PLpro protease small-molecule inhibitor for treating or preventing coronavirus infection and application of PLpro protease small-molecule inhibitor

Abstract

The invention relates to a PLpro protease small-molecule inhibitor for treating or preventing coronavirus infection and application of the PLpro protease small-molecule inhibitor. Specifically, the invention relates to a compound shown as a formula (I) or an isotope labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or an 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 medicament for treating or preventing coronavirus infection or diseases or symptoms caused by coronavirus.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of small molecule compounds in medicine, in particular, the present application relates to a PLpro protease small molecule inhibitor for treating or preventing coronavirus infection and use thereof. BACKGROUND

[0002] Novel coronavirus (SARS-CoV-2) is a positive-strand RNA virus with the largest genome among currently known RNA viruses. PLpro protease (i.e. papain-like protease) plays a pivotal role in the life cycle of this virus and is a highly potential antiviral drug target. It is responsible for cleaving the viral polyprotein to produce multiple non-structural proteins, which is a key step for the virus to complete replication and proliferation. Moreover, PLpro protease also has deubiquitination and deISGylation activities, thereby interfering with the host innate immune response, allowing the virus to "run wild" in the host body.

[0003] At present, although much progress has been made in vaccine development, there are still shortcomings in specific treatment drugs for SARS-CoV-2, and it is urgent to develop drugs with strong inhibitory effect on PLpro protease. Although some potential inhibitors have been discovered in existing research, most of them still have problems such as poor activity and insufficient specificity. In view of the structural similarity between PLpro and human deubiquitinating enzymes, it is very challenging to design a highly selective PLpro inhibitor. However, due to the key position of PLpro in the survival and reproduction of the virus, overcoming this challenge is expected to fundamentally block viral replication and enhance the body's antiviral immune defense. SUMMARY

[0004] In a first aspect, the present application provides a compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

[0005]

[0006] wherein,

[0007] R1and R2are each independently selected from hydrogen, halogen, or C1-C6alkyl, or R1and R2together with the carbon atom to which they are attached form a C3-C6cycloalkyl;

[0008] R3, R4, R5, and R6are each independently selected from hydrogen, halogen, or C1-C6alkyl, or R3and R4, R5and R6are each independently together with the carbon atom to which they are attached form a 3-6 membered ring, or R3and R5form a carbon bridge with a length of 1 to 2;

[0009] L1, L2, L3, and L4are each independently selected from a bond, -(CH2)p NH(CH2) q -、-(CH2) p O(CH2) q -, C1-C6 alkylene, C3-C6 cycloalkylene, -(CH2) p NHCO(CH2) q -、-(CH2) p NHSO(CH2) q -or-(CH2) p NHSO2(CH2) q -, optionally substituted with halogen, hydroxyl, amino, nitro, C1-C3 alkyl, C1-C3 hydroxyalkyl or C1-C3 alkoxy, and optionally cyclic when multiple substituents selected from C1-C3 alkyl, C1-C3 hydroxyalkyl and / or C1-C3 alkoxy are present on the same carbon atom, wherein each p and q is independently selected from any integer between 0 and 3;

[0010] X1, X2, X3, and X4 are each independently selected from hydrogen, halogen, hydroxyl, amino, borate, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-8 heterocyclic alkyl, 5-6 aryl, or 5-6 heteroaryl, optionally substituted with halogen, hydroxyl, amino, nitro, C1-C3 alkyl, C1-C3 hydroxyalkyl, or C1-C3 alkoxy, and optionally cyclic when multiple substituents selected from C1-C3 alkyl, C1-C3 hydroxyalkyl, and / or C1-C3 alkoxy are present on the same carbon atom;

[0011] n is selected from 0 or 1; and

[0012] Ar is selected from 8- to 12-membered aryl rings or 11- to 16-membered biaryl rings, which optionally contain one or more heteroatoms and are optionally substituted.

[0013] In one embodiment of the invention, the compound of formula (I) may more particularly have the following formula (Ia):

[0014]

[0015] in,

[0016] R1 to R6, L1 to L4 and X1 to X4 are as defined in claim 1;

[0017] Each A is independently selected from carbon, nitrogen, oxygen, or sulfur atoms;

[0018] Each n is independently selected from 0 or 1; and

[0019] R7, R8, R9, R 10 and R11 each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, C1-C6alkyl, C1-C6alkoxyl, C3-C6cycloalkyl, C1-C3acyl, amido, sulfonyl, 3-8 membered heterocycloalkyl, or 5-6 membered heteroaryl, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxyl; wherein optionally, any two of R7, R8, R9, R 10 and R 11 any two together with the ring atoms to which they are attached form a 4-6 membered ring.

[0020] In one embodiment of the compound of formula (Ia) of the present application, Ar can be selected from any one of the following, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxyl:

[0021]

[0022]

[0023] In one embodiment of the present application, the compound of formula (I) can more particularly have the following formula (Ib):

[0024]

[0025] wherein,

[0026] R1to R6, L1to L4, and X1to X4are as defined in claim 1;

[0027] each A is independently selected from a carbon, nitrogen, oxygen, or sulfur atom;

[0028] each n is independently selected from 0 or 1; and

[0029] R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, phenyl, or 5-6 membered heteroaryl, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxyl.

[0030] In one embodiment of the compound of formula (Ib) of the present application, Ar can be selected from any one of the following, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxyl:

[0031]

[0032] In another embodiment of the present application,

[0033] - L1-X1, -L2-X2, -L3-X3, -L4-X4may each independently be selected from any one of the following, which is optionally substituted with halo, hydroxyl, amino, nitro, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxy:

[0034]

[0035]

[0036] In any of the foregoing embodiments of the application, each halo can be independently selected from fluorine, chlorine, or bromine; each C1-C3alkyl or C1-C6alkyl can be independently selected from methyl, ethyl, n-propyl, or i-propyl; each C1-C3hydroxyalkyl can be independently selected from hydroxymethyl, hydroxyethyl, or hydroxypropyl; each C1-C3alkoxy or C1-C6alkoxy can be independently selected from methoxy, ethoxy, or propoxy; each C3-C6cycloalkyl can be independently selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each 3-8 membered heterocycloalkyl can be independently selected from aziridinyl, azetidinyl, azolidinyl, azacyclohexyl, azacycloheptyl, or azacyclooctyl; and / or each 5-6 membered heteroaryl can be independently selected from furan, thiophene, pyrrole, imidazole, thiazole, oxazole, pyrazole, pyridine, pyrimidine, pyrazine, or thiazine.

[0037] For the sake of brevity, hereinafter the term "compounds of Formula (I)" or "compounds of the present application" can also encompass any isotopically-labeled compounds of Formula (I), or optical isomers, geometric isomers, tautomers, or isomer mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof.

[0038] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can exist in either the R or S configuration, and the various isomers resulting from the configuration of such chiral centers are optical isomers. Optical isomers include all diastereomeric, enantiomeric, meso forms, or mixtures thereof. Optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0039] The term "geometric isomer" means that when a compound has a double bond, the compound can exist as a cis isomer, a trans isomer, an E isomer, and a Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.

[0040] The term "tautomer" refers to isomers of a molecule that can be converted to each other. It is understood by those skilled in the art that tautomers can interconvert and can exist in a state of equilibrium with each other.

[0041] Unless otherwise specified, reference to a "compound of Formula (I)" or "compounds of the application" herein is also meant to encompass isotopically-labeled compounds, which are identical to those recited

[0042] Examples of isotopes suitable for inclusion in the compounds of the application 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 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, and isotopes of sulfur, such as 35 S.

[0043] Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples and Preparations, by using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0044] The compounds of Formula (I) can exist in pharmaceutically acceptable salt forms, such as acid addition salts and / or base addition salts of the compounds of Formula (I). As used herein, "pharmaceutically acceptable salt" includes an acid addition salt or a base addition salt that can occur as a result of the formation of the compounds of Formula (I), unless otherwise indicated.

[0045] Pharmaceutically acceptable salts of the compounds of formula (I) include acid and base addition salts thereof. Suitable acid addition salts are formed from acids which form nontoxic salts. Examples of such acids include, but are not limited to, acetic, adipic, aspartic, benzoic, benzenesulfonic, bicarbonic / carbonic, bisulfic, boric, camphorsulfonic, citric, cyclohexylaminosulfonic, ethanedisulfonic, formic, fumaric, glucoheptonic, gluconic, glucuronic, hexafluorophosphoric, 2-(4-hydroxybenzoyl)benzoic, hydrochloric / chloride, hydrobromic / bromide, hydroiodic / iodide, 2-hydroxyethansulfonic, lactic, malic, maleic, malonic, methanesulfonic, methylsulfuric, naphthalenesulfonic, 2-naphthalenesulfonic, nicotinic, nitric, orotic, oxalic, palmitic, phosphoric / diphosphoric / biphosphoric, pyroglutamic, saccharic, stearic, salicylic, tannic, tartaric, toluenesulfonic, and trifluoroacetic. Suitable base addition salts are formed from bases which form nontoxic salts. Examples of such bases include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Acid and base half-salts, such as hemisulfates and hemicalcium salts, can also be formed. For a review on 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.

[0046] Certain compounds of the present application can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the compounds of formula (I) whether in solvated or unsolvated form, are included within the scope of the present application.

[0047] Certain compounds of the present application can exist in different crystalline or amorphous forms, and all such forms are included within the scope of the present application.

[0048] To avoid ambiguity, the following terms are defined below as used herein. Unless otherwise specified, the terms used herein have the meanings ascribed to them below.

[0049] The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to a human. Preferably, the term means that the compound is certified by any national regulatory agency, such as CFDA (China), EMEA (Europe), FDA (USA) etc. for use in mammals, preferably humans.

[0050] A "prodrug" means a derivative of a compound of the application that is converted into the compound under physiological conditions, e.g., by hydrolysis in a living organism, in vivo, in an enzymatic or chemical reaction.

[0051] A "metabolite" means any molecule derived from any compound of the application in a cell or organism, preferably a human.

[0052] As used herein, the term "cyano" means -CN; the term "hydroxy" means -OH; the term "amino" means -NH2; the term "amido" means -CONH2; and the term "sulfonyl" means -SO2H.

[0053] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms of a group are independently replaced with a corresponding number of substituents. As used herein, when there are multiple substituents selected from the group consisting of C1-C3 alkyl, C1-C3 hydroxyalkyl and / or C1-C3 alkoxy on the same carbon atom, they are optionally cyclized, e.g., when two hydrogens on a carbon atom are both replaced with a methyl group, the two methyl groups together with the carbon atom can cyclize to form a cycloalkyl group, as shown in compounds P258 and P259 in the Examples.

[0054] As used herein, the term "independently" means that when the number of substituents is more than one, the substituents can be the same or different.

[0055] As used herein, the term "optionally" or "optional" means that the event described can or can not occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

[0056] As used herein, the term "heteroatom" represents 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).

[0057] As used herein, the term "alkyl" means a saturated aliphatic hydrocarbon, including straight chain and branched chain. 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" means a straight chain or branched chain radical having 1-8 carbon atoms. The term "C 1-8 alkyl" includes within its definition the term "C 1-6"alkyl", "C1-C3 alkyl", and "C1-C4 alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, etc. The alkyl group may optionally be substituted by one or more (e.g., 1 to 5) suitable substituents.

[0058] As used herein, the term "n-membered heterocyclic alkyl" refers to a cycloalkyl group having m carbon atoms forming a ring and (nm) heteroatoms forming a ring, wherein the heteroatoms are selected from O, S, and N. For example, 3-7-membered heterocyclic alkyl groups include, but are not limited to, oxetane, thiobutane, azite, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothioran, piperidine, morpholine, piperazine, oxetane, thiobutane, and azite. Heterocyclic alkyl groups may optionally be substituted with one or more suitable substituents.

[0059] 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, pyrazines, pyrazoles, pyrroles, furans, thiophenes, thiazoles, and pyridines. The heteroaryl group may optionally be substituted with one or more suitable substituents.

[0060] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (at most fully haloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). For example, the term "C 1-6 "Halogenated alkyl" refers to a C-shaped alkyl group having one or more halogen substituents. 1-6 Alkyl groups (at most fully haloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). Another example is the term "C". 1-4 "Halogenated alkyl" refers to a C-shaped alkyl group having one or more halogen substituents. 1-4 Alkyl groups (at most fully haloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); the term "C" 1-3 "Halogenated alkyl" refers to a C-shaped alkyl group having one or more halogen substituents. 1-3 Alkyl groups (at most fully haloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); and the term "C" 1-2 "Halogenated alkyl" refers to a C-shaped alkyl group having one or more halogen substituents. 1-2alkyl groups (i.e., methyl or ethyl) (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). By way of further example, the term "C1haloalkyl" 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.

[0061] Herein, numerical ranges for quantities, such as number of substituents, number of carbon atoms, number of ring atoms, are presented in a "to" format, indicating that the range is inclusive of the recited integers. For example, "1-4 substituents" indicates that there are 1, 2, 3, or 4 substituents. Thus, numerical ranges for quantities, such as number of substituents, number of carbon atoms, number of ring atoms, encompass any and all subranges therein. For example, a range of "1- 4 substituents" is inclusive of the subranges "1-3 substituents", "2-4 substituents", "2-3 substituents", "1-3.5 substituents", "3.7-4 substituents", and the like.

[0062] The compounds of the present application can be prepared in a variety of ways known to one skilled in the art of organic synthesis. One skilled in the art can refer to the synthetic routes of specific compounds in the specific examples of the present application, and make appropriate modifications to the starting materials and reaction conditions to obtain synthetic methods for other compounds.

[0063] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

[0064] The pharmaceutically acceptable carrier can be an organic or inorganic inert carrier material, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, mannitol, cellulose, cellulose derivatives, sodium saccharin, glucose, sucrose, magnesium carbonate, saline, glycerol, ethanol, and the like. In addition, the pharmaceutical composition can also contain other pharmaceutical additives, such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, diluents, binding agents, wetting agents, disintegrating agents, lubricants, glidants, and the like.

[0065] The dosage form of the pharmaceutical composition of the present application can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), an eye drop, a nose drop, a lotion and a liniment, etc.; the solid dosage form can be a tablet (including ordinary tablet, enteric-coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, oral disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric-coated capsule), a granule, a powder, a pill, a suppository, a film, a patch, an aerosol, a spray, etc.; the semi-solid dosage form can be an ointment, a gel, a paste, etc. The pharmaceutical composition of the present application can be prepared into ordinary preparation, sustained-release preparation, controlled-release preparation, targeted preparation and various microparticle drug delivery systems.

[0066] In some embodiments, the dosage form of the pharmaceutical composition is selected from a tablet, a granule, a powder, a syrup, an inhalant and an injection.

[0067] Solid dosage forms for oral administration can 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) such as sodium citrate or dicalcium phosphate, and can further include: (a) fillers or combining agents such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate; (e) solution retarders such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin and bentonite clay; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.

[0068] Formulations suitable for parenteral administration, such as injection, can include aqueous and nonaqueous, isotonic sterile solutions, which can contain antioxidants, buffers, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, viscosity regulators, stabilizers, and the like. Parenteral formulations provided herein optionally are enclosed in unit dosage or multi-dosage containers, for example, ampules, and can be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Examples of suitable diluents for reconstituting the pharmaceutical composition, for example, prior to injection, include bacteriostatic water for injection, 5% dextrose in water, phosphate-buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.

[0069] Sprays can contain excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Inhalants can comprise excipients such as lactose, or aqueous solutions comprising, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration as nasal drops or sprays, or in the form of gels.

[0070] The content of the compounds of the present application in their pharmaceutical compositions can be adjusted according to the actual needs (e.g. dosage form, mode of administration, subject of administration, etc.), for example, 0.1-95% by weight, for example, 1-95% by weight, 5-90% by weight, 10-80% by weight, etc.

[0071] Specifically, the pharmaceutical composition of the present application can particularly comprise 0.01-10 g (e.g. 0.05 g, 0.1 g, 0.5 g, 1 g or 5 g, etc.) of the compound of the present application.

[0072] In a third aspect, the present application provides use of a compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a medicament for treating or preventing a coronavirus infection or a disease or a symptom caused by a coronavirus in a subject in need thereof. The compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof can be used for treating or preventing a coronavirus infection or a disease or a symptom caused by a coronavirus in a subject in need thereof.

[0073] 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 of any age. Preferably, the subject is a human.

[0074] The term "treatment" as used herein includes treatment of a disease or symptom in a mammal, particularly in a human and includes: (a) inhibiting the infection, disease or symptom, i.e. arresting or reducing the development of the infection, disease or symptom; (b) relieving the infection, disease or symptom, i.e. causing the regression of the disease or symptom, and / or (c) curing the infection, disease or symptom.

[0075] The term "prevent," as used herein, includes prophylactic therapy in a mammal, particularly a human, with the aim to reduce the likelihood of infection, disease or symptoms from occurring. Patients for prophylactic therapy can be selected based on factors that increase the risk of infection or having the disease or symptoms as compared to the general population. "Prevention" can include treatment of a subject who has not yet presented with an infection or clinical condition, and prevention of a second occurrence of the same or similar infection or clinical condition.

[0076] The inventors of the present application have found that the compounds of the present application are capable of achieving inhibition of coronavirus infection, for example, are capable of acting as reversible covalent small molecule inhibitors against the PLpro protease of the novel coronavirus (i.e., PLpro protease inhibitors), thereby inhibiting viral replication of the coronavirus. Thus, the compounds of the present application can be used for preventing or treating coronavirus infection or a disease or symptoms caused by the coronavirus.

[0077] In some embodiments, 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), murine hepatitis coronavirus (MHV), and a coronavirus having greater than 85% homology to any one of the above and having viral activity. In some embodiments, the coronavirus is novel coronavirus (SARS-CoV-2).

[0078] In some embodiments, the disease or symptoms caused by the coronavirus include respiratory infection, acute respiratory syndrome (SARS), pneumonia (including severe pneumonia), gastroenteritis (including acute gastroenteritis), cough, fever, chills, vomiting, headache, chill, shortness of breath, cytokine storm, and the like caused by the virus.

[0079] In a fourth aspect, the present application provides a method of treating or preventing coronavirus infection or a disease or symptoms caused by the coronavirus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof.

[0080] In some embodiments, the compounds of the present application can be administered by oral, parenteral, intravenous injection, intramuscular injection, subcutaneous injection, nasal, oral mucosal, ocular, transpulmonary, transrespiratory, transvaginal, transrectal, intraperitoneal, intralesional, perilesional, and the like.

[0081] A "therapeutically effective amount" means the amount of the compound of the present application that, when administered alone or in combination, is effective to treat or prevent coronavirus infection or a disease or symptoms caused by the coronavirus.

[0082] The specific dose will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician, who will determine the individual regimen and dosage level most appropriate for a particular patient. For example, the daily dose of a compound of the application can be specifically 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.).

[0083] The specific frequency of administration can be determined by the skilled person in the relevant art, for example 1 time per day, 1 time per 2 days, 1 time per 3 days, 1 time per 4 days, 1 time per 5 days, 1 time per 6 days, 2 times per day, 3 times per day, etc.

[0084] The person skilled in the art understands that the definitions and preferences described in one aspect of the application apply equally to the other aspects. The person skilled in the art understands that the embodiments of the various aspects of the application can be combined in various ways without deviating from the subject matter and idea of the application, and that these combinations are included in the scope of the application. DETAILED DESCRIPTION

[0085] The compounds of formula (I) of the present application can be synthesized by a variety of methods familiar to one skilled in the art of organic synthesis. Some exemplary methods for synthesizing compounds of formula (I) are given in the following specific examples, which are well known in the art of synthetic chemistry. It will be apparent to one skilled in the art, with the benefit of hindsight, referring to the exemplary schemes in the present patent, that other synthetic routes for compounds of formula (I) can be readily designed by appropriate adaptation of reactants, reaction conditions, and protecting groups.

[0086] The application is further illustrated below in connection with the examples; the examples do not limit the scope of the application. Unless otherwise stated, all the reagents used in the examples were obtained from commercial sources; the instruments and equipment used in the synthesis experiments and the analysis of the products are the conventional instruments and equipment commonly used in organic synthesis.

[0087] Synthesis of common intermediate C1

[0088]

[0089] Compound 2 (6.87 g, 29.0 mmol, 1.2 eq) and compound 1 (6 g, 24.1 mmol, 1 eq) were dissolved in dioxane (60 mL) and H2O (18 mL), and Cs2CO3 (23.6 g, 72.4 mmol, 3 eq), RuPhos (1.13 g, 2.41 mmol, 0.1 eq) and Pd(OAc)2 (542 mg, 2.41 mmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 100 °C for 16 h under nitrogen protection, and LCMS detection showed that the reaction was completed. Ice water (50 mL) was added to the reaction solution, and extraction was performed with EtOAc (20 mL*3), and the organic phase was combined and concentrated under reduced pressure to obtain compound C1 (2.3 g, 8.77 mmol, 36.3% yield) as a yellow solid by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*70mm*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25%-50% B in 17.0 min). ESI-MS: [M+H] + , 263.2.

[0090] Synthesis of common intermediate C2

[0091] 1) Synthesis operation steps of intermediate C2I1

[0092]

[0093] Compound C2S1 (20 g, 80.5 mmol, 1 eq, HCl) was dissolved in DCM (400 mL), and TEA (16.3 g, 161 mmol, 22.4 mL, 2 eq) and TFAA (25.4 g, 121 mmol, 16.8 mL, 1.5 eq) were added dropwise successively at 0 °C. The reaction mixture was reacted at 0 °C for 2 h, and LCMS detection showed that the reaction was completed. Water (300 mL) was added to the reaction solution, and the mixture was extracted with DCM (100 mL*3), and the organic phase was combined and washed with saturated sodium chloride (150 mL). The washed organic phase was concentrated under reduced pressure, and the target compound C2I1 (23 g, 67.2 mmol, 83.5% yield, 90% purity) was obtained as a yellow solid by column separation (SiO2, petroleum ether / EtOAc = 100 / 1 to 3 / 1). ESI-MS: [M+H] + , 307.9.

[0094] 2) Synthesis operation steps of intermediate C2I2

[0095]

[0096] Compound C2I1 (23 g, 74.7 mmol, 1 eq) was dissolved in THF (460 mL), n-BuLi (2.5 M, 59.7 mL, 2 eq) was added dropwise slowly under nitrogen atmosphere at -78 °C, after the reaction mixture was reacted at -78 °C for 1 h, 1-Boc-3-azetidinone (25.6 g, 149 mmol, 2 eq) was added to the above reaction solution. The reaction mixture was continued to react at -78 °C for 2 h, and LCMS detection showed that the reaction was completed. The reaction solution was slowly added to ice water (600 mL) under nitrogen protection, extracted with EtOAc (200 mL*3), and the organic phase was combined and washed with saturated sodium chloride (200 mL). The washed organic phase was concentrated under reduced pressure, and purified by column separation (SiO2, petroleum ether / EtOAc = 5 / 1 to 1 / 10) to obtain the target compound C2I2 (17 g, 44.7 mmol, 59.9% yield, 80% purity) as a yellow oil. ESI-MS: [M+H] + , 305.2.

[0097] 3) Synthesis operation steps of intermediate C2I3

[0098]

[0099] Compound C2I2 (17 g, 55.9 mmol, 1 eq) was dissolved in DCM (340 mL), and TEA (11.3 g, 112 mmol, 15.6 mL, 2 eq) and TFAA (17.6 g, 83.8 mmol, 11.6 mL, 1.5 eq) were added dropwise successively at 0 °C. The reaction mixture was reacted at 25 °C for 16 h, and LCMS detection showed that the reaction was completed. Water (400 mL) was added to the reaction solution, and the mixture was extracted with DCM (100 mL*3), and the organic phase was combined and washed with saturated sodium chloride (150 mL). The washed organic phase was concentrated under reduced pressure, and purified by column separation (SiO2, petroleum ether / EtOAc = 10 / 1 to 3 / 1) to obtain the target compound C2I3 (16 g, 36.0 mmol, 64.4% yield, 90% purity) as a yellow solid. ESI-MS: [M+H] + , 401.1.

[0100] 4) Synthesis operation steps of intermediate C2I4

[0101]

[0102] Compound C2I3 (16 g, 40.0 mmol, 1 eq) and TFA (96 mL) were dissolved in DCM (384 mL), the reaction mixture was reacted at 25 °C for 1 h, and LCMS was used to detect the completion of the reaction. The reaction mixture was concentrated under reduced pressure, MeOH (1 L) was added to the concentrate, the pH of the solution was adjusted to 8-9 by adding basic resin, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound C2I4 (12 g, 28.0 mmol, 70.0% yield, 70% purity) as a yellow solid. ESI-MS: [M+H] + , 301.1.

[0103] 5) Synthesis operation steps of intermediate C2I5

[0104]

[0105] Compound C2I4 (12 g, 40.0 mmol, 1 eq), HCHO (12 g, 400 mmol, 11 mL, 37%, 10 eq) and AcOH (4.8 g, 80 mmol, 4.58 mL, 2 eq) were sequentially dissolved in MeOH (240 mL). After the reaction mixture was stirred at 60 °C for 1 h, NaBH3CN (7.53 g, 120 mmol, 3 eq) was added to the above reaction solution at 25 °C. The reaction mixture was continuously reacted at 60 °C for 15 h, and LCMS was used to detect the completion of the reaction. After the reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the concentrate, and EtOAc (70 mL*5) was used to extract, and the organic phase was combined and washed with saturated sodium chloride (100 mL). The organic phase after washing was concentrated under reduced pressure, and purified by column separation (SiO2, petroleum ether / EtOAc = 10 / 1 to 1 / 10) to obtain the target compound C2I5 (5 g, 11.1 mmol, 27.9% yield, 70% purity) as a yellow solid. ESI-MS: [M+H] + , 315.1.

[0106] 6) Synthesis operation steps of common intermediate C2

[0107]

[0108] Compound C2I5 (2 g, 6.36 mmol, 1 eq) and K2CO3 (2.64 g, 19.1 mmol, 3 eq) were sequentially dissolved in a mixed solution of MeOH (20 mL) and H2O (2 mL). The reaction mixture was reacted at 50 °C for 4 h, and LCMS detection showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The filtrate was diluted with EtOAc (100 mL) and then filtered. The filtrate was concentrated under reduced pressure. This operation was repeated three times to remove residual K2CO3. The filtrate from the last filtration was concentrated under reduced pressure, and the target compound, Common Intermediate C2 (500 mg, 1.95 mmol, 30.6% yield, 85% purity), was obtained as a yellow solid by purification through high performance liquid chromatography (column: Welch Xtimate C18 250*100mm#10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 0% - 30% B in 18.0 min). ESI-MS: [M+H] + , 219.1.

[0109] Example 1: Compound P1.

[0110]

[0111] Compound P1S1 (500 mg, 2.36 mmol, 1 eq) and compound P1S2 (401 mg, 2.36 mmol, 358 μL, 1 eq) were dissolved in MeOH (10 mL), and AcOH (141 mg, 2.36 mmol, 134 μL, 1 eq) was added at 25 °C. The reaction mixture was reacted at 50 °C for 1 h, and then NaBH3CN (222 mg, 3.54 mmol, 1.5 eq) was added to the reaction mixture. The reaction mixture was continuously reacted at 50 °C for 15 h, and LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, and then water (20 mL) was added to the mixture. The mixture was extracted with EtOAc (4 mL*3), and the organic phase was combined and washed with saturated sodium chloride (20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound P1 (180 mg, 491 μmol, 20.8% yield) was obtained as a yellow solid by purification through silica gel plate (petroleum ether / EtOAc = 5 / 1). ESI-MS: [M+H]+, 366.1

[0112] Example 2: Compound P2.

[0113] 1) Synthesis procedure of Intermediate P2I1

[0114]

[0115] Compound P1 (180 mg, 491 pmol, 1 eq) and compound P2S1 (137 mg, 737 pmol, 1.5 eq) were dissolved in THF (3.6 mL), t-BuONa (141 mg, 1.47 mmol, 3 eq) and tBuXPhos Pd G3 (39.0 mg, 49.1 pmol, 0.1 eq) were added at 25 °C, the reaction mixture was reacted at 80 °C for 16 h under N2protection, the reaction solution was concentrated under reduced pressure, then water (10 mL) was added to it, extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, purified by silica gel plate (petroleum ether / EtOAc = 2 / 1) to obtain the target compound P2I1 (170 mg, 360 pmol, 73.4% yield) as a yellow oil. ESI-MS: [M+H] + , 472.3

[0116] 1 H NMR (400 MHz, DMSO-d6) d 8.54 - 8.41 (m, 1H), 7.96 - 7.87 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.57 - 7.45 (m, 3H), 6.92 (d, J = 8.3 Hz, 1H), 6.73 (dd, J = 2.3, 8.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 4.37 - 4.26 (m, 1H), 3.71 (d, J = 15.1 Hz, 1H), 3.54 (s, 1H), 3.42 - 3.37 (m, 4H), 3.05 - 2.91 (m, 4H), 2.75 - 2.60 (m, 4H), 1.50 (d, J = 6.6 Hz, 3H), 1.40 (s, 9H).

[0117] 2) Preparation of compound P2

[0118]

[0119] Compound GDI19-036 (129 mg, 273 µmol, 1 eq) was dissolved in DCM (1.3 mL), HCl / dioxane (4 M, 1.3 mL) was added at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction solution was concentrated under reduced pressure, purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 55% - 85% B in 8.0 min) to give compound GDI19-033 (38.2 mg, 102 µmol, 37.5% yield) as a white solid. ESI-MS: [M+H] + ,372.3

[0120] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 3.4, 5.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.52-7.46 (m, 3H), 6.89 (d, J = 8.5 Hz, 1H), 6.69 (dd, J = 2.4, 8.5 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 4.30 (d, J = 6.7 Hz, 1H), 3.73 (d, J = 15.2 Hz, 1H), 3.52 (d, J = 14.9 Hz, 1H), 2.96-2.86 (m, 4H), 2.77 (s, 4H), 2.71-2.57 (m, 4H), 1.69-1.61 (m, 1H), 1.49 (d, J = 6.5 Hz, 3H)

[0121] Example 3-4: Compound P3 and Compound P4.

[0122]

[0123] Compound P2 (30 mg, 80.7 µmol, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3·H2O)]; B%: 40%, isocratic elution mode) to give target compounds P3 (6.6 mg, 17.7 µmol, 22.0% yield) and P4 (7.1 mg, 19.1 µmol, 23.6% yield) as white solids. ESI-MS: [M+H] + ,372.3

[0124] P3: 1 H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.44 (m, 1H), 7.95 - 7.89 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.53 - 7.46 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 2.4, 8.3 Hz, 1H), 6.50 (d, J = 2.1 Hz, 1H), 4.30 (br d, J = 6.5 Hz, 1H), 3.73 (br d, J = 15.0 Hz, 1H), 3.52 (br d, J = 15.0 Hz, 1H), 3.30 - 3.29 (m, 1H), 2.96 - 2.85 (m, 4H), 2.82 - 2.63 (m, 7H), 2.60 - 2.53 (m, 1H), 1.49 (d, J = 6.6 Hz, 3H)

[0125] P4: 1 H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.44 (m, 1H), 7.95 - 7.89 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.6 Hz, 1H), 7.49 (dt, J = 2.8, 6.3 Hz, 3H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 2.5, 8.4 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 4.30 (br d, J = 6.4 Hz, 1H), 3.73 (br d, J = 15.0 Hz, 1H), 3.52 (br d, J = 15.0 Hz, 1H), 3.30 - 3.29 (m, 1H), 2.98 - 2.86 (m, 4H), 2.80 - 2.63 (m, 7H), 2.61 - 2.55 (m, 1H), 1.49 (d, J = 6.6 Hz, 3H)

[0126] Example 5: Compound P5.

[0127] 1) Intermediate P2I1 synthesis procedure

[0128]

[0129] Compound P1 (80 mg, 218 pmol, 1 eq) and compound P5S1 (65.8 mg, 262 pmol, 1.2 eq) were dissolved in dioxane (0.8 mL) and H20 (0.25 mL), and then Cs2C03(214 mg, 655 pmol, 3 eq), Ruphos (10.2 mg, 21.8 pmol, 0.1 eq) and Pd(OAc)2(4.90 mg, 21.8 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 100 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. Water (4 mL) was added to the reaction solution, and EtOAc (2 mL*3) was used for extraction. The combined organic phase was washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification on a silica gel plate (petroleum ether / EtOAc = 5 / 1) gave the target compound P5 (25 mg, 58.1 pmol, 26.6% yield) as a yellow solid. ESI-MS: [M+H] + , 431.3

[0130] 2) Synthesis procedure of compound P5

[0131]

[0132] Compound P5I1 (25 mg, 58.1 pmol, 1 eq) was dissolved in DCM (0.5 mL), and then HCl / dioxane (4 M, 0.5 mL) was added. The reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and then purified by high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H20 (0.04% HCl)-ACN]; gradient: 1%-35% B in 8.0 min) to give the target compound P5 (13 mg, 39.3 pmol, 67.8% yield, 100% purity, HC1) as a white solid. ESI-MS: [M+H] + , 331.3

[0133] 1H NMR (400 MHz, DMSO-d6) d = 11.46 - 11.18 (m, 1H), 8.34 - 8.19 (m, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 7.9 Hz, 3H), 7.91 (br s, 1H), 7.74 - 7.52 (m, 3H), 7.26 - 7.19 (m, 1H), 7.19 - 6.73 (m, 2H), 5.64 - 5.40 (m, 1H), 4.98 - 4.48 (m, 1H), 4.16 - 3.99 (m, 1H), 3.65 - 3.41 (m, 1H), 3.29 - 3.09 (m, 2H), 3.05 - 2.99 (m, 1H), 2.99 - 2.77 (m, 3H), 2.77 - 2.69 (m, 1H), 1.93 - 1.83 (m, 3H)

[0134] Example 6-7: Compound P6 and Compound P7.

[0135]

[0136] Compound P5 (12 mg, 30.91 pmol, 94.5% purity) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [C02-MeOH (0.1% NH3H20)]; B%: 40%, isocratic elution mode) to give P6 (1.6 mg, 4.84 pmol, 8.00% yield) and P7 (2.2 mg, 6.66 pmol, 11.0% yield). ESI-MS: [M+H] + ,331.2

[0137] P6: 1 H NMR (400 MHz, DMSO-d6) d = 8.54 - 8.41 (m, 1H), 7.96 - 7.88 (m, 1H),

[0138] 7.83 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.02 - 6.95 (m, 1H), 6.94 - 6.88 (m, 1H), 6.81 (s, 1H), 4.33 (q, J = 6.5 Hz, 1H), 3.78 (d, J = 14.9 Hz, 1H), 3.55 (d, J = 15.1 Hz, 1H), 3.18 - 2.97 (m, 1H), 2.78 - 2.61 (m, 6H), 2.60 - 2.52 (m, 2H), 1.50 (d, J = 6.6 Hz, 3H)

[0139] P7: 1 H NMR (400 MHz, DMSO-d6) d = 8.54-8.42 (m, 1H), 7.95-7.88 (m, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.56-7.44 (m, 3H), 6.98-6.94 (m, 1H), 6.93-6.88 (m, 1H), 6.81 (s, 1H), 4.33 (q, J = 6.3 Hz, 1H), 3.77 (d, J = 15.0 Hz, 1H), 3.55 (d, J = 14.9 Hz, 1H), 3.18-3.02 (m, 1H), 2.78-2.61 (m, 6H), 2.60-2.51 (m, 3H), 1.50 (d, J = 6.5 Hz, 3H)

[0140] Example 8: Synthesis procedure of compound P8.

