3CL protease inhibitor for treating or preventing coronavirus infection and use thereof

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

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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

[0003] The present application relates to the field of biomedicine, and in particular to 3CL protease inhibitors and their uses for treating or preventing coronavirus infection. Background Art

[0004] The novel 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 novel 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 proteins required. 3CL proteases recognize specific cleavage sites and cut the polyprotein precursor into multiple non-structural proteins. They are essential to 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 novel coronavirus 3CL protease in vitro, but have been shown to have no positive effect on patients infected with the novel coronavirus in clinical trials. Therefore, strong inhibitors specific for the novel coronavirus 3CL protease are clinically needed.

[0005] Summary of the Invention

[0006] In the first aspect, the present application provides 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,

[0007] in,

[0008] X 1 and X 2 One of them is N, and the other is N or CH;

[0009] Y 1 and Y 2 At most one of them 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 Y 2 is a hydroxyl group or a carbonyl group, Y1 With P 1 or P 3 and the carbon atom or nitrogen atom to which they are attached together form a C3-C6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a phenyl group, or a five-membered to six-membered heteroaryl group optionally substituted with halogen or C1-C3 alkyl;

[0010] P 1 and P 3 One of them is -L 1 -Z 1 -, the other is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl optionally substituted by halogen or cyano, or Y 1 and the carbon atom or nitrogen atom to which they are attached together form a C3-C6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a phenyl group or a five-membered to six-membered heteroaryl group which is optionally substituted with halogen or C1-C3 alkyl; 2 -L 2 -Z 2 -;

[0011] L 1 is selected from a bond, -CH2-, -NH- or -O-; L 2 is selected from a bond or -CH2-;

[0012] Z 1 for wherein the ring optionally has 1 or 2 N heteroatoms;

[0013] Z 2 is selected from a five-membered to ten-membered heteroaryl group, wherein optionally Z 2 One or more hydrogen atoms in are independently substituted by halogen, hydroxy, cyano, sulfo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0014] R 1 、R 2 and R 5 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C1-C6 alkyl or C1-C6 alkoxy, and optionally R 1 、R 2 and R 5 One or more hydrogen atoms are independently substituted by halogen, hydroxy, amino, C1-C6 alkyl or C3-C6 cycloalkyl;

[0015] R 3 and R 4 One of them is H, and the other is selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, amide, carboxyl, C1-C6 alkyl, C3-C6 cycloalkyl, -O(CH2) n1 CR6 R 7 R 8 、-NH(CH2) n1 R 10 、-O(CH2) n1 R 11 、-(CH2) n1 NH(CH2) n2 R 12 、-(CH2) n1 NHCOR 13 、-(CH2) n1 NHSO2R 14 or -(CH2) n1 R 15 , and optionally R 3 and R 4 One or more hydrogen atoms are independently substituted by halogen, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or hydroxy protecting group;

[0016] R 6 and R 7 Selected from hydrogen, or together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl group or a C3-C6 heterocycloalkyl group;

[0017] R 8 Selected from -NH2, -NHCOR 9 or -NHSO2R 9 , where R 9 Selected from C1-C6 alkyl or phenyl;

[0018] R 10 、R 11 、R 12 、R 13 and R 14 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three-membered to six-membered heterocycloalkyl, phenyl, or five-membered to six-membered heteroaryl;

[0019] R 15 is selected from a three-membered to six-membered heterocycloalkyl group containing at least one nitrogen atom;

[0020] n1 and n2 are selected from 0, 1, 2 or 3; and

[0021] ○ is used to indicate that the ring is unsaturated.

[0022] In a preferred embodiment of the present invention, when P 1 -L 1 -Z 1 -When P 3 Selected from H or C1-C6 alkyl substituted by cyano, or Y 1and the carbon atoms to which they are attached together form a phenyl group optionally substituted with halogen or C1-C3 alkyl; and when P 3 -L 1 -Z 1 -When P 1 is selected from C1-C6 alkyl optionally substituted by halogen or cyano, preferably -CH2CN, -(CH2)2CN, -CF3 or -CH2CF3, or with Y 1 Together with the carbon atom or nitrogen atom to which they are attached, they form a pyridyl or hexahydropyridyl group which is optionally substituted with halogen or C1-C3 alkyl.

[0023] In another preferred embodiment of the present invention, Z 2 It can be selected from a five-membered to ten-membered heteroaryl group containing 1 to 3 nitrogen atoms. Preferably, Z 2 can be selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazole or quinolinyl, wherein optionally Z 2 One or more hydrogen atoms in each of these may be optionally substituted by halogen, hydroxy, cyano, methyl, ethyl, trifluoromethyl or methoxy.

[0024] In another preferred embodiment of the present invention, R 3 and R 4 One of them is H, and the other can be selected from any one of the following groups:

[0025] In another preferred embodiment of the present invention, R 15 It may be selected from tetrahydropyrrolyl, hexahydropyridinyl, morpholinyl or thiomorpholinyl.

[0026] In another preferred embodiment of the present invention, halogen may be selected from F, Cl or Br; C1-C6 alkyl may be selected from methyl, ethyl, propyl or isopropyl; C1-C6 haloalkyl may be selected from monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl or trichloromethyl; C1-C6 alkoxy may be selected from methoxy, ethoxy or propoxy; C1-C6 haloalkoxy may be selected from trifluoromethoxy or trifluoroethoxy; and / or C3-C6 cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0027] 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:

[0028] 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.

[0029] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can exist in the R configuration or the S configuration, and the various isomers thus formed are optical isomers. Optical isomers include all diastereomers, enantiomers, meso-isomers, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0030] The term "geometric isomer" means that when a compound has a double bond, 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 mixtures thereof.

[0031] The term "tautomer" refers to isomers that result from the rapid shift of an atom between two positions in a molecule. Those skilled in the art will appreciate that tautomers can transform into each other and, under certain conditions, may reach an equilibrium state and coexist.

[0032] Unless otherwise indicated, references herein to "a compound of formula (I)" or "a compound of the present invention" also encompass isotopically labeled compounds in which any atom in the compound is replaced by an isotope thereof. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compound of formula (I) in which one or more atoms are replaced by an atom having the same atomic number as the atom commonly found in nature but a different atomic mass or mass number.

[0033] 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 as15 O. 17 O and 18 O, and isotopes of sulfur such as 35 S.

[0034] 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.

[0035] 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 be present in the compounds of formula (I).

[0036] Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamates, 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 with bases which 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 hemisulfate 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.

[0037] 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.

[0038] 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.

[0039] To avoid ambiguity, the following definitions are given for the terms used in this document. Unless otherwise specified, the meanings of the terms used in this document are as follows.

[0040] The term "pharmaceutically acceptable" refers to a compound, carrier or molecule that is suitable for administration to a human. Preferably, the term refers to a compound, carrier or molecule that is approved by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA) for use in mammals, preferably humans.

[0041] "Prodrug" refers to a derivative that is converted into the compound of the present invention by reactions with enzymes, gastric acid, etc. under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc., each catalyzed by an enzyme.

[0042] "Metabolites" refer to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

[0043] As used herein, the term "hydroxyl" refers to -OH; the term "cyano" refers to -CN; the term "amino" refers to -NH2; and the term "nitro" refers to -NO2. As used herein, the term "hydroxyl protecting group" refers to a protecting group introduced into a hydroxyl group to prevent the hydroxyl group from undergoing side reactions or unwanted chemical changes during the reaction. Common hydroxyl protecting groups include, but are not limited to, Boc, Ms, TMS, TBS, and the like.

[0044] 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.

[0045] As used herein, the term "each independently" means that when there are more than one substituent, the substituents may be the same or different.

[0046] 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.

[0047] As used herein, the term "heteroatom" refers to oxygen (O), nitrogen (N), or S (O)m (wherein m can be 0, 1 or 2, i.e. a sulfur atom S, or a sulfoxide group SO, or a sulfonyl group S(O)2).

[0048] 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 chain radical having 1 to 8 carbon atoms. 1-8 "Alkyl" includes in its definition the term "C 1-6 Examples of alkyl groups 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, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0049] 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- to 7-membered heteroaryl groups include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, and pyridine. The heteroaryl group may be optionally substituted with one or more suitable substituents.

[0050] 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 replaced by a halogen atom). For example, the term "C 1-6 "Haloalkyl" refers to a C 1-6 Alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); the term "C 1-3 "Haloalkyl" refers to a C 1-3 alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); and the term "C 1-2 "Haloalkyl" refers to a C 1-2An alkyl group (i.e., methyl or ethyl) (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C1 haloalkyl" refers to a methyl group having 1, 2, or 3 halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, and the like.

[0051] As used herein, numerical ranges related to the number of substituents, carbon atoms, or ring atoms represent a complete enumeration of all integers within the range, and ranges are intended merely as a simplified notation. 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, numerical ranges related to the number of substituents, carbon atoms, or ring atoms also encompass any subranges thereof, and each subrange is considered disclosed herein.

[0052] The compounds of the present invention can be prepared by various methods 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 examples of the present invention and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain synthetic methods for other compounds.

[0053] 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.

[0054] 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, petrolatum, 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.

[0055] 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 an aqueous injection, a powder injection and an infusion), an eye drop, a nasal drop, a lotion and a 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.

[0056] In some embodiments, the dosage form of the pharmaceutical composition is selected from tablets, granules, powders, syrups, inhalants and injections.

[0057] 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) and 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 (e.g., agar); (e.g., fat-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarding agents (e.g., paraffin); (f) absorption promoters (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 glycol, sodium lauryl sulfate), or mixtures thereof.

[0058] 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-dried (lyophilized) conditions requiring 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.

[0059] 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, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as 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.

[0060] 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 target, etc.), for example, 0.1-95% by weight, such as 1-95% by weight, 5-90% by weight, 10-80% by weight, etc.

[0061] 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.

[0062] In a third aspect, the application provides 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 for use 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.

[0063] 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.

[0064] As used herein, the term "treat" includes treatment of a disease or symptom in a mammal, particularly a human, and includes: (a) inhibiting the infection, disease or symptom, i.e., arresting or delaying the development of the infection, disease or symptom; (b) relieving the infection, disease or symptom, i.e., causing regression of the disease or symptom, and / or (c) curing the infection, disease or symptom.

[0065] As used herein, the term "prophylaxis" includes prophylactic therapy in mammals, particularly humans, to reduce the likelihood of developing an infection, disease, or symptom. Patients may be selected for prophylactic therapy based on their increased risk of developing an infection, disease, or symptom compared to the general population. "Prophylaxis" may include treatment of subjects who have not yet developed an infection or clinical condition, and prevention of a second occurrence of the same or similar infection or clinical condition.

[0066] The inventors of this application have discovered that the compounds of this 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 this application can be used to prevent or treat coronavirus infection or diseases or symptoms caused by coronavirus.

[0067] 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 a coronavirus 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).

[0068] In some embodiments, the diseases or symptoms caused by 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.

[0069] 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.

[0070] In some embodiments, the compounds of the present invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, orally, through the oral mucosa, ophthalmically, through the lungs, through the respiratory tract, through the vagina, through the rectum, intraperitoneally, intralesionally, or around the lesion.

[0071] "Therapeutically effective amount" refers to an amount of the compound of the present invention that is effective in treating or preventing coronavirus infection or diseases or symptoms caused by coronavirus when administered alone or in combination.

[0072] 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.).

[0073] The specific administration frequency can be determined by technicians in the relevant field, 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.

[0074] 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 the 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

[0075] The compounds of formula (I) of the present application can be synthesized using a variety of 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, by referring to the exemplary schemes in this patent, those skilled in the art can easily design synthetic routes for other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0076] The present invention is further illustrated below with reference to examples; however, these examples are not intended to limit the scope of the present invention. Unless otherwise stated, all reactants used in the examples were obtained from commercial sources; and the instruments and equipment used in the synthesis experiments and product analysis and testing were conventional instruments and equipment commonly used in organic synthesis.

[0077] Synthesis route of intermediate Int I

[0078] 1) Synthesis steps of compound 2

[0079] Compound 1 (180 g, 1.25 mol, 1 eq) was dissolved in dioxane (1.80 L), and 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. Under nitrogen protection, the reaction was carried out at 100°C for 16 hours. LCMS showed that the reaction was complete. 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.

[0080] 2) Synthesis steps of compound 3

[0081] Compound 2 (130 g, 604 mmol, 1 eq) was dissolved in acetonitrile (1.30 L). NIS (177 g, 785 mmol, 1.3 eq) and TFA (34.4 g, 302 mmol, 0.5 eq) were then added at 25 ° C. Under nitrogen protection, the reaction was carried out at 45 ° C for 16 hours. LCMS detection showed that the reaction was complete. 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, dried under reduced pressure, and purified by column chromatography (SiO2, PE / EA, 50 / 1 to 10 / 1) (TLC, PE / EA, 3 / 1, R f =0.5) to obtain the target compound 3 (85.0 g, 249 mmol, 20.6% yield) as a white solid. ESI-MS: [M+H] + ,341.9.

[0082] 3) Synthesis steps of compound 5

[0083] 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), Na2CO3 (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. Under nitrogen protection, the reaction was carried out at 100°C for 16 hours. LCMS detection showed that the reaction was complete. 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, dried under reduced pressure, and purified by column chromatography (SiO2, PE / EA, 50 / 1 to 10 / 1) (TLC, PE:EA, 1 / 1, R f=0.3) to give the target compound 5 (4.2 g, 12.3 mmol, 47.0% yield) as a yellow oil. ESI-MS: [M+H] + ,343.1.

[0084] 4) Synthesis steps of compound Int I

[0085] Palladium on 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 hydrogen (50 Psi) protection, the reaction was carried out at 50°C for 16 hours. TLC detection showed that the reaction was complete. The reaction solution was filtered through celite 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.

[0086] 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).

[0087] Example 1: Preparation of compound GDI15-5623

[0088] 1) Synthesis steps of compound 3

[0089] Dissolve 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) in DMF (15 mL) and add KCO (2.00 g, 14.46 mmol). Stir the reaction at 85°C for 12 hours. After completion, cool to room temperature. Add water (100 mL) and extract with ethyl acetate. Dry over anhydrous NaSO, filter, and concentrate under vacuum. Purify by silica gel chromatography to yield 1-bromo-3-chloro-5-(2,2,2-trifluoroethoxy)benzene (1.3 g, 4.49 mmol, 93.16% yield) as a yellow oil.

[0090] 2) Synthesis steps of compound 4

[0091] 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). (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (4.51 mg, 31.71 μmol), CuI (3.02 mg, 15.86 μmol), and Cs2CO3 (103.32 mg, 317.12 μmol) were added. The reaction was stirred at 100°C for 12 hours. After completion, the reaction was cooled to room temperature. The product was extracted with water (10 mL) and ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, and concentrated under vacuum by 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.

[0092] 3) Synthesis steps of compound GDI15-5623

[0093] 1-[3-chloro-5-(2,2,2-trifluoroethoxy)phenyl]-3-(4-isoquinolyl)-4-methoxypyridine-2-one (40 mg, 86.80 μmol) was dissolved in DMF (2 mL), and LiCl (36.79 mg, 867.99 μmol) and TsOH (149.47 mg, 867.99 μmol) were added. The reaction was heated to 140°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with water (20 mL) and ethyl acetate (20 mL*3), dried over anhydrous Na2SO4, and concentrated under vacuum filtration. The residue was purified and prepared by silica gel chromatography to give 1-[3-chloro-5-(2,2,2-trifluoroethoxy)phenyl]-4-hydroxy-3-(4-isoquinolinyl)pyridin-2-one (4 mg, 8.59 μmol, 9.90% yield, 96% purity) as an off-white solid.

[0094] 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).

[0095] Example 2: Preparation of compound GDI15-5431

[0096] 1) Synthesis steps of compound 7

[0097] 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), Cs2CO3 (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 sequentially at 25°C. Under nitrogen protection, the reaction was continued at 100°C for 16 hours, and the reaction was completed by LCMS. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified on a silica gel plate (SiO2, 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.

[0098] 2) Synthesis steps of compound GDI15-5431

[0099] Compound 7 (200 mg, 462 μmol, 1 eq) was dissolved in DMF (2 mL). LiCl (97.9 mg, 2.31 mmol, 47.3 μL, 5 eq) and TsOH (397 mg, 2.31 mmol, 5 eq) were added sequentially at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was complete 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 (NH4HCO3)-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.

[0100] 1H 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)

[0101] Example 3: Preparation of compound GDI15-6491

[0102] 1) Synthesis steps of compound 6

[0103] Compound 5 (230 mg, 419 μmol, 1 eq) was dissolved in NMP (4.6 mL). 1-Decanethiol (365 mg, 2.10 mmol, 5 eq) and K2CO3 (116 mg, 839 μmol, 2 eq) were added sequentially at 25°C. The reaction was stirred at 140°C for 16 hours. LCMS confirmed the reaction was complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 mL x 3). The product remained in the aqueous phase. The aqueous phase was lyophilized, washed with DCM / MeOH (10 / 1, 50 mL), and filtered. The filtrate was concentrated under reduced pressure and purified on a silica gel plate to yield the desired product 6 (210 mg, 393 μmol, 93.7% yield) as a yellow solid. ESI-MS: [M+H] + ,478.1.

[0104] 2) Synthesis steps of compound GDI15-6491

[0105] 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. LCMS confirmed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure and purified by HPLC (column: 2-Phenomenex Gemini C18 75*40 mm*3 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 10%-40% B over 8.0 min) to yield the target compound GDI15-6491 (190 mg, crude, 2HCl) as a white solid. ESI-MS: [M+H] + ,434.0.

[0106] 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)

[0107] Example 4: Preparation of compound GDI15-6450

[0108] 1) Synthesis steps of compound 7

[0109] Compound 6 (80 mg, 165 μmol, 1 eq) was dissolved in DCM (1.6 mL). 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 then added sequentially at 0°C. Under nitrogen protection, the mixture was allowed to react at 0°C for 2 hours. LCMS confirmed the reaction was complete. Water (2 mL) was added to the reaction solution, which was then extracted with DCM (2 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and dried under reduced pressure. The product was then purified by silica gel chromatography (PE / EtOAc, 10 / 1) to afford the target compound 7 (70 mg, 129 μmol, 77.9% yield) as a white solid. ESI-MS: [M+H] + ,544.0.

[0110] 2) Synthesis steps of compound GDI15-6450

[0111] Compound 7 (50 mg, 91.9 μmol, 1 eq) was dissolved in DMF (1.0 mL). LiCl (19.5 mg, 460 μmol, 9.42 μL, 5 eq) and TsOH (79.2 mg, 460 μmol, 5 eq) were then added sequentially at 25°C. The mixture was allowed to react at 140°C under nitrogen for 16 hours, and the reaction was complete by LCMS. The reaction solution was evaporated to dryness under reduced pressure and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 20%-50% B over 8 min) to afford the target product, GDI15-6450 (4.5 mg, 8.49 μmol, 9.24% yield), as a white solid. ESI-MS: [M+H] + ,530.0.

[0112] 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)

[0113] Example 5: Preparation of compound GDI15-6405

[0114] 1) Synthesis steps of compound 10

[0115] Compound 6 (80 mg, 165 μmol, 1 eq) was dissolved in DCM (1.6 mL). TEA (50.1 mg, 496 μmol, 68.9 μL, 3 eq) and compound 9 (30.2 mg, 215 μmol, 1.3 eq) were then added at 0°C. Under nitrogen protection, the mixture was reacted at 0°C for 2 hours. LCMS confirmed the reaction was complete. 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 compound 10 (40 mg, 72.5 μmol, 43.9% yield) was obtained by silica gel plate purification (DCM / MeOH, 10 / 1) as a yellow solid. ESI-MS: [M+H] + ,552.2.

[0116] 2) Synthesis steps of compound GDI15-6405

[0117] Compound 10 (40 mg, 72.5 μmol, 1 eq) was dissolved in NMP (1.0 mL). KCO (20 mg, 144.9 μmol, 2 eq) and 1-decanethiol (63.2 mg, 362.3 μmol, 5 eq) were then added at 25°C. The mixture was allowed to react at 140°C for 16 hours under nitrogen protection, and the reaction was complete by LCMS. The reaction solution was filtered at atmospheric pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 25%-55% B over 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.

[0118] 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).

[0119] Example 6: Preparation of compound GDI15-6490

[0120] 1) Synthesis steps of compound 12

[0121] Compound GDI15-6491 (150 mg, 318 μmol, 1 eq, HCl) was dissolved in MeCN (2.7 mL) and DMF (0.3 mL). 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) were then added sequentially at 0°C. Under nitrogen protection, the reaction was allowed to proceed at 25°C for 2 hours. LCMS confirmed the reaction was complete. Water (10 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 purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) (TLC, EtOAc / MeOH, 10 / 1, R f =0.51) to give the target compound 12 (100 mg, 149 μmol, 47.0% yield) as a white solid. ESI-MS: [M+H] + ,667.3.

[0122] 2) Synthesis steps of compound GDI15-6490

[0123] 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. LCMS confirmed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure and purified by HPLC (column: 2-Phenomenex Gemini C18 75*40 mm*3 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 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.

[0124] 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).

[0125] Example 7: Preparation of compound GDI15-6403

[0126] 1) Synthesis steps of compound 12

[0127] 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. The mixture was 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. LCMS detection showed that the reaction was complete. 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 column chromatography (PE / EtOAc, 5 / 1) (TLC, PE / EtOAc, 5 / 1, R f =0.51) to give the target compound 12 (80 mg, 137 μmol, 66.5% yield) as a white solid. ESI-MS: [M+H] +,582.1.

[0128] 2) Synthesis steps of compound GDI15-6403

[0129] Compound 12 (80 mg, 137 μmol, 1 eq) was dissolved in NMP (1.6 mL). 1-Decanethiol (119 mg, 687 μmol, 5 eq) and K2CO3 (37.9 mg, 274 μmol, 2 eq) were added sequentially at 25°C. The reaction was stirred at 140°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 BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 15%-45% B over 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.

[0130] 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).

[0131] Example 8: Preparation of compound GDI15-6290

[0132] The crude product was purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-50%, 8 min) to afford the desired product, GDI15-6290 (1.10 mg, 2.15 μmol, 5.50% yield), as a yellow solid. ESI-MS: [M+H]+, 512.2.

[0133] 1H 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).

[0134] Example 9: Preparation of compound GDI15-6452

[0135] 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 sequentially at 0°C. The mixture was allowed to react at 0°C under nitrogen for 2 hours. LCMS confirmed the reaction was complete. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The mixture was purified by HPLC (column: Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase: [water (FA)-ACN]; gradient: 1% to 35% B over 8 min) to obtain the target product GDI15-6452 (14.2 mg, 30.9 μmol, 63.0% yield, 97.9% purity) as a yellow solid. ESI-MS: [M+H] + ,450.1.

[0136] 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)

[0137] Example 10: Preparation of compound GDI15-5944

[0138] 1) Synthesis steps of compound GDI15-5944

[0139] Compound GDI15-5903 (20.0 mg, 49.0 μmol, 1 eq) was dissolved in DCM (1.0 mL). TEA (12.4 mg, 122.6 μmol, 17.1 M, 2.5 eq) and Boc2O (13.9 mg, 63.7 μmol, 14.7 μL, 1.3 eq) were then added dropwise at 0°C. The reaction was allowed to react at 25°C for 16 hours, and the reaction was complete by LCMS. Water (5 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The target product, GDI15-5944 (2 mg, 3.94 μmol, 8.0% yield), was obtained as a white solid. ESI-MS: [M+H] + ,508.1.

[0140] 1 H 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).

[0141] Example 11: Preparation of compound GDI15-6383

[0142] 1) Synthesis steps of compound 2

[0143] Compound 1 (100 mg, 218 μmol, 1 eq) was dissolved in DCM (2 mL). 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 then added dropwise at 0°C. The mixture was reacted under nitrogen atmosphere at 0°C for 2 hours. 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 dried under reduced pressure and separated and purified by silica gel plate (DCM / MeOH, 10 / 1) (TLC, DCM / MeOH, 10 / 1, R f =0.45, 0.55) to give the target compound 2 (70 mg, 135 μmol, 62.0% yield) as a white solid. ESI-MS: [M+H] + ,518.1.

[0144] 2) Synthesis steps of compound GDI15-6383

[0145] 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 sequentially at 25°C. The mixture was reacted at 140°C under nitrogen atmosphere for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was evaporated to dryness under reduced pressure and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 15%-55% B over 8 minutes) and SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 50%-50% over 9 minutes) 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.

[0146] 1 H 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).

[0147] Example 12: Preparation of compound GDI15-6337

[0148] 1) Synthesis steps of compound 5

[0149] 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 confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford the target compound 5 (43 mg, 93.8 μmol, 97.9% yield, HCl) as a yellow oil. ESI-MS: [M+H] + ,422.1.

[0150] 2) Synthesis steps of compound 7

[0151] Compound 5 (43 mg, 93.8 μmol, 1 eq, HCl) was dissolved in DCM (0.86 mL). 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 sequentially at 0°C. The reaction was stirred at 0°C for 2 hours. LCMS confirmed the reaction was complete. Ice water (5 mL) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with 5 mL of saturated sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and spun down to dryness to obtain the crude product. Methanol (1 mL) was added to dissolve the crude product, followed by potassium carbonate (25.9 mg, 188 μmol, 2 eq). 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 (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.

