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

Abstract

The present application relates to a 3CL protease inhibitor for treating or preventing coronavirus infections 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 infections or diseases or symptoms caused by 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. 202311156881.1 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] Y 1 and Y 2 are each independently selected from hydrogen, halogen, cyano, amino, C1-C6 alkylamino or C1-C6 alkyl optionally substituted with halogen or cyano; or Y 1 and Y 2 together to form a carbonyl group; or Y 1 and Y 2and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or three- to six-membered heterocycloalkyl group optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino;

[0009] Y 3 and Y 4 are each independently selected from hydrogen, halogen, cyano, amino, C1-C6 alkylamino or C1-C6 alkyl optionally substituted with halogen or cyano; or Y 3 and Y 4 together to form a carbonyl group; or Y 3 and Y 4 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or three- to six-membered heterocycloalkyl group optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino;

[0010] Y 5 and Y 6 are each independently selected from hydrogen, halogen, cyano, amino, C1-C6 alkylamino or C1-C6 alkyl optionally substituted with halogen or cyano; or Y 5 and Y 6 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or three- to six-membered heterocycloalkyl group optionally substituted with halogen, hydroxy, keto, -OMs, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, or C1-C3 alkylamino; and

[0011] Optionally, Y 5 and Y 6 One of them and Y 1 、Y 2 、Y 3 and Y 4 One of them and the carbon atom to which they are attached together form a C3-C6 cycloalkyl or phenyl group optionally substituted with halogen or C1-C3 alkyl;

[0012] Furthermore, P 1 -L 1 -Z 1 -;P 2 -L 2 -Z 2 -;L 1 is selected from a bond, -CH2-, -NH- or -O-; L 2 is selected from a bond or -CH2-;

[0013] Z 1 for wherein the ring optionally has 1 or 2 N heteroatoms;

[0014] Z 2 is selected from a five-membered to ten-membered heteroaryl group, wherein optionally Z 2 One or more hydrogen atoms are independently substituted by halogen, hydroxyl, cyano, C2-C6 ester, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0015] 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;

[0016] 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 are independently substituted by halogen, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or hydroxy protecting group;

[0017] 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;

[0018] R 8Selected from -NH2, -NHCOR 9 or -NHSO2R 9 , where R 9 Selected from C1-C6 alkyl or phenyl;

[0019] R 10 、R 11 、R 12 、R 13 and R 14 Each is independently selected from hydrogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, three-membered to six-membered heterocycloalkyl, phenyl or five-membered to six-membered heteroaryl;

[0020] R 15 is selected from a three- to seven-membered heterocycloalkyl group containing at least one nitrogen atom; and

[0021] n1 and n2 are selected from 0, 1, 2 or 3.

[0022] In a preferred embodiment of the present invention,

[0023] Y 1 and Y 2 Together they form a carbonyl group;

[0024] Y 3 and Y 4 are each independently selected from hydrogen, halogen, cyano or C1-C6 alkyl optionally substituted by halogen or cyano; or Y 3 and Y 4 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or three- to six-membered heterocycloalkyl group optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino;

[0025] Y 5 and Y 6 are each independently selected from hydrogen, halogen, cyano or C1-C6 alkyl optionally substituted by halogen or cyano; or Y 5 and Y 6 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or a three- to six-membered heterocycloalkyl optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino; and optionally,

[0026] Y 5 and Y 6 One of them and Y 3 and Y 4One of them and the carbon atom to which they are attached together form a C3-C6 cycloalkyl or phenyl group optionally substituted with halogen or C1-C3 alkyl; and

[0027] Preferably, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 The total number of loops formed is no more than one.

[0028] 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.

[0029] 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:

[0030] In another preferred embodiment of the present invention, R 15 It may be selected from tetrahydropyrrolyl, hexahydropyridinyl, morpholinyl or thiomorpholinyl.

[0031] 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.

[0032] 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 any one of the following structures:

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C. 13 C and 14 C, isotopes of chlorine, such as 37 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O. 17 O and 18 O, and isotopes of sulfur such as35 S.

[0039] 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.

[0040] 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).

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] "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.

[0047] "Metabolites" refer to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

[0048] 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.

[0049] 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.

[0050] As used herein, the term "each independently" means that when there are more than one substituent, the substituents may be the same or different.

[0051] 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.

[0052] 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).

[0053] 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 "C1-C3 alkyl" and "C1-C4 alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0054] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from O, S, and N. For example, 5-7 membered heteroaryl 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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 conventional 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 conventional preparation, a sustained-release preparation, a controlled-release preparation, a targeted preparation and various microparticle delivery systems.

[0061] In some embodiments, the dosage form of the pharmaceutical composition is selected from tablets, granules, powders, syrups, inhalants and injections.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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).

[0073] 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.

[0074] 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.

[0075] 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.

[0076] "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.

[0077] 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.).

[0078] 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.

[0079] 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

[0080] 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.

[0081] 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.

[0082] Example 1: Preparation of compound GDI15-7099

[0083] 1) Synthesis steps of compound 3

[0084] Under nitrogen at 0°C, DIPEA (3.59 g, 27.8 mmol) and T3P (8.85 g, 27.8 mmol) were slowly added to a DMF (10 mL) solution of compound 1 (2 g, 13.9 mmol) and compound 2 (1.27 g, 0.14.0 mmol). The mixture was allowed to react at room temperature for 1 hour. After the reaction, water (100 mL) was added 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 (MeOH / DCM, 5% to 10%) to afford compound 3 (2 g, 72.66% yield) as a yellow solid. ESI-MS: [M+H] + ,198.9.

[0085] 2) Synthesis steps of compound 5

[0086] Compound 4 (2.6 g, 20.18 mmol) was added to a solution of compound 3 (2.0 g, 10.09 mmol) in EtOH (5 mL), and the mixture was reacted at 80°C for 12 h. After the reaction, water (50 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 column chromatography (MeOH / DCM, 9% to 10%) to afford compound 5 (1.6 g, 48.67% yield) as a brown oil. ESI-MS: [M+H] + ,326.0.

[0087] 3) Synthesis steps of compound GDI15-7099

[0088] Toluene (5 mL) was added to a mixture of compound 5 (500 mg, 1.53 mmol) and CDI (497.67 mg, 3.07 mmol). The mixture was heated to 100°C under nitrogen and allowed to react for 3 h. After completion of the reaction, the system was cooled to room temperature, filtered, and the filtrate was concentrated. Water was then added to the concentrate and extracted with EtOAc. 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 GDI15-7099 (38.21 mg) as a white solid. ESI-MS: [M+H] + ,352.0.

[0089] 1H NMR (400MHz, DMSO) δ9.41(s,1H),8.49(s,1H),8.26(d,J=8.2Hz,1H),7.99(d,J=8.3Hz,1H),7.86(t,J=7.6Hz,1H),7.77(t,J=7.5Hz,1H),7.56 (d,J=1.5Hz,1H),7.43(dd,J=15.8,7.1Hz,2H),7.34(d,J=7.7Hz,1H),4.15(d,J=5.6Hz,2H),3.26(dd,J=15.6,7.5Hz,1H),3.15-3.04(m,1H).

[0090] Example 2: Preparation of compound GDI15-7245

[0091] 1) Synthesis steps of compound 3

[0092] To a solution of compound 1 (4.0 g, 27.74 mmol) in DMF (40 mL) at room temperature under nitrogen was added compound 2 (2.0 g, 27.74 mmol), T3P (17.65 g, 27.74 mmol, 50% wt), and DIPEA (10.76 g, 83.23 mmol). The reaction was then continued at room temperature for 3 hours. After completion of the reaction, water (10 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 (PE / EtOAc, 10% to 20%) to afford compound 3 (2.2 g, 40.0% yield) as a white solid. ESI-MS: [M+H] + ,198.95.

[0093] 2) Synthesis steps of compound 4

[0094] Under nitrogen at room temperature, compound 7 (1.63 g, 6.97 mmol) and K2CO3 (2.89 g, 20.90 mmol) were added to a solution of compound 6 (1.0 g, 6.97 mmol) in DMF (10 mL). The reaction was then incubated at 50°C for 16 h. After completion of the reaction, water (5 mL) was added to the system, 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 column chromatography (PE / EtOAc, 10:1) to afford compound 4 (1.0 g, 57.02% yield) as a colorless oil. ESI-MS: [M+H] + ,226.00.

[0095] 3) Synthesis steps of compound 5

[0096] Compound 3 (699.80 mg, 3.53 mmol) was added to a solution of compound 2 (400 mg, 1.77 mmol) in AcOH (4 mL) at room temperature under nitrogen protection. The mixture was reacted at 110°C for 5 h. 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 dried by column chromatography (DCM / MeOH, 20:1) to afford compound 5 (170 mg, 20.40% yield) as a white solid. ESI-MS: [M+H] + ,424.00.

[0097] 3) Synthesis steps of compound GDI15-7245

[0098] To a mixture of compound 5 (150 mg, 0.35 mmol) and CDI (343.51 mg, 2.12 mmol) was added toluene (2 mL) and reacted at 110°C for 3 h. After completion of the reaction, the system was concentrated in vacuo and further purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% NH4OH) to afford compound GDI15-7245 (30.14 mg, 18.89% yield) as a white solid. ESI-MS: [M+H] + ,450.10.

[0099] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.45(s,1H),8.23(d,J=8.2Hz,1H),7.95(d,J=8.2Hz,1H),7.84(t,J=7.5Hz,1H),7.75(t ,J=7.2Hz,1H),7.25(s,1H),7.15(dd,J=5.9,1.8Hz,2H),4.85(m,2H),4.13(m,2H),3.25-3.21(m,1H),3.11-3.04(m,1H).

[0100] Example 3: Preparation of compound GDI15-7434

[0101] 1) Synthesis steps of compound 3

[0102] Compound 1 (1 g, 5.76 mmol, 1 eq) was dissolved in MeCN (10 mL). K2CO3 (1.19 g, 8.63 mmol, 1.5 eq) and compound 2 (933 mg, 6.91 mmol, 1.1 eq) were added sequentially at 20°C. The reaction mixture was allowed to react at 80°C for 16 hours. LCMS confirmed the reaction was complete. Water (20 mL) was added to the reaction solution, which was then extracted with EtOAc (20 mL x 3). The organic phases were combined and dried under reduced pressure to afford the target compound 3 (1.2 g, 5.27 mmol, 91.5% yield) as a brown oil. ESI-MS: [M+H] + ,228.0.

[0103] 2) Synthesis steps of compound 4

[0104] Compound 3 (1.2 g, 5.27 mmol, 1 eq) was dissolved in EtOH (24 mL) and H₂O (6 mL). NH₄Cl (1.69 g, 31.6 mmol, 6 eq) was added at 20°C. The temperature was then raised to 80°C, and iron powder (1.77 g, 31.6 mmol, 6 eq) was added portionwise at 80°C. The reaction mixture was allowed to react at 80°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered while hot and rinsed with hot ethanol. The organic phases were combined and dried under reduced pressure to afford the target compound 4 (0.9 g, 4.55 mmol, 86.4% yield) as a brown oil. ESI-MS: [M+H] + ,198.1.

[0105] 3) Synthesis steps of compound 6

[0106] Compound 4 (0.4 g, 2.02 mmol, 1 eq) was dissolved in AcOH (4 mL), and compound 5 (802 mg, 4.05 mmol, 2 eq) was added at 20°C. Under nitrogen, the reaction mixture was incubated at 110°C for 5 hours. LCMS confirmed the reaction was complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (8 mL x 3). The organic phases were combined, dried under reduced pressure, and purified by silica gel chromatography (DCM / MeOH, 20 / 1) to afford the target compound 6 (140 mg, 354 μmol, 17.5% yield) as a white solid. ESI-MS: [M+H] + ,396.1.

[0107] 4) Synthesis steps of compound GDI15-7434

[0108] Compound 6 (120 mg, 303 μmol, 1 eq) was dissolved in toluene (2.4 mL). CDI (295.9 mg, 1.82 mmol, 6 eq) was added at 20°C. The reaction mixture was incubated at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure and further purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 45%-75% B over 8.0 min) to yield the target compound GDI15-7434 (74.3 mg, 176 μmol, 58.1% yield) as a white solid. ESI-MS: [M+H] + ,422.1.

[0109] 1H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.45 (s, 1H), 8.23 ​​(d, J = 8.1Hz, 1H), 7.94 (d, J = 7.9Hz ,1H),7.84(dt,J=1.1,7.6Hz,1H),7.77-7.72(m,1H),7.11(t,J=1.8Hz,1H),7.01(t,J =2.0Hz,1H),6.93(t,J=2.0Hz,1H),4.16-4.06(m,2H),3.86(d,J=7.0Hz,2H),3.28-3. 19(m,1H),3.14-3.03(m,1H),1.25-1.16(m,1H),0.59-0.54(m,2H),0.34-0.30(m,2H).

[0110] Example 4: Preparation of compound GDI15-7521

[0111] Compound GDI15-7574 (30 mg, 81.6 μmol, 1 eq) and compound 8 (14.6 mg, 97.8 μmol, 11.0 μL, 1.2 eq) were dissolved in MeCN (1.5 mL). KCO (45.1 mg, 326 μmol, 4 eq) was added 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 purified by HPLC (column: Phenomenex Luna C18 100*30 mm*3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 25%-65% B over 8.0 min) to obtain the target compound GDI15-7521 (8.6 mg, 19.0 μmol, 23.3% yield, 96.4% purity) as a white solid. ESI-MS: [M+H] + ,436.1.

[0112] 1 H NMR (400MHz, DMSO) δ9.43(s,1H),8.52(s,1H),8.30(d,J=8.1Hz,1H),8.01(d,J=8.4Hz ,1H),7.90(dt,J=1.1,7.7Hz,1H),7.84-7.76(m,1H),7.18(t,J=1.7Hz,1H),7.08(t,J =1.9Hz,1H),7.01(t,J=2.0Hz,1H),4.22-4.13(m,2H),4.05(d,J=6.8Hz,2H),3.34-3. 24(m,1H),3.19-3.09(m,1H),2.80-2.71(m,1H),2.16-2.07(m,2H),2.01-1.85(m,4H)

[0113] Example 5: Preparation of compound GDI15-7522

[0114] Compound GDI15-7574 (30 mg, 81.6 μmol, 1 eq) and compound 8 (18.1 mg, 97.8 μmol, 1.2 eq) were dissolved in MeCN (1.5 mL). KCO (45.1 mg, 326 μmol, 4 eq) was added 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 solution was filtered, and the filtrate was purified by HPLC (column: Phenomenex Luna C18 100*30 mm*3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 25%-65% B over 8.0 min) to obtain the target compound GDI15-7522 (7.0 mg, 14.6 μmol, 17.9% yield, 98.2% purity) as a white solid. ESI-MS: [M+H] + ,472.1.

[0115] 1 H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.45 (s, 1H), 8.23 ​​(d, J = 8.1Hz, 1H), 7.94 (d, J =8.4Hz,1H),7.83(dt,J=1.0,7.6Hz,1H),7.77-7.69(m,1H),7.15(t,J=1.7Hz, 1H),7.03(t,J=1.9Hz,1H),6.97(t,J=2.0Hz,1H),4.16-4.05(m,4H),3.28-3.1 7(m,1H),3.12-3.03(m,1H),2.75-2.65(m,2H),2.61-2.54(m,1H),2.44(s,1H)

[0116] Example 6: Preparation of compound GDI15-7549

[0117] GDI15-7574 (30 mg, 81.6 μmol, 1 eq) and PPh3 (320 mg, 1.22 mmol, 15 eq) were dissolved in toluene (0.6 mL). Compound 1 (21.08 mg, 245 μmol, 23.4 μL, 3 eq) and DIAD (33.0 mg, 163 μmol, 31.6 μL, 2 eq) were added at 25°C. Under nitrogen, the reaction mixture was incubated at 100°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and then purified by HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 40%-70% B over 8.0 min) to obtain the target compound GDI15-7549 (9.2 mg, 21.1 μmol, 25.9% yield) as a white solid. ESI-MS: [M+H] + ,435.8.

[0118] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.45(s,1H),8.23(d,J=8.0Hz,1H),7.94(d,J =8.4Hz,1H),7.88-7.79(m,1H),7.77-7.72(m,1H),7.11(t,J=1.8Hz,1H),7.01( t,J=2.1Hz,1H),6.92(t,J=2.1Hz,1H),4.18-4.06(m,2H),3.79(s,2H),3.27-3. 20(m,1H),3.15-3.03(m,1H),1.16(s,3H),0.56-0.48(m,2H),0.44-0.35(m,2H)

[0119] Example 7: Preparation of compound GDI15-7546

[0120] 1) Synthesis steps of compound 2

[0121] GDI15-7574 (50 mg, 136 μmol, 1 eq) and compound 1 (68.0 mg, 272 μmol, 2 eq) were dissolved in MeCN (2 mL). KCO (75.2 mg, 544 μmol, 4 eq) was added at 25°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (petroleum ether / EtOAc, 1 / 2) to afford the target compound 2 (35 mg, 52.6 μmol, 38.7% yield, 78.4% purity) as a yellow oil. ESI-MS: [M+H] + ,536.8.

[0122] 2) Synthesis steps of compound GDI15-7546

[0123] Compound 2 (30 mg, 55.9 μmol, 1 eq) was dissolved in DCM (0.6 mL) and HCl / dioxane (0.6 mL, 4 M). The reaction mixture was allowed to react at 25°C for 1 hour, and the reaction was complete by LCMS. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.04% HCl)-ACN]; gradient: 1%-36% B over 8.0 min) to obtain the target compound GDI15-7546 (10.9 mg, 22.9 μmol, 41.0% yield, 99.5% purity, HCl) as a white solid. ESI-MS: [M+H] + ,436.8.

[0124] 1 H NMR(400MHz,DMSO)δ9.43(s,1H),8.51(d,J=6.8Hz,4H),8.28(d,J=8.4Hz,1H ),7.98(d,J=8.5Hz,1H),7.88(t,J=7.5Hz,1H),7.80-7.74(m,1H),7.20(t,J =1.6Hz,1H),7.08(t,J=2.1Hz,1H),6.99(t,J=1.9Hz,1H),4.16-4.08(m,4H) ,3.34-3.19(m,2H),3.15-3.04(m,1H),1.09-1.04(m,2H),0.96-0.89(m,2H).

