 is selected from _C1 - _C6 alkyl optionally substituted by halogen or cyano, preferably _-CH2CN , -( _CH2 ) _2CN , _-CF3 or _-CH2CF3 , or together with ^Y1 and ^the carbon atom or nitrogen atom to which they are attached, forms _a pyridyl or hexahydropyridyl group optionally substituted by halogen or C1- _{C3 alkyl} . The compound of formula (I) according to claim 1 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein: Z ² is selected from a five-membered to ten-membered heteroaryl group containing 1 to 3 nitrogen atoms, preferably, Z ² is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazole or quinolyl, wherein optionally one or more hydrogen atoms in Z ² are each optionally substituted by halogen, hydroxyl, cyano, methyl, ethyl, trifluoromethyl or methoxy. The compound of formula (I) according to claim 1 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein: One of ^R3 and ^R4 is H, and the other is selected from any one of the following groups:
The compound of formula (I) according to claim 1 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein: R ¹⁵ is selected from tetrahydropyrrolyl, hexahydropyridinyl, morpholinyl or thiomorpholinyl. The compound of formula (I) according to claim 1 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein: Halogen is selected from F, Cl or Br; C ₁ -C ₆ alkyl is selected from methyl, ethyl, propyl or isopropyl; C ₁ -C ₆ haloalkyl is selected from monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl or trichloromethyl; C ₁ -C ₆ alkoxy is selected from methoxy, ethoxy or propoxy; C ₁ -C ₆ haloalkoxy is selected from trifluoromethoxy or trifluoroethoxy; and/or The C ₃ -C ₆ cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The compound of formula (I) according to any one of claims 1 to 6, or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, which has any one of the following structures:







A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 8, wherein the dosage form is selected from tablets, granules, powders, syrups, inhalants and injections. Use of a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a medicament for treating or preventing coronavirus infection or a disease or symptom caused by coronavirus in a subject in need thereof. The use according to claim 10, wherein the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), new coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus OC43 (HCoV-OC43), mouse hepatitis coronavirus (MHV) and a coronavirus with a homology greater than 85% with any of the above coronaviruses and having viral activity. The use according to claim 10 or 11, wherein the disease or symptom caused by coronavirus is selected from one or more of the following: respiratory infection, acute respiratory syndrome (SARS), pneumonia (including severe pneumonia), gastroenteritis (including acute gastroenteritis), cough, fever, chills, vomiting, headache, chills, shortness of breath and cytokine storm.