[0141] 1) Synthesis procedure of intermediate P8I1

[0142]

[0143] Compound P1 (200 mg, 545 μmol, 1 eq) and compound P8S1 (149 mg, 654 μmol, 1.2 eq) were dissolved in dioxane (2 mL) and H2O (0.6 mL), Cs2CO3 (533 mg, 1.64 mmol, 3 eq), Ruphos (25.5 mg, 54.7 μmol, 0.1 eq) and Pd(OAc)2 (12.3 mg, 54.6 μmol, 0.1 eq) were added at room temperature. The reaction mixture was heated at 100 °C for 16 h under nitrogen protection. LCMS showed the reaction was completed. Water (4 mL) was added to the reaction solution, and extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the target compound P8I1 (100 mg, 240 μmol, 58.6% yield) was obtained as a yellow solid by silica gel plate purification (petroleum ether / EtOAc = 5 / 1). ESI-MS: [M+H] + , 417.4.

[0144] 2) Synthesis procedure of compound P8

[0145]

[0146] Compound P8I1 (100 mg, 240 pmol, 1 eq) was dissolved in DCM (0.5 mL), then HCl / dioxane (4 M, 0.5 mL) was added. The reaction mixture was reacted at 25 °C for 1 h, and LCMS detected that the reaction was completed. The reaction was concentrated under reduced pressure, and then purified by high performance liquid chromatography (column: 3_Phenomenex Luna CI 7 75*30mm*3um; mobile phase: [H20 (0.04% HC1)-ACN]; gradient: 1%-35% B in 8.0 min) to give the target compound P8 (73 mg, 230 pmol, 96.0% yield, 99.9% purity, HC1) as a white solid. ESI-MS: [M+H]+, 317.4.

[0147] 1 H NMR (400 MHz, DMSO-d6) d = 12.00-11.71 (m, 1H), 8.51 (br s, 2H), 8.41-8.30 (m, 2H), 8.05 (d, J = 9.0 Hz, 2H), 7.74-7.56 (m, 3H), 7.42-7.27 (m, 2H), 7.23

[0148] -6.91 (m, 1H), 5.68-5.47 (m, 1H), 4.96-4.54 (m, 1H), 4.24-4.05 (m, 1H), 4.00 (q, J = 5.6 Hz, 1H), 3.92-3.81 (m, 1H), 3.69-3.55 (m, 1H), 3.34-2.71 (m, 3H), 1.96-1.86 (m, 3H)

[0149] Example 9-10: Compound P9 and Compound P10.

[0150]

[0151] Compound P8 (73 mg, 230 mΐ, HC1) was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H20 (10 mM NH4HC03)-ACN]; gradient: 35% - 70% B in 8.0 min) to give P8 (33 mg, 104 mΐ, 100% purity), which was purified by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); mobile phase: [Heptane-EtOH (0.1% IPAm)]; B%: 10%, isocratic elution mode) to give the target compounds P9 (7.8 mg, 22.9 mΐ, 21.2% yield, 93.0% purity) and P10 (6.6 mg, 20.8 mΐ, 20.0 yield, 100% purity) as yellow oil. ESI-MS: [M+H] + ,317.2

[0152] P9: 1 H NMR (400 MHz, DMSO-d6) d = 8.52 - 8.44 (m, 1H), 7.97 - 7.90 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 7.56 - 7.43 (m, 3H), 7.09 - 6.95 (m, 2H), 6.93 (s, 1H), 4.34 (q, J = 6.6 Hz, 1H), 3.75 (d, J = 15.0 Hz, 1H), 3.63 - 3.40 (m, 3H), 2.79 - 2.64 (m, 4H), 1.51 (d, J = 6.5 Hz, 3H)

[0153] P10: 1 H NMR (400 MHz, DMSO-d6) d = 8.52 - 8.44 (m, 1H), 7.97 - 7.90 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 7.56 - 7.43 (m, 3H), 7.09 - 6.95 (m, 2H), 6.93 (s, 1H), 4.34 (q, J = 6.6 Hz, 1H), 3.75 (d, J = 15.0 Hz, 1H), 3.63 - 3.40 (m, 3H), 2.79 - 2.64 (m, 4H), 1.51 (d, J = 6.5 Hz, 3H)

[0154] Example 11 : Compound P11.

[0155] 1) Intermediate P8I1 synthesis procedure

[0156]

[0157] Compound P1 (200 mg, 546 pmol, 1 eq) and BocNH2 (127 mg, 1.09 mmol, 2 eq) were dissolved in dioxane (4 mL), and Cs2CO3 (355 mg, 1.09 mmol, 2 eq), Xantphos (63.1 mg, 109 pmol, 0.2 eq) and Pd2(dba)3 (50.0 mg, 54.6 pmol, 0.1 eq) were added successively at room temperature. The reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and then water (10 mL) was added to it. The mixture was extracted with ethyl acetate (4 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target compound P11I1 (60 mg, 74.5 pmol, 28.4% yield) was obtained as a yellow solid by silica gel plate purification (petroleum ether / EtOAc = 5 / 1). ESI-MS: [M+H] + , 403.2.

[0158] 2) Synthesis procedure of compound P11

[0159]

[0160] Compound P11I1 (60 mg, 74.5 pmol, 1 eq) was dissolved in DCM (0.6 mL) and HCl / dioxane (0.6 mL, 4 M), and the reaction mixture was reacted at room temperature for 2 h. LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge BEH CI 18 100*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 48% - 74% B in 8.0 min) to obtain the target compound P11 (12.8 mg, 42.3 pmol, 56.8% yield) as a white solid. ESI-MS: [M+H] + , 303.2

[0161] 1H NMR (400 MHz, DMSO-d6) δ = 8.54-8.40 (m, 1H), 7.96-7.89 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.52-7.45 (m, 3H), 6.70 (d, J = 8.1 Hz, 1H), 6.34 (dd, J = 2.3, 8.0 Hz, 1H), 6.16 (d, J = 2.1 Hz, 1H), 4.71 (s, 2H), 4.35-4.20 (m, 1H), 3.65 (d, J = 14.7 Hz, 1H), 3.43 (d, J = 14.9 Hz, 1H), 2.71-2.54 (m, 4H), 1.48 (d, J = 6.6 Hz, 3H)

[0162] Example 12: Compound P12.

[0163]

[0164] Compound P11 (50 mg, 165 μmol, 1 eq) and TEA (20.1 mg, 198 μmol, 1.2 eq) were dissolved in DCM (1 mL), Ac20 (20.2 mg, 198 μmol, 18.6 μL, 1.2 eq) was added at 0 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, and purified by high performance liquid chromatography (column: Waters xbridge 150*25mm10um; mobile phase: [H20 (10 mM NH4HCO3) - ACN]; gradient: 50% - 90% B in 8.0 min) to give the target compound P12 (20.9 mg, 60.6 μmol, 36.7% yield) as a white solid. ESI-MS: [M+H] + ,344.2

[0165] 1 H NMR (400 MHz, DMSO-d6) δ = 9.76 (s, 1H), 8.50-8.41 (m, 1H), 7.96-7.88 (m, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.52-7.47 (m, 3H), 7.29 (s, 1H), 7.20 (br d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.34 (br d, J = 6.4 Hz, 1H), 3.76 (br d, J = 14.5 Hz, 1H), 3.53 (br d, J = 15.0 Hz, 1H), 2.75-2.59 (m, 4H), 1.98 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H)

[0166] Example 13: Compound P13.

[0167]

[0168] Compound P1 (150 mg, 409 μmol, 1 eq) and compound P13S1 (61.5 mg, 614 μmol, 68.1 μL, 1.5 eq) were dissolved in THF (3 mL), t-BuONa (118 mg, 1.23 mmol, 3 eq) and tBuXPhos PdG3 (32.5 mg, 40.9 μmol, 0.1 eq) were added successively at 25 °C, the reaction mixture was reacted at 80 °C for 16 h under nitrogen protection, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 57% - 85% B in 8.0 min) to give the target compound P13 (21.1 mg, 54.7 μmol, 13.4% yield) as a white solid. ESI-MS: [M+H] + ,386.2

[0169] 1 H NMR (400 MHz, DMSO-d6) δ = 8.47 (dd, J = 3.1, 6.3 Hz, 1H), 7.95 - 7.90 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.52 - 7.46 (m, 3H), 6.90 (d, J = 8.4 Hz, 1H), 6.71 (dd, J = 2.6, 8.3 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 4.30 (q, J = 6.7 Hz, 1H), 3.72 (d, J = 14.9 Hz, 1H), 3.52 (d, J = 15.0 Hz, 1H), 3.05 - 2.96 (m, 4H), 2.73 - 2.57 (m, 4H), 2.43 - 2.36 (m, 4H), 2.18 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H)

[0170] Example 14: Compound P14.

[0171]

[0172] Compound P1 (150 mg, 409 µmol, 1 eq) and compound P14S1 (77.52 mg, 614 µmol, 1.5 eq) were dissolved in THF (3 mL), t-BuONa (118 mg, 1.23 mmol, 3 eq) and tBuXPhos Pd G3 (32.5 mg, 40.9 µmol, 0.1 eq) were added successively at 25 °C, the reaction mixture was reacted at 80 °C for 16 h, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 1% - 35% B in 8.0 min) to give the target compound GDI19-042 (42.8 mg, 103 µmol, 25.4% yield) as a white solid. ESI-MS: [M+H] + ,412.2

[0173] 1 H NMR (400 MHz, DMSO-d6) d = 8.51 - 8.44 (m, 1H), 7.96 - 7.88 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.53 - 7.45 (m, 3H), 6.86 (d, J = 8.3 Hz, 1H), 6.44 (dd, J = 2.3, 8.2 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 4.30 (q, J = 6.7 Hz, 1H), 3.71 (d, J = 14.9 Hz, 1H), 3.51 (d, J = 14.9 Hz, 1H), 3.21 (t, J = 8.1 Hz, 2H), 2.97 (dd, J = 2.2, 9.5 Hz, 2H), 2.82 (br s, 2H), 2.72 - 2.64 (m, 3H), 2.62 - 2.54 (m, 3H), 2.40 - 2.33 (m, 2H), 2.22 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H)

[0174] Example 15: Compound P15.

[0175] 1) Intermediate P15I1 synthesis procedure

[0176]

[0177] Compound P1 (150 mg, 409 pmol, 1 eq) and compound P15S1 (104 mg, 491 pmol, 1.2 eq) were dissolved in THF (3 mL), t-BuONa (118 mg, 1.23 mmol, 3 eq), BINAP (25.5 mg, 40.9 pmol, 0.1 eq) and Pd2(dba)3 (37.5 mg, 40.9 pmol, 0.1 eq) were added successively at room temperature, the reaction mixture was reacted at 80 °C for 16 hours under nitrogen protection, and LCMS detection showed that the reaction was completed. After the reaction solution was concentrated under reduced pressure, water (10 mL) was added to it, and EtOAc (2 mL*3) was used for extraction, and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to obtain compound P15I1 (85 mg, 170 pmol, 41.7% yield) as a yellow solid. ESI-MS: [M+H] + ,498.4

[0178] 2) Synthesis procedure of compound P15

[0179]

[0180] Compound P15I1 (85 mg, 170 pmol, 1 eq) was dissolved in DCM (1.36 mL), TFA (0.34 mL) was added at 25 °C, and the reaction mixture was reacted at 25 °C for 1 hour, and LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and then the target compound P15 (40 mg, 90.1 pmol, 52.8% yield, FA) was obtained by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-35% B in 8.0 min) as a yellow solid. ESI-MS: [M+H] + ,398.3

[0181] 1H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 3.1, 5.4 Hz, 1H), 8.15 (s, 1H), 7.93 (dd, J = 3.2, 6.3 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.52 - 7.47 (m, 3H), 6.93 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 2.1, 8.3 Hz, 1H), 6.51 (s, 1H), 4.36 - 4.25 (m, 1H), 4.06 (br s, 2H), 3.68 (d, J = 14.8 Hz, 1H), 3.55 - 3.48 (m, 3H), 2.89 (d, J = 12.1 Hz, 2H), 2.74 - 2.66 (m, 3H), 2.62 (br s, 1H), 1.89 (br s, 4H), 1.50 (d, J = 6.5 Hz, 3H)

[0182] Example 16: Compound P16.

[0183] 1) Synthesis procedure of intermediate P16I1

[0184]

[0185] Compound P1 (100 mg, 273 μmol, 1 eq) and compound P16S1 (54.1 mg, 273 μmol, 1 eq) were dissolved in THF (2 mL), t-BuONa (78.7 mg, 819 μmol, 3 eq), BINAP (17.0 mg, 27.3 μmol, 0.1 eq) and Pd2(dba)3 (25.0 mg, 27.3 μmol, 0.1 eq) were added successively at 25 °C, the reaction mixture was reacted at 80 °C for 16 hours under nitrogen protection, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (5 mL) was added, extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (3 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel plate (petroleum ether / EtOAc = 5 / 1) to give the target compound P16I1 (60 mg, 124 μmol, 45.4% yield) as a yellow solid. ESI-MS: [M+H] + ,484.2

[0186] 2) Synthesis procedure of compound P16

[0187]

[0188] Compound P16I1 (70 mg, 144 pmol, 1 eq) was dissolved in DCM (1.2 mL), then TFA (0.3 mL) was added, the reaction mixture was reacted at 20 °C for 2 h, LCMS detection showed that the reaction was completed. The reaction solution was rotary evaporated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, then purified by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 45%-65% B in 8.0 min) to obtain the target compound P16 (25.4 mg, 66.2 pmol, 45.8% yield) as a white solid. ESI-MS: [M+H] + , 384.2.

[0189] 1 H NMR (400 MHz, DMSO-d6) d = 8.59-8.42 (m, 1H), 7.93 (dd, J = 3.5, 6.0 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 7.53-7.44 (m, 3H), 7.00-6.93 (m, 3H), 4.33 (q, J = 6.4 Hz, 1H), 3.74 (d, J = 15.1 Hz, 1H), 3.56 (d, J = 15.0 Hz, 1H), 2.80-2.61 (m, 4H), 2.20 (br s, 2H), 1.51 (d, J = 6.6 Hz, 3H), 0.90-0.73 (m, 4H)

[0190] Example 17-18: Compound P17 and Compound P18.

[0191]

[0192] Compound P16 (19 mg, 49.5 pmol, 1 eq) was resolved by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um); mobile phase: [Heptane-EtOH (0.1% IPAm)]; B%: 10%, isocratic elution mode) to obtain the target compounds P17 (3.1 mg, 7.82 pmol, 15.8% yield) and P18 (5 mg, 13.0 pmol, 26.3% yield) as white solids. ESI-MS: [M+H] + , 384.2.

[0193] P17: 1H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 4.1 Hz, 1H), 7.96 - 7.89

[0194] H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 4.1 Hz, 1H), 7.96 - 7.89

[0195] P18: 1 H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 4.1 Hz, 1H), 7.96 - 7.89

[0196] H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 4.1 Hz, 1H), 7.96 - 7.89

[0197] Example 19: Compound P19.

[0198] 1) Intermediate P19I1 synthesis procedure

[0199]

[0200] Compound P1 (100 mg, 273 pmol, 1 eq) and compound P19S1 (43.0 mg, 327 pmol, 1.2 eq) were dissolved in THF (2 mL), t-BuONa (78.7 mg, 819 pmol, 3 eq) and tBuXPhos Pd G3 (21.7 mg, 27.3 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (5 mL) was added, and extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (3 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 2 / 1) to give the target compound P19I1 (90 mg, 216 pmol, 79.1% yield) as a yellow solid. ESI-MS: [M+H] + , 417.4.

[0201] 2) Synthesis procedure of compound P19

[0202]

[0203] Compound P19I1 (90 mg, 216 pmol, 1 eq) and TFA (0.36 mL) were added successively into DCM (1.44 mL), and the reaction mixture was reacted at room temperature for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, and CH3CN (2 mL) was added to the residue, then NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and then purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%-45% B in 8.0 min) to give the target compound P19 (29.4 mg, 92.9 pmol, 43.0% yield) as a white solid. ESI-MS: [M+H] + , 317.2.

[0204] 1H NMR (400 MHz, Methanol-d4) d = 8.29 (d, J = 8.0 Hz, 1H), 8.02 - 7.92 (m, 2H), 7.80 (d, J = 7.1 Hz, 1H), 7.66 - 7.52 (m, 3H), 6.95 (d, J = 8.3 Hz, 1H), 6.57 (dd, J = 2.3, 8.3 Hz, 1H), 6.27 (br s, 1H), 5.06 (br s, 1H), 4.37 - 4.15 (m, 1H), 4.01 (d, J = 12.1 Hz, 1H), 3.22 (br s, 2H), 3.05 - 2.78 (m, 2H), 2.71 (s, 3H), 1.80 (d, J = 6.6 Hz, 3H)

[0205] Example 20: Compound P20.

[0206] 1) Synthesis procedure of intermediate P20I1

[0207]

[0208] Five reactions were run in parallel, compound P1 (50 mg, 97.34 pmol, 1 eq) and compound P20S1 (47.1 mg, 273 pmol, 2 eq) were dissolved in dioxane (1 mL), Cs2CO3 (133 mg, 409 pmol, 3 eq) and RuPhos Pd G3 (11.4 mg, 13.6 pmol, 0.1 eq) were added in turn at 20 °C, the reaction mixture was reacted at 100 °C for 16 hours under nitrogen protection, and LCMS detection showed that the reaction was completed. The five parallel reactions were combined, water (10 mL) was added to the reaction, extracted with ethyl acetate (7 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by silica gel plate (PE / EA = 1 / 1) to give the target compound P20I1 (180 mg, 393 pmol, 57.6% yield) as a white solid. ESI-MS: [M+H] + ,458.2.

[0209] 2) Synthesis procedure of compound P20

[0210]

[0211] Compound P20I1 (100 mg, 218 µmol, 1 eq) and TFA (0.4 mL) were sequentially dissolved in DCM (1.6 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (1.8 mL) was added, the solution pH was adjusted to 7-8 with NH3 H2O, and the target compound P20 (57.1 mg, 159 µmol, 73.1% yield) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min). ESI-MS: [M+H] + , 358.2.

[0212] 1 H NMR (400 MHz, Methanol-d4) δ = 8.37 (br s, 1H), 8.22 (br d, J = 8.1 Hz, 1H), 8.04-7.95 (m, 2H), 7.84 (d, J = 7.1 Hz, 1H), 7.67-7.53 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 6.47 (dd, J = 1.8, 8.3 Hz, 1H), 6.19 (s, 1H), 5.32 (br d, J = 6.4 Hz, 1H), 4.38 (br d, J = 15.0 Hz, 1H), 4.19 (br d, J = 15.1 Hz, 1H), 4.16-4.03 (m, 3H), 3.82 (br s, 2H), 3.51-3.35 (m, 2H), 3.08-2.87 (m, 2H), 1.87 (d, J = 6.6 Hz, 3H)

[0213] Example 21: Compound P21.

[0214] 1) Intermediate P21I1 synthesis procedure

[0215]

[0216] Compound P1 (100 mg, 273 pmol, 1 eq) and compound P21S1 (50.8 mg, 273 pmol, 1 eq) were dissolved in THF (2 mL), t-BuONa (78.7 mg, 819 pmol, 3 eq), BINAP (17.0 mg, 27.3 pmol, 0.1 eq) and Pd2(dba)3 (25.0 mg, 27.3 pmol, 0.1 eq) were added successively at 25 °C, and the reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, water (5 mL) was added, and the mixture was extracted with EtOAc (2 mL*3). The combined organic phase was washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel plate (petroleum ether / EtOAc = 5 / 1) gave the target compound P21I1 (40 mg, 84.8 pmol, 15.5% yield) as a yellow solid. ESI-MS: [M+H] + , 472.2.

[0217] 2) Synthesis procedure of compound P21

[0218]

[0219] Compound P21I1 (40 mg, 84.8 pmol, 1 eq) was dissolved in DCM (0.8 mL), and TFA (0.2 mL) was added at 25 °C. The reaction mixture was reacted at 25 °C for 2 h, and LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and then purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min) to give the target compound P21 (21.9 mg, 58.9 pmol, 69.5% yield) as a white solid. ESI-MS: [M+H] + , 372.2.

[0220] 1H NMR (400 MHz, DMSO-d6) d = 8.56 - 8.44 (m, 1H), 8.33 (br s, 1H), 7.93 (dd, J = 3.0, 6.4 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.0 Hz, 1H), 7.56 - 7.42 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.63 (s, 1H), 4.47 (br s, 1H), 4.34 (q, J = 6.3 Hz, 1H), 4.16 (br s, 1H), 4.05 (d, J = 9.9 Hz, 1H), 3.76 (d, J = 15.3 Hz, 2H), 3.67 (br s, 1H), 3.57 (d, J = 15.0 Hz, 1H), 2.79 - 2.58 (m, 4H), 2.39 (br s, 1H), 2.23 (br s, 1H), 1.51 (d, J = 6.6 Hz, 3H)

[0221] Example 22: Compound P22.

[0222] 1) Synthesis procedure of intermediate P22I1

[0223]

[0224] Compound P1 (400 mg, 1.09 mmol, 1 eq) and compound P22S1 (306 mg, 1.64 mmol, 1.5 eq) were dissolved in THF (8 mL), t-BuONa (314 mg, 3.28 mmol, 3 eq) and tBuXPhos Pd G3 (86.7 mg, 109 µmol, 0.1 eq) were added at 25 ℃, the reaction mixture was reacted at 80 ℃ for 16 hours under nitrogen protection, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (10 mL) was added, extracted with EtOAc (4 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give compound P22I1 (220 mg, 430 µmol, 39.4% yield, 92.5% purity) as a yellow solid. ESI-MS: [M+H] + , 473.4.

[0225] 2) Synthesis procedure of compound P22

[0226]

[0227] Compound P22I1 (200 mg, 423 µmol, 1 eq) was dissolved in DCM (3.2 mL), TFA (0.8 mL) was added at 25 °C. The reaction mixture was reacted at 25 °C for 2 h, LCMS detected the reaction was completed. The reaction was concentrated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added to adjust pH to ~8, then the target compound P22 (24.6 mg, 66.0 µmol, 15.6% yield) was obtained by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) as a white solid. ESI-MS: [M+H] + , 373.2.

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 5.4 Hz, 1H), 8.21 (s, 1H), 7.97-7.91 (m, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 7.53-7.47 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 2.4, 8.3 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 4.66-4.57 (m, 1H), 4.35 (d, J = 4.4 Hz, 1H), 4.24-4.16 (m, 1H), 4.16-4.09 (m, 1H), 3.92

[0229] -3.86 (m, 1H), 3.83-3.77 (m, 1H), 3.76 (br s, 1H), 3.57 (d, J = 15.6 Hz, 1H), 2.77-2.70 (m, 3H), 2.70-2.64 (m, 1H), 2.46-2.40 (m, 1H), 2.34-2.26 (m, 1H), 1.51 (d, J = 6.7 Hz, 3H)

[0230] Example 23: Compound P23.

[0231]

[0232] Compound P22 (120 mg, 322 pmol, 1 eq) and 37% formaldehyde aqueous solution (96.7 mg, 3.22 mmol, 88.7 pL, 10 eq) were dissolved in MeOH (2.4 mL), AcOH (19.3 mg, 322 pmol, 18.4 pL, 1 eq) was added at 25 °C, after the reaction mixture was reacted at 25 °C for 1 h, NaBH3CN (30.3 mg, 483 pmol, 1.5 eq) was added to the above reaction solution, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection reaction was completed. The reaction solution was concentrated under reduced pressure, then water (5 mL) was added, extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (3 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the reaction solution was purified by high performance liquid chromatography (column: Waters Xbridge BEH CI 8 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 55% - 90% B in 8.0 min) to give the target compound P23 (32.1 mg, 83.0 pmol, 25.7% yield, 100% purity) as a yellow solid. ESI-MS: [M+H] + , 387.2.

[0233] 1 H NMR (400 MHz, DMSO-d6) d 8.51 - 8.45 (m, 1H), 7.97 - 7.92 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.54 - 7.48 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 2.6, 8.3 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.34 (q, J = 6.3 Hz, 1H), 3.87 (d, J = 5.4 Hz, 2H), 3.78 (d, J = 15.1 Hz, 1H), 3.56 (d, J = 15.0 Hz, 1H), 3.29 - 3.22 (m, 2H), 2.77 - 2.64 (m, 5H), 2.24 (s, 3H), 2.00 - 1.93 (m, 1H), 1.90 - 1.81 (m, 1H), 1.51 (d, J = 6.5 Hz, 3H)

[0234] Example 24: Compound P24.

[0235]

[0236] Compound P1 (100 mg, 273 pmol, 1 eq) and compound P24S1 (54.1 mg, 327 pmol, 1.2 eq) were dissolved in dioxane (2 mL) and H20 (0.6 mL), and Cs2C03(266 mg, 819 pmol, 3 eq), RuPhos (12.7 mg, 27.3 pmol, 0.1 eq) and Pd(OAc)2(6.13 mg, 27.3 pmol, 0.1 eq) were added successively at room temperature. The reaction mixture was reacted at 100 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H20 (10 mM NH4HC03)-ACN]; gradient: 60%-95% B in 8.0 min) to give the target compound P24 (28.6 mg, 83 pmol, 30.4% yield) as a white solid. ESI-MS: [M+H] + , 345.2.

[0237] 1 H NMR (400 MHz, DMSO-d6) d = 8.54-8.40 (m, 1H), 7.96-7.90 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 6.7 Hz, 1H), 7.53-7.46 (m, 3H), 7.00 (s, 2H), 6.90 (s, 1H), 4.38-4.29 (m, 1H), 3.81 (d, J = 14.9 Hz, 1H), 3.56 (d, J = 14.9 Hz, 1H), 3.26 (s, 2H), 2.77-2.70 (m, 2H), 2.69-2.65 (m, 2H), 2.09 (s, 6H), 1.51 (d, J = 6.6 Hz, 3H)

[0238] Example 25: Compound P25.

[0239] 1) Intermediate P25I1 synthesis procedure

[0240]

[0241] Compound P1 (0.2 g, 546 pmol, 1 eq) and compound P25S1 (144 mg, 546 pmol, 1 eq) were dissolved in DMAC (2 mL), LiCl (23.2 mg, 546 pmol, 11.2 pL, 1 eq), zinc powder (35.7 mg, 546 pmol, 1 eq), 2-imidazolidinylpyridine hydrochloride (17.2 mg, 109 pmol, 0.2 eq) and NiBr2DME (33.7 mg, 109 pmol, 0.2 eq) were added successively at 25 °C, the reaction mixture was reacted at 50 °C for 16 hours under nitrogen protection, and LCMS detection showed that the reaction was completed. Water (5 mL) and HC1 (2 M, 3 mL) were added to the reaction solution, and EtOAc (2 mL*3) was used for extraction, and the organic phase was combined. The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 2 / 1) to obtain the target compound P25I1 (190 mg, 258 pmol, 47.3% yield, 64% purity) as a white solid. ESI-MS: [M+H] + , 471.5.

[0242] 2) Synthesis procedure of compound P25

[0243]

[0244] Compound P25I1 (190 mg, 258 pmol, 47.3% yield, 64% purity) was dissolved in DCM (3.2 mL), and TFA (0.8 mL) was added at 25 °C. The reaction mixture was reacted at 25 °C for 1 hour, and LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and then purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 60%-90% B in 8.0 min) to obtain the target compound P25 (4 mg, 10.8 pmol, 4.18% yield) as a white solid. ESI-MS: [M+H] + , 371.5.

[0245] 1H NMR (400 MHz, DMSO-d6) d = 8.47 (dd, J = 3.6, 5.5 Hz, 1H), 7.97 - 7.88 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.53 - 7.44 (m, 3H), 6.95 (q, J = 8.0 Hz, 2H), 6.82 (s, 1H), 4.33 (q, J = 5.9 Hz, 1H), 3.78 (d, J = 15.0 Hz, 1H), 3.55 (d, J = 14.8 Hz, 1H), 2.96 (d, J = 11.6 Hz, 2H), 2.78 - 2.52 (m, 6H), 2.44 (d, J = 3.0 Hz, 2H), 1.60 (d, J = 12.1 Hz, 2H), 1.50 (d, J = 6.6 Hz, 3H), 1.46 - 1.38 (m, 2H)

[0246] Example 26: Synthesis procedure of compound P26.

[0247] 1) Synthesis procedure of intermediate P25I1

[0248]

[0249] Compound P1 (240 mg, 655 pmol, 1 eq) and compound P26S1 (154 mg, 655 pmol, 1 eq) were dissolved in DMAc (2.4 mL), LiCl (27.7 mg, 655 pmol, 13.4 pL, 1 eq), zinc powder (42.8 mg, 655 pmol, 1 eq), 2-imidazolidinylpyridine hydrochloride (10.3 mg, 65.5 pmol, 0.1 eq) and NiBr2DME (20.2 mg, 65.5 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 50 °C for 16 hours under nitrogen protection, and LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (10 mL) was added, and extracted with EtOAc (4 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 5 / 1) to give the target compound P26I1 (120 mg, 271.13 pmol, 41.4% yield) as a yellow solid. ESI-MS: [M+H] + ,443.2.

[0250] 2) Synthesis procedure of compound P26

[0251]

[0252] Compound P26I1 (120 mg, 271.13 pmol, 1 eq) was dissolved in DCM (2 mL), TFA (0.5 mL) was added at 25 °C. The reaction mixture was reacted at 25 °C for 1 h, LCMS detected the completion of the reaction. The reaction solution was concentrated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust pH to ~8, then purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) to obtain the target compound P26 (50.5 mg, 147 pmol, 54.4% yield) as a white solid. ESI-MS: [M+H] + , 343.2.

[0253] 1 H NMR (400 MHz, DMSO-d6) d = 9.15-8.82 (m, 1H), 8.75-8.51 (m, 1H), 8.45 (d, J = 0.8 Hz, 1H), 8.14 (s, 1H), 7.98-7.92 (m, 1H), 7.88 (d, J = 6.9 Hz, 1H), 7.68 (br s, 1H), 7.58-7.47 (m, 3H), 7.12 (br s, 2H), 7.06 (br s, 1H), 4.85-4.32 (m, 1H), 4.20 (br s, 2H), 4.00 (br s, 3H), 3.92-3.54 (m, 2H), 2.82 (d, J = 3.1 Hz, 4H), 1.57 (br s, 3H)

[0254] Example 27: Compound P27.

[0255] 1) Intermediate P27I1 synthesis procedure

[0256]

[0257] Compound P1 (200 mg, 546 pmol, 1 eq) was dissolved in toluene (4 mL), TBE (216 mg, 600 pmol, 202 pL, 1.1 eq) and Pd(PPh3)2Cl2(3.83 mg, 5.46 pmol, 0.01 eq) were added successively at 25 °C. The reaction mixture was reacted at 100 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (10 mL) was added, and the mixture was extracted with EtOAc (4 mL*3). The combined organic phase was washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel plate (petroleum ether / EtOAc = 5 / 1) gave the target compound P27I1 (110 mg, 333 pmol, 61.2% yield) as a yellow solid. ESI-MS: [M+H] + , 330.2.

[0258] 2) Synthesis procedure of compound P27

[0259]

[0260] Compound P27I1 (90 mg, 273 pmol, 1 eq) and AcOH (32.8 mg, 546 pmol, 31.28 pL, 2 eq) were dissolved in NH3 / MeOH (7 M, 1.8 mL), and the reaction mixture was stirred at 60 °C for 1 h. NaBH3CN (25.7 mg, 409 pmol, 1.5 eq) was added to the above reaction solution, and the reaction mixture was reacted at 60 °C for 5 h. LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min) to give the target compound P27 (24.8 mg, 75.1 pmol, 27.5% yield) as a white solid. ESI-MS: [M+H] + , 331.2.

[0261] 1H NMR (400 MHz, DMSO-d6) d = 8.52-8.42 (m, 1H), 7.96-7.88 (m, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.53-7.45 (m, 3H), 7.09-7.03 (m, 1H), 6.97 (d, J = 7.9 Hz, 2H), 4.33 (q, J = 6.7 Hz, 1H), 3.85 (q, J = 6.6 Hz, 1H), 3.75 (d, J = 15.1 Hz, 1H), 3.55 (d, J = 14.8 Hz, 1H), 2.76-2.61 (m, 4H), 2.10-1.77 (m, 2H), 1.51 (d, J = 6.5 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H)

[0262] Example 28: Compound P28.

[0263] 1) Synthesis procedure of intermediate P28I1

[0264]

[0265] Compound P1 (0.5 g, 1.24 mmol, 1 eq) was dissolved in DMF (10 mL), under nitrogen protection, Zn(CN)2(291 mg, 2.48 mmol, 157 μL, 2 eq) and Pd(PPh3)4(143 mg, 124 μmol, 0.1 eq) were added at 25 °C, the reaction mixture was reacted at 110 °C for 2 hours, LCMS detected that the reaction was completed. The reaction was concentrated under reduced pressure, then water (10 mL) was added, extracted with EtOAc (15 mL*3), the organic phase was combined and washed with saturated sodium chloride (20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to give compound P28I1 (310 mg, 992 μmol, 79.9% yield) as a white solid. ESI-MS: [M+H] + , 313.2.

[0266] 2) Synthesis procedure of compound P28

[0267]

[0268] Compound P28I1 (0.15 g, 480 μmol, 1 eq) was dissolved in THF (3 mL), Ti(Oi-Pr)4 (150 mg, 528 μmol, 155 μL, 1.1 eq) and EtMgBr (3 M, 352 μL, 2.2 eq) were added successively under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 10 min, then warmed to 15 °C for 1 h. Then BF3.Et2O (136 mg, 960 μmol, 118 μL, 2 eq) was added to the reaction solution at 0 °C, the reaction mixture was reacted at 15 °C for 5 h, LCMS detection showed that the reaction was completed. The reaction solution was extracted with MeOH (1 mL) at 0 °C, concentrated under reduced pressure, then purified by silica gel plate (SiO2, EtOAc / MeOH = 10 / 1) and high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 53% - 85% B in 8.0 min) to give the target compound P28 (20 mg, 58.4 μmol, 12.1% yield) as a white solid. ESI-MS: [M+H] + , 343.1.

[0269] 1 H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.45 (m, 1H), 7.92 (dd, J = 3.5, 6.0 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.55 - 7.44 (m, 3H), 7.01 - 6.90 (m, 3H), 4.33 (q, J = 6.6 Hz, 1H), 3.74 (d, J = 15.1 Hz, 1H), 3.55 (d, J = 15.0 Hz, 1H), 2.76 - 2.62 (m, 4H), 2.19 (brs, 2H), 1.51 (d, J = 6.6 Hz, 3H), 0.90 - 0.82 (m, 2H), 0.82 - 0.75 (m, 2H)

[0270] Example 29: Compound P29.