[0125] Example 8: Preparation of compound GDI15-7547

[0126] Compound GDI15-7502 (90 mg, 167 μmol, 1 eq) was dissolved in DCM (0.45 mL) and HCl / dioxane (0.45 mL, 4 M). The reaction mixture was allowed to react 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: Phenomenex Luna C1875*30 mm*3 μm; mobile phase: [water (0.04% HCl)-ACN]; gradient: 1%-36% B over 8.0 min) to obtain the target compound GDI15-7547 (21 mg, 41.4 μmol, 24.7% yield, 93.4% purity, HCl) as a white solid. ESI-MS: [M+H] + ,437.2.

[0127] 1H NMR (400MHz, DMSO) δ9.55 (s, 1H), 9.16-8.96 (m, 2H), 8.59 (s, 1H), 8.35 (d, J = 8.1Hz, 1H), 8.06 (d,J=8.4Hz,1H),7.95(t,J=7.5Hz,1H),7.88-7.78(m,1H),7.18(t,J=1.8Hz,1H),7.09(t,J= 2.0Hz,1H),7.03(t,J=2.0Hz,1H),4.19(d,J=5.8Hz,2H),4.16-4.11(m,2H),4.09-4.02(m,3H ),3.80-3.75(m,2H),3.27(ddd,J=5.8,8.0,16.7Hz,1H),3.21-3.13(m,1H),3.13-3.04(m,1H)

[0128] Example 9: Preparation of compound GDI15-7502

[0129] Compound GDI15-7574 (20 mg, 54.3 μmol, 1 eq) and K2CO3 (11.2 mg, 81.5 μmol, 1.5 eq) were dissolved in MeCN (1 mL). Compound 8 (16.3 mg, 65.2 μmol, 1.2 eq) was added at 25°C. The reaction mixture was allowed to react at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was filtered, and the filtrate was purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 40%-75% B over 8.0 min) to obtain the target compound GDI15-7502 (5.5 mg, 10.2 μmol, 18.8% yield) as a white solid. ESI-MS: [M+H] + ,537.2.

[0130] 1 H NMR (400MHz, CDCl3) δ9.36 (s, 1H), 8.50 (s, 1H), 8.16 (d, J = 8.3Hz, 1H), 7.89-7.85 (m, 1H), 7.77-7.70 (m, 2H), 7.27 (s, 7H), 7.01 (s, 1H), 6.90 (s, 1H),6.83(s,1H),4.14(td,J=6.7,9.1Hz,2H),4.10-4.07(m,4H),3.77( dd,J=5.1,8.7Hz,2H),3.25-3.19(m,1H),2.97-2.91(m,1H),1.45(s,9H)

[0131] Example 10: Preparation of compound GDI15-7649

[0132] GDI15-7574 (110 mg, 299 μmol, 1 eq) was dissolved in toluene (2.2 mL). PPh3 (314 mg, 1.20 mmol, 4 eq) and compound 3 (314 mg, 1.20 mmol, 4 eq) were added at 25°C. DIAD (120 mg, 598 μmol, 116 μL, 2 eq) was then added dropwise under a nitrogen atmosphere. The reaction mixture was incubated at 100°C under a nitrogen atmosphere for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and then purified by silica gel plate separation (Petroleum ether / EtOAc, 1 / 2) to obtain GDI15-7649 (80 mg). 30 mg of the product was purified by HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 35%-70% B over 8.0 min) to obtain the target compound GDI15-7649 (15.9 mg, 34.4 μmol, 15.8% yield) as a white solid. ESI-MS: [M+H] + ,551.1.

[0133] 1H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.45 (s, 1H), 8.23 ​​(d, J = 8.0Hz, 1H), 7.94 ( d,J=8.3Hz,1H),7.83(t,J=7.4Hz,1H),7.78-7.72(m,1H),7.14(s,1H),7.0 5(d,J=14.4Hz,1H),6.99(s,1H),4.16-4.03(m,3H),3.98(dd,J=6.9,18.4H z,2H),3.29-3.20(m,3H),3.13-3.02(m,1H),2.03-1.77(m,4H),1.40(s,9H)

[0134] Example 11: Preparation of compound GDI15-7548

[0135] 1) Synthesis steps of compound 2

[0136] GDI15-7574 (200 mg, 544 μmol, 1 eq) and compound 1 (183 mg, 816 μmol, 1.5 eq) were dissolved in MeCN (4 mL). KCO (113 mg, 816 μmol, 1.5 eq) was added at 25°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (petroleum ether / EtOAc, 1 / 2) to afford the target compound 2 (160 mg, 219 μmol, 40.3% yield, 70% purity) as a yellow solid. ESI-MS: [M+H] + ,511.2.

[0137] 2) Synthesis steps of compound GDI15-7548

[0138] Compound 2 (160 mg, 313 μmol, 1 eq) was dissolved in DCM (0.8 mL) and HCl / dioxane (0.8 mL, 4 M). The reaction mixture was allowed to react at 25°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to yield a crude product (160 mg). A portion of the crude product, GDI15-7548 (60 mg), was purified by HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.04% HCl)-ACN]; gradient: 1%-36% B over 8.0 min) to yield the target compound, GDI15-7548 (21 mg, 46.4 μmol, 14.8% yield, 98.9% purity, HCl)) as a white solid. ESI-MS: [M+H] + ,437.2.

[0139] 1 H NMR(400MHz, DMSO)δ9.49(s,1H),8.55(s,1H),8.32(d,J=8.1Hz,1H),8.13(s,3H),8.03(d,J=8.5Hz,1H),7.96-7.89(m,1H),7.86-7.76(m,1H),7 .20(t,J=1.8Hz,1H),7.07(t,J=2.1Hz,1H),7.00(t,J=2.0Hz,1H),4.22( t,J=5.0Hz,2H),4.15-4.08(m,2H),3.31-3.18(m,3H),3.12-3.00(m,1H)

[0140] Example 12: Preparation of compound GDI15-7501

[0141] 1) Synthesis steps of compound 3

[0142] Compound 1 (1 g, 5.76 mmol, 1 eq) and K2CO3 (1.19 g, 8.64 mmol, 1.5 eq) were dissolved in CH3CN (20 mL), and compound 2 (1.42 g, 6.34 mmol, 1.1 eq) was added at 20°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was complete after LCMS analysis. The reaction solution was directly dried under reduced pressure and purified by column chromatography (SiO2, Petroleum ether / EtOAc, 10 / 1 to 5 / 1) to obtain the target compound 3 (1.2 g, 3.18 mmol, 55.2% yield, 84% purity) as a yellow solid. ESI-MS: [M+H] + ,317.0.

[0143] 2) Synthesis steps of compound 4

[0144] Compound 3 (1.2 g, 3.79 mmol, 1 eq) was dissolved in DCM (6 mL) and HCl / dioxane (4 M, 6 mL) was added at 0°C. The reaction mixture was incubated at 25°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was then spin-dried to afford the target compound 4 (0.87 g, 3.44 mmol, 90.7% yield, HCl) as a white solid. ESI-MS: [M+H] + ,217.0.

[0145] 3) Synthesis steps of compound 5

[0146] Compound 4 (0.87 g, 3.44 mmol, 1 eq, HCl) was dissolved in DCM (10 mL). TEA (1.04 g, 10.3 mmol, 1.44 mL, 3 eq) and MsCl (0.390 g, 3.40 mmol, 264 μL, 1 eq) were added sequentially at 0°C. The reaction mixture was incubated at 0°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was poured into ice water (15 mL) and extracted with DCM (6 mL x 3). The organic phases were combined, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EtOAc, 20 / 1 to 10 / 1) to afford the target compound 5 (0.64 g, 2.06 mmol, 59.8% yield, 94.7% purity) as a white solid. ESI-MS: [M+H] + ,295.0.

[0147] 4) Synthesis steps of compound 6

[0148] Compound 5 (0.64 g, 2.17 mmol, 1 eq) was dissolved in EtOH (13 mL) and H₂O (3.2 mL). NH₄Cl (697 mg, 13.0 mmol, 6 eq) was added at 20°C. The mixture was heated to 80°C, and Fe powder (728 mg, 13.0 mmol, 6 eq) was added portionwise. The reaction mixture was reacted at 80°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered through celite while hot, and the filter cake was rinsed with hot EtOH (20 mL). The filtrate was concentrated under reduced pressure and dried by spin drying. The mixture was then purified by silica gel chromatography (Petroleum ether / EtOAc, 1 / 1) to afford compound 6 (0.5 g, 1.62 mmol, 74.8% yield, 86% purity) as a white solid. ESI-MS: [M+H] + ,265.1.

[0149] 5) Synthesis steps of compound 8

[0150] Compound 6 (0.45 g, 1.70 mmol, 1 eq) was dissolved in AcOH (1 mL) and compound 7 (674 mg, 3.40 mmol, 2 eq) was added at 25°C. The reaction mixture was reacted at 110°C for 5 hours, and the reaction was complete by LCMS. The reaction solution was evaporated to dryness under reduced pressure, and the concentrate was added to ice water (3 mL). The mixture was extracted with EtOAc (1 mL*3). The organic phases were combined, concentrated under reduced pressure, and evaporated to dryness. The target compound 8 (150 mg, 256 μmol, 15.1% yield, 79% purity) was obtained by silica gel plate purification (Petroleum ether / EtOAc, 0 / 1) as a yellow solid. ESI-MS: [M+H] + ,463.1.

[0151] 6) Synthesis steps of compound GDI15-7501

[0152] Compound 8 (0.15 g, 324 μmol, 1 eq) was dissolved in toluene (3 mL) and CDI (315 mg, 1.94 mmol, 6 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 5 hours. LCMS confirmed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure. Ice water (3 mL) was poured into the concentrate and extracted with EtOAc (1 mL x 3). The organic phases were combined, concentrated under reduced pressure, and evaporated to dryness. Compound GDI15-7501 (0.016 g, 31.1 μmol, 9.60% yield, 95.0% purity) was purified by silica gel plate separation (Ethyl acetate / MeOH, 10 / 1) and HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 21%-51% B over 8.0 min) as a white solid. ESI-MS: [M+H] + ,488.9.

[0153] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.45(s,1H),8.23(d,J=8.1Hz,1H),7.94(d,J=8.4H z,1H),7.83(dt,J=1.1,7.6Hz,1H),7.75(d,J=7.3Hz,1H),7.37-7.23(m,1H),7.15(t ,J=1.7Hz,1H),7.04(t,J=1.9Hz,1H),6.97(t,J=1.9Hz,1H),4.15-4.10(m,2H),4.07 (t,J=5.4Hz,2H),3.25(ddd,J=6.1,7.9,16.6Hz,3H),3.12-3.03(m,1H),2.94(s,3H)

[0154] Example 13: Preparation of compound GDI15-7611

[0155] GDI15-7574 (80 mg, 218 μmol, 1 eq) was dissolved in toluene (1.6 mL). PPh3 (114 mg, 436 μmol, 2 eq) and compound 3 (48.8 mg, 435 μmol, 2 eq) were added at 25°C. DIAD (87.9 mg, 435 μmol, 84.3 μL, 2 eq) was then added dropwise under a nitrogen atmosphere. The reaction mixture was incubated at 100°C under a nitrogen atmosphere for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (Petroleum ether / EtOAc, 1 / 2) and high-performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-60% B over 8.0 min) to obtain the target compound GDI15-7611 (15.9 mg, 34.4 μmol, 15.8% yield) as a white solid. ESI-MS: [M+H] + ,462.0.

[0156] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.45(s,1H),8.23(d,J=8.1Hz,1H),7.94(d,J=8.4Hz,1H),7.83(dt,J=1.1,7.7Hz,1H),7.78(s,2H),7.49 (s,1H),7.12(t,J=1.8Hz,1H),7.06(t,J=2.0Hz,1H),7.01(t,J=2.1Hz,1H),4.99(s,2H),4.22-4.05(m,2H),3.80(s,3H),3.24-3.05(m,2H)

[0157] Example 14: Preparation of compound GDI15-7612

[0158] GDI15-7574 (80 mg, 218 μmol, 1 eq) was dissolved in toluene (1.6 mL). PPh3 (114 mg, 436 μmol, 2 eq) and compound 2 (48.8 mg, 435 μmol, 2 eq) were added sequentially at 25°C. DIAD (87.9 mg, 435 μmol, 84.3 μL, 2 eq) was then added dropwise under a nitrogen atmosphere. The reaction mixture was incubated at 100°C under a nitrogen atmosphere for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and then purified by silica gel plate separation (Petroleum ether / EtOAc, 1 / 2) and high-performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-60% B over 8.0 min) to obtain the target compound GDI15-7612 (33.4 mg, 71.9 μmol, 33.1% yield, 99.5% purity) as a white solid. ESI-MS: [M+H] + ,462.1.

[0159] 1 H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.45 (s, 1H), 8.23 ​​(d, J = 8.1Hz, 1H), 7.94 (d, J = 8 .4Hz,1H),7.83(ddd,J=1.2,7.0,8.3Hz,1H),7.74(dt,J=1.0,7.5Hz,1H),7.66(d ,J=2.1Hz,1H),7.15-7.11(m,1H),7.09(t,J=2.1Hz,1H),7.06-7.00(m,1H),6.30 (d,J=2.3Hz,1H),5.04(s,2H),4.16-4.04(m,2H),3.81(s,3H),3.25-3.04(m,2H)

[0160] Example 15: Preparation of compound GDI15-7613

[0161] GDI15-7574 (80 mg, 218 μmol, 1 eq) was dissolved in toluene (1.6 mL). PPh3 (114 mg, 436 μmol, 2 eq) and compound 1 (71.2 mg, 652 μmol, 3 eq) were added sequentially at 25°C. DIAD (87.9 mg, 435 μmol, 84.3 μL, 2 eq) was then added dropwise under a nitrogen atmosphere. The reaction mixture was incubated at 100°C under a nitrogen atmosphere for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (Petroleum ether / EtOAc, 1 / 2) and high-performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-60% B over 8.0 min) to obtain the target compound GDI15-7613 (36.6 mg, 79.8 μmol, 36.7% yield) as a white solid. ESI-MS: [M+H] + ,459.1.

[0162] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.59(d,J=5.8Hz,2H),8.45(s,1H),8.23(d,J=8.1Hz,1H),7.94(d,J=8.4Hz,1H),7.83(dt,J=1.1,7.6Hz,1H),7.79- 7.69(m,1H),7.44(d,J=5.8Hz,2H),7.20-7.16(m,1H),7.14(t,J=2.0Hz,1H ),7.06(t,J=2.0Hz,1H),5.23(s,2H),4.21-4.02(m,2H),3.23-3.00(m,2H)

[0163] Example 16: Preparation of compound GDI15-7520

[0164] 1) Synthesis steps of compound 3

[0165] Compound 1 (400 mg, 2.30 mmol, 1 eq) and compound 2 (691 mg, 2.77 mmol, 1.2 eq) were dissolved in MeCN (8 mL), and K2CO3 (477 mg, 3.46 mmol, 1.5 eq) was added at 25°C. The reaction mixture was reacted at 80°C for 16 hours, and the reaction was complete by LCMS. The reaction solution was poured into water (50 mL) and extracted with EtOAc (20 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (Petroleum ether / EtOAc, 1 / 1) to obtain the target compound 3 (480 mg, 1.40 mmol, 60.7% yield) as a yellow oil. ESI-MS: [M+H] + ,343.2.

[0166] 2) Synthesis steps of compound 5

[0167] Compound 3 (480 mg, 1.40 mmol, 1 eq) was dissolved in DCM (8 mL) and TFA (2 mL). The reaction mixture was allowed to react at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford the target compound 5 (660 mg, TFA, crude) as a yellow oil. ESI-MS: [M+H] + ,357.2.

[0168] 3) Synthesis steps of compound 7

[0169] Compound 5 (0.66 g, 2.72 mmol, 1 eq) was dissolved in DCM (13 mL). TEA (550 mg, 5.44 mmol, 757 μL, 2 eq) and compound 6 (458 mg, 3.26 mmol, 378 μL, 1.2 eq) were slowly added at 0°C. The reaction mixture was allowed to react at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was poured into ice water (30 mL) and extracted with DCM (10 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (Petroleum ether / EtOAc, 0 / 1) to afford the target compound 7 (350 mg, 1.01 mmol, 37.1% yield) as a yellow oil. ESI-MS: [M+H] + ,347.2.

[0170] 4) Synthesis steps of compound 8

[0171] Compound 7 (350 mg, 1.01 mmol, 1 eq) and NH4Cl (323 mg, 6.06 mmol, 6 eq) were dissolved in EtOH (3.5 mL) and H2O (1.1 mL). Fe (338 mg, 6.06 mmol, 6 eq) was added portionwise at 80°C. The reaction mixture was stirred at 80°C for 2 hours. LCMS confirmed the reaction was complete. Celite was added and filtered while hot. The filter cake was rinsed with hot ethanol (200 mL). The filtrate was filtered under reduced pressure and dried. The target compound 8 (300 mg, 947 μmol, 93.8% yield) was purified by silica gel chromatography (Petroleum ether / EtOAc, 5 / 1) to obtain the target compound 8 (300 mg, 947 μmol, 93.8% yield) as a yellow oil. ESI-MS: [M+H] + ,317.2.

[0172] 5) Synthesis steps of compound 9

[0173] Compound 8 (300 mg, 947 μmol, 1 eq) and compound 4 (375 mg, 1.89 mmol, 2 eq) were dissolved in AcOH (6 mL). The reaction mixture was incubated at 110°C for 5 hours. LCMS confirmed the reaction was complete. The reaction solution was poured into ice water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (Petroleum ether / EtOAc, 0 / 1) to afford the target compound 9 (120 mg, 233 μmol, 22.6% yield) as a yellow oil. ESI-MS: [M+H] + ,516.2.

[0174] 6) Synthesis steps of compound GDI15-7520

[0175] Compound 9 (120 mg, 233 μmol, 1 eq) and CDI (226 mg, 1.40 mmol, 6 eq) were dissolved in toluene (2.4 mL). The mixture was stirred at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 35%-65% B over 8.0 min) to yield the target compound GDI15-7520 (56 mg, 90.4 μmol, 38.7% yield) as a white solid. ESI-MS: [M+H] + ,542.2.

[0176] 1H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.85 (s, 1H), 8.44 (s, 1H), 8.23 ​​(d, J = 8.3Hz, 1H), 7. 93(d,J=8.4Hz,1H),7.85-7.80(m,3H),7.77-7.71(m,1H),7.53-7.46(m,1H),7.45-7 .39(m,2H),7.10(t,J=1.6Hz,1H),7.01(t,J=1.9Hz,1H),6.92(t,J=1.9Hz,1H),4.19 (s,2H),4.12-4.02(m,2H),3.26-3.16(m,1H),3.09-2.97(m,1H),0.95-0.87(m,4H).