[0152] 3) Preparation of compound GDI15-6337

[0153] Compound 7 (25 mg, 47.5 μmol, 1 eq) was dissolved in NMP (1 mL). 1-Decanethiol (41.4 mg, 237 μmol, 5 eq) and K₂CO₃ (13.1 mg, 95.0 μmol, 2 eq) were added sequentially at 25°C. The reaction was stirred at 140°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: [water (NH₄HCO₃)-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.

[0154] 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).

[0155] Example 13: Preparation of compound GDI15-6349

[0156] 1) Synthesis steps of compound 4

[0157] 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 sequentially at 0 ° C. Under nitrogen protection, the reaction was carried out at 0 ° C for 2 hours. LCMS detection showed 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, dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and separated and purified by silica gel plate (DCM / MeOH, 10 / 1) (TLC, DCM / MeOH, 10 / 1, R f =0.6) to obtain the target compound 4 (70 mg, 130 μmol, 59.4% yield) as a white solid. ESI-MS: [M+H] + ,540.2.

[0158] 2) Preparation of compound GDI15-6349

[0159] Compound 4 (70 mg, 130 μmol, 1 eq) was dissolved in NMP (1.0 mL), followed by the addition of KCO (35.8 mg, 259 μmol, 2 eq) and 1-decanethiol (113 mg, 648 μmol, 5 eq) at 25°C. The reaction was allowed to proceed at 140°C under nitrogen for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered under atmospheric pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 15%-45% B over 8 min) to afford 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.

[0160] 1 H 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).

[0161] Example 14: Preparation of compound GDI15-6335

[0162] 1) Synthesis steps of compound 2

[0163] 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 CH3CN (1.26 mL). HATU (71.7 mg, 188 μmol, 1.1 eq) and DIEA (66.5 mg, 514 μmol, 89.6 μL, 3 eq) were added sequentially at 0°C. Under nitrogen protection, the reaction was stirred at 25°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into 10 mL of ice water and extracted with ethyl acetate (2 mL*3). The mixture was concentrated under reduced pressure to obtain the target compound 2 (80 mg, 124 μmol, 72.7% yield) as a yellow oil. ESI-MS: [M+H] + ,641.2.

[0164] 2) Preparation of compound GDI15-6335

[0165] 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. LCMS confirmed the reaction was complete. 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 (NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to yield 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.

[0166] 1 H 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).

[0167] Example 15: Preparation of compound GDI15-6341

[0168] 1) Preparation of compound GDI15-6341

[0169] 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). MsCl (120 mg, 1.05 mmol, 81.0 μL, 6.1 eq) was added with stirring at 0°C. The reaction was stirred at 0°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with 5 mL of saturated sodium chloride solution. The organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain the crude product. Methanol (1.4 mL) was added to dissolve the crude product, followed by the addition of KCO (47.4 mg, 343 μmol, 2 eq). The reaction was stirred at 25°C for 1 hour. The reaction mixture was dried and purified by HPLC (Phenomenex C18 75*30mm*3μm column; mobile phase: [water(NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to obtain the target compound GDI15-6341 (1.8 mg, 3.67 μmol, 11.4% yield, 98.9% purity) as a white solid. ESI-MS: [M+H] + ,486.1.

[0170] 1 H 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).

[0171] Example 16: Preparation of compound GDI15-6348

[0172] 1) Synthesis steps of compound 2

[0173] Compound 1 (100 mg, 218.2 μmol, 1 eq) was dissolved in DCM (2.0 mL). TEA (66.2 mg, 655 μmol, 91.1 μL, 3 eq) and TosCl (54.1 mg, 284 μmol, 1.3 eq) were then added at 0°C. The mixture was reacted at 0°C for 2 hours under nitrogen protection. 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, filtered under reduced pressure and dried, and separated and purified by silica gel plate (DCM / MeOH, 10 / 1) (TLC, DCM / MeOH, 10 / 1, R f =0.6) to obtain the target compound 2 (40 mg, 69.4 μmol, 31.8% yield) as a white solid. ESI-MS: [M+H] + ,576.1.

[0174] 2) Preparation of compound GDI15-6348

[0175] Compound 2 (40 mg, 69.4 μmol, 1 eq) was dissolved in NMP (1.0 mL), followed by the addition of KCO (19.2 mg, 139 μmol, 2 eq) and 1-decanethiol (60.5 mg, 347 μmol, 5 eq) at 25°C. The reaction was allowed to proceed at 140°C for 16 hours under nitrogen protection, and the reaction was complete by LCMS. The reaction solution was filtered under atmospheric pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 15%-45% B over 8 min) to afford 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.

[0176] 1 H 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)

[0177] Example 17: Preparation of compound GDI15-6351

[0178] 1) Synthesis steps of compound 3

[0179] Compound 1 (1.0 g, 4.82 mmol, 1 eq) was dissolved in DMF (10.0 mL). Compound 2 (1.19 g, 5.78 mmol, 1.1 eq) and K2CO3 (1.67 g, 12.1 mmol, 2.5 eq) were then added sequentially at 25°C. The mixture was reacted under nitrogen at 25°C for 16 hours, and the reaction was complete by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 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 dryness to afford the target compound 3 (3 g, 9.04 mmol, crude) as a colorless oil.

[0180] 2) Synthesis steps of compound 4

[0181] Compound Int I (100 mg, 396 μmol, 1 eq) was dissolved in DMF (1.0 mL), and compound 3 (229 mg, 476 μmol, 1.2 eq, 69% purity), Cs2CO3 (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 sequentially at 25°C. The mixture was reacted under nitrogen at 100°C for 16 hours, and the reaction was complete 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 then purified by silica gel plate separation (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.

[0182] 3) Preparation of compound GDI15-6351

[0183] Compound 4 (80 mg, 159 μmol, 1 eq) was dissolved in NMP (2.0 mL). KCO (43.9 mg, 318 μmol, 2 eq) and 1-decanethiol (138.5 mg, 795 μmol, 5 eq) were then added sequentially at 25°C. The mixture was reacted at 140°C under nitrogen for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered at atmospheric pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%-75% B over 8 min) to obtain 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.

[0184] 1 H 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).

[0185] Example 18: Preparation of compound GDI15-6352

[0186] 1) Synthesis steps of compound 3

[0187] Compound 1 (1.0 g, 4.82 mmol, 1 eq) was dissolved in DMF (10.0 mL). Compound 2 (1.09 g, 5.3 mmol, 1.1 eq) and K2CO3 (1.67 g, 12.1 mmol, 2.5 eq) were then added sequentially at 25°C. The mixture was reacted under nitrogen at 25°C for 16 hours, and the reaction was complete by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with 15 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to dryness, yielding the target compound 3 (2.4 g, 3.61 mmol, crude) as a colorless oil.

[0188] 2) Synthesis steps of compound 4

[0189] 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), Cs2CO3 (387 g, 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 sequentially at 25°C. Under nitrogen protection, the reaction was carried out at 100°C for 16 hours. LCMS confirmed the completion of the reaction. 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 purified by silica gel plate separation (EtOAc / MeOH, 10 / 1) (TLC, EtOAc / MeOH, 10 / 1, R f =0.48) to obtain the target compound 4 (110 mg, 218 μmol, 55.1% yield) as a brown oil. ESI-MS: [M+H] + ,503.1.

[0190] 3) Preparation of compound GDI15-6352

[0191] Compound 4 (50 mg, 99.3 μmol, 1 eq) (two parallel reactions) was dissolved in NMP (1.5 mL). KCO (27.4 mg, 198 μmol, 2 eq) and 1-decanethiol (86.5 mg, 496 μmol, 5 eq) were then added sequentially at 25°C. The reaction was allowed to proceed at 140°C under nitrogen for 16 hours, and LCMS confirmed the reaction was complete. The reaction solution was filtered at atmospheric pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60% B over 8 min) to afford the desired product, GDI15-6352 (50.1 mg, 101 μmol, 50.6% yield, 98.1% purity), as a yellow solid. ESI-MS: [M+H] + ,489.1.

[0192] 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).

[0193] Example 19: Preparation of compound GDI15-5885

[0194] 1) Synthesis steps of compound 3

[0195] Compound 1 (0.2 g, 968 μmol, 1 eq) was dissolved in DMF (2 mL), followed by the addition of compound 2 (99.2 mg, 581 μmol, 69.0 μL, 0.6 eq) and CS2CO3 (315 mg, 969 μmol, 1 eq) at 25°C. The reaction was allowed to proceed at 100°C for 16 hours under nitrogen. LCMS analysis revealed ~40% of compound 1 remaining and ~40% of compound 3 formed. Water (5 mL) was added to the reaction solution, which was then extracted with ethyl acetate (2 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (PE / EtOAc, 0 / 1) to afford the target compound 3 (110 mg, 371 μmol, 38.3% yield) as a red oil. ESI-MS: [M+H]+, 295.2 & 297.9.

[0196] 2) Synthesis steps of compound 5

[0197] Compound Int I (80 mg, 317 μmol, 1 eq) was dissolved in DMF (2.0 mL), and compound 3 (110 mg, 371 μmol, 1.17 eq), Cs2CO3 (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 sequentially at 25°C. Under nitrogen protection, the reaction was continued at 100°C for 16 hours, and the reaction was completed by LCMS. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (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.

[0198] 3) Synthesis steps of compound GDI15-5885

[0199] Compound 5 (80 mg, 171 μmol, 1 eq) was dissolved in DMF (2 mL). LiCl (36.2 mg, 855 μmol, 17.5 μL, 5 eq) and TsOH (147 mg, 855 μmol, 5 eq) were added sequentially at 25°C. The reaction was stirred at 140°C for 16 hours, and the reaction was complete 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 over 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.

[0200] 1 H 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).

[0201] Example 20: Preparation of compound GDI15-5915

[0202] 1) Synthesis steps of compound 3

[0203] 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). Cs2CO3 (473 mg, 1.45 mmol, 1 eq) was then added at 25°C. Under nitrogen, the reaction was allowed to proceed at 100°C for 16 hours. LCMS analysis indicated that ~40% of the starting material 1 remained and ~40% of the product 3 was generated. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (PE / EtOAc, 0 / 1) to afford the target compound 3 (160 mg, 508 μmol, 35.0% yield) as a white solid. ESI-MS: [M+H] + ,313.8.

[0204] 2) Synthesis steps of compound 5

[0205] Compound Int I (153 mg, 610 μmol, 1.2 eq) was dissolved in DMF (3.2 mL), and compound 3 (0.16 g, 508 μmol, 1 eq), Cs2CO3 (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 sequentially at 25°C. Under nitrogen protection, the reaction was continued at 100°C for 16 hours, and the reaction was completed by LCMS. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (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.

[0206] 3) Synthesis steps of compound GDI15-5915

[0207] Compound 5 (170 mg, 349 μmol, 1 eq) was dissolved in DMF (3.4 mL), followed by the addition of TsOH (301 mg, 1.75 mmol, 5 eq) and LiCl (74.1 mg, 1.75 mmol, 35.8 μL, 5 eq). The reaction was allowed to proceed at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered under atmospheric pressure and purified by HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (FA)-ACN]; gradient: 20% - 45% B over 8 min) to obtain the target product GDI15-5915 (33.7 mg, 71.4 μmol, 20.4% yield) as a yellow solid. ESI-MS: [M+H] + ,472.2.

[0208] 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).

[0209] Example 21: Preparation of compound GDI15-5916

[0210] 1) Synthesis steps of compound 3

[0211] 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 Cs2CO3 (315 mg, 968 μmol, 1 eq) was added at 25°C. Under nitrogen, the reaction was allowed to proceed at 25°C for 16 hours. LCMS analysis indicated that ~50% of the starting material 1 remained, and ~26% of the product 3 was produced. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (PE / EtOAc, 5 / 1) to afford the target compound 3 (95 mg, 286 μmol, 29.6% yield) as a yellow oil. ESI-MS: [M+H] + ,331.8.

[0212] 2) Synthesis steps of compound 5

[0213] Compound Int I (65 mg, 257 μmol, 1 eq) was dissolved in DMF (2.0 mL), and compound 3 (95 mg, 286 μmol, 1.11 eq), Cs2CO3 (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, 128 μmol, 0.5 eq) were added sequentially at 25°C. Under nitrogen protection, the reaction was incubated at 100°C for 16 hours, and the reaction was complete by LCMS. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (EtOAc) to obtain the target compound 5 (90 mg, 179 μmol, 69.5% yield) as a yellow oil. ESI-MS: [M+H] + ,502.1.

[0214] 3) Synthesis steps of compound GDI15-5916

[0215] Compound 5 (90 mg, 179 μmol, 1 eq) was dissolved in DMF (0.9 mL), followed by the addition of TsOH (154 mg, 895 μmol, 5 eq) and LiCl (37.9 mg, 895 μmol, 18.3 μL, 5 eq). The reaction was allowed to proceed at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered under atmospheric pressure and purified by HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (FA)-ACN]; gradient: 25%-50% B over 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.

[0216] 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).

[0217] Example 22: Preparation of compound GDI15-6339

[0218] 1) Synthesis steps of compound 2

[0219] Compound 1 (1 g, 4.62 mmol, 1 eq) was dissolved in THF (20 mL) under nitrogen atmosphere. BH₃.THF (1 M, 11.5 mL, 2.5 eq) was added dropwise at 0°C. The reaction was stirred at 65°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was cooled, and MeOH (10 mL) was added dropwise at 0°C. The reaction was then stirred at 65°C for 2 hours. H₂O (10 mL) and HCl (3 N) were then added sequentially to the reaction solution until the pH reached 2-3. The reaction solution was concentrated under reduced pressure to remove methanol, and then extracted with ethyl acetate (15 mL x 2) to remove impurities. Sat. aq. Na₂CO₃ (~6 mL) was added to the aqueous phase until the pH reached 8-9. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with 20 mL of saturated sodium chloride solution. The washed organic phases were 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 (0.45 g, 1.75 mmol, 37.9% yield, HCl) as a white solid. ESI-MS: [M+H] + ,220.0&222.0

[0220] 2) Synthesis steps of compound 3

[0221] 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) and stirred at 20°C. 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 Cs2CO3 (517 mg, 1.59 mmol, 4 eq) were added sequentially. Under nitrogen protection, the reaction was stirred at 100°C for 16 hours. The reaction was complete by LCMS. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (5 mL x 6). The combined organic phases were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The product was purified by HPLC (column: Waters Xbridge BEH C18 250 x 50 mm x 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%-40%, 10 min) to afford the title compound 3 (0.056 g, 143 μmol, 36.1% yield) as a light yellow solid. ESI-MS: [M+H]+ ,392.1

[0222] 3) Preparation of compound GDI15-6339

[0223] 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. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [water (NH4HCO3)-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

[0224] 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).

[0225] Example 23: Preparation of compound GDI15-6332

[0226] 1) Synthesis steps of compound 2

[0227] 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). 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 Cs2CO3 (465 mg, 1.43 mmol, 3 eq) were added sequentially with stirring at 20°C. The mixture was stirred at 100°C under nitrogen for 16 hours. The reaction was complete by LCMS. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate and dried under reduced pressure. The mixture was purified on a preparative plate (SiO2, EtOAc / MeOH, 10 / 1) to afford the title compound 2 (0.16 g, 329 μmol, 69.2% yield, 95.1% purity) as a white solid. ESI-MS: [M+H] + ,486.1

[0228] 2) Synthesis steps of compound GDI15-6332

[0229] Compound 2 (0.08 g, 164 μmol, 1 eq, two parallel reactions) was dissolved in NMP (1.6 mL) and stirred at 25°C. KCO (45.5 mg, 329 μmol, 2 eq) and 1-decanethiol (143 mg, 823 μmol, 5 eq) were added sequentially. The reaction was stirred at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered under atmospheric pressure and purified by HPLC (column: Waters Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [water (NH4HCO3)-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

[0230] 1H 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).

[0231] Example 24: Preparation of compound GDI15-6326

[0232] 1) Synthesis steps of compound 2

[0233] 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). Cs2CO3 (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, 151 μmol, 0.5 eq) were added sequentially at 25°C. The reaction was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. Ice water (50 mL) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with 50 mL of 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 (40 mg, 79.6 μmol, 26.3% yield) as a yellow solid. ESI-MS: [M+H] + ,503.3.

[0234] 2) Preparation of compound GDI15-6326

[0235] Compound 2 (40 mg, 79.6 μmol, 1 eq) was dissolved in NMP (1 mL). KCO (147 mg, 458 μmol, 1.1 eq) and 1-decanethiol (69.4 mg, 398 μmol, 5 eq) were added sequentially at 25°C. The reaction was stirred at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into ice water (5 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with 5 mL of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification by silica gel plate separation (PE / EA, 0 / 1) and SFC separation (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 36%-66%, 8 min) afforded the target product GDI15-6326 (8.40 mg, 16.5 μmol, 19.7% yield) as a yellow solid. ESI-MS: [M+H] + ,489.2.

[0236] 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).

[0237] Example 25: Preparation of compound GDI15-5731

[0238] 1) Synthesis steps of compound 2

[0239] At 0°C under 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 completion, the reaction was quenched by the addition of saturated NaHCO3 solution, extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na2SO4, and concentrated under vacuum filtration. Purification by silica gel chromatography afforded (3-bromo-5-chloro-phenyl)methanamine (400 mg, 1.81 mmol, 39.27% ​​yield) as an off-white solid.

[0240] 2) Synthesis steps of compound 4

[0241] 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 N₂. The reaction was stirred at room temperature for 6 hours. After completion, a saturated NaHCO₃ solution was added dropwise, and the mixture was extracted with DCM (20 mL x 3), dried over anhydrous Na₂SO₄, and concentrated under vacuum filtration. Purification by silica gel chromatography afforded N-[(3-bromo-5-chloro-phenyl)methyl]acetamide (40 mg, 152.36 μmol, 8.84% yield) as a yellow oil.

[0242] 3) Synthesis steps of compound 5

[0243] 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). (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (2.82 mg, 19.82 μmol), CuI (9.44 mg, 49.55 μmol), and Cs2CO3 (96.87 mg, 297.30 μmol) were added. The reaction was stirred at 100°C for 8 hours. After completion of the reaction, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL*3), dried over anhydrous Na2SO4, and concentrated under vacuum by filtration. The residue was purified by silica gel chromatography to give 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.

[0244] 4) Synthesis steps of compound GDI15-5731

[0245] 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), and LiCl (13.68 mg, 322.67 μmol) and TsOH (16.81 mg, 322.67 μmol) were added. The reaction was stirred at 140°C for 18 hours. The reaction was cooled to room temperature, water (10 mL) was added, and the product was extracted with ethyl acetate (10 mL x 3), dried over anhydrous Na2SO4, and concentrated under vacuum filtration. Purification by silica gel chromatography afforded 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.

[0246] 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).

[0247] Example 29: Preparation of compound GDI15-5591

[0248] 1) Synthesis steps of compound GDI15-5591

[0249] The crude product was purified from GHDDI by high performance liquid chromatography (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 20%-50% B, in 8min) to obtain the target product GDI15-5591 (0.2mg, 4.35e -1 μmol, 1.11% yield) as a white solid. ESI-MS: [M+H] + ,460.1.

[0250] 1H 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).

[0251] Example 27: Preparation of compound GDI15-6340

[0252] 1) Synthesis steps of compound 2

[0253] Compound 1 (1.5 g, 6.51 mmol, 1 eq) was dissolved in THF (30 mL). Under nitrogen, BH₃.THF (1 M, 16.3 mL, 2.5 eq) was added dropwise at 0°C. The reaction was stirred at 65°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was cooled, and MeOH (16 mL) was added dropwise at 0-5°C. The reaction was then stirred at 65°C for 2 hours. H₂O (16 mL) and HCl (3 N) were added sequentially to the reaction solution until the pH reached 2-3. The reaction solution was concentrated under reduced pressure to remove methanol, and then extracted with ethyl acetate (20 mL x 2) to remove impurities. Sat. aq. Na₂CO₃ (~10 mL) was added to the aqueous phase until the pH reached 8-9. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with 30 mL of saturated sodium chloride solution. The washed organic phases were 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

[0254] 2) Synthesis steps of compound 3

[0255] 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) and stirred at 20°C. 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 Cs2CO3 (517 mg, 1.59 mmol, 4 eq) were added sequentially. Under nitrogen protection, the reaction was stirred at 100°C for 16 hours. The reaction was complete by LCMS. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (5 mL x 6). The combined organic phases were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The product was purified by HPLC (column: Waters Xbridge BEH C18 250 x 50 mm x 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-45%, 10 min) to afford the title compound 4 (70 mg, 172 μmol, 43.5% yield) as a light yellow solid. ESI-MS: [M+H] + ,406.2.

[0256] 3) Synthesis steps of compound GDI15-6340

[0257] 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. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [water (NH4HCO3)-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.

[0258] 1H 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).

[0259] Example 28: Preparation of compound GDI15-5736

[0260] 1) Synthesis steps of compound 3C-2

[0261] Compound 3C-1 (1.00 g, 4.34 mmol, 1 eq) was dissolved in ethanol (20 mL). CoCl₂.6H₂O (2.06 g, 8.68 mmol, 2 eq) and NaBH₄ (340 mg, 8.99 mmol, 2.07 eq) were then added sequentially at 0°C. The mixture was allowed to react at 25°C under nitrogen for 16 hours, and the reaction was complete by LCMS. The reaction mixture was poured into ice water (50 mL) in batches and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Ethyl acetate (10 mL) was added to the crude product, and HCl / EtOAc (3 mL) was added dropwise with stirring. The mixture was stirred for 10 minutes. Filtration afforded the target compound 3C-2 (1 g, 3.69 mmol, 85.1% yield, HCl) as a white solid.

[0262] 2) Synthesis steps of compound 3C

[0263] Compound 3C-2 (400 mg, 1.48 mmol, 1 eq, HCl) was dissolved in methanol (4 mL) and acetic acid (0.4 mL). Paraformaldehyde (177 mg, 5.90 mmol, 162 μL, 4 eq) was then added at 25°C and stirred for 1 hour. NaBH3CN (250 mg, 3.99 mmol, 2.7 eq) was then added. The reaction was allowed to react at 25°C for 15 hours, and the reaction was complete by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and washed with 5 mL of saturated sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to dryness, affording the target compound 3C (300 mg, 1.14 mmol, 77.4% yield) as a yellow oil.

[0264] 3) Synthesis steps of compound 7

[0265] 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), Cs2CO3 (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 sequentially at 25°C. Under nitrogen protection, the reaction was continued at 100°C for 16 hours, and the reaction was completed by LCMS. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified on a silica gel plate (SiO2, 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.

[0266] 4) Synthesis steps of compound GDI15-5736

[0267] Compound 7 (60.0 mg, 138 μmol, 1 eq) was dissolved in HBr / AcOH (10 V, 33% purity). The reaction was allowed to proceed at 120°C for 16 hours, and the reaction was complete after LCMS analysis. The reaction solution was evaporated to dryness under reduced pressure and purified by HPLC (column: Phenomenex luna C18 80*40 mm*3 μm; 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.

[0268] 1 H 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).

[0269] Example 29: Preparation of compound GDI15-5737

[0270] 1) Synthesis steps of compound 3D

[0271] Compound 3C-2 (400 mg, 1.48 mmol, 1 eq, HCl) was dissolved in DCM (1.3 mL) and pyridine (2.6 mL). Acetyl chloride (79.7 mg, 1.01 mmol, 72.4 μL, 1.1 eq) was then added dropwise at 0°C. The mixture was allowed to react at 25°C for 3 hours, and the reaction was complete by LCMS. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to dryness. The target compound 3D (200 mg, 723 μmol, 78.4% yield) was obtained as a yellow oil.

[0272] 2) Synthesis steps of compound 7

[0273] Compound Int I (150 mg, 594 μmol, 1 eq) was dissolved in DMF (3 mL), and compound 3 (328 mg, 1.19 mmol, 2 eq), Cs2CO3 (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 sequentially at 25°C. Under nitrogen protection, the reaction was continued at 100°C for 16 hours, and the reaction was completed by LCMS. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified on a silica gel plate (SiO2, 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.

[0274] 3) Synthesis steps of compound GDI15-5737

[0275] Compound 7 (60.0 mg, 133 μmol, 1 eq) was dissolved in HBr / AcOH (10 V, 33% purity). The reaction was allowed to proceed at 120°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was then dried under reduced pressure and purified by HPLC (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.

[0276] 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).

[0277] Example 30: Preparation of compound GDI15-6288

[0278] 1) Synthesis steps of compound 2

[0279] Compound 1 (20 g, 92.3 mmol, 1 eq) was dissolved in EtOH (400 mL). CoCl2.6H2O (43.9 g, 184 mmol, 2 eq) and NaBH4 (8.74 g, 230 mmol, 2.5 eq) were added sequentially with stirring at 0°C. The mixture was stirred at 25°C for 4 hours. LCMS confirmed the reaction was complete. The reaction solution was poured into ice water (1 L) and extracted with ethyl acetate (300 mL*3). The combined organic phases were washed with 1 L of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and HCl-EtOAc (5 mL) was added during the vacuum spin-drying process. Solid precipitation was observed. The solid was filtered and the filter cake was washed with ethyl acetate. The filter cake was then purified by vacuum spin-drying to obtain the target compound 2 (4.8 g, 18.6 mmol, 20.2% yield, HCl) as a white solid. ESI-MS: [M+H] + ,219.9&221.9.

[0280] 2) Synthesis steps of compound 3

[0281] 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 Boc2O (5.30 g, 24.2 mmol, 5.58 mL, 1.3 eq) were added sequentially with stirring, and the mixture was stirred at 25°C for 16 hours. LCMS and TLC (PE / EtOAc, 5 / 1, R f =0.57) to detect the completion of the reaction. The reaction solution was poured into ice water (200 mL) and extracted with ethyl acetate (70 mL*3). The combined organic phases were washed with 300 mL of saturated sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by column chromatography (SiO2, 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.