[0271]

[0272] Compound P28I1 (50 mg, 160 μmol, 1 eq) was dissolved in THF (1 mL), MeMgBr (3 M, 320 μL, 6 eq) was added under nitrogen protection at 25 °C, the reaction mixture was reacted at 25 °C for 0.5 h, then Ti(OiPr)4 (90.8 mg, 320 μmol, 94.4 μL, 1 eq) was added to the above mixture, and then the reaction mixture was continued to react at 25 °C for 16 h, the reaction mixture was continued to react at 50 °C for 1 h, and LCMS detection showed that the reaction was completed. The reaction solution was added to an ammonium chloride solution (5 mL), extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 10% - 42% B in 8.0 min) to give the target compound P29 (3.4 mg, 9.87 μmol, 6.17% yield) as a white solid. ESI-MS: [M+H] + ,345.2.

[0273] 1 H NMR (400 MHz, Methanol-d4) δ 8.44 - 8.41 (m, 1H), 8.38 (br d, J = 1.5 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.51 - 7.46 (m, 3H), 7.26 (br d, J = 8.1 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 4.50 (br d, J = 6.5 Hz, 1H), 3.94 (br d, J = 14.9 Hz, 1H), 3.72 (br d, J = 14.9 Hz, 1H), 2.98 - 2.82 (m, 4H), 1.73 - 1.59 (m, 9H)

[0274] Example 30: Compound P30.

[0275] 1) Synthesis procedure of intermediate P30I1

[0276]

[0277] Compound Pll (120 mg, 396 pmol, leq) and compound P30S1 (119 mg, 595 pmol, 1.5 eq) were dissolved in MeCN (2.15 mL) and DMF (0.25 mL), TCFH (133 mg, 476 pmol, 1.2 eq) and NMI (97.7 mg, 1.19 mmol, 94.8 pL, 3 eq) were added sequentially at 25 °C, the reaction mixture was reacted at 25 °C for 2 h, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (10 mL) was added, extracted with EtOAc (4 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 1 / 1) to give the target compound P30I1 (140 mg, 288 pmol, 72.7% yield) as a yellow solid. ESI-MS: [M+H] + , 486.2.

[0278] 2) Synthesis procedure of compound P30

[0279]

[0280] Compound P30I1 (120 mg, 247 pmol, leq) and TFA (0.4 mL) were sequentially dissolved in DCM (2 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, CH3CN (1.8 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 80*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) to give the target compound P30 (50.4 mg, 130 pmol, 52.9% yield) as a white solid. ESI-MS: [M+H] + , 386.2.

[0281] 1H NMR (400 MHz, Methanol-d4) d = 8.38 - 8.31 (m, 1H), 8.02 - 7.91 (m, 2H), 7.80 (d, J = 7.0 Hz, 1H), 7.65 - 7.53 (m, 3H), 7.46 - 7.37 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 5.10 (dd, J = 7.9, 9.3 Hz, 1H), 5.02 (d, J = 6.5 Hz, 1H), 4.26 (d, J = 15.3 Hz, 1H), 4.21 - 4.11 (m, 1H), 4.07 - 3.93 (m, 2H), 3.29 - 3.14 (m, 2H), 3.10 - 2.83 (m, 3H), 2.72 - 2.53 (m, 1H), 1.81 (d, J = 6.6 Hz, 3H)

[0282] Example 31: Compound P31.

[0283] 1) Synthesis procedure of intermediate P31I1

[0284]

[0285] Compound P11 (100 mg, 331 pmol, 1 eq) and compound P31S1 (85. mg, 397 pmol, 1.2 eq) were dissolved in CH3CN (1.8 mL) and DMF (0.2 mL), TCFH (111.3 mg, 397 pmol, 1.2 eq) and NMI (81.5 mg, 992 pmol, 79.1 pL, 3 eq) were added successively at 25 °C, the reaction mixture was reacted at 25 °C for 2 hours, LCMS detection reaction was completed. Water (5 mL) was added to the reaction solution, extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 1 / 2) to give the target compound P31I1 (90 mg, 180.13 pmol, 54.5% yield) as a yellow solid. ESI-MS: [M+H] + ,500.5.

[0286] 2) Synthesis procedure of compound P31

[0287]

[0288] Compound P31I1 (90 mg, 181.5 pmol, 1 eq) and TFA (0.4 mL) were dissolved in DCM (1.6 mL), the reaction mixture was reacted at 25 °C for 2 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added to adjust the pH to ~8, and the target compound P31 (7.4 mg, 18.5 pmol, 10.2% yield) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%-45% B in 8.0 min). ESI-MS: [M+H] + , 400.2.

[0289] 1 H NMR (400 MHz, Methanol-d4) d = 8.36 (d, J = 8.0 Hz, 2H), 7.98-7.84 (m, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.58-7.48 (m, 3H), 7.37-7.28 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 6.7 Hz, 1H), 4.40-4.29 (m, 1H), 4.08 (d, J = 15.2 Hz, 1H), 3.83 (d, J = 15.2 Hz, 1H), 3.51-3.33 (m, 2H), 3.08-2.99 (m, 2H), 2.98-2.78 (m, 2H), 2.54-2.40 (m, 1H), 2.13-1.97 (m, 3H), 1.70 (d, J = 6.7 Hz, 3H)

[0290] Example 32: Compound P32.

[0291] 1) Intermediate P32I1 synthesis procedure

[0292]

[0293] Compound Pll (100 mg, 331 pmol, 1 eq) and compound P32S1 (108 mg, 496 pmol, 1.5 eq) were dissolved in CH3CN (1.8 mL) and DMF (0.2 mL), and TCFH (111.3 mg, 397 pmol, 1.2 eq) and NMI (81.5 mg, 992 pmol, 79.1 pL, 3 eq) were added sequentially at 25 °C. The reaction mixture was reacted at 25 °C for 2 h, and LCMS detection showed that the reaction was complete. Water (5 mL) was added to the reaction solution, and EtOAc (3 mL*3) was used for extraction. The organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification was performed by silica gel plate (petroleum ether / EtOAc = 1 / 2) to obtain the target compound P32I1 (110 mg, 239 pmol, 72.4% yield) as a yellow solid. ESI-MS: [M+H] + , 460.4.

[0294] 2) Synthesis procedure of compound P32

[0295]

[0296] Compound P32I1 (90 mg, 181.5 pmol, 1 eq) and TFA (0.4 mL) were sequentially dissolved in DCM (1.6 mL), and the reaction mixture was reacted at 25 °C for 2 h. LCMS detection showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and CH3CN (1.8 mL) was added to the residue. NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8. Purification was performed by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound P32 (23.6 mg, 65.7 pmol, 27.4% yield) as a white solid. ESI-MS: [M+H] + , 360.1.

[0297] 1H NMR (400 MHz, Methanol-d4) d = 8.33 (d, J = 7.4 Hz, 2H), 8.06 - 7.87 (m, 2H), 7.76 (d, J = 7.2 Hz, 1H), 7.60 - 7.49 (m, 3H), 7.39 - 7.29 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 4.89 - 4.87 (m, 1H), 4.17 (d, J = 15.3 Hz, 1H), 3.93 (d, J = 15.2 Hz, 1H), 3.80 (s, 2H), 3.19 - 3.10 (m, 2H), 3.04 - 2.83 (m, 2H), 1.77 (d, J = 6.6 Hz, 3H)

[0298] Example 33: Compound P33.

[0299] 1) Synthesis procedure of intermediate P33I1

[0300]

[0301] Compound P11 (100 mg, 330 pmol, 1 eq) and compound P33S1 (108 mg, 496 pmol, 1.5 eq) were dissolved in MeCN (1.8 mL) and DMF (0.2 mL), TCFH (111 mg, 396 pmol, 1.2 eq) and NMI (81.5 mg, 992 mmol, 79.1 pL, 3 eq) were added successively at 25 °C, the reaction mixture was reacted at 25 °C for 2 hours, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (10 mL) was added, extracted with EtOAc (4 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 1 / 2) to give the target compound P33I1 (110 mg, 239 pmol, 72.4% yield) as a yellow solid. ESI-MS: [M+H] + , 502.4.

[0302] 2) Synthesis procedure of compound P33

[0303]

[0304] Compound P33I1 (110 mg, 239 mΐioΐ, 1 eq) and TFA (0.2 mL) were sequentially dissolved in DCM (2 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (1.8 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and the target compound P33 (50.4 mg, 130 mΐioΐ, 52.9% yield) was obtained as a white solid by purification through high performance liquid chromatography (column: Phenomenex Luna C18 80*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min). ESI-MS: [M+H] + ,402.4.

[0305] 1 H NMR (400 MHz, Methanol-d4) d = 8.27 (br d, J = 7.9 Hz, 1H), 8.07-7.93 (m, 2H), 7.86 (d, J = 7.1 Hz, 1H), 7.71-7.56 (m, 3H), 7.53-7.42 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H), 5.41 (br d, J = 6.6 Hz, 1H), 5.02 (d, J = 6.8 Hz, 2H), 4.58 (d, J = 6.6 Hz, 2H), 4.50 (br d, J = 15.1 Hz, 1H), 4.31 (br d, J = 15.3 Hz, 1H), 3.58-3.38 (m, 2H), 3.18-2.98 (m, 2H), 1.92 (d, J = 6.6 Hz, 3H)

[0306] Example 34: Compound P34.

[0307]

[0308] Compound P11 (150 mg, 360 µmol, 1 eq, TFA) and compound P34S1 (45.3 mg, 595 µmol, 1.2 eq) were dissolved in MeCN (2.7 mL) and DMF (0.3 mL), TCFH (121 mg, 432 µmol, 1.2 eq) and NMI (88.7 mg, 1.08 mmol, 86.1 µL, 3 eq) were added sequentially at 25 °C, the reaction mixture was reacted at 25 °C for 2 h, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 10% - 75% B in 8.0 min) to give the target compound P34 (23.5 mg, 65.2 µmol, 18.1% yield) as a white solid. ESI-MS: [M+H] + , 361.2.

[0309] 1 H NMR (400 MHz, DMSO-d6) d = 9.46 (s, 1H), 8.53-8.37 (m, 1H), 7.96-7.89 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 6.7 Hz, 1H), 7.54-7.46 (m, 3H), 7.42-7.32 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 5.63 (t, J = 6.0 Hz, 1H), 4.39-4.31 (m, 1H), 3.93 (d, J = 5.8 Hz, 2H), 3.76 (d, J = 15.1 Hz, 1H), 3.55 (d, J = 15.0 Hz, 1H), 2.78-2.60 (m, 4H), 1.51 (d, J = 6.7 Hz, 3H)

[0310] Example 35: Compound P35.

[0311] 1) Synthesis procedure of intermediate P35I1

[0312]

[0313] Compound Pll (80 mg, 265 pmol, leq) and compound P35S1 (63.9 mg, 317 pmol, 1.2 eq) were dissolved in MeCN (1.44 mL) and DMF (0.16 mL), TCFH (89.1 mg, 317 pmol, 1.2 eq) and NMI (65.2 mg, 794 mmol, 63.3 pL, 3 eq) were added sequentially at 25 °C, the reaction mixture was reacted at 25 °C for 2 h, and LCMS detection showed that the reaction was complete. The reaction was concentrated under reduced pressure, water (5 mL) was added to it, and EtOAc (3 mL*3) was used for extraction, and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 2 / 1) to obtain the target compound P35I1 (110 mg, 227 pmol, 85.6% yield) as a yellow solid. ESI-MS: [M+H] + , 486.5.

[0314] 2) Synthesis procedure of compound P35

[0315]

[0316] Compound P35I1 (110 mg, 227 pmol, leq) and TFA (0.2 mL) were sequentially dissolved in DCM (2 mL), the reaction mixture was reacted at 25 °C for 1 h, and LCMS detection showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 80*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) to obtain the target compound P35 (29.1 mg, 75.5 pmol, 33.3% yield) as a white solid. ESI-MS: [M+H] + , 386.5.

[0317] 1H NMR (400 MHz, Methanol-d4) d = 8.29 (br d, J = 8.0 Hz, 1H), 8.02 - 7.92 (m, 2H), 7.80 (d, J = 7.1 Hz, 1H), 7.66 - 7.52 (m, 3H), 6.95 (d, J = 8.3 Hz, 1H), 6.57 (dd, J = 2.3, 8.3 Hz, 1H), 6.27 (br s, 1H), 5.06 (br s, 1H), 4.37 - 4.15 (m, 1H), 4.01 (br d, J = 12.1 Hz, 1H), 3.22 (br s, 2H), 3.05 - 2.78 (m, 2H), 2.71 (s, 3H), 1.80 (d, J = 6.6 Hz, 3H)

[0318] Example 36: Compound P36.

[0319] 1) Synthesis procedure of intermediate P36I1

[0320]

[0321] Compound P11 (100 mg, 330 pmol, 1 eq) and compound P36S1 (75.8 mg, 330 pmol, 1 eq) were dissolved in pyridine (2 mL), EDCI (126 mg, 661 pmol, 2 eq) was added portionwise at 25 °C. The reaction mixture was reacted at 25 °C for 2 hours, LCMS detected that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (10 mL) was added to it, extracted with EtOAc (4 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 5 / 1) to give the target compound P36I1 (40 mg, 77.8 pmol, 23.6% yield) as a yellow solid. ESI-MS: [M+H] + , 514.2.

[0322] 2) Synthesis procedure of compound P36

[0323]

[0324] Compound P36I1 (0.04 g, 77.8 μmol, 1 eq) was dissolved in DCM (0.6 mL), then TFA (0.2 mL) was added. The reaction mixture was reacted at 20 °C for 1 h, and LCMS detected the completion of the reaction. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust pH to ~8, then purified by high performance liquid chromatography (column: Waters Xbridge BEH CI 1000*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 50% - 80% B in 8.0 min) to give the target compound P36 (20 mg, 48.3 μmol, 62.1% yield) as a white solid. ESI-MS: [M+H] + ,414.2.

[0325] 1H NMR (400 MHz, DMSO-d6) d = 9.43 (br s, 1H), 8.49 - 8.43 (m, 1H), 7.95 - 7.90 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 7.53 - 7.45 (m, 3H), 7.33 (s, 1H), 7.29 (dd, J = 1.6, 8.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 4.40 - 4.27 (m, 1H), 3.76 (d, J = 15.0 Hz, 1H), 3.54 (d, J = 15.1 Hz, 1H), 3.21 - 3.12 (m, 1H), 2.93 (d, J = 12.9 Hz, 1H), 2.76 - 2.55 (m, 5H), 2.35 - 2.21 (m, 1H), 1.80 - 1.68 (m, 2H), 1.53 - 1.45 (m, 4H), 1.42 - 1.28 (m, 3H)

[0326] Example 37: Compound P37.

[0327] 1) Synthesis procedure of intermediates P11A and P11B

[0328]

[0329] GDI19-047 (900 mg, 2.98 mmol, 1 eq) was resolved by SFC (column: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 um); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 60%, isocratic elution mode) to give the target compounds GDI19-047A (150 mg, 495 pmol, 16.1% yield) and GDI19-047B (140 mg, 462 pmol, 14.9% yield) as white solids. ESI-MS: [M+H] + , 303.1.

[0330] 2) Synthesis procedure of intermediate P36I1A

[0331]

[0332] Compound P11A (100 mg, 330 pmol, 1 eq) and compound P36S1 (75.8 mg, 330 pmol, 1 eq) were dissolved in pyridine (2 mL), EDCI (126 mg, 661 pmol, 2 eq) was added portionwise at 25 °C, the reaction mixture was reacted at 25 °C for 2 hours, LCMS detected that the reaction was completed. The reaction solution was concentrated under reduced pressure, then water (10 mL) was added to it, extracted with EtOAc (4 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 5 / 1) to give the target compound P36I1A (110 mg, 272 pmol, 66.2% yield) as a yellow solid. ESI-MS: [M+H] + , 514.2.

[0333] 3) Synthesis procedure of compound P37

[0334]

[0335] Compound P36I1A (100 mg, 194 pmol, 1 eq) was dissolved in DCM (1.6 mL) and TFA (0.4 mL), the reaction mixture was reacted at 25 °C for 2 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added to adjust the pH to ~8, and the target compound P37 (51 mg, 123 pmol, 63.4% yield) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex Luna C18 80*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-50% B in 8.0 min). ESI-MS: [M+H] + ,414.2

[0336] 1 H NMR (400 MHz, DMSO-d6) d = 9.44 (br s, 1H), 8.51-8.41 (m, 1H), 7.96-7.89 (m, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.53-7.45 (m, 3H), 7.36-7.23 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 4.41-4.27 (m, 1H), 3.76 (br d, J = 15.2 Hz, 1H), 3.54 (br d, J = 14.6 Hz, 1H), 3.16 (br d, J = 7.3 Hz, 1H), 2.93 (br d, J = 12.7 Hz, 1H), 2.75-2.57 (m, 4H), 2.36-2.22 (m, 1H), 1.75 (br d, J = 9.4 Hz, 2H), 1.55-1.43 (m, 4H), 1.42-1.27 (m, 3H)

[0337] Example 38: Compound P38.

[0338] 1) Synthesis procedure of intermediate P36I1B

[0339]

[0340] Compound PllB (140 mg, 462 pmol, leq) and compound P36S1 (106 mg, 462 pmol, leq) were dissolved in pyridine (2.8 mL), EDCI (176.4 mg, 925 pmol, 2eq) was added portionwise at 25 °C, the reaction mixture was reacted at 25 °C for 2 hours, LCMS detection of reaction completion. The reaction was concentrated under reduced pressure, then water (10 mL) was added to it, extracted with EtOAc (4 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 5 / 1) to obtain the target compound P36I1B (120 mg, 297 pmol, 51.6% yield) as a yellow solid. ESI-MS: [M+H] + , 514.2.

[0341] 2) Synthesis procedure of compound P38

[0342]

[0343] Compound P36I1B (120 mg, 232 pmol, leq) and TFA (0.4 mL) were dissolved in DCM (2 mL), the reaction mixture was reacted at 25 °C for 2 hours, LCMS detection of reaction completion. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 80*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-50% B in 8.0 min) to obtain the target compound P38 (68 mg, 164 pmol, 70.3% yield) as a white solid. ESI-MS: [M+H] + , 414.2.

[0344] 1H NMR (400 MHz, Methanol-d4) d = 8.51-8.37 (m, 1H), 7.90 (br d, J = 9.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.56-7.42 (m, 3H), 7.31-7.21 (m, 2H), 7.05 (d, J = 8.1 Hz, 1H), 4.40 (br d, J = 6.6 Hz, 1H), 3.92 (d, J = 15.0 Hz, 1H), 3.61 (d, J = 15.0 Hz, 1H), 3.36-3.34 (m, 2H), 3.11 (br d, J = 13.1 Hz, 1H), 2.93-2.63 (m, 5H), 2.01-1.86 (m, 2H), 1.65 (br s, 1H), 1.61 (d, J = 6.6 Hz, 3H), 1.59-1.45 (m, 3H)

[0345] Example 39: Compound P39.

[0346] 1) Synthesis procedure of intermediate P39I1

[0347]

[0348] Compound P11 (200 mg, 590 pmol, 1 eq, HCI) and compound P39S1 (135 mg, 590 pmol, 1 eq) were sequentially dissolved in pyridine (4 mL), EDCI (226 mg, 1.18 mmol, 2 eq) was added portionwise at 25 °C, the reaction mixture was reacted at 25 °C for 2 hours, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, then purified by silica gel plate (petroleum ether / EtOAc = 1 / 1) to obtain the target compound P39I1 (50 mg, 97.3 pmol, 16.5% yield) as a white solid. ESI-MS: [M+H] + , 514.2.

[0349] 2) Synthesis procedure of compound P39

[0350]

[0351] Compound P39I1 (50 mg, 97.34 pmol, 1 eq) and TFA (0.2 mL) were sequentially dissolved in DCM (0.8 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added to the residue, NH3.H2O (30% purity) was slowly added dropwise to adjust the pH to ~8, and the target compound P39 (6.7 mg, 16.2 pmol, 16.6% yield) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min). ESI-MS: [M+H] + ,414.2.

[0352] 1 H NMR (400 MHz, DMSO-d6) d = 9.94 (br s, 1H), 8.52-8.41 (m, 1H), 7.96-7.90 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.0 Hz, 1H), 7.53-7.46 (m, 3H), 7.34-7.25 (m, 2H), 7.02 (d, J = 8.6 Hz, 1H), 4.43-4.27 (m, 1H), 3.78 (br d, J = 15.1 Hz, 1H), 3.62-3.51 (m, 2H), 3.13 (br d, J = 12.6 Hz, 1H), 2.89-2.52 (m, 6H), 2.06-1.94 (m, 1H), 1.79 (br d, J = 7.0 Hz, 1H), 1.66-1.57 (m, 1H), 1.55-1.44 (m, 6H)

[0353] Example 40: Compound P40.

[0354] 1) Intermediate P40I1 synthesis procedure

[0355]

[0356] Compound Pll (200 mg, 661 μmol, 1 eq) and compound P40S1 (152 mg, 661 μmol, 1 eq) were dissolved in MeCN (3.6 mL) and DMF (0.4 mL), TCFH (222 mg, 793 μmol, 1.2 eq) and NMI (162 mg, 1.98 mmol, 158 μL, 3 eq) were added successively at 20 °C, the reaction mixture was reacted at 25 °C for 16 h, and LCMS detection showed that the reaction was completed. Water (5 mL) was added to the reaction solution, and EtOAc (3 mL*3) was used for extraction. The organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 1 / 1) to obtain the target compound P40I1 (180 mg, 349. μmol, 52.8% yield) as a white solid. ESI-MS: [M+H] + , 517.2.

[0357] 2) Synthesis procedure of compound P40

[0358]

[0359] Compound P40I1 (180 mg, 349 μmol, 1 eq) and TFA (0.72 mL) were successively dissolved in DCM (2.88 mL), and the reaction mixture was reacted at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, CH3CN (1.8 mL) was added, and the solution pH was adjusted to 7-8 with NH3·H2O. Purification by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min) to obtain the target compound P40 (105 mg, 253 μmol, 72.7% yield) as a white solid. ESI-MS: [M+H] + , 416.2.

[0360] 1H NMR (400 MHz, Methanol-d4) d = 8.26 (br d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 7.2 Hz, 1H), 7.66 - 7.53 (m, 3H), 7.43 - 7.33 (m, 2H), 7.18 (d, J = 8.9 Hz, 1H), 5.23 (br d, J = 6.4 Hz, 1H), 4.37 (br d, J = 15.3 Hz, 1H), 4.26 - 4.12 (m, 2H), 4.06 (dd, J = 3.5, 9.7 Hz, 1H), 3.97 (br d, J = 12.6 Hz, 1H), 3.79 - 3.64 (m, 2H), 3.34 (br d, J = 6.9 Hz, 2H), 3.27 - 3.18 (m, 1H), 3.11 - 2.93 (m, 2H), 1.85 (d, J = 6.7 Hz, 3H)

[0361] Example 41: Compound P4

[0362] 1) Synthesis procedure of intermediate P42I1

[0363]

[0364] A 100 mL three-necked flask was charged with compound P1 (150 mg, 0.41 mmol) and compound P42S1 (140 mg, 0.61 mmol), Cs2CO3 (400 mg, 1.23 mmol), BINAP (51 mg, 0.08 mmol) and Pd2(dba)3 (37.5 mg, 0.041 mmol), then 1,4-dioxane (10 mL) was added, and stirred at 100 °C under nitrogen protection for 12 h. LCMS showed the starting material was consumed completely and the target product was generated. The solution was poured into H2O (20 mL). The solution was extracted with EtOAc (20 mL*3), dried over anhydrous Na2SO4, filtered and concentrated to get a residue. The residue was purified by trituration with DCM:MeOH (50v:1v to 20v:1v) to get the target product P42I1 (50 mg, 0.10 mmol, 23.76% yield) as a yellow solid. ESI-MS: [M+H] + 514.3.

[0365] 2) Synthesis procedure of compound P42

[0366]

[0367] Compound P42I1 (50 mg, 0.097 mmol) was dissolved in HC1 / EtOAc (3 mL) solution and stirred at 25 °C for 5 h under nitrogen. LCMS showed the starting material was consumed and the target product was generated. The reaction mixture was concentrated in vacuum, the residue was further purified by preparative HPLC (Gemini 5um C18 column, 150*21.2 mm, eluted with 10% to 20% ACN / H20) to give the target compound P42 as a white solid (14.89 mg, 0.036 mmol, 37.00% yield). ESI-MS: [M+H] + ,414.2.

[0368] 1 H NMR (400 MHz, DMSO) d 11.36 (s, 1H), 10.38 (d, J = 58.7 Hz, 1H), 9.02 (m, 2H), 8.33 (m, 2H), 8.06 (d, J = 8.0 Hz, 2H), 7.64 (m, 3.6H), 7.39 (t, J = 8.0 Hz, 1H), 7.15 (m, 1.4H), 5.54 (m, 1H), 4.89 (m, 0.5H), 4.59 (m, 0.5H), 4.05 (m, 1H), 3.32 (d, J = 10.7 Hz, 1H), 3.15 (m, 3H), 2.91 (m, 4.5H), 2.54 (s, 0.5H), 2.01 (m, 1H), 1.80 (m, 5H), 1.60 (m, 1H).

[0369] Example 42: Compound P43.

[0370] 1) Intermediate P43I1 synthesis procedure

[0371]

[0372] Compound P1 (150 mg, 0.41 mmol) and compound P43S1 (140 mg, 0.61 mmol) were dissolved in 1,4-dioxane (10 mL), then Cs2CO3 (400 mg, 1.23 mmol), BINAP (51 mg, 0.08 mmol) and Pd2(dba)3 (37.5 mg, 0.041 mmol) were added, and the mixture was stirred at 100 °C under nitrogen protection for 12 h. LCMS showed that the starting material was consumed and the target product was generated. The solution was poured into H2O (20 mL). The solution was extracted with EtOAc (20 mL*3), dried over anhydrous Na2SO4, filtered and concentrated to get a residue. The residue was purified by DCM:MeOH (50v:1v to 20v:1v) to get the target compound P43I1 as a yellow solid (52 mg, 0.10 mmol, 24.71% yield). ESI-MS: [M+H] + , 514.3.

[0373] 2) Synthesis procedure of compound P43

[0374]

[0375] Compound P43I1 (52 mg, 0.101 mmol) was dissolved in HCl / EtOAc (5 mL) solution, stirred at 25 °C under nitrogen protection for 5 hours. LCMS showed that the starting material was consumed and the target product was detected. The reaction mixture was concentrated in vacuum, and the residue was further purified by preparative HPLC (Gemini 5um C18 column, 150*21.2mm, eluted with 10% to 20% ACN / H2O) to get the target compound P43 as a white solid (14.36 mg, 0.035 mmol, 34.29% yield). ESI-MS: [M+H] + , 414.2.

[0376] 1 H NMR (400 MHz, DMSO) d 11.50 (s, 1H), 10.28 (m, 1H), 9.18 (m, 1H), 8.86 (m, 1H), 8.33 (m, 2H), 8.06 (d, J = 8.1 Hz, 2H), 7.64 (m, 3.6H), 7.39 (d, J = 7.9 Hz, 1H), 7.16 (m, 1.4H), 5.54 (m, 1H), 4.88 (m, 0.5H), 4.61 (m, 0.5H), 4.03 (m, 1H), 3.19 (m, 5H), 2.80 (m, 4H), 1.87 (m, 7H).

[0377] Example 43: Compound P45.

[0378]

[0379] Compound P1 (150 mg, 0.41 mmol) and 3-pyridinecarboxamide (75 mg, 0.61 mmol) were dissolved in 1,4-dioxane (10 mL), then Cs2CO3(400 mg, 1.23 mmol), BINAP (51 mg, 0.08 mmol) and Pd2(dba)3(37.5 mg, 0.041 mmol) were added, and the mixture was stirred at 100 °C under nitrogen protection for 12 h. LCMS showed that the starting material was consumed and the target product was generated. The solution was poured into H2O (20 mL). The solution was extracted with EtOAc (20 mL*3), dried with anhydrous Na2SO4, filtered and concentrated to obtain a residue. The residue was purified by DCM:MeOH (50v:1v to 20v:1v) to obtain the target compound P45 as a yellow solid (20.99 mg, 0.05 mmol, 12.6% yield). ESI-MS: [M+H] + , 408.2.

[0380] 1 H NMR (400 MHz, DMSO) δ 11.28 (s, 1H), 10.71 (m, 1H), 9.22 (m, 1H), 8.87 (m, 1H), 8.42 (m, 3H), 8.06 (t, J = 7.5 Hz, 2H), 7.90 (s, 0.7H), 7.69 (m, 5H), 7.40 (s, 0.3H), 7.24 (m, 1H), 5.59 (m, 1H), 4.95 (d, J = 14.2 Hz, 0.7H), 4.65 (m, 0.3H), 4.10 (m, 1H), 3.20 (m, 3.3H), 2.82 (d, J = 17.0 Hz, 0.7H), 1.90 (d, J = 6.5 Hz, 3H).

[0381] Example 44: Compound P46.

[0382] 1) Intermediate P46I1 synthesis procedure

[0383]

[0384] Compound P1 (130 mg, 355 pmol, 1 eq) and compound P46S1 (85.3 mg, 426 pmol, 1.2 eq) were dissolved in DMF (2.6 mL), K3PO4 (113 mg, 532 pmol, 1.5 eq), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (25.2 mg, 177 pmol, 0.5 eq) and Cul (27.0 mg, 142 pmol, 0.4 eq) were added successively at 25 °C. The reaction mixture was reacted at 110 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. Water (10 mL) was added to the reaction solution, and EtOAc (3 mL*3) was used for extraction. The organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification was performed by silica gel plate (petroleum ether / EtOAc = 3 / 1) to obtain the target compound P46I1 (70 mg, 144 pmol, 40.6% yield) as a yellow solid. ESI-MS: [M+H] + , 486.2.

[0385] 2) Synthesis procedure of compound P46

[0386]

[0387] Compound P46I1 (70 mg, 144 pmol, 1 eq) and TFA (0.28 mL) were dissolved in DCM (1.12 mL), and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, CH3CN (1 mL) was added to the residue, and the solution pH was adjusted to 7-8 with NH3H2O. Purification was performed by high performance liquid chromatography (column: Phenomenex Luna C18 80*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) to obtain the target compound P46 (25 mg, 64.9 pmol, 45.0% yield) as a white solid. ESI-MS: [M+H] + , 386.2.

[0388] 1H NMR (400 MHz, Methanol-d4) d = 8.35 (br d, J = 8.3 Hz, 2H), 8.04 - 7.85 (m, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.58 - 7.45 (m, 4H), 7.34 (br s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.81 (q, J = 6.3 Hz, 1H), 4.22 - 4.08 (m, 2H), 3.97 - 3.79 (m, 3H), 3.09 (br d, J = 5.1 Hz, 2H), 3.03 - 2.82 (m, 2H), 2.72 - 2.57 (m, 1H), 2.19 - 2.01 (m, 1H), 1.73 (d, J = 6.7 Hz, 3H)

[0389] Example 45: Compound P50.

[0390] 1) Synthesis procedure of intermediate P50I1

[0391]

[0392] Compound P11 (100 mg, 330 pmol, 1 eq) and compound P50S1 (66.5 mg, 330 pmol, 1 eq) were dissolved in MeCN (1.8 mL) and DMF (0.2 mL), TCFH (139 mg, 496 pmol, 1.5 eq) and NMI (81.4 mg, 992 pmol, 79.1 pL, 3 eq) were added successively at 20 °C, and the reaction mixture was reacted at 20 °C for 2 h. LCMS detection showed that the reaction was completed. The reaction solution was poured into water (10 mL), extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by silica gel plate (Si02, petroleum ether / EtOAc = 1 / 1) to give the target compound P50I1 (100 mg, 201 pmol, 60.9% yield, 97.8% purity) as a yellow oil. ESI-MS: [M+H] + ,486.3.

[0393] 2) Synthesis procedure of compound P50

[0394]

[0395] Compound P50I1 (100 mg, 205 mol, 1 eq) was dissolved in DCM (2 mL), TFA (0.4 mL) was added at 20 °C, the reaction mixture was reacted at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure, then CH3CN (2 mL) was added, the solution was adjusted to pH = 7-8 with NH3H2O, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-45% B in 8.0 min) to give the target compound P50 (58.6 mg, 152 mol, 73.8% yield) as a white solid. ESI-MS: [M+H] + ,386.2.

[0396] 1 H NMR (400 MHz, Methanol-d4) d 8.30-8.25 (m, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.81 (d, J = 6.9 Hz, 1H), 7.64-7.54 (m, 3H), 7.43 (br s, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 5.27-5.09 (m, 1H), 4.87-4.78 (m, 2H), 4.34 (br d, J = 15.1 Hz, 1H), 4.30-4.17 (m, 4H), 4.13 (br d, J = 14.8 Hz, 1H), 3.78 (t, J = 8.0 Hz, 1H), 3.09-2.92 (m, 2H), 1.84 (d, J = 6.7 Hz, 3H)

[0397] Example 46: Compound P51.

[0398]

[0399] Compound P11 (100 mg, 330 µmol, 1 eq) and compound P51S1 (57.1 mg, 496 µmol, 1.5 eq) were dissolved in MeCN (1.8 mL) and DMF (0.2 mL), TCFH (139 mg, 496 µmol, 1.5 eq) and NMI (81.4 mg, 992 µmol, 79.1 µL, 3 eq) were added sequentially at 20 °C, and the reaction mixture was reacted at 25 °C for 2 h. LCMS detection showed that the reaction was completed. The reaction solution was purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 15% - 85% B in 8.0 min) to obtain the target compound P51 (28.5 mg, 68.5 µmol, 20.7% yield, 96.1% purity) as a white solid. ESI-MS: [M+H] + , 400.2.

[0400] 1 H NMR (400 MHz, Methanol-d4) δ 8.42 (br d, J = 7.2 Hz, 1H), 7.88 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.26 (br d, J = 8.2 Hz, 1H), 7.23 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 4.38 (br d, J = 6.4 Hz, 1H), 3.90 (br d, J = 14.8 Hz, 1H), 3.63 - 3.53 (m, 3H), 3.41 - 3.33 (m, 3H), 2.85 - 2.80 (m, 2H), 2.78 - 2.69 (m, 2H), 2.33 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H)

[0401] Example 47: Compound P52.

[0402]

[0403] Compound P8 (65 mg, 189 pmol, 1 eq, HC1) was dissolved in DCM (1.3 mL), then triethylamine (18.6 mg, 184 pmol, 25.6 pL, 1 eq) was added to give free compound P8. Compound P52S1 (34.7 mg, 184 pmol, 21.9 pL, 1 eq) was diluted with DCM (0.2 mL) and added dropwise to the above reaction solution. The reaction mixture was stirred at 20 °C for 1 h, and LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure and dried, then the reaction mixture was dissolved in MeOH (1.3 mL), Na2C03 (39.0 mg, 368 pmol, 2 eq) was added at 20 °C, and the reaction mixture was reacted at 70 °C for 1 h, and LCMS detection showed that the reaction was completed. The reaction solution was added to water (5 mL) and extracted with EtOAc (2 mL*3), the organic phase was combined and concentrated under reduced pressure and dried, and purified by high performance liquid chromatography (olumn: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H20 (0.2% FA) - ACN]; gradient: 1% - 40% B in 8.0 min) to give the target compound P52 (15.3 mg, 42.5 pmol, 23.1% yield, 99.8% purity) as a white solid. ESI-MS: [M+H] + ,360.1

[0404] 1H NMR (400 MHz, DMSO-d6) d = 8.55 - 8.42 (m, 1H), 8.17 (s, 1H), 7.99 - 7.89 (m, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.55 - 7.43 (m, 3H), 7.07 - 6.93 (m, 2H), 6.85 (s, 1H), 6.29 (t, J = 5.8 Hz, 1H), 5.45 (s, 2H), 4.41 - 4.25 (m, 1H), 4.06 (d, J = 6.0 Hz, 2H), 3.75 (br d, J = 15.1 Hz, 1H), 3.55 (br d, J = 14.9 Hz, 1H), 2.79 - 2.60 (m, 4H), 1.51 (d, J = 6.6 Hz, 3H)

[0405] Example 48: Compound P53.