[0177] Example 17: Preparation of compound GDI15-7617

[0178] 1) Synthesis steps of compound 2

[0179] Compound 1 (500 mg, 2.90 mmol, 1 eq) and TEA (879 mg, 8.69 mmol, 1.21 mL, 3 eq) were dissolved in DCM (10 mL). TFAA (912 mg, 4.35 mmol, 604 μL, 1.5 eq) was added dropwise at 0°C. The reaction mixture was reacted at 0°C for 1 hour. LCMS detected the reaction to be complete. The reaction solution was diluted with water (30 mL) and extracted with EtOAc (30 mL*3). The organic phases were combined and washed with 50 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to give the target compound 2 (770 mg, 2.87 mmol, 98.9% yield) as a yellow oil. ESI-MS: [M+H] + ,317.3.

[0180] 2) Synthesis steps of compound 3

[0181] Compound 2 (770 mg, 2.87 mmol, 1 eq) was dissolved in EtOH (15.4 mL) and H₂O (4 mL). NH₄Cl (920 mg, 17.2 mmol, 6 eq) was added at 25°C. The temperature was raised to 60°C, and Fe powder (480 mg, 8.60 mmol, 3 eq) was added portionwise to the reaction mixture. The reaction mixture was allowed to react at 80°C for 1 hour. LCMS confirmed the reaction was complete. The reaction mixture was filtered through Celite while hot. The filtrate was concentrated under reduced pressure and diluted with water (30 mL). The mixture was then extracted with EtOAc (30 mL x 3). The organic phases were combined and washed with 50 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and evaporated to dryness to afford the target compound 3 (710 mg, 2.56 mmol, 89.3% yield, 86% purity) as a yellow oil. ESI-MS: [M+H] + ,239.0.

[0182] 3) Synthesis steps of compound 5

[0183] Compound 3 (710 mg, 2.98 mmol, 1 eq) was dissolved in THF (7.1 mL) and BH3.THF (1 M, 14.8 mL, 5 eq) was added dropwise at 25°C. The reaction mixture was allowed to react at 60°C for 1 hour. LCMS confirmed the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to a saturated NH4Cl solution (50 mL). The mixture was extracted with EtOAc (30 mL x 3). The organic phases were combined and washed with 50 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and spun down to dryness to afford the target compound 5 (670 mg, 2.18 mmol, 73.2% yield, 73% purity) as a yellow oil. ESI-MS: [M+H] + ,225.1

[0184] 4) Synthesis steps of compound 6

[0185] Compound 5 (670 mg, 2.18 mmol, 1 eq) and compound 4 (496 mg, 2.50 mmol, 1.15 eq) were dissolved in AcOH (5 mL) and the mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (5 mL) was added. The mixture was extracted with EtOAc (3 mL*3). The organic phases were combined and washed with 5 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified on a silica gel plate (Petroleum ether / EtOAc, 0 / 1) to obtain the target compound 6 (74 mg, 175 μmol, 8.04% yield) as a yellow solid. ESI-MS: [M+H] +,423.1.

[0186] 5) Synthesis steps of compound GDI15-7617

[0187] Compound 10 (74 mg, 175 μmol, 1 eq) was dissolved in toluene (1.5 mL). CDI (170 mg, 1.05 mmol, 6 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (3 mL) was added. The mixture was extracted with EtOAc (2 mL x 3). The organic phases were combined and washed with 5 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 35% to 65% B over 8.0 min) to afford the target compound GDI15-7617 (9.5 mg, 21.2 μmol, 12.1% yield) as a yellow oil. ESI-MS:[M+H] + ,449.1.

[0188] 1 H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.44 (s, 1H), 8.23 ​​(d, J = 8.1Hz, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.86-7.80 (m, 1H) ,7.78-7.71(m,1H),6.80-6.73(m,2H),6.73-6.63(m,2H),4.10-3.94(m,4H),3.25-3.18(m,1H),3.08(s,1H).

[0189] Example 18: Preparation of compound GDI15-7550

[0190] 1) Synthesis steps of compound 2

[0191] Compound 4 (2.15 g, 10.8 mmol, 1 eq) and compound 1 (3.74 g, 21.6 mmol, 2 eq) were dissolved in AcOH (21.5 mL). The reaction mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL*3). The organic phases were combined and washed with 50 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by column separation (SiO2, Petroleum ether / EtOAc, 20 / 1 to 1 / 1) to obtain the target compound 2 (826 mg, 2.23 mmol, 20.5% yield) as a yellow solid. ESI-MS: [M+H] + ,371.0

[0192] 2) Synthesis steps of compound 3

[0193] Compound 2 (820 mg, 2.21 mmol, 1 eq) was dissolved in toluene (16.4 mL), and CDI (2.15 g, 13.2 mmol, 6 eq) was added at 25°C. The reaction mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added. The mixture was extracted with EtOAc (8 mL*3). The organic phases were combined and washed with 30 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (SiO2, Petroleum ether / EtOAc, 0 / 1) to obtain the target compound 3 (448 mg, 1.13 mmol, 51.1% yield) as a yellow oil. ESI-MS: [M+H] + ,397.1

[0194] 3) Synthesis steps of compound 5

[0195] Compound 3 (448 mg, 1.03 mmol, 1 eq) was dissolved in EtOH (9 mL) and H₂O (2.3 mL). NH₄Cl (330 mg, 6.19 mmol, 6 eq) was added at 25°C. The temperature was raised to 80°C, and Fe (172 mg, 3.09 mmol, 3 eq) was added portionwise to the mixture. The reaction mixture was allowed to react at 80°C for 3 hours. LCMS confirmed the reaction was complete. Celite was added to filter the mixture while hot, and the filter cake was rinsed with hot ethanol (20 mL). The filtrate was concentrated under reduced pressure to yield the target compound 5 (380 mg, 936 μmol, 90.8% yield, 90.4% purity) as a yellow oil. ESI-MS: [M+H] + ,367.1

[0196] 4) Synthesis steps of compound GDI15-7550

[0197] Compound 5 (70 mg, 190 μmol, 1 eq) and compound 7 (24.1 mg, 286 μmol, 1.5 eq) were dissolved in MeOH (1.4 mL). AcOH (11.4 mg, 190 μmol, 10.9 μL, 1 eq) was added at 25°C. After the reaction mixture was reacted at 25°C for 1 hour, NaBH3CN (17.9 mg, 286 μmol, 1.5 eq) was added to the above mixture. The reaction mixture was further reacted at 25°C for 1 hour. The reaction was completed by LCMS detection. The reaction mixture was purified by HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 35%-65% B over 8.0 min) to afford the target compound GDI15-7550 (51.7 mg, 118 μmol, 62.3% yield) as a white solid. ESI-MS: [M+H] + ,435.2.

[0198] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.45(s,1H),8.24(d,J=8.0Hz,1H),7.92(d,J=8.6Hz,1H),7.83(t,J=7.1Hz,1H),7.78-7.72(m,1H),6.62(d,J =1.6Hz,2H),6.52(t,J=1.8Hz,1H),6.09(t,J=5.8Hz,1H),4.05(dt,J=2.4,6.5Hz,2H),3.23-3.19(m, 1H),3.06(d,J=16.7Hz,1H),2.89(d,J=5.3Hz,2H),1.10(s,3H),0.43-0.38(m,2H),0.30-0.26(m,2H)

[0199] Example 19: Preparation of compound GDI15-7787

[0200] 1) Synthesis steps of compound GDI15-7787

[0201] GDI15-7618 (50 mg, 116 μmol, 1 eq) and morpholine (15.2 mg, 174 μmol, 15.3 μL, 1.5 eq) were dissolved in dioxane (1 mL). Cs3CO3 (228 mg, 870 μmol, 4 eq), Xantphos (6.72 mg, 11.6 μmol, 0.1 eq), and Pd(OAc)2 (2.61 mg, 11.6 μmol, 0.1 eq) were added sequentially at 25°C. Under a nitrogen atmosphere, the reaction mixture was incubated at 80°C for 16 hours. The reaction was complete by LCMS. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined, filtered under reduced pressure, and then purified by silica gel plate separation (SiO2, EtOAc / MeOH = 10 / 1) and high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 50%-80% B over 8.0 min) to obtain the target compound GDI15-7787 (24.6 mg, 54.8 μmol, 23.6% yield, 97.4% purity) as a white solid. ESI-MS: [M+H] + ,437.2.

[0202] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.44(s,1H),8.23(d,J=8.1Hz,1H),7.93(d,J=8.3Hz,1H),7.83(s,1H),7.75(d,J=7.9H z,1H),7.00-6.82(m,3H),4.13-4.04(m,2H),3.74-3.70(m,4H),3.26-3.20(m,1H),3.18-3.12(m,4H),3.10-3.02(m,1H).

[0203] Example 20: Preparation of compound GDI15-8096

[0204] 1) Synthesis steps of compound 3

[0205] To compound 1 (1 g, 5.7 mmol) was added DMSO (10 mL), followed by compound 2 (0.63 g, 6.2 mmol) and K2CO3 (2.36 g, 17.1 mmol). The reaction was continued at 60°C under N2 protection for 16 h. After the reaction, water (50 mL) was added and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The product was further purified by column chromatography (EA / PE, 5% to 10%) to afford compound 3 (0.8 g, 54.39% yield) as a yellow solid.

[0206] 1H NMR (400MHz, DMSO) δ7.63(d,J=1.9Hz,1H),7.55(s,1H),7.43(s,1H),3.92(m,1H),3.81(d,J=12.1Hz, 1H),3.69(d,J=12.2Hz,1H),3.60(m,2H),2.80(m,1H),2.45(d,J=10.8Hz,1H),1.16(d,J=6.2Hz,3H).

[0207] 2) Synthesis steps of compound 4

[0208] Compound 3 (1.1 g, 4.3 mmol) was added to a 1:1 EtOH / H₂O (20 mL) mixture, followed by the slow addition of NH₄Cl (1.15 g, 21.5 mmol) and Fe (720 mg, 12.9 mmol). The reaction was carried out at 80°C under nitrogen for 10 h. After completion of the reaction, the system was cooled to room temperature, filtered, and the solvent was evaporated in vacuo. Water was added to the residue and extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to afford compound 4 (880 mg, 90.70% yield) as a white solid. ESI-MS: [M+H] + ,227.15.

[0209] 3) Synthesis steps of compound 6

[0210] Compound 4 (321 mg, 1.24 mmol) was added to a DCM (5 mL) solution, followed by the slow addition of compound 5 (280 mg, 1.24 mmol), TFA (2.5 mL), and Et3SiH (406 mg, 2.47 mmol). The reaction was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, a saturated Na2CO3 solution was added to adjust the pH to 8-9. The mixture was then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The mixture was further purified by column chromatography (EtOAc / PE, 40% to 42%) to afford compound 6 (200 mg, 38.11% yield) as a white solid. ESI-MS: [M+H] + ,425.10.

[0211] 4) Synthesis steps of compound GDI15-8096

[0212] Compound 6 (200 mg, 0.47 mmol) was added toluene (5 mL) and subsequently CDI (382 mg, 2.35 mmol). The mixture was stirred at 110°C for 2 h. LCMS confirmed the reaction was complete. The solution was then vacuum-dried and further purified by prep-HPLC (Gemini 5 μm C18 column, 150×21.2 mm, eluent with 75% to 95% MeCN / H2O containing 0.1% FA) to afford compound GDI15-8096 (89.51 mg, 42.17% yield) as a yellow solid. ESI-MS: [M+H] + ,451.15.

[0213] 1H NMR (400MHz, DMSO) δ9.36(s,1H),8.45(s,1H),8.23(d,J=8.1Hz,1H),7.93(d,J=8.4Hz,1H),7.83(t,J=7.6Hz,1H),7.74(t,J=7.5Hz,1H), 6.93(m,3H),4.08(m,2H),3.90(m,1H),3.59(m,4H),3.24(m,1H),3.07(m,1H),2.69(m,1H),2.37(t,J=11.1Hz,1H),1.15(d,J=6.1Hz,3H).

[0214] Example 21: Preparation of compound GDI15-8051

[0215] 1) Synthesis steps of compound 3

[0216] To a mixture of compound 1 (500 mg, 2.80 mmol) and compound 2 (1 / 1) (480 mg, 4.21 mmol) was added DMSO (5 mL), followed by the addition of K2CO3 (1.16 g, 8.40 mmol) with stirring. The mixture was stirred at 60°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 subjected to spin chromatography (PE / EtOAc, 0% to 10) to afford compound 3 (380 mg, 1.40 mmol) as a yellow solid.

[0217] 1 H NMR (400MHz, DMSO) δ7.68-7.52(m,2H),7.12(t,J=1.9Hz,1H),3.79(m,2H),3.60-3.45(m,2H),2.53(t,J=11.2Hz,2H),1.29(d,J=6.3Hz,6H).

[0218] 2) Synthesis steps of compound 4

[0219] A 1:1 EtOH / H₂O (6 mL) mixture was added to a solution of compound 3 (380 mg, 1.40 mol) and Fe (392 mg, 7.02 mmol), followed by NH₄Cl (375 mg, 7.02 mmol). The mixture was reacted at 80°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 and dried over anhydrous sodium sulfate to yield compound 4 (300 mg, 1.23 mmol) as a yellow oil. ESI-MS: [M+H] + ,241.10.

[0220] 3) Synthesis steps of compound 6

[0221] To a mixture of compound 4 (250 mg, 0.96 mmol) and compound 5 (254 mg, 1.06 mmol) was added DCM (3 mL). TES (394 mg, 2.40 mmol) and TFA (1 mL) were added at room temperature under nitrogen. The reaction was continued at room temperature for 2 h. After completion of the reaction, the solution was adjusted to pH 7-8 with aqueous NaHCO₃ solution and 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 (DCM / MeOH, 0% to 5%) to afford compound 6 (200 mg, 0.46 mmol) as a yellow solid. ESI-MS: [M+H] + ,439.10.

[0222] 3) Synthesis steps of compound GDI15-8051

[0223] Toluene (3 mL) was added to a mixture of compound 6 (200 mg, 0.46 mmol) and CDI (443 mg, 2.73 mol). The mixture was heated to 100°C and stirred 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, concentrated, and further purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluent with 30% to 90% MeCN / H2O containing 0.1% FA) to yield compound GDI15-8051 (58 mg, 0.12 mmol) as a white solid. ESI-MS: [M+H] + ,465.10.

[0224] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.44(s,1H),8.23(d,J=8.2Hz,1H),7.93(d,J=8.4Hz,1H),7.83(t,J=7.1Hz,1H),7.74(t,J=7.1Hz,1H),6.96(s,1H ),6.93-6.88(m,2H),4.16-4.03(m,2H),3.65(t,J=11.2Hz,4H),3.27-3.2 0(m,1H),3.11-3.03(m,1H),2.29(t,J=11.4Hz,2H),1.15(d,J=6.2Hz,6H).

[0225] Example 22: Preparation of compound GDI15-8054

[0226] 1) Synthesis steps of compound 3

[0227] To compound 1 (500 mg, 5.10 mmol) and compound 2 (660 mg, 5.71 mmol) was added DMF (5 mL), followed by K2CO3 (1.58 g, 11.40 mmol). The system was stirred at 60°C for 8 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 10%) to afford compound 3 (350 mg, 1.28 mol) as a yellow oil. ESI-MS: [M+H] + ,270.08.

[0228] 2) Synthesis steps of compound 4

[0229] To a mixture of compound 3 (300 mg, 1.10 mmol) and Fe (309 mg, 5.54 mmol) was added an EtOH / H2O 1:1 solution (6 mL), followed by NH4Cl (296 mg, 5.54 mmol). The mixture was heated to 80°C for 2 h. After the reaction, water was added and the mixture was extracted with EtOAc (10 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain compound 4 (240 mg, 0.90 mmol) as a yellow oil. ESI-MS: [M+H] + ,241.00.

[0230] 3) Synthesis steps of compound 7

[0231] To compound 5 (10.00 g, 0.074 mol), compound 6 (7.6 g, 0.050 mol), and pyridine (48.50 g, 0.38 mol) was added DCM (100 mL). POCl3 (34.50 g, 0.23 mol) was slowly added at 0°C, and the reaction was continued at 0°C for 2 h. After the reaction, the system was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (PE / EtOAc, 0% to 50%) to afford compound 7 (4 g, 0.021 mol) as a yellow solid. ESI-MS: [M+H] + ,261.20.

[0232] 3) Synthesis steps of compound 8

[0233] To compound 7 (200 mg, 0.77 mmol) and compound 4 (203 mg, 0.84 mmol) was added DCM (3 mL). TES (316 mg, 1.92 mmol) and TFA (0.8 mL) were added under nitrogen, and the reaction was continued at room temperature for 2 h. After the reaction, aqueous NaHCO₃ was added to adjust the pH to 7-8 and extracted with 10 mL of water (3 times). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH, 0% to 5%) to afford compound 8 (260 mg, 0.59 mmol) as a yellow solid. ESI-MS: [M+H] + ,439.15.

[0234] 4) Synthesis steps of compound GDI15-8054

[0235] Toluene (3 mL) was added to compound 8 (260 mg, 0.59 mmol) and CDI (576 mg, 3.55 mol), and the mixture was stirred at 100°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 dried. The product was further purified by prep-HPLC (Gemini 5 μm C18 column, 150 x 21.2 mm, eluent with 30% to 90% MeCN / H2O containing 0.1% NH3 / H2O) to afford GD115-8054 (82 mg, 0.17 mmol) as a white solid. ESI-MS: [M+H] + ,465.15.

[0236] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.44(s,1H),8.23(d,J=8.1Hz,1H),7.93(d,J=8.4Hz,1H),7.83(t,J=7.6Hz,1H),7.74(t,J=7.5 Hz,1H),6.96-6.86(m,3H),4.17-4.03(m,2H),3.79-3.70(m,2H),3.28-3.20(m,1H),3.13-3.03(m,3H),3.00(s,2H),1.21(s,6H).