[0282] 3) Synthesis steps of compound 4

[0283] 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). 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 Cs2CO3 (387 mg, 1.19 mmol, 3 eq) were added sequentially under stirring at room temperature. The mixture was stirred at 100°C under nitrogen for 16 hours. LCMS and TLC (EtOAc / MeOH, 10 / 1, R f =0.51) to detect the completion of the reaction. The reaction solution was poured into ice water (5 mL) and extracted with ethyl acetate (1 mL*3). The organic phases were combined and washed with 5 mL of saturated sodium chloride solution. The washed organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel plate purification (SiO2, 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.

[0284] 4) Preparation of compound GDI15-6288

[0285] 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. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-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.

[0286] 1 H 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).

[0287] Example 31: Preparation of compound GDI15-6327

[0288] 1) Preparation of compound GDI15-6327

[0289] 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 stirred for 1 hour at 0°C. LCMS confirmed the reaction was complete. The reaction solution was poured into ice water (5 mL) and extracted with ethyl acetate (1 mL x 3). The combined organic phases were washed with 5 mL of saturated sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and dissolved in methanol (1 mL). KCO (36.5 mg, 264 μmol, 5 eq) was added and stirred at 25°C for 1 hour. The reaction solution was then evaporated to dryness. The target compound GDI15-6327 (10 mg, 21.9 μmol, 41.4% yield) was obtained as a white solid by purification on silica gel plates (EtOAc / MeOH, 2 / 1) and HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-35%, 8 min). ESI-MS: [M+H] + ,456.1.

[0290] 1 H 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).

[0291] Example 32: Preparation of compound GDI15-6396

[0292] 1) Synthesis steps of compound 2

[0293] Compound 1 (2 g, 16 mmol), compound 2 (2.49 g, 16 mmol), and K2CO3 (4.42 g, 32 mmol) were dissolved in DMF (20 mL) and stirred at 60°C under nitrogen for 3 h. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After the reaction, water (200 mL) was added, the precipitate was filtered and washed with water, and the solution was concentrated under reduced pressure to give the crude product (2.5 g, 9.6 mmol, 60% yield) as a white solid. ESI-MS: [M+H] + ,260.60

[0294] 2) Synthesis steps of compound 4

[0295] Compound 5 (2.5 g, 9.6 mmol) and NBS (1.54 g, 8.64 mmol) were dissolved in DMF (25 mL) and stirred at room temperature under nitrogen for 2 hours. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After overnight reaction, water (300 mL) was added, the precipitate was filtered and washed with water, and the solution was evaporated to dryness under reduced pressure to afford crude product 4 (2.3 g, 6.8 mmol, 71% yield) as a white solid. ESI-MS: [M+H] + ,338.50.

[0296] 1 H NMR (400MHz, DMSO) δ8.30(d,J=2.4Hz,1H),7.99(m,1H),7.90(d,J=7.8Hz,1H),7.71(d,J=8.6Hz,1H),6.64(d,J=7.9Hz,1H),4.02(s,3H).

[0297] 3) Synthesis steps of compound 6

[0298] Compound 4 (410 mg, 1.2 mmol), compound 5 (276 mg, 1.08 mmol), CsF (547 mg, 3.6 mmol), and Pd(DtBPF)Cl2 (77 mg, 0.12 mmol) were dissolved in DMF / H2O (8 mL / 2 mL) and stirred at 70°C under nitrogen for 5 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, water (20 mL) was added to the system. The product was extracted with EtOAc (20 mL x 3) and dried over Na2SO4. The product was filtered and dried by spin-drying. Further column chromatography on PE:EtOAc (1 v:1 v to 1 v:2 v) afforded compound 6 (170 mg, 0.44 mmol, 36.7% yield) as a yellow solid. ESI-MS: [M+H] + ,388.00.

[0299] 4) Synthesis steps of compound 7

[0300] Compound 6 (170 mg, 0.44 mmol) and NiCl2.6H2O (157 mg, 0.66 mmol) were dissolved in MeOH (5 mL) and stirred at 0°C under nitrogen for 5 minutes. Sodium borohydride (50 mg, 1.32 mmol) was then added in three portions. The reaction was stirred at 0°C for 10 minutes. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. Boc2O (288 mg, 1.32 mmol) was then added dropwise, and the mixture was gradually warmed to room temperature and allowed to react for 1 hour. After the reaction, water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 3), dried over Na2SO4, filtered, and spun down. The mixture was further purified by column chromatography (PE:EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 7 (80 mg, 0.17 mmol, 37.5% yield) as a yellow solid. ESI-MS: [M+H] + ,492.00.

[0301] 5) Synthesis steps of compound GDI15-6396

[0302] 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 for 2 hours. LCMS monitored the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solvent was evaporated, and the residue was further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6396 (4.7 mg, 6% yield) as a white solid. ESI-MS: [M+H] + ,378.00.

[0303] 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).

[0304] Example 33: Preparation of compound GDI15-6505

[0305] 1) Synthesis steps of compound 3

[0306] Compound 1 (1 g, 8 mmol), compound 2 (1.17 g, 7.6 mmol), and K2CO3 (3.32 g, 24 mmol) were dissolved in DMF (20 mL) under nitrogen atmosphere and reacted at 46°C for 1 h. LCMS confirmed the reaction was complete. Water (200 mL) was added, the mixture was filtered, washed with water, and the solution was spin-dried to give the crude product, compound 3 (1.05 g, 3.6 mmol, 45.0% yield), as a white solid. ESI-MS: [M+H] + ,278.8.

[0307] 2) Synthesis steps of compound 4

[0308] Compound 3 (1.05 g, 3.6 mmol) and NBS (510 mg, 2.8 mmol) were dissolved in DMF (13 mL) under nitrogen protection and reacted at room temperature for 2 h. The reaction was completed by LCMS. Water (100 mL) was added, the solid was filtered and washed with water, and the solvent was dried to give compound 4 (1.05 g, 2.9 mmol, 80.56% yield). ESI-MS: [M+H] + ,356.55.

[0309] 3) Synthesis steps of compound 6

[0310] 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)Cl2 (270 mg, 4.2 mmol) were dissolved in DMF / H2O (5 mL / 1 mL) and reacted at 50°C for 2 h under nitrogen. The reaction was monitored by LCMS, and the solvent was evaporated. Column chromatography (PE / EtOAc, 1 v:0 v to 10 v:1 v) afforded compound 6 (260 mg, 0.6 mmol, 21.43% yield) as a yellow oil. ESI-MS: [M+H] + ,405.70.

[0311] 4) Synthesis steps of compound 8

[0312] Compound 6 (210 mg, 0.52 mmol) and NiCl2.6H2O (192 mg, 0.78 mmol) were dissolved in MeOH (2 mL) and reacted at 0°C for 10 min under nitrogen. NaBH4 (78 mg, 2.07 mmol) was then added in three portions. The reaction was continued at 0°C for 10 min. LCMS monitored the reaction for completion, followed by the dropwise addition of Boc2O (451 mg, 2.07 mmol). The reaction was allowed to warm to room temperature and allowed to react for 1 h. The solvent was then dried and column chromatography using DCM:MeOH (20:1 to 10:1) afforded compound 7 (160 mg, 0.25 mmol, 48.5% yield) as a brown oil. ESI-MS: [M+H] + ,509.85.

[0313] 4) Synthesis steps of compound GDI15-6505

[0314] Compound 8 (130 mg, 0.25 mmol) was dissolved in HBr / HOAc (6 mL) under nitrogen and stirred at 100°C for 6 h. The reaction was monitored for completion by LCMS, and the solvent was evaporated. The product was then purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford GDI15-6505 (3.24 mg, 3.22% yield) as a white solid. ESI-MS: [M+H] + ,395.70.

[0315] 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).

[0316] Example 34: Preparation of compound GDI15-6590

[0317] 1) Synthesis steps of compound 3

[0318] Compound 1 (2.0 g, 16 mmol) was dissolved in DMF (20 mL). K2CO3 (6.6 g, 48 mmol) and compound 2 (3.1 g, 18 mmol) were then slowly added to the system under nitrogen at 0°C. The mixture was heated to 60°C and reacted for 16 h. The mixture was then extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Further purification by column chromatography (EtOAc / PE, 30% to 40%) afforded compound 3 (1.2 g, 26.25% yield) as a white solid. ESI-MS: [M+H] + ,278.80.

[0319] 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).

[0320] 2) Synthesis steps of compound 3

[0321] Compound 3 (1.0 g, 3.59 mmol) and NiCl2.6H2O (1.3 g, 5.38 mmol) were dissolved in MeOH (20 mL) and reacted at 0°C under nitrogen for 5 min. Sodium borohydride (406.94 mg, 10.77 mmol) was then added in two batches. The mixture was allowed to react at 0°C for 10 min. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. Subsequently, Boc2O (2.3 g, 10.77 mmol) was added dropwise, and the mixture was slowly warmed to room temperature and allowed to react for 1 h. The system was further purified by column chromatography (EtOAc / PE, 45% to 50%) to afford compound 4 (700 mg, 50.96% yield) as a white solid. ESI-MS: [M+H] + ,383.05.

[0322] 1 H 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).

[0323] 3) Synthesis steps of compound 5

[0324] 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 desired product. After the reaction, water (50 mL) was added to the system, the solid was filtered and washed with water, and the solution was concentrated and dried to give the crude product, Compound 5 (400 mg, 47.38% yield), as a white solid. ESI-MS: [M+H] + ,462.90.

[0325] 4) Synthesis steps of compound 7

[0326] Compound 5 (300 mg, 0.65 mmol), compound 6 (199 mg, 0.78 mmol), CsF (296 mg, 1.95 mmol), and Pd(DtBPF)Cl2 (43 mg, 0.0650 mmol) were dissolved in DMF / H2O (1 mL / 0.2 mL) and stirred at 50°C under nitrogen for 5 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (20 mL) was added, and the solid residue was filtered and washed with water. The solution was extracted with EtOAc (20 mL x 3) and dried over Na2SO4. The mixture was filtered and dried, and further purified by column chromatography (PE:EtOAc, 20:80 to 0:100) to afford compound 7 (150 mg, 0.37 mmol, 56.88% yield) as a yellow solid. ESI-MS: [M+H] + ,510.10.

[0327] 5) Synthesis steps of compound GDI15-6590

[0328] Compound 7 (100 mg, 0.20 mmol) was dissolved in AcOH. A solution of HBr in AcOH (5 mL, 33%) was added dropwise under nitrogen and stirred. The mixture was reacted at 100°C for 10 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. The solvent was evaporated in vacuo and further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6590 (6.42 mg, 4.08% yield). ESI-MS: [M+H] + ,395.75.

[0329] 1 H 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).

[0330] Example 35: Preparation of compound GDI15-6624

[0331] 1) Synthesis steps of compound 3

[0332] Compound 1 (124 mg, 0.71 mmol), compound 2 (200 mg, 0.79 mmol), and K2CO3 (329 mg, 2.38 mmol) were dissolved in DMF (5 mL) and stirred at 60°C under nitrogen for 5 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, 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.

[0333] 2) Synthesis steps of compound 4

[0334] Compound 3 (220 mg, 0.54 mmol) and NiCl2.6H2O (193 mg, 0.81 mmol) were dissolved in MeOH (5 mL) and stirred at 0°C for 5 min. Sodium borohydride (61 mg, 1.63 mmol) was then added in three batches and allowed to react at 0°C for 10 min. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. Boc2O (355 mg, 1.63 mmol) was then added dropwise. After the addition was complete, the reaction system was gradually warmed to room temperature and allowed to react for 1 h. After completion of the reaction, the system was extracted with H2O (20 mL) and DCM (20 mL x 3). The mixture was dried over Na2SO4, filtered, and dried by column chromatography (PE:EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 4 (110 mg, 0.22 mmol, 39.79% yield) as a yellow solid. ESI-MS: [M+H] + ,510.10.

[0335] 3) Synthesis steps of compound GDI15-6624

[0336] Compound 4 (110 mg, 0.22 mmol, 1 eq) was dissolved in HBr / AcOH (3 mL) and stirred at 100°C for 5 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, NaHCO₃ (36.24 mg, 0.43 mmol, 2 eq) was added dropwise. The mixture was filtered and dried, and further purified by prep-HPLC (Gemini 5μm C₁₈ column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H₂O containing 0.1% TFA) to afford compound GDI15-6624 (31.43 mg, 36.8% yield) as a white solid. ESI-MS: [M+H] + ,396.05.

[0337] 1 H 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).

[0338] Example 36: Preparation of compound GDI15-6548

[0339] 1) Synthesis steps of compound 2

[0340] Compound 1 (4 g, 16.4 mmol), Zn(CN)2 (2.31 g, 19.7 mmol), and Pd(PPh3)4 (1.9 g, 16.4 mmol) were dissolved in DMF (30 mL) and stirred at 100°C under nitrogen for 16 hours. LCMS monitoring revealed the disappearance of the starting materials and the appearance of the desired product. After the reaction, water (200 mL) was added to the system, the solid residue was filtered, and the solution was concentrated and dried to give the crude product, Compound 2 (2 g, 10.5 mmol, 64.0% yield), as a white solid. ESI-MS: [M+H] + ,190.00.

[0341] 2) Synthesis steps of compound 4

[0342] Compound 3 (851 mg, 6.8 mmol), compound 2 (1.3 g, 6.8 mmol), and K2CO3 (1.88 g, 13.6 mmol) were dissolved in DMF (10 mL) and stirred at 60°C under nitrogen for 3 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, water (20 mL) was added to the system, and the solid residue was filtered and washed with water. The filtrate was concentrated and dried to give the crude product, compound 4 (0.8 g, 2.7 mmol, 39.7% yield), as a white solid.

[0343] 3) Synthesis steps of compound 5

[0344] Compound 4 (800 mg, 2.71 mmol) and NBS (434.22 mg, 2.44 mmol) were dissolved in DMF (8 mL) and stirred at room temperature under nitrogen for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of 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 give the crude product, compound 5 (520 mg, 1.39 mmol, 51.29% yield), as a white solid. ESI-MS: [M+H] + ,374.85.

[0345] 4) Synthesis steps of compound 7

[0346] Compound 5 (470 mg, 1.26 mmol), compound 6 (321 mg, 1.26 mmol), CsF (382 mg, 2.51 mmol), and Pd(DtBPF)Cl2 (82 mg, 0.13 mmol) were dissolved in DMF / H2O (5 mL / 1 mL) and stirred at 70°C under nitrogen for 5 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, water (20 mL) was added to the system, and the mixture was extracted with EtOAc (20 mL x 3), dried over Na2SO4, and filtered to dryness using column chromatography (PE:EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 7 (230 mg, 0.5447 mmol, 43.35% yield) as a yellow solid. ESI-MS: [M+H] + ,422.00.

[0347] 5) Synthesis steps of compound 8

[0348] Compound 7 (200 mg, 0.47 mmol) and NiCl2.6H2O (169 mg, 0.71 mmol) were dissolved in MeOH (5 mL) and reacted at 0°C under nitrogen for 5 minutes. Sodium borohydride (54 mg, 1.42 mmol) was then added in three portions. The reaction was continued at 0°C for 10 minutes. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. Boc2O (310 mg, 1.42 mmol) was then added dropwise. The mixture was slowly warmed to room temperature and reacted for 1 hour. After the reaction, water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 3), dried over Na2SO4, filtered, and subjected to spin chromatography (PE:EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 8 (80 mg, 0.15 mmol, 32.09% yield) as a yellow solid. ESI-MS: [M+H] + ,526.05.

[0349] 6) Synthesis steps of compound GDI15-6548

[0350] 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 for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solvent was evaporated and the product was further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford GDI15-6548 (3.12 mg, 7.6 μmol, 4.98% yield) as a white solid. ESI-MS: [M+H] + ,412.00.

[0351] 1 H 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).

[0352] Example 37: Preparation of compound GDI15-6623

[0353] 1) Synthesis steps of compound 2

[0354] Compound 1 (10 g, 69.2 mmol) was dissolved in TFA (46 mL). NIS (17.13 g, 76.1 mmol) was added at room temperature under nitrogen protection. The mixture was allowed to react for 16 h. Upon completion of the reaction, the solvent was evaporated under reduced pressure and EtOAc was added. The mixture was extracted with Na₂O₃S₂ (40 mL x 5). The combined organic phases were washed with water (30 mL x 2) and saturated brine (40 mL x 1), dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product, Compound 2 (17 g, 91% yield), as a colorless oil.

[0355] 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).

[0356] 2) Synthesis steps of compound 3

[0357] Compound 2 (5 g, 18.5 mmol) and Zn(CN)2 (1.09 g, 9.2 mmol) were dissolved in DMF (50 mL). Pd(PPh3)4 (2.14 g, 1.8 mmol) was added under nitrogen and heated to 90°C for 12 h. After the reaction, water (10 mL) was added and the mixture was extracted with EtOAc (40 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (PE / EtOAc, 10:1) to afford compound 3 (1 g, 32% yield) as a white solid.

[0358] 1 H NMR (400MHz, DMSO) δ7.98 (d, J = 7.1Hz, 1H), 7.80 (d, J = 9.3Hz, 1H), 2.32 (s, 3H).

[0359] 3) Synthesis steps of compound 5

[0360] Compound 3 (1.05 g, 6.2 mmol) was dissolved in DMF (13 mL). Compound 4 (0.78 g, 6.2 mmol) and KCO (2.57 g, 18.6 mmol) were added at room temperature under nitrogen. The reaction was incubated at 60°C for 3 h. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After the reaction, water (10 mL) was added, and the solid residue was filtered and washed with water. The solution was then evaporated to dryness under reduced pressure to afford the crude product, Compound 5 (890 mg, 50% yield), as a white solid.

[0361] 4) Synthesis steps of compound 6

[0362] Compound 5 (890 mg, 3.2 mmol) was dissolved in DMF (9 mL). NBS (461.31 mg, 2.6 mmol) was added at room temperature under nitrogen protection, and the reaction was continued at room temperature for another 3 h. After the reaction, water (10 mL) was added to the system, the residue was filtered and washed with water, and the solution was dried to give the crude product, compound 6 (1.0 g, 83% yield), as a white solid. ESI-MS: [M+H] + ,394.90.

[0363] 5) Synthesis steps of compound 8

[0364] 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)Cl2 (0.18 g, 0.28 mmol) were dissolved in DMF / H2O (10 mL / 2.5 mL) and stirred at 70°C under nitrogen for 2 hours. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, water (5 mL) was added to the system and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 1% to 80%) to afford compound 8 (430 mg, 38.22% yield) as a white solid.

[0365] 1 H 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).

[0366] 6) Synthesis steps of compound 9

[0367] Compound 8 (430 mg, 1.07 mmol) and NiCl2.6H2O (350.32 mg, 1.61 mmol) were dissolved in methanol (MeOH) (5 mL) and stirred at 0°C under nitrogen for 10 minutes. Sodium borohydride (121.46 mg, 3.21 mmol) was then added in three portions and the reaction continued at 0°C for 20 minutes. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. Boc2O (2.3 g, 10.70 mmol) was then added dropwise and the reaction was allowed to warm to room temperature for 1 hour. After the reaction, the product was purified by column chromatography (EtOAc / PE, 1% to 80%) to afford compound 9 (450 mg, 74.80% yield) as a green solid. ESI-MS: [M+H] + ,506.10.

[0368] 7) Synthesis steps of compound GDI15-6623

[0369] Compound 9 (150 mg, 370.5 μmol) was dissolved in HBr in AcOH (2 mL) at room temperature under nitrogen. The mixture was heated to 100°C for 16 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. The solvent was concentrated under reduced pressure and then purified by rep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6623 (3.37 mg, 2.33% yield) as a white solid. ESI-MS: [M+H] + ,392.10.

[0370] 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).

[0371] Example 38: Preparation of compound GDI15-6672

[0372] 1) Synthesis steps of compound 2

[0373] Compound 1 (5 g, 26.8 mmol) was dissolved in 3M H2SO4 (22 mL) at 0°C, followed by the addition of NaNO2 (1.85 g, 26.8 mmol). The mixture was allowed to react at 0°C for 1 hour. KI (4.45 g, 26.8 mmol) and UREA (0.32 g, 5.3 mmol) were dissolved in water (2 mL) and added to the mixture. The reaction was continued at 0°C for 1 hour, then gradually warmed to room temperature for 2 hours. After completion, the reaction was quenched with water (5 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and flash column chromatography was performed to yield compound 2 (4.2 g) as a white solid.

[0374] 1 H NMR (400MHz, DMSO) δ8.26(s,1H),8.06(s,1H),2.44(s,3H).

[0375] 2) Synthesis steps of compound 3

[0376] 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, and the mixture was heated at 90°C for 4 h. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with DCM (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to flash column chromatography to afford compound 3 (2 g) as a white solid.

[0377] 3) Synthesis steps of compound 4

[0378] Compound NHBoc2 (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 at this temperature for 10 min. Subsequently, a solution of compound 3 (2 g, 5.3 mmol) in DMF (10 mL) was added dropwise to the system. After the addition was complete, the mixture was gradually warmed to room temperature and stirred at room temperature for 4 h. Water (30 mL) was added to quench the reaction and the mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by flash column chromatography to obtain compound 4 (2.5 g) as a colorless oil. ESI-MS: [M+H] + ,575.9.

[0379] 4) Synthesis steps of compound 6

[0380] 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). KCO (81 mg, 0.59 mmol) was then added all at once, and the system was reacted at 140°C for 1 h. After the reaction, the mixture was cooled to room temperature and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by flash column chromatography (DCM / MeOH, 0% to 10%) to afford compound 6 (18 mg, 0.057 mmol) as a yellow solid. ESI-MS: [M+H] + ,523.00.

[0381] 5) Synthesis steps of compound GDI-6672

[0382] Compound 6 (30 mg, 0.0574 mmol) was dissolved in HCl in ethyl acetate (2 mL) and stirred at room temperature for 2 h. After the reaction, the solvent was evaporated and purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6672 (2.12 mg, 0.005 mmol) as a yellow solid. ESI-MS: [M+H] + ,423.10.

[0383] 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).

[0384] Example 39: Preparation of compound GDI15-6591

[0385] 1) Synthesis steps of compound 3

[0386] Compound 1 (1.5 g, 4.4 mmol), compound 2 (0.57 g, 3.9 mmol), and CsF (2.01 g, 13.2 mmol) were dissolved in DMF / H2O (20 mL). Pd-118 (0.29 g, 0.4 mmol) was added under nitrogen. The system was heated to 70°C under nitrogen for 4 h. After the reaction, water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 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 afford compound 3 (0.95 g, 54.55% yield) as a brown solid. ESI-MS: [M+H] + ,388.00.

[0387] 2) Synthesis steps of compound 4

[0388] Compound 3 (200 mg, 0.52 mmol) and K2CO3 (143 mg, 1.0 mmol) were dissolved in DMSO (2 mL). H2O2 (0.2 mL, 30%) was added at 0°C under nitrogen protection, and the mixture was allowed to warm to room temperature for 2 h. After the reaction, ice water was added to the system and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (PE / EtOAc, 10% to 60%) to afford compound 4 (160 mg, 76.44% yield) as a white solid. ESI-MS: [M+H] + ,406.00.

[0389] 3) Synthesis steps of compound GDI15-6591

[0390] Compound 4 (130 mg, 0.32 mmol) was dissolved in DMAC (2 mL). Under nitrogen at room temperature, decane-1-thiol (111.70 mg, 0.64 mmol) and NaOH (25.63 mg, 0.64 mmol) were added. The reaction was continued at 100°C for 3 h. The product was then purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6591 (10.17 mg, 8.11% yield) as a white solid. ESI-MS: [M+H] + ,392.10.

[0391] 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).

[0392] Example 40: Preparation of compound GDI15-6564

[0393] 1) Synthesis steps of compound 2

[0394] 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 Cs2CO3 (1.03 g, 3.17 mmol, 2 eq) were added sequentially at 25°C. Under nitrogen protection, the reaction was allowed to proceed at 25°C for 2 hours. LCMS detection showed that the reaction was complete. 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 washed 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.

[0395] 2) Synthesis steps of compound 3

[0396] Compound 2 (0.61 g, 1.50 mmol, 1 eq) was dissolved in EtOH (6 mL) and H₂O (1.8 mL). NH₄Cl (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 portionwise. The reaction mixture was stirred at 80°C for 3 hours. LCMS confirmed the reaction was complete. The hot reaction mixture was filtered through celite, and the filter cake was rinsed with hot ethanol. The filtrate was concentrated under reduced pressure to obtain the crude product. Water (50 mL) was poured into the crude product, and the product was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with 100 mL of saturated sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to afford the target compound 3 (480 mg, 1.27 mmol, 84.9% yield) as a yellow solid. MS: [M+H] + ,378.1.

[0397] 3) Synthesis steps of compound GDI15-6564

[0398] Compound 3 (50 mg, 132 μmol, 1 eq) was dissolved in NMP (2 mL). 1-Decanethiol (115 mg, 661 μmol, 5 eq) and KCO (36.5 mg, 264 μmol, 2 eq) were added sequentially at 25°C. The reaction mixture was stirred at 140°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: [H2O(10 mM NH4HCO3)-ACN]; gradient: 20%-50% B over 8.0 min) to afford the target product GDI15-6564 (20.2 mg, 55.5 μmol, 41.9% yield) as a brown solid. ESI-MS: [M+H] + ,364.0.