[0406]

[0407] Compound P80 (60 mg, 173 pmol, 1 eq, HC1) was dissolved in DCM (1.2 mL), then triethylamine (17.4 mg, 173 pmol, 1 eq) was added to free compound P80. Compound P53S1 (32.6 mg, 173 pmol, 1 eq) was diluted with DCM (0.2 mL) and added dropwise to the above reaction solution. The reaction mixture was stirred at 20 °C for 1 h, and LCMS detection showed that the reaction was completed. After the reaction solution was concentrated under reduced pressure and dried, the reaction mixture was dissolved in MeOH (1.2 mL), Na2C03 (26.1 mg, 246 pmol, 2 eq) was added at 20 °C, and the reaction mixture was reacted at 70 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction solution was added to water (5 mL) and extracted with EtOAc (2 mL * 3). The organic phase was combined, concentrated under reduced pressure and dried, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 100 * 30 mm * 3 pm; mobile phase: [H20 (0.2% FA) - ACN]; gradient: 5% - 35% B in 8.0 min) to obtain the target compound P53 (8.3 mg, 20.5 pmol, 9.79% yield, 96% purity) as a white solid. ESI-MS: [M+Na]+, 412.2

[0408] 1 H NMR (400 MHz, DMSO-d6) d = 8.43 (br d, J = 7.9 Hz, 1H), 8.20 (br d, J = 3.8 Hz, 1H), 8.17 (d, J = 1.5 Hz, 1H), 7.54 - 7.42 (m, 3H), 7.01 - 6.90 (m, 3H), 6.84 (s, 1H), 6.29 (br t, J = 5.8 Hz, 1H), 5.46 (s, 2H), 4.32 - 4.23 (m, 1H), 4.05 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.71 (br d, J = 15.2 Hz, 1H), 3.55 (br d, J = 15.3 Hz, 1H), 2.75 - 2.61 (m, 4H), 1.49 (d, J = 6.6 Hz, 3H).

[0409] Example 49: Compound P54.

[0410] 1) Intermediate P54I1 synthesis procedure

[0411]

[0412] Compound P8 (50 mg, 0.16 mmol), compound P54S1 (41 mg, 0.19 mmol) and TCFH (89 mg, 0.32 mmol) were dissolved in MeCN (1 mL), and NMI (26 mg, 0.32 mmol) was added at once while cooling to 0 °C. The reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was extracted with EtOAc and washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography (eluted with PE / EtOAc, 0% to 50%) to give the target compound P54I1 as a brown solid (56 mg, 0.11 mmol). ESI-MS: [M+H] + , 514.3

[0413] 2) Synthesis procedure of compound P54

[0414]

[0415] Compound P54I1 (56 mg, 0.11 mmol) was dissolved in DCM (1 mL), and TFA (0.3 mL) was added, and stirred at 25 °C for 2 h. The resulting residue was evaporated, and the pH was adjusted to 7-8 with NaHCO3. The residue was purified by preparative HPLC (Gemini 5um C18 column, 150*21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% TFA), to give the target compound P54 as a white solid (36 mg, 0.087 mol). ESI-MS: [M+H] + , 414.2

[0416] 1 H NMR (400 MHz, DMSO) d 8.27 (s, 0.5H), 8.04 (dd, J = 14.9, 8.9 Hz, 2.5H), 7.86 (d, J = 6.8 Hz, 1H), 7.70 - 7.56 (m, 3H), 7.25 (s, 2.7H), 6.78 (s, 0.3H), 5.58 (d, J = 5.9 Hz, 1H), 4.32 (d, J = 65.6 Hz, 6H), 3.64 - 3.31 (m, 4H), 3.09 - 2.95 (m, 1H), 2.39 (s, 1H), 2.06 - 1.90 (m, 6H).

[0417] Example 50: Compound P55.

[0418] 1) Synthesis procedure of intermediate P55I1

[0419]

[0420] To a solution of compound P8 (50 mg, 0.16 mmol), compound P55S1 (41 mg, 0.19 mmol) and TCFH (89 mg, 0.32 mmol) in MeCN (1 mL) was added NMI (26 mg, 0.32 mmol) in one portion at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was extracted with EtOAc and washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography (eluting with PE / EtOAc, 0% to 50%) to give the target compound P55I1 as a brown solid (25 mg, 0.047 mmol). ESI-MS: [M+H] + , 528.2

[0421] 2) Synthesis procedure of compound P55

[0422]

[0423] Compound P55I1 (25 mg, 0.047 mmol) was dissolved in DCM (1 mL), TFA (0.3 mL) was added, stirred at 25 °C for 2 h, the resulting mixture was evaporated, the pH was adjusted to 7-8 with NaHCO3, the residue was purified by prep-HPLC (Gemini 5um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% TFA), to give the target compound P55 as a white solid (2.08 mg, 4.9 mmol). ESI-MS: [M+H] + , 428.3

[0424] 1 H NMR (400 MHz, DMSO) d 8.26 (s, 0.6 H), 8.04 (dd, J = 14.5, 8.5 Hz, 2.5 H), 7.86 (d, J = 6.4 Hz, 1 H), 7.69 - 7.59 (m, 3 H), 7.24 (s, 2.7 H), 6.77 (s, 0.3 H), 5.56 (s, 1 H), 4.45 (m, 3 H), 4.17 (s, 1 H), 3.77 (s, 2 H), 3.38 (m, 3 H), 3.00 (s, 2 H), 2.22 - 2.13 (m, 1 H), 1.96 (d, J = 6.7 Hz, 3 H), 1.88 (d, J = 14.9 Hz, 2 H), 1.64 (s, 3 H).

[0425] Example 51: Compound P56.

[0426] 1) Synthesis procedure of intermediate P56I1

[0427]

[0428] To a solution of compound P8 (50 mg, 0.158 mmol), compound P56S1 (41 mg, 0.19 mmol) and NMI (25.94 mg, 0.32 mmol) in MeCN (2 mL) was added TCFH (25.94 mg, 0.32 mmol) slowly at 0 °C under N2. The mixture was heated at 20 °C for 2 h. The resulting mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (MeOH / DCM, 4% to 5% elution) to give the target compound P56I1 (38 mg, 45.57% yield) as a yellow solid. ESI-MS: [M+H] + ,528.2

[0429] 2) Synthesis procedure for compound P56

[0430]

[0431] Compound P56I1 (38 mg, 0.072 mmol) was dissolved in DCM (1 mL) followed by the addition of trifluoroacetic acid (0.5 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Biotage Isolera One (C18 column, eluted with 10% to 90% MeCN / H2O with 0.1% TFA) to give the target compound P56 (26.39 mg, 85.69% yield) as a white solid. ESI-MS: [M+H] + ,428.3

[0432] 1 H NMR (400 MHz, MeOD) d 8.28 (s, 0.5H), 8.05 (m, 2H), 7.85 (s, 1H), 7.72 - 7.57 (m, 3H), 7.24 (s, 2.5H), 6.75 (s, 0.5H), 5.58 (d, J = 6.0 Hz, 1H), 4.59 (m, 1H), 4.41 - 4.17 (m, 3H), 3.70 (m, 2H), 3.38 (d, J = 13.2 Hz, 3H), 3.00 (s, 2H), 2.15 (s, 1H), 1.96 (d, J = 6.8 Hz, 3H), 1.88 (d, J = 14.8 Hz, 2H), 1.64 (s, 3H).

[0433] Example 52: Compound P57.

[0434] 1) Synthesis procedure for intermediate P57I1

[0435]

[0436] To a solution of compound P8 (50 mg, 0.16 mmol), compound P57S1 (37.41 mg, 0.17 mmol) and NMI (25.94 mg, 0.32 mmol) in MeCN (2 mL) was added TCFH (88.66 mg, 0.32 mmol) slowly at 0 °C under N2. The mixture was heated at 20 °C for 2 h. Then the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (MeOH / DCM, 4% to 5%) to give the target compound P57I1 (58 mg, yield 71.46%) as a brown solid. ESI-MS: [M+H] + ,514.3

[0437] 2) Synthesis procedure of compound P57

[0438]

[0439] Compound P57I1 (20 mg, 0.0389 mmol) was dissolved in 1.4-dioxane (0.3 mL), added HCl dioxane solution (4 M, 0.5 mL), stirred at room temperature for 2 h, concentrated under reduced pressure. The residue was purified on Biotage Isolera One (C18 column, eluted with 10% to 90% MeCN / H2O containing 0.1% NH4OH) to give the target compound P57 (2.19 mg, yield 13.62%) as a white solid. ESI-MS: [M+H] + ,414.2

[0440] 1H NMR (400 MHz, DMSO) δ 8.50 - 8.43 (m, 1H), 8.27 (t, J = 6.4 Hz, 1H), 7.95 - 7.90 (m, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.52 - 7.45 (m, 3H), 6.98 (dd, J = 19.2, 8.0 Hz, 2H), 6.84 (s, 1H), 4.34 (d, J = 6.68 Hz, 1H), 4.16 (m, 2H), 3.75 (d, J = 14.8 Hz, 1H), 3.55 (d, J = 14.8 Hz, 1H), 3.52 - 3.47 (m, 1H), 2.82 - 2.63 (m, 6H), 1.96 - 1.87 (m, 1H), 1.67 - 1.53 (m, 3H), 1.50 (d, J = 6.4 Hz, 3H).

[0441] Example 53: Compound P58.

[0442]

[0443] The two reactions were carried out in parallel. Compound P1 (50 mg, 136 μmol, 1 eq) and compound P58S1 (24.0 mg, 273 μmol, 29.8 μL, 2 eq) were dissolved in THF (1 mL), and t-BuONa (39.3 mg, 409 μmol, 3 eq) and tBuXPhos Pd G3 (10.8 mg, 13.6 μmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and then water (5 mL) was added to it. Extraction was performed with DCM (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure. Purification was performed by high performance liquid chromatography (column: Waters xbridge 150*25mm 10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 40% - 90% B in 8.0 min) to obtain the target compound P58 (53 mg, 141 μmol, 51.9% yield) as a white solid. ESI-MS: [M+H] + , 374.2.

[0444] 1H NMR (400 MHz, DMSO-d6) d = 8.57 - 8.43 (m, 1H), 8.01 - 7.89 (m, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 6.6 Hz, 1H), 7.56 - 7.44 (m, 3H), 6.78 (d, J = 8.3 Hz, 1H), 6.40 (dd, J = 2.3, 8.1 Hz, 1H), 6.19 (d, J = 2.0 Hz, 1H), 5.03 (t, J = 5.5 Hz, 1H), 4.36 - 4.23 (m, 1H), 3.71 (s, 1H), 3.49 (br d, J = 14.9 Hz, 1H), 3.00 (q, J = 6.4 Hz, 2H), 2.75 - 2.60 (m, 3H), 2.38 (t, J = 6.6 Hz, 2H), 2.15 (s, 6H), 1.50 (d, J = 6.6 Hz, 3H)

[0445] Example 54: Compound P59.

[0446]

[0447] Compound P1 (200 mg, 546 µmol, 1 eq) and compound P59S1 (173 mg, 819 µmol, 82.2 µL, 1.5 eq) were dissolved in THF (4 mL), t-BuONa (157 mg, 1.64 mmol, 3 eq) and tBuXPhos Pd G3 (43.3 mg, 54.6 µmol, 0.1 eq) were added sequentially under nitrogen protection at 25 °C. The reaction mixture was reacted at 80 °C for 16 hours, and LCMS detection showed that the reaction was completed. The reaction solution was added to water (10 mL), extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and the target compound P59 (39.9 mg, 94.8 µmol, 17.3% yield, FA) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 10%-45% B in 8.0 min). ESI-MS: [M+H] + ,375.3

[0448] 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.45-8.36 (m, 1H), 7.93-7.86 (m, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.72-7.67 (m, 1H), 7.52-7.45 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 6.79 (dd, J = 2.6, 8.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 4.54-4.39 (m, 1H), 4.24-4.11 (m, 2H), 3.92 (d, J = 15.0 Hz, 1H), 3.66 (d, J = 14.9 Hz, 1H), 3.29-3.26 (m, 2H), 2.91-2.76 (m, 4H), 2.75 (s, 6H), 1.62 (d, J = 6.6 Hz, 3H)

[0449] Example 55: Compound P60.

[0450]

[0451] Compound P32 (111 mg, 308 µmol, 1 eq) and compound P60 S1 (21.6 mg, 308 µmol, 23.1 µL, 1 eq), AcOH (18.5 mg, 308 µmol, 17.6 µL, 1 eq) were dissolved in MeOH (2.2 mL) sequentially. The reaction mixture was stirred at 20 °C for 5 hours. NaBH3CN (29.1 mg, 463 µmol, 1.5 eq) was added to the above reaction solution. The reaction mixture was reacted at 20 °C for 1 hour. LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure. Purification by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 5%-45% B in 8.0 min) to give the target compound P60 (11.4 mg, 27.5 µmol, 8.9% yield) as a white solid. ESI-MS: [M+H] + ,414.2.

[0452] 1H NMR (400 MHz, Methanol-d4) d = 8.38 (br d, J = 8.1 Hz, 1H), 8.33-8.27 (m, 1H), 7.98-7.93 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.1 Hz, 1H), 7.60-7.49 (m, 3H), 7.38-7.30 (m, 2H), 7.14 (br d, J = 8.5 Hz, 1H), 4.80-4.75 (m, 1H), 4.11 (br d, J = 14.6 Hz, 1H), 3.95 (s, 2H), 3.91-3.84 (m, 1H), 3.11-3.04 (m, 2H), 3.02-2.85 (m, 4H), 1.73 (d, J = 6.5 Hz, 3H), 1.17-1.07 (m, 1H), 0.78-0.69 (m, 2H), 0.43 (q, J = 5.3 Hz, 2H)

[0453] Example 56: Compound P63.

[0454]

[0455] To a solution of compound P62 (90 mg, 0.29 mmol) in DMSO (2 mL) was added K2CO3 (119.27 mg, 0.86 mmol) and hydrogen peroxide (59.39 mg, 0.58 mmol) slowly at 0 °C under N2. The mixture was left at room temperature for 2 hours. Then the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on Biotage Isolera One (C18 column, eluted with 10% to 90% MeCN / H2O containing 0.1% NH4OH) to give the target compound P63 (41.23 mg, yield 43.32%) as a white solid. ESI-MS: [M+H] + , 331.1.

[0456] 1H NMR (400 MHz, DMSO) δ 8.50 - 8.44 (m, 1H), 7.96 - 7.89 (m, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.62 (dd, J = 14.8, 7.2 Hz, 2H), 7.50 (m, 4H), 7.19 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 4.37 (d, J = 6.4 Hz, 1H), 3.81 (d, J = 15.2 Hz, 1H), 3.62 (d, J = 14.8 Hz, 1H), 2.85 - 2.69 (m, 4H), 1.52 (d, J = 6.4 Hz, 3H).

[0457] Example 57: Compound P66.

[0458]

[0459] Compound P1 (100 mg, 273 μmol, 1 eq) was dissolved in EtOH (7 mL), under nitrogen protection, compound P66S1 (48.9 mg, 546 μmol, 2 eq), KOAc (80.3 mg, 819 μmol, 3 eq), XPhos (2.60 mg, 5.46 μmol, 0.02 eq) and XPHOS-PD-G2 (2.15 mg, 2.73 μmol, 0.01 eq) were added in turn at 25 °C, the reaction mixture was reacted at 70 °C for 16 hours under nitrogen protection, LCMS detection reaction was completed. The reaction liquid was added to water (10 mL), extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the target compound P66 (52.5 mg, 158 μmol, 58.1% yield) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 15% - 55% B in 8.0 min). ESI-MS: [M+H] + , 332.1.

[0460] 1H NMR (400 MHz, Methanol-d4) d 8.40 (br s, 1H), 8.31 (br d, J = 7.7 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.76 (d, J = 7.1 Hz, 1H), 7.60 - 7.52 (m, 3H), 7.51 - 7.40 (m, 1H), 7.29 (br s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 4.92 (br s, 1H), 4.25 (br d, J = 15.0 Hz, 1H), 3.98 (br d, J = 14.8 Hz, 1H), 3.14 (br s, 2H), 3.05 - 2.87 (m, 2H), 1.76 (d, J = 6.7 Hz, 3H)

[0461] Example 58: Compound P67.

[0462] 1) Synthesis procedure of intermediate P67I1

[0463]

[0464] Compound P1 (500 mg, 1.37 mmol, 1 eq) was dissolved in THF (10 mL), under nitrogen protection, n-BuLi (2.5 M, 1.09 mL, 2 eq) was added dropwise at -78 °C, after the reaction mixture was reacted at -78 °C for 1 hour, compound P67S1 (43 mg, 2.73 mmol, 2 eq) was added dropwise into the reaction solution. The reaction mixture was continued to react at -78 °C for 3 hours, LCMS detection reaction was completed. The reaction was poured into ice saturated NH4Cl aqueous solution (20 mL), extracted with EtOAc (5 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, purified by silica gel plate (petroleum ether / EtOAc = 3 / 1) to give the target compound P67I1 (200 mg, 224 μmol, 16.4% yield, 50.0% purity) as a yellow solid. ESI-MS: [M+H] + ,447.2.

[0465] 2) Synthesis procedure of compound P67

[0466]

[0467] Compound P67I1 (200 mg, 448 µmol, 50.0% purity) and TFA (0.8 mL) were dissolved in DCM (3.2 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution was adjusted to pH = 7-8 with NH3·H2O, purified by high performance liquid chromatography (column: Phenomenex Luna C18 80*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) to give the target compound P67 (34.5 mg, 99.6 µmol, 44.5% yield) as a white solid. ESI-MS: [M+H] + , 347.2.

[0468] 1 H NMR (400 MHz, Methanol-d4) d = 8.37 (br d, J = 7.4 Hz, 1H), 8.29 (br s, 1H), 7.99-7.81 (m, 2H), 7.73 (d, J = 6.9 Hz, 1H), 7.56-7.45 (m, 3H), 7.27-7.13 (m, 2H), 7.06 (s, 1H), 4.79 (dd, J = 3.2, 9.4 Hz, 1H), 4.70 (br d, J = 6.7 Hz, 1H), 4.08 (br d, J = 15.9 Hz, 1H), 3.89-3.76 (m, 1H), 3.17-2.77 (m, 7H), 1.69 (d, J = 6.6 Hz, 3H)

[0469] Example 59: Compound P68.

[0470] 1) Synthesis procedure of intermediate P68I1

[0471]

[0472] Pd2(dba)3(31.3 mg, 34.1 μmol, 0.05 eq), Cs2CO3(159 mg, 819 μmol, 1.2 eq) and t-Bu Xphos (29.0 mg, 68.3 μmol, 0.1 eq) were added into the reaction vial in turn, then toluene (5 mL) was added. Compound P68S1 (182 mg, 1.37 mmol, 151 μL, 2 eq) and P1 (0.25 g, 683 μmol, 1 eq) were added at 25 °C respectively. The reaction mixture was reacted at 70 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, ice water (5 mL) was added to the concentrate, and EtOAc (3 mL*3) was used for extraction. The organic phase was combined and concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 0 / 1) to obtain the target compound P68I1 (205 mg, 460 μmol, 67.5% yield, 94% purity) as a yellow oil. ESI-MS: [M+H] + , 419.2.

[0473] 2) Synthesis procedure of compound P68

[0474]

[0475] Compound P68I1 (150 mg, 358 μmol, 1 eq) was dissolved in THF (3 mL), and LAH (2.5 M, 430 μL, 3 eq) was added dropwise at 0 °C. The reaction mixture was reacted at 0 °C for 2 h, and then naturally warmed to 25 °C for continuous reaction for 16 h. LCMS detection showed that the reaction was completed. NaSO4·10H2O (1 g) was added to the reaction solution to quench LAH, and after stirring for 0.5 h, it was filtered. The filtrate was concentrated under reduced pressure, and purified by high performance liquid chromatography (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O (0.05% NH3H2O + 10 mM NH4HCO3) - ACN]; gradient: 35%-65% B in 8.0 min) to obtain the target compound P68 (9.4 mg, 26.3 μmol, 7.33% yield, 96.9% purity) as a white solid. ESI-MS: [M+H] + , 347.2.

[0476] 1H NMR (400 MHz, DMSO-d6) d = 8.56 - 8.41 (m, 1H), 7.92 (dd, J = 2.9, 6.7 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 7.56 - 7.43 (m, 3H), 7.09 - 7.01 (m, 1H), 7.01 - 6.92 (m, 2H), 4.67 (br d, J = 0.9 Hz, 1H), 4.39 - 4.25 (m, 1H), 3.83 - 3.69 (m, 2H), 3.56 (br d, J = 14.8 Hz, 1H), 3.41 - 3.35 (m, 1H), 3.26 - 3.14 (m, 1H), 2.78 - 2.61 (m, 4H), 2.08 - 1.66 (m, 2H), 1.51 (d, J = 6.7 Hz, 3H)

[0477] Example 60: Compound P69.

[0478] 1) Synthesis procedure of intermediate P69I1

[0479]

[0480] Compound P1 (100 mg, 273 pmol, 1 eq) was dissolved in THF (2 mL), n-BuLi (2.5 M, 109 pL, 1 eq) was added under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 1 h, compound P69S1 (95.1 mg, 546 pmol, 104 pL, 2 eq) was added to the above reaction solution, the reaction mixture was continued to react at -70 °C for 1 h, LCMS detection reaction was completed. The reaction solution was poured into aqueous ammonium chloride solution (10 mL), extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The washed organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P69I1 (80 mg, 173 pmol, 63.4% yield) as a white solid. ESI-MS: [M+H] + , 462.2.

[0481] 2) Synthesis procedure of compound P69

[0482]

[0483] Compound P69I1 (80 mg, 173 pmol, 1 eq) was dissolved in DCM (1.4 mL), TFA (0.35 mL) was added at 20 °C, the reaction mixture was reacted at 25 °C for 1 h. LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH = 8-9 was adjusted with NH3H2O, and the target compound P69 (17.1 mg, 43.4 pmol, 25.1% yield, FA) was obtained as a white solid by high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 10% - 40% B in 8.0 min). ESI-MS: [M+H] + , 348.1.

[0484] 1 H NMR (400 MHz, DMSO-d6) d 8.46 (br d, J = 5.0 Hz, 1H), 7.98 - 7.88 (m, 1H), 7.84 (br d, J = 7.4 Hz, 1H), 7.63 (br s, 1H), 7.55 - 7.44 (m, 3H), 7.05 (br s, 1H), 7.03 - 6.98 (m, 1H), 6.94 (br s, 1H), 5.06 (br s, 1H), 4.62 (br t, J = 5.6 Hz, 1H), 4.49 - 4.26 (m, 2H), 3.86 - 3.70 (m, 1H), 3.65 - 3.50 (m, 1H), 3.38 - 3.35 (m, 2H), 2.83 - 2.62 (m, 4H), 1.61 - 1.43 (m, 3H)

[0485] Example 61: Compound P71.

[0486] 1) Intermediate P71I1 synthesis procedure

[0487]

[0488] Compound P1 (300 mg, 819 pmol, 1 eq) was dissolved in THF (6 mL), n-BuLi (2.5 M, 655 pL, 2 eq) was added under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 1 h, compound P71S1 (283 mg, 1.64 mmol, 2 eq) was added to the above reaction solution, the reaction mixture was continued to react at -70 °C for 1 h, LCMS detection reaction was completed. The reaction solution was poured into an aqueous solution of ammonium chloride (10 mL), extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P71I1 (235 mg, 510 pmol, 62.2% yield) as a yellow solid. ESI-MS: [M+H] + , 461.3.

[0489] 2) Synthesis procedure of compound P71

[0490]

[0491] Compound P71I1 (230 mg, 499 pmol, 1 eq) was dissolved in DCM (4 mL), TFA (0.8 mL) was added at 20 °C, the reaction mixture was reacted at 25 °C for 1 h. LCMS detection reaction was completed. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added to the concentrate, the solution pH was adjusted to 7-8 with NH3, purified by high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-35% B in 8.0 min) to give the target compound P71 (164 mg, 403 pmol, 80.7% yield, FA) as a white solid. ESI-MS: [M+H] + , 361.2.

[0492] 1H NMR (400 MHz, Methanol-d4) d 8.30 (br d, J = 5.0 Hz, 2H), 7.98 - 7.89 (m, 2H), 7.78 (d, J = 7.1 Hz, 1H), 7.61 - 7.50 (m, 3H), 7.29 - 7.24 (m, 1H), 7.24 - 7.17 (m, 1H), 7.09 (br s, 1H), 4.98 (br d, J = 6.5 Hz, 1H), 4.24 (br d, J = 15.1 Hz, 1H), 4.01 (br d, J = 15.3 Hz, 1H), 3.29 - 2.87 (m, 7H), 2.72 (s, 3H), 1.78 (d, J = 6.6 Hz, 3H)

[0493] Examples 62-63: Compound P72 and Compound P73.

[0494]

[0495] Compound P71 (90 mg, 250 pmol, 1 eq) was resolved by SFC (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 pm); mobile phase: [C02-EtOH (0.1% NH3H20)]; B%: 60%, isocratic elution mode) to give the target compounds P72 (23 mg, 60.61 pmol, 95% purity, 24.2% yield) and P73 (30 mg, 81.56 pmol, 98% purity, 31.6% yield) as white solids. ESI-MS: [M+H] + , 361.2.

[0496] P72: 1 H NMR (400 MHz, DMSO-d6) d = 8.56 - 8.37 (m, 1H), 7.99 - 7.90 (m,

[0497] 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.0 Hz, 1H), 7.55 - 7.44 (m, 3H), 7.12 - 6.91 (m, 3H), 5.32 - 4.98 (m, 1H), 4.57 - 4.46 (m, 1H), 4.38 - 4.27 (m, 1H), 3.79 (br dd, J = 4.7, 14.8 Hz, 1H), 3.56 (br dd, J = 1.8, 15.1 Hz, 1H), 2.79 - 2.64 (m, 4H), 2.53 (br d, J = 3.9 Hz, 1H), 2.52 - 2.50 (m, 3H), 2.27 (s, 2H), 1.51 (d, J = 6.6 Hz, 3H)

[0498] P73: 1 H NMR (400 MHz, DMSO-d6) d = 8.46 (br d, J = 5.1 Hz, 1H), 7.93 (dd, J = 3.4, 6.0 Hz, 1H), 7.84 (br d, J = 8.1 Hz, 1H), 7.63 (br d, J = 6.9 Hz, 1H), 7.53 - 7.41 (m, 3H), 7.18 - 7.05 (m, 2H), 7.00 (br d, J = 4.0 Hz, 1H), 6.05 (br s, 1H), 4.76 (br d, J = 9.9 Hz, 1H), 4.38 (br s, 1H), 3.84 - 3.69 (m, 1H), 3.60 (br d, J = 11.9 Hz, 1H), 3.12 - 3.02 (m, 1H), 3.00 - 2.88 (m, 1H), 2.74 (br d, J = 12.0 Hz, 4H), 2.56 (s, 3H), 1.52 (br d, J = 6.4 Hz, 3H)

[0499] = 3.4, 6.0 Hz, 1H), 7.84 (br d, J = 8.1 Hz, 1H), 7.63 (br d, J = 6.9 Hz, 1H), 7.53 - 7.41 (m, 3H), 7.18 - 7.05 (m, 2H), 7.00 (br d, J = 4.0 Hz, 1H), 6.05 (br s, 1H), 4.76 (br d, J = 9.9 Hz, 1H), 4.38 (br s, 1H), 3.84 - 3.69 (m, 1H), 3.60 (br d, J = 11.9 Hz, 1H), 3.12 - 3.02 (m, 1H), 3.00 - 2.88 (m, 1H), 2.74 (br d, J = 12.0 Hz, 4H), 2.56 (s, 3H), 1.52 (br d, J = 6.4 Hz, 3H)

[0500] Example 64: Compound P74.

[0501]

[0502] Compound 71 (60 mg, 166 μmol, 1 eq) was dissolved in MeOH (1.2 mL), TEA (16.7 mg, 166 μmol, 1 eq) was added at 20 °C, and the pH of the reaction solution was measured to be 7-8. Then AcOH (9.99 mg, 166 μmol, 9.53 μL, 1 eq) was added to the mixture, and the pH of the reaction solution was measured to be ~ 6. Then 37% aqueous formaldehyde solution (49.9 mg, 1.66 mmol, 45.8 μL, 10 eq) was added to the above reaction solution. After the reaction mixture was reacted at 25 °C for 1 h, NaBH3CN (15.6 mg, 249 μmol, 1.5 eq) was added to the above reaction solution, and the reaction mixture was continuously reacted at 25 °C for 2 h. LCMS detection showed that the reaction was completed. The reaction solution was subjected to high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 5%-35% B in 8.0 min) to obtain the target compound P74 (32.1 mg, 85.7 μmol, 51.5% yield) as a white solid. ESI-MS: [M+H] + ,375.2

[0503] 1H NMR (400 MHz, Methanol-d4) δ 8.39 (br d, J = 6.4 Hz, 2H), 7.91 (d, J = 6.7 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.56 - 7.45 (m, 3H), 7.23 (br d, J = 7.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 4.96 (dd, J = 3.7, 10.4 Hz, 1H), 4.67 - 4.58 (m, 1H), 4.02 (br d, J = 14.9 Hz, 1H), 3.78 (br d, J = 15.3 Hz, 1H), 3.27 - 3.16 (m, 2H), 2.97 (br s, 3H), 2.92 (s, 6H), 2.88 (br s, 1H), 1.67 (d, J = 6.6 Hz, 3H)

[0504] Example 65: Compound P75.

[0505]

[0506] Compound P71 (46 mg, 132 μmol, 1 eq) and TEA (40.3 mg, 398 μmol, 55.4 μL, 3 eq) were dissolved in DCM (1 mL), and Ac2O (20.3 mg, 199 μmol, 18.7 μL, 1.5 eq) was added at 25 °C. The reaction mixture was reacted at 25 °C for 2 hours. LCMS detection showed that the reaction was completed. The reaction solution was poured into water (10 mL), extracted with DCM (3 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by high performance liquid chromatography (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 37% - 67% B in 8.0 min) to give the target compound P75 (13.8 mg, 35.5 μmol, 26.7% yield) as a yellow oil. ESI-MS: [M+H] + , 389.2.

[0507] 1H NMR (400 MHz, Methanol-d4) δ 8.43 (br d, J = 9.1 Hz, 1H), 7.88 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.51 - 7.43 (m, 3H), 7.12 (d, J = 7.3 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 4.65 (dd, J = 4.8, 7.9 Hz, 1H), 4.39 (q, J = 6.1 Hz, 1H), 3.94 (br d, J = 14.9 Hz, 1H), 3.62 (br d, J = 15.3 Hz, 1H), 3.41 - 3.36 (m, 1H), 3.29 - 3.22 (m, 1H), 2.88 - 2.71 (m, 4H), 1.90 (s, 3H), 1.60 (d, J = 6.6 Hz, 3H)

[0508] Example 66: Compound P76.

[0509] 1) Synthesis procedure of intermediate P76I1

[0510]

[0511] Compound P1 (1 g, 2.73 mmol, 1 eq) was dissolved in dioxane (10 mL), compound P76S1 (1.08 g, 3.00 mmol, 1.01 mL, 1.1 eq) and Pd(pph3)2Cl2 (95.8 mg, 137 μmol, 0.05 eq) were added at 20 °C. The reaction mixture was reacted at 100 °C for 16 hours under nitrogen atmosphere, LCMS detection showed the reaction was completed. The reaction mixture was cooled to room temperature, HCl (2 M, 1 mL) was added at 25 °C, the mixture was stirred at 25 °C for one hour, then the reaction solution was added to saturated aqueous potassium fluoride solution (10 mL), green solid was generated, the suspension was filtered under normal pressure, the filtrate was extracted with EtOAc (5 mL*3), the organic phase was combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, to obtain the target compound P76I1 (1 g, 2.43 mmol, 88.9% yield, 80% purity) as a yellow oil. ESI-MS: [M+H] + , 330.2.

[0512] 2) Synthesis procedure of intermediate P76I2

[0513]

[0514] Compound P76I1 (500 mg, 1.52 mmol, 1 eq) was dissolved in CH2Cl2(5 mL), compound TMSCN (331 mg, 3.34 mmol, 418 μL, 2.2 eq) and ZnI2(484 mg, 1.52 mmol, 1 eq) were added successively at 20 °C. The reaction mixture was reacted at 30 °C for 16 hours, LCMS detection showed the reaction was completed. The reaction mixture was cooled to room temperature, the reaction was blown dry with nitrogen, THF (5 mL) was added at 25 °C, HCl (6 M, 1 mL) was added dropwise at 0 °C, the reaction mixture was stirred at 25 °C for one hour, then the reaction was blown dry with nitrogen, to obtain the target compound P76I2 (1 g, crude) as a yellow oil. ESI-MS: [M+H] + , 357.2.

[0515] 3) Synthesis procedure of compound P76

[0516]

[0517] Compound P76I2 (30 mg, 84.2 μmol, 1 eq) was dissolved in THF (0.9 mL), compound BH3.THF (1 M, 126.24 μL, 1.5 eq) was added at 0 °C under nitrogen protection. The reaction mixture was reacted at 50 °C for 5 hours, LCMS detection showed the reaction was completed. MeOH (2 mL) was added dropwise at 0 °C, the reaction mixture was reacted at 70 °C for 1 hour. The reaction was blown dry with nitrogen, P76 (10 mg, 27.7 μmol, 33.0% yield, 100% purity) was obtained as a white solid by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 45% - 90% B in 8.0 min). ESI-MS: [M+H] + , 361.2.

[0518] 1H NMR (400 MHz, Methanol-d4) d = 8.50 - 8.31 (m, 1H), 7.91 - 7.85 (m, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.55 - 7.39 (m, 3H), 7.20 (d, J = 8.4 Hz, 1H), 7.11 - 6.96 (m, 2H), 4.40 (br d, J = 6.5 Hz, 1H), 3.93 (d, J = 14.8 Hz, 1H), 3.63 (d, J = 14.9 Hz, 1H), 2.92 - 2.72 (m, 6H), 1.60 (d, J = 6.6 Hz, 3H), 1.45 (s, 3H)

[0519] Example 67: Compound P77.