[0237] Example 23: Preparation of compound GDI15-7886

[0238] Compound GDI15-7618 (200 mg, 464 μmol, 1 eq) and compound 1 (69.1 mg, 697 μmol, 1.5 eq) were dissolved in dioxane (4 mL). Cs2CO3 (454 mg, 1.39 mmol, 3 eq), Xantphos (26.9 mg, 46.4 μmol, 0.1 eq), and Pd(OAc)2 (10.4 mg, 46.4 μmol, 0.1 eq) were added sequentially at 25°C. Under a nitrogen atmosphere, the reaction mixture was incubated at 80°C for 16 hours. LCMS confirmed the reaction was complete. Water (10 mL) was added, and the mixture was extracted with EtOAc (5 mL x 3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (SiO2, EtOAc / Methanol, 10 / 1) and high-performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 80*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 25%-60% B over 8.0 min) to yield the target compound GDI15-7886 (37.8 mg, 83.4 μmol, 18.0% yield, 99.0% purity) as a white solid. ESI-MS: [M+H] + ,449.1.

[0239] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.45(s,1H),8.23(d,J=8.1Hz,1H),7.98-7.89(m,1H),7.83(dt,J=1.1,7.6Hz,1H),7.78-7.68(m,1H),6.81(t ,J=1.8Hz,1H),6.43(t,J=1.9Hz,1H),6.36(t,J=1.9Hz,1H),4.70(s,4H ),4.09-4.03(m,2H),4.01(s,4H),3.26-3.18(m,1H),3.10-2.97(m,1H).

[0240] Example 24: Preparation of compound GDI15-7888

[0241] Compound GDI15-7618 (200 mg, 464 μmol, 1 eq) and compound 1 (49.5 mg, 697 μmol, 58.2 μL, 1.5 eq) were dissolved in dioxane (4 mL). Cs2CO3 (454 mg, 1.39 mmol, 3 eq), Xantphos (26.9 mg, 46.4 μmol, 0.1 eq), and Pd(OAc)2 (10.4 mg, 46.4 μmol, 0.1 eq) were added sequentially at 25°C. Under a nitrogen atmosphere, the reaction mixture was incubated at 80°C for 16 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 and washed with saturated sodium chloride (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel plate separation (SiO2, EtOAc / Methanol, 10 / 1) and high-performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-60% B over 8.0 min) to obtain the target compound GDI15-7888 (32.2 mg, 72.8 μmol, 15.7% yield, 95.1% purity) as a white solid. ESI-MS: [M+H] + ,421.1.

[0242] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.45(s,1H),8.23(d,J=8.1Hz,1H),7.93(d,J=8.4Hz,1H),7.83(dt,J=1.1,7.6Hz,1H),7.77-7.71(m,1H),6. 70(t,J=1.6Hz,1H),6.53(t,J=1.9Hz,1H),6.43(t,J=1.9Hz,1H),4.13 -3.99(m,2H),3.25-3.19(m,5H),3.12-3.01(m,1H),1.97-1.92(m,4H).

[0243] Example 25: Preparation of compound GDI15-7970

[0244] 1) Synthesis steps of compound 2

[0245] Compound GDI15-7618 (200 mg, 464 μmol, 1 eq) and compound 1 (50.9 mg, 697 μmol, 1.5 eq) were dissolved in dioxane (4 mL), and Cs2CO3 (454 mg, 1.39 mmol, 3 eq), Xantphos (26.9 mg, 46.4 μmol, 0.1 eq) and Pd(OAc)2 (10.4 mg, 46.4 μmol, 0.1 eq) were added sequentially at 25 °C. Under nitrogen protection, the reaction mixture was reacted at 80 °C for 16 hours. The reaction was completed by LCMS detection. Water (8 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel plate separation (EtOAc / Methanol, 10 / 1) and high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 8.0 min) to obtain the target compound GDI15-7970 (10 mg, 23.1 μmol, 4.97% yield, 97.6% purity) as a white solid. ESI-MS: [M+H] + ,423.1.

[0246] 1 H NMR(400MHz,DMSO)δ9.36(s,1H),8.44(s,1H),8.23(d,J=8.0Hz,1H),7.93(d,J =8.7Hz,1H),7.86-7.81(m,1H),7.77-7.71(m,1H),6.87(d,J=6.6Hz,1H),6.72 (s,1H),6.57-6.50(m,1H),6.37(s,1H),4.83(t,J=6.5Hz,2H),4.58-4.50(m,1 H),4.40-4.33(m,2H),4.09-3.98(m,2H),3.27-3.16(m,1H),3.11-3.00(m,1H).

[0247] Example 26: Preparation of compound GDI15-7646

[0248] 1) Synthesis steps of compound 2

[0249] Compound 4 (730 mg, 3.68 mmol, 1 eq) and compound 1 (804 mg, 5.52 mmol, 1.5 eq) were dissolved in AcOH (7.3 mL) and the mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined and washed with 20 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified on a silica gel plate (Petroleum ether / EtOAc = 1 / 1) to afford the target compound 2 (220 mg, 639 μmol, 17.4% yield) as a white solid. ESI-MS: [M+H]+, 344.2.

[0250] 2) Synthesis steps of compound GDI15-7646

[0251] Compound 2 (230 mg, 669 μmol, 1 eq) was dissolved in toluene (4.6 mL). CDI (650 mg, 4.01 mmol, 6 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (7 mL x 3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by HPLC (column: CAPCELL PAK ADME 20 x 150 mm 5u; mobile phase: [H₂O (0.1% TFA)-ACN]; gradient: 20% to 50% B over 15.0 min) to afford the target compound GDI15-7646 (111 mg, 301 μmol, 45.0% yield) as a white solid. ESI-MS: [M+H]+, 370.2.

[0252] 1H NMR (400MHz, DMSO) δ9.37(s,1H),8.46(s,1H),8.23(d,J=8.1Hz,1H),7.96(d,J=8.3Hz,1H),7.86-7.80(m,1H ),7.77-7.72(m,1H),7.45(s,1H),7.40-7.33(m,2H),4.19-4.13(m,2H),3.27-3.21(m,1H),3.11-3.04(m,1H)

[0253] Example 27: Preparation of compound GDI15-7703

[0254] 1) Synthesis steps of compound 2

[0255] Compound 4 (500 mg, 2.52 mmol, 1 eq) and compound 1 (613 mg, 3.78 mmol, 1.5 eq) were dissolved in AcOH (5 mL). The reaction mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and water (20 mL) was added. The mixture was extracted with EtOAc (10 mL*3). The organic phases were combined and washed with 20 mL of saturated sodium chloride. The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel chromatography (Petroleum ether / EtOAc, 1 / 1) to obtain the target compound 2 (170 mg, 471 μmol, 18.7% yield) as a white solid. ESI-MS: [M+H] + ,361.2.

[0256] 2) Synthesis steps of compound GDI15-7703

[0257] Compound 2 (170 mg, 471 μmol, 1 eq) was dissolved in toluene (2 mL). CDI (382 mg, 2.36 mmol, 6 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (7 mL x 3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 37% to 65% B over 8.0 min) to afford the target compound GDI15-7703 (80.8 mg, 209 μmol, 44.3% yield) as a white solid. ESI-MS:[M+H] + ,387.2.

[0258] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.45(s,1H),8.23(d,J=8.2Hz,1H),7.96(d,J=8.3Hz,1H),7.83(dt,J=1.1,7.7Hz,1H),7.7 8-7.72(m,1H),7.57(d,J=1.9Hz,2H),7.54-7.51(m,1H),4.20-4.11(m,2H),3.30-3.20(m,1H),3.08(td,J=6.1,16.7Hz,1H)

[0259] Example 28: Preparation of compound GDI15-7650

[0260] 1) Synthesis steps of compound 2

[0261] Compound 4 (730 mg, 3.68 mmol, 1 eq) and compound 2 (1.08 g, 5.52 mmol, 1.5 eq) were dissolved in AcOH (7.3 mL) and the mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined and washed with 20 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified on a silica gel plate (Petroleum ether / EtOAc, 1 / 1) to afford the target compound 3 (270 mg, 639 μmol, 20% purity) as a white solid. ESI-MS: [M+H]+, 394.2.

[0262] 2) Synthesis steps of compound GDI15-7650

[0263] Compound 3 (270 mg, 685 μmol, 1 eq) was dissolved in toluene (6 mL). CDI (555 mg, 3.43 mmol, 5 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (7 mL x 3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 40% to 70% B over 8.0 min) to afford the target compound GDI15-7650 (128 mg, 304 μmol, 44.3% yield) as a white solid. ESI-MS: [M+H]+, 420.2.

[0264] 1H NMR (400MHz, DMSO) δ9.37(s,1H),8.47(s,1H),8.24(d,J=8.2Hz,1H),7.98(d,J=8.4Hz,1H),7.89(s ,1H),7.86-7.80(m,2H),7.78-7.72(m,2H),4.25-4.15(m,2H),3.30-3.22(m,1H),3.15-3.05(m,1H)

[0265] Example 29: Preparation of compound GDI15-7702

[0266] 1) Synthesis steps of compound 2

[0267] Compound 4 (300 mg, 1.51 mmol, 1 eq) and compound 1 (480 mg, 2.27 mmol, 1.5 eq) were dissolved in AcOH (3 mL). The reaction mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (5 mL*3). The organic phases were combined and washed with 20 mL of saturated sodium chloride. The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by silica gel chromatography (Petroleum ether / EtOAc = 1 / 1) to obtain the target compound 2 (140 mg, 341 μmol, 22.6% yield) as a white solid. ESI-MS: [M+H] + ,410.2.

[0268] 2) Synthesis steps of compound GDI15-7702

[0269] Compound 2 (120 mg, 292 μmol, 1 eq) was dissolved in toluene (2 mL). CDI (237 mg, 1.46 mmol, 6 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (7 mL x 3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by HPLC (column: 3-Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 25% to 55% B over 8.0 min) to afford the target compound GDI15-7702 (42.6 mg, 97.7 μmol, 33.4% yield) as a white solid. ESI-MS:[M+H]+ ,436.2.

[0270] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.47(s,1H),8.29-8.19(m,1H),7.97(d,J=8.2Hz,1H),7.88-7.80(m,1H),7.79-7 .70(m,1H),7.64(t,J=1.7Hz,1H),7.49(d,J=14.7Hz,2H),4.26-4.13(m,2H),3.28-3.23(m,1H),3.15-3.05(m,1H).

[0271] Example 30: Preparation of compound GDI15-7737

[0272] 1) Synthesis steps of compound 2

[0273] Compound 1 (3 g, 13.3 mmol, 1 eq) was dissolved in DMF (60 mL), and NaH (798 mg, 19.9 mmol, 60% purity, 1.5 eq) was added portionwise at 0°C. After the reaction mixture was allowed to react at 0°C for 1 hour, MeI (2.27 g, 15.9 mmol, 994 μL, 1.2 eq) was added to the mixture. The reaction mixture was allowed to react at 25°C for another 2 hours. LCMS confirmed the reaction was complete. The reaction solution was added dropwise to saturated ammonium chloride solution (100 mL) at 0°C and extracted with EtOAc (50 mL x 3). The organic phases were combined and washed with 200 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to dryness, yielding compound 2 (3.2 g, 12.9 mmol, 97.4% yield, 97% purity) as a yellow oil.

[0274] 2) Synthesis steps of compound 3

[0275] Compound 2 (3.2 g, 13.3 mmol, 1 eq) and BocNH2 (3.13 g, 26.7 mmol, 2 eq) were dissolved in dioxane (64 mL). Cs2CO3 (8.71 g, 26.7 mmol, 2 eq), Pd2(dba)3 (1.22 g, 1.34 mmol, 0.1 eq), and Xantphos (1.55 g, 2.67 mmol, 0.2 eq) were added sequentially under nitrogen. The reaction mixture was reacted at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered, and the filtrate was purified by column chromatography (SiO2, Petroleum ether / EtOAc, 20 / 1 to 5 / 1) to afford compound 3 (3.2 g, 11.6 mmol, 86.8% yield) as a yellow solid. ESI-MS: [M+H] + ,235.2

[0276] 3) Synthesis steps of compound 4

[0277] Compound 3 (3.2 g, 11.6 mmol, 1 eq) was dissolved in DCM (32 mL), and HCl / dioxane (32 mL, 4 M) was added at 25 ° C. The reaction mixture was reacted at 25 ° C for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and EtOAc (20 mL) was added. The mixed solution was filtered, and water (30 mL) was added to the filter cake after collection. The pH was adjusted to 8 with saturated sodium carbonate solution. It was then extracted with EtOAc (20 mL * 3), the organic phases were combined, and washed with saturated sodium chloride (80 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to give compound 4 (1.67 g, 9.51 mmol, 81.9% yield) as a yellow solid. ESI-MS: [M+H] + ,176.1

[0278] 4) Synthesis steps of compound 6

[0279] Compound 5 (250 mg, 1.26 mmol, 1 eq) and compound 4 (332 mg, 1.89 mmol, 1.5 eq) were dissolved in AcOH (2.5 mL) and the mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (2 mL*3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (SiO2, PE / EtOAc, 0 / 1) to obtain the target compound 6 (130 mg, 347 μmol, 27.6% yield) as a yellow solid. ESI-MS: [M+H] + ,374.2.

[0280] 5) Synthesis steps of compound GDI15-7737

[0281] Compound 6 (50 mg, 133 μmol, 1 eq) was dissolved in toluene (1 mL). CDI (130 mg, 802 μmol, 6 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (2 mL x 3). The organic phases were combined and washed with 10 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then spin-dried. HPLC (Aters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 40% to 70% B over 8.0 min) yielded the target compound GDI15-7737 (19.4 mg, 47.3 μmol, 35.3% yield, 97.4% purity) as a yellow solid. ESI-MS:[M+H] + ,400.1.

[0282] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.46(s,1H),8.24(d,J=8.2Hz,1H),7.95(d,J=8.4Hz,1H),7.84(t,J=7.2Hz,1H),7. 75(t,J=7.6Hz,1H),7.28(dt,J=2.4,6.8Hz,2H),4.18-4.06(m,2H),3.89(s,3H),3.29-3.22(m,1H),3.15-3.05(m,1H)

[0283] Example 31: Preparation of compound GDI15-7727

[0284] 1) Synthesis steps of compound 3

[0285] To a solution of compound INT-4 (500 mg, 1.92 mmol) in DCM (5 mL) were added TFA (2.5 mL), compound 5 (246.95 mg, 1.92 mmol), and Et3SiH (558.36 mg, 4.80 mmol), and the mixture was allowed to react at room temperature for 3 h. LCMS monitored the reaction completion. After completion, the system was concentrated, and the pH was adjusted to 7-8 with saturated aqueous NaOH. The filter cake was collected by filtration and washed with water to yield compound 6 (300 mg, 47.79% yield) as a brown solid. ESI-MS: [M+H] + ,327.0.

[0286] 2) Synthesis steps of compound GDI15-7727

[0287] To a solution of compound 6 (300 mg, 0.918 mmol) in toluene (3 mL) was slowly added CDI (893.07 mg, 5.508 mmol). The mixture was heated to 100°C and reacted for 3 h. The product was then isolated and purified using a Biotage Isolera One C18 column (eluting with 10% to 90% MeCN / H2O containing 0.1% formic acid) to afford compound GDI-7727 (18.15 mg, 5.60% yield) as a yellow solid. ESI-MS: [M+H] + ,353.10.

[0288] 1 H NMR (400MHz, DMSO) δ9.44(s,1H),8.67(d,J=2.1Hz,1H),8.52(s,1H),8.52(s,1H),8.28(d,J=8.1Hz,1H),8.08(t,J=2.2Hz,1H),8.0 2(d,J=8.1Hz,1H),7.88(t,J=7.6Hz,1H),7.79(t,J=7.5Hz,1H),4.23-4.20(m,2H),3.33-3.25(m,1H),3.12(dd,J=14.6,7.6Hz,1H).

[0289] Example 32: Preparation of compound GDI15-7543

[0290] 1) Synthesis steps of compound 3

[0291] To a mixture of compound 1 (4.5 g, 0.021 mol), compound 2 (3 g, 0.021 mol), and HATU (15.74 g, 0.042 mol) was added DMF (45 mL) and DIPEA (8.03 g, 0.062 mol). The mixture was stirred at room temperature for 12 hours. After the reaction, EtOAc (50 mL x 3) was added for extraction. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by pre-TLC (DCM / MeOH, 5%) to afford compound 3 (500 mg, 1.30 mmol) as a yellow solid. ESI-MS: [M+H] + ,344.05.

[0292] 2) Synthesis steps of compound 4

[0293] To a solution of compound 3 (500 mg, 1.300 mmol) in EtOAc (2 mL) was added HCl-EtOAc (4 mL), and the reaction was stirred at room temperature for 2 h. After the reaction, NaHCO₃ solution was added to adjust the pH to 7-8, and the organic phase was separated and concentrated to yield compound 4 (320 mg, 1.052 mmol) as a yellow solid. ESI-MS: [M+H] + ,244.00.

[0294] 3) Synthesis steps of compound 5

[0295] Toluene solution (4 mL) was added to a mixture of compound 4 (320 mg, 1.052 mmol), CDI (1.3 g, 7.891 mmol), and DIPEA (510 mg, 3.946 mmol). The system was then heated to 110°C and allowed to react for 2 h. After completion of the reaction, water and EtOAc (10 mL x 3) were added for extraction. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to spin chromatography (DCM / MeOH, 0% to 5%) to afford compound 5 (100 mg, 0.371 mmol) as a yellow solid. ESI-MS: [M+H] + ,270.10.

[0296] 4) Synthesis steps of compound GDI15-7543

[0297] To a mixture of compound 5 (100 mg, 0.371 mmol), compound 6 (150 mg, 0.446 mmol), Pd2(dba)3 (68 mg, 0.074 mmol), xantphos (107 mg, 0.186 mmol), and Cs2CO3 (363 mg, 1.114 mmol) was added 1,4-dioxane (2 mL). The mixture was heated to 100°C and stirred under nitrogen for 3 h. After completion of the reaction, the mixture was filtered, concentrated, and further purified by prep-HPLC (Gemini 5um C18 column, 150x21.2 mm, eluent with 30% to 90% MeCN / H2O containing 0.1% FA) to yield compound GDI15-7543 (30 mg, 0.062 mmol) as a yellow solid. ESI-MS: [M+H] + ,478.00.

[0298] Example 33: Preparation of compound GDI15-7567

[0299] 1) Synthesis steps of compound 3

[0300] To a mixture of compound 1 (1 g, 9 mmol), compound 2 (1.3 g, 9 mmol), HATU (4.11 g, 10.7 mmol), and DIPEA (3.48 g, 26.9 mmol) was added DMF (20 mL), followed by stirring at room temperature 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 further purified by column chromatography (EtOAc / PE, 10% to 50%) to afford compound 3 (1.1 g, 51.11% yield) as a brown solid.