[0399] 1 H 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).

[0400] Example 41: Preparation of compound GDI15-6579

[0401] 1) Synthesis steps of compound 4

[0402] 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 with stirring at 20 ° C. The reaction mixture was reacted at 35 ° C for 16 hours. LCMS detection showed that the reaction was complete. Water (3 mL) was added to the reaction solution, and it was extracted with DCM (3 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel plate separation (EtOAc / MeOH, 10 / 1) (TLC, EtOAc / MeOH, 10 / 1, R f=0.62) to give a crude product of compound 4 (0.12 g) as a yellow solid.

[0403] 2) Synthesis steps of compound GDI15-6579

[0404] Compound 4 (0.1 g, 238 μmol, 1 eq) was dissolved in HBr / AcOH (2 mL, 33% purity). The reaction mixture was allowed to react at 120°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was then filtered under reduced pressure and dried by spin drying. The product was then purified by HPLC (Phenomenex Gemini-NX 80*40 mm*3 μm column; mobile phase: [H₂O(10 mM NH₄HCO₃)-ACN]; gradient: 1%-30% B over 8.0 min) to afford 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.

[0405] 1H NMR(400MHz,DMSO)δ9.60-9.41(m,1H),9.24(s,1H),8.37-8.27(m,1H),8.17-8.07( 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).

[0406] Example 42: Preparation of compound GDI15-6576

[0407] 1) Synthesis steps of compound 3

[0408] Compound Int I (150 mg, 595 μmol, 1 eq) was dissolved in HBr / AcOH (2 mL, 33% purity). The reaction mixture was allowed to react at 120°C for 16 hours. LCMS confirmed the reaction was complete, and the reaction solution was filtered under reduced pressure and dried. The mixture was then purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 1%-25% B over 8.0 min) to afford the title compound 3 (75 mg, 315 μmol, 52.9% yield) as a white solid. ESI-MS: [M+H]+, 293.0.

[0409] 2) Synthesis steps of compound GDI15-6576

[0410] Compound 3 (40 mg, 168 μmol, 1 eq) was dissolved in DMF (2 mL). Compound 1 (54.1 mg, 201 μmol, 1.2 eq), Cs2CO3 (164 mg, 505 μmol, 3 eq) were added in sequence at 25°C.

[0411] (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. The reaction was completed by LCMS. Ice water (3 mL) was added to the reaction solution and extracted with DCM (2 mL*4). The organic phases were combined and concentrated under reduced pressure. The product was purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-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.

[0412] 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).

[0413] Example 43: Preparation of compound GDI15-6592

[0414] 1) Synthesis steps of compound 7

[0415] Compound 6 (550 mg, 1.4 mmol) was dissolved in 4M HCl / MeOH (10 mL) and heated to 100°C for 4 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, the solvent was evaporated under reduced pressure to afford the crude product, compound 7 (500 mg, 1.18 mmol, 83.78% yield), as a yellow solid. ESI-MS: [M+H]+ ,420.90.

[0416] 2) Synthesis steps of compound 8

[0417] 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. The mixture was stirred at 0°C for 20 min. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, NH4Cl was added to the system, and the solvent was removed under reduced pressure. DCM was added, and the residue was filtered to obtain a solution, which was then dried to afford compound 8 (200 mg, 0.36 mmol, 75.00% yield) as a brown oil. ESI-MS: [M+H] + ,392.95.

[0418] 3) Synthesis steps of compound 7

[0419] Compound 8 (180 mg, 0.46 mmol) and decane-1-thiol (160 mg, 0.92 mmol) were dissolved in DMAc (2 mL). NaOH (37 mg, 0.91 mmol) was added at room temperature under nitrogen. The mixture was reacted at 100°C for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solvent was evaporated in vacuo and further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6592 (3.24 mg, 1.88% yield) as a white solid. ESI-MS: [M+H] + ,379.00.

[0420] 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).

[0421] Example 44: Preparation of compound GDI15-6706

[0422] 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). CuI (1.6 mg, 8.40 μmol, 0.2 eq) and K2CO3 (17.4 mg, 126 μmol, 3 eq) were then added sequentially at 20°C. The mixture was reacted at 140°C under nitrogen for 3 hours. The reaction was complete by LCMS. The reaction mixture was slowly added to ice water (2 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined and dried under reduced pressure. HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 27%-57% B over 8.0 min) was used 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.

[0423] 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).

[0424] Example 45: Preparation of compound GDI15-6766

[0425] 1) Synthesis steps of compound 3

[0426] To a solution of compound 1 (1 g, 3.6 mmol) in DMF (10 mL) was added NaH (0.1 g, 3.9 mmol) under nitrogen at 0°C. The mixture was allowed to react for 30 min at 0°C, followed by the dropwise addition of SEMCl (0.78 g, 4.6 mmol). After the addition was complete, the mixture was allowed to react for 1.5 h at the same temperature. After the reaction, water (2 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic fractions were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH, 20:1) to afford compound 2 (1.34 g, 86.11% yield) as an orange-red liquid. ESI-MS: [M+H] + ,408.75.

[0427] 2) Synthesis steps of compound 4

[0428] Under nitrogen 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). The mixture was stirred at 100°C for 8 h. After the reaction, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product, compound 4 (1.2 g, 87.26% yield), as a black oil. ESI-MS: [M+H] + ,391.85.

[0429] 3) Synthesis steps of compound 5

[0430] 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). The mixture was stirred at room temperature for 3 h. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product, compound 5 (1.8 g, 87.10% yield), as a black oil. ESI-MS: [M+H] + ,405.90.

[0431] 4) Synthesis steps of compound 6

[0432] Compound 5 (1 g, 2.5 mmol) and NBS (0.36 g, 2.0 mmol) were added with DMF (10 mL) and stirred at room temperature under nitrogen for 3 h. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (EtOAc / PE, 50% to 80%) to afford compound 6 (160 mg, 12% yield) as a yellow solid. ESI-MS: [M+H] + ,485.85.

[0433] 5) Synthesis steps of compound 8

[0434] A mixed solution of DMF / H2O (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). The mixture was stirred at 70°C under nitrogen for 3 h. After the reaction, water (2 mL) was added 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 by column chromatography (DCM / MeOH, 20:1) to afford compound 8 (70 mg, 49% yield) as a yellow solid. ESI-MS: [M+H] + ,533.10.

[0435] 6) Synthesis steps of compound GDI15-6766

[0436] A solution of HBr in AcOH (1 mL) was added to compound 6 (60 mg, 0.11 mmol), and the reaction was stirred at 100°C under nitrogen for 16 hours. After completion of the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6766 (20 mg, 46% yield) as a white solid. ESI-MS: [M+H] + ,389.05.

[0437] 1 H 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).

[0438] Example 46: Preparation of compound GDI15-6549

[0439] 1) Synthesis steps of compound 3

[0440] 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 the disappearance of the starting material and the appearance of the desired product. After the reaction, water (5 mL) was added, and the solid was filtered under reduced pressure to obtain the crude product, compound 3 (1.27 g, 66.25% yield), as a white solid.

[0441] 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).

[0442] 2) Synthesis steps of compound 4

[0443] Compound 3 (1.27 g, 5.3 mmol) was dissolved in DMF (13 mL) and NBS (0.75 g, 4.2 mmol) was added at room temperature under nitrogen. The mixture was allowed to react for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (3 mL) was added, and the solid was filtered 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.

[0444] 3) Synthesis steps of compound 6

[0445] 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)Cl2 (161.33 mg, 0.25 mmol) were dissolved in DMF / H2O (8 mL / 2 mL) and stirred at 70°C for 2 h. LCMS monitored the disappearance of the starting material and the appearance of the desired product. After completion of 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 over a spin column chromatography (PE / EtOAc, 10:1) to afford compound 8 (430 mg, 47.28% yield) as a yellow solid.

[0446] 1H 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).

[0447] 4) Synthesis steps of compound 8

[0448] Compound 6 (430 mg, 1.2 mmol) and NiCl2.6H2O (417.29 mg, 1.8 mmol) were dissolved in MeOH (5 mL) and stirred at 0°C under nitrogen for 10 minutes. Sodium borohydride (398.52 mg, 10.5 mmol) was then added in three batches. The mixture was allowed to react at 0°C for another 20 minutes. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. Boc2O (2.55 g, 11.7 mmol) was added dropwise to the mixture, and the mixture was allowed to warm to room temperature for 1 hour. After the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc, 1% to 80%) to afford compound 8 (160 mg, 28.99% yield) as a yellow solid. ESI-MS: [M+H] + ,472.00.

[0449] 5) Synthesis steps of compound GDI15-6549

[0450] 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. The reaction system was allowed to react at 100°C for 3 h. After completion, the mixture was concentrated under reduced pressure and purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6549 (9.16 mg, 7.56% yield) as a white solid. ESI-MS: [M+H] + ,357.75.

[0451] 1H 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).

[0452] Example 47: Preparation of compound GDI15-6550

[0453] 1) Synthesis steps of compound 3

[0454] Compound 1 (2 g, 16 mmol) was dissolved in DMF (20 mL). Compound 2 (3.35 g, 18 mmol) and K2CO3 (6.6 g, 48 mmol) were added at 0°C under nitrogen. The temperature was raised to 60°C and the reaction continued at this temperature for 16 hours. After the reaction, water (100 mL) was added and the mixture was extracted with EtOAc (100 mL x 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 yield compound 3 (1.7 g, 36.25% yield) as a white solid. ESI-MS: [M+H] + ,294.90.

[0455] 2) Synthesis steps of compound 4

[0456] Compound 3 (1.5 g, 4.6 mmol) was dissolved in DMF (15 mL). NBS (0.8 g, 4.2 mol) was slowly added to the mixture at 0°C under nitrogen. The mixture was then allowed to react at room temperature for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (100 mL) was added to the mixture, and the residue was filtered and washed with water. The filtrate was then dried to give the crude product, compound 4 (1.5 g, 4.2 mmol, 89.93% yield), as a white solid. ESI-MS: [M+H] + ,374.90.

[0457] 3) Synthesis steps of compound 6

[0458] 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)Cl2 (261.30 mg, 0.40 mmol) were dissolved in DMF / H2O (10 mL / 2 mL) and heated at 70°C for 4 h. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After the reaction, water (200 mL) was added to the system and the mixture was washed with EtOAc (200 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 40% to 50%) to afford compound 6 (500 mg, 1.2 mmol, 44% yield) as a brown solid. ESI-MS: [M+H] + ,421.90.

[0459] 4) Synthesis steps of compound 7

[0460] Compound 6 (400 mg, 0.95 mmol) and NiCl2·6H2O (338 mg, 1.42 mmol) were dissolved in MeOH (20 mL) and stirred at 0°C under nitrogen for 5 minutes. Sodium borohydride (107 mg, 2.84 mmol) was then added in three portions. The reaction was continued at 0°C for 10 minutes. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. Subsequently, Boc2O (620 mg, 2.84 mmol) was slowly added to the system. After the addition was complete, the system was warmed to room temperature and reacted for 2 hours. After the reaction, the solvent was evaporated and the product was further purified by column chromatography (EtOAc / PE, 45% to 50%) to afford compound 7 (300 mg, 60.17% yield) as a yellow solid. ESI-MS: [M+H] + ,526.15.

[0461] 5) Synthesis steps of compound GDI15-6550

[0462] 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 for 2 h. LCMS monitored the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the system was purified by spin-drying column chromatography (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6550 (6.63 mg, 8.48% yield) as a white solid. ESI-MS: [M+H] + ,411.80.

[0463] 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).

[0464] Example 48: Preparation of compound GDI15-6625

[0465] 1) Synthesis steps of compound 3

[0466] Compound 1 (200 mg, 1 mmol) was dissolved in DMF (2 mL). Compound 2 (252.27 mg, 1 mmol) and KCO (414.63 mg, 3 mmol) were added at room temperature under nitrogen. 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 give the crude product, Compound 3 (334 mg, 61.81% yield), as a white solid. ESI-MS: [M+H] + ,433.80.

[0467] 2) Synthesis steps of compound 4

[0468] Compound 3 (170 mg, 0.39 mmol) and NiCl2.6H2O (140.23 mg, 0.59 mmol) were dissolved in MeOH (2 mL) and stirred at 0°C under nitrogen for 10 minutes. NaBH4 (44.6 mg, 1.18 mmol) was then slowly added and the reaction continued at 0°C for 20 minutes. LCMS analysis revealed the disappearance of the starting material and the appearance of the desired product. Boc2O (429.19 mg, 2.00 mmol) was then added dropwise. The reaction temperature was raised to room temperature and stirring continued for 10 hours. The solution was then evaporated to dryness under reduced pressure and purified by column chromatography (EtOAc / PE, 80% to 1%) to afford compound 4 (190 mg, 54.03% yield) as a pale yellow solid. ESI-MS: [M+H] + ,536.10.

[0469] 3) Synthesis steps of compound GDI15-6625

[0470] Compound 4 (150 mg, 0.28 mmol) was dissolved in HBr in AcOH (2 mL). The mixture was heated to 100°C under nitrogen for 16 h. The mixture was then concentrated under reduced pressure and purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6625 (10.36 mg, 8.48% yield) as a white solid. ESI-MS: [M+H] + ,422.00.

[0471] 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).

[0472] Example 49: Preparation of compound GDI15-6918

[0473] 1) Synthesis steps of compound 3

[0474] Compound 1 (2 g, 7.9 mmol) and compound 2 (1.41 g, 7.1 mmol) were dissolved in 10 mL of DMF. Under nitrogen, K2CO3 (3.28 g, 23.7 mmol) was added. The reaction was incubated at 100°C for 3 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (100 mL) was added and the mixture was extracted with DCM (50 mL x 2). Column chromatography (DCM / MeOH, 1 v:0 v to 10 v:1 v) afforded compound 3 (1.3 g, 3 mmol, 37.97% yield) as a yellow solid. ESI-MS: [M+H] + ,431.75.

[0475] 2) Synthesis steps of compound 4

[0476] Compound 3 (200 mg, 0.46 mmol) was dissolved in 6 mL of THF. The system was cooled to 0°C and a THF solution of LiAlH4 (0.2 mL, 0.23 mmol) was added dropwise under nitrogen. The reaction was continued at 0°C for 1 h. After completion, 0.3 mL of NH4Cl solution was added to quench the reaction. The system was concentrated and purified by column chromatography (DCM / H2O, 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.

[0477] 3) Synthesis steps of compound 5

[0478] Compound 4 (70 mg, 0.17 mmol) was dissolved in 5 mL of DCM, and a solution of PBr (70.45 mg, 0.26 mmol) in 1 mL of DCM was slowly added at 0°C under nitrogen. The reaction system was stirred at room temperature for 0.5 h, then quenched with 10 mL of H2O, extracted with DCM, and the organic phase concentrated to dryness to afford compound 5 (65 mg, 0.11 mmol, 77.8% yield) as a yellow oil. ESI-MS: [M+H] + ,466.05.

[0479] 4) Synthesis steps of compound 6

[0480] To a solution of compound 5 (55 mg, 0.12 mmol) in 2 mL of THF was added 2 mL of aqueous ammonia. The reaction was allowed to proceed under nitrogen at room temperature for 3 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the system was concentrated and dried to afford the crude product, compound 6 (60 mg, 0.32 mmol, 77.8% yield), as a yellow solid. ESI-MS: [M+H] + ,403.15.

[0481] 5) Synthesis steps of compound 7

[0482] Compound 6 (60 mg, 0.15 mmol) was dissolved in 4 mL of MeOH. Boc2O (65 mg, 0.30 mmol) was added dropwise at room temperature under nitrogen. The reaction was stirred for 16 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, the solution was concentrated and dried, and purified on a TLC plate (TLC:DCM:MeOH, 15:1) to afford compound 7 (30 mg, 0.054 mmol, 36.02% yield) as a yellow solid. ESI-MS: [M+H] +,403.15.

[0483] 5) Synthesis steps of compound GDI15-6918

[0484] Compound 7 (140 mg, 0.28 mmol) was dissolved in 4 mL of HBr / HOAc solution and stirred at 100°C for 16 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solvent was evaporated in vacuo and further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6918 (0.91 mg, 0.0023 mmol, 0.83% yield) as a yellow solid. ESI-MS: [M+H] + ,389.15.

[0485] 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).

[0486] Example 50: Preparation of compound GDI15-6467

[0487] 1) Synthesis steps of compound 3

[0488] Compound 1 (450 mg, 1.2 mmol), compound 2 (290 mg, 1.3 mmol), CsF (604 mg, 4.0 mmol), and Pd(DtBPF)Cl2 (172 mg, 0.26 mmol) were dissolved in DMF / H2O (8 mL / 2 mL) and stirred at 70°C under nitrogen for 5 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered through a spin-dried column (PE / EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 3 (300 mg, 0.81 mmol, 61.1% yield) as a black oil. ESI-MS: [M+H] + ,351.85.

[0489] 2) Synthesis steps of compound 4

[0490] Compound 3 (300 mg, 0.76 mmol) and NiCl2.6H2O (303 mg, 1.28 mmol) were dissolved in MeOH (5 mL) and stirred at 0°C under nitrogen for 5 minutes. Sodium borohydride (97 mg, 1.7 mmol) was then added in three portions. The reaction was continued at 0°C for 10 minutes. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. Boc2O (288 mg, 1.32 mmol) was then added dropwise to the reaction system. The system was allowed to warm to room temperature and allowed to react for 1 hour. After the reaction, H2O (10 mL) was added and the mixture was extracted with DCM (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM / MeOH, 20:1 to 10:1) to afford compound 4 (300 mg, 0.65 mmol, 85.5% yield) as a black oil. ESI-MS: [M+H] + ,456.10.

[0491] 3) Synthesis steps of compound GDI15-6467

[0492] 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 for 2 hours. LCMS monitored the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the mixture was spin-dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6467 (5.11 mg, 4.3% yield) as a white solid. ESI-MS: [M+H] + ,342.00.

[0493] 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).

[0494] Example 51: Preparation of compound GDI15-6506

[0495] 1) Synthesis steps of compound 3

[0496] Compound 1 (2 g, 16 mmol), compound 2 (2.49 g, 16 mmol), and potassium carbonate (6.63 g, 48 mmol) were dissolved in DMF (20 mL) and stirred at 60°C under nitrogen for 3 h. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After the reaction, water (10 mL) was added to the system, and the solid was filtered and washed with water. The filtrate was then dried to give the crude product, compound 3 (2.5 g, 9.1 mmol, 60% yield), as a white solid. ESI-MS: [M+H] + ,261.00.

[0497] 2) Synthesis steps of compound 4

[0498] Compound 3 (2.5 g, 9.6 mmol) and NiCl2.6H2O (3.42 g, 14.4 mmol) were dissolved in MeOH (30 mL) and stirred at 0°C under nitrogen for 5 minutes. Sodium borohydride (1.09 g, 28.8 mmol) was then added in three portions. The reaction was continued at 0°C for 10 minutes. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. Boc2O (6.29 g, 28.8 mmol) was added dropwise to the reaction mixture, and the mixture was allowed to warm to room temperature and continue reacting for 1 hour. After the reaction, water (30 mL) was added and the mixture was extracted with DCM (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to spin chromatography (DCM:MeOH, 20:1 to 10:1) to afford compound 4 (460 mg, 1.3 mmol, 13.54% yield) as a yellow solid. ESI-MS: [M+H] + ,365.00.

[0499] 3) Synthesis steps of compound 5

[0500] Compound 4 (460 mg, 1.26 mmol) and NBS (202 mg, 1.13 mmol) were dissolved in DMF (5 mL) and stirred at room temperature under nitrogen for 2 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM:MeOH, 20:1 to 10:1) to afford compound 5 (260 mg, 0.59 mmol, 46.47% yield) as a yellow solid.

[0501] 1H 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).

[0502] 4) Synthesis steps of compound 7

[0503] 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)Cl2 (33.78 mg, 0.052 mmol) were dissolved in DMF / H2O (3 mL / 0.75 mL) and stirred at 50°C under nitrogen for 3 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (10 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by spin chromatography (DCM / MeOH, 20:1 to 10:1) to afford compound 7 (166 mg, 0.45 mmol, 87.32% yield) as a yellow oil.

[0504] 1 H NMR (400MHz, CDCl3) 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).

[0505] 4) Synthesis steps of compound GDI15-6506

[0506] 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 for 2 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solvent was evaporated and the product was further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6506 (10.08 mg, 7.94% yield) as a white solid. ESI-MS: [M+H] + ,353.05.

[0507] 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).

[0508] Example 52: Preparation of compound GDI15-6461

[0509] 1) Synthesis steps of compound 3

[0510] 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 / H2O (8 mL / 2 mL) and stirred at 50°C under nitrogen for 2 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to spin chromatography (PE / EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 3 (320 mg, 0.90 mmol, 61.22% yield) as a yellow solid. ESI-MS: [M+H] + ,355.65.

[0511] 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).

[0512] 2) Synthesis steps of compound 4

[0513] Compound 3 (320 mg, 0.90 mmol) and NiCl2.6H2O (320.76 mg, 1.35 mmol) were dissolved in MeOH (5 mL) and reacted at 0°C under nitrogen for 5 min. Sodium borohydride (102.14 mg, 2.7 mmol) was then added in three portions. The mixture was stirred at 0°C for 10 min. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. Boc2O (589.1 mg, 2.7 mmol) was added dropwise to the mixture. The reaction was allowed to warm to room temperature and allowed to react for 1 h. After completion of the reaction, water (20 mL) and DCM (20 mL x 3) were added to the mixture for extraction. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to spin chromatography (PE:EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 4 (180 mg, 0.39 mmol, 43.5% yield) as a yellow solid. ESI-MS:[M+H] + ,459.95.

[0514] 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).

[0515] 3) Synthesis steps of compound GDI15-6461

[0516] 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 for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solvent was evaporated and the product was further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6461 (11.91 mg, 10.45% yield) as a white solid. ESI-MS: [M+H] + ,346.05.

[0517] 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).

[0518] Example 53: Preparation of compound GDI15-6651

[0519] 1) Synthesis steps of compound 2

[0520] Compound 1 (5 g, 23.10 mmol) was dissolved in dry THF (50 mL). BH3-THF (1 M in cyclohexane, 69.3 mL, 69.30 mmol) was added dropwise at 20°C under nitrogen. After completion of the addition, 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. The system was then heated to 70°C for another 1 h. After completion of the reaction, NaOH (50 mL, 2 mol / L) aqueous solution was added to quench the reaction and extracted with DCM (200 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness 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.

[0521] 2) Synthesis steps of compound 3

[0522] Compound 2 (500 mg, 2.27 mmol), BOC2O (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 for 2 h. After the reaction, water (100 mL) was added to the system, and the mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 5% to 25%) to afford compound 3 (400 mg, 52.27% yield) as a white solid.

[0523] 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).

[0524] 3) Synthesis steps of compound 4

[0525] Compound 3 (500 mg, 1.56 mmol), bis(pyrinato)diboron (990 mg, 3.90 mmol), potassium acetate (459 mg, 4.68 mmol), and Pd(dppf)Cl2 (127 mg, 0.16 mmol) were dissolved in 1,4-dioxane (6 mL) and stirred at 100°C under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After the reaction, H2O (200 mL) was added to the system and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 10:90) to afford compound 4 (200 mg, 34.88% yield) as a yellow solid. ESI-MS: [M+H] + ,368.1.

[0526] 4) Synthesis steps of compound 6

[0527] Compound 4 (100 mg, 0.27 mmol), compound 5 (45 mg, 0.14 mmol), CsF (124 mg, 0.82 mmol), and Pd(DtBPF)Cl2 (18 mg, 0.027 mmol) were dissolved in DMF / H2O (0.5 mL / 0.1 mL) and reacted at 50°C under nitrogen for 4 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, H2O (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM / MeOH, 96:4 to 95:5) to afford compound 6 (50 mg, 37.35% yield) as a brown solid. ESI-MS: [M+H] + ,492.15.

[0528] 5) Synthesis steps of compound GDI15-6461

[0529] Compound 6 (50 mg, 0.10 mmol) was dissolved in 33% HBr in AcOH (3 mL) and stirred at 100°C under nitrogen for 16 h. After completion of the reaction, aqueous NaCO (20 mL) was added to adjust the pH to 6-7. The crude product was further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6651 (3.26 mg, 8.46% yield) as a white solid. ESI-MS: [M+H] + ,378.1.

[0530] 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).

[0531] Example 54: Preparation of compound GDI15-6798

[0532] 1) Synthesis steps of compound 3

[0533] Compound 1 (200.00 mg, 0.79 mmol) and K2CO3 (328.72 mg, 2.38 mol) were dissolved in DMF (4 mL). Bromoacetonitrile (190.20 mg, 1.59 mol) was slowly added under nitrogen. The mixture was reacted at 50°C for 5 h. After the reaction, water (30 mL) was added. The solid residue was filtered, washed with water, dried, and then spin-dried to give the crude product, Compound 3 (160 mg, 69.28% yield), as an off-white solid. ESI-MS: [M+H] + ,292.

[0534] 2) Synthesis steps of compound 4

[0535] 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) was added DMF (1 mL) under nitrogen protection. The reaction was stirred at 20°C for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. 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 subjected to column chromatography (EtOAc / PE, 70:30) to afford compound 4 (80 mg, 74.75% yield) as a brown solid. ESI-MS: [M+H] + ,372.1.