[0520] 1) Synthesis procedure of intermediate P77I1

[0521]

[0522] Compound P1 (0.5 g, 1.37 mmol, 1 eq) was dissolved in THF (10 mL), n-BuLi (2.5 M, 1.09 mL, 1 eq) was added at -70 °C under nitrogen protection, the reaction mixture was reacted at -70 °C for 0.5 h. Compound P77S1 (192 mg, 1.64 mmol, 1.2 eq) was dissolved in THF (0.5 mL) and added dropwise to the above reaction solution, the reaction mixture was reacted at -70 °C for 1.5 h, LCMS detected that the raw material was completely consumed, and 15% of the product was generated. The reaction solution was poured into an aqueous solution of ammonium chloride (10 mL), extracted with EtOAc (5 mL*3), the organic phase was combined and concentrated under reduced pressure, purified by high performance liquid chromatography (column: Phenomenex luna C18 250*50mm*15um; mobile phase: [H2O (0.1% TFA) - ACN]; gradient: 15% - 45% B in 10.0 min) to obtain the target compound P77I1 (55 mg, 148 µmol, 10.8% yield) as a white solid. ESI-MS: [M+H] + ,373.2.

[0523] 2) Synthesis procedure of compound P77

[0524]

[0525] Compound P77I1 (55 mg, 148 pmol, 1 eq) was dissolved in MeOH (1.1 mL), LiBH4 (2 M, 148 pL, 2 eq) was added dropwise at 0 °C under nitrogen protection. The reaction mixture was reacted at 0 °C for 2 hours, and LCMS detected that the reaction was completed. The reaction solution was poured into aqueous ammonium chloride solution (5 mL), extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 10.0 min) to obtain P77 (16.1 mg, 43.0 pmol, 29.1% yield, 100% purity) as a white solid. ESI-MS: [M+H] + , 375.1.

[0526] 1 H NMR (400 MHz, DMSO-d6) d = 8.47 (br d, J = 5.3 Hz, 1H), 7.96-7.89 (m, 1H), 7.83 (br d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.1 Hz, 1H), 7.56-7.44 (m, 3H), 7.11 (br d, J = 7.8 Hz, 1H), 7.04-6.92 (m, 2H), 5.96 (br t, J = 4.1 Hz, 1H), 4.77 (br d, J = 2.3 Hz, 1H), 4.41-4.28 (m, 1H), 3.77 (br d, J = 14.8 Hz, 1H), 3.56 (br d, J = 14.6 Hz, 1H), 2.79-2.61 (m, 4H), 2.56 (d, J = 4.6 Hz, 3H), 1.51 (d, J = 6.5 Hz, 3H)

[0527] Example 68: Compound P79.

[0528]

[0529] Compound P76I2 (1 g, crude) was dissolved in dioxane (10 mL), HC1 (6 M, 1 V) was added at 20 °C. The reaction mixture was reacted at 90 °C for 2 h, LCMS was used to monitor the reaction completion. The reaction mixture was cooled to room temperature, the reaction was blown dry with nitrogen, the pH of the reaction was adjusted to 5-6 with saturated NaHC03 aqueous solution, filtered at normal pressure, the filtrate was purified by high performance liquid chromatography (column: WePure Biotech XP tC18 150*40*70um; mobile phase: [H20 (10 mM NH4HC03) - ACN]; gradient: 30% - 85% B in 8.0 min) and (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H20 (0.2% FA) - ACN]; gradient: 1% - 40% B in 8.0 min) to give the target compound P79 (2 mg, 5.13 pmol, 3.3% for step 2) as a yellow oil. ESI-MS: [M+H] + ,357.2.

[0530] 1 H NMR (400 MHz, DMSO-d6) d = 8.53 - 8.40 (m, 1H), 8.23 (s, 1H), 7.97 - 7.91 (m, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.58 - 7.41 (m, 3H), 7.25 (d, J = 7.6 Hz, 1H), 7.20 - 7.08 (m, 2H), 7.00 (br d, J = 7.9 Hz, 2H), 5.83 - 5.70 (m, 1H), 4.42 - 4.27 (m, 1H), 3.85 - 3.76 (m, 1H), 3.59 (br d, J = 3.5 Hz, 1H), 2.71 (br d, J = 6.9 Hz, 3H), 1.61 - 1.49 (m, 6H)

[0531] Example 69: Compound P80.

[0532] 1) Intermediate P80I1 synthesis procedure

[0533]

[0534] To a solution of compound P80S1 (200.00 mg, 1.26 mmol) and 4-methoxynaphthalen-9- enamine (253.13 mg, 1.26 mmol) in MeOH (2 mL) was added formic acid (174.56 mg, 3.79 mmol) and NaBH3CN (101.40 mg, 6.32 mmol) slowly at 20 °C under N2. The mixture was heated at 70 °C for 16 h. Then the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with EtOAc / PE, 5% to 10%) to give the target compound P80I1 (60 mg, yield 13.86%) as a brown solid. ESI-MS: [M+H] + , 343.1.

[0535] 2) Synthesis procedure of compound P80

[0536]

[0537] Compound P80I1 (60 mg, 0.18 mmol) was dissolved in THF (6 mL) at 0 °C, and LiAlH4 (0.2 mL, 1 mol / L) was added. After addition, it was stirred at 50 °C for 1 h, cooled to room temperature, and H2O was added dropwise at 20 °C to terminate the reaction. The crude product was purified by preparative HPLC (Gemini 5um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN / H2O containing 0.1% TFA) to give the target compound P80 (42.89 mg, yield 70.66%) as a white solid. ESI-MS: [M+H] + , 347.2.

[0538] 1H NMR (400 MHz, DMSO) δ = 10.29 (s, 1H), 8.31 (m, 3H), 8.10 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.74 - 7.56 (m, 2H), 7.38 - 7.21 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 9.6 Hz, 1H), 5.52 (d, J = 27.6 Hz, 1H), 4.77 (d, J = 15.2 Hz, 0.5H), 4.59 - 4.49 (m, 0.5H), 4.24 - 4.09 (m, 1H), 4.04 (s, 4.5H), 3.89 (d, J = 5.2 Hz, 1H), 3.54 (s, 0.5H), 3.38 (s, 0.5H), 3.20 (s, 1.5H), 2.95 (m, 1H), 1.85 (d, J = 6.0 Hz, 3H).

[0539] Examples 70-71: Compound P81 and Compound P82.

[0540]

[0541] Compound P80 (39 mg, 113 mmol, 1 eq) was purified by SFC ((column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) to give the target compounds P81 (1.6 mg, 4.61 pmol, 4.10% yield) and P82 (2.9 mg, 9.31 pmol, 8.41% yield) as white solids. ESI-MS: [M+H] + ,347.2.

[0542] P81: 1 H NMR (400 MHz, Methanol-d4) δ = 8.37 (br d, J = 8.3 Hz, 1H), 8.30 - 8.24

[0543] (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 - 7.38 (m, 2H), 7.13 - 7.02 (m, 2H), 6.98 - 6.86 (m, 2H), 4.30 (br d, J = 6.6 Hz, 1H), 4.01 (s, 3H), 3.88 (br d, J = 14.9 Hz, 1H), 3.76 (s, 2H), 3.61 (br d, J = 14.9 Hz, 1H), 2.91 - 2.81 (m, 2H), 2.81 - 2.73 (m, 2H), 1.58 (d, J = 6.6 Hz, 3H)

[0544] P82: 1 H NMR (400 MHz, Methanol-d4) d = 8.37 (br d, J = 8.1 Hz, 1H), 8.27 (dd, J = 1.2, 8.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.51 - 7.37 (m, 2H), 7.11 - 7.00 (m, 2H), 6.97 - 6.87 (m, 2H), 4.30 (q, J = 6.5 Hz, 1H), 4.01 (s, 3H), 3.88 (br d, J = 15.1 Hz, 1H), 3.75 (br s, 2H), 3.61 (br d, J = 15.5 Hz, 1H), 2.92 - 2.81 (m, 2H), 2.80 - 2.70 (m, 2H), 1.58 (d, J = 6.6 Hz, 3H)

[0545] Example 72: Compound P83.

[0546] 1) Intermediate P83I1 synthesis procedure

[0547]

[0548] To a solution of compound P83S1 (185 mg, 1.17 mmol) and P83S2 (200 mg, 1.06 mmol) in MeOH (3 mL) was added formic acid (147 mg, 3.19 mmol) and NaBH3CN (334 mg, 5.31 mmol) slowly at 20 °C under N2protection. The mixture was heated at 70 °C for 16 h. Then the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 5% to 10%) to give the target compound P83I1 (51 mg, yield 14.53%) as a white solid.

[0549] 1 H NMR (400 MHz, DMSO) d = 8.49 (d, J = 6.4 Hz 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.67 - 7.58 (m, 3H), 7.57 (d, J = 10.0 Hz, 1H), 7.53 (s, 1H), 7.31 (m, 2H), 4.38 (q, 1H), 3.82 (d, J = 16.0 Hz, 1H), 3.64 (d, J = 15.2 Hz, 1H), 2.86 - 2.68 (m, 4H), 1.50 (d, J = 6.4 Hz, 3H).

[0550] 2) Synthesis procedure of compound P83

[0551]

[0552] Compound P83I1 (50 mg, 0.15 mmol) was dissolved in THF (5 mL) at 0 °C, LiAlH4(0.2 mL, 1 mol / L) was added, after addition, it was stirred at 50 °C for 1 h, cooled to room temperature, H2O was added dropwise at 20 °C to terminate the reaction. The crude product was purified by preparative HPLC (Gemini 5um C18 column, 150*21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% TFA), to give the target compound P83 (34.45 mg, yield 68.08%) as a white solid. ESI-MS: [M+H] + , 335.2.

[0553] 1 H NMR (400 MHz, DMSO) d = 10.55 (s, 1H), 8.57 - 8.37 (m, 1H), 8.30 (s, 1H), 8.18 (s, 2H), 7.97 (s, 1H), 7.75 (s, 2H), 7.54 (s, 1H), 7.31 (m, 2H), 6.99 (s, 1H), 5.60 (d, J = 28.4 Hz, 1H), 4.81 (d, J = 12..8 Hz, 1H), 4.56 (s, 1H), 4.16 (s, 1H), 4.02 (s, 1.5H), 3.89 (s, 1H), 3.57 (s, 0.5H), 3.38 (s, 0.5H), 3.22 (s, 1H), 2.98 (m, 1H), 1.86 (s, 3H).

[0554] Example 73: Compound P84.

[0555] 1) Synthesis procedure of intermediate P84I1

[0556]

[0557] Compound P84S1 (2 g, 9.43 mmol, 1 eq) and compound P84S2 (2.27 g, 11.32 mmol, 1.2 eq) were dissolved in MeOH (40 mL), AcOH (566 mg, 9.43 mmol, 540 μL, 1 eq) was added at 25 °C, the reaction mixture was reacted at 70 °C for 16 h, the reaction solution was cooled, NaBH3CN (1.19 g, 18.86 mmol, 2 eq) was added to the above reaction solution at 25 °C, the reaction mixture was continued to react at 70 °C for 16 h, LCMS detection showed that the reaction was completed. The reaction solution was added to water (50 mL), extracted with EtOAc (20 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by column separation (SiO2, petroleum ether / EtOAc = 5 / 1 to 3 / 1) and silica gel plate purification (SiO2, petroleum ether / EtOAc = 3 / 1) to give the target compound P84I1 (200 mg, 505 μmol, 5.35% yield) as a yellow oil. ESI-MS: [M+H] + , 396.8.

[0558] 2) Synthesis procedure of intermediate P84I2

[0559]

[0560] Compound P84I1 (300 mg, 757 μmol, 1 eq) and BocNH2 (177 mg, 1.51 mmol, 2 eq) were dissolved in dioxane (6 mL), Cs2CO3 (739.90 mg, 2.27 mmol, 3 eq) and RuPhos Pd G3 (63.31 mg, 75.70 μmol, 0.1 eq) were added in turn at 25 °C, the reaction mixture was reacted at 100 °C for 16 h under nitrogen protection, LCMS detection showed that the reaction was completed. Water (10 mL) was added to the reaction solution, extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by silica gel plate purification (SiO2, petroleum ether / EtOAc = 3 / 1) to give the target compound P84I2 (230 mg, 531 μmol, 70.2% yield) as a yellow solid. ESI-MS: [M+H] + , 433.3.

[0561] 3) Synthesis procedure of intermediate P84I3

[0562]

[0563] Compound P84I2 (230 mg, 531 μmol, 1q) was dissolved in DCM (2.3 mL), HCl / dioxane (4 M, 2.3 mL) was added at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection reaction was completed. The reaction mixture was rotary evaporated under reduced pressure to obtain compound P84I3 (230 mg, crude, HCl) as a yellow solid. ESI-MS: [M+H] + , 333.3.

[0564] 4) Synthesis procedure of intermediate P84I4

[0565]

[0566] Compound P84I3 (130 mg, 352 μmol, 1 eq, HCl) and compound P84S3 (74.53 mg, 325.29 μmol, 1.2 eq) were dissolved in MeCN (2.34 mL) and DMF (0.26 mL), TCFH (91.3 mg, 325 μmol, 1.2 eq) and NMI (66.8 mg, 813 μmol, 64.8 μL, 3 eq) were added sequentially at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection reaction was completed. The reaction was concentrated under reduced pressure, then water (5 mL) was added, extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 0 / 1) to obtain the target compound P84I4 (127 mg, 233 μmol, 66.2% yield) as a yellow solid. ESI-MS: [M+H] + , 544.3.

[0567] 5) Synthesis procedure of compound P84

[0568]

[0569] Compound P84I4 (119 mg, 219 mol, 1 eq) was dissolved in DCM (2.0 mL), TFA (0.4 mL) was added at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH = 7-8 was adjusted with NH3H2O, and the target compound P84 (26.8 mg, 60.2 mol, 27.5% yield, FA) was obtained by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-40% B in 8.0 min) as a white solid. ESI-MS: [M+H] + , 446.2.

[0570] 1 H NMR (400 MHz, DMSO) d = 10.64 (s, 0.5H), 10.50 (s, 0.5H), 10.25 (s, 1H), 9.08 (m, 1H), 8.77 (m, 1H), 8.32 (dd, J = 19.6, 8.4 Hz, 1H), 8.18 (s, 1H), 7.88 (m, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.61 (dd, J = 14.0, 6.8 Hz, 2H), 7.43 (t, J = 9.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 0.5H), 7.17 (m, 2H), 5.50 (s, 1H), 4.89 (d, J = 14.8 Hz, 1H), 4.57 (m, 1H), 4.29 (d, J = 14.8 Hz, 0.5H), 4.16 (m, 0.5H), 4.05 (s, 3H), 3.91 (m, 1H), 3.44 (s, 0.5H), 3.30 (s, 1.5H), 3.23 - 3.05 (m, 1.5H), 2.92 (m, 2H), 2.37 (s, 0.5H), 2.18 (m, 1H), 2.04 - 1.79 (m, 4H), 1.63 (m, 4H).

[0571] Examples 74-75: Compound P85 and Compound P86.

[0572]

[0573] Compound P84 (20 mg, 45.1 μmol, 1 eq) was resolved by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) to give the target compound P85 (2.5 mg, 5.64 μmol, 12.5% yield) and P86 (3.1 mg, 6.99 μmol, 15.5% yield) as white solids. ESI-MS: [M+H] + ,444.2.

[0574] P85: 1 H NMR (400 MHz, Methanol-d4) d = 8.37 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H),

[0575] 7.57 (d, J = 8.1 Hz, 1H), 7.51-7.41 (m, 2H), 7.28-7.20 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.36-4.26 (m, 1H), 4.02 (s, 3H), 3.87 (d, J = 14.8 Hz, 1H), 3.64-3.52 (m, 1H), 3.13 (br dd, J = 1.7, 3.2 Hz, 1H), 2.89-2.64 (m, 6H), 1.95-1.87 (m, 2H), 1.63-1.48 (m, 7H)

[0576] P86: 1 H NMR (400 MHz, Methanol-d4) d = 8.37 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H),

[0577] Example 76: Compound P87.

[0578] 1) Intermediate P87I1 synthesis procedure

[0579]

[0580] To a solution of 7-nitro-l,2,3,4-tetrahydroisoquinoline (10 g, 0.056 mol), TEA (14.19 g, 0.14 mol) and DMAP (0.69 g, 5.61 mmol) in DCM (400 mL) was added benzyl chloroformate (10.53 g, 0.062 mol) slowly under N2protection at room temperature. The mixture was heated at 20 °C for 16 h. Then the resulting mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 20% to 30%) to give the target compound P87I1(3.1 g, yield 17.65%) as brown oil. ESI-MS: [M+H] + , 313.2.

[0581] 2) Synthesis procedure of intermediate P87I2

[0582]

[0583] To a solution of P87I1(3.1 g, 9.93 mmol) and NH4CI (1.06 g, 19.85 mmol) in EtOH (30 mL) / H2O (5 mL) was added Fe (5.54 g, 99.26 mmol) slowly under N2protection at 70 °C. The mixture was heated at 70 °C for 2 h. Then the resulting mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 25% to 30%) to give the target compound (2.7 g, yield 96.35%) as brown oil. ESI-MS: [M+H] + , 283.1.

[0584] 3) Synthesis procedure of intermediate P87I3

[0585]

[0586] To a solution of compound P87I2 (2.7 g, 9.6 mmol), (2R)-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (2.20 g, 9.6 mmol) and NMI (2.36 g, 28.8 mmol) in MeCN (45 mL) was added TCFH (5.39 g, 0.0192 mol) slowly at 0 °C under N2protection. The mixture was heated at 20 °C for 2 h. The precipitate was collected by filtration to give the target compound P87I3 (3.07 g, yield 64.58%) as a white solid. ESI-MS: [M+Na] + , 516.1.

[0587] 4) Synthesis procedure steps of intermediate P87I4

[0588]

[0589] To a solution of compound P87I3 (3.0 g, 6.08 mmol) in MeOH (60 mL) was added 10% Pd / C (300 mg). The mixture was vacuumed and backfilled with hydrogen three times, then charged with hydrogen. The resulting mixture was stirred at room temperature for 16 h. Then the mixture was filtered through celite. The filtrate was concentrated under vacuum to give the crude target compound P87I4 (2.1 g), which was used directly in the next step without further purification. ESI-MS: [M+H] + , 360.2.

[0590] 5) Synthesis procedure steps of intermediate P87I5

[0591]

[0592] A mixture of compound P87I4 (200 mg, 0.556 mmol), 4-fluoronaphthalen-1- enamine (115.18 mg, 0.61 mmol) and Rh2(OAc)4 (2.46 mg, 5.6 μmol) was placed in THF (3 mL) and heated to 100 °C under CO (4 MPa) in a high-pressure reactor for 20 h, then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 10% to 15%) to give the target compound P87I5 (60 mg, yield 20.29%) as a brown solid. ESI-MS: [M+H] + , 532.3.

[0593] 6) Synthesis procedure steps of compound P87

[0594]

[0595] Compound P87I5 (60 mg, 0.1129 mmol) was dissolved in DCM (1 mL) followed by the addition of trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by Biotage Isolera One (C18 column eluted with 10% to 90% MeCN / H2O containing 0.1% formic acid) to give the target compound P87 (30 mg, 61.56% yield) as a white solid. ESI-MS: [M+H] + , 432.2.

[0596] 1 H NMR (400 MHz, DMSO) d = 10.63 (s, 0.5H), 10.48 (s, 0.5H), 10.38 (s, 1H), 9.08 (s, 1H), 8.78 (s, 1H), 8.48 (d, J = 7.6 Hz, 0.5H), 8.32 (s, 0.5H), 8.19 (s, 1H), 7.96 (s, 1H), 7.77 (m, 2H), 7.59 (m, 1.5H), 7.42 (s, 1H), 7.16 (m, 1.5H), 5.57 (s, 1H), 4.91 (d, J = 15.2 Hz, 1H), 4.59 (s, 1H), 4.37 - 3.99 (m, 1H), 3.89 (m, 1H), 3.22 (m, 3H), 2.92 (m, 3H), 2.19 (m, 1H), 1.91 - 1.46 (m, 8H).

[0597] Example 77: Compound P88.

[0598] 1) Intermediate P88I1 synthesis procedure

[0599]

[0600] Compound P84I2 (130 mg, 352 pmol, 1 eq, HC1) and compound P88S1 (75.22 mg, 325.29 pmol, 1.2 eq) were dissolved in MeCN (2.34 mL) and DMF (0.26 mL), TCFH (91.3 mg, 325 pmol, 1.2 eq) and NMI (66.8 mg, 813 pmol, 64.8 pL, 3 eq) were added sequentially at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, and LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, water (5 mL) was added to it, and EtOAc (3 mL*3) was used for extraction, and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 0 / 1) to obtain the target compound P88I1 (120 mg, 220 pmol, 62.8% yield) as a yellow solid. ESI-MS: [M+H] + , 546.3.

[0601] 2) Synthesis procedure of compound P88

[0602]

[0603] Compound P88I1 (120 mg, 219 pmol, 1 eq) was dissolved in DCM (2.0 mL), TFA (0.4 mL) was added at 25 °C, and the reaction mixture was reacted at 25 °C for 1 h, and LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added, and the solution pH was adjusted to 7-8 with NH3-H2O, and the target compound P88 (25.2 mg, 51.2 pmol, 23.3% yield, FA) was obtained as a yellow oil by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 pm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-40% B in 8.0 min). ESI-MS: [M+H] + , 446.2.

[0604] 1H NMR (400 MHz, Methanol-d4) d = 8.39 (br s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.23 (br d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.54 - 7.46 (m, 1H), 7.40 - 7.29 (m, 2H), 7.14 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 5.02 - 4.92 (m, 1H), 4.23 (br d, J = 15.1 Hz, 1H), 4.11 - 4.00 (m, 5H), 3.88 - 3.77 (m, 2H), 3.71 - 3.56 (m, 2H), 3.28 - 3.19 (m, 2H), 3.16 - 3.03 (m, 2H), 3.02 - 2.88 (m, 2H), 1.78 (d, J = 6.7 Hz, 3H)

[0605] Example 78: Compound P89.

[0606] 1) Synthesis operation steps of intermediate P89I1

[0607]

[0608] Compound P84I1 (500 mg, 1.26 mmol, 1 eq) and compound P89S1 (250 mg, 1.26 mmol, 1 eq) were dissolved in THF (10 mL), to the mixture was added BINAP (78.5 mg, 126 pmol, 0.1 eq), Pd2(dba)3 (115 mg, 126 pmol, 0.1 eq) and t-BuONa (363 mg, 3.78 mmol, 3 eq) under nitrogen protection, the reaction mixture was reacted at 80 °C for 16 hours, LCMS detection reaction was completed. The reaction was concentrated under reduced pressure, added to H2O (30 mL), extracted with EtOAc (15 mL*3), the organic phase was combined and washed with saturated sodium chloride (60 mL). The washed organic phase was concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 0 / 1) to give the target compound P89I1 (455 mg, 885 pmol, 70.2% yield) as a white solid. ESI-MS: [M+H] + , 514.3.

[0609] 2) Synthesis operation steps of compound P89

[0610]

[0611] Compound P89I1 (455 mg, 885 µmol, 1 eq) was dissolved in DCM (4 mL), TFA (1 mL) was added at 20 °C, the mixture was reacted at 25 °C for 1 h. LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution was adjusted to pH = 8-9 with NH3·H2O, and purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 1% - 40% B in 8.0 min) to give the target compound P89 (700 mg, 663 µmol, 74.9% yield, 50% purity, TFA) as a yellow oil. ESI-MS: [M+H] + ,414.2.

[0612] 1 H NMR (400 MHz, DMSO-d6) d = 8.44 (br d, J = 7.9 Hz, 1H), 8.19 (dd, J = 1.5, 8.1 Hz, 1H), 8.16 (s, 1H), 7.54 - 7.45 (m, 3H), 6.96 (dd, J = 5.4, 8.3 Hz, 2H), 6.55 (dd, J = 2.1, 8.4 Hz, 1H), 6.39 - 6.35 (m, 1H), 4.40 (br d, J = 5.1 Hz, 2H), 4.26 (br d, J = 6.4 Hz, 1H), 3.97 (s, 3H), 3.75 - 3.65 (m, 4H), 3.60 - 3.53 (m, 4H), 2.72 (br s, 2H), 2.69 - 2.56 (m, 2H), 1.49 (d, J = 6.6 Hz, 3H)

[0613] Example 79: Compound P90.

[0614]

[0615] Compound P89 (130 mg, 314 µmol, 1 eq) was dissolved in EtOH (2.6 mL), TFA (31.7 mg, 314 µmol, 1 eq) was added to the reaction until the pH of the system was 8-9. Then 37% formaldehyde aqueous solution (94.3 mg, 3.14 mmol, 86.5 µL, 10 eq) and Ti(i-PrO)4 (1.3 mL) were added to the reaction. After the reaction mixture was stirred at 50 °C for 5 h, NaBH3CN (39.5 mg, 628 µmol, 2 eq) was added to the above reaction, and the reaction mixture was continuously reacted at 50 °C for 16 h, and LCMS detection showed that the reaction was completed. A mixture of H2O (10 mL) and EtOAc (5 mL) was added to the reaction, and yellow insoluble substances were generated. The suspension was filtered, and the filtrate was extracted with EtOAc (5 mL*3), and the organic phase was combined and concentrated under reduced pressure. Purification by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) -ACN]; gradient: 10%-40% B in 8.0 min) gave the target compound P90 (8.8 mg, 20.5 µmol, 6.55% yield) as a yellow oil. ESI-MS: [M+H] + , 428.3.

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (br d, J = 8.1 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.16 (s, 1H), 7.54-7.45 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.22 (dd, J = 1.9, 8.1 Hz, 1H), 6.09-6.05 (m, 1H), 4.21 (br d, J = 6.4 Hz, 1H), 4.14 (br d, J = 5.4 Hz, 2H), 3.97 (s, 3H), 3.68 (br d, J = 14.9 Hz, 1H), 3.51-3.48 (m, 1H), 2.91 (br dd, J = 3.3, 10.9 Hz, 2H), 2.76-2.59 (m, 6H), 2.34 (br d, J = 6.6 Hz, 1H), 2.07 (s, 3H), 1.92 (d, J = 7.4 Hz, 1H), 1.47 (d, J = 6.5 Hz, 3H)

[0617] Example 80: Compound P91.

[0618] 1) Intermediate P91I1 synthesis procedure

[0619]

[0620] Compound P89 (140 mg, 338 pmol, 1 eq) and compound P91S1 (80.9 mg, 338 pmol, 1 eq) were dissolved in DMF (2.8 mL), K2CO3 (140 mg, 1.02 mmol, 3 eq) was added to the above reaction solution, and the reaction mixture was reacted at 50 °C for 16 h. LCMS detection showed that the reaction was completed. The reaction solution was added to H2O (10 mL), extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The washed organic phase was concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 1 / 1) to obtain the target compound P91I1 (46 mg, 80.4 pmol, 23.7% yield) as a yellow oil. ESI-MS: [M+H] + , 572.5.

[0621] 2) Synthesis procedure of compound P91

[0622]

[0623] Compound P91I1 (10 mg, 17.4 pmol, 1 eq) was dissolved in DCM (0.8 mL), TFA (0.2 mL) was added at 20 °C, and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3·H2O, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-50% B in 8.0 min) to obtain the target compound P91 (3.5 mg, 7.65 pmol, 43.7% yield) as a yellow oil. ESI-MS: [M+H] + , 458.2.

[0624] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (br d, J = 8.0 Hz, 1H), 8.19 (br d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 7.57 - 7.41 (m, 3H), 6.95 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.44 - 6.23 (m, 1H), 6.22 - 6.08 (m, 1H), 4.24 (br d, J = 6.1 Hz, 1H), 4.14 (br d, J = 5.3 Hz, 1H), 3.97 (s, 3H), 3.74 - 3.62 (m, 3H), 3.52 (br s, 2H), 3.36 (br t, J = 6.3 Hz, 2H), 2.98 (br d, J = 10.9 Hz, 2H), 2.78 (br d, J = 11.1 Hz, 2H), 2.67 (br s, 2H), 2.57 (br d, J = 6.3 Hz, 2H), 2.38 - 2.29 (m, 2H), 1.48 (br d, J = 6.4 Hz, 3H)

[0625] Example 81: Compound P92.

[0626] 1) Synthesis procedure of intermediate P92I1

[0627]

[0628] Compound P84I1 (150 mg, 378 pmol, 1 eq) and compound P92S1 (96.4 mg, 454 pmol, 1.2 eq) were dissolved in THF (3 mL), BINAP (130 mg, 541 pmol, 0.2 eq), t-BuONa (109 mg, 1.14 mmol, 3 eq) and Pd2(dba)3 (34.7 mg, 37.9 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. Water (5 mL) was added to the reaction solution, extracted with EtOAc (2 mL*3), the organic phase was combined, washed with saturated aqueous sodium chloride solution (5 mL), the washed organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and the target compound P92I1 (170 mg, 277 pmol, 73.2% yield, 86% purity) was obtained as a yellow solid by silica gel plate purification (SiO2, petroleum ether / EtOAc = 3 / 1). ESI-MS: [M+H] + , 528.2.

[0629] 2) Synthesis procedure of compound P92

[0630]

[0631] Compound P92I1 (170 mg, 322 µmol, 1 eq) and TFA (0.7 mL) were dissolved in DCM (2.7 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution was adjusted to pH = 8-9 with NH3·H2O, purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 5% - 45% B in 8.0 min) to give the target compound P92 (86.3 mg, 157 µmol, 48.7% yield, 98.5% purity, TFA) as a white solid. ESI-MS: [M+H] + , 428.3.

[0632] 1 H NMR (400 MHz, Methanol-d4) d = 8.35 (d, J = 8.8 Hz, 1H), 8.20 (br d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.63-7.45 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.83 (br d, J = 8.8 Hz, 1H), 6.55 (br s, 1H), 5.10-4.98 (m, 1H), 4.92 (br s, 1H), 4.59 (br s, 2H), 4.33 (br s, 2H), 4.26-4.13 (m, 1H), 4.06 (s, 3H), 3.26 (br d, J = 12.5 Hz, 2H), 3.02 (br d, J = 11.8 Hz, 2H), 2.98-2.93 (m, 1H), 2.27-2.11 (m, 2H), 2.08-1.91 (m, 2H), 1.81 (br d, J = 6.6 Hz, 3H).

[0633] Example 82: Compound P93.

[0634] 1) Synthesis procedure of intermediate P93I1

[0635]

[0636] Compound P84I1 (150 mg, 378 pmol, 1 eq) and compound P93S1 (75 mg, 378 pmol, 1 eq) were dissolved in THF (3 mL), BINAP (23.6 mg, 37.9 pmol, 0.2 eq), t-BuONa (109 mg, 1.14 mmol, 3 eq) and Pd2(dba)3 (34.7 mg, 37.9 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. Water (5 mL) was added to the reaction solution, extracted with EtOAc (2 mL*3), the combined organic phase was washed with saturated aqueous sodium chloride solution (5 mL), the washed organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and the target compound P93I1 (130 mg, 232 pmol, 61.3% yield, 91.7% purity) was obtained as a white solid by silica gel plate purification (SiO2, petroleum ether / EtOAc = 3 / 1). ESI-MS: [M+H] + , 514.2.

[0637] 2) Synthesis procedure of compound P93

[0638]

[0639] Compound P93I1 (130 mg, 253 pmol, 1 eq) and TFA (0.5 mL) were dissolved in DCM (2.5 mL), and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3H2O, and the target compound P93 (72.1 mg, 136 pmol, 53.9% yield, 99.8% purity, TFA salt) was obtained as a yellow solid by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min). ESI-MS: [M+H] + , 414.2.

[0640] 1H NMR (400 MHz, DMSO-d6) d = 8.44 (br d, J = 7.4 Hz, 1H), 8.27 - 8.08 (m, 2H), 7.62 - 7.42 (m, 3H), 6.93 (dd, J = 8.2, 14.6 Hz, 2H), 6.51 - 6.38 (m, 1H), 6.25 (br s, 1H), 4.48 (br s, 1H), 4.33 (br s, 1H), 4.23 (br dd, J = 6.5, 13.9 Hz, 1H), 3.97 (s, 3H), 3.71 - 3.63 (m, 1H), 3.61 - 3.55 (m, 1H), 3.54 - 3.48 (m, 2H), 3.18 - 3.02 (m, 4H), 2.76 - 2.56 (m, 4H), 2.05 (br d, J = 10.8 Hz, 1H), 1.84 (br d, J = 10.4 Hz, 1H), 1.48 (d, J = 6.4 Hz, 3H)

[0641] Example 83: Compound P94.

[0642] 1) Synthesis operation steps of intermediate P94I1

[0643]

[0644] Compound P84I1 (50 mg, 126 pmol, 1 eq) and compound P94S1 (32.1 mg, 151 pmol, 1.2 eq) were dissolved in THF (1 mL), and BINAP (11.6 mg, 12.6 pmol, 0.1 eq), t-BuONa (36.4 mg, 378 mmol, 3 eq) and Pd2(dba)3 (7.8 mg, 12.6 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 80 °C for 16 hours under nitrogen protection, and LCMS detection showed that the reaction was completed. Water (5 mL) was added to the reaction solution, and EtOAc (2 mL*3) was used for extraction. The organic phase was combined and concentrated under reduced pressure, and then purified by silica gel plate (SiO2, petroleum ether / EtOAc = 3 / 1) to obtain the target compound P94I1 (40 mg, 71.4 pmol, 56.6% yield, 94.2% purity) as a yellow solid. ESI-MS: [M+H] + , 528.3.

[0645] 2) Synthesis operation steps of compound P94

[0646]

[0647] Compound P94I1 (40 mg, 71.4 pmol, 1 eq) and TFA (0.12 mL) were sequentially dissolved in DCM (0.68 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3H2O, and the target compound P94 (20.1 mg, 36.6 pmol, 48.2% yield, 98.5% purity, TFA) was obtained as a white solid by purification through high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-45% B in 8.0 min). ESI-MS: [M+H] + , 428.3.

[0648] 1 H NMR (400 MHz, DMSO-d6) d = 8.43 (br d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 8.23-8.14 (m, 1H), 7.54-7.42 (m, 3H), 6.93 (dd, J = 8.3, 11.0 Hz, 2H), 6.67 (br d, J = 8.4 Hz, 1H), 6.48 (s, 1H), 4.26-4.19 (m, 1H), 3.97 (s, 3H), 3.92 (br s, 1H), 3.62 (br d, J = 4.5 Hz, 4H), 3.11 (br s, 2H), 2.81-2.64 (m, 6H), 1.87-1.74 (m, 2H), 1.48 (d, J = 6.5 Hz, 3H).

[0649] Example 84: Compound P95.

[0650] 1) Intermediate P95I1 synthesis procedure

[0651]

[0652] Compound P84I1 (150 mg, 378 pmol, 1 eq) and compound P95S1 (80.4 mg, 378 pmol, 1 eq) were dissolved in THF (3 mL), BINAP (23.6 mg, 37.9 pmol, 0.1 eq), t-BuONa (109 mg, 378 mmol, 3 eq) and Pd2(dba)3 (34.7 mg, 37.9 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. Water (10 mL) was added to the reaction solution, and EtOAc (5 mL*3) was used for extraction. The organic phase was combined and concentrated under reduced pressure, and then purified by silica gel plate (SiO2, petroleum ether / EtOAc = 3 / 1) to obtain the target compound P95I1 (190 mg, 341 pmol, 89.9% yield, 94.6% purity) as a yellow solid. ESI-MS: [M+H] + , 528.3.