[0301] 2) Synthesis steps of compound 4

[0302] Under nitrogen protection, NiCl2.6H2O (3.08 g, 12.96 mmol) was added to a solution of compound 3 (2.05 g, 8.64 mmol) in MeOH (20 mL) at 0°C. The reaction was continued at this temperature for 10 min. NaBH4 (1.63 g, 43.20 mmol) was then added to the system in three batches and stirred for another 20 min. Upon completion of the reaction as monitored by LCMS, Boc2O (7.54 g, 34.56 mmol) was added dropwise to the system. The system was slowly warmed to room temperature and allowed to react for 16 h at room temperature. The reaction was then completed as monitored by LCMS. The solvent was then concentrated under reduced pressure, and water (200 mL) was added to the system, followed by extraction with EtOAc (200 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then purified by column chromatography (MeOH / DCM, 5% to 10%) to afford compound 4 (910 mg, 30.85% yield) as a gray-brown solid. ESI-MS: [M+H] + ,342.1.

[0303] 3) Synthesis steps of compound 5

[0304] A 2M solution of HCl in EtOAc (10 mL) was added to compound 4 (900 mg, 2.64 mmol) and stirred at room temperature for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the system was concentrated and treated with EtOAc and 1M NaOH, respectively. The organic phases were separated and washed with water. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spun down to afford compound 5 (360 mg, 48.11% yield) as a gray-brown solid. ESI-MS: [M+H] + ,242.1.

[0305] 4) Synthesis steps of compound 6

[0306] To a toluene (4 mL) solution of compound 5 (350 mg, 1.45 mmol) was added CDI (470 mg, 2.90 mmol), and the mixture was heated to 110°C under nitrogen for 2 h. Following completion of the reaction, the mixture was concentrated under reduced pressure, and water (50 mL) was added. 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 (MeOH / DCM, 5% to 10%) to afford compound 6 (160 mg, 41.27% yield) as a reddish-brown oil. ESI-MS: [M+H] + ,268.1.

[0307] 5) Synthesis steps of compound GDI15-7567

[0308] To a solution of compound 6 (160 mg, 0.5986 mmol) in 1,4-dioxane (2 mL) were added compound 7 (303.03 mg, 0.8979 mmol), Xantphos (34.64 mg, 0.05986 mmol), Cs2CO3 (585.11 mg, 1.7958 mmol), and Pd2(dba)3 (54.82 mg, 0.0598 mmol). The mixture was heated to 100°C under nitrogen for 16 h. After completion of the reaction, the product was concentrated and further purified by prep-HPLC (Gemini 5um C18 column, 150x21.2 mm, eluent with 90% to 95% ACN / H2O containing 0.05% NH3 / H2O) to afford compound GDI15-7567 (15.8 mg, 5.54% yield) as a white solid. ESI-MS:[M+H] + ,476.0.

[0309] 1H NMR (400MHz, DMSO) δ9.37(s,1H),8.47(s,1H),8.24(d,J=7.9Hz,1H),7.86-7.82(m,2H),7.77-7.69(m,1H ),7.24(s,1H),7.13(s,2H),4.88-4.81(m,2H),4.12-4.04(m,2H),1.37-1.31(m,2H),1.28-1.21(m,2H).

[0310] Example 34: Preparation of compound GDI15-7842

[0311] 1) Synthesis steps of compound 3

[0312] Compound 1 (10.00 g, 0.0799 mol) and compound 2 (1.94 g, 0.0759 mol) were dissolved in pyridine (100 mL). Under nitrogen, POCl (73.51 g, 0.4794 mol) was slowly added at 0°C. The mixture was allowed to react for 0.5 h. After the reaction, water (200 mL) and EtOAc (500 mL x 3) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 50% to 60%) to afford compound 3 (8.5 g, 42.30% yield) as a brown solid. ESI-MS: [M+H] +,252.3.

[0313] 2) Synthesis steps of compound 4

[0314] Compound 3 (5 g, 19.9 mmol) was dissolved in MeOH (50 mL), followed by the dropwise addition of NiCl2.6H2O (7.09 g, 29.8 mmol). The reaction was incubated at 0°C under N2 protection. NaBH4 (2.3 g, 59.7 mmol) was then slowly added, and the reaction continued at 0°C for 30 minutes. Finally, Boc2O (13 g, 59.7 mmol) was added dropwise. The temperature was then slowly raised to room temperature, and the reaction was stirred at room temperature for 1 hour. After the reaction, water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EtOAc / PE, 8% to 10%) to afford compound 4 (800 mg, 11.28% yield) as a brown solid. ESI-MS: [M+H] + ,356.1.

[0315] 3) Synthesis steps of compound 5

[0316] To compound 4 (1.0 g, 2.8055 mmol) was added dioxane (2 mL), followed by the dropwise addition of HCl in dioxane (2.1 mL, 4 mol / L) at room temperature. The mixture was allowed to react for 2 h at room temperature, after which the solvent was removed by spin drying. MeOH and NaHCO₃ were added, and the remaining solvent was removed by spin drying and lyophilized to yield the final product, compound 5. ESI-MS: [M+H] + ,256.1.

[0317] 4) Synthesis steps of compound 7

[0318] Compound 5 (190 mg, 0.7442 mmol) was added with DMSO (5 mL), followed by compound 6 (200.93 mg, 0.5954 mmol), K2CO3 (411.41 mg, 2.9768 mmol), and copper (I) iodide (141.73 mg, 0.7442 mmol). The reaction was carried out under a nitrogen atmosphere and microwave-assisted at 100°C for 1 hour. After the reaction, the mixture was cooled to room temperature, filtered, and concentrated in vacuo. Water was then added to the residue, and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to dryness. Further purification by prep-TLC (EtOAc / PE, 1 / 1) afforded compound 7 (30 mg, 8.67% yield) as a white solid. ESI-MS: [M+H]+ ,492.15.

[0319] 5) Synthesis steps of compound GDI15-7842

[0320] Compound 7 (15 mg, 0.03 mmol) was added with MeCN (3 mL) solution, followed by the slow addition of CDI (261.86 mg, 1.6 mmol) at 0°C under nitrogen protection. The mixture was allowed to react at 80°C for 16 h. After completion of the reaction, water (20 mL) was added to the system and the mixture was extracted with EtOAc (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. Further purification by prep-TLC (EtOAc / PE, 1 / 1) afforded the final compound GDI15-7842 (2.39 mg, 15.17% yield) as a white solid.

[0321] ESI-MS:[M+H] + ,490.2. 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.45(s,1H),8.25(d,J=8.0Hz,1H),7.88-7.82(m,1H),7.76(dd,J=14.8,7.2Hz,2H),7.27( s,1H),7.16(s,2H),4.86(q,J=8.8Hz,2H),4.25(q,J=12.4Hz,2H),2.62-2.53(m,2H),2.25-2.09(m,3H),2.00-1.92(m,1H).

[0322] Example 35: Preparation of compound GDI15-7945

[0323] 1) Synthesis steps of compound 2

[0324] Compound 1 (10 g, 54.8 mmol, 1 eq) and CBr4 (38.2 g, 115 mmol, 2.1 eq) were dissolved in DCM (200 mL). PPh3 (30.2 g, 115 mmol, 2.1 eq) was added at 0°C. The reaction mixture was incubated at 25°C for 4 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc, 20 / 1 to 8 / 1) to obtain the target compound 2 (14 g, 45.4 mmol, 82.8% yield) as a colorless oil.

[0325] 2) Synthesis steps of compound 4

[0326] Compound 2 (7.5 g, 24.3 mmol, 1 eq) and compound 3 (3.62 g, 36.5 mmol, 3.22 mL, 1.5 eq) were dissolved in DMF (75 mL). K2CO3 (13.4 g, 97.4 mmol, 4 eq) was added at 25°C. The reaction mixture was reacted at 90°C for 4 hours. LCMS confirmed the reaction was complete. The reaction solution was cooled and slowly poured into water (300 mL). The mixture was extracted with EtOAc (100 mL*3). The organic phases were combined and washed with saturated sodium chloride (300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried, and purified by column chromatography (PE / EtOAc, 20 / 1 to 2 / 1) to obtain the target compound 4 (5.4 g, 22.0 mmol, 90.4% yield) as a yellow oil. ESI-MS: [M+H] + ,246.2.

[0327] 3) Synthesis steps of compound 5

[0328] Compound 4 (5.4 g, 22.0 mmol, 1 eq) was dissolved in THF (108 mL) and H2O (32 mL). LiOH.H2O (1.85 g, 44.0 mmol, 2 eq) was added at 0°C. The reaction mixture was allowed to react at 0°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was slowly poured into water (100 mL) and extracted with EtOAc (40 mL) to remove impurities. The aqueous phase was then adjusted to pH 4 with HCl (1 M) and extracted with EtOAc (40 mL*3). The organic phases were combined and washed with saturated sodium chloride (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to afford the target compound 5 (5 g, 20.4 mmol, 98.2% yield) as a yellow oil. ESI-MS: [M+H] + ,232.2.

[0329] 4) Synthesis steps of compound 7

[0330] Compound 6 (3.43 g, 23.7 mmol, 1.1 eq) and compound 5 (5 g, 21.6 mmol, 1 eq) were dissolved in pyridine (100 mL). EDCI (6.22 g, 32.4 mmol, 1.5 eq) was added portionwise at 0°C. The reaction mixture was stirred at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added. The mixture was extracted with EtOAc (30 mL*3). The organic phases were combined and washed with saturated sodium chloride (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by column chromatography (SiO2, PE / EtOAc, 20 / 1 to 1 / 1) to obtain compound 7 (4.1 g, 11.4 mmol, 53.1% yield) as a yellow oil. ESI-MS: [M+H] + ,358.2.

[0331] 5) Synthesis steps of compound 8

[0332] Compound 7 (3.4 g, 9.51 mmol, 1 eq) was dissolved in MeOH (34 mL), and NiCl2.6H2O (3.39 g, 14.2 mmol, 1.5 eq) was added at 25°C. The mixture was reacted at 0°C for 10 minutes. NaBH4 (1.80 g, 47.5 mmol, 5 eq) was then added portionwise to the reaction solution. The reaction mixture was stirred at 0°C for 2 hours. LCMS confirmed the reaction was complete. Boc2O (8.30 g, 38.1 mmol, 8.74 mL, 4 eq) was added to the reaction solution, and the reaction mixture was reacted at 25°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into water (100 mL) and filtered under reduced pressure. The filtrate was extracted with EtOAc (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride (150 mL). The washed organic phases were concentrated under reduced pressure and purified by column separation (SiO2, Petroleum ether / EtOAc = 20 / 1 to 0 / 1) to obtain compound 8 (650 mg, 1.80 mmol, 18.9% yield) as a yellow oil. ESI-MS: [M+H] + ,462.3.

[0333] 6) Synthesis steps of compound 9

[0334] Compound 8 (550 mg, 1.19 mmol, 1 eq) was dissolved in DCM (3 mL) and HCl / dioxane (4 M, 3 mL) was added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. LCMS detected the reaction to be complete. The reaction solution was concentrated under reduced pressure and water (10 mL) was added. The pH was adjusted to 8 with saturated sodium carbonate solution and extracted with EtOAc (2 mL*3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and dried to give compound 9 (400 mg, 1.11 mmol, 92.8% yield) as a yellow solid. ESI-MS: [M+H] + ,362.2.

[0335] 7) Synthesis steps of compound 10

[0336] Compound 9 (400 mg, 1.11 mmol, 1 eq) was dissolved in toluene (8 mL), and CDI (1.08 g, 6.64 mmol, 6 eq) was added at 25°C. The reaction mixture was reacted at 110°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (2 mL x 3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The washed organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (SiO2, EtOAc / Methanol, 10 / 1) to obtain the target compound 10 (212 mg, 547 μmol, 49.4% yield) as a yellow solid. ESI-MS: [M+H] + ,388.2.

[0337] 8) Synthesis steps of compound 12

[0338] Compound 10 (210 mg, 542 μmol, 1 eq) and compound 11 (273 mg, 813 μmol, 1.5 eq) were dissolved in dioxane (4.2 mL). Cs2CO3 (529 mg, 1.63 mmol, 3 eq), Xantphos (31.3 mg, 54.2 μmol, 0.1 eq), and Pd2(dba)3 (49.6 mg, 54. 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 solution was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with EtOAc (2 mL*3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by silica gel chromatography (SiO2, PE / EtOAc, 0 / 1) to afford the target compound 12 (64 mg, 107 μmol, 19.8% yield) as a yellow oil. ESI-MS: [M+H] + ,596.2.

[0339] 9) Synthesis steps of compound GDI15-7945

[0340] Compound 12 (64 mg, 107 μmol, 1 eq) was dissolved in DCM (2.5 mL) and Eaton's reagent (757 mg, 3.18 mmol, 0.5 mL, 29.6 eq) was added at 25°C. The reaction mixture was allowed to react at 25°C for 1 hour, and the reaction was complete by LCMS. The reaction mixture was added directly to water (5 mL), and the pH was adjusted to 9 with saturated Na2CO3. The mixture was then extracted with DCM (2 mL*3). The organic phases were combined and concentrated under reduced pressure. HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 38%-68% B over 8.0 min) afforded the target compound GDI15-7945 (9.8 mg, 19.3 μmol, 18.1% yield, 100% purity) as a white solid. ESI-MS:[M+H] + ,506.1.

[0341] 1H NMR (400MHz, DMSO) δ9.37(s,1H),8.48-8.41(m,1H),8.24(d,J=8.1Hz,1H),7.89-7.78(m,2H),7.75(t,J=7.4Hz,1H),7.25(s, 1H),7.15(dd,J=1.9,3.4Hz,2H),5.33(s,1H),4.87(q,J=8.8Hz,2H),4.28-4.15(m,3H),2.91-2.79(m,2H),2.18-2.00(m,2H)

[0342] Example 36: Preparation of compound GDI15-8075

[0343] Compound 10 (53.0 mg, 88.9 μmol, 1 eq) was dissolved in DCM (1 mL) and Eaton's reagent (0.2 mL) was added at 25°C. The reaction mixture was allowed to react for 1 hour at 25°C. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The pH of the reaction solution was adjusted to 8 with saturated NaHCO₃ solution, and then extracted with DCM (2 mL x 3). The organic phases were combined and washed with saturated sodium chloride (3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by HPLC (column: Waters xbridge 150 x 25 mm 10 μm; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 30% to 60% B over 8.0 min) to afford the target compound GDI15-8075 (2 mg, 3.42 μmol, 3.85% yield) as a yellow solid. ESI-MS:[M+H] + ,584.1.

[0344] 1 H NMR(400MHz,Chloroform-d3)δ9.25(s,1H),8.34(s,1H),8.02(d,J=8.3Hz,1H),7.73-7 .66(m,1H),7.63-7.57(m,1H),7.47(d,J=8.1Hz,1H),7.02(t,J=1.7Hz,1H),6.87(t,J=2 .1Hz,1H),6.81(t,J=1.9Hz,1H),5.19(t,J=6.4Hz,1H),4.28(q,J=7.9Hz,2H),4.18-4.0 0(m,2H),3.22-3.13(m,2H),3.01-2.95(m,3H),2.60(d,J=6.0Hz,1H),2.49-2.37(m,1H)

[0345] Example 37: Preparation of compound GDI15-8392

[0346] Compound GDI15-7945 (10 mg, 19.7 μmol, 1 eq) was dissolved in DCM (0.5 mL). DMP (12.5 mg, 29.6 μmol, 9.19 μL, 1.5 eq) was added at 25°C. The reaction mixture was allowed to react at 25°C for 1 hour. LCMS confirmed the reaction was complete. Water (2 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 mL x 3). The organic phases were combined, concentrated under reduced pressure, and purified by HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 40% to 70% B over 8.0 min) to afford the target compound GDI15-8392 (4.1 mg, 7.85 μmol, 39.7% yield, 96.9% purity) as a white solid. ESI-MS:[M+H] + ,506.2.

[0347] 1 H NMR (400MHz, DMSO) δ9.39 (s, 1H), 8.55 (s, 1H), 8.25 (d, J = 8.3Hz, 1H), 7.92-7.81 (m, 2H), 7.80-7.71 (m, 1H), 7.30 (s, 1H), 7.18 (d,J=6.3Hz,2H),4.86(q,J=8.6Hz,2H),4.53-4.44(m,1H),4.43-4.37(m,1H),3.73-3.60(m,2H),3.47(dd,J=6.7,12.4Hz,2H)

[0348] Example 38: Preparation of compound GDI15-8505

[0349] 1) Synthesis steps of compound 1

[0350] Compound GDI15-8392 (40 mg, 79.3 μmol, 1 eq) and BnNH2 (25.5 mg, 238 μmol, 25.9 μL, 3 eq) and Ti(i-PrO)4 (90.2 mg, 317 μmol, 93.7 μL, 4 eq) were dissolved in EtOH (2 mL) in sequence. The reaction mixture was reacted at 50°C for 5 hours, then cooled to 25°C, and NaBH3CN (14.9 mg, 238 μmol, 3 eq) was added. The reaction mixture was continued to react at 50°C for 16 hours. The reaction was completed by LCMS detection. The reaction mixture was dried under reduced pressure and purified by HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 35%-70% B over 8.0 min) to afford the title compound 1 (16 mg, 2.58 μmol, 3.25% yield, 96% purity) as a white solid. ESI-MS: [M+H] + ,596.2.

[0351] 1 H NMR (400MHz, DMSO) δ9.37 (s, 1H), 8.44 (d, J = 13.6Hz, 1H), 8.24 (d, J = 8.0Hz, 1H), 7.88-7.82 (m, 1H) ,7.80-7.72(m,2H),7.32-7.23(m,3H),7.27-7.23(m,1H),7.23-7.18(m,1H),7.17-7.13(m,2H),5. 76(s,1H),4.89-4.82(m,2H),4.23(q,J=12.4Hz,1H),4.17(s,1H),3.63(d,J=4.6Hz,2H),3.48(t,J =7.7Hz,1H),2.80-2.73(m,1H),2.34-2.22(m,2H),2.12-2.03(m,1H),1.98(dd,J=7.4,12.6Hz,1H)

[0352] 2) Synthesis steps of compound GDI15-8505

[0353] Under argon, Pd / C (90.1 mg, 84.7 μmol, 10% purity) was added to a reaction flask, followed by EtOAc (6 mL) added along the side of the flask. Compound 1 (30 mg, 50.4 μmol, 1 eq) and ZnBr (11.3 mg, 50.4 μmol, 2.52 μL, 1 eq) were added sequentially under argon. Under a hydrogen balloon, the reaction mixture was allowed to react at 40°C for 16 hours, and the reaction was complete by LCMS. The reaction mixture was filtered through Celite, and the filtrate was evaporated to dryness under reduced pressure. The product was purified by HPLC (column: Waters xbridge 150*25 mm 10 μm; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 27%-52% B over 8.0 min) to afford the target compound GDI15-8505 (5 mg, 8.32 μmol, 16.5% yield, 84% purity) as a white solid. ESI-MS: [M+H]+, 505.2.