[0536] 3) Synthesis steps of compound 6

[0537] A mixed solvent of dioxane (8 mL) and H2O (1 mL) was added to a system containing compound 4 (80.00 mg, 0.22 mmol), compound 5 (33.79 mg, 0.22 mmol), Pd(dppf)Cl2 (31.62 mg, 0.043 mmol), and K3PO4 (91.74 mg, 0.43 mmol). The mixture was refluxed at 60°C under nitrogen for 2 h. After completion of the reaction, the mixture was cooled to room temperature and filtered. 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 purified by column chromatography (MeOH / DCM, 4% to 5%) to afford compound 6 (40 mg, 46.07% yield) as a brown solid. ESI-MS: [M+H] + ,402.0.

[0538] 4) Synthesis steps of compound GDI15-6798

[0539] DMAc (2 mL) was added to a solution 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). The mixture was reacted at 50°C under nitrogen for 1 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solution was spin-dried and further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6798 (13.36 mg, 16.88% yield) as a yellow solid. ESI-MS: [M+H] + ,492.15.

[0540] 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).

[0541] Example 55: Preparation of compound GDI15-6936

[0542] 1) Synthesis steps of compound 3

[0543] Compound 1 (178.78 mg, 0.49 mmol), compound 2 (150 mg, 0.41 mmol), Pd(PPh3)2Cl2 (28.44 mg, 0.0405 mmol), and K3PO4 (172.02 mg, 0.81 mmol) were dissolved in dioxane (5 mL) and water (1 mL) and stirred at 60°C under nitrogen for 1.5 h. After completion of the reaction, 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 subjected to column chromatography (MeOH / DCM, 5% to 6%) to afford compound 3 (100 mg, 46.67% yield) as a brown solid. ESI-MS: [M+H] + ,531.2.

[0544] 2) Synthesis steps of compound GDI15-6936

[0545] 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. After the addition was complete, the reaction was stirred at 80°C for 16 hours. The resulting mixture was further purified via Biotage Isolera One (C18 column, eluent: 10% to 90% MeCN / H2O containing 0.1% FA formic acid) to afford compound GDI15-6936 (16.22 mg, 48.94% yield) as a yellow solid. ESI-MS: [M+H] + ,417.1.

[0546] 1 H 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).

[0547] Example 56: Preparation of compound GDI15-6845

[0548] 1) Synthesis steps of compound 3

[0549] DMF (2 mL) was added to a mixture of compound 1 (200 mg, 0.79 mmol), compound 2 (236.52 mg, 1.59 mmol), and K2CO3 (328.72 mg, 2.38 mmol). The reaction was stirred at 75°C under nitrogen for 16 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (20 mL) was added, the solid residue was filtered and washed with water, and the filtrate was dried to give the crude product, compound 3 (150 mg, 0.49 mmol, 61.97% yield), as a white solid. ESI-MS: [M+H] + ,306.1.

[0550] 2) Synthesis steps of compound 4

[0551] DMF (2 mL) was added to a mixture of compound 3 (150 mg, 0.49 mmol), NBS (437.21 mg, 2.46 mmol), and TFA (112 mg, 0.98 mmol). The reaction was stirred at room temperature under nitrogen for 1 hour. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (30 mL) was added, the solid residue was filtered, and washed with water. The filtrate was concentrated and dried to give the crude product, compound 4 (130 mg, 0.34 mmol, 68.86% yield), as a white solid. ESI-MS: [M+H] + ,384.00.

[0552] 3) Synthesis steps of compound 6

[0553] A DMF / H2O (2 mL) mixture was added to compound 4 (130 mg, 0.34 mmol), compound 5 (53 mg, 0.34 mmol), potassium phosphate (144 mg, 0.68 mmol), and Pd(dtbpf)Cl2 (28 mg, 0.034 mmol). The mixture was stirred at 60°C under nitrogen for 1 hour. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Further purification by column chromatography (PE / EtOAc, 1 v:1 v to 1 v:2 v) afforded compound 6 (60 mg, 0.14 mmol, 42.65% yield) as a yellow solid. ESI-MS: [M+H] + ,416.05.

[0554] 4) Synthesis steps of compound GDI15-6845

[0555] Compound 6 (60 mg, 0.14 mmol, 1 eq), PPTS (181 mg, 0.72 mmol), and LiCl (30.58 mg, 0.72 mmol) were added with NMP (3 mL). The reaction was stirred at 120°C under nitrogen for 1 hour. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the solution was concentrated and quenched with dropwise addition of NaHCO₃ (24 mg, 0.28 mmol, 2 eq). The solution was filtered and concentrated, and further purified by prep-HPLC (Gemini 5μm C₁₈ column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H₂O containing 0.1% ammonia) to afford compound GDI15-6845 (11.04 mg, 19.06% yield) as a white solid. ESI-MS: [M+H]+ ,402.10.

[0556] 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).

[0557] Example 57: Preparation of compound GDI15-6967

[0558] 1) Synthesis steps of compound 3

[0559] Compound 1 (1.0 g, 3.96 mmol) was dissolved in DMF (10 mL). Compound 2 (1.34 g, 5.94 mmol) and K2CO3 (1.64 g, 11.89 mmol) were added to the mixture under nitrogen. The mixture was stirred at 80°C for 6 h. After the reaction, water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (MeOH / DCM, 3% to 5%) to afford compound 3 (610 mg, 1.75 mmol, 44.2% yield) as a white solid. ESI-MS: [M+H] + ,349.1.

[0560] 2) Synthesis steps of compound 4

[0561] 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 for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% aqueous ammonia) to afford compound 4 (320 mg, 0.75 mmol, 42.8% yield) as a white solid. ESI-MS: [M+H] + ,426.90.

[0562] 3) Synthesis steps of compound 6

[0563] Compound 4 (320 mg, 0.75 mmol), compound 5 (175 mg, 1.12 mmol), and K3PO4 (476 mg, 2.24 mmol) were dissolved in 5 mL of dioxane:water (10:1). xphos-Pd-G2 (117 mg, 0.15 mmol) was added under nitrogen at 60°C, and the reaction was continued at 60°C for 4 h. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to spin chromatography (DCM:MeOH, 1v:1v to 10v:1v) to afford compound 6 (58 mg, 0.13 mmol, 16.87% yield) as a yellow solid. ESI-MS: [M+H] + ,459.05.

[0564] 4) Synthesis steps of compound GDI15-6967

[0565] 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 under nitrogen for 1 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluent 30% to 90%).

[0566] MeCN / H2O containing 0.1% ammonia) to give compound GDI15-6967 (3.09 mg, 5.67% yield) as a white solid. ESI-MS: [M+H] + ,445.0.

[0567] 1 H 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).

[0568] Example 58: Preparation of compound GDI15-7065

[0569] 1) Synthesis steps of compound 1

[0570] To a solution 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) were added DMSO (10 mL) and TEA (211 mg, 2.09 mmol, 1.5 eq). CO protection was applied and the mixture was heated to 90°C with stirring for 8 h. After completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying. Flash column chromatography (PE / EtOAc, 1:2) afforded compound 1 (160 mg, 0.41 mmol, 29.42% yield) as a white solid. ESI-MS: [M+H] + ,391.15.

[0571] 2) Synthesis steps of compound 2

[0572] To a three-necked round-bottom flask equipped with a stir bar, reflux condenser, and addition funnel was added potassium tert-butoxide (1M in THF, 1 mL, 1 mmol). The flask was cooled in a dry ice-acetonitrile bath and a solution of TosMIC (120 mg, 0.61 mmol) in DME (1.5 mL) was added. After stirring for several minutes, a solution of compound 1 (160 mg, 0.41 mmol) in DME (1.5 mL) was added dropwise over 30 minutes. The reaction was allowed to proceed in an ice bath for two hours, then gradually returned to room temperature. Methanol (4 mL) was added and the reaction continued at room temperature for 14 hours. The system was concentrated in vacuo, followed by addition of 20 mL of dichloromethane. The reaction was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and subjected to spin column chromatography (PE / EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 2 (50 mg, 0.12 mmol, 30.39% yield) as a yellow solid. ESI-MS:[M+H] + ,402.05.

[0573] 3) Synthesis steps of compound GDI15-7065

[0574] 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 under nitrogen for 2 hours. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% aqueous ammonia) to afford compound GDI15-7065 (4.28 mg, 8.84% yield) as a yellow solid. ESI-MS: [M+H] + ,387.95.

[0575] 1 H 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).

[0576] Example 59: Preparation of compound GDI15-6920

[0577] 1) Synthesis steps of compound 3

[0578] To a solution of compound 1 (5.0 g, 39.96 mmol) in DMF (20 mL) were added bromoacetonitrile (5.8 mg, 47.95 mmol) and K2CO3 (16.6 mg, 119.88 mmol), and the mixture was stirred at 50°C for 2 h. After the reaction, water (200 mL) was added and the mixture was extracted with EtOAc (200 mL x 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 afford compound 3 (4.5 g, 68.60% yield) as a yellow solid.

[0579] 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).

[0580] 2) Synthesis steps of compound 4

[0581] DMF (10 mL) was added to compound 3 (4.50 g, 27.41 mmol) and NBS (4.4 g, 15.57 mmol). The reaction was stirred at room temperature under nitrogen for 2 h. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After the reaction, water (300 mL) was added to the system, the solid residue was filtered and washed with water, and the filtrate was concentrated and dried to give compound 4 (5.1 g, 8.86 mmol, 76.55% yield) as a white solid. ESI-MS: [M+H] + ,245.0.

[0582] 3) Synthesis steps of compound 6

[0583] To a solution 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)Cl2 (106.26 mg, 0.16 mmol) was added DMF / H2O (4 mL / 1 mL). The mixture was stirred at 70°C under nitrogen for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, water (100 mL) was added to the solution, and the mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to spin chromatography (PE / EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 6 (500 mg, 1.29 mmol, 58.2% yield) as a yellow solid. ESI-MS: [M+H] + ,266.9.

[0584] 4) Synthesis steps of compound 7

[0585] DMF (5 mL) was added to compound 6 (400 mg, 1.50 mmol) and NBS (267.38 mg, 1.50 mmol). The reaction was stirred at room temperature under nitrogen for 2 h. LCMS monitoring indicated the disappearance of the starting material and the appearance of the desired product. After the reaction, water (100 mL) was added to the system, the residue was filtered and washed with water, and the filtrate was concentrated and dried to give the crude product, compound 7 (510 mg, 1.48 mmol, 98.36% yield), as a yellow solid. ESI-MS: [M+H] + ,346.9.

[0586] 5) Synthesis steps of compound 9

[0587] A mixture of dioxane (12 mL) and H2O (3 mL) was added to compound 7 (300 mg, 0.87 mmol), compound 8 (135.92 mg, 0.87 mmol), Pd(dppf)Cl2 in DCM (71.01 mg, 0.087 mmol), and K3PO4 (369.01 mg, 1.74 mmol). The mixture was stirred at 60°C under nitrogen for 1 h. After the reaction, water (50 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 50% to 60%) to afford compound 9 (210 mg, 64.12% yield) as a brown solid. ESI-MS: [M+H] + ,377.1.

[0588] 6) Synthesis steps of compound GDI15-6920

[0589] 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) was added DMAc (3 mL). The mixture was stirred at 50°C under nitrogen for 2 h. LCMS monitoring revealed the disappearance of the starting material and the appearance of the desired product. After completion of the reaction, the mixture was concentrated to dryness and further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6920 (3.09 mg, 1.47% yield) as a yellow solid. ESI-MS: [M+H] + ,363.1.

[0590] 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).

[0591] Example 60: Preparation of compound GDI15-6937

[0592] 1) Synthesis steps of compound 3

[0593] To a mixture 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) was added 20 mL of a 5:1 DMF:H2O mixture. Pd-118 (268.15 mg, 0.41 mmol) was added at room temperature under nitrogen protection. The temperature was raised to 70°C and the reaction was allowed to react for 16 hours. LCMS monitored the reaction for completion. After completion, the reaction was concentrated to dryness 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.

[0594] 2) Synthesis steps of compound 6

[0595] To a mixture of compound 4 (200 mg, 0.60 mmol), compound 5 (112.31 mg, 0.72 mmol), and K3PO4 (381.13 mg, 1.79 mmol) was added 2 mL of a 5:1 1,4-dioxane / water buffer. Pd(dppf)Cl2 (65 mg, 0.09 mmol) was added under nitrogen. The mixture was stirred at 60°C for 1 h. The reaction was monitored for completion by LCMS. After completion, the reaction mixture was concentrated and purified by thin-layer chromatography (DCM:MeOH, 15:1) to afford the crude product, compound 6 (200 mg, 0.55 mmol, 91.35% yield), as a yellow solid. ESI-MS: [M+H] + ,366.15.

[0596] 2) Synthesis steps of compound GDI15-6937

[0597] Compound 6 (90 mg, 0.25 mmol) and PPTS (309.1 mg, 1.23 mmol) were dissolved in 3 mL of NMP. LiCl (52.14 mg, 1.23 mmol) was added at room temperature under nitrogen and stirred. The mixture was stirred at 120°C for 2 h. LCMS monitored the reaction for completion. After completion, the mixture was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-6937 (50.46 mg, 0.143 mmol, 58.29% yield) as a white solid. ESI-MS: [M+H] + ,352.10.

[0598] 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).

[0599] Example 61: Preparation of compound GDI15-7085

[0600] 1) Synthesis steps of compound 2

[0601] Compound 1 (700 mg, 3.08 mmol, 1 eq) was dissolved in 1,4-dioxane (7 mL), followed by the addition of hexamethyltin (1.11 g, 3.39 mmol, 703 μL, 1.1 eq) and Pd(PPh3)2Cl2 (649 mg, 925 μmol, 0.3 eq) at 25°C. Under nitrogen, the reaction mixture was stirred at 100°C for 1 hour. LCMS confirmed the reaction was complete. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (5 mL x 3). The organic phases were combined, filtered under reduced pressure, and purified by silica gel chromatography (PE / EtOAc, 10 / 1) to afford the target compound 2 (250 mg, 595 μmol, 19.3% yield) as a white solid. ESI-MS: [M+H] + ,311.9.

[0602] 2) Synthesis steps of compound 4

[0603] Compound Int L (150 mg, 405 μmol, 1 eq) was dissolved in 1,4-dioxane (4.5 mL). 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)Cl2 (29.7 mg, 40.5 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was directly spin-dried and purified on a silica gel plate (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.

[0604] 3) Synthesis steps of compound GDI15-7085

[0605] 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 30%-60% B over 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.

[0606] 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).

[0607] Example 62: Preparation of compound GDI15-6973

[0608] 1) Synthesis steps of compound 3

[0609] Compound 1 (2 g, 7.93 mmol, 1 eq) was dissolved in DMF (40 mL). Compound 2 (2.40 g, 31.7 mmol, 2.01 mL, 4 eq) and K2CO3 (2.19 g, 15.8 mmol, 2 eq) were added sequentially at 20°C under nitrogen and allowed to react at 50°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, followed by the addition of water (50 mL) and ethyl acetate (20 mL). Insoluble solids formed in the mixture, which were filtered and the filter cake was dried using an oil pump to yield the target compound 3 (1.27 g, 4.38 mmol, 55.2% yield) as a light yellow solid. [M+H] + ,292.2.

[0610] 2) Synthesis steps of compound 4

[0611] Compound 3 (2 g, 6.87 mmol, 1 eq) was dissolved in MeCN (40 mL) and subsequently treated with TFA (235 mg, 2.06 mmol, 0.3 eq) and NBS (1.22 mg, 6.87 mmol, 1 eq) at 20°C. Under nitrogen, the reaction was allowed to proceed at 40°C for 2 hours. LCMS confirmed the reaction was complete. Water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried to afford the target compound 4 (2.5 g, 5.74 mmol, 83.6% yield) as a brown solid. [M+H] + ,370.0.

[0612] 3) Synthesis steps of compound 6

[0613] 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 H₂O (0.4 mL). Pd(dppf)Cl₂ (19.8 mg, 27.0 μmol, 0.1 eq) and K₃PO₄ (143 mg, 675 μmol, 2.5 eq) were then added sequentially at 25°C. The reaction mixture was allowed to react at 100°C for 6 hours, and the reaction was complete as determined by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (PE / EtOAc, 1 / 1) to afford the target compound 6 (23 mg, 25.7 μmol, 9.51% yield, 45% purity) as a yellow solid. ESI-MS: [M+H] + ,403.1.

[0614] 4) Synthesis steps of compound GDI15-6973

[0615] 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 sequentially at 20°C. The reaction mixture was incubated at 80°C under nitrogen for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 10%-50% B over 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

[0616] 1H NMR(400MHz,DMSO)δ13.35-12.69(m,1H),9.28(s,1H),8.93-8.73(m,1H),8.3 6(s,1H),8.22-7.93(m,3H),7.76-7.58(m,3H),7.56-7.42(m,1H),5.10(s,2H)

[0617] Example 63: Preparation of compound GDI15-7004

[0618] 1) Synthesis steps of compound 3

[0619] 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). Tri-n-butylphosphine (145 mg, 718 μmol, 177 μL, 1.6 eq) and azodicarbonyldipiperidine (181 mg, 718 μmol, 1.6 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (0.14 g, 166 μmol, 37.0% yield, 65% purity) as a yellow solid. [M+H] + ,548.3

[0620] 2) Synthesis steps of compound 4

[0621] 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. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain crude compound 4 (120 mg, 248 μmol, 97.0% yield, HCl) as a white solid. ESI-MS: [M+H] + ,448.2.

[0622] 3) Synthesis steps of compound 6

[0623] 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. LCMS confirmed the reaction was complete. The reaction solution was poured into ice water (5 mL), extracted with DCM (2 mL*3), and 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 (SiO2, EtOAc / MeOH, 10 / 1) to obtain a white solid. ESI-MS: [M+H] + ,552.

[0624] 4) Synthesis steps of compound GDI15-7004

[0625] Compound 6 (30 mg, 54.4 μmol, 1 eq) was dissolved in NMP (1 mL), followed by the addition of KCO (22.5 mg, 163 μmol, 3 eq) and 1-decanethiol (47.4 mg, 272 μmol, 5 eq) at 25°C. The reaction was allowed to proceed at 140°C for 16 hours under nitrogen, and the reaction was complete by LCMS. The reaction solution was filtered under atmospheric pressure and purified by HPLC using a Waters Xbridge BEH C18 100*30 mm*10 μm column; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 8.0 min to afford the desired product, GDI15-7004 (5.6 mg, 10.4 μmol, 19.2% yield), as a white solid. ESI-MS: [M+H] + ,538.2.

[0626] 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)

[0627] Example 64: Preparation of compound GDI15-7219

[0628] 1) Synthesis steps of compound 2

[0629] 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 K2CO3 (547 mg, 3.96 mmol, 2 eq) were added at 25°C. The reaction mixture was allowed to react at 50°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 2 (360 mg, 1.18 mmol, 59.5% yield) as a yellow solid. ESI-MS: [M+H] + ,306.1.

[0630] 2) Synthesis steps of compound 3

[0631] Compound 2 (420 mg, 1.38 mmol, 1 eq) was dissolved in MeCN (8.4 mL). 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 allowed to react at 40°C for 1 hour. LCMS confirmed the reaction was complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and spun down to dryness to afford 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.

[0632] 3) Synthesis steps of compound 5

[0633] 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 H₂O (0.8 mL). K₃PO₄ (276 mg, 1.30 mmol, 2.5 eq) and Pd(dppf)Cl₂ (38.1 mg, 52.1 μmol, 0.1 eq) were added at 25°C. Under nitrogen, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was then dried under reduced pressure and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 5 (50 mg, 102 μmol, 19.7% yield) as a yellow oil. ESI-MS: [M+H] + ,486.1.

[0634] 4) Synthesis steps of compound GDI15-7219

[0635] 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 incubated at 80°C for 16 hours, and the reaction was complete after LCMS analysis. The reaction mixture was purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 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.

[0636] 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)

[0637] Example 65: Preparation of compound GDI15-7278

[0638] 1) Synthesis steps of compound 3

[0639] Compound 2 (4.20 g, 29.3 mmol), Pd(PPh3)4 (1.02 g, 0.8 mol), and CsF (13.35 g, 87.9 mmol) were added to a solution of compound 1 (10 g, 29.3 mmol) in DMF (50 mL). The mixture was stirred at 75°C under nitrogen for 1 h. After the reaction, water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 0% to 50%) to afford compound 3 (9.5 g, 94.54% yield) as an orange oil. ESI-MS: [M+H] + ,343.05.

[0640] 2) Synthesis steps of compound 4

[0641] To a solution of compound 3 (5 g, 14.6 mmol) in DMF (30 mL) were added NBS (10.39 g, 58.4 mmol) and trifluoroacetic acid (0.17 g, 1.4 mmol). The mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction, water (5 mL) was added and the mixture was extracted with EtOAc (5 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (EtOAc / PE, 0% to 50%) to afford compound 4 (5.14 g, 83.56% yield) as a yellow solid. ESI-MS: [M+H] + ,420.65.

[0642] 3) Synthesis steps of compound 6

[0643] Compound 4 (3 g, 7.1 mmol) was added with a 5 / 1 dioxane / water solution (25 mL / 5 mL). Compound 5 (1.11 g, 7.1 mmol), XPhos Pd G2 (0.56 g, 0.7 mol), and K2CO3 (2.94 g, 21.3 mmol) were then added. The mixture was stirred at 100°C under nitrogen for 16 h. After the reaction, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 0% to 50%) to afford compound 6 (1.94 g, 60.56% yield) as an orange oil. ESI-MS: [M+H] + ,453.0

[0644] 4) Synthesis steps of compound 7

[0645] A mixture of HBr and AcOH (2 mL) was added to compound 6 (300 mg, 0.66 mmol) and stirred at room temperature under nitrogen for 16 h. After the reaction, the system was concentrated, and EtOAc (2 mL) was added. The solid was filtered to yield compound 7 (180 mg, 74.89% yield) as a yellow solid. ESI-MS: [M+H] + ,362.95.

[0646] 5) Synthesis steps of compound 9

[0647] To a solution of compound 7 (170 mg, 0.47 mmol) in DMF (5 mL) were added compound 8 (56.21 mg, 0.47 mmol) and K2CO3 (194.29 mg, 1.41 mmol). The mixture was stirred at 50°C under nitrogen for 4 h. After the reaction, water (5 mL) was added and the mixture was extracted with EtOAc (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 0% to 50%) to afford compound 9 (155 mg, 82.31% yield) as a yellow solid.

[0648] 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).

[0649] 6) Synthesis steps of compound 11

[0650] To a solution of compound 9 (100 mg, 0.25 mmol) in DMSO (5 mL) were added compound 10 (108.24 mg, 0.30 mmol) and DBU (113.68 mg, 0.75 mmol). The mixture was stirred at room temperature under nitrogen 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 by column chromatography (EtOAc / PE, 0% to 50%) to give compound 11 (60 mg, 56.33% yield) as a white solid.

[0651] 1H 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).

[0652] 7) Synthesis steps of compound GDI15-7278

[0653] To a mixture of compound 11 (60 mg, 0.14 mmol) in NMP (3 mL) were added PPTS (176.16 mg, 0.70 mmol) and LiCl (29.72 mg, 0.70 mmol). The mixture was stirred at 140°C under nitrogen for 4 h. After the reaction, water (5 mL) was added and the mixture was extracted with EtOAc (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography on a Biotage Isolera One (C18 column, eluent: 10% to 90% MeCN / H2O containing 0.1% NH4OH) to afford compound GDI15-7278 (5.12 mg, 8.84% yield) as a yellow solid. ESI-MS: [M+H] + ,413.95.

[0654] 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).

[0655] Example 66: Preparation of compound GDI15-7138

[0656] 1) Synthesis steps of compound 3

[0657] 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). K₃PO₄ (215 mg, 1.01 mmol, 2.5 eq) and Pd(dppf)Cl₂ (29.7 mg, 40.5 μmol, 0.1 eq) were added sequentially at 25°C. Under nitrogen, the reaction was stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 mL x 3). The organic phases were combined and washed with 20 mL of saturated sodium chloride solution. The washed organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target compound 3 (120 mg, 291 μmol, 71.8% yield) was purified by silica gel chromatography (SiO₂, EtOAc / MeOH, 10 / 1) to afford the target compound 3 as a red solid (100 mg, 291 μmol, 71.8% yield). ESI-MS:[M+H] + ,413.2.

[0658] 2) Synthesis steps of compound GDI15-7138

[0659] Compound 3 (0.1 g, 242.48 μmol, 1 eq) was dissolved in NMP (2 mL). PPTS (304.68 mg, 1.21 mmol, 5 eq) and LiCl (51.39 mg, 1.21 mmol, 24.85 μL, 5 eq) were added sequentially 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 (neutral condition) using a Waters Xbridge BEH C18 100*30 mm*10 μm column; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 10%-40% B over 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.

[0660] 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)

[0661] Example 67: Preparation of compound GDI15-7139

[0662] 1) Synthesis steps of compound 6

[0663] 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 H2O (0.6 mL). K3PO4 (215 mg, 1.01 mmol, 2.5 eq) and Pd(dppf)Cl2 (29.6 mg, 40.5 μmol, 0.1 eq) were added sequentially at 25°C. Under N2 protection, the reaction was stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete. Ice 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 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.

[0664] 2) Synthesis steps of compound GDI15-7139

[0665] Compound 6 (63 mg, 165 μmol, 1 eq) was dissolved in NMP (1.2 mL). PPTS (207 mg, 825 μmol, 5 eq) and LiCl (35.0 mg, 825 μmol, 16.9 μL, 5 eq) were added sequentially at 25°C. The mixture was allowed to react at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered, and the filtrate was transferred to a separate tube. High-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 10%-45% B over 8.0 min) afforded the target compound GDI15-7139 (23.6 mg, 64.2 μmol, 38.9% yield, 100% purity) as a white solid. ESI-MS: [M+H] + ,368.0.