[0653] 2) Synthesis procedure of compound P95

[0654]

[0655] Compound P95I1 (190 mg, 341 pmol, 1 eq) and TFA (0.8 mL) were dissolved in DCM (3 mL), and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (3 mL) was added, and the solution pH was adjusted to 8-9 with NH3H2O. Purification by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-45% B in 8.0 min) to obtain the target compound P95 (151.4 mg, 354 pmol, 61.9% yield, 98.7% purity, TFA) as a white solid. ESI-MS: [M+H] + , 428.3.

[0656] 1H NMR (400 MHz, Methanol-d4) d = 8.41-8.31 (m, 1H), 8.11 (br d, J = 8.3 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.64-7.50 (m, 2H), 7.13 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.94 (dd, J = 2.4, 8.5 Hz, 1H), 6.60 (br s, 1H), 5.27 (br d, J = 6.8 Hz, 1H), 4.36-4.27 (m, 1H), 4.23-4.13 (m, 1H), 4.06-4.05 (m, 1H), 4.07 (s, 2H), 3.59-3.42 (m, 2H), 3.35 (br d, J = 1.8 Hz, 4H), 3.16 (s, 2H), 3.12-2.96 (m, 2H), 1.88 (d, J = 6.8 Hz, 3H), 1.04-0.99 (m, 2H), 0.96-0.89 (m, 2H).

[0657] Example 85: Compound P96.

[0658] 1) Synthesis operation steps of intermediate P96I1

[0659]

[0660] Compound P144I3 (120 mg, 284 pmol, 1 eq) and compound P96S1 (56.3 mg, 284 pmol, 3 eq) were dissolved in THF (2.4 mL), BINAP (17.7 mg, 28.4 pmol, 0.1 eq), t-BuONa (81.9 mg, 852 pmol, 3 eq) and Pd2(dba)3 (26.0 mg, 28.4 pmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 80 °C for 16 hours under nitrogen protection. LCMS detection showed that the reaction was completed. Water (5 mL) was added to the reaction solution, extracted with EtOAc (2 mL*3), the organic phase was combined, washed with saturated aqueous sodium chloride solution (5 mL), the washed organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and the target compound P96I1 (10 mg, 18.5 pmol, 6.52% yield) was obtained as a yellow solid by silica gel plate purification (SiO2, petroleum ether / EtOAc = 3 / 1). ESI-MS: [M+H] + , 540.3.

[0661] 2) Synthesis operation steps of compound P96

[0662]

[0663] Compound P96I1 (10 mg, 18.5 µmol, 1 eq) and TFA (0.2 mL) were dissolved in DCM (0.8 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (1 mL) was added, the solution was adjusted to pH = 8-9 with NH3·H2O, purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 5% - 45% B in 8.0 min) to give the target compound P96 (2.1 mg, 4.78 µmol, 21.9% yield, 98.5% purity) as a white solid. ESI-MS: [M+H] + , 440.3.

[0664] 1 H NMR (400 MHz, DMSO-d6) d = 8.57 (br dd, J = 1.3, 6.6 Hz, 1H), 8.43 (br d, J = 9.3 Hz, 1H), 8.28 (s, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.60 - 7.54 (m, 2H), 6.92 (d, J = 8.5 Hz, 1H), 6.50 (br d, J = 8.5 Hz, 1H), 6.31 (s, 1H), 4.37 (br d, J = 6.0 Hz, 1H), 3.79 - 3.71 (m, 3H), 3.15 - 3.03 (m, 8H), 2.67 (br s, 2H), 1.55 - 1.44 (m, 5H), 1.16 (t, J = 7.0 Hz, 4H).

[0665] Example 86: Compound P97.

[0666] 1) Synthesis procedure of intermediate P97I1

[0667]

[0668] Compound P152I2 (300 mg, 1.41 μmol, 1 eq), compound P97S1 (300 mg, 1.41 μmol, 12.8 μL, 1 eq) and Ti(i-PrO)4 (3 mL) were dissolved in EtOH (6 mL) sequentially, the reaction mixture was stirred at 50 °C for 16 h. NaBH3CN (178 mg, 2.83 mmol, 2 eq) was added to the above reaction solution at 25 °C, the reaction mixture was reacted at 50 °C for 16 h, and LCMS detection showed that the reaction was completed. The reaction solution was added to a mixed solvent of H2O (20 mL) and EtOAc (10 mL), and yellow insoluble substances were generated. The suspension was filtered, and the filtrate was extracted with EtOAc (10 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, and the target compound P97I1 (510 mg, 1.22 mmol, 84.6% yield, 95.8% purity) was obtained as a yellow oil by silica gel plate purification (SiO2, petroleum ether / EtOAc = 2 / 1). ESI-MS: [M+H] + , 409.4.

[0669] 2) Synthesis operation steps of intermediate P97I2

[0670]

[0671] Compound P97I1 (200 mg, 490 μmol, 1 eq) and compound P97S2 (97.1 mg, 490 μmol, 1 eq) were dissolved in THF (4 mL), and BINAP (30.5 mg, 49.0 μmol, 0.1 eq), t-BuONa (141 mg, 1.47 mmol, 3 eq) and Pd2(dba)3 (44.9 mg, 49.0 μmol, 0.1 eq) were added sequentially at 25 °C, and the reaction mixture was reacted at 80 °C for 16 h under nitrogen protection. LCMS detection showed that the reaction was completed. Water (10 mL) was added to the reaction solution, and the organic phase was extracted with EtOAc (5 mL*3), combined and concentrated under reduced pressure, and then purified by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to obtain the target compound P97I2 (180 mg, 240 μmol, 48.9% yield, 70% purity) as a yellow solid. ESI-MS: [M+H] + , 526.2.

[0672] 3) Synthesis operation steps of compound P97

[0673]

[0674] Compound P97I2 (180 mg, 240 µmol, 1 eq) and TFA (0.7 mL) were sequentially dissolved in DCM (2.9 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (3 mL) was added, the solution pH was adjusted to 8-9 with NH3·H2O, purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-45% B in 8.0 min) and (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 35%-65% B in 8.0 min) respectively to give the target compound P97 (10.3 mg, 24.0 µmol, 9.9% yield, 98.2% purity) as a white solid. ESI-MS: [M+H] + , 426.2.

[0675] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.34 (br d, J = 8.5 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.44 (dd, J = 7.0, 8.6 Hz, 1H), 7.18 (d, J = 7.3 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.39 (dd, J = 2.0, 8.2 Hz, 1H), 6.19 (d, J = 2.0 Hz, 1H), 5.09 (s, 4H), 4.26-4.18 (m, 1H), 4.12 (br d, J = 4.6 Hz, 2H), 3.85 (d, J = 14.5 Hz, 1H), 3.57 (d, J = 15.0 Hz, 1H), 3.44 (br d, J = 12.9 Hz, 2H), 2.91 (d, J = 12.7 Hz, 2H), 2.85-2.77 (m, 2H), 2.76-2.63 (m, 3H), 1.71 (d, J = 8.3 Hz, 1H), 1.57 (d, J = 6.7 Hz, 3H).

[0676] Example 87: Compound P98.

[0677] 1) Synthesis procedure of intermediate P98I1

[0678]

[0679] Compound P1 (50 mg, 136 μmol, 1 eq) was dissolved in THF (1 mL), n-BuLi (2.5 M, 60.1 μL, 1.1 eq) was added under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 1 h, then a THF (0.15 mL) solution of compound P98S1 (15.4 mg, 163 μmol, 14.7 μL, 1.2 eq) was added dropwise to the above reaction solution at -70 °C, the reaction mixture was continued to react at 15 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was added to NH4Cl solution (5 mL), extracted with DCM (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 3 / 1) to give the target compound P98I1 (34 mg, 101 μmol, 74.6% yield) as a yellow oil. ESI-MS: [M+H] + , 334.2.

[0680] 2) Synthesis procedure of compound P98

[0681]

[0682] Compound P98I1 (34 mg, 101 μmol, 1 eq) was dissolved in MeOH (1 mL), NH2COOH.NH3 (39.8 mg, 509 μmol, 5 eq) and compound P98S2 (98.5 mg, 305 μmol, 3 eq) were added successively at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was added to NaHCO3 (10 mL), extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Waters Xbridge BEH C18 150*25mm*5um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 40% - 70% B in 8.0 min) to give the target compound P98 (15.9 mg, 43.6 μmol, 42.7% yield) as a white solid. ESI-MS: [M+H] + , 365.1.

[0683] 1H NMR (400 MHz, Methanol-d4) d 8.47 - 8.42 (m, 1H), 7.91 - 7.85 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (dd, J = 1.8, 8.1 Hz, 1H), 7.67 (d, J = 7.0 Hz, 1H), 7.64 (s, 1H), 7.52 - 7.42 (m, 3H), 7.33 (d, J = 8.1 Hz, 1H), 4.42 (br d, J = 6.5 Hz, 1H), 4.01 (dd, J = 2.6, 15.6 Hz, 1H), 3.72 (br d, J = 15.3 Hz, 1H), 3.09 (s, 3H), 2.99 - 2.78 (m, 4H), 1.61 (d, J = 6.6 Hz, 3H)

[0684] Example 88: Compound P99.

[0685] 1) Synthesis operation steps of intermediate P99I1

[0686]

[0687] Compound P99S1 (405 mg, 1.91 mmol, 1.5 eq) and 5-acetyl-1,2- dihydroacenaphthylene (250 mg, 1.27 mmol, 1 eq) were dissolved in MeOH (5 mL), AcOH (76.5 mg, 1.27 mmol, 72.9 μL, 1 eq) was added at 25 °C, the reaction mixture was reacted at 70 °C for 16 h, the reaction solution was cooled, NaBH3CN (120 mg, 1.91 mmol, 1.5 eq) was added to the above reaction solution at 25 °C, the reaction mixture was continued to react at 70 °C for 16 h, LCMS detection showed that the reaction was completed. The reaction solution was added to water (10 mL), extracted with DCM (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the target compound P99I1 (150 mg, 382 μmol, 30.1% yield) was obtained as a yellow oil by silica gel plate purification (SiO2, petroleum ether / EtOAc = 3 / 1). ESI-MS: [M+H] + , 392.1.

[0688] 2) Synthesis operation steps of intermediate P99I2

[0689]

[0690] Compound P99I1 (145 mg, 369 mΐΐ, 1 eq) was dissolved in THF (2.9 mL), n-BuLi (2.5 M, 162 pL, 1.1 eq) was added at -70 °C under nitrogen protection, the reaction mixture was reacted at -70 °C for 1 h, a THF (0.3 mL) solution of compound P99S2 (104 mg, 1.11 mmol, 99.8 pL, 3 eq) was added dropwise to the above reaction solution at -70 °C, the reaction mixture was continued to react at 15 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was added to NH4CI solution (10 mL), extracted with DCM (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P99I2 (113 mg, 314 mΐΐ, 85.1% yield) as a yellow oil. ESI-MS: [M+H] + , 360.2.

[0691] 3) Synthesis procedure of compound P99

[0692]

[0693] Compound P99I2 (13 mg, 36.1 mΐΐ, 1 eq) was dissolved in MeOH (0.5 mL), NH2COOH.NH3 (14.1 mg, 180 mΐΐ, 5 eq) and compound P99S3 (34.9 mg, 108 mΐΐ, 3 eq) were added successively at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was added to saturated aqueous NaHCO3 solution (10 mL), extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-45% B in 8.0 min) to give the target compound P99 (2.3 mg, 5.89 mΐΐ, 16.2% yield) as a white solid. ESI-MS: [M+H] + , 391.1.

[0694] 1H NMR (400 MHz, Methanol-d4) d 7.99 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 1.8, 8.0 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.42 (dd, J = 6.9, 8.3 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 3.9, 6.8 Hz, 2H), 4.38 (q, J = 6.6 Hz, 1H), 4.03 (br d, J = 15.1 Hz, 1H), 3.73 (br d, J = 15.4 Hz, 1H), 3.43 - 3.36 (m, 4H), 3.09 (s, 3H), 2.99 - 2.82 (m, 4H), 1.63 (d, J = 6.6 Hz, 3H)

[0695] Example 89: Compound P100.

[0696] 1) Synthesis operation steps of intermediate P100I1

[0697]

[0698] Compound P84I1 (200 mg, 505 µmol, 1 eq) was dissolved in THF (4 mL), n-BuLi (2.5 M, 111 µL, 1.1 eq) was added at -70 ℃ under nitrogen protection, the reaction mixture was reacted at -70 ℃ for 1 h, a THF (0.2 mL) solution of compound P100S1 (57.0 mg, 606 µmol, 54.5 µL, 1.2 eq) was added dropwise to the above reaction solution at -70 ℃, the reaction mixture was reacted at 15 ℃ for 1 h, and LCMS detection showed that the reaction was completed. The reaction solution was added to saturated NH4Cl solution (5 mL), extracted with DCM (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 3 / 1) to give the target compound P100I1 (120 mg, 330 µmol, 65.4% yield) as a yellow oil. ESI-MS: [M+H] + ,364.2.

[0699] 2) Synthesis operation steps of compound P100

[0700]

[0701] Compound P100I1 (120 mg, 330 µmol, 1 eq) was dissolved in MeOH (3.6 mL), NH2COOH.NH3 (129 mg, 1.65 mmol, 5 eq) and compound P100S2 (319 mg, 990 µmol, 3 eq) were added successively at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was added to saturated NaHCO3 aqueous solution (5 mL), extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, successively by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%-45% B in 8.0 min) and high performance liquid chromatography (column: Waters Xbridge BEH C18 150*25mm*5um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 40%-70% B in 8.0 min) to give the target compound P100 (15.9 mg, 43.6 µmol, 42.7% yield) as a white solid. ESI-MS: [M+H] + , 395.1.

[0702] 1 1H NMR (400 MHz, Methanol-d4) d = 8.38 (br d, J = 8.0 Hz, 1H), 8.33-8.22 (m, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.51-7.41 (m, 2H), 7.33 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.44-4.27 (m, 1H), 4.01 (s, 3H), 3.97 (br d, J = 15.6 Hz, 1H), 3.71 (br d, J = 15.8 Hz, 1H), 3.09 (s, 3H), 2.97-2.71 (m, 4H), 1.60 (d, J = 6.7 Hz, 3H)

[0703] Example 90: Compound P101.

[0704] 1) Synthesis procedure of intermediate P101I1

[0705]

[0706] Compound P1 (100 mg, 273 pmol, 1 eq) was dissolved in THF (2 mL), n-BuLi (2.5 M, 218 pL, 2 eq) was added under nitrogen protection at -70 °C, and the reaction mixture was reacted at -70 °C for 1 h. Compound P101S1 (71.0 mg, 546 pmol, 2 eq) was added to the above reaction solution, and the reaction mixture was reacted at -70 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction solution was poured into ice water (10 mL), extracted with EtOAc (5 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered under reduced pressure to give the target compound P101I1 (110 mg, 263 pmol, 96.5% yield) as a yellow oil. ESI-MS: [M+H] + , 418.2.

[0707] 2) Synthesis procedure of compound P101

[0708]

[0709] Compound P101I1 (110 mg, 263 pmol, 1 eq) was dissolved in MeOH (2.2 mL), and HCl (3 M, 1.1 mL) was added at 25 °C, and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. Water (10 mL) was added to the reaction mixture, extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered under reduced pressure to give the target compound P101 (45.4 mg, 120 pmol, 45.6% yield) as a white solid. ESI-MS: [M+H] + , 378.2.

[0710] 1H NMR (400 MHz, Methanol-d4) d 8.46 - 8.39 (m, 1H), 7.91 - 7.85 (m, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.52 - 7.42 (m, 3H), 7.26 (dd, J = 1.6, 8.0 Hz, 1H), 7.13 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 4.39 (br d, J = 6.5 Hz, 1H), 3.93 (d, J = 14.8 Hz, 1H), 3.78 - 3.60 (m, 5H), 2.89 - 2.71 (m, 4H), 1.60 (d, J = 6.7 Hz, 3H)

[0711] Example 91: Compound P102.

[0712] 1) Synthesis operation steps of intermediate P102I1

[0713]

[0714] Compound P84I1(100 mg, 252 µmol, 1 eq) was dissolved in THF (2 mL), n-BuLi (2.5 M, 201 µL, 2 eq) was added under nitrogen protection at -70 ℃, the reaction mixture was reacted at -70 ℃ for 1 h. Compound P102S1(65.6 mg, 504 µmol, 2 eq) was added to the above reaction solution, and the reaction mixture was reacted at -70 ℃ for 1 h. LCMS detection showed that the reaction was completed. The reaction solution was poured into ice water (10 mL), extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered under reduced pressure to give the target compound P102I1(110 mg, 245 µmol, 97.4% yield) as a yellow oil. ESI-MS: [M+H] + , 448.2.

[0715] 2) Synthesis operation steps of compound P102

[0716]

[0717] Compound P102I1 (110 mg, 245 mΐioΐ, 1 eq) was dissolved in MeOH (2.2 mL), HCl (3 M, 1.1 mL) was added at 25 °C, the reaction mixture was reacted at 25 °C for 1 h. LCMS detected that the reaction was completed. Water (10 mL) was added to the reaction mixture, extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the target compound P102 (43.7 mg, 107 mΐioΐ, 43.6% yield) was obtained by high performance liquid chromatography (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 35% - 65% B in 8.0 min) as a white solid. ESI-MS: [M+H] + , 408.2.

[0718] 1 H NMR (400 MHz, Methanol-d4) d 8.36 (br d, J = 8.4 Hz, 1H), 8.27 (dd, J = 1.3, 8.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.25 (dd, J = 1.6, 7.9 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 4.32 (br d, J = 6.7 Hz, 1H), 4.01 (s, 3H), 3.90 (d, J = 14.9 Hz, 1H), 3.77 - 3.59 (m, 5H), 2.89 - 2.79 (m, 2H), 2.79 - 2.70 (m, 2H), 1.58 (d, J = 6.7 Hz, 3H)

[0719] Example 92: Compound P103.

[0720] 1) Intermediate P103I1 synthesis procedure

[0721]

[0722] Compound P99I1 (500 mg, 1.27 mmol, 1 eq) was dissolved in MeNO2 (10 mL) and dioxane (1 mL), and Cs2CO3 (456 mg, 1.40 mmol, 1.1 eq), 4A MS (60 mg, 1.26 mmol, 1 eq), XPhos (121 mg, 254 μmol, 0.2 eq) and Pd2(dba)3 (116 mg, 127 μmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 60 °C for 7 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was blown dry with nitrogen at 60 °C, water (10 mL) was added to the reaction mixture, and extracted with EtOAc (5 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the target compound P103I1 (258 mg, 692 μmol, 54.3% yield) was obtained as a yellow oil by silica gel plate purification (SiO2, petroleum ether / EtOAc = 5 / 1). ESI-MS: [M+H] + , 373.2.

[0723] 2) Synthesis procedure of compound P103

[0724]

[0725] Compound P103I1 (230 mg, 444 μmol, 1 eq) was dissolved in EtOH (4.6 mL) and dioxane (1.8 mL), and NaOH (1 mg, 22.2 μmol, 0.05 eq) was dissolved in HCHO (721 mg, 8.89 mmol, 662 μL, 37% purity, 20 eq) and added dropwise to the reaction solution at 20 °C. The reaction mixture was reacted at 20 °C for 1 h, and LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and H2O (10 mL) was added thereto, extracted with EtOAc (3 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the target compound P103 (150 mg, 346 μmol, 78.0% yield) was obtained as a white solid by silica gel plate purification (SiO2, petroleum ether / EtOAc = 0 / 1). ESI-MS: [M+H] + , 433.2.

[0726] 1H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.31 - 7.24 (m, 2H), 7.16 - 7.04 (m, 2H), 6.96 (s, 1H), 4.37 (d, J = 11.5 Hz, 2H), 4.35 - 4.24 (m, 3H), 3.90 (s, 1H), 3.62 (s, 1H), 3.42 - 3.34 (m, 4H), 2.90 - 2.71 (m, 4H), 1.59 (d, J = 6.5 Hz, 3H)

[0727] Example 93: Compound P104.

[0728]

[0729] Raney-Ni (23.8 mg) was placed in a hydrogenation bottle, the water in the catalyst was replaced with MeOH for three times, MeOH (6 mL) was added along the bottle wall into the reaction bottle, compound P103 (60 mg, 139 μmol, 1 eq) was added into the above reaction solution, the reaction mixture was reacted at 50 psi, 25 °C for 7 hours under hydrogen atmosphere, LCMS detection showed that the reaction was completed. After the supernatant of the reaction was taken out, it was concentrated under reduced pressure, purified by high performance liquid chromatography (column: WePure Biotech XP tC18 250*70*10um; mobile phase: [H2O (1M NH4HCO3)-ACN]; gradient: 20%-55% B in 20.0 min) to obtain the target compound P104 (5.9 mg, 14.7 μmol, 10.6% yield) as a white powder. ESI-MS: [M+H] + ,403.2.

[0730] 1H NMR (400 MHz, Methanol-d4) d = 7.96 (br d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.30-7.19 (m, 3H), 7.16-7.07 (m, 2H), 5.58 (dd, J = 3.6, 10.1 Hz, 1H), 4.42 (dd, J = 10.4, 12.0 Hz, 1H), 4.29 (br d, J = 6.6 Hz, 1H), 3.93 (br dd, J = 4.8, 14.9 Hz, 1H), 3.80 (dd, J = 3.3, 12.2 Hz, 1H), 3.61 (br dd, J = 5.8, 15.3 Hz, 1H), 3.45-3.36 (m, 5H), 2.93-2.72 (m, 4H), 1.59 (d, J = 6.6 Hz, 3H)

[0731] Example 94: Compound P105.

[0732] 1) Synthesis operation steps of intermediate P105I1

[0733]

[0734] Compound P84I1 (500 mg, 1.26 mmol, 1 eq) was dissolved in MeNO2 (10 mL), and Cs2CO3 (452 mg, 1.39 mmol, 1.1 eq), 4AMS (60 mg, 1.26 mmol, 1 eq), XPhos (120 mg, 252 µmol, 0.2 eq) and Pd2(dba)3 (115 mg, 126 µmol, 0.1 eq) were added successively at 25 °C. The reaction mixture was reacted at 60 °C for 1 h under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was blown dry with nitrogen at 60 °C, water (10 mL) was added to the reaction mixture, and extracted with EtOAc (5 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to obtain the target compound P105I1 (400 mg, 967 µmol, 76.6% yield, 91% purity) as a yellow oil. ESI-MS: [M+H] + ,377.2.

[0735] 2) Synthesis operation steps of compound P105

[0736]

[0737] Compound P105I1 (400 mg, 1.06 mmol, 1 eq) was dissolved in EtOH (8 mL) and dioxane (3.2 mL), NaOH (2.13 mg, 53.1 μmol, 0.05 eq) was dissolved in HCHO (1.72 g, 21.2 mmol, 1.58 mL, 37% purity, 20 eq) was added dropwise to the reaction solution at 20 °C, the reaction mixture was reacted at 20 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, added to H2O (10 mL), extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 0 / 1) to give the target compound P105 (210 mg, 481 μmol, 45.3% yield) as a white solid. ESI-MS: [M+H] + , 437.1.

[0738] 1 H NMR (400 MHz, DMSO-d6) d = 8.42 (br d, J = 8.3 Hz, 1H), 8.24-8.12 (m, 1H), 7.53-7.42 (m, 3H), 7.12-7.05 (m, 1H), 7.04-6.99 (m, 1H), 6.98-6.90 (m, 2H), 5.26 (d, J = 4.8 Hz, 2H), 4.28-4.11 (m, 5H), 3.97 (s, 3H), 3.77 (br d, J = 15.3 Hz, 1H), 3.57 (br d, J = 15.4 Hz, 1H), 2.82-2.71 (m, 2H), 2.69-2.58 (m, 2H), 1.48 (d, J = 6.5 Hz, 3H)

[0739] Example 95: Compound P106.

[0740]

[0741] Ni (31 mg, 367 mmol, 2 eq) was placed in a hydrogenation bottle under argon protection, the water in the catalyst was replaced with MeOH for three times, MeOH (8 mL) was added into the reaction bottle along the bottle wall slowly, compound P105 (80 mg, 183 pmol, 1 eq) was added into the above reaction solution, the reaction mixture was reacted at 25 °C for 7 hours under hydrogen atmosphere (50 Psi), LCMS detection showed that the reaction was completed. After the supernatant of the reaction was taken out, it was concentrated under reduced pressure, and purified by high performance liquid chromatography (column: WePure Biotech XP tC18 250*70*10um; mobile phase: [H2O (1M NH4HCO3)-ACN]; gradient: 20%-55% B in 20.0 min) to obtain the target compound P106 (31 mg, 76.2 pmol, 41.6% yield) as a white powder. ESI-MS: [M+H] + , 407.2.

[0742] 1 H NMR (400 MHz, DMSO-d6) d = 8.44 (br d, J = 8.0 Hz, 1H), 8.18 (dd, J = 1.3, 8.2 Hz, 1H), 7.55-7.42 (m, 3H), 7.27-7.20 (m, 1H), 7.28-7.14 (m, 1H), 7.10 (s, 1H), 6.95 (d, J = 8.0 Hz, 2H), 4.54 (t, J = 5.5 Hz, 2H), 4.25 (br d, J = 6.6 Hz, 1H), 3.72 (br d, J = 15.0 Hz, 1H), 3.55 (br d, J = 14.5 Hz, 1H), 3.49-3.37 (m, 4H), 2.76-2.58 (m, 4H), 1.65 (br s, 2H), 1.49 (d, J = 6.5 Hz, 3H)

[0743] Example 96: Compound P107.

[0744]

[0745] Compound P106 (24 mg, 61.0 μmol, 1 eq) was dissolved in DCM (0.5 mL), TEA (18.7 mg, 184 μmol, 25.7 μL, 3 eq) was added at 20 °C. Then the mixture was cooled to 0 °C, Ac2O (12.6 mg, 123 μmol, 11.6 μL, 2 eq) was dissolved in DCM (0.5 mL) and added dropwise to the reaction mixture, the reaction mixture was stirred at 20 °C for 1 h, LCMS detection showed that the reaction was completed, and the by-product of the upper two acetyl groups was generated. The DCM was blown dry with nitrogen, and DMF (1 mL) and K2CO3 (17.0 mg, 123. μmol, 2 eq) were added at 20 °C. The reaction mixture was reacted at 60 °C for 1 h, and LCMS detection showed that the reaction was completed. H2O (5 mL) was added to the reaction solution, extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to give the target compound P107 (10.4 mg, 23.2 μmol, 37.7% yield) as a white solid. ESI-MS: [M+H]+, 449.3.

[0746] 1 H NMR (400 MHz, Methanol-d4) d = 8.35 (br d, J = 8.1 Hz, 1H), 8.27 (dd, J = 1.2, 8.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.14-7.08 (m, 1H), 7.07-7.01 (m, 1H), 6.98-6.87 (m, 2H), 4.36 (br d, J = 4.4 Hz, 1H), 4.01 (s, 3H), 3.97-3.93 (m, 2H), 3.92-3.83 (m, 3H), 3.66 (br s, 1H), 2.89-2.71 (m, 4H), 2.04 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H)

[0747] Example 97: Compound P109.

[0748]

[0749] Compound P108 (50 mg, 129 pmol, 1 eq) was dissolved in THF (0.5 mL), compound BH3.THF (2.5 M, 77.6 pL, 1.5 eq) was added at 0 °C under nitrogen protection. The reaction mixture was reacted at 50 °C for 5 h, LCMS detected the reaction was completed. MeOH (1 mL) was added at 0 °C and the reaction mixture was reacted at 70 °C for 1 h. The reaction was blown dry with nitrogen, and P109 (14 mg, 32.7 pmol, 25.3% yield, 91.2% purity) was obtained as a white solid by high performance liquid chromatography (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 45% - 90% B in 8.0 min). ESI-MS: [M+H] + , 391.2.

[0750] 1 H NMR (400 MHz, DMSO-d6) d = 8.44 (br d, J = 8.1 Hz, 1H), 8.23 - 8.14 (m, 1H), 7.48 - 7.43 (m, 1H), 7.54 - 7.43 (m, 2H), 7.19 - 7.08 (m, 1H), 7.03 (br d, J = 2.3 Hz, 1H), 6.94 (s, 1H), 7.00 - 6.90 (m, 1H), 4.76 (br s, 1H), 4.25 (br d, J = 5.5 Hz, 1H), 3.97 (s, 3H), 3.75 (br d, J = 14.9 Hz, 1H), 3.56 (br d, J = 14.8 Hz, 1H), 2.78 - 2.53 (m, 6H), 1.49 (d, J = 6.6 Hz, 3H), 1.34 - 1.27 (m, 3H)

[0751] Example 98: Compound P111.

[0752]

[0753] Compound P110 (25 mg, 61.7 μmol, 1 eq) and NH4CI (3.96 mg, 73.9 μmol, 1.2 eq) were dissolved in THF (0.5 mL), BOP (27.3 mg, 61.7 μmol, 1 eq) and DIEA (15.9 mg, 12 μmol, 21.5 μL, 2 eq) were added at 25 °C, the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, then purified by high performance liquid chromatography (column: Waters Xbridge BEH CI 100*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 45% - 80% B in 8.0 min) to give the target compound P111 (3 mg, 6.75 μmol, 11.0% yield, 91% purity) as a yellow solid. ESI-MS: [M+H] + , 405.2.

[0754] 1 H NMR (400 MHz, DMSO-d6) d = 8.45 (br d, J = 8.3 Hz, 1H), 8.21 - 8.14 (m, 1H), 7.55 - 7.50 (m, 2H), 7.50 - 7.46 (m, 1H), 7.24 (br d, J = 7.9 Hz, 1H), 7.17 - 7.11 (m, 2H), 6.99 - 6.94 (m, 2H), 7.01 (s, 1H), 5.77 (d, J = 3.9 Hz, 1H), 4.31 - 4.20 (m, 1H), 3.98 (s, 3H), 3.74 (br dd, J = 3.7, 15.0 Hz, 1H), 3.58 (br d, J = 3.3 Hz, 1H), 2.77 - 2.62 (m, 5H), 1.53 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H)

[0755] Example 99: Compound P112.

[0756] 1) Intermediate P112I1 synthesis procedure

[0757]

[0758] Compound P84I1 (200 mg, 505 mΐioΐ, 1 eq) was dissolved in THF (4 mL), n-BuLi (2.5 M, 403 pL, 2 eq) was added at -78 °C, the reaction mixture was reacted at -78 °C for 0.5 h, then compound P112S1 (161 mg, 1.01 mmol, 2 eq) was dissolved in THF (1 mL) and added dropwise to the reaction, the reaction mixture was continued to react at -78 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction was poured into saturated aqueous ammonium chloride solution (10 mL), extracted with EtOAc (3 mL*3), and the organic phase was combined. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P112I1 (70 mg, 74.4 mΐioΐ, 14.5% yield, 50% purity) as a yellow solid. ESI-MS: [M+H] + , 477.2.

[0759] 2) Synthesis procedure of compound P112

[0760]

[0761] Compound P112I1 (70 mg, 73.4 mΐioΐ, 1 eq) and TFA (0.4 mL) were dissolved in DCM (1 mL), the reaction mixture was reacted at 20 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 7-8 with NH3-H2O, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-45% B in 8.0 min) to give the target compound P112 (9.9 mg, 26.3 mΐioΐ, 35.8% yield) as a white solid. ESI-MS: [M+H] + , 377.2.

[0762] 1H NMR (400 MHz, Methanol-d4) d = 8.35 (br d, J = 8.5 Hz, 1H), 8.25-8.13 (m, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.63-7.46 (m, 2H), 7.31-7.26 (m, 1H), 7.24-7.19 (m, 1H), 7.10 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.13-5.02 (m, 1H), 4.81 (dd, J = 2.8, 9.7 Hz, 1H), 4.31 (br d, J = 15.0 Hz, 1H), 4.11 (br d, J = 14.6 Hz, 1H), 4.06 (s, 3H), 3.14-2.88 (m, 4H), 1.82 (d, J = 6.7 Hz, 3H)

[0763] Example 100: Compound P113.

[0764] 1) Synthesis procedure steps of intermediates P84I1-A and P84I1-B

[0765]

[0766] Compound P84I1 (2 g, 5.05 mmol, 1 eq) was resolved by SFC (Column: DAICEL CHIRALCEL OD (250 mm*50 mm, 10 um); Mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) to give the target compounds 3P84I1-A (950 mg, 2.40 mmol, 47.5% yield) and P84I1-B (950 mg, 2.40 mmol, 47.5% yield) as white solids. ESI-MS: [M+H] + 396.2.

[0767] 2) Synthesis procedure steps of intermediate P113I1

[0768]

[0769] Compound P84I1-A (0.25 g, 631 μmol, 1 eq) was dissolved in THF (5 mL), n-BuLi (2.5 M, 378 μL, 1.5 eq) was added under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 0.5 h, DMF (138 mg, 1.89 mmol, 146 μL, 3 eq) was dissolved in THF (0.2 mL), then added dropwise into the above reaction solution. The reaction mixture was reacted at -70 °C for 1.5 h, LCMS detection showed that the reaction was completed. The reaction solution was poured into an aqueous solution of ammonium chloride (10 mL), extracted with EtOAc (5 mL*3), the organic phase was combined and concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P113I1 (0.32 g, 926 μmol, 73.4% yield) as a yellow solid. ESI-MS: [M+H] + , 346.1.

[0770] 3) Synthesis procedure of intermediates P113I2 and P113I3

[0771]

[0772] Compound P113I1 (100.00 mg, 289 μmol, 1 eq) was dissolved in DCM (5 mL), TMSCN (63 mg, 578 mmol, 2 eq) and zinc iodide (92.4 mg, 289 μmol, 1 eq) were added successively at 20 °C. The reaction mixture was reacted at 20 °C for 3 h under nitrogen protection, LCMS detection showed that the raw material was completely consumed, 55% of compound P113I2 and 44% of compound P113I3 were generated. The reaction solution was poured into water (10 mL), extracted with DCM (5 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure to give the mixture of target compounds P113I2 and P223I3 (105 mg, crude) as a yellow solid. Cpd. P113I2: ESI-MS: [M+H] + , 445.2; P113I3: ESI-MS: [M+H] + , 373.1.

[0773] 4) Synthesis procedure of compound P113

[0774]

[0775] A mixture of compounds P113I2 and P113I3 (105 mg, 113 μmol, 1 eq) was dissolved in THF (3.2 mL), BH3.THF (1 M, 226 μL, 2 eq) was added dropwise at 0 °C under nitrogen protection. The reaction mixture was reacted at 50 °C for 5 h. LCMS showed the starting material was consumed completely. MeOH (1 mL) was added dropwise at 0 °C. The reaction mixture was continued to react at 70 °C for 1 h. LCMS showed 40% of product was generated. The reaction was concentrated under reduced pressure. Purification by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 1% - 30% B in 8.0 min) gave P113 (32.8 mg, 83.2 μmol, 73.8% yield, 95.5% purity) as a yellow solid. ESI-MS: [M+H] + , 377.1.