[0354] 1H NMR (400MHz, DMSO) δ9.37 (s, 1H), 8.48-8.40 (m, 1H), 8.24 (d, J = 8.4Hz, 1H), 7.88-7.76 (m, 2H), 7.76-7.72 (m, 1H), 7.29-7.23 (m, 1H), 7.18-7.1 2(m,2H),4.90-4.82(m,2H),4.25-4.13(m,2H),3.60-3.39(m,1H),2.8 4-2.75(m,1H),2.69-2.63(m,1H),2.29-2.12(m,1H),2.05-1.82(m,2H)

[0355] Example 39: Preparation of compound GDI15-8660

[0356] Compound 11 (49.4 mg, 417 μmol, 3 eq, HCl) was dissolved in EtOH (3.5 mL). TEA (56.2 mg, 556 μmol, 77.4 μL, 4 eq) was added at 25°C, and the pH of the reaction solution was measured to be 7-8. Compound GDI15-8392 (70 mg, 139 μmol, 1 eq) and Ti(i-PrO)4 (158 mg, 556 μmol, 164 μL, 4 eq) were then added sequentially to the reaction solution. The reaction mixture was stirred at 50°C for 5 hours, and then NaBH3CN (43.7 mg, 695 μmol, 5 eq) was added. The reaction mixture was allowed to react at 50°C for another 16 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, added to H2O (5 mL), and extracted with EtOAc (5 mL x 3). The organic phases were combined and washed with saturated sodium chloride (5 mL). The combined organic phases were concentrated under reduced pressure and purified by HPLC (Phenomenex luna C18 100*40mm*5um column; mobile phase: [H2O(0.2% FA)-ACN)) to yield the target compound GDI15-8660 (12.7 mg, 22.3 μmol, 16.0% yield, 100% purity) as a white solid. ESI-MS: [M+H]+, 570.1.

[0357] 1H NMR(400MHz,Chloroform-d3)δ9.32(s,1H),8.50-8.36(m,1H),8.10(d,J=8.0Hz,1H),7.80(t,J=7.4Hz,1H), 7.74-7.66(m,1H),7.64-7.52(m,1H),7.21-7.06(m,1H),7.02-6.94(m,1H),6.92-6.77(m,1H),4.42-4.30(m ,2H),4.23-4.11(m,1H),4.10-4.00(m,1H),3.94-3.67(m,1H),3.20-3.11(m,0.5H),2.80(ddd,J=3.8,7.6,1 1.8Hz,0.5H),2.73-2.64(m,1H),2.62-2.55(m,1H),2.23-1.96(m,1H),1.32-1.16(m,2H),1.13-0.99(m,2H)

[0358] Example 40: Preparation of compound GDI15-8661

[0359] Compound 11 (50.5 mg, 298 μmol, 3 eq, HCl) was dissolved in EtOH (2.5 mL). TEA (40.2 mg, 397 μmol, 55.3 μL, 4 eq) was added at 20°C, and the pH of the reaction solution was measured to be 7-8. Compound GDI15-8392 (50 mg, 99.2 μmol, 1 eq) and Ti(i-PrO)4 (113 mg, 397 μmol, 117 μL, 4 eq) were then added sequentially to the reaction solution. The reaction mixture was stirred at 50°C for 5 hours, and then NaBH3CN (31.2 mg, 496 μmol, 5 eq) was added. The reaction mixture was allowed to react at 50°C for 16 hours, and the reaction was complete as determined by LCMS. The reaction solution was concentrated under reduced pressure, added to H2O (5 mL), and extracted with EtOAc (5 mL x 3). The organic phases were combined and washed with saturated sodium chloride (5 mL). The combined organic phases were concentrated under reduced pressure and purified by HPLC (Phenomenex luna C18 100*40mm*5um column; mobile phase: [H2O(0.2% FA)-ACN)) to yield the target compound GDI15-8661 (28.7 mg, 46.2 μmol, 46.6% yield, 100% purity) as a white solid. ESI-MS: [M+H]+, 621.2.

[0360] 1H NMR (400MHz, Chloroform-d3) δ9.32 (s, 1H), 8.41 (s, 1H), 8.09 (d, J = 8.0Hz, 1H), 7.81-7. 72(m,1H),7.71-7.63(m,1H),7.55(dd,J=3.7,8.4Hz,1H),7.17-7.09(m,1H),7.03-6.95 (m,1H),6.88(s,1H),4.41-4.32(m,2H),4.31-4.22(m,1H),4.16-4.03(m,1H),3.48-3.3 8(m,4H),2.84-2.57(m,7H),2.41-2.33(m,0.5H),2.25-2.15(m,1H),2.10-2.04(m,0.5H)

[0361] Example 41: Preparation of compound GDI15-7945

[0362] Compound GDI15-8392 (50 mg, 99.2 μmol, 1 eq) was dissolved in THF (2 mL). CsF (22.6 mg, 149 μmol, 1.5 eq) and TMSCF₃ (28.2 mg, 198 μmol, 2 eq) were added sequentially at 0°C. The reaction mixture was allowed to react at 25°C under nitrogen for 5 hours. The reaction solution was concentrated under reduced pressure and analyzed by HPLC (column: WePure Biotech XP tC18 150*40*7 μm; mobile phase: [H₂O(10 mM NH₄HCO₃)-CN]; gradient: 45%-75% B over 8.0 min) to obtain the TMS-protected product. After two freeze-drying cycles, the TMS was completely removed to obtain the final product, GDI15-8574 (2.5 mg, 4.3 μmol, 89.8% purity, 3.94% yield), as a white solid. ESI-MS: [M+H] + ,574.1.

[0363] 1H NMR (400MHz, DMSO) δ9.39 (s, 1H), 8.50 (s, 1H), 8.26 (d, J = 8.1Hz, 1H), 7.86 (d, J = 3.8Hz, 2H), 7.76 (td, J = 4. 0,8.1Hz,1H),7.28(s,1H),7.17(s,2H),6.84(s,1H),4.86(q,J=8.8Hz,2H),4.11(s,2H),2.85-2.59(m,4H)

[0364] Example 42: Preparation of compound GDI15-7597

[0365] 1) Synthesis steps of compound 2

[0366] To a mixture of compound 1 (2.00 g, 13.5 mmol), LiOH (0.62 g, 14.9 mmol) and H2O (0.49 g, 27.0 mmol) was added THF (20 mL) and stirred at 70°C for 4 h. The mixture was then lyophilized to obtain the target compound 2.

[0367] 1 H NMR (400MHz, DMSO) δ4.72 (t, J = 5.6 Hz, 1H), 3.20 (s, 6H), 2.24 (d, J = 5.6 Hz, 2H).

[0368] 2) Synthesis steps of compound 4

[0369] To a solution of compound 3 (1 g, 0.0071 mol) in DMF (5 mL) were slowly added HATU (5.40 g, 14.2 mmol), DIPEA (2.75 g, 21.3 mmol), and compound 3 (0.85 g, 7.1 mmol). The reaction was stirred at room temperature under nitrogen for 12 h. After the reaction, water (50 mL) was added 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 dried. The mixture was further purified by column chromatography (EtOAc / PE, 40% to 50%) to afford compound 4 (1.0 g, 60.56% yield) as a colorless oil. ESI-MS: [M+H] + ,236.0

[0370] 3) Synthesis steps of compound 6

[0371] To a solution of compound 4 (600 mg, 2.55 mmol) in DCM (6 mL) were slowly added compound 5 (577.97 mg, 2.55 mmol), TFA (3 mL), and Et3SiH (741.40 mg, 6.38 mmol), followed by stirring at room temperature for 16 h. After completion of the reaction, Na2CO3 solution was added, the solution was adjusted to pH 8-9, and 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 column chromatography (EtOAc / PE, 40% to 42%) to afford compound 6 (400 mg, 39.23% yield) as a white solid. ESI-MS: [M+H] + ,399.0.

[0372] 3) Synthesis steps of compound GDI15-7597

[0373] To a toluene solution (3 mL) of compound 6 (300.00 mg, 0.75 mmol) was added CDI (730.02 mg, 4.50 mmol), and the mixture was stirred at 110°C for 2.5 hours. After the reaction, water (100 mL) was added 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 column chromatography (EtOAc / PE, 30% to 35%) to afford compound GDI15-7597 (105.62 mg, 33.06% yield) as a white solid. ESI-MS: [M+H] + , 425.1.

[0374] 1H NMR (400MHz, DMSO) δ9.04(d,J=1.6Hz,1H),8.82(d,J=2.0Hz,1H),8.37(m,1H),7.24(t,1H ),7.17–7.11(m,2H),4.85(q,J=8.8Hz,2H),3.98(t,J=6.4Hz,2H),3.04(t,J=6.4Hz,2H).

[0375] Example 43: Preparation of compound GDI15-7639

[0376] 1) Synthesis steps of compound 3

[0377] Under nitrogen at room temperature, HATU (5.40 g, 0.0142 mol), DIPEA (2.56 g, 0.0213 mol), and compound 2 (0.80 g, 0.0071 mol) were slowly added to a solution of compound 1 (1.00 g, 0.0071 mol) in DMF (10 mL). The mixture was allowed to react for 12 hours at room temperature. LCMS monitored the reaction completion. After completion, 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 dried. Further purification by column chromatography (EtOAc / PE, 30% to 35%) afforded compound 3 (1 g, 61.97% yield) as a yellow oil. ESI-MS: [M+H] + ,228.9.

[0378] 2) Synthesis steps of compound 5

[0379] To a solution of compound 3 (600 mg, 2.63 mmol) in DCM (6 mL) was slowly added compound 4 (595.74 mg, 2.63 mmol), TFA (3 mL), and Et3SiH (1079.66 mg, 6.57 mmol) at room temperature under nitrogen. The mixture was allowed to react for 16 h. After completion of the reaction, saturated sodium bicarbonate solution was added to adjust the pH to 8-9, 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 column chromatography (EtOAc / PE, 30% to 35%) to afford compound 5 (400 mg, 38.74% yield) as a yellow solid. ESI-MS: [M+H] + ,392.1.

[0380] 3) Synthesis steps of compound GDI15-7639

[0381] To a toluene solution (3 mL) of compound 5 (300.00 mg, 0.7638 mmol) was added CDI (743.06 mg, 4.58 mmol), and the reaction mixture was heated to 110°C for 2.5 hours. 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 (EtOAc / PE, 30% to 35%) to afford compound GDI-7639 (47.03 mg, 14.70% yield) as a white solid. ESI-MS: [M+H] + ,418.0.

[0382] 1 H NMR (400MHz, DMSO) δ8.62(d,J=2.4Hz,1H),8.40(t,1H),7.82(dt,J=9.6,2.0Hz,1H),7.23(t,1H) ,7.14(dd,J=3.8,1.8Hz,2H),4.85(q,J=8.8Hz,2H),3.97(t,J=6.6Hz,2H),3.02(t,J=6.4Hz,2H).

[0383] Example 44: Preparation of compound GDI15-7820

[0384] 1) Synthesis steps of compound 3

[0385] Compound 1 (2 g, 11.5 mmol, 1 eq) and compound 2 (3.63 g, 17.3 mmol, 1.70 mL, 1.5 eq) were sequentially dissolved in MeCN (40 mL). K2CO3 (6.37 g, 46.1 mmol, 4 eq) was added at 25°C. 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 water (20 mL) was added. The mixture was extracted with EtOAc (10 mL x 3). The organic phases were combined and washed with saturated sodium chloride (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / EtOAc, 20 / 1 to 5 / 1) to afford the target compound 3 (1.8 g, 6.43 mmol, 55.8% yield, 91.3% purity) as a yellow oil. ESI-MS: [M+H] + ,255.9.

[0386] 2) Synthesis steps of compound 4

[0387] Compound 3 (1.8 g, 7.04 mmol, 1 eq) was dissolved in EtOH (36 mL) and H₂O (9 mL). NH₄Cl (2.26 g, 42.3 mmol, 6 eq) was added at 25°C. The temperature was raised to 60°C, and Fe powder (2.36 g, 42.3 mmol, 6 eq) was added portionwise. The reaction mixture was allowed to react at 80°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was filtered while hot, concentrated to dryness under reduced pressure, and extracted with EtOAc (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by column chromatography (SiO₂, Petroleum ether / EtOAc, 20 / 1 to 3 / 1) to afford compound 4 (1.6 g, 6.10 mmol, 86.6% yield, 86.0% purity) as a yellow oil. ESI-MS: [M+H] + ,226.1.

[0388] 3) Synthesis steps of compound 5

[0389] Compound 5-1 (2.0 g, 21.3 mmol, 1 eq) and compound 5-2 (1.53 g, 21.3 mmol, 1 eq) were dissolved in pyridine (20 mL), and EDCI (4.07 g, 21.3 mmol, 1 eq) was added portionwise at 0°C. The reaction mixture was reacted at 25°C for 2 hours, and the reaction was complete by LCMS. The reaction solution was concentrated under reduced pressure, and water (5 mL) was added. The mixture was extracted with EtOAc (3 mL*3). The organic phases were combined and washed with saturated sodium chloride (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by column chromatography (SiO2, Petroleum ether / EtOAc, 20 / 1 to 5 / 1) to obtain the target compound 5 (1.11 g, 7.49 mmol, 35.3% yield) as a yellow oil. ESI-MS: [M+H] + ,149.1.

[0390] 4) Synthesis steps of compound 6

[0391] Compound 5 (0.3 g, 2.02 mmol, 1 eq) and compound 4 (548 mg, 2.43 mmol, 1.2 eq) were sequentially dissolved in AcOH (3 mL). The reaction mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (5 mL) was added. The mixture was extracted with EtOAc (3 mL x 3). The organic phases were combined and washed with saturated sodium chloride (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified on a silica gel plate (SiO2, petroleum ether / EtOAc, 1 / 1) to obtain the target compound 6 (0.24 g, 591 μmol, 29.2% yield, 92% purity) as a yellow solid. ESI-MS: [M+H] + ,374.1.

[0392] 5) Synthesis steps of compound GDI15-7820

[0393] Compound 6 (120 mg, 2.02 mmol, 1 eq) and compound CDI (315 mg, 1.94 mmol, 6 eq) were dissolved in toluene (2.4 mL). The reaction mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (5 mL) was added. The mixture was extracted with EtOAc (3 mL x 3). The organic phases were combined, filtered under reduced pressure, and dried by spin drying. The mixture was then purified by HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 21%-51% B in 8.0 min SiO2, petroleum ether / EtOAc, 1 / 1) to afford the target compound GDI15-7820 (16.4 mg, 40.4 μmol, 12.6% yield, 98.6% purity) as a yellow solid. ESI-MS: [M+H]+, 400.1.

[0394] 1 H NMR (400MHz, DMSO) δ8.55(dd,J=1.5,4.8Hz,1H),8.46(d,J=2.2Hz,1H),7.76-7.70(m,1H),7.50(dd,J=4.8,8.1Hz,1 H),7.22(t,J=1.7Hz,1H),7.13(q,J=2.1Hz,2H),4.84(d,J=8.8Hz,2H),3.97(t,J=6.5Hz,2H),3.02(t,J=6.5Hz,2H)

[0395] Example 45: Preparation of compound GDI15-7958

[0396] 1) Synthesis steps of compound 3

[0397] To a mixture of compound 1 (500 mg, 4.03 mmol, 1 eq) and compound 2 (540 mg, 4.03 mmol, 1 eq) was added DMF (5 mL). HATU (2.29 g, 6.05 mmol) and DIPEA (1.56 g, 12.09 mmol) were then added under nitrogen at 0°C. The mixture was allowed to react for 12 h at room temperature. After completion of the reaction, water (10 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with saturated brine, dried over sulfuric acid, filtered, and subjected to spin chromatography (MeOH / DCM, 0% to 2%) to afford compound 3 (600 mg, 62% yield) as a brown oil. ESI-MS: [M+H]+, 241.05.

[0398] 2) Synthesis steps of compound 5

[0399] To a mixture of compound 3 (550 mg, 2.28 mmol) and compound 4 (513 mg, 2.28 mmol) was added DCM (5 mL). Et3SiH3 (663 mg, 5.7 mmol) and TFA (2.28 mL) were then added under nitrogen at room temperature. The mixture was stirred at room temperature for 1 h. After the reaction, aqueous NaHCO3 was added to adjust the pH to 8-9. The mixture was filtered, and the filter cake was collected and washed with water to yield compound 5 (600 mg, 71% yield) as a white solid. ESI-MS: [M+H]+, 404.00.

[0400] 3) Synthesis steps of compound GDI15-7958

[0401] Toluene (5 mL) was added to compound 5 (300 mg, 0.74 mmol), followed by CDI (722 mg, 4.45 mmol). The mixture was stirred at 100°C for 2 h. After the reaction, the mixture was concentrated, and the remaining residue was further purified by prep-HPLC (Gemini 5 μm C18 column, 150×21.2 mm, eluent with 75% to 95% MeCN / H2O containing 0.1% TFA) to afford compound GDI15-7958 (17.97 mg, 6.25% yield) as a white solid.

[0402] ESI-MS: [M+H]+, 430.00. 1 H NMR (400MHz, DMSO) δ8.31(d,J=2.8Hz,1H),8.09(d,J=1.6Hz,1H),7.43-7.38(m,1H),7.23(t,J=1.6Hz,1H), 7.13(dd,J=3.2,2.0Hz,2H),4.85(q,J=8.8Hz,2H),3.97(t,J=6.4Hz,2H),3.84(s,3H),3.01(t,J=6.4Hz,2H).