[0666] 1H 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)

[0667] Example 68: Preparation of compound GDI15-7142

[0668] 1) Synthesis steps of compound 2

[0669] Compound Int L (150 mg, 405 μmol, 1 eq) was dissolved in dioxane (2.5 mL) and H₂O (0.5 mL). Compound 1 (89.3 mg, 608 μmol, 1.5 eq), K₃PO₄ (215 mg, 1.01 mmol, 2.5 eq), and Pd(dppf)Cl₂ (29.7 mg, 40.5 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was then spin-dried and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 2 (100 mg, 306 μmol, 75.5% yield) as a brown solid. ESI-MS: [M+H] + ,393.1.

[0670] 2) Synthesis steps of compound GDI15-7142

[0671] Compound 2 (0.1 g, 255 μmol, 1 eq) was dissolved in NMP (2 mL). PPTS (320 mg, 1.27 mmol, 5 eq) and LiCl (54.0 mg, 1.27 mmol, 26.1 μL, 5 eq) were added sequentially 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: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 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.

[0672] 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)

[0673] Example 69: Preparation of compound GDI15-6996

[0674] 1) Synthesis steps of compound 2

[0675] Compound 1 (60 mg, 162 μmol, 1 eq) and compound 2 (100 mg, 324 μmol, 2 eq) were dissolved in dioxane (1 mL) and H₂O (0.2 mL). K₃PO₄ (103 mg, 486 μmol, 126 μL, 3 eq) and Pd(dppf)Cl₂ (11.9 mg, 16.2 μmol, 0.1 eq) were then added sequentially at 20°C. The reaction mixture was allowed to react at 60°C for 5 hours, and the reaction was complete as determined by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford 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

[0676] 2) Synthesis steps of compound 2

[0677] Compound 2 (30 mg, 63.6 μmol, 1 eq) was dissolved in NMP (1 mL) and subsequently added with 1-decanethiol (55.4 mg, 318 μmol, 5 eq) and K₂CO₃ (17.6 mg, 127 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 100°C for 5 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C₁₈ 100*30 mm*10 μm; mobile phase: [H₂O(10 mM NH₄HCO₃)-ACN]; gradient: 25%-65% B over 8.0 min) to afford 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.

[0678] 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=8.0Hz ,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)

[0679] Example 70: Preparation of compound GDI15-7082

[0680] 1) Synthesis steps of compound 3

[0681] 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 H₂O (3.2 mL). Pd(dppf)Cl₂ (198 mg, 270 μmol, 0.1 eq) and K₃PO₄ (1.72 g, 8.10 mmol, 3 eq) were then added sequentially at 20°C. Under a nitrogen atmosphere, the reaction mixture was incubated at 60°C for 16 hours. LCMS analysis revealed 30% of Int L remaining and 14% of product formed. Pd(dppf)Cl₂ (198 mg, 270 μmol, 0.1 eq) was then added to the reaction mixture, and the reaction was continued at 60°C for 5 hours. LCMS analysis indicated the reaction was complete. The reaction mixture 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

[0682] 2) Synthesis steps of compound 5

[0683] 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). Then, n-Bu3P (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 sequentially at 20°C. Under a nitrogen atmosphere, the reaction mixture was allowed to react at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford the target compound 5 (0.12 g, 143 μmol, 19.9% ​​yield, 70% purity) as a yellow solid. ESI-MS: [M+H] + ,587.3

[0684] 3) Synthesis steps of compound GDI15-7082

[0685] Compound 5 (70 mg, 53.6 μmol, 70% purity, 1 eq) was dissolved in NMP (1.4 mL). PPTS (67.3 mg, 268 μmol, 5 eq) and LiCl (11.4 mg, 268 μmol, 5.49 μL, 5 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 80°C for 40 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 20%-50% B over 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

[0686] 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,4 H),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)

[0687] Example 71: Preparation of compound GDI15-7126

[0688] 1) Synthesis steps of compound 9

[0689] 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 allowed to react at 25°C for 5 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure to afford 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.

[0690] 2) Synthesis steps of compound 10

[0691] 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 incubated at 0°C for 1 hour, and the reaction was complete by LCMS. Ice water (10 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL x 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 give 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.

[0692] 3) Synthesis steps of compound 11

[0693] Compound 10 (380 mg, 908 μmol, 1 eq) was dissolved in dioxane (7.6 mL). BPD (276 mg, 1.09 mmol, 1.2 eq), KOAc (267 mg, 2.73 mmol, 3 eq), and Pd(dppf)Cl2 (66.4 mg, 90.8 μmol, 0.1 eq) were added sequentially at 25°C. Under nitrogen protection, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was purified by silica gel chromatography (PE / EtOAc, 8 / 1) to afford the target compound 11 (270 mg, 631 μmol, 69.4% yield) as a yellow oil. ESI-MS: [M+H] + ,428.2.

[0694] 4) Synthesis steps of compound 12

[0695] 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 H₂O (0.8 mL). K₃PO₄ (186 mg, 877 μmol, 2.5 eq) and Pd(dppf)Cl₂ (25.6 mg, 35.1 μmol, 0.1 eq) were added sequentially at 25°C. Under N₂ protection, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. Ice water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (2 mL x 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. The product was 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.

[0696] 5) Synthesis steps of compound GDI15-7126

[0697] Compound 12 (105 mg, 177 μmol, 1 eq) was dissolved in NMP (2.1 mL). PPTS (223 mg, 888 μmol, 5 eq) and LiCl (37.6 mg, 888 μmol, 18.2 μL, 5 eq) were added sequentially at 25°C. The reaction mixture was allowed to react at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered, and the filtrate was transferred to a separate tube. High-performance liquid chromatography (HPLC) (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 8.0 min) afforded the target compound GDI15-7126 (42.5 mg, 72.1 μmol, 40.6% yield, 97.9% purity) as a white solid. ESI-MS: [M+H] + ,577.0.

[0698] 1H 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)

[0699] Example 72: Preparation of compound GDI15-6968

[0700] 1) Synthesis steps of compound 3

[0701] To a mixture of compound 1 (1 g, 4.8 mmol) and compound 2 (1.69 g, 7.2 mmol) were added DMF (10 mL) and potassium carbonate (1.33 mg, 9.6 mmol), and the mixture was stirred at 50°C for 12 h. After the reaction, water was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EtOAc, 0% to 2%) to afford compound 3 (900 mg, 2.8 mmol) as a yellow oil.

[0702] 1 H NMR (400MHz, DMSO) δ7.21(t,J=1.6Hz,1H),7.03-6.99(m,1H),6.90(t,J=2.0Hz,1H),4.32(q,J=7.9Hz,2H).

[0703] 2) Synthesis steps of compound 4

[0704] 1,4-Dioxane (9 mL) was added to compound 3 (900 mg, 3.10 mmol), B2Pin2 (253 mg, 0.31 mmol), Pd(dppf)Cl2 (912 mg, 9.29 mmol), and KOAc (1.57 g, 6.20 mmol). The mixture was stirred at 100°C under nitrogen for 18 h. After the reaction, water was added to the system, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was purified by column chromatography (PE / EtOAc, 0% to 2%) to afford compound 4 (400 mg, 1.17 mmol) as a yellow solid.

[0705] 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).

[0706] 3) Synthesis steps of compound 6

[0707] To a system of compound 4 (180 mg, 0.53 mmol), compound 5 (148 mg, 0.40 mmol), K3PO4 (340 mg, 1.60 mmol), and Pd(dppf)Cl2 (44 mg, 0.0533 mmol) was added 1,4-dioxane / water (6:1) (3 mL), and the system was stirred at 50°C for 2 h. After the reaction, water was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (PE / EtOAc, 0% to 2%) to afford compound 6 (100 mg, 0.20 mmol) as a yellow solid. ESI-MS: [M+H] + ,500.00.

[0708] 4) Synthesis steps of compound GDI15-6968

[0709] Compound 6 (90 mg, 0.18 mmol) and PPTS (225 mg, 0.90 mmol) were dissolved in NMP (2 mL). LiCl (38 mg, 0.90 mmol) was added, and the reaction was stirred at 120°C for 1 h. After completion of the reaction, the mixture was filtered and further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% NH3H2O) to afford compound GDI15-6968 (23 mg, 0.047 mmol) as a yellow solid. ESI-MS: [M+H] + ,486.00.

[0710] 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).

[0711] Example 73: Preparation of compound GDI15-7084

[0712] 1) Synthesis steps of compound 2

[0713] Compound 1 (200 mg, 479 μmol, 1 eq) was dissolved in DMF (4.0 mL). Compound 2 (81.9 mg, 479 μmol, 0.9 eq) and K2CO3 (198 mg, 1.44 mmol, 3.0 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was allowed to react at 50°C for 5 hours. LCMS analysis revealed 14% starting material and 12% byproducts with two benzyl groups, with only 24% of product 2 formed. Water (5 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (5 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The mixture was then purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 2 (16 mg, 31.5 μmol, 6.7% yield) as a brown solid. ESI-MS: [M+H] + ,508.1.

[0714] 2) Synthesis steps of compound GDI15-7084

[0715] Compound 2 (16 mg, 31.5 μmol, 1 eq) was dissolved in NMP (1 mL). LiCl (6.68 mg, 157 μmol, 5 eq) and PPTS (39.6 mg, 157 μmol, 5 eq) were then added sequentially at 20°C. Under nitrogen, the reaction was stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) to obtain the target product GDI15-7084 (2.1 mg, 4.25 μmol, 13.5% yield) as a white solid. ESI-MS: [M+H] + ,494.1.

[0716] 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)

[0717] Example 74: Preparation of compound GDI15-7140

[0718] 1) Synthesis steps of compound 3

[0719] 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 then added to the reaction mixture. The reaction mixture was allowed to react at 30°C for another 16 hours. LCMS confirmed the reaction was complete. Ice water (80 mL) was added to the reaction mixture, which was then extracted with EtOAc (30 mL x 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 then purified by column chromatography (SiO2, 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.

[0720] 2) Synthesis steps of compound 4

[0721] Compound 3 (1 g, 3.37 mmol, 1 eq) was dissolved in dioxane (20 mL). BPD (1.03 g, 4.05 mmol, 1.2 eq), KOAc (992 mg, 10.1 mmol, 3 eq), and Pd(dppf)Cl2 (246 mg, 337 μmol, 0.1 eq) were added sequentially at 25°C. Under nitrogen protection, the mixture was allowed to react at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was purified by silica gel chromatography (PE / EtOAc, 8 / 1) to afford the target compound 4 (1 g, 2.91 mmol, 86.3% yield) as a yellow oil. ESI-MS: [M+H] + ,344.1.

[0722] 3) Synthesis steps of compound 5

[0723] 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 H2O (0.8 mL). K3PO4 (286 mg, 1.35 mmol, 2.5 eq) and Pd(dppf)Cl2 (39.5 mg, 54.0 μmol, 0.1 eq) were added sequentially at 25°C. Under N2 protection, the reaction was allowed to proceed at 80°C for 16 hours. LCMS confirmed the reaction was complete. Ice water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (2 mL x 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. The product was 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.

[0724] 4) Synthesis steps of compound GDI15-7140

[0725] Compound 5 (190 mg, 374 μmol, 1 eq) was dissolved in NMP (3.8 mL). PPTS (470 mg, 1.87 mmol, 5 eq) and LiCl (79.4 mg, 1.87 mmol, 38.4 μL, 5 eq) were added sequentially at 25°C. The mixture was allowed to react at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered, and the filtrate was transferred to a separate pipette. The product was purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 35%-65% B over 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.

[0726] 1H 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)

[0727] Example 75: Preparation of compound GDI15-7125

[0728] 1) Synthesis steps of compound 13

[0729] 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). MsCl (180 mg, 1.57 mmol, 121 μL, 1.5 eq) was added at 0°C. The reaction mixture was incubated at 0°C for 1 hour. LCMS confirmed the reaction was complete. Ice water (10 mL) was added to the reaction solution, which was then extracted with DCM (2 mL x 3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The organic phases were dried over anhydrous sodium sulfate and filtered under reduced pressure to dryness to afford the target compound 13 (342 mg, 964 μmol, 91.9% yield) as a yellow oil.

[0730] 2) Synthesis steps of compound 14

[0731] Compound 13 (340 mg, 958 μmol, 1 eq) was dissolved in dioxane (6.8 mL). BPD (292 mg, 1.15 mmol, 1.2 eq), KOAc (282 mg, 2.88 mmol, 3 eq), and Pd(dppf)Cl2 (70.1 mg, 95.8 μmol, 0.1 eq) were added sequentially at 25°C. Under nitrogen protection, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was purified by silica gel chromatography (PE / EtOAc, 8 / 1) to afford the target compound 14 (250 mg, 622 μmol, 64.9% yield) as a yellow oil. ESI-MS: [M+H] + ,424.1.

[0732] 3) Synthesis steps of compound 15

[0733] 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 H₂O (1 mL). K₃PO₄ (258 mg, 1.22 mmol, 2.5 eq) and Pd(dppf)Cl₂ (35.5 mg, 48.6 μmol, 0.1 eq) were added sequentially at 25°C. Under N₂ protection, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. Ice water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (2 mL x 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 then purified on a silica gel plate (EtOAc / Methanol, 10 / 1) to obtain the target compound 15 (170 mg, 229 μmol, 47.2% yield, 76.4% purity) as a yellow oil. ESI-MS: [M+H] + ,565.1.

[0734] 4) Synthesis steps of compound GDI15-7125

[0735] Compound 15 (160 mg, 283 μmol, 1 eq) was dissolved in NMP (3.2 mL). PPTS (355 mg, 1.42 mmol, 5 eq) and LiCl (60.0 mg, 1.42 mmol, 29.0 μL, 5 eq) were added sequentially at 25°C. The reaction mixture was allowed to react at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered, and the filtrate was transferred to a separate pipette. HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 20%-50% B over 8.0 min) was performed to obtain the target compound GDI15-7125 (41.8 mg, 73.5 μmol, 25.9% yield, 96.9% purity) as a white solid. ESI-MS: [M+H] + ,551.2.

[0736] 1H 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)

[0737] Example 76: Preparation of compound GDI15-7185

[0738] 1) Synthesis steps of compound 3

[0739] Compound 1 (2 g, 9.64 mmol, 1 eq) was dissolved in DMF (40 mL). Compound 2 (4.32 g, 19.3 mmol, 2 eq), K2CO3 (2.66 g, 19.3 mmol, 2 eq), and KI (320 mg, 1.93 mmol, 0.2 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was allowed to react at 20°C for 16 hours. LCMS confirmed the reaction was complete. Water (40 mL) was added to the reaction solution, which was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined and evaporated to dryness under reduced pressure to afford the target compound 3 (2 g, 5.70 mmol, 59.2% yield) as a colorless oil.

[0740] 2) Synthesis steps of compound 4

[0741] Compound 3 (1 g, 2.85 mmol, 1 eq) was dissolved in DCM (5 mL). Hydrochloric acid / dioxane (4 N, 5 mL) was slowly added dropwise to the reaction mixture at 0°C. The mixture was allowed to react at 20°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture 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.

[0742] 3) Synthesis steps of compound 5

[0743] 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, the reaction mixture was allowed to react at 0°C for 1 hour. LCMS confirmed the reaction was complete. Water (20 mL) was added to the reaction solution, which was then extracted with DCM (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and spun down to afford the target compound 5 (1 g, 3.04 mmol, 87.3% yield) as a yellow solid. ESI-MS: [M+H] + ,327.9.

[0744] 4) Synthesis steps of compound 6

[0745] Compound 5 (0.5 g, 1.52 mmol, 1 eq) was dissolved in dioxane (10 mL). BPD (464 mg, 1.83 mmol, 1.2 eq), KOAc (448 mg, 4.56 mmol, 2 eq), and Pd(dppf)Cl2 (111 mg, 152 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen protection, the reaction mixture was reacted at 80°C for 16 hours. LCMS analysis showed that the reaction was complete, and the reaction solution was used directly in the next step. ESI-MS: [M+H] + ,376.1.

[0746] 5) Synthesis steps of compound 7

[0747] To the reaction mixture of compound 5, 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 sequentially. Under nitrogen, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was then dried under reduced pressure and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 7 (220 mg, 286 μmol, 44.1% yield) as a brown solid. ESI-MS: [M+H] + ,539.1.

[0748] 6) Synthesis steps of compound GDI15-7185

[0749] Compound 7 (200 mg, 371 μmol, 1 eq) was dissolved in NMP (4.0 mL) and subsequently treated with LiCl (78.7 mg, 1.86 mmol, 5 eq) and PPTS (466 mg, 1.86 mmol, 5 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 10%-40% B over 18.0 min) to afford the target compound GDI15-7185 (80 mg, 152 μmol, 41.1% yield) as a yellow solid. ESI-MS: [M+H] + ,525.1.

[0750] 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,1H) ,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).

[0751] Example 77: Preparation of compound GDI15-7083

[0752] 1) Synthesis steps of compound 3

[0753] 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 H₂O (0.4 mL). Pd(dppf)Cl₂ (39.5 mg, 54.0 μmol, 0.1 eq) and K₃PO₄ (344 mg, 1.62 mmol, 420 μL, 3 eq) were then added sequentially at 20°C. The reaction mixture was allowed to react at 60°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford 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

[0754] 2) Synthesis steps of compound 5

[0755] Compound 4 (18.7 mg, 174 μmol, 19.0 μL, 1.5 eq) and compound 3 (50 mg, 116 μmol, 1 eq) were dissolved in DCM (2.5 mL). KOAc (13.7 mg, 140 μmol, 1.2 eq) and AcOH (698 μg, 11.6 μmol, 6.66 e-1 μL, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (32.1 mg, 151 μmol, 1.3 eq) was then added. The reaction was stirred at 20°C under nitrogen for 16 hours. The reaction was complete by LCMS. The reaction mixture 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

[0756] 3) Synthesis steps of compound GDI15-7083

[0757] Compound 5 (30 mg, 57.6 μmol, 1 eq) was dissolved in NMP (1.0 mL). PPTS (72.4 mg, 288 μmol, 5 eq) and LiCl (12.2 mg, 288 μmol, 5.90 μL, 5 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 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.

[0758] 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)

[0759] Example 78: Preparation of compound GDI15-7053

[0760] 1) Synthesis steps of compound 3

[0761] Compound 1 (1 g, 4.84 mmol, 1 eq) was dissolved in DCM (20 mL). Compound 2 (680 mg, 4.84 mmol, 545 μL, 1 eq) and KOAc (570 mg, 5.81 mmol, 1.2 eq) were added sequentially at 25°C. The reaction mixture was allowed to react at 25°C for 1 hour, followed by the addition of NaBH(OAc)3 (1.33 g, 6.30 mmol, 1.3 eq). The reaction mixture was allowed to react at 25°C for 15 hours, and the reaction was complete by LCMS. The reaction mixture was added to water (50 mL) and extracted with EtOAc (20 mL x 3). The organic phases were combined and washed with 100 mL of saturated sodium chloride. The organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (PE / EtOAc, 8 / 1) to afford the target compound 3 (710 mg, 2.14 mmol, 44.3% yield) as a yellow oil. ESI-MS:[M+H] + ,330.0.

[0762] 2) Synthesis steps of compound 4

[0763] Compound 3 (660 mg, 1.99 mmol, 1 eq) was dissolved in dioxane (13.2 mL). BPD (607 mg, 2.39 mmol, 1.2 eq), KOAc (587 mg, 5.98 mmol, 3 eq), and Pd(dppf)Cl2 (145 mg, 199 μmol, 0.1 eq) were added sequentially at 25°C. The reaction mixture was allowed to react at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was purified by silica gel chromatography (PE / EtOAc, 8 / 1) to afford the target compound 4 (510 mg, 1.35 mmol, 67.6% yield) as a yellow oil. ESI-MS: [M+H]+ ,378.2.

[0764] 3) Synthesis steps of compound 5

[0765] Compound Int L (120 mg, 324 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H₂O (0.5 mL). Compound 4 (183 mg, 486 μmol, 1.5 eq), Pd(dppf)Cl₂ (23.7 mg, 32.4 μmol, 0.1 eq), and K₃PO₄ (172 mg, 810 μmol, 2.5 eq) were added sequentially at 25°C. The reaction mixture was allowed to react at 60°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was added to water (10 mL) and extracted with EtOAc (2 mL x 3). 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 purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford compound 5 (70 mg, 129 μmol, 39.9% yield) as a yellow oil. ESI-MS:[M+H] + ,541.2.

[0766] 3) Synthesis steps of compound GDI15-7053

[0767] Compound 5 (70 mg, 129 μmol, 1 eq) was dissolved in NMP (1.4 mL). KCO (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 allowed to react at 100°C for 2 hours, and the reaction was complete after LCMS analysis. The reaction mixture was filtered, and the filtrate was transferred to a separate pipette. The mixture was purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 30%-70% B over 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.

[0768] 1H 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)

[0769] Example 79: Preparation of compound GDI15-7086

[0770] 1) Synthesis steps of compound 1

[0771] 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, and the mixture was 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.

[0772] 2) Synthesis steps of compound 3

[0773] Compound 1 (200 mg, 604 μmol, 1 eq) was dissolved in dioxane (3.5 mL) and H₂O (0.7 mL). Compound 2 (142 mg, 906 μmol, 1.2 eq), Na₂CO₃ (160 mg, 1.51 mmol, 2.5 eq), and Pd(dppf)Cl₂ (44.2 mg, 60.4 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. Water (5 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (5 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The resulting mixture was then purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (50 mg, 276 μmol, 22.8% yield) as a brown solid. ESI-MS: [M+H] + ,363.1.

[0774] 3) Synthesis steps of compound GDI15-7086

[0775] Compound 1 (50 mg, 138 μmol, 1 eq) was dissolved in NMP (1 mL), followed by the addition of KCO (57.1 mg, 413 μmol, 3 eq) and 1-decanethiol (120 mg, 689 μmol, 5 eq) at 25°C. The reaction was stirred at 140°C under nitrogen for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered under atmospheric pressure, and the filtrate was evaporated to dryness. The product was purified by HPLC using a Waters Xbridge BEH C18 100*30 mm*10 μm column, mobile phase: H2O (10 mM NH4HCO3)-ACN, gradient: 15%-45% B over 8.0 min to afford the target product GDI15-7086 (21.8 mg, 62.5 μmol, 45.4% yield) as a white solid. ESI-MS: [M+H] + ,349.1.

[0776] 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)

[0777] Example 80: Preparation of compound GDI15-7182

[0778] 1) Synthesis steps of compound 3

[0779] Compound 1 (100 mg, 302 μmol, 1 eq) was dissolved in dioxane (1.6 mL) and H₂O (0.4 mL). Compound 2 (121 mg, 393 μmol, 1.3 eq), Na₂CO₃ (62.7 mg, 755 μmol, 2.5 eq), and Pd(dppf)Cl₂ (22.1 mg, 30.2 μmol, 0.1 eq) were added sequentially at 20°C under nitrogen. The reaction mixture was incubated at 100°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was then spin-dried and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (20 mg, 46.2 μmol, 15.3% yield) as a brown solid. ESI-MS: [M+H] + ,433.1.

[0780] 2) Synthesis steps of compound GDI15-7182

[0781] Compound 3 (20 mg, 46.2 μmol, 1 eq) was dissolved in NMP (1.0 mL) and subsequently added with 1-decanethiol (40.3 mg, 231 μmol, 5 eq) and K₂CO₃ (12.8 mg, 92.4 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C₁₈ 100*30 mm*10 μm; mobile phase: [H₂O(10 mM NH₄HCO₃)-ACN]; gradient: 15%-45% B over 8.0 min) to afford the target compound GDI15-7182 (4 mg, 9.55 μmol, 20.7% yield) as a white solid. ESI-MS: [M+H] + ,419.1.

[0782] 1H 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)

[0783] Example 81: Preparation of compound GDI15-7254

[0784] 1) Synthesis steps of compound 3

[0785] Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H₂O (0.5 mL). Compound 2 (200 mg, 471 μmol, 1.3 eq), Na₂CO₃ (106 mg, 1.09 mmol, 3 eq), Cata Xium A (13.0 mg, 36.2 μmol, 0.1 eq), and Cata Xium A Pd G₃ (26.4 mg, 36.2 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 90°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was then concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (100 mg, 180 μmol, 45.3% yield) as a yellow solid. ESI-MS: [M+H] + ,548.2.

[0786] 2) Synthesis steps of compound GDI15-7254

[0787] Compound 3 (99.3 mg, 181 μmol, 1 eq) was dissolved in NMP (2.0 mL) and subsequently treated with LiCl (38.4 mg, 9.06 mmol, 18.6 μL, 5 eq) and PPTS (228 mg, 9.06 mmol, 5 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 100°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered at atmospheric pressure and purified by HPLC (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 3%-33% B over 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.

[0788] 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)

[0789] Example 82: Preparation of compound GDI15-7223

[0790] 1) Synthesis steps of compound 3

[0791] Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H₂O (0.5 mL). Compound 2 (201 mg, 471 μmol, 1.3 eq), Na₂CO₃ (115 mg, 1.09 mmol, 3 eq), CatacXium A (13.0 mg, 36.2 μmol, 0.1 eq), and CatacXium A Pd G₃ (26.4 mg, 36.2 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 90°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was directly spin-dried and purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (90 mg, 163 μmol, 45.0% yield) as a brown solid. ESI-MS: [M+H] + ,552.2.