[0776] 1 H NMR (400 MHz, DMSO-d6) d = 8.43 (br d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 8.22 - 8.16 (m, 1H), 7.53 - 7.42 (m, 3H), 7.08 (br d, J = 5.9 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.99 (br d, J = 6.3 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 4.65 (br d, J = 7.4 Hz, 1H), 4.33 - 4.19 (m, 1H), 3.97 (s, 3H), 3.74 (br dd, J = 6.4, 15.2 Hz, 1H), 3.58 (br dd, J = 3.3, 15.1 Hz, 1H), 2.93 (br d, J = 10.6 Hz, 1H), 2.83 - 2.57 (m, 5H), 1.49 (d, J = 6.5 Hz, 3H)

[0777] Example 101: Compound P114.

[0778] 1) Synthesis procedure of intermediate P114I1

[0779]

[0780] Compound P84I1-B (0.5 g, 1.26 mmol, 1 eq) was dissolved in THF (10 mL), n-BuLi (2.5 M, 757 μL, 1.5 eq) was added under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 0.5 h, DMF (277 mg, 3.78 mmol, 291 μL, 3 eq) was dissolved in THF (0.2 mL), then added dropwise into the above reaction solution. The reaction mixture was reacted at -70 °C for 1.5 h, LCMS detection showed that the reaction was completed. The reaction solution was poured into an aqueous solution of ammonium chloride (20 mL), extracted with EtOAc (10 mL*3), the organic phase was combined and concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P114I1 (0.24 g, 695 μmol, 55.1% yield) as a yellow solid. ESI-MS: [M+H] + , 344.1.

[0781] 2) Synthesis procedure of intermediates P114I2 and P114I3

[0782]

[0783] Compound P114I1 (240 mg, 695 μmol, 1 eq) was dissolved in DCM (4.8 mL), TMSCN (151 mg, 1.53 mmol, 2.2 eq) and zinc iodide (222 mg, 695 μmol, 1 eq) were added successively at 20 °C. The reaction mixture was reacted at 20 °C for 3 h under nitrogen protection, LCMS detection showed that the raw material was completely consumed, 54% of compound P114I2 and 43% of compound P114I3 were generated. The reaction solution was poured into water (10 mL), extracted with DCM (5 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure to give a mixture of target compounds P114I2 and P114I3 (250 mg, crude) as a yellow solid. P114I2: ESI-MS: [M+H] + , 445.1; P114I3: ESI-MS: [M+H] + , 373.1.

[0784] 3) Synthesis procedure of compound P114

[0785]

[0786] A mixture of compound P114I2 and P114I3 (250 mg, 304 μmol, 1 eq) was dissolved in THF (7.5 mL), BH3.THF (1 M, 607 μL, 2 eq) was added dropwise at 0 °C under nitrogen protection. The reaction mixture was reacted at 50 °C for 3 h. LCMS showed the starting material was consumed completely. MeOH (3 mL) was added dropwise at 0 °C. The reaction mixture was continued to react at 70 °C for 1 h. LCMS showed 39% of product was formed. The reaction was concentrated under reduced pressure. Purification by high performance liquid chromatography (column: Phenomenex Luna C18 100*30 mm*3 um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 1% - 30% B in 8.0 min) gave P114 (92 mg, 244 μmol, 80.2% yield, 99.7% purity) as a yellow solid. ESI-MS: [M+H] + , 377.1.

[0787] 1 H NMR (400 MHz, DMSO-d6) d = 8.42 (br d, J = 7.8 Hz, 1H), 8.32 (s, 2H), 8.23 - 8.14 (m, 1H), 7.52 - 7.43 (m, 3H), 7.12 - 7.07 (m, 1H), 7.06 - 7.03 (m, 1H), 6.99 (br d, J = 5.8 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.68 (br d, J = 7.9 Hz, 1H), 4.26 (br d, J = 4.4 Hz, 1H), 3.97 (s, 3H), 3.75 (br dd, J = 6.0, 15.1 Hz, 1H), 3.63 - 3.51 (m, 1H), 2.95 (br d, J = 11.5 Hz, 1H), 2.84 - 2.61 (m, 5H), 1.49 (d, J = 6.5 Hz, 3H)

[0788] Example 102: Compound P115.

[0789] 1) Intermediate P115I1 synthesis procedure

[0790]

[0791] Compound P84I1-B (400 mg, 1.01 mmol, 1 eq) was dissolved in THF (8 mL), n-BuLi (2.5 M, 403 μL, 1 eq) was added under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 1 h, compound P115S1 (174 mg, 1.01 mmol, 1 eq) was added to the above reaction solution, the reaction mixture was reacted at -70 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was poured into an aqueous solution of ammonium chloride (20 mL), extracted with EtOAc (5 mL*3), the organic phase was combined and washed with saturated sodium chloride (20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to obtain the target compound P115I1 (257 mg, 497 μmol, 49.3% yield, 95.0% purity) as a white solid. ESI-MS: [M+H] + , 491.2.

[0792] 2) Synthesis procedure of compound P115

[0793]

[0794] Compound P115I1 (257 mg, 523 μmol, 1 eq) and TFA (1 mL) were dissolved in DCM (4 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3·H2O, and the target compound P115 (112 mg, 221 μmol, 42.3% yield, TFA) was obtained by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-45% B in 8.0 min) as a white solid. ESI-MS: [M+H] + , 391.2.

[0795] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (br d, J = 7.9 Hz, 1H), 8.22 - 8.16 (m, 2H), 7.53 - 7.42 (m, 3H), 7.13 - 7.04 (m, 2H), 7.00 - 6.92 (m, 2H), 4.73 (dd, J = 2.5, 9.6 Hz, 1H), 4.28 (br s, 1H), 3.97 (s, 3H), 3.72 (br dd, J = 8.8, 15.0 Hz, 1H), 3.60 - 3.56 (m, 1H), 3.01 (br dd, J = 3.0, 12.5 Hz, 1H), 2.91 (br d, J = 9.9 Hz, 1H), 2.79 - 2.67 (m, 4H), 2.54 - 2.52 (m, 3H), 1.50 (d, J = 6.5 Hz, 3H)

[0796] Example 103: Compound P116.

[0797] 1) Synthesis procedure of intermediate P116I1

[0798]

[0799] Compound P84I1-A (0.5 g, 1.26 mmol, 1 eq) was dissolved in THF (10 mL), n-BuLi (2.5 M, 1.01 mL, 2 eq) was added dropwise under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 0.5 h, compound P116S1 (262 mg, 1.51 mmol, 1.2 eq) was dissolved in THF (0.5 mL), then slowly added to the above reaction solution. The reaction mixture was reacted at -70 °C for 1.5 h, LCMS detected that the raw material was completely consumed, and 17% of the product was generated. The reaction solution was poured into an aqueous solution of ammonium chloride (20 mL), extracted with EtOAc (10 mL*3), the organic phase was combined, concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 3 / 1) to obtain the target compound P116I1 (0.18 g, 257 μmol, 20.4% yield, 70% purity) as a yellow solid. ESI-MS: [M+H] + ,491.3.

[0800] 2) Synthesis procedure of compound P116

[0801]

[0802] Compound P116I1 (180 mg, 257 µmol, 1 eq) and TFA (0.7 mL) were dissolved in DCM (2.9 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution was adjusted to pH = 8-9 with NH3·H2O, purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-30% B in 8.0 min) to give the target compound P116 (65 mg, 166 µmol, 64.8% yield, 100% purity, TFA) as a yellow solid. ESI-MS: [M+H] + , 391.2.

[0803] 1 H NMR (400 MHz, DMSO-d6) d = 8.43 (br d, J = 8.0 Hz, 1H), 8.26 (br s, 1H), 8.21-8.13 (m, 1H), 7.55-7.41 (m, 3H), 7.13-7.02 (m, 2H), 7.00-6.90 (m, 2H), 4.71 (br d, J = 7.3 Hz, 1H), 4.32-4.22 (m, 1H), 3.97 (s, 3H), 3.73 (br dd, J = 7.8, 14.9 Hz, 1H), 3.57 (br dd, J = 3.8, 15.2 Hz, 1H), 2.96-2.89 (m, 1H), 2.86-2.80 (m, 1H), 2.80-2.64 (m, 4H), 2.48 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H)

[0804] Example 104: Compound P117.

[0805]

[0806] Compound P115 (74 mg, 189 μmol, 1 eq) and 37% formaldehyde aqueous solution (76.8 mg, 947 μmol, 70.5 μL, 5 eq) were dissolved in MeOH (1.5 mL) sequentially, TEA (19.1 mg, 189 μmol, 1 eq) was added to the reaction solution until the pH of the system was ~8. Then AcOH (11.3 mg, 189 μmol, 10.8 μL, 1 eq) was added to the reaction solution, and the pH of the system was ~6. After the reaction mixture was stirred at 25 °C for 1 h, NaBH3CN (23.8 mg, 378 μmol, 2 eq) was added to the above reaction solution, and the reaction mixture was continuously reacted at 25 °C for 2 h, and LCMS detection showed that the reaction was completed. The reaction solution was purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) to obtain the target compound P117 (35 mg, 86.5 μmol, 45.6% yield) as a yellow oil. ESI-MS: [M+H] + , 405.2.

[0807] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (br d, J = 8.1 Hz, 1H), 8.20-8.18 (m, 2H), 7.55-7.43 (m, 3H), 7.09-7.03 (m, 1H), 7.03-6.99 (m, 1H), 6.98-6.91 (m, 2H), 4.60 (br dd, J = 4.4, 8.6 Hz, 1H), 4.29-4.24 (m, 1H), 3.97 (s, 3H), 3.73 (br dd, J = 4.5, 15.0 Hz, 2H), 3.56 (br d, J = 14.8 Hz, 2H), 2.76-2.64 (m, 4H), 2.30 (s, 6H), 1.49 (d, J = 6.6 Hz, 3H)

[0808] Example 105: Compound P118.

[0809]

[0810] Compound P116 (40 mg, 79.3 μmol, 1 eq, TFA) and 37% formaldehyde aqueous solution (64.3 mg, 793 μmol, 59.0 μL, 10 eq) were dissolved in MeOH (0.8 mL) sequentially, and TEA (8.02 mg, 79.3 μmol, 11.0 μL, 1 eq) was added to the reaction solution until the pH of the system was ~8. Then AcOH (4.76 mg, 79.3 μmol, 4.54 μL, 1 eq) was added to the reaction solution, and the pH of the system was ~6. After the reaction mixture was reacted at 25 °C for 1 h, NaBH3CN (9.96 mg, 159 μmol, 2 eq) was added to the above reaction solution, and the reaction mixture was continuously reacted at 25 °C for 3 h, and LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-30% B in 8.0 min) to obtain the target compound P118 (13.2 g, 32.4 μmol, 40.8% yield, 99.2% purity) as a brown solid. ESI-MS: [M+H] + , 405.2.

[0811] 1 H NMR (400 MHz, DMSO-d6) d = 8.43 (br d, J = 7.8 Hz, 1H), 8.19 (br d, J = 7.2 Hz, 2H), 7.54-7.39 (m, 3H), 7.10-7.04 (m, 1H), 7.03-6.98 (m, 1H), 6.95 (br d, J = 7.7 Hz, 2H), 4.61 (br dd, J = 4.6, 8.5 Hz, 1H), 4.29-4.22 (m, 1H), 3.97 (s, 3H), 3.75-3.71 (m, 1H), 3.58 (br s, 1H), 2.77-2.63 (m, 4H), 2.58-2.52 (m, 1H), 2.47-2.43 (m, 1H), 2.31 (s, 6H), 1.49 (d, J = 6.5 Hz, 3H)

[0812] Examples 106-107: Compound P119 and Compound P120.

[0813]

[0814] Compound P118 (11 mg, 27.2 μmol, 1 eq) was purified by SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um); mobile phase: [CO2-MeOH (0.1% NH3-H2O)]; B%: 55%, isocratic elution mode) to give the target compounds P119 (1.6 mg, 3.91 μmol, 14.4% yield, 98.9% purity) and P120 (2.2 mg, 5.36 μmol, 19.7% yield, 98.6% purity) as white solids. ESI-MS: [M+H] + , 405.2.

[0815] P119: 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 (br d, J = 7.8 Hz, 1H), 8.29-

[0816] 8.14 (m, 1H), 7.57 - 7.39 (m, 3H), 7.08 - 7.01 (m, 1H), 7.01 - 6.90 (m, 3H), 4.79 (d, J = 3.6 Hz, 1H), 4.52 (td, J = 3.9, 7.5 Hz, 1H), 4.25 (br d, J = 6.4 Hz, 1H), 3.97 (s, 3H), 3.75 (br d, J = 15.5 Hz, 1H), 3.55 (br d, J = 14.9 Hz, 1H), 2.78 - 2.69 (m, 2H), 2.69 - 2.60 (m, 2H), 2.39 - 2.32 (m, 1H), 2.24 (dd, J = 4.8, 12.4 Hz, 1H), 2.16 (s, 6H), 1.49 (br d, J = 6.5 Hz, 3H)

[0817] P120: 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 (br d, J = 7.8 Hz, 1H), 8.29-

[0818] 8.09(m,1H),7.55-7.39(m,3H),7.07-7.02(m,1H),7.01-6.97(m,1H),6.96-6.89(m,2H),4.79(br s,1H),4.52(br dd,J=5.1,7.4Hz,1H),4.34-4.19(m,1H),3.97(s,3H),3.74(br d,J=15.0Hz,1H),3.56(br d,J=15.1Hz,1H),2.76-2.69(m,2H),2.69-2.59(m,2H),2.39-2.32(m,1H),2.29-2.22(m,1H),2.16(s,6H),1.49(d,J=6.5Hz,3H)

[0819] Examples 108-109: Compounds P121 and P122.

[0820]

[0821] Compound P117 (14.4 mg, 35.6 μmol, 1 eq) was resolved by SFC (column: DAICL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 55%, isocrine mode) to give target compounds P121 (4 mg, 9.89 μmol, 27.7% yield) and P122 (3.5 mg, 8.65 μmol, 24.3% yield) as white solids. ESI-MS: [M+H] + ,405.2.

[0822] P121: 1 H NMR (400MHz, DMSO-d6) δ8.44 (br d, J=8.0Hz, 1H), 8.19 (d, J=

[0823] 7.6 Hz, 1 H), 7.54-7.45 (m, 3 H), 7.07-7.03 (m, 1 H), 7.01-6.91 (m, 3 H), 4.80 (br d, J = 3.3 Hz, 1 H), 4.53 (br s, 1 H), 4.31-4.21 (m, 1 H), 3.98 (s, 3 H), 3.75 (d, J = 15.0 Hz, 1 H), 3.56 (d, J = 14.9 Hz, 1 H), 2.78-2.64 (m, 4 H), 2.39-2.34 (m, 1 H), 2.26 (dd, J = 4.8, 12.3 Hz, 1 H), 2.17 (s, 6 H), 1.50 (d, J = 6.6 Hz, 3 H)

[0824] P122: 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (br d, J = 8.0 Hz, 1 H), 8.19 (d, J = 2.2 Hz, 1 H), 7.56-7.44 (m, 3 H), 7.06-7.02 (m, 1 H), 7.02-6.91 (m, 3 H), 4.82 (br s, 1 H), 4.53 (br s, 1 H), 4.26 (br d, J = 6.5 Hz, 1 H), 3.98 (s, 3 H), 3.76 (br d, J = 15.0 Hz, 1 H), 3.56 (br d, J = 15.0 Hz, 1 H), 2.78-2.63 (m, 4 H), 2.38 (dd, J = 8.3, 12.4 Hz, 1 H), 2.27 (dd, J = 4.7, 12.3 Hz, 1 H), 2.18 (s, 6 H), 1.50 (d, J = 6.6 Hz, 3 H)

[0825] 8.2 Hz, 1 H), 7.56-7.44 (m, 3 H), 7.06-7.02 (m, 1 H), 7.02-6.91 (m, 3 H), 4.82 (br s, 1 H), 4.53 (br s, 1 H), 4.26 (br d, J = 6.5 Hz, 1 H), 3.98 (s, 3 H), 3.76 (br d, J = 15.0 Hz, 1 H), 3.56 (br d, J = 15.0 Hz, 1 H), 2.78-2.63 (m, 4 H), 2.38 (dd, J = 8.3, 12.4 Hz, 1 H), 2.27 (dd, J = 4.7, 12.3 Hz, 1 H), 2.18 (s, 6 H), 1.50 (d, J = 6.6 Hz, 3 H)

[0826] Example 110: Compound P123.

[0827] 1) Intermediate P123I1 synthesis procedure

[0828]

[0829] P123S1 (25 g, 80.1 mmol, 1 eq) was dissolved in THF (500 mL) and fed into the flow reactor at a flow rate of 54.8 mL / min, while n-BuLi (80.1 mL, 200 mmol, 2.5 eq) was fed into the flow reactor from a second tube at a flow rate of 13.1 mL / min. DMF (17.6 g, 240 mmol, 3 eq) was dissolved in THF (250 mL) and fed into the flow reactor at a flow rate of 28.0 mL / min, combined with the previous two reagents. The reaction mixture was kept at -20 °C for 4 seconds before being fed into an aqueous NH4Cl solution (300 ml) to quench the reaction. Then the reaction mixture was extracted with EtOAc (200 mL*3), the organic phase was combined and concentrated under reduced pressure, then purified by silica gel column (SiO2, Petroleum ether / EtOAc = 50 / 1 to 5 / 1) to give compound P123I1 (7 g, 9.38 mmol, 23.8% yield, 85% purity) as a yellow oil. ESI-MS: [M+H] + , 247.1.

[0830] 2) Synthesis procedure of intermediate P123I2

[0831]

[0832] Compound P123I2 (4.42 g, 20.1 mmol, 1 eq) was dissolved in DMSO (105 mL), NaH (1.07 g, 26.8 mmol, 60% purity, 2 eq) was added portionwise at 25 °C under nitrogen atmosphere. The reaction mixture was kept at 25 °C for 1 h, then compound P123S2 (3.5 g, 13.4 mmol, 1 eq) was dissolved in DMSO (7 mL) and added dropwise into the above reaction mixture, the mixture was kept at room temperature for 2 h, LCMS showed the reaction was completed. The reaction mixture was poured into an aqueous NH4Cl solution (300 mL), extracted with EtOAc (200 mL*3), the organic phase was combined and washed with brine (200 mL). The washed organic phase was concentrated under reduced pressure, purified by silica gel column (SiO2, Petroleum ether / EtOAc = 10 / 1 to 1 / 1) to give compound P123I2 (1.35 g, 4.74 mmol, 35.4% yield, 96.6% purity) as a yellow solid. ESI-MS: [M+H] + , 261.3.

[0833] 3) Synthesis procedure of intermediates P123I3 and P123I4

[0834]

[0835] Compound P123I2 (1.25 g, 4.54 mmol, 1 eq) was dissolved in EtOH (37.5 mL), and cyclobutylamine (2.59 g, 45.4 mmol, 3.06 mL 10 eq) was added at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, and LCMS detection showed that the reaction was complete. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 to 0 / 1) to give the target compound P123I3 (0.8 g, 2.30 mmol, 50.7% yield, 95.6% purity) and compound P123I4 (0.7 g, 1.98 mmol, 43.6% yield, 94% purity) as colorless oil. ESI-MS: [M+H] + , 333.2.

[0836] 4) Synthesis procedure of intermediate P123I5

[0837]

[0838] Compound P123I3 (0.2 g, 602 µmol 1 eq) was dissolved in DCM (1.6 mL), and TFA (0.4 mL) was added at 20 °C. The reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was complete. The reaction mixture was rotary evaporated under reduced pressure, and EtOH (2 mL) was added to the concentrate. The pH of the system was adjusted to 7 with basic resin. Then the filtrate was collected by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure to give the target compound P123I5 (0.14 g, 475 µmol, 78.9% yield, 78.8% purity) as yellow oil. ESI-MS: [M+H] + , 233.1

[0839] 5) Synthesis procedure of compound P123

[0840]

[0841] Compound P123I5 (140 mg, 603 µmol 1 eq) and compound P123S3 (121 mg, 603 µmol, 1 eq) were dissolved in EtOH (2.8 mL), to the mixture was added Ti(i-PrO)4 (1.4 mL) at 25 °C. After the reaction mixture was stirred at 50 °C for 8 h, NaBH3CN (75.7 mg, 1.21 mmol, 2 eq) was added to the above reaction solution, the reaction mixture was continued to react at 50 °C for 16 h, LCMS detection reaction was completed. To the reaction mixture was added a mixture of H2O (10 mL) and EtOAc (5 mL), a yellow insoluble substance was generated, the suspension was filtered, the filtrate was extracted with EtOAc (5 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The washed organic phase was concentrated under reduced pressure, purified by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 8.0 min) to give the target compound P123 (21 mg, 49.6 µmol, 8.22% yield, 98.3% purity) as a yellow solid. ESI-MS: [M+H] + ,417.2.

[0842] 1 H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.30-8.24 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.50-7.40 (m, 2H), 7.13 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.34 (t, J = 4.6 Hz, 0.4H), 4.65 (d, J = 6.3 Hz, 0.6H), 4.59 (s, 1H), 4.32 (d, J = 5.8 Hz, 1H), 4.01 (s, 3H), 3.87 (d, J = 15.0 Hz, 1H), 3.74 (d, J = 4.2 Hz, 3H), 3.61 (d, J = 15.1 Hz, 1H), 3.00 (d, J = 6.1 Hz, 1H), 2.88-2.76 (m, 4H), 2.34-2.23 (m, 2H), 2.22-2.15 (m, 1H), 1.58 (d, J = 6.6 Hz, 3H).

[0843] Example 111: Compound P124.

[0844]

[0845] Compound P84I1 (500 mg, 1.26 mmol, 1 eq) was dissolved in THF (10 mL), n-BuLi (2.5 M, 504 μL, 1 eq) was added under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 1 hour, compound P124S1 (215 mg, 1.26 mmol, 1 eq) was added to the above reaction solution, the reaction mixture was reacted at -70 °C for 1 hour, LCMS detection reaction was completed. The reaction solution was poured into aqueous ammonium chloride solution (10 mL), extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) and high performance liquid chromatography (column: Phenomenex Genimi NX C18 150*40mm*5um; mobile phase: [H2O (10mM NH4HCO3) - ACN]; gradient: 50% - 80% B in 8.0 min) to give the target compound P124 (424 mg, 867 μmol, 68.7% yield) as a white solid. ESI-MS: [M+H] + , 489.3.

[0846] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (br d, J = 8.0 Hz, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.54 - 7.44 (m, 3H), 7.19 (dd, J = 1.6, 7.8 Hz, 1H), 7.09 (d, J = 1.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 4.26 (br d, J = 6.4 Hz, 1H), 3.97 (s, 7H), 3.78 (br d, J = 15.1 Hz, 1H), 3.59 (br d, J = 15.1 Hz, 1H), 2.80 - 2.71 (m, 2H), 2.71 - 2.64 (m, 2H), 1.49 (d, J = 6.6 Hz, 3H), 1.38 (s, 9H)

[0847] Example 112: Compound P125.

[0848]

[0849] Compound P124 (70 mg, 143 pmol, 1 eq) was dissolved in DCM (1.2 mL), TFA (0.3 mL) was added at 20 °C, the reaction mixture was reacted at 25 °C for 1 h. LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution was adjusted to pH = 8-9 with NH3H2O, and the target compound P125 (32.2 mg, 82.8 pmol, 57.8% yield) was obtained by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-35% B in 8.0 min) as a white solid. ESI-MS: [M+H] + , 389.2.

[0850] 1 H NMR (400 MHz, DMSO-d6) d 8.44 (br d, J = 8.0 Hz, 1H), 8.19 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 7.54 - 7.43 (m, 3H), 7.24 (br d, J = 7.9 Hz, 1H), 7.18 - 7.09 (m, 2H), 6.95 (d, J = 8.1 Hz, 1H), 6.50 (br s, 1H), 4.29 (br d, J = 6.3 Hz, 1H), 4.24 (br d, J = 11.4 Hz, 2H), 4.02 - 3.94 (m, 5H), 3.73 - 3.66 (m, 1H), 3.63 - 3.57 (m, 1H), 2.78 (br d, J = 7.3 Hz, 4H), 1.51 (d, J = 6.5 Hz, 3H)

[0851] Example 113: Compound P126.

[0852] 1) Intermediate P126I1 synthesis procedure

[0853]

[0854] Compound P124 (80 mg, 164 μmol, 1 eq) was dissolved in THF (16 mL), NaH (9.82 mg, 246 μmol, 60% purity, 1.5 eq) was added at 0 °C under nitrogen atmosphere. The mixture was reacted at 0 °C for 1 h, then CH3I (34.9 mg, 246 μmol, 15.3 μL, 1.5 eq) was added dropwise into the above reaction solution, the reaction mixture was continued to react at 20 °C for 3 h, LCMS detection reaction was completed. The reaction solution was added to saturated aqueous ammonium chloride solution (5 mL), extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure to obtain the target compound P126I1 (80 mg, crude) as a yellow solid. ESI-MS: [M+H] + ,501.2.

[0855] 2) Synthesis procedure of compound P126

[0856]

[0857] Compound P126I1 (100 mg, crude) was dissolved in DCM (1.6 mL), TFA (0.4 mL) was added at 20 °C, the reaction mixture was reacted at 25 °C for 1 h. LCMS detection reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3·H2O, the target compound P126 (32.2 mg, 59.1 μmol, 29.7% yield, 94.8% purity, TFA) was obtained by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-40% B in 10.0 min) as a light yellow solid. ESI-MS: [M+H] + ,403.2.

[0858] 1H NMR (400 MHz, DMSO-d6) d = 8.43 (br d, J = 8.7 Hz, 1H), 8.25 - 8.12 (m, 2H), 7.54 - 7.41 (m, 3H), 7.18 - 7.09 (m, 2H), 7.06 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.29 (br d, J = 6.4 Hz, 1H), 4.08 - 4.02 (m, 2H), 4.01 - 3.94 (m, 5H), 3.75 (br d, J = 14.9 Hz, 1H), 3.61 (br d, J = 15.3 Hz, 1H), 2.91 (s, 3H), 2.83 - 2.68 (m, 4H), 1.50 (d, J = 6.7 Hz, 3H)

[0859] Example 114: Compound P127.

[0860] 1) Synthesis operation steps of intermediate P127I1

[0861]

[0862] Compound P124 (80 mg, 164 pmol, 1 eq) was dissolved in dichloromethane (4 mL), and DAST (79.2 mg, 491 pmol, 64.9 pL, 3 eq) was added dropwise to the above reaction solution at -70 °C. The reaction mixture was reacted at -70 °C for 3 hours under nitrogen protection. LCMS detection showed that the reaction was completed. The reaction solution was poured into ice water (10 mL), extracted with DCM (5 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 1 / 1) to obtain the target compound P127I1 (45 mg, 91.7 pmol, 56.0% yield) as a white solid. ESI-MS: [M+H] + , 491.3.

[0863] 2) Synthesis operation steps of compound P127

[0864]

[0865] Compound P127I1 (57 mg, 116 pmol, 1 eq) was dissolved in DCM (0.8 mL), TFA (0.2 mL) was added at 20 °C, the reaction mixture was reacted at 25 °C for 1 h. LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3H2O, and the target compound P127 (18 mg, 32.4 pmol, 27.9% yield, 90.9% purity, TFA) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-50% B in 10.0 min). ESI-MS: [M+H] + , 391.2.

[0866] 1 H NMR (400 MHz, DMSO-d6) d = 8.43 (br d, J = 7.7 Hz, 1H), 8.23-8.14 (m, 2H), 7.57-7.38 (m, 3H), 7.27-7.22 (m, 1H), 7.20-7.12 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 4.33-4.25 (m, 1H), 4.14-4.01 (m, 4H), 3.97 (s, 3H), 3.77 (br d, J = 15.4 Hz, H), 3.62 (br d, J = 15.2 Hz, 1H), 2.84-2.68 (m, 4H), 1.50 (d, J = 6.7 Hz, 3H)

[0867] Example 115: Compound P128.

[0868]

[0869] Compound P128 (25 mg, 61.7 μmol, 40.0% yield, 99.4% purity) was obtained as a white solid. ESI-MS: [M+H] 403.2. + ,403.2.

[0870] 1 H NMR (400 MHz, DMSO-d6) d = 8.44 (br d, J = 8.3 Hz, 1H), 8.23-8.14 (m, 2H), 7.57-7.40 (m, 3H), 7.30 (br d, J = 7.9 Hz, 1H), 7.19 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 4.27 (br d, J = 6.4 Hz, 1H), 3.97 (s, 3H), 3.79-3.71 (m, 3H), 3.58 (br d, J = 14.9 Hz, 1H), 3.45 (br d, J = 8.0 Hz, 2H), 2.82-2.60 (m, 4H), 2.46 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H)

[0871] Example 116: Compound P129.

[0872] 1) Intermediate P129I1 synthesis procedure

[0873]

[0874] A mixture of 7-cyano-l,2,3,4-tetrahydroisoquinoline (200 mg, 1.26 mmol), 4- methylacetonaphthone (232.91 mg, 1.26 mmol) and Rh2(OAc)4(27.94 mg, 0.063 mmol) was dissolved in THF (2 mL) and heated to 100 °C in a high-pressure reactor under CO atmosphere (6 MPa) for 20 h. The resulting mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 5% to 10%) to give the target compound P129I1(400 mg, yield 29.12%) as a brown solid. ESI-MS: [M+H] + , 327.1.

[0875] 2) Synthesis procedure of compound P129

[0876]

[0877] To a solution of compound P129I1(150 mg, 0.46 mmol) in THF (1 mL) was slowly added LiAlH4(1.4 mL, 1 mol / L) at 0 °C under N2protection. The mixture was heated at 50 °C for 1 h. The resulting mixture was then diluted with water (10 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on Biotage Isolera One (C18 column, eluted with 10% to 90% MeCN / H2O containing 0.1% formic acid) to give the target compound P129 (11.45 mg, yield 7.53%) as a white solid. ESI-MS: [M+H] + , 331.2.

[0878] 1 H NMR (400 MHz, DMSO) d 8.48 (d, J = 8.0 Hz, 1H), 8.33 (s, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.57 - 7.49 (m, 3H), 7.37 (d, J = 7.2 Hz, 1H), 7.15 (m, 2H), 7.02 (s, 1H), 4.35 (d, J = 6.4 Hz, 1H), 3.89 (s, 2H), 3.70 (d, J = 15.2 Hz, 1H), 3.58 (d, J = 14.8 Hz, 1H), 2.83 - 2.70 (m, 4H), 2.64 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H).

[0879] Example 117: Compound P130.

[0880] 1) Synthesis operation steps of intermediate P130I1

[0881]

[0882] To a solution of 5-bromo-8-methylquinoline (1 g, 4.5 mmol) and tributyl(1- ethoxyvinyl)stannane (1.9 g, 5.3 mmol) in 1,4-dioxane (10 mL) was added Pd(PPh3)4 (520 mg, 4.0 mmol) in one portion. The reaction mixture was stirred at 80 °C for 5 h. The resulting mixture was extracted with EtOAc (20 mL X 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with PE / EtOAc, 0% to 10%). The target compound P130I1 (800 mg, 3.6 mmol) was obtained as a yellow solid. ESI-MS: [M+H] + , 214.1.

[0883] 2) Synthesis operation steps of intermediate P130I2

[0884]

[0885] To a solution of compound P130I1 (800 mg, 3.6 mmol) in THF (8 mL) was added 2N HCl (3.8 mL) dropwise. The reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was concentrated and the pH was adjusted to 7-8 with NaHCO3. The residue was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluted with DCM / MeOH, 0% to 10%). The target compound P130I2 (500 mg, 2.7 mmol) was obtained as a yellow solid. ESI-MS: [M+H] + , 186.2

[0886] 3) Synthesis operation steps of intermediate P130I3

[0887]

[0888] To a solution of compound P130I2 (316 mg, 1.7 mmol) and 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (300 mg, 1.9 mmol) in THF (2 mL) was added Rh2(OAc)4 (42 mg, 0.095 mmol) in one portion. The reaction mixture was stirred at 100 °C under CO atmosphere (6 MPa) for 12 h. The residue was extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc, 0% to 30%) to give the target compound P130I3 (45 mg, 0.14 mmol) as a yellow solid. ESI-MS: [M+H] + , 328.5

[0889] 4) Synthesis procedure of compound P130

[0890]

[0891] To a solution of compound P130I3 (45 mg, 0.14 mmol) in THF (1 mL) was added LiAlH4 (10 mg, 0.24 mmol) dropwise at 0 °C. The reaction mixture was stirred at 50 °C for 0.5 h. The resulting mixture was quenched with 1 N HCI and concentrated. The residue was purified by preparative HPLC (Gemini 5um C18 column, 150*21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% TFA) to give the target compound P130 (10 mg, 0.30 mmol) as a yellow solid. ESI-MS: [M+H] + , 331.2

[0892] 1 H NMR (400 MHz, DMSO) δ 10.62 (s, 0.9H), 9.03 (s, 1H), 8.81 (d, J = 38.7 Hz, 1H), 8.23 (d, J = 49.7 Hz, 3H), 7.96 (d, J = 5.9 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.70 (s, 1H), 7.37 - 6.95 (m, 3H), 5.57 (d, J = 28.1 Hz, 1H), 4.01 (t, J = 48.6 Hz, 4H), 3.61 - 2.89 (m, 4H), 2.78 (s, 3H), 1.86 (d, J = 5.9 Hz, 3H).

[0893] Example 118: Compound P131.

[0894] 1) Synthesis procedure of intermediate P131I1

[0895]

[0896] A mixture of compound P87I4 (200 mg, 0.56 mmol), compound P130I2 (97.90 mg, 0.53 mmol) and Rh2(OAc)4 (12.30 mg, 0.028 mmol) was placed in THF (2 mL) and heated to 100 °C under CO (6 MPa) in a high-pressure reactor for 20 h. The resulting mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 15% to 20%) to give the target compound P131I1 (100 mg, 17.00% yield) as a red solid. ESI-MS: [M+H] + ,529.3

[0897] 2) Synthesis procedure of compound P131

[0898]

[0899] A solution of compound P131I1 (60 mg, 0.1135 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.5 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Biotage Isolera One (C18 column, eluted with 10% to 90% MeCN / H2O containing 0.1% TFA) to give the target compound P131 (41.65 mg, 85.64% yield) as a white solid. ESI-MS: [M+H] + ,349.2

[0900] 1 H NMR (400 MHz, MeOD) δ 9.00 (d, J = 3.6 Hz, 1H), 8.69 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.55 (q, J = 6.4 Hz, 1H), 4.40 (s, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.56 (s, 1H), 3.49 - 3.38 (m, 1H), 3.08 (m, 4H), 2.85 (s, 3H), 2.27 (d, J = 12.0 Hz, 1H), 2.02 - 1.83 (m, 6H), 1.81 - 1.58 (m, 3H).

[0901] Example 119: Compound P132.