[0403] Example 46: Preparation of compound GDI15-7987

[0404] 1) Synthesis steps of compound 3

[0405] Compound 1 (800 mg, 7.41 mmol, 1 eq) and compound 2 (1 g, 7.41 mmol, 1 eq) were added with DMF (8 mL). HATU (4.25 g, 11.1 mmol) and DIPEA (2.87 g, 22.2 mmol) were then added under nitrogen at 0°C. The mixture was stirred at room temperature for 12 h. After completion of 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 purified by column chromatography (MeOH / DCM, 0% to 5%) to afford compound 3 (1.3 g, 78% yield) as a red solid. ESI-MS: [M+H]+, 242.95.

[0406] 2) Synthesis steps of compound 5

[0407] To a mixture of compound 3 (300 mg, 1.34 mmol) and compound 4 (302 mg, 1.34 mmol) was added DCM (5 mL). Et3SiH3 (390 mg, 3.35 mmol) and TFA (1.34 mL) were then slowly added under nitrogen at room temperature. The mixture was allowed to react for 1 h. After completion of the reaction, aqueous NaHCO3 solution was added to the mixture, adjusting the pH to 8-9. The mixture was filtered, and the filter cake was washed with water to yield compound 5 (350 mg, 67% yield) as a white solid. ESI-MS: [M+H]+, 388.05.

[0408] 3) Synthesis steps of compound GDI15-7987

[0409] Toluene (5 mL) was added to compound 5 (350 mg, 0.90 mmol), followed by CDI (877 mg, 5.41 mmol). The reaction was stirred at 100°C for 2 h. After completion of the reaction, the system was concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150×21.2 mm, eluent with 75% to 95% MeCN / H₂O containing 0.1% TFA) to afford compound GDI15-7987 (52.11 mg, 13.94% yield) as a white solid. ESI-MS: [M+H]⁺, 414.00.

[0410] 1 H NMR (400MHz, DMSO) δ8.46(s,1H),8.34(d,J=7.6Hz,1H),7.69(s,1H),7.22(t,J=1.6Hz,1H),7.1 5-7.07(m,2H),4.83(t,J=8.8Hz,2H),3.97(t,J=6.4Hz,2H),3.01(t,J=6.4Hz,2H),2.36(s,3H).

[0411] Example 47: Preparation of compound GDI15-8050

[0412] 1) Synthesis steps of compound 3

[0413] Compound 1 (1 g, 5.4 mmol), compound 2 (1.17 g, 6.4 mmol), t-BuOK (1.82 g, 16.2 mmol), BINAP (1.34 g, 2.1 mmol), and Pd2(dba)3 were dissolved in toluene (25 mL) and stirred at 90°C under nitrogen for 16 h. LCMS confirmed the reaction was complete. After returning to room temperature, 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 purified by column chromatography (DCM / TEA, 200 v:1 v) to afford compound 3 (1.4 g, 4.9 mmol, 90.74% yield) as a yellow solid. ESI-MS: [M+H]+, 287.15.

[0414] 2) Synthesis steps of compound 4

[0415] Under nitrogen at room temperature, HCl / MeOH (20 mL) was added to compound 3 (1.4 g, 4.9 mmol) and stirred at room temperature for 2 h. After the reaction, the system was concentrated in vacuo to dryness to obtain the crude product, compound 4 (520 mg, 87.76% yield), as a yellow solid. ESI-MS: [M+H]+, 123.0.

[0416] 3) Synthesis steps of compound 6

[0417] Compound 4 (520 mg, 4.26 mmol) was added with DMF (6 mL), followed by compound 5 (628 mg, 4.68 mmol), DIPEA (1.65 g, 12.77 mmol), and HATU (2.4 g, 6.38 mmol) under nitrogen. The reaction was stirred at room temperature for 16 h. After completion of the reaction, water (10 mL) 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 (MeOH / DCM, 2% to 3%) to afford compound 6 (210 mg, 20.71% yield) as a yellow solid. ESI-MS: [M+H]+, 239.3.

[0418] 4) Synthesis steps of compound 8

[0419] Compound 6 (210 mg, 0.88 mmol) was added with DCM (5 mL), followed by the slow addition of compound 7 (240 mg, 1.06 mmol), TFA (1 mL), and Et3SiH (290 mg, 1.76 mmol). The reaction was allowed to proceed under nitrogen for 16 h at room temperature. After completion of the reaction, sodium carbonate solution was added, the pH was adjusted to 8-9, 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 column chromatography (EtOAc / PE, 40% to 42%) to afford compound 8 (130 mg, 36.62% yield) as a white solid. ESI-MS: [M+H]+, 402.15.

[0420] 5) Synthesis steps of compound GDI15-8050

[0421] Toluene (5 mL) was added to compound 8 (130 mg, 0.32 mmol), followed by 262 mg (1.61 mmol). The mixture was allowed to react at 110°C for 2 h, and the reaction was complete by LCMS. The mixture was then concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150×21.2 mm, eluent: 75% to 95% MeCN / H₂O containing 0.1% FA) to afford compound GDI15-8050 (4.88 mg, 3.53% yield) as a white solid. ESI-MS: [M+H]⁺, 428.0.

[0422] 1 H NMR (400MHz, DMSO) δ8.31 (s, 1H), 8.18 (s, 1H), 7.22 (t, J = 1.7Hz, 1H), 7.13 (m, 2 H),4.83(t,J=8.9Hz,2H),4.02(m,2H),3.06(m,2H),2.27(s,3H),2.04(s,3H).

[0423] Example 48: Preparation of compound GDI15-8208

[0424] 1) Synthesis steps of compound 2

[0425] To compound 1 (1 g, 4 mmol) and 1) was added dioxane (15 mL). Tert-butyl carbamate (790 mg, 6.7 mmol), Cs2CO3 (4.4 g, 13.4 mmol), Xantphos (1.04 g, 1.8 mmol), and Pd2(dba)3 (820 mg, 0.9 mmol) were then added under nitrogen. The mixture was stirred at 100°C for 16 h. After completion of the reaction, water (5 mL) 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 (MeOH / DCM, 2% to 3%) to afford compound 2 (1.1 g, 95.56% yield) as a yellow solid. ESI-MS: [M+H]+, 259.20.

[0426] 2) Synthesis steps of compound 3

[0427] To compound 1 (1.1 g, 4.3 mmol) was added dropwise HCl / MeOH (10 mL) at 0°C. The mixture was then slowly warmed to room temperature and stirred for 2 h. A small amount of a MeOH / DCM mixed solution and NaHCO₃ (1.08 g, 12.9 mmol) were then added. After completion of the reaction, the mixture was filtered and concentrated in vacuo to afford the crude product, compound 3 (600 mg, 88.37% yield), which was used directly in the next step without further purification. ESI-MS: [M+H]⁺, 159.28.

[0428] 3) Synthesis steps of compound 5

[0429] Compound 3 (560 mg, 3.54 mmol), compound 4 (570 mg, 4.25 mmol), pyridine (1.4 g, 17.70 mmol), and POCl3 (1.09 g, 7.08 mmol) were added with DCM (10 mL). The mixture was stirred at room temperature under nitrogen for 3 h. LCMS confirmed the reaction was complete. After completion, 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 (DCM / MeOH, 20 v:1 v) to afford compound 5 (220 mg, 0.80 mmol, 22.66% yield) as a yellow solid. ESI-MS: [M+H]+, 275.0.

[0430] 4) Synthesis steps of compound 7

[0431] Compound 5 (220 mg, 0.80 mmol) was added with DCM (4 mL). Compound 6 (200 mg, 0.88 mmol), TFA (1 mL), and Et3SiH (395 mg, 2.4 mmol) were then slowly added under nitrogen. The mixture was stirred at room temperature for 16 h. After completion of the reaction, sodium carbonate solution was added to adjust the pH to 8-9 and the mixture was extracted with EtOAc (20 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, 40% to 42%) to afford compound 7 (150 mg, 36.62% yield) as a white solid. ESI-MS: [M+H]+, 438.0.

[0432] 4) Synthesis steps of compound GDI15-8208

[0433] Toluene (5 mL) was added to compound 7 (150 mg, 0.34 mmol), followed by the addition of CDI (554 mg, 3.42 mmol). The mixture was stirred at 110°C for 12 h. LCMS confirmed the reaction was complete, and the reaction mixture was concentrated. The residue was further purified by prep-HPLC (Gemini 5 μm C18 column, 150×21.2 mm, eluent with 75% to 95% MeCN / H₂O containing 0.1% FA) to afford compound GDI15-8208 (35.84 mg, 22.56% yield) as a white solid. ESI-MS: [M+H]⁺, 464.05.

[0434] 1H NMR (400MHz, DMSO) δ9.27(s,1H),8.39(s,1H),8.12(d,J=8.4Hz,1H),7.66(s,1H),7.57(d,J=8.5Hz,1H ),7.26(t,J=1.8Hz,1H),7.15(m,2H),4.86(m,2H),4.14(m,2H),3.25(m,1H),3.07(m,1H),2.55(s,3H).

[0435] Example 49: Preparation of compound GDI15-8242

[0436] 1) Synthesis steps of compound 3

[0437] Compound 1 (250 mg, 1.54 mmol) was added with DCM (5 mL). Compound 2 (227 mg, 1.70 mmol), DIPEA (598 mg, 4.63 mmol), and POCl₃ (473 mg, 3.08 mmol) were then added under nitrogen. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the system was concentrated, and the residue was further purified by prep-HPLC (Gemini 5 μm C₁₈ column, 150×21.2 mm, eluent with 30% to 90% MeCN / H₂O containing 0.1% FA) to afford compound 3 (109 mg, 25.41% yield) as a yellow solid. ESI-MS: [M+H]₁, 279.10.

[0438] 2) Synthesis steps of compound 5

[0439] Compound 3 (109 mg, 0.39 mmol) was added with DCM (5 mL). Compound 4 (98 mg, 0.43 mmol), TFA (1 mL), and Et3SiH (193 mg, 1.18 mmol) were then slowly added under nitrogen at room temperature. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, aqueous Na2CO3 solution was added to adjust the pH to 8-9. 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, 40% to 42%) to afford compound 5 (45 mg, 25.94% yield) as a yellow oil. ESI-MS: [M+H]+, 441.95.

[0440] 3) Synthesis steps of compound GDI15-8242

[0441] Toluene (5 mL) was added to compound 5 (20 mg, 0.045 mmol), followed by CDI (44 mg, 0.27 mmol). The mixture was stirred at 110°C for 2 h. LCMS confirmed the reaction was complete. After completion, the system was concentrated, and the remaining residue was further purified by prep-HPLC (Gemini 5 μm C18 column, 150×21.2 mm, eluent with 75% to 95% MeCN / H2O containing 0.1% FA) to afford compound GDI15-8242 (3.00 mg, 14.16% yield) as a white solid. ESI-MS: [M+H]+, 468.00.

[0442] 1H NMR (400MHz, DMSO) δ9.37(s,1H),8.48(s,1H),8.36(m,1H),7.82(d,J=10.0Hz,1H),7.66(m,1H),7.26(s,1H ),7.14(d,J=6.2Hz,2H),4.84(t,J=8.8Hz,2H),4.13(m,2H),3.26(d,J=8.3Hz,1H),3.03(d,J=16.6Hz,1H).

[0443] Example 50: Preparation of compound GDI15-8241

[0444] 1) Synthesis steps of compound 2

[0445] Compound 1 (6 g, 32.1 mmol) and PhSO₃H (50 mg, 0.3 mmol) were dissolved in HFIP (60 mL), followed by the addition of DBDMH (5.5 g, 19.2 mmol). The mixture was stirred at 60°C for 12 h, followed by addition of water and extraction 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 (PE / EtOAc, 0% to 50%) to afford compound 2 (1.8 g, 6.8 mmol) as a yellow solid. ESI-MS: [M+H] + ,265.85.

[0446] 2) Synthesis steps of compound 3

[0447] To compound 2 (1.8 g, 6.8 mmol), NH2Boc (1.1 g, 8.8 mmol), Pd2(dba)3 (190 mg, 0.2 mmol), and Xantphos (200 mg, 0.3 mmol) was added dioxane (20 mL), followed by Cs2CO3 (4.4 g, 13.6 mmol). The mixture was stirred at 100°C for 16 h. After completion of the reaction, water was added and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (PE / EtOAc, 0% to 50%) to afford compound 3 (1.1 g, 3.6 mmol) as a yellow solid. ESI-MS: [M+H]+, 303.15.

[0448] 3) Synthesis steps of compound 4

[0449] To compound 3 (1.1 g, 3.6 mmol) was added 1M HCl in EtOAc (15 mL). The reaction was stirred at room temperature for 2 h. After completion of the reaction, the mixture was filtered, and the filter cake was dissolved in MeOH. NaHCO3 solution was then added, and the pH was adjusted to 7-8. The mixture was concentrated to afford compound 4 (700 mg, 3.4 mmol) as a yellow solid. ESI-MS: [M+H]+, 203.00.

[0450] 4) Synthesis steps of compound 6

[0451] To a mixture of compound 4 (700 mg, 3.4 mmol), compound 5 (652 mg, 4.1 mmol), and pyridine (1.4 g, 17.0 mmol) was added DCM (10 mL). POCl3 (1.5 g, 9.7 mmol) was then slowly added at 0°C. The mixture was gradually warmed to room temperature and stirred for 2 h. After completion of the reaction, sodium carbonate solution was added to quench the reaction. The combined organic phases were extracted, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (DCM / MeOH, 0% to 10%) to afford compound 6 (370 mg, 1.1 mmol) as a yellow solid. ESI-MS: [M+H] + ,318.95.

[0452] 4) Synthesis steps of compound 8

[0453] To compound 6 (370 mg, 1.1 mmol), compound 7 (237 mg, 1.1 mmol), and TFA (1.1 mL) was added DCM (4 mL). TES (479 mg, 2.9 mmol) was then slowly added to the mixture. The mixture was stirred at room temperature for 2 h. After the reaction, NaHCO₃ was added and the pH was adjusted to 7-8. Filtering afforded compound 8 (200 mg, 0.4 mmol) as a white solid. ESI-MS: [M+H] + ,482.00.

[0454] 5) Synthesis steps of compound GDI15-8241

[0455] To a solution of compound 8 (70 mg, 0.1 mmol) in MeCN (2 mL) was added CDI (1.12 g, 7.2 mmol). The reaction was stirred at 100°C for 1 h. After completion of 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 50%) to afford compound GDI15-8241 (30 mg, 0.06 mol) as a white solid. ESI-MS: [M+H]+, 508.00.

[0456] 1H NMR (400MHz, DMSO) δ9.50(s,1H),8.61(s,1H),8.39(d,J=8.6Hz,2H),8.23-8.12(m,1H),7.27(s,1H),7.22(d,J =13.2Hz,2H),4.86(q,J=8.8Hz,2H),4.23-4.07(m,2H),3.95(s,3H),3.30(d,J=5.8Hz,1H),3.19-2.99(m,1H).

[0457] Example 51: Preparation of compound GDI15-8110

[0458] 1) Synthesis steps of compound 1-3

[0459] Compound 1-1 (1 g, 4.44 mmol, 1 eq) and compound 1-2 (2.79 g, 13.3 mmol, 1.31 mL, 3 eq) were dissolved in DMF (20 mL). K2CO3 (2.45 g, 17.7 mmol, 4 eq) was added at 25°C. The reaction mixture was allowed to react at 100°C for 36 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined and washed with 100 mL of saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and separated by column chromatography (SiO2, petroleum ether / EtOAc, 20 / 1 to 5 / 1) to afford the target compound 1-3 (1.12 g, 3.64 mmol, 82.1% yield) as a colorless oil.

[0460] 2) Synthesis steps of compounds 1-4

[0461] Compound 1-3 (1.1 g, 3.58 mmol, 1 eq) was dissolved in dioxane (22 mL). BocNH2 (838 mg, 7.16 mmol, 2 eq), Cs2CO3 (2.33 g, 7.16 mmol, 2 eq), Xantphos (414 mg, 715 μmol, 0.2 eq), and Pd2(dba)3 (327 mg, 357 μmol, 0.1 eq) were added sequentially 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 filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (SiO2, Petroleum ether / EtOAc, 20 / 1 to 5 / 1) to afford the target compound 1-4 (0.83 g, 2.41 mmol, 67.5% yield) as a yellow solid. ESI-MS: [M+H] + ,288.2.

[0462] 3) Synthesis steps of compound 1

[0463] Compound 1-4 (830 mg, 2.41 mmol, 1 eq) was dissolved in DCM (8.3 mL) and 4 M HCl / dioxane (8.3 mL) was added at 25°C. The reaction mixture was allowed to react at 25°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and then added with water (10 mL). The pH was adjusted to 8 with saturated sodium carbonate solution, then extracted with EtOAc (5 mL*3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to give compound 1 (610 mg, 2.25 mmol, 93.3% yield, 90% purity) as a yellow solid. ESI-MS: [M+H] + ,244.0.

[0464] 4) Synthesis steps of compound 5

[0465] Compound 4 (250 mg, 1.26 mmol, 1 eq) and compound 1 (307 mg, 1.26 mmol, 1 eq) were dissolved in AcOH (2.5 mL). The reaction mixture was reacted at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (5 mL*3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and purified by silica gel chromatography (SiO2, Petroleum ether / EtOAc, 0 / 1) to obtain the target compound 5 (117 mg, 264 μmol, 21.0% yield) as a yellow solid. ESI-MS: [M+H] + ,442.2.

[0466] 5) Synthesis steps of compound GDI15-8110

[0467] Compound 5 (117 mg, 264 μmol, 1 eq) was dissolved in toluene (2.3 mL). CDI (257 mg, 1.59 mmol, 6 eq) was added at 25°C. The reaction mixture was allowed to react at 110°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with EtOAc (2 mL x 3). The organic phases were combined and washed with saturated sodium chloride (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure, and then purified by HPLC (column: 2-Phenomenex Gemini C18 75 x 40 mm x 3 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) to afford the target compound GDI15-8110 (50.6 mg, 108 μmol, 40.8% yield) as a yellow solid. ESI-MS:[M+H] + ,468.1.

[0468] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.45(s,1H),8.24(d,J=8.0Hz,1H),7.96-7.91(m,1H),7.84(t,J=7.2Hz,1H),7.7 7-7.71(m,1H),7.46-7.40(m,2H),4.93(q,J=8.7Hz,2H),4.16-4.06(m,2H),3.30-3.22(m,1H),3.13-3.05(m,1H).

[0469] Example 52: Preparation of compound GDI15-8320

[0470] 1) Synthesis steps of compound 1-3

[0471] Compound 1 (500 mg, 3.93 mmol) was added with DMF (5 mL). Compound 2 (1105 mg, 4.72 mmol) and K2CO3 (1.63 g, 11.8 mmol) were then added to the system under nitrogen at room temperature. The system was stirred at 60°C for 16 hours. After the reaction, water (50 mL) was added 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, 20% to 30%) to afford compound 3 (310 mg, 37.50% yield) as a brown solid. ESI-MS: [M+H] + ,209.95.