[0792] 2) Synthesis steps of compound GDI15-7223

[0793] Compound 3 (90 mg, 191 μmol, 1 eq) was dissolved in NMP (1.8 mL) and subsequently reacted with 1-decanethiol (158 mg, 905 μmol, 5 eq) and KCO (75.1 mg, 543 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and then purified by HPLC (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 3%-33% B over 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.

[0794] 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)

[0795] Example 83: Preparation of compound GDI15-7222

[0796] 1) Synthesis steps of compound 3

[0797] Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and H₂O (0.5 mL). Compound 2 (201 mg, 471 μmol, 1.3 eq), Na₂CO₃ (115 mg, 1.09 mmol, 3 eq), CatacXium A (13.0 mg, 36.2 μmol, 0.1 eq), and Cataxium A Pd G₃ (26.4 mg, 36.2 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 90°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was then spin-dried and purified on silica gel (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (100 mg, 217 μmol, 45.0% yield) as a yellow solid. ESI-MS: [M+H]⁺, 461.1.

[0798] 2) Synthesis steps of compound GDI15-7222

[0799] Compound 3 (100 mg, 217 μmol, 1 eq) was dissolved in NMP (2.0 mL). KCO (60.0 mg, 434 μmol, 2 eq) and 1-decanethiol (189 mg, 1.08 mmol, 5 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25%-75% B over 8.0 min) to afford the target compound GDI15-7222 (43.2 mg, 96.7 μmol, 44.6% yield) as a white solid. ESI-MS: [M+H]+, 447.1.

[0800] 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,1H ),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).

[0801] Example 84: Preparation of compound GDI15-7207

[0802] 1) Synthesis steps of compound 3

[0803] Compound 1 (250 mg, 755 μmol, 1 eq) was dissolved in dioxane (4 mL) and H₂O (1 mL). Compound 2 (338 mg, 981 μmol, 1.3 eq), Na₂CO₃ (200 mg, 1.89 mmol, 2.5 eq), and Pd(dppf)Cl₂ (55.2 mg, 75.5 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 100°C for 16 hours. LCMS analysis confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (27 mg, 57.6 μmol, 7.63% yield) as a brown solid. ESI-MS: [M+H] + ,469.1.

[0804] 2) Synthesis steps of compound GDI15-7207

[0805] Compound 3 (27 mg, 57.6 μmol, 1 eq) was dissolved in NMP (1.0 mL). 1-Decanethiol (50.2 mg, 288 μmol, 5 eq) and KCO (15.9 mg, 115 μmol, 2 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) to afford the target compound GDI15-7207 (8 mg, 17.6 μmol, 30.5% yield) as a white solid. ESI-MS: [M+H] + ,455.1.

[0806] 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).

[0807] Example 85: Preparation of compound GDI15-7256

[0808] 1) Synthesis steps of compound 3

[0809] Compound 1 (120 mg, 362 μmol, 1 eq) was dissolved in dioxane (2.4 mL) and water (0.5 mL). Compound 2 (162 mg, 471 μmol, 1.3 eq), Na2CO3 (106 mg, 1.09 mmol, 3 eq), Cata Xium A (13.0 mg, 36.2 μmol, 0.1 eq), and Cata Xium A Pd G3 (26.4 mg, 36.2 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 90°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was directly concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (90 mg, 192 μmol, 53.1% yield) as a yellow solid. ESI-MS: [M+H] + ,468.1.

[0810] 2) Synthesis steps of compound GDI15-7256

[0811] Compound 3 (90 mg, 192 μmol, 1 eq) was dissolved in NMP (1.8 mL). 1-Decanethiol (168 mg, 962 μmol, 5 eq) and KCO (53.2 mg, 382 μmol, 2 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 8.0 min) to afford the target compound GDI15-7256 (8.0 mg, 17.6 μmol, 9.16% yield) as a white solid. ESI-MS: [M+H] + ,454.1.

[0812] 1H 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).

[0813] Example 86: Preparation of compound GDI15-7382

[0814] 1) Synthesis steps of compound 3

[0815] Compound 2 (2 g, 6.97 mmol, 1 eq, HCl) was dissolved in DCM (20 mL). 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 sequentially at 0°C. The reaction mixture was stirred at 0°C for 1 hour. LCMS confirmed the reaction was complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the target compound 3 (2 g, 4.87 mmol, 69.9% yield, 80% purity) as a white solid. ESI-MS: [M+H] + ,326.9.

[0816] 2) Synthesis steps of compound 4

[0817] Compound 3 (500 mg, 1.52 mmol, 1 eq.) was dissolved in dioxane (10 mL). BPD (463 mg, 1.83 mmol, 1.2 eq), KOAc (448 mg, 4.56 mmol, 3 eq), and Pd(dppf)Cl2 (111 mg, 152 μmol, 0.1 eq) were added sequentially at 25°C. Under nitrogen protection, the reaction mixture was stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was used directly in the next step without further treatment. ESI-MS: [M+H] + ,375.1.

[0818] 3) Synthesis steps of compound 6

[0819] 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). Na2CO3 (169 mg, 160 mmol, 3 eq), CatacXium A Pd G3 (38.8 mg, 53.2 μmol, 0.1 eq), and CatacXium A (19.0 mg, 53.2 μmol, 0.1 eq) were added sequentially at 25°C. Under nitrogen, the reaction mixture was stirred at 90°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into ice water (5 mL) and extracted with EtOAc (3 mL x 3). The organic phases were combined and washed with 10 mL of saturated sodium chloride solution. The washed organic phases were 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.

[0820] 4) Synthesis steps of compound GDI15-915

[0821] Compound 6 (50 mg, 100 μmol, 1 eq) was dissolved in NMP (2 mL). 1-Decanethiol (87.2 mg, 500 μmol, 5 eq) and KCO (41.5 mg, 300 μmol, 3 eq) were added sequentially at 25°C. The reaction mixture was stirred at 120°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1% to 40% B over 8.0 min). The target product, GDI15-7382 (5.10 mg, 10.4 μmol, 10.4% yield), was obtained as a white solid. ESI-MS: [M+H] + ,486.1.

[0822] 1H 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)

[0823] Example 87: Preparation of compound GDI15-7141

[0824] 1) Synthesis steps of compound 2

[0825] Compound 1 (300 mg, 906 μmol, 1 eq) was dissolved in DMF (6 mL) and sequentially added with CH₃I (103 mg, 725 μmol, 0.8 eq) and K₂CO₃ (250 mg, 1.81 mmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 0°C for 2 hours. LCMS confirmed the reaction was complete. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (5 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried to afford the title compound 2 (250 mg, 724 μmol, 80.0% yield) as a white solid. ESI-MS: [M+H]⁺, 345.0.

[0826] 2) Synthesis steps of compound 4

[0827] Compound 2 (250 mg, 724 μmol, 1 eq) was dissolved in dioxane (6 mL) and H₂O (1.2 mL). Compound 3 (170 mg, 1.09 mmol, 1.2 eq), K₃PO₄ (384 mg, 1.81 mmol, 2.5 eq), and Pd(dppf)Cl₂ (53.0 mg, 72.4 μmol, 0.1 eq) were added sequentially at 20°C. Under nitrogen, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was then spin-dried and purified on silica gel (EtOAc / MeOH, 10 / 1) to afford the target compound 4 (100 mg, 265 μmol, 36.6% yield) as a brown solid. ESI-MS: [M+H]⁺, 377.1.

[0828] 3) Synthesis steps of compound GDI15-7141

[0829] Compound 4 (100 mg, 265 μmol, 1 eq) was dissolved in NMP (2.0 mL) and subsequently added with 1-decanethiol (231 mg, 1.33 mmol, 5 eq) and KCO (73.4 mg, 531 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 8.0 min) to afford the target compound GDI15-7141 (60.8 mg, 168 μmol, 63.2% yield) as a yellow solid. ESI-MS: [M+H]+, 363.1.

[0830] 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).

[0831] Example 88: Preparation of compound GDI15-6801

[0832] 1) Synthesis steps of compound 3

[0833] DMAc (145 mL) was added to a mixture of compound 1 (6 g, 48 mmol), compound 2 (8.7 g, 50.4 mmol), and K2CO3 (19.9 g, 144 mmol). The reaction was allowed to proceed at 100°C under nitrogen for 4 h. LCMS confirmed the reaction was complete. After completion, the solution was dried and purified by column chromatography (DCM:MeOH, 1 v:0 v to 20 v:1 v) to afford compound 3 (1.6 g, 5.8 mmol, 12.08% yield) as a yellow solid. ESI-MS: [M+H]+, 279.90.

[0834] 2) Synthesis steps of compound 4

[0835] Compound 3 (700 mg, 2.5 mmol) was added with MeOH (20 mL). Ammonium formate (1.7 g, 27.73 mmol) was added at room temperature under nitrogen. The reaction was stirred at 60°C for 1 h, cooled to 0°C, and then added with 633.6 mg of benzophenone (10.08 mmol). The reaction was continued at 60°C for 18 h, and the reaction was complete by LCMS. The reaction was cooled to 0°C, and BOC2O (1.38 g, 6.3 mmol) was added. The mixture was then returned to room temperature and allowed to react for 1 h, and the reaction was complete by LCMS. After the reaction, the solvent was dried and the mixture was further purified by column chromatography (DCM:MeOH, 1v:0v to 20v:1v) to afford compound 4 (400 mg, 1.06 mmol, 41.89% yield) as a green oil. ESI-MS: [M+H]+, 379.10.

[0836] 3) Synthesis steps of compound 5

[0837] To a mixture of compound 4 (360 mg, 0.95 mmol) and NBS (135.3 mg, 0.76 mmol) was added DMF (8 mL) and the mixture was stirred at room temperature for 2 h. LCMS monitored the reaction for completion. After the reaction, water (30 mL) was added, the solid was filtered and washed with water, and the filtrate was dried to give compound 5 (260 mg, 0.568 mmol, 59.78% yield) as a yellow solid. ESI-MS: [M+H] + ,459.05.

[0838] 4) Synthesis steps of compound 7

[0839] To a mixture of compound 5 (250 mg, 0.546 mmol), compound 6 (85 mg, 0.49 mmol), and CsF (249 mg, 1.64 mmol) was added 2 mL of a 5:1 DMF:H₂O mixture. Pd-118 (71 mg, 0.11 mmol) was added at room temperature under nitrogen protection. The reaction was carried out at 50°C for 2 h. The mixture was concentrated and further purified by column chromatography (DCM:H₂O, 1v:0v to 10v:1v) to afford pure compound 7 (60 mg, 0.12 mmol, 21.71% yield) as a yellow solid. ESI-MS: [M+H]⁺, 506.00.

[0840] 5) Synthesis steps of compound GDI15-6801

[0841] Compound 7 (60 mg, 0.12 mmol) was added with HBr / HOAc (6 mL), and the mixture was stirred at 100°C under nitrogen for 16 h. LCMS confirmed the reaction was complete. Further purification by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) afforded compound GDI15-6801 (16.67 mg, 0.042 mmol, 35.8% yield) as a white solid. ESI-MS: [M+H] + ,392.10.

[0842] 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).

[0843] Example 89: Preparation of compound GDI15-6919

[0844] 1) Synthesis steps of compound 3

[0845] To a mixture of compound 1 (300 mg, 1.89 mmol), compound 2 (477.32 g, 1.89 mmol), and K2CO3 (785 mg, 5.68 mmol) was added DMF (5 mL) and stirred at 100°C for 2 h. LCMS confirmed the reaction was complete. After completion, water (10 mL) was added, and the solid was filtered and washed with water. The filtrate was concentrated to afford compound 3 (410 mg, 1.049 mmol, 55.45% yield) as a white solid. ESI-MS: [M+H] + ,391.00.

[0846] 2) Synthesis steps of compound 4

[0847] To compound 3 (410 mg, 1.05 mmol) were added ammonium acetate solution (280.58 mg, 5.24 mmol, 5 mL), NaCN (77 mg, 1.57 mmol), aqueous ammonia (35% w / w; 5 mL), and ethanol (5 mL). The mixture was stirred at 50°C under nitrogen for 2.5 h. The mixture was then extracted with DCM (50 mL x 2). The combined organic phases were washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM:MeOH, 20 v:1 v to 10 v:1 v) to afford compound 4 (180 mg, 0.43 mmol, 42.3% yield) as a yellow solid. ESI-MS: [M+H] + ,417.00.

[0848] 3) Synthesis steps of compound 5

[0849] MeOH (5 mL) was added to a mixture of compound 4 (180 mg, 0.43 mmol) and NiCl₂.6H₂O (154 mg, 0.65 mmol). The mixture was reacted at 0°C under nitrogen for 5 minutes. Sodium borohydride (49 mg, 1.30 mmol) was then added in three portions, and the mixture was stirred at 0°C for 10 minutes. After the reaction, water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM:MeOH, 10 v:1 v to 8 v:1 v) to afford compound 5 (130 mg, 0.21 mmol, 48.47% yield) as a yellow solid. ESI-MS: [M+H] + ,421.10.

[0850] 4) Synthesis steps of compound GDI15-6919

[0851] Compound 5 (130 mg, 0.21 mmol, 1 eq) was added with HBr / AcOH (5 mL), and the mixture was stirred at 100°C for 5 h. LCMS confirmed the reaction was complete. After completion, the mixture was concentrated, and NaHCO₃ (35.2 mg, 0.42 mmol, 2 eq) was added dropwise. The mixture was filtered, concentrated under reduced pressure, and further purified by prep-HPLC (Gemini 5μm C₁₈ column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H₂O containing 0.1% TFA) to afford GDI15-6919 (12.42 mg, 14.57% yield) as a white solid. ESI-MS: [M+H] + ,407.05.

[0852] 1H 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).

[0853] Example 90: Preparation of compound GDI15-6926

[0854] 1) Synthesis steps of compound 8

[0855] Compound 4 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL). 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 sequentially at 20°C. The reaction mixture was stirred at 20°C for 1 hour under nitrogen protection. NaBH(OAc)3 (56.4 mg, 266 μmol, 1.3 eq) was then added to the reaction mixture. The reaction mixture was stirred at 20°C for 1 hour under nitrogen protection. The reaction was complete as determined by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The mixture was then purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 8 (70 mg, 139 μmol, 68.1% yield) as a white solid. ESI-MS: [M+H] + ,502.1.

[0856] 2) Synthesis steps of compound GDI15-6926

[0857] Compound 8 (70 mg, 139 μmol, 1 eq) was dissolved in NMP (1.4 mL). 1-Decanethiol (121 mg, 697 μmol, 5 eq) and KCO (38.5 mg, 279 μmol, 2 eq) were then added sequentially at 20°C. Under nitrogen, the mixture was allowed to react at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 8.0 min) to afford the target product GDI15-6926 (36.3 mg, 74.9 μmol, 53.8% yield) as a white solid. ESI-MS: [M+H]+, 488.1.

[0858] 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,3 H),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)

[0859] Example 91: Preparation of compound GDI15-6928

[0860] 1) Synthesis steps of compound 10

[0861] Compound 4 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL). 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 sequentially at 20°C. The mixture was stirred at 20°C for 1 hour under nitrogen protection. NaBH(OAc)3 (56.4 mg, 266 μmol, 1.3 eq) was then added to the reaction mixture. The reaction mixture was stirred at 20°C for 1 hour under nitrogen protection. The reaction was complete as determined by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, filtered under reduced pressure, and then dried. The mixture was purified by silica gel chromatography (EtOAc / MeOH, 1 / 1) to afford the target compound 8 (80 mg, 166 μmol, 81.1% yield) as a white solid. [M+H] + ,482.1.

[0862] 2) Synthesis steps of compound GDI15-6928

[0863] Compound 10 (80 mg, 166 μmol, 1 eq) was dissolved in NMP (1.6 mL). 1-Decanethiol (145 mg, 890 μmol, 5 eq) and K2CO3 (45.9 mg, 332 μmol, 2 eq) were then added sequentially at 20°C. Under nitrogen protection, the mixture was reacted at 140°C for 16 hours. LCMS analysis showed that the reaction was complete. The reaction solution was filtered and dried, and the product was analyzed by high-performance liquid chromatography (column: Waters Xbridge BEH C 18 Purification (using a 100x30mmx10μm column; mobile phase: [H₂O (10mM NH₄HCO₃)-ACN]; gradient: 20%-50% B over 8.0 min) afforded the desired product, GDI15-6928 (17.7 mg, 37.8 μmol, 22.8% yield), as a white solid. ESI-MS: [M+H]⁺, 468.1.

[0864] 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)

[0865] Example 92: Preparation of compound GDI15-6972

[0866] 1) Synthesis steps of compound 3

[0867] Compound 1 (50 mg, 128 μmol, 1 eq) was dissolved in DCM (1.0 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (35.3 mg, 166 μmol, 1.3 eq) was then added. The reaction was stirred at 20°C for 1 hour under nitrogen. The reaction was complete by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The mixture was then purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (40 mg, 77.5 μmol, 60.5% yield) as a white solid. ESI-MS: [M+H] + ,516.1.

[0868] 2) Synthesis steps of compound GDI15-6972

[0869] 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 K2CO3 (21.4 mg, 155 μmol, 2 eq) were added at 20 ° C. Under nitrogen protection, the reaction mixture was reacted at 140 ° C for 16 hours. LCMS detection showed that the reaction was complete. The reaction solution was filtered and dried, and the product was analyzed by high performance liquid chromatography (column: Waters Xbridge BEH C 18 Purification (using a 100x30mmx10μm column; mobile phase: [H₂O (10mM NH₄HCO₃)-ACN]; gradient: 15%-45% B over 8.0 min) afforded the desired product, GDI15-6972 (17.6 mg, 35.0 μmol, 45.2% yield), as a white solid. ESI-MS: [M+H]⁺, 502.1.

[0870] 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), 7.59-7.5 1(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)

[0871] Example 93: Preparation of compound GDI15-6927

[0872] 1) Synthesis steps of compound 12

[0873] Compound 4 (90 mg, 230 μmol, 1 eq) was dissolved in DCM (1.8 mL). 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 sequentially at 20°C. The reaction mixture was stirred at 20°C for 1 hour under nitrogen protection. NaBH(OAc)3 (63.4 mg, 299 μmol, 1.3 eq) was then added to the reaction mixture. The reaction mixture was stirred at 20°C for another 1 hour under nitrogen protection. The reaction was then determined to be complete by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The mixture was then purified on a silica gel plate (EtOAc / MeOH, 1 / 1) to afford the target compound 12 (90 mg, 174 μmol, 75.7% yield) as a white solid. ESI-MS: [M+H] + ,516.1.

[0874] 2) Synthesis steps of compound GDI15-6927

[0875] Compound 12 (90 mg, 174 μmol, 1 eq) was dissolved in NMP (1.8 mL). 1-Decanethiol (152 mg, 871 μmol, 5 eq) and KCO (48.2 mg, 348 μmol, 2 eq) were then added sequentially at 20°C. The mixture was allowed to react at 140°C for 16 hours under nitrogen protection, and the reaction was complete by LCMS. The reaction solution was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 20%-50% B over 8.0 min) to obtain the target product GDI15-6927 (25.6 mg, 51.0 μmol, 29.2% yield) as a white solid. ESI-MS: [M+H]+, 502.1.

[0876] 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), 7.55-7.4 7(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)

[0877] Example 94: Preparation of compound GDI15-7007

[0878] 1) Synthesis steps of compound 11

[0879] Compound 9 (50 mg, 132 μmol, 1 eq) was dissolved in DCM (2.0 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (35.3 mg, 166 μmol, 1.3 eq) was then added. The reaction mixture was stirred at 20°C for 3 hours under nitrogen, then heated to 40°C and stirred for 3 hours. The reaction was complete by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified on a silica gel plate (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.

[0880] 2) Synthesis steps of compound GDI15-7007

[0881] Compound 11 (55 mg, 107 μmol, 1 eq) was dissolved in NMP (1.5 mL) and subsequently added with 1-decanethiol (92.8 mg, 533 μmol, 5 eq) and K₂CO₃ (29.4 mg, 213 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and purified by HPLC (column: Waters Xbridge BEH C₁₈ 100*30 mm*10 μm; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 15%-45% B over 8.0 min) and silica gel chromatography (EtOAc / MeOH, 3 / 1) to afford the target product GDI15-7007 (3.0 mg, 5.85 μmol, 5.49% yield, 98% purity) as a white solid. ESI-MS: [M+H]+, 502.4.

[0882] 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)

[0883] Example 95: Preparation of compound GDI15-6998

[0884] 1) Synthesis steps of compound 3

[0885] 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 N₂ protection, 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. The reaction mixture was allowed to react at 20°C for 1 hour, and then NaBH(OAc)₃ (81.3 mg, 383 μmol, 3 eq) was added. The reaction mixture was allowed to react at 20°C for another 15 hours, and the reaction was complete as determined by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 1 / 1) to afford the target compound 3 (60 mg, 120 μmol, 93.8% yield) as a yellow oil. ESI-MS: [M+H] + ,500.1.

[0886] 2) Synthesis steps of compound GDI15-6998

[0887] Compound 3 (60 mg, 120 μmol, 1 eq) was dissolved in NMP (1.2 mL). KCO (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 allowed to react at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered, and the filtrate was transferred to a separate pipette. The product was purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 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.

[0888] 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)

[0889] Example 96: Preparation of compound GDI15-6999

[0890] 1) Synthesis steps of compound 5

[0891] 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 N₂ protection, KOAc (15.1 mg, 153 μmol, 1.2 eq) and AcOH (0.76 mg, 12.7 μmol, 0.1 eq) were added sequentially at 20°C. After reacting at 20°C for 1 hour, NaBH(OAc)₃ (81.3 mg, 383 μmol, 3 eq) was added. The reaction mixture was allowed to react at 20°C for another 15 hours, and the reaction was complete as determined by LCMS. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 1 / 1) to afford the target compound 5 (58 mg, 116 μmol, 90.6% yield) as a yellow oil. ESI-MS: [M+H] + ,500.1.

[0892] 2) Synthesis steps of compound GDI15-6999

[0893] Compound 5 (58 mg, 116 μmol, 1 eq) was dissolved in NMP (1.2 mL). Under N protection, KCO (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 allowed to react at 140°C for 16 hours, and the reaction was complete after LCMS analysis. The reaction mixture was filtered, and the filtrate was transferred to a separate pipette. The product was purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 8.0 min) to obtain the target compound GDI15-6999 (20.5 mg, 42.1 μmol, 36.2% yield, 99.7% purity) as a yellow solid. ESI-MS: [M+H] + ,486.0.

[0894] 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)

[0895] Example 97: Preparation of compound GDI15-7002

[0896] 1) Synthesis steps of compound 7

[0897] 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). Under N₂ protection, 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. After reacting at 20°C for 1 hour, NaBH(OAc)₃ (81.3 mg, 383 μmol, 3 eq) was added. The reaction mixture was allowed to react at 20°C for another 15 hours, and the reaction was complete as determined by LCMS. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / MeOH, 1 / 1) to afford the target compound 7 (55 mg, 110 μmol, 85.9% yield) as a yellow oil. ESI-MS: [M+H] + ,500.1.

[0898] 2) Synthesis steps of compound GDI15-7002

[0899] Compound 7 (55 mg, 110 μmol, 1 eq) was dissolved in NMP (1.1 mL). Under N protection, KCO (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 allowed to react at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered, and the filtrate was transferred to a separate pipette. The product was purified by HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 8.0 min) to obtain the target compound GDI15-7002 (11.2 mg, 23.1 μmol, 20.9% yield, 100% purity) as a yellow solid. ESI-MS: [M+H] + ,486.0.

[0900] 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)

[0901] Example 98: Preparation of compound GDI15-7000

[0902] 1) Synthesis steps of compound 3

[0903] Compound 1 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (2.0 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (56.4 mg, 266 μmol, 1.3 eq) was then added. The reaction was stirred at 20°C for 1 hour under nitrogen. LCMS confirmed the reaction was complete. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL*3). The organic phases were combined, concentrated under reduced pressure, and purified on a silica gel plate (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.

[0904] 2) Synthesis steps of compound GDI15-7000

[0905] Compound 3 (70 mg, 144 μmol, 1 eq) was dissolved in NMP (1.4 mL) and subsequently added with 1-decanethiol (126 mg, 720 μmol, 5 eq) and KCO (39.8 mg, 288 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 1%-30% B over 8.0 min)-ACN; gradient: 15%-45% B over 8.0 min) to afford the target product, GDI15-7000 (36 mg, 76.3 μmol, 53.0% yield), as a white solid. ESI-MS: [M+H]+, 472.1.

[0906] 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),7.52( 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)

[0907] Example 99: Preparation of compound GDI15-7005

[0908] 1) Synthesis steps of compound 3

[0909] Compound 1 (50 mg, 128 μmol, 1 eq) was dissolved in DCM (1.0 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (35.3 mg, 166 μmol, 1.3 eq) was then added. The reaction was stirred at 20°C for 1 hour under nitrogen. The reaction was complete by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The mixture was then purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 3 (40 mg, 82.3 μmol, 64.3% yield) as a white solid. ESI-MS: [M+H]+ ,486.2.