[0472] 2) Synthesis steps of compound 5

[0473] Compound 3 (245 mg, 0.94 mmol) was added with DCM (5 mL). Compound 4 (180 mg, 0.86 mmol), TFA (1 mL), and Et3SiH (422 mg, 2.57 mmol) were then added at room temperature under nitrogen. The mixture was allowed to react for 16 h. After completion of the reaction, the mixture was adjusted to pH 8-9 with aqueous Na2CO3 solution and 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 column chromatography (EtOAc / PE, 40% to 42%) to afford compound 5 (125 mg, 35.74% yield) as a white solid. ESI-MS: [M+H] + ,408.10.

[0474] 3) Synthesis steps of compound GDI15-8320

[0475] Toluene (5 mL) was added to compound 5 (125 mg, 0.31 mmol), followed by the addition of 298 mg (1.84 mmol). The mixture was reacted at 110°C for 2 h. LCMS confirmed the reaction was complete. The solution was concentrated and further purified by prep-HPLC (Gemini 5 μm C18 column, 150×21.2 mm, eluent with 75% to 95% MeCN / H2O containing 0.1% FA) to afford compound GDI15-8320 (80.92 mg, 60.86% yield) as a white solid. ESI-MS: [M+H] + ,434.05.

[0476] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.46(s,1H),8.24(d,J=8.1Hz,1H),7.94(d,J=8.4Hz,1H),7.84(t,J=7.6Hz,1H),7.7 5(t,J=7.5Hz,1H),7.03(d,J=6.0Hz,2H),6.96(d,J=10.6Hz,1H),4.83(m,2H),4.14(m,2H),3.25(m,1H),3.08(m,1H).

[0477] Example 53: Preparation of compound GDI15-8319

[0478] 1) Synthesis steps of compound 3

[0479] Compound 2 (631 mg, 2.70 mmol) and K2CO3 (932 mg, 6.74 mmol) were added to a solution of compound 1 (400 mg, 2.25 mmol) in DMF (5 mL). The mixture was reacted at 60°C under nitrogen for 16 h. After the reaction, water (50 mL) was added 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, 20% to 30%) to afford compound 3 (190 mg, 32.39% yield) as a brown solid. ESI-MS: [M+H] + ,260.0.

[0480] 2) Synthesis steps of compound 5

[0481] To a solution of compound 3 (208 mg, 0.80 mmol) in DCM (5 mL) were added compound 4 (190 mg, 0.73 mmol), TFA (1 mL), and Et3SiH (359 mg, 2.18 mmol). The mixture was reacted under nitrogen for 16 h at room temperature. After completion of the reaction, the pH of the reaction mixture was lowered to 8-9 with saturated Na2CO3 solution and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then subjected to column chromatography. Further purification by column chromatography (EtOAc / PE, 40% to 42%) afforded compound 5 (120 mg, 35.90% yield) as a yellow solid. ESI-MS: [M+H] + ,458.0.

[0482] 3) Synthesis steps of compound GDI15-8319

[0483] To a toluene (5 mL) solution of compound 5 (120 mg, 0.26 mmol) was added CDI (254 mg, 1.57 mmol). The mixture was stirred at 110°C for 2 hours. LCMS confirmed the reaction was complete. After completion, the mixture was concentrated and further purified by prep-HPLC (Gemini 5um C18 column, 150 x 21.2 mm, eluent: 75% to 95% MeCN / H2O containing 0.1% FA) to afford compound GDI15-8319 (75.22 mg, 59.32% yield) as a yellow solid. ESI-MS: [M+H] + ,484.0.

[0484] 1 H NMR (400MHz, DMSO) δ9.40(s,1H),8.48(s,1H),8.26(d,J=8.3Hz,1H),7.96(d,J=8.3Hz,1H),7.86(t,J=7.7Hz,1H ),7.76(t,J=7.4Hz,1H),7.50(s,1H),7.41(s,1H),4.93(m,2H),4.16(d,J=5.4Hz,2H),3.26(s,1H),3.12(s,1H).

[0485] Example 54: Preparation of compound GDI15-8688

[0486] 1) Synthesis steps of compound 3

[0487] Toluene (15 mL) was added to a mixture of compound 1 (1.5 g, 7.2 mmol), compound 2 (1.96 g, 10.8 mmol), t-BuONa (2.08 g, 21.6 mmol), BINAP (1.79 g, 2.8 mmol), and Pd2(dba)3 (1.32 g, 1.4 mmol). The mixture was stirred at 110°C under nitrogen for 16 h. LCMS monitored the reaction for completion. After completion, H2O (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 (MeOH / DCM, 3% to 5%) to afford compound 3 (1.3 g, 4.2 mmol, 58.33% yield) as a yellow solid. ESI-MS: [M+H] + ,310.0.

[0488] 2) Synthesis steps of compound 4

[0489] A mixed solution of HCl / MeOH (15 mL) was added to compound 3 (1.3 g, 4.2 mmol) and stirred at room temperature under nitrogen for 2 h. After the reaction, the system was concentrated to give the crude product, compound 4 (0.5 g, 80.95% yield), as a yellow solid. ESI-MS: [M+H] + ,146.2.

[0490] 3) Synthesis steps of compound 6

[0491] To a solution of compound 4 (510 mg, 3.51 mmol) and compound 5 (1.23 g, 5.27 mmol) in DMF (10 mL) was added K2CO3 (1.46 g, 10.54 mmol), and the mixture was stirred at 60°C for 12 h. After the reaction, water was added 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 column chromatography (PE / EtOAc, 0% to 10%) to afford compound 6 (260 mg, 1.14 mol, 32.43% yield) as a yellow oil. ESI-MS: [M+H] + ,227.95.

[0492] 3) Synthesis steps of compound 8

[0493] To a solution of compound 6 (260 mg, 1.14 mmol) and compound 7 (445 mg, 1.71 mmol) in DCM (5 mL) was added TFA (1 mL) and stirred at room temperature for 30 minutes. TES (562 mg, 3.42 mmol) was then added, and the mixture was stirred at room temperature for 12 hours. After the reaction, saturated sodium bicarbonate was added to adjust the pH to 7-8. The solid was filtered and washed with water to obtain compound 8 (140 mg, 0.33 mmol, 28.81% yield) as a white solid. ESI-MS: [M+H] + ,426.05.

[0494] 4) Synthesis steps of compound GDI15-8688

[0495] To a toluene solution (5 mL) of compound 8 (140 mg, 0.33 mmol) was added CDI (319 mg, 1.97 mmol), and the mixture was stirred at 100°C for 6 h. After the reaction, water was added and the mixture was extracted with EtOAc (80 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH, 0% to 5%) to afford compound GDI15-8688 (19.32 mg, 0.04 mmol, 13% yield) as a white solid. ESI-MS: [M+H] + ,452.0.

[0496] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.45(s,1H),8.24(d,J=8.2Hz,1H),7.93(d,J=8.3Hz,1H),7.84(t,J =7.3Hz,1H),7.75(t,J=7.4Hz,1H),7.31(m,2H),4.94(m,2H),4.11(m,2H),3.26(m,1H),3.10(m,1H).

[0497] Example 55: Preparation of compound GDI15-8532

[0498] 1) Synthesis steps of compound 3

[0499] Toluene (30 mL) was added to a mixture of compound 1 (2 g, 8.9 mmol), compound 2 (2.42 g, 13.3 mmol), t-BuONa (2.57 g, 26.7 mmol), BINAP (1.11 g, 1.7 mmol), and Pd2(dba)3 (0.81 g, 0.8 mmol). The mixture was stirred at 110°C under nitrogen for 16 h. LCMS confirmed the reaction was complete. After completion, 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 using MeOH / DCM (3% to 5%) to afford compound 3 (2.8 g, 8.6 mmol, 96.63% yield) as a yellow solid. ESI-MS: [M+H] + ,326.0.

[0500] 2) Synthesis steps of compound 4

[0501] To compound 3 (2.8 g, 8.6 mmol) was added HCl / MeOH (30 mL) solution and the mixture was allowed to react at room temperature under nitrogen for 2 h. The system was concentrated to give crude product 4 (1.2 g, 86.05% yield) as a yellow solid. ESI-MS: [M+H] + ,226.10.

[0502] 3) Synthesis steps of compound 6

[0503] To a solution of compound 4 (2.6 g, 11.1 mmol) in DMF (12 mL) was added K2CO3 (3.07 g, 22.2 mmol). The mixture was stirred at 50°C for 12 h. After the reaction, water 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 (PE / EtOAc, 0% to 10%) to afford compound 6 (680 mg, 2.8 mmol, 37.84% yield) as a yellow solid. ESI-MS: [M+H] + ,243.95.

[0504] 4) Synthesis steps of compound 10

[0505] To a solution of compound 6 (350 mg, 1.43 mmol) and compound 9 (372 mg, 1.43 mmol) in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at room temperature under nitrogen for 30 minutes. TES (528 mg, 4.29 mmol) was then added and the reaction continued at room temperature for 12 hours. After the reaction, saturated sodium bicarbonate solution was added to adjust the pH to 7-8. The solid was filtered and washed with water to afford compound 10 (180 mg, 0.41 mol, 28.41% yield) as a white solid. ESI-MS: [M+H] + ,442.1.

[0506] 5) Synthesis steps of compound GDI15-8532

[0507] To a mixture of compound 10 (180 mg, 0.41 mmol) and CDI (527 mg, 3.25 mmol) was added 5 mL of the solution, and the mixture was stirred at 110°C under nitrogen for 12 hours. LCMS confirmed the reaction was complete. The mixture was then concentrated and further analyzed by prep-HPLC (Gemini 5um C18 column, 150 x 21.2 mm, eluent: 10% to 20% ACN / H2O) to afford compound GDI15-8532 (61.57 mg, 0.13 mmol, 32.30% yield) as a yellow solid. ESI-MS: [M+H] + ,468.00.

[0508] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.46(s,1H),8.24(d,J=8.2Hz,1H),7.93(d,J=8.4Hz,1H),7.83(t,J =7.2Hz,1H),7.75(t,J=7.2Hz,1H),7.30(m,2H),4.95(m,2H),4.16(m,2H),3.26(m,1H),3.10(m,1H).

[0509] Example 56: Preparation of compound GDI15-8533

[0510] 1) Synthesis steps of compound 3

[0511] Toluene (15 mL) was added to compound 1 (1.5 g, 7.2 mmol), compound 2 (1.96 g, 10.8 mmol), t-BuONa (2.08 g, 21.6 mmol), BINAP (1.79 g, 2.8 mmol), and Pd2(dba)3 (1.32 g, 1.4 mmol). The mixture was stirred at 110°C under nitrogen for 16 h. LCMS confirmed the reaction was complete. After completion, 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 (MeOH / DCM, 3% to 5%) to afford compound 3 (1.3 g, 4.2 mmol, 58.33% yield) as a yellow solid. ESI-MS: [M+H] + ,310.00.

[0512] 2) Synthesis steps of compound 4

[0513] A mixed solution of HCl / MeOH (15 mL) was added to compound 3 (1.3 g, 4.2 mmol) and the mixture was stirred at room temperature under nitrogen for 2 h. The system was concentrated to give the crude product, compound 4 (0.5 g, 80.95% yield), as a yellow solid. ESI-MS: [M+H] + ,146.20.

[0514] 3) Synthesis steps of compound 6

[0515] To a solution of compound 4 (510 mg, 3.51 mmol) and compound 5 (1.23 g, 5.27 mmol) in DMF (10 mL) was added K2CO3 (1.46 g, 10.54 mmol), and the mixture was stirred at 60°C for 12 h. After the reaction, water was added 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 column chromatography (PE / EtOAc, 0% to 10%) to afford compound 6 (260 mg, 1.14 mol, 32.43% yield) as a yellow oil. ESI-MS: [M+H] + ,227.95.

[0516] 4) Synthesis steps of compound 8

[0517] To a solution of compound 6 (260 mg, 1.14 mmol) and compound 7 (445 mg, 1.71 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 30 minutes. TES (562 mg, 3.42 mmol) was then added and the reaction continued with stirring at room temperature for 12 hours. After the reaction, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, and the mixture was filtered and washed with water to obtain compound 9 (140 mg, 0.33 mmol, 28.81% yield) as a white solid. ESI-MS: [M+H] + ,426.05.

[0518] 5) Synthesis steps of compound GDI15-8533

[0519] To a toluene solution (5 mL) of compound 8 (140 mg, 0.33 mmol) was added CDI (319 mg, 1.97 mmol), and the mixture was stirred at 100°C for 6 h. After the reaction, water was added and the mixture was extracted with EtOAc (80 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to column chromatography (DCM / MeOH, 0% to 5%) to afford compound GDI15-8533 (19.32 mg, 0.04 mmol, 13% yield) as a white solid. ESI-MS: [M+H] + ,452.00.

[0520] 1 H NMR (400MHz, DMSO) δ9.37(s,1H),8.45(s,1H),8.24(d,J=8.2Hz,1H),7.93(d,J=8.3Hz,1H),7.84(t,J =7.3Hz,1H),7.75(t,J=7.4Hz,1H),7.31(m,2H),4.94(m,2H),4.11(m,2H),3.26(m,1H),3.10(m,1H).

[0521] Test Example 1: Activity determination of compounds

[0522] SARS-CoV-2 / HeLa-ACE Test

[0523] Compounds were transferred to 384-well plates (Greiner, Part No. 781090-2B) and then added to HeLa-ACE cells (cell density 5000 cells / 20 μL of MEM with 2% FBS). The seeded plates were transferred to a BSL3 laboratory. SARS-CoV-2 (proliferating in USA-WA1 / 2020 Vero E6 cells) was diluted to an MOI of 0.75 to 1, achieving ~30–60% cell infection. The plates were incubated at 37°C in 5% CO2 for 48 hours, and then the cells were fixed by adding formaldehyde to a final concentration of 4%. Human polyclonal serum antibodies were used as primary antibodies, and goat anti-human H+L conjugated to Alexa 488 (Thermo Fisher Scientific A11013) was used as a secondary antibody. DAPI (Thermo Fisher Scientific D1306) was used for DNA staining.

[0524] Uninfected cell toxicity test

[0525] Compounds were transferred to a 1536-well plate (Corning No. 9006BC) and then added to Hela-ACE cells (cell density: 600 cells / 5 μL of MEM supplemented with 2% FBS). The plates were incubated at 37°C, 5% CO₂ for 48 hours, and then cell viability was measured. The compounds were diluted in 2 μL of 50% Cell-Titer Glo (Promega No. G7573) in water and added to the cell plates. The cells were then read using an EnVision Plate Reader (Perkin Elmer).

[0526] Enzyme activity test

[0527] Inhibition assays were performed using 200 nM recombinant SARS-CoV-2 main protease and 15 μM fluorogenic substrate (Dabcyl-TSAVL QSGFRK-Glu (EDANS); Genscript). The assay buffer consisted of 50 mM Tris-HCl, pH 7.3, 1 mM EDTA. SARS-CoV-2 3CLpro was dissolved in 25 μL assay buffer and mixed with various concentrations of the compound. The mixture was incubated at 37°C for 30 minutes. The reaction was then initiated by adding the substrate dissolved in 25 μL assay buffer. The fluorescence signal at 350 nm (excitation) / 490 nm (emission) was immediately measured every 1 minute for 10 minutes at 37°C using an M5 multi-mode microplate reader. The RFU at the 6th minute of the reaction with different concentrations of the compound was used to generate the IC value compared to the reaction with the lowest concentration. 50For each compound, the IC against SARS-CoV-2 3CLpro was measured at 12 concentrations. 50 The experimental data were analyzed by GraphPad Prism software.

[0528] The activity results of the exemplary compounds are shown in Tables 1 and 2 below.

[0529] Table 1: Activity results of exemplary compounds

[0530] Table 2: Activity results of exemplary compounds

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, Y 1 and Y 2 are each independently selected from hydrogen, halogen, cyano, amino, C1-C6 alkylamino or C1-C6 alkyl optionally substituted by halogen or cyano; or Y 1 and Y 2 together to form a carbonyl group; or Y 1 and Y 2 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or a three-membered to six-membered heterocycloalkyl group optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino; Y 3 and Y 4 are each independently selected from hydrogen, halogen, cyano, amino, C1-C6 alkylamino or C1-C6 alkyl optionally substituted by halogen or cyano; or Y 3 and Y 4 together to form a carbonyl group; or Y 3 and Y 4 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or a three-membered to six-membered heterocycloalkyl group optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino; Y 5 and Y 6 are each independently selected from hydrogen, halogen, cyano, amino, C1-C6 alkylamino or C1-C6 alkyl optionally substituted by halogen or cyano; or Y 5 and Y 6 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or a three-membered to six-membered heterocycloalkyl optionally substituted by halogen, hydroxy, keto, -OMs, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino; and Optionally, Y 5 and Y 6 One of them and Y 1 , Y 2 , Y 3 and Y 4 One of them and the carbon atom to which they are attached together form a C3-C6 cycloalkyl or phenyl group optionally substituted with halogen or C1-C3 alkyl; Further, among them, P 1 For -L 1 -Z 1 -; 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 each independently substituted by halogen, hydroxyl, cyano, C2-C6 ester, 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, cyano, 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 seven-membered heterocycloalkyl group containing at least one nitrogen atom; and n1 and n2 are selected from 0, 1, 2 or 3.

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: Y 1 and Y 2 Together they form a carbonyl group; Y 3 and Y 4 are each independently selected from hydrogen, halogen, cyano or C1-C6 alkyl optionally substituted by halogen or cyano; or Y 3 and Y 4 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or a three-membered to six-membered heterocycloalkyl group optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino; Y 5 and Y 6 are each independently selected from hydrogen, halogen, cyano or C1-C6 alkyl optionally substituted by halogen or cyano; or Y 5 and Y 6 and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl or a three-membered to six-membered heterocycloalkyl optionally substituted by halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino or C1-C3 alkylamino; and Optionally, Y 5 and Y 6 One of them and Y 3 and Y 4 One of them and the carbon atom to which they are attached together form a C3-C6 cycloalkyl or phenyl group optionally substituted with halogen or C1-C3 alkyl; and Preferably, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 The total number of rings formed is no more than one.

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 quinolyl, 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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