[0910] 2) Synthesis steps of compound GDI15-7005

[0911] Compound 3 (40 mg, 82.3 μmol, 1 eq) was dissolved in NMP (1.0 mL) and subsequently added with 1-decanethiol (71.8 mg, 412 μmol, 5 eq) and KCO (22.8 mg, 165 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 5%-35% B over 8.0 min) to afford the desired product, GDI15-7005 (6 mg, 12.7 μmol, 15.5% yield), as a white solid. ESI-MS: [M+H]+, 472.1.

[0912] 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)

[0913] Example 100: Preparation of compound GDI15-6997

[0914] 1) Synthesis steps of compound 4

[0915] Compound 3 (50 mg, 132 μmol, 1 eq) was dissolved in DCM (2.0 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (36.5 mg, 172 μmol, 1.3 eq) was then added. The reaction was stirred at 20°C under nitrogen for 16 hours. The reaction was complete by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 4 (34 mg, 61.4 μmol, 46.4% yield, 87% purity) as a yellow solid. ESI-MS: [M+H] + ,482.1.

[0916] 2) Synthesis steps of compound GDI15-6997

[0917] Compound 4 (34 mg, 70.5 μmol, 1 eq) was dissolved in NMP (1 mL) and subsequently added with 1-decanethiol (61.5 mg, 353 μmol, 5 eq) and K₂CO₃ (19.5 mg, 141 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C₁₈ 100*30 mm*10 μm; mobile phase: [H₂O(10 mM NH₄HCO₃)-ACN]; gradient: 20%-55% B over 8.0 min) to afford the target product GDI15-6997 (9.4 mg, 19.4 μmol, 27.5% yield, 96.4% purity) as a yellow solid. ESI-MS: [M+H] + ,468.0.

[0918] 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)

[0919] Example 101: Preparation of compound GDI15-7068

[0920] 1) Synthesis steps of compound 3

[0921] Compound 1 (100 mg, 0.26 mmol) and triethylamine (40.18 mg, 0.40 mmol) were dissolved in MeOH (2 mL) and stirred at room temperature under nitrogen for 30 minutes. Compound 2 (37.21 mg, 0.26 mmol) and acetic acid (0.05 mL) were then added. The reaction continued at room temperature for 1 hour. NaBH3CN (33.27 mg, 0.53 mmol) was then added dropwise. After the addition was complete, the reaction was stirred at room temperature for 1.5 hours. After the reaction, water (5 mL) was added and the mixture was extracted with EtOAc (15 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM:MeOH, 20:1 to 10:1) to afford compound 3 (55 mg, 40.23% yield) as a yellow solid. ESI-MS: [M+H] + ,392.05.

[0922] 2) Synthesis steps of compound GDI15-7068

[0923] 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 under nitrogen for 8 h. After completion of the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% aqueous ammonia) to afford compound GDI15-7068 (7 mg, 17.94% yield) as a yellow solid. ESI-MS: [M+H] + ,502.05.

[0924] 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).

[0925] Example 102: Preparation of compound GDI15-6995

[0926] 1) Synthesis steps of compound 3

[0927] Compound 1 (50 mg, 128 μmol, 1 eq) was dissolved in DCM (1.0 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (35.3 mg, 166 μmol, 1.3 eq) was then added. The reaction was stirred at 20°C for 1 hour under nitrogen. The reaction was complete by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the title compound 3 (30 mg, 62.1 μmol, 48.6% yield) as a white solid. ESI-MS: [M+H]+, 483.2.

[0928] 2) Synthesis steps of compound GDI15-6995

[0929] Compound 3 (30 mg, 62.1 μmol, 1 eq) was dissolved in NMP (1.0 mL) and subsequently added with 1-decanethiol (54.2 mg, 311 μmol, 5 eq) and KCO (17.2 mg, 124 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 10%-45% B over 8.0 min) to afford the target product GDI15-6995 (19.1 mg, 40.7 μmol, 65.6% yield) as a white solid. ESI-MS: [M+H] + ,469.1.

[0930] 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),7.60- 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)

[0931] Example 103: Preparation of compound GDI15-7003

[0932] 1) Synthesis steps of compound 3

[0933] Compound 1 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (56.4 mg, 266 μmol, 1.3 eq) was then added. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. The reaction was complete as determined by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified on a silica gel plate (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.

[0934] 2) Synthesis steps of compound GDI15-7003

[0935] Compound 3 (70 mg, 145 μmol, 1 eq) was dissolved in NMP (1.4 mL) and subsequently added with 1-decanethiol (126 mg, 725 μmol, 5 eq) and KCO (40.1 mg, 290 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15%-45% B over 8.0 min) to afford the target product GDI15-7003 (34.6 mg, 74.8 μmol, 50.9% yield) as a white solid. ESI-MS: [M+H] + ,469.1.

[0936] 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)

[0937] Example 104: Preparation of compound GDI15-7001

[0938] 1) Synthesis steps of compound 3

[0939] Compound 1 (80 mg, 205 μmol, 1 eq) was dissolved in DCM (1.6 mL). 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 sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 20°C for 1 hour. NaBH(OAc)3 (56.4 mg, 266 μmol, 1.3 eq) was then added. The reaction was stirred at 20°C for 1 hour under nitrogen. The reaction was complete by LCMS. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the title compound 3 (70 mg, 145 μmol, 70.8% yield) as a white solid. ESI-MS: [M+H]+, 483.2.

[0940] 2) Synthesis steps of compound GDI15-7001

[0941] Compound 3 (70 mg, 145 μmol, 1 eq) was dissolved in NMP (1.4 mL) and subsequently added with 1-decanethiol (126 mg, 725 μmol, 5 eq) and KCO (40.1 mg, 290 μmol, 2 eq) at 20°C. Under nitrogen, the reaction mixture was incubated at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 5%-35% B over 8.0 min) to afford the target product GDI15-7001 (33.8 mg, 72.1 μmol, 49.7% yield) as a white solid. ESI-MS: [M+H]+, 469.1.

[0942] 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), 7.7 3-7.56(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)

[0943] Example 105: Preparation of compound GDI15-6988

[0944] 1) Synthesis steps of compound 3

[0945] To a mixture of compound 1 (700 mg, 4 mmol), compound 2 (1 g, 4 mmol), and K2CO3 (1.66 g, 12 mmol) was added DMF (10 mL). The mixture was stirred at 60°C under nitrogen for 3 hours. LCMS confirmed the reaction was complete. After the reaction, water (20 mL) was added, the mixture was filtered, and washed with water. The filtrate was dried to give the crude product, compound 3 (850 mg, 2.08 mmol, 52.21% yield), as a yellow solid. ESI-MS: [M+H] + ,407.95

[0946] 2) Synthesis steps of compound 4

[0947] A mixture of EtOH (10 mL) and H₂O (2 mL) was added to compound 3 (850 mg, 2.08 mmol), Fe (349 mg, 6.25 mmol), and NH₄Cl (557 mg, 10.42 mmol). The mixture was allowed to react at 50°C under nitrogen for 6 h. LCMS confirmed the reaction was complete. The reaction solution was filtered, concentrated, and purified by column chromatography (DCM / MeOH, 20 / 1 to 10 / 1) to afford compound 4 (610 mg, 1.61 mmol, 77.46% yield) as a yellow solid. ESI-MS: [M+H] + ,378.05

[0948] 3) Synthesis steps of compound GDI15-6988

[0949] Compound 4 (110 mg, 0.29 mmol), PPTS (366 mg, 1.46 mmol), and LiCl (62 mg, 1.46 mmol) were added with NMP (5 mL). The reaction was stirred at 150°C under nitrogen for 2 hours. LCMS confirmed the reaction was complete. After completion, the system was concentrated and further purified by prep-HPLC (Gemini 5μm C18 column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% NH3 / H2O) to afford compound GDI15-6988 (41.99 mg, 39.64% yield) as a white solid. ESI-MS: [M+H] + ,364.00.

[0950] 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).

[0951] Example 106: Preparation of compound GDI15-7800

[0952] 1) Synthesis steps of compound 2

[0953] MeOH (4 mL) was added to a mixture of compound 1 (200 mg, 0.52 mmol) and NiCl2.6H2O (294.18 mg, 1.24 mmol). The mixture was reacted at 0°C under nitrogen for 10 min. NaBH4 (93.57 mg, 2.48 mmol) was then slowly added. The reaction was continued at 0°C for 20 min. Boc2O (900.39 mg, 4.13 mmol) was then added dropwise. The mixture was slowly warmed to room temperature and reacted at room temperature for 1 h. The mixture was concentrated and further purified by column chromatography (EtOAc / PE, 50% to 80%). A 4M solution of HCl in MeOH (4 mL) was added to the resulting compound, and the reaction was continued at room temperature under nitrogen for 30 min. The mixture was concentrated and dried to give compound 2 (100 mg, 30.93% yield) as a gray-green solid. ESI-MS: [M+H] + ,491.95.

[0954] 2) Synthesis steps of compound 3

[0955] 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). The reaction was stirred at room temperature under nitrogen for 16 hours. After the reaction, water (2 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM / MeOH, 10:1) to afford compound 3 (22 mg, 20.54% yield) as a white solid. ESI-MS: [M+H] + ,420.10.

[0956] 3) Synthesis steps of compound GDI15-7800

[0957] A solution of HBr in AcOH (1 mL) was added to compound 3 (20 mg, 0.0476 mmol), and the reaction was stirred at 100°C under nitrogen for 16 hours. After completion of the reaction, the mixture was concentrated in vacuo and further purified by prep-HPLC (Gemini 5μm C18 column, 150x21.2 mm, eluent: 30% to 90% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-7800 (2 mg, 10.29%) as a white solid. ESI-MS: [M+H] + ,406.10.

[0958] 1H 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).

[0959] Example 107: Preparation of compound GDI15-6799

[0960] 1) Synthesis steps of compound 2

[0961] Compound 1 (500 mg, 1.29 mmol, 1 eq) was added to a HCl / MeOH (10 mL) mixture and stirred at 100°C under nitrogen for 5 h. LCMS confirmed the reaction was complete. After completion, the system was concentrated, and NaHCO₃ (217 mg, 2.58 mmol, 2 eq) was slowly added dropwise to the organic phase to quench the reaction. The system was then spin-dried and purified by column chromatography (PE:EtOAc, 1 v:1 v to 1 v:2 v) to afford compound 2 (420 mg, 1.0 mmol, 77.5% yield) as a yellow solid. ESI-MS: [M+H]⁺, 421.05.

[0962] 2) Synthesis steps of compound 3

[0963] Compound 2 (420 mg, 1.0 mmol) was added to THF (4 mL). The mixture was stirred at 0°C under nitrogen for 5 minutes. iAlH4 / THF (1N, 0.5 mL, 0.50 mmol) was then added in three portions. The reaction was continued at 0°C for 55 minutes. LCMS confirmed the reaction was complete. After completion, the reaction was quenched with NH4Cl / H2O (5 mL) and extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (DCM / MeOH, 20:1 to 10:1) to afford compound 3 (230 mg, 0.59 mmol, 58.67% yield) as a yellow solid. ESI-MS: [M+H]+, 393.10.

[0964] 3) Synthesis steps of compound 4

[0965] Compound 3 (230 mg, 0.59 mmol) was added with DCM (4 mL) and stirred at 0°C under nitrogen for 5 minutes. PBr3 (158.5 mg, 0.59 mmol) was then added in three portions. The system was allowed to react at 0°C for 25 minutes. LCMS confirmed the reaction was complete. After the reaction, water (10 mL) was added and the mixture was extracted with DCM (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to afford compound 4 (190 mg, 0.42 mmol, 71.2% yield) as a brown solid. ESI-MS: [M+H] + ,457.05.

[0966] 4) Synthesis steps of compound 5

[0967] Compound 4 (60 mg, 0.13 mmol) and pyrrole (28 mg, 0.40 mmol) were added with DCM (2 mL) and stirred at room temperature for 1 h. LCMS confirmed the reaction was complete. Water (10 mL) was then added to the system, and the mixture was extracted with DCM (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH, 15:1) to afford compound 6 (30 mg, 0.067 mmol, 51.10% yield) as a yellow solid. ESI-MS: [M+H] + ,446.10.

[0968] 5) Synthesis steps of compound GDI15-6799

[0969] Compound 6 (30 mg, 0.067 mmol, 1 eq) was added to a HBr / AcOH (2 mL) mixture and stirred at 110°C under nitrogen for 16 h. LCMS confirmed the reaction was complete. After completion, the system was concentrated, and the organic phase was gradually quenched with NaHCO₃ (11 mg, 0.13 mmol, 2 eq). The product was filtered, concentrated, and further purified by prep-HPLC (Gemini 5μm C₁₈ column, 150 x 21.2 mm, eluent: 30% to 90% MeCN / H₂O containing 0.1% TFA) to afford compound GDI15-6799 (4.18 mg, 14.41% yield) as a white solid. ESI-MS: [M+H] + ,432.15.

[0970] 1H 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).

[0971] Example 108: Preparation of compound GDI15-6675

[0972] 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). The mixture was stirred at 140°C under nitrogen for 2 h. LCMS confirmed the reaction was complete. Water (10 mL) was then added to the system and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to yield compound GDI15-6675 (10.20 mg, 22.9 μmol, 2.29% yield) as a white solid. ESI-MS: [M+H] + ,446.05.

[0973] 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).

[0974] Example 109: Preparation of compound GDI15-6780

[0975] 1) Synthesis steps of compound 3

[0976] 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 K2CO3 (22.1 g, 160 mmol, 2 eq) was added at 20°C. Under nitrogen, the reaction mixture was stirred at 60°C for 5 hours. LCMS confirmed the reaction was complete. Water (200 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (100 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried by spin drying. The target compound 3 (17 g, 65.2 mmol, 81.6% yield) was purified by column chromatography (SiO2, 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.

[0977] 2) Synthesis steps of compound 4

[0978] 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. LCMS confirmed the reaction was complete. Water (80 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. EtOAc (30 mL) was added to the residue, stirred at room temperature for 15 minutes, 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.

[0979] 3) Synthesis steps of compound 6

[0980] Compound 4 (10 g, 29.4 mmol, 1 eq) was dissolved in dioxane (200 mL) and H₂O (40 mL). Compound 5 (9.25 g, 44.2 mmol, 1.5 eq), Na₂CO₃ (7.8 g, 73.3 mmol, 2.5 eq), and Pd(dppf)Cl₂ (2.15 g, 2.94 mmol, 0.1 eq) were then added sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. Water (300 mL) was added to the reaction solution, which was then extracted with EtOAc (50 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The resulting mixture was purified by column chromatography (SiO₂, PE / EtOAc, 50 / 1 to 10 / 1) to afford the target compound 6 (7.4 g, 19.1 mmol, 32.4% yield) as a brown solid. [M+H]+ ,388.1.

[0981] 4) Synthesis steps of compound 7

[0982] Compound 6 (1 g, 2.58 mmol, 1 eq) was dissolved in MeOH (50 mL). NiCl.6H2O (6.13 g, 25.8 mmol, 10 eq) was then added at 0°C and stirred for 5 min. A LiBH4 / THF solution (12.9 mL, 25.8 mmol, 10 eq, 2 M) was then slowly added dropwise at 0°C. Under nitrogen, the reaction mixture was stirred at 0°C for 16 hours. LCMS analysis showed that the starting material was completely consumed. Boc2O (1.69 g, 7.74 mmol, 10 eq, 1.78 mL) was then added to the reaction mixture, and the mixture was allowed to react at 20°C for 1 hour. LCMS analysis showed that the reaction was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The mixture was purified by silica gel chromatography (PE / EtOAc, 0 / 1) to afford the target compound 7 (0.44 g, 894 μmol, 34.7% yield) as a brown solid. ESI-MS: [M+H] + ,492.2.

[0983] 5) Synthesis steps of compound 8

[0984] Compound 7 (0.44 g, 894 μmol, 1 eq) was dissolved in DCM (2 mL). HCl / dioxane (2 mL, 4 M) was then added at 20°C. The reaction mixture was stirred at 20°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was evaporated to dryness under reduced pressure to afford the target compound 8 (0.31 g, 667 μmol, 74.5% yield) as a yellow solid. ESI-MS: [M+H] + ,392.1.

[0985] 6) Synthesis steps of compound 9

[0986] Compound 8 (70 mg, 151 μmol, 1 eq) was dissolved in DCM (1.4 mL). TEA (45.7 mg, 452 μmol, 3 eq) and trifluoroacetic anhydride (41.1 mg, 196 μmol, 1.3 eq) were then added sequentially at 0°C. Under nitrogen protection, the reaction mixture was stirred at 0°C for 1 hour. LCMS detected the reaction completion. Water (2 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL*3). The organic phases were combined, filtered under reduced pressure, and dried. The target compound 9 (45 mg, 92.2 μmol, 61.2% yield) was obtained by silica gel plate purification (EtOAc / MeOH, 10 / 1) as a brown solid. ESI-MS: [M+H] + ,488.1.

[0987] 7) Synthesis steps of compound GDI15-6780

[0988] Compound 9 (30 mg, 61.5 μmol, 1 eq) was dissolved in NMP (3 mL). 1-Decanethiol (53.6 mg, 307 μmol, 5 eq) and K2CO3 (17 mg, 123 μmol, 2 eq) were then added sequentially at 20°C. Under nitrogen, the reaction mixture was stirred at 140°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered and dried, and then purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15%-55% B over 8.0 min) to afford the target product, GDI15-6780 (11.7 mg, 24.7 μmol, 40.2% yield), as a yellow solid. ESI-MS: [M+H] + ,474.1.

[0989] 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)

[0990] Example 110: Preparation of compound GDI15-6745

[0991] 1) Synthesis steps of compound 3

[0992] 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 K2CO3 (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. LCMS detected that the reaction was complete. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, filtered under reduced pressure and dried, and purified by column chromatography (SiO2, 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.

[0993] 2) Synthesis steps of compound 4

[0994] 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, the reaction was stirred at 20°C for 3 hours. LCMS confirmed the reaction was complete. Water (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried by evaporation. A mixed solvent of MTBE / EtOAc (5 / 1, 15 mL) was then added at 20°C. The mixture was stirred for 15 minutes, filtered, and the filter cake was dried under reduced pressure to yield the target compound 4 (20 g, 58.9 mmol, 90.3% yield) as a white solid. ESI-MS: [M+H]+, 338.9.

[0995] 3) Synthesis steps of compound 6

[0996] Compound 4 (10 g, 29.4 mmol, 1 eq) was dissolved in dioxane (200 mL) and H2O (40 mL). Compound 5 (9.25 g, 44.2 mmol, 1.5 eq), Na2CO3 (7.8 g, 73.3 mmol, 2.5 eq) and Pd(dppf)Cl2 (2.15 g, 2.94 mmol, 0.1 eq) were then added sequentially at 20°C. Under nitrogen protection, the mixture was reacted at 100°C for 16 hours. LCMS detection showed that the reaction was complete. 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 under reduced pressure and dried, and purified by column chromatography (SiO2, 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

[0997] 4) Synthesis steps of compound 6

[0998] Compound 6 (1 g, 2.58 mmol, 1 eq) was dissolved in MeOH (50 mL). NiCl.6H2O (6.13 g, 25.8 mmol, 10 eq) was then added at 0°C and stirred for 5 min. A LiBH4 / 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 was allowed to proceed at 0°C for 16 hours, and the reaction was complete as determined by LCMS. Boc2O (1.69 g, 7.74 mmol, 3 eq, 1.78 mL) was then added to the reaction solution, and the reaction was allowed to proceed at 20°C for 1 hour, and the reaction was complete as determined by LCMS. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried. The mixture was then purified by silica gel chromatography (PE / EtOAc, 0 / 1) to afford the target compound 7 (0.44 g, 894 μmol, 34.7% yield) as a brown solid. ESI-MS: [M+H] + ,492.2.

[0999] 5) Synthesis steps of compound 8

[1000] Compound 7 (0.44 g, 894 μmol, 1 eq) was dissolved in DCM (2 mL). HCl / dioxane (2 mL, 4 M) was then added at 20°C. The reaction was allowed to react at 20°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was evaporated to dryness under reduced pressure to afford the target compound 8 (0.31 g, 667 μmol, 74.5% yield) as a yellow solid. ESI-MS: [M+H] + ,392.1.

[1001] 6) Synthesis steps of compound 10

[1002] 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. Under nitrogen protection, the mixture was allowed to react at 0°C for 1 hour. LCMS confirmed the reaction was complete. Water (3 mL) was added to the reaction solution, which was then extracted with DCM (3 mL*3). The organic phases were combined, filtered under reduced pressure, and dried. The resulting mixture was then purified on a silica gel plate (EtOAc / MeOH, 10 / 1) to afford the target compound 10 (20 mg, 40.3 μmol, 34.5% yield) as a brown solid. ESI-MS: [M+H] + ,496.1.

[1003] 7) Synthesis steps of compound GDI15-6745

[1004] Compound 10 (20 mg, 40.3 μmol, 1 eq) was dissolved in NMP (1 mL). 1-Decanethiol (35.2 mg, 202 μmol, 5 eq) and K2CO3 (11.2 mg, 80.7 μmol, 2 eq) were then added sequentially at 20°C. The mixture was allowed to react at 140°C under nitrogen for 16 hours, and the reaction was complete by LCMS. The reaction solution was filtered and dried, and then purified by HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15%-55% B over 8.0 min) to afford the target product GDI15-6745 (7.8 mg, 16.2 μmol, 40.1% yield) as a white solid. ESI-MS: [M+H] + ,482.1.

[1005] 1H N...

Claims

1. 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, X 1 and X 2 One of them is N, and the other is N or CH; Y 1 and Y 2 At most one of them 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 Y 2 is a hydroxyl group or a carbonyl group, Y 1 With P 1 or P 3 and the carbon atom or nitrogen atom to which they are attached together form a C3-C6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a phenyl group, or a five-membered to six-membered heteroaryl group optionally substituted with halogen or C1-C3 alkyl group; P 1 and P 3 One of them is -L 1 -Z 1 -, the other is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl optionally substituted by halogen or cyano, or Y 1 and the carbon atom or nitrogen atom to which they are attached together form a C3-C6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a phenyl group, or a five-membered to six-membered heteroaryl group optionally substituted with halogen or C1-C3 alkyl group; P 2 For -L 2 -Z 2 -; L 1 is selected from a bond, -CH2-, -NH- or -O-; L 2 is selected from a bond or -CH2-; Z 1 for wherein the ring optionally has 1 or 2 N heteroatoms; Z 2 is selected from a five-membered to a ten-membered heteroaryl group, wherein optionally Z 2 One or more hydrogen atoms in are independently substituted by halogen, hydroxyl, cyano, sulfo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 1 , R 2 and R 5 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, C1-C6 alkyl or C1-C6 alkoxy, and optionally R 1 , R 2 and R 5 One or more hydrogen atoms in are independently substituted by halogen, hydroxyl, amino, C1-C6 alkyl or C3-C6 cycloalkyl; R 3 and R 4 One of them is H, and the other is selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, amide, carboxyl, C1-C6 alkyl, C3-C6 cycloalkyl, -O(CH2) n1 CR 6 R 7 R 8 、-NH(CH2) n1 R 10 、-O(CH2) n1 R 11 、-(CH2) n1 NH(CH2) n2 R 12 、-(CH2) n1 NHCOR 13 、-(CH2) n1 NHSO2R 14 or -(CH2) n1 R 15 , and optionally R 3 and R 4 One or more hydrogen atoms in are independently substituted by halogen, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or hydroxyl protecting group; R 6 and R 7 Selected from hydrogen, or together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 8 Selected from -NH2, -NHCOR 9 or -NHSO2R 9 , where R 9 Selected from C1-C6 alkyl or phenyl; R 10 , R 11 , R 12 , R 13 and R 14 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 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.

2. 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: When P 1 For -L 1 -Z 1 -When P 3 is selected from H or C1-C6 alkyl substituted by cyano, or 1 and the carbon atoms to which they are attached together form a phenyl group optionally substituted with halogen or C1-C3 alkyl; and When P 3 For -L 1 -Z 1 -When P 1 is selected from C1-C6 alkyl optionally substituted by halogen or cyano, preferably -CH2CN, -(CH2)2CN, -CF3 or -CH2CF3, or with Y 1 Together with the carbon atom or nitrogen atom to which they are attached, they form a pyridyl or hexahydropyridyl group which is optionally substituted by halogen or C1-C3 alkyl.

3. 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 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms, preferably, Z 2 is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazole or quinolinyl, wherein optionally Z 2 One or more hydrogen atoms in each of the groups are optionally substituted by halogen, hydroxy, cyano, methyl, ethyl, trifluoromethyl or methoxy.

4. 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 3 and R 4 One of them is H, and the other is selected from any one of the following groups:

5. 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 Selected from tetrahydropyrrolyl, hexahydropyridinyl, morpholinyl or thiomorpholinyl.

6. 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; C1-C6 alkyl is selected from methyl, ethyl, propyl or isopropyl; C1-C6 haloalkyl is selected from monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl or trichloromethyl; C1-C6 alkoxy is selected from methoxy, ethoxy or propoxy; C1-C6 haloalkoxy is selected from trifluoromethoxy or trifluoroethoxy; and / or The C3-C6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

7. A 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, having any one of the following structures:

8. 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.

9. The pharmaceutical composition according to claim 8, wherein the dosage form is selected from the group consisting of tablets, granules, powders, syrups, inhalants and injections.

10. 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 for use in the preparation of a medicament for use in a subject in need thereof for treating or preventing a coronavirus infection or a disease or symptom caused by a coronavirus.

11. The method of claim 10, wherein the coronavirus is selected from the group consisting of 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 a coronavirus having a homology greater than 85% with any of the above coronaviruses and having viral activity.

12. The method of 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.

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