[0902] 1) Synthetic procedure step of intermediate P132I1

[0903]

[0904] A mixture of 5-acetyl-1,2-dihydrocymene (150 mg, 0.71 mmol) and 7-cyano-1,2,3,4-tetrahydroisoquinoline (121 mg, 0.71 mmol) and Rh2(OAc)4(17 mg, 0.040 mmol) was dissolved in THF (1 mL) and heated to 100 °C in a high-pressure reactor under a CO atmosphere (6 MPa) for 24 h. The resulting mixture was then diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 12% to 17%) to give the target compound P132I1(60 mg, 0.17 mmol) as a brown solid. ESI-MS: [M+H] + , 339.1

[0905] 2) Synthetic procedure step of compound P132

[0906]

[0907] To a solution of compound P132I1(60 mg, 0.17 mmol) in THF (2 mL) was added LiAlH4(14 mg, 0.35 mmol) dropwise at 0 °C. The reaction mixture was stirred at 50 °C for 0.5 h. The resulting mixture was quenched with 1 N HCI and concentrated. The residue was purified by preparative HPLC (Gemini 5um C18 column, 150*21.2 mm, eluted with 30% to 90% MeCN / H2O containing 0.1% HCI) to give the target compound P132(15 mg, 0.041 mmol) as a yellow solid. ESI-MS: [M+H] + , 343.2

[0908] 1H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.49 (s, 1.3H), 8.31 (s, 1H), 8.22 (dd, J = 11.9, 7.3 Hz, 1H), 8.03 (dd, J = 27.4, 8.5 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.47-7.34 (m, 3.6H), 7.25 (dd, J = 26.8, 7.8 Hz, 1H), 6.98 (s, 0.5H), 5.48 - 5.39 (m, 0.5H), 5.35 (s, 0.5H), 4.84 (d, J = 13.7 Hz, 0.6H), 4.57-4.55 (m, 0.6H), 4.21 - 4.04 (m, 1H), 4.02 - 3.76 (m, 4.7H), 3.60 - 3.46 (m, 1H), 3.29 (d, J = 6.7 Hz, 1H), 3.13 (d, J = 10.9 Hz, 1.5H), 2.82 (d, J = 15.0 Hz, 0.5H), 2.54 (s, 0.9H), 1.91 - 1.89 (m, 3H).

[0909] Example 120: Compound P133.

[0910] 1) Synthesis procedure step of intermediate P133I1

[0911]

[0912] A mixture of 5-acetyl-1,2-dihydrocumen (150.00 mg, 0.76 mmol), compound P87I4 (274.77 mg, 0.76 mmol) and Rh2(OAc)4 (16.89 mg, 0.0382 mmol) was placed in THF (2 mL) and heated to 100 °C under CO atmosphere (6 MPa) in a high-pressure reactor for 72 h. The resulting mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with EtOAc / PE, 12% to 17%) to give the target compound P133I1 (72 mg, yield 17.43%) as a brown solid. ESI-MS: [M+H] + ,538.3

[0913] 2) Synthesis procedure step of compound P133

[0914]

[0915] Compound P133I1 (72 mg, 0.13 mmol) was dissolved in 1,4-dioxane (0.5 mL), HCl dioxane solution (4 M, 0.3 mL) was added, stirred at room temperature for 2 hours, concentrated under reduced pressure. The residue was purified on Biotage Isolera One (C18 column, eluted with 10% to 90% MeCN / H2O containing 0.1% NH4OH) to give the target compound P133 (17.25 mg, yield 29.39%) as a white solid. ESI-MS: [M+H] + ,440.2

[0916] 1 H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.33 (s, 1H), 7.30 - 7.25 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 4.19 (q, J = 6.4 Hz, 1H), 3.75 (d, J = 14.8 Hz, 1H), 3.49 (d, J = 15.6 Hz, 1H), 3.35 (s, 2H), 3.17 (d, J = 7.2 Hz, 1H), 2.93 (d, J = 13.2 Hz, 1H), 2.61 (m, 6H), 1.75 (d, J = 9.2 Hz, 2H), 1.49 (d, J = 6.4 Hz, 3H), 1.35 (m, 5H).

[0917] Example 121: Compound P134.

[0918] 1) Synthesis procedure of intermediate P134I1

[0919]

[0920] Compound P99I1 (270 mg, 688 μmol, 1 eq) was dissolved in THF (5.4 mL), n-BuLi (2.5 M, 550 μL, 2 eq) was added under nitrogen protection at -70 °C, after 1 hour of reaction at -70 °C, compound P134S1 (219 mg, 1.38 mmol, 2 eq) was added to the above reaction solution, the reaction mixture was continued to react at -70 °C for 1 hour. LCMS detection showed that the reaction was completed. The reaction solution was poured into ice water (10 mL), extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P134I1 (110 mg, 162 μmol, 23.6% yield, 70% purity) as a yellow oil. ESI-MS: [M+H] + , 473.3.

[0921] 2) Synthesis procedure of compound P134

[0922]

[0923] Compound P134I1 (110 mg, 162 μmol, 1 eq) was dissolved in DCM (2 mL), TFA (0.4 mL) was added at 25 °C, the reaction mixture was reacted at 25 °C for 1 hour. LCMS detection showed that the reaction was completed. The reaction mixture was reacted at 25 °C for 1 hour, LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 7-8 with NH3·H2O, the reaction solution was concentrated under reduced pressure, and the target compound P134 (10.5 mg, 25.1 μmol, 15.4% yield, FA) was obtained by high performance liquid chromatography (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-40% B in 8.0 min) as a white solid. ESI-MS: [M+H] + , 373.2.

[0924] 1H NMR (400 MHz, Methanol-d4) d 8.38 (br s, 1H), 7.94 (dd, J = 2.3, 8.5 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 6.7 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 4.81 - 4.76 (m, 1H), 4.62 - 4.54 (m, 1H), 4.04 (s, 1H), 3.81 (br s, 1H), 3.44 - 3.39 (m, 4H), 3.10 - 2.87 (m, 6H), 1.69 (d, J = 6.6 Hz, 3H)

[0925] Example 122: Compound P135.

[0926] 1) Synthesis procedure of intermediate P135I1

[0927]

[0928] Compound P135S1 (3.7 g, 21.2 mmol, 1 eq) was dissolved in CH3CN (74 mL), NBS (3.78 g, 21.2 mmol, 1 eq) was added to the mixture at 0 °C, the reaction mixture was reacted at 25 °C for 16 hours, LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure, then purified by column separation (SiO2, petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give the target compound P135I1 (5.2 g, 17.6 mmol, 83.2% yield, 86% purity) as a yellow solid. ESI-MS: [M+H] + , 253.1 & 255.1.

[0929] 2) Synthesis procedure of intermediate P135I2

[0930]

[0931] Compound P135I1 (5.2 g, 20.5 mmol, 1 eq) and compound P135S2 (10.9 g, 30.4 mmol, 10.2 mL, 1.48 eq) were dissolved in dioxane (78 mL), Pd(PPh3)2Cl2 (721 mg, 1.03 mmol, 0.05 eq) was added to the mixture at 25 °C, the reaction mixture was reacted at 100 °C for 16 hours under nitrogen protection, and LCMS detection showed that the reaction was completed. The reaction mixture was cooled to room temperature, HCI (30 mL, 2M) was added to the mixture, and the reaction mixture was stirred at 25 °C for 1 hour. Then the reaction solution was added to saturated potassium fluoride aqueous solution (100 mL), and green solid was generated. The suspension was filtered under normal pressure, and the filtrate was extracted with EtOAc (30 mL*3). The organic phases were combined and concentrated under reduced pressure, and purified by silica gel column (SiO2, petroleum ether / EtOAc = 10 / 1 to 1 / 1) to obtain the target compound P135I2 (3.3 g, 15.2 mmol, 74.2% yield) as a yellow solid. ESI-MS: [M+H] + , 217.1.

[0932] 3) Synthesis operation steps of intermediate P135I3

[0933]

[0934] Compound P135I2 (700 mg, 3.24 mmol, 1 eq) was dissolved in MeCN (14 mL), and NBS (576 mg, 3.24 mmol, 1 eq) was added at 0 °C. The reaction solution was naturally raised to room temperature, and the reaction mixture was reacted at 25 °C for 2 hours. LCMS detection showed that the reaction was completed. The reaction solution was poured into water (50 mL) and extracted with EtOAc (30 mL*3). The combined organic phases were washed with saturated sodium chloride (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound P135I3 (1.03 g, 2.78 mmol, 85.8% yield, 79.6% purity) as a green solid. ESI-MS: [M+H] + , 295 & 257.

[0935] 4) Synthesis operation steps of intermediate P135I4

[0936]

[0937] Compound P135I3 (850 mg, 2.88 mmol, 1 eq) and TEA (582 mg, 5.76 mmol, 801 μL, 2 eq) were dissolved in DCM (17 mL), Tf20 (975 mg, 3.46 mmol, 570 μL, 1.2 eq) was added to the mixture at -70 °C, the reaction was allowed to naturally rise to 25 °C, the reaction mixture was stirred at 25 °C for 2 h, LCMS detection showed that the reaction was completed. The reaction was poured into water (20 mL), extracted with EtOAc (7 mL*3), the organic phase was combined and washed with saturated sodium chloride (30 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound P135I4 (1.17 g, 2.19 mmol, 76.1% yield, 80% purity) as a yellow oil.

[0938] 5) Synthesis procedure of intermediate P135I5

[0939]

[0940] Compound P135I4 (1.17 g, 2.74 mmol, 1 eq) and compound P135S3 (3.5 M, 1.57 mL, 2 eq) were dissolved in dioxane (23.4 mL) and H20 (7 mL), K2C03(1.14 g, 8.22 mmol, 3 eq) and Pd(dppf)Cl2(200 mg, 274 μmol, 0.1 eq) were added to the mixture at 20 °C, the reaction mixture was reacted at 80 °C for 16 h, LCMS detection showed that the reaction was completed. The reaction was concentrated under reduced pressure, H20 (50 mL) was added, extracted with EtOAc (30 mL*3), the organic phase was combined and washed with saturated sodium chloride (100 mL). The combined organic phase was concentrated under reduced pressure, purified by silica gel plate (Si02, petroleum ether / EtOAc = 5 / 1) to obtain the target compound P135I5 (314 mg, 1.38 mmol, 50.2% yield) as a yellow oil. ESI-MS: [M+H] + , 229.2.

[0941] 6) Synthesis procedure of intermediate P135I6

[0942]

[0943] Compound P135I5 (100 mg, 438 pmol, 1 eq) and compound common intermediate CI (114 mg, 438 pmol, 1 eq) were dissolved in EtOH (2 mL), and Ti(i-PrO)4 (1 mL) was added at 20 °C. After the reaction mixture was stirred at 50 °C for 5 h, NaBH3CN (55.1 mg, 876 pmol, 2 eq) was added to the above reaction solution, and the reaction mixture was continuously reacted at 50 °C for 16 h. LCMS detection showed that the reaction was completed. A mixture of H2O (5 mL) and EtOAc (2 mL) was added to the reaction solution, and yellow insoluble matter was generated. The suspension was filtered, and the filtrate was extracted with EtOAc (3 mL*3). The organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, and the target compound P135I6 (140 mg, 294 pmol, 67.3% yield) was obtained as a white solid by silica gel plate purification (SiO2, petroleum ether / EtOAc = 2 / 1). ESI-MS: [M+H] + , 475.3.

[0944] 7) Synthesis procedure of compound P135

[0945]

[0946] Compound P135I6 (140 mg, 294 pmol, 1 eq) was dissolved in DCM (2.24 mL), and TFA (0.56 mL) was added at 20 °C. The reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, CH3CN (2 mL) was added, and the solution pH was adjusted to 8-9 with NH3-H2O. The target compound P135 (94.7 mg, 193 pmol, 65.7% yield, TFA) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-45% B in 8.0 min). ESI-MS: [M+H] + , 375.2.

[0947] 1H NMR (400 MHz, Methanol-d4) d 8.27 - 8.16 (m, 1H), 7.41 (d, J = 11.0 Hz, 2H), 7.30 - 7.21 (m, 2H), 7.12 (dd, J = 2.5, 9.4 Hz, 1H), 7.08 (s, 1H), 4.83 - 4.75 (m, 1H), 4.17 (br d, J = 15.3 Hz, 1H), 4.02 (s, 2H), 3.98 (br s, 1H), 3.94 (s, 3H), 3.25 - 3.10 (m, 2H), 3.08 - 2.94 (m, 2H), 2.59 (s, 3H), 2.51 (s, 3H), 1.74 (d, J = 6.6 Hz, 3H)

[0948] Example 123: Compound P136.

[0949] 1) Synthesis procedure of intermediate P136I1

[0950]

[0951] Compound P136S1 (0.3 g, 1.40 mmol, 1 eq) was dissolved in CH3CN (6 mL), NBS (249 mg, 1.40 mmol, 1 eq) was added into the reaction solution at 0 °C. The reaction mixture was reacted at 25 °C for 4 h, LCMS detection showed the reaction was completed. The reaction solution was concentrated under reduced pressure, purified by silica gel plate (SiO2, Petroleum ether / EtOAc = 5 / 1) to give the target compound P136I1 (0.24 g, 819 pmol, 58.5% yield) as a yellow solid. ESI-MS: [M+H] + , 293.0 & 295.0.

[0952] 2) Synthesis procedure of intermediate P136I2

[0953]

[0954] Compound P136I1 (85 mg, 290 μmol, 1 eq), compound common intermediate CI (91.3 mg, 348 μmol, 1.2 eq) and Ti(i-PrO)4 (0.85 mL) were dissolved in EtOH (1.7 mL) successively, the reaction mixture was reacted at 50 °C for 5 h, NaBH3CN (36.4 mg, 580 μmol, 2 eq) was added to the above reaction solution at 25 °C, the reaction mixture was reacted at 50 °C for 16 h, LCMS detection showed that the reaction was completed. A mixture of H2O (5 mL) and EtOAc (2 mL) was added to the reaction solution, and yellow insoluble matter was generated. The suspension was filtered, and the filtrate was extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to obtain the target compound P136I2 (80 mg, 148 μmol, 51.1% yield) as a yellow oil. ESI-MS: [M+H] + , 539.2 & 541.2.

[0955] 3) Synthesis procedure of compound P136

[0956]

[0957] Compound P136I3 (80 mg, 148 μmol, 1 eq) was dissolved in DCM (1.6 mL), TFA (0.4 mL) was added at 20 °C, and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, and the solution pH was adjusted to 8-9 with NH3 H2O. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, and the solution pH was adjusted to 7-8 with NH3 H2O. Purification by high performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-45% B in 10.0 min) to obtain the target compound GDI19-211 (33 mg, 59.6 μmol, 40.2% yield, 100% purity, TFA) as a yellow solid. ESI-MS: [M+H] + , 439.1 & 441.1.

[0958] 1H NMR (400 MHz, DMSO-d6) d = 8.64 (br d, J = 9.0 Hz, 1H), 8.12 - 7.85 (m, 2H), 7.44 (d, J = 9.5 Hz, 1H), 7.38 (s, 2H), 7.21 - 7.09 (m, 2H), 7.02 (s, 1H), 4.31 (br d, J = 2.1 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 2H), 3.65 - 3.52 (m, 2H), 3.03 (s, 3H), 2.85 - 2.66 (m, 4H), 1.49 (d, J = 6.5 Hz, 3H)

[0959] Example 124: Compound P137.

[0960] 1) Synthesis procedure of intermediate P137I1

[0961]

[0962] Compound P136I1 (110 mg, 375 pmol, 1 eq), trimethyl cyclo-trioxonium (3.5 M, 129 pL, 1.2 eq) were sequentially dissolved in dioxane (2.2 mL) and H20 (0.66 mL), K2CO3 (156 mg, 1.13 mmol, 3 eq) and Pd(dppf)Cl2 (27.5 mg, 37.5 pmol, 0.1 eq) were added to the above reaction solution, the reaction mixture was reacted at 80 °C for 16 h under nitrogen protection, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, and purified by silica gel plate (SiO2, EtOAc / methanol = 5 / 1) to obtain the target compound P137I1 (90 mg, 347 pmol, 92.5% yield, 88% purity) as a yellow oil. ESI-MS: [M+H] + , 229.2.

[0963] 2) Synthesis procedure of intermediate P137I1

[0964]

[0965] Compound P137I1 (90 mg, 394 μmol, 1 eq), compound common intermediate C1 (114 mg, 434 μmol, 1.1 eq) and Ti(i-PrO)4 (0.9 mL) were dissolved in EtOH (1.8 mL) sequentially, the reaction mixture was reacted at 50 °C for 5 h, NaBH3CN (49.6 mg, 788 μmol, 2 eq) was added to the above reaction solution at 25 °C, the reaction mixture was reacted at 50 °C for 16 h, LCMS detection showed that the reaction was completed. A mixture of H2O (5 mL) and EtOAc (2 mL) was added to the reaction solution, and yellow insoluble matter was generated. The suspension was filtered, and the filtrate was extracted with EtOAc (2 mL*3), and the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to obtain the target compound P137I2 (80 mg, 169 μmol, 42.8% yield) as a yellow oil. ESI-MS: [M+H] + , 475.3.

[0966] 3) Synthesis procedure of compound P137

[0967]

[0968] Compound P137I2 (80 mg, 169 μmol, 1 eq) was dissolved in DCM (1.6 mL), TFA (0.4 mL) was added at 20 °C, and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, and the solution pH was adjusted to 8-9 with NH3·H2O. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, and the solution pH was adjusted to 7-8 with NH3·H2O. Purification by high performance liquid chromatography (column: Phenomenex Luna C18 100*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-35% B in 8.0 min) to obtain the target compound P137 (46.5 mg, 94.3 μmol, 56.0% yield, 99.1% purity, TFA) as a yellow solid. ESI-MS: [M+H] + , 375.2.

[0969] 1H NMR (400 MHz, DMSO-d6) d = 8.41 (br d, J = 8.3 Hz, 1H), 8.28 (br s, 1H), 7.33 (d, J = 9.5 Hz, 1H), 7.30-7.27 (m, 1H), 7.23-7.19 (m, 1H), 7.18-7.12 (m, 1H), 7.12-7.07 (m, 1H), 7.02 (s, 1H), 4.25 (br d, J = 5.5 Hz, 1H), 3.86 (s, 5H), 3.67-3.61 (m, 1H), 3.58-3.51 (m, 1H), 2.84 (s, 3H), 2.81-2.65 (m, 7H), 1.48 (d, J = 6.6 Hz, 3H)

[0970] Example 125: Compound P138.

[0971] 1) Synthesis operation steps of intermediate P138I1

[0972]

[0973] Compound 3 (0.4 g, 1.85 mmol, 1 eq) and imidazole (504 mg, 7.40 mmol, 4 eq) were dissolved in DMF (4 mL) successively, TBSCl (502 mg, 3.33 mmol, 410 μL, 1.8 eq) was added at 0 °C in batches, the reaction mixture was reacted at 25 °C for 16 hours, LCMS detection showed that the reaction was completed. Water (15 mL) was added to the reaction mixture, extracted with EtOAc (10 mL*3), the organic phase was combined, washed with saturated sodium chloride (20 mL), the washed organic phase was concentrated under reduced pressure, purified by silica gel plate (petroleum ether / EtOAc = 5 / 1) to obtain the target compound 5 (0.38 g, 1.15 mmol, 62.2% yield) as a yellow oil. ESI-MS: [M+H] + ,331.1

[0974] 2) Synthesis operation steps of intermediate P138I2

[0975]

[0976] Compound P138I1 (330 mg, 999 pmol, 1 eq), Common Intermediate CI (314 mg, 1.20 mmol, 1.2 eq) and Ti(i-PrO)4 (3.3 mL) were sequentially dissolved in EtOH (6.6 mL), the reaction mixture was stirred at 50 °C for 5 h, at 25 °C, NaBH3CN (125 mg, 2.00 mmol, 2 eq) was added to the above reaction solution, the reaction mixture was reacted at 50 °C for 16 h, LCMS detection had 15% of the remaining raw material, the product was the main peak. A mixture of H2O (20 mL) and EtOAc (10 mL) was added to the reaction solution, a yellow insoluble substance was generated, the suspension was filtered, the filtrate was extracted with EtOAc (10 mL*3), the organic phase was combined and washed with saturated sodium chloride (50 mL). The washed organic phase was concentrated under reduced pressure, and the target compound P138I2 (0.18 g, 296 pmol, 29.7% yield, 95% purity) was obtained as a yellow solid by silica gel plate purification (SiO2, petroleum ether / EtOAc = 5 / 1). ESI-MS: [M+Na] + , 599.4.

[0977] 3) Synthesis procedure of compound P138

[0978]

[0979] Compound P138I2 (80 mg, 139 pmol, 1 eq) was dissolved in DCM (2 mL), at 0 °C, 2,6-lutidine (44.6 mg, 416 pmol, 48.5 pL, 3 eq) and TMSOTf (61.7 mg, 277 pmol, 50.1 pL, 2 eq) were sequentially added. The reaction mixture was reacted at 25 °C for 16 h, LCMS detection had 7% of the remaining raw material, the product was the main peak. The reaction solution was added to an aqueous solution (5 mL), the filtrate was extracted with EtOAc (5 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, and the target compound P138 (24.8 mg, 43.5 pmol, 31.3% yield, 91.6% purity, FA) was obtained as a white solid by high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA) -ACN]; gradient: 20%-50% B in 8.0 min). ESI-MS: [M+Na] + , 499.2.

[0980] 1H NMR (400 MHz, Methanol-d4) d = 8.49 (s, 1H), 8.33 (d, J = 9.3 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.18 (s, 2H), 7.12 (dd, J = 2.8, 9.4 Hz, 1H), 7.03 (s, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.32 (q, J = 6.3 Hz, 1H), 4.00 (s, 2H), 3.92 - 3.83 (m, 4H), 3.65 (d, J = 15.0 Hz, 1H), 2.95 - 2.76 (m, 4H), 1.59 (d, J = 6.6 Hz, 3H), 1.14 (s, 9H), 0.30 (d, J = 2.9 Hz, 6H)

[0981] Example 126: Compound P139.

[0982] 1) Synthesis procedure of intermediate P139I1

[0983]

[0984] Compound P139S1 (2.5 g, 12.4 mmol, 1 eq) was dissolved in AcOH (25 mL), Br2 (4.94 g, 30.9 mmol, 1.59 mL, 2.5 eq) was dissolved in AcOH (25 mL) and added dropwise into the reaction solution at 0 °C. The reaction mixture was reacted at 20 °C for 2 hours, and LCMS detection showed that the reaction was completed. The reaction solution was poured into saturated aqueous Na2S2O4 solution (50 mL), extracted with EtOAc (10 mL*3), and the combined organic phase was washed with saturated sodium chloride (10 mL). The washed organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the target compound P139I1 (2.6 g, 9.25 mmol, 74.8% yield) as a yellow oil. ESI-MS: [M+H] + , 281.2.

[0985] 2) Synthesis procedure of intermediate P139I2

[0986]

[0987] Compound P139I1 (1 g, 3.56 mmol, 1 eq), trimethyl cyclo trioxane (3.5 M, 1.22 mL, 1.2 eq) were dissolved in dioxane (10 mL) and H2O (3 mL) successively, K2CO3 (2.46 g, 17.79 mmol, 5 eq) and Pd(dppf)Cl2 (260 mg, 356 μmol, 0.1 eq) were added to the above reaction solution at 25 °C, the reaction mixture was reacted at 100 °C for 2 hours under nitrogen protection, LCMS detection reaction was completed. H2O (10 mL) was added to the reaction solution, the filtrate was extracted with EtOAc (5 mL*3), the combined organic phase was washed with saturated sodium chloride (10 mL). The washed organic phase was concentrated under reduced pressure, purified by silica gel plate (SiO2, EtOAc / methanol = 10 / 1) to obtain the target compound P139I2 (330 mg, 1.53 mmol, 42.9% yield) as a brown solid. ESI-MS: [M+H] + , 217.2.

[0988] 3) Synthesis operation steps of intermediate P139I3

[0989]

[0990] Compound P139I2 (330 mg, 1.53 mmol, 1 eq), methoxymethylamine (179 mg, 1.83 mmol, 1.2 eq, HCl) were dissolved in DMF (6.6 mL) successively, TCFH (514 mg, 1.83 mmol, 1.2 eq) and NMI (376 mg, 4.58 mmol, 365 μL, 3 eq) were added to the above reaction solution at 25 °C, the reaction mixture was reacted at 25 °C for 16 hours, LCMS detection reaction was completed. H2O (10 mL) was added to the reaction solution, extracted with EtOAc (5 mL*3), the combined organic phase was washed with saturated sodium chloride (10 mL). The washed organic phase was concentrated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to obtain the target compound P139I3 (200 mg, 617 μmol, 40.4% yield, 80% purity) white solid. ESI-MS: [M+H] + , 217.2.

[0991] 4) Synthesis operation steps of intermediate P139I4

[0992]

[0993] Compound P139I3 (200 mg, 617 pmol, 1 eq) was dissolved in THF (4 mL), MeMgBr (3 M, 266 pL, 1 eq) was added dropwise to the above reaction solution at 0 °C, the reaction mixture was reacted at 0 °C for 3 h, and the reaction was detected by LCMS. The reaction solution was poured into ice H2O (10 mL), extracted with EtOAc (5 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The washed organic phase was concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to obtain the target compound P139I4 (150 mg, 560 pmol, 70.2% yield, 80% purity) as a yellow solid. ESI-MS: [M+H] + , 215.2.

[0994] 5) Synthesis procedure of intermediate P139I5

[0995]

[0996] Compound P139I4 (150 mg, 597 pmol, 1 eq), public intermediate C1 (188 mg, 717 pmol, 1.2 eq) and Ti(i-PrO)4 (1.5 mL) were sequentially dissolved in EtOH (3 mL), and the reaction mixture was reacted at 50 °C for 5 h. NaBH3CN (75.1 mg, 1.19 mmol, 2 eq) was added to the above reaction solution at 25 °C, and the reaction mixture was reacted at 50 °C for 16 h. The reaction was detected by LCMS. A mixture of H2O (20 mL) and EtOAc (5 mL) was added to the reaction solution, and yellow insoluble matter was generated. The suspension was filtered, the filtrate was extracted with EtOAc (5 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The washed organic phase was concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 1 / 1) to obtain the target compound P139I5 (70 mg, 152 pmol, 25.4% yield) as a yellow oil. ESI-MS: [M+H] + , 461.3.

[0997] 6) Synthesis procedure of compound P139

[0998]

[0999] Compound P139I5 (70 mg, 151.97 umol, 1 eq) was dissolved in DCM (1.2 mL), TFA (0.2 mL) was added at 20 °C, the reaction mixture was reacted at 20 °C for 1 h. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH = 7-8 was adjusted with NH3H2O, the target compound P139 (41 mg, 84.9 umol, 55.9% yield, 98.3% purity, TFA) was obtained as a white solid by high performance liquid chromatography (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-45% B in 8.0 min). ESI-MS: [M+H] + ,361.2.

[1000] 1 H NMR (400 MHz, DMSO-d6) d = 10.49-10.15 (m, 1H), 8.34-8.18 (m, 3H), 8.17-7.98 (m, 3H), 7.86-7.75 (m, 1H), 7.67 (br d, J = 4.8 Hz, 1H), 7.58-7.48 (m, 1H), 7.41-7.17 (m, 3H), 6.97 (br s, 1H), 5.72-5.44 (m, 1H), 4.90-4.77 (m, 1H), 4.69-4.53 (m, 1H), 4.23-4.10 (m, 1H), 4.03 (br s, 1H), 3.95 (br s, 3H), 3.90 (br s, 1H), 3.27-3.12 (m, 2H), 3.10-2.77 (m, 2H), 2.52 (br s, 3H), 1.85 (br s, 3H)

[1001] Example 127: Compound P140.

[1002] 1) Intermediate P140I1 synthesis procedure

[1003]

[1004] Compound P135I2 (1.4 g, 6.47 mmol, 1 eq) and TEA (1.31 g, 13.0 mmol, 1.80 mL, 2 eq) were dissolved in DCM (28 mL) sequentially, then the reaction mixture was cooled to -70 °C, Tf20 (2.19 g, 7.77 mmol, 1.28 mL, 1.2 eq) was added dropwise into the reaction mixture under nitrogen atmosphere. The reaction mixture was continued to react at -70 °C for 5 h. TLC on silica gel plate showed that the starting material 4 was consumed completely, and a new spot was generated obviously. Ice water C (20 mL) was added to the reaction solution, and DCM (20 mL*3) was used for extraction. The organic phase was combined and concentrated under reduced pressure, and purified by silica gel plate (Si02, petroleum ether / Ethyl acetate = 5 / 1) to obtain the target compound P140I1 (1.2 g, 3.45 mmol, 53.2% yield) as a yellow solid.

[1005] 2) Synthesis operation steps of intermediate P140I2

[1006]

[1007] Compound P140I1 (0.9 g, 2.58 mmol, 1 eq) and compound trimethyltrisboroxine (3.5 M, 886 μL, 1.2 eq) were dissolved in dioxane (18 mL) and H20 (5.4 mL), K2C03(1.07 g, 7.75 mmol, 3 eq) and Pd(dppf)Cl2(189 mg, 258 μmol, 0.1 eq) were added into the reaction mixture sequentially at 20 °C. The reaction mixture was reacted at 80 °C for 16 h under nitrogen atmosphere, and LCMS showed that the reaction was completed. H20 (20 mL) was added thereto, and EtOAc (10 mL*3) was used for extraction. The organic phase was combined and concentrated under reduced pressure and rotary evaporation, and purified by silica gel plate (Si02, petroleum ether / EtOAc = 5 / 1) to obtain the target compound P140I2 (0.52 g, 2.43 mmol, 93.9% yield) as a yellow solid. ESI-MS: [M+H] + , 215.2.

[1008] 3) Synthesis operation steps of intermediate P140I3

[1009]

[1010] Compound P140I2 (0.2 g, 933 pmol, 1 eq), common intermediate CI (269 mg, 1.03 mmol, 1.1 eq) and Ti(i-PrO)4 (2 mL) were sequentially dissolved in EtOH (4 mL), the reaction mixture was stirred at 50 °C for 5 h, at 25 °C, NaBH3CN (117 mg, 1.87 mmol, 2 eq) was added to the above reaction solution, the reaction mixture was reacted at 50 °C for 16 h, LCMS detection showed that the reaction was completed. A mixture of H2O (20 mL) and EtOAc (10 mL) was added to the reaction solution, and yellow insoluble matter was generated. The suspension was filtered, and the filtrate was extracted with EtOAc (10 mL*3), and the organic phase was combined and washed with saturated sodium chloride (10 mL). The washed organic phase was concentrated under reduced pressure, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 1 / 1) to obtain the target compound P140I3 (0.21 g, 383 pmol, 41.0% yield, 84% purity) as a yellow oil. ESI-MS: [M+H] + , 461.3.

[1011] 4) Synthesis procedure of compound P140

[1012]

[1013] Compound P140I3 (80 mg, 174 pmol, 1 eq) and TFA (0.4 mL) were dissolved in DCM (1.6 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3H2O, and purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-40% B in 8.0 min) to obtain the target compound P140 (43 mg, 72.5 pmol, 41.7% yield, 99.2% purity, 2TFA) as a yellow solid. ESI-MS: [M+H] + , 361.1.

[1014] 1H NMR (400 MHz, Methanol-d4) d = 8.27 (br d, J = 9.3 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.31 - 7.23 (m, 2H), 7.23 - 7.17 (m, 1H), 7.09 (s, 1H), 4.95 - 4.89 (m, 1H), 4.22 (br d, J = 15.4 Hz, 1H), 4.03 (s, 3H), 3.95 (s, 3H), 3.27 - 3.15 (m, 2H), 3.10 - 2.92 (m, 2H), 2.68 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H)

[1015] Example 128: Compound P141.

[1016] 1) Synthesis operation steps of intermediate P141I1

[1017]

[1018] Compound P141S1 (1 g, 5.31 mmol, 1 eq) was dissolved in CH3CN (10 mL), NBS (1 g, 5.31 mmol, 1 eq) was added at 20 °C, the reaction mixture was stirred at 25 °C for 2 hours, LCMS detection reaction was completed. The reaction liquid was rotary evaporated under reduced pressure, purified by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to obtain the target compound P141I1 (1.2 g, 4.49 mmol, 84.9% yield) as a yellow solid. ESI-MS: [M+H] + , 267.1.

[1019] 2) Synthesis operation steps of intermediate P141I2

[1020]

[1021] Compound P141I1 (1.2 g, 4.49 mmol, 1 eq) was dissolved in dioxane (18 mL), compound P141S2 (1.78 g, 4.94 mmol, 1.67 mL, 1.1 eq) and Pd(pph3)2Cl2 (158 mg, 225 μmol, 0.05 eq) were added successively at 20 °C, the reaction mixture was reacted at 100 °C for 16 h under nitrogen atmosphere, LCMS detection showed that the reaction was completed. HCl (2 M, 2 mL) was added dropwise to the reaction solution at 0 °C, the reaction mixture was stirred at 20 °C for 1 h. The reaction solution was added to saturated aqueous potassium fluoride solution (20 mL), a large amount of green solid was generated, the suspension was filtered at normal pressure, the filtrate was extracted with EtOAc (10 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, the target compound P141I2 (1 g, 3.60 mmol, 80.2% yield, 83% purity) was obtained as a white solid by purification with (petroleum ether: MTBE = 1:1, 5 mL, 25 °C) beating. ESI-MS: [M+H] + , 231.2.

[1022] 3) Synthesis procedure of intermediate P141I3

[1023]

[1024] Compound P141I2 (15 mg, 651 μmol, 1 eq), common intermediate C1 (205 mg, 782 μmol, 1.2 eq) and Ti(i-PrO)4 (1.5 mL) were dissolved in EtOH (1.5 mL) successively, the reaction mixture was stirred at 50 °C for 5 h, NaBH3CN (81.87 mg, 1.30 mmol, 2 eq) was added to the above reaction solution at 20 °C, the reaction mixture was reacted at 50 °C for 16 h, LCMS detection showed that the reaction was completed. The reaction solution was concentrated under reduced pressure, H2O (10 mL) was added thereto, yellow insoluble substance was generated, the suspension was filtered, the filtrate was extracted with EtOAc (3 mL*3), the organic phase was combined and washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, the target compound P141I3 (80 mg, 131 μmol, 20.1% yield, 78% purity) was obtained as a white solid by purification through a silica gel plate (SiO2, petroleum ether / EtOAc = 3 / 1). ESI-MS: [M+H] + , 477.3.

[1025] 4) Synthesis procedure of compound P141

[1026]

[1027] Compound P141I3 (72 mg, 131 μmol, 1 eq) and TFA (0.3 mL) were dissolved in DCM (1.2 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detection reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution was adjusted to pH = 7-8 with NH3H2O, the reaction solution was rotary evaporated under reduced pressure, purified by high performance liquid chromatography (column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound P141 (31.4 mg, 83.4 μmol, 47.7% yield) as a white solid. ESI-MS: [M+H] + ,377.3.

[1028] 1 H NMR (400 MHz, Methanol-d4) d = 8.12 (br d, J = 8.4 Hz, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.60 (br d, J = 8.0 Hz, 1H), 7.42-7.22 (m, 3H), 7.21-7.08 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.23 (br dd, J = 2.1, 5.2 Hz, 1H), 4.99-4.92 (m, 1H), 4.60-4.32 (m, 1H), 4.30-4.16 (m, 1H), 4.07 (s, 3H), 4.05 (s, 2H), 3.94 (s, 3H), 3.46-3.36 (m, 1H), 3.18-2.97 (m, 2H), 1.88 (br d, J = 6.4 Hz, 3H)

[1029] Example 129: Compound P142.

[1030] 1) Intermediate P142I1 synthesis procedure

[1031]

[1032] Compound P142S1 (3 g, 15.9 mmol, 1 eq) was dissolved in THF (45 mL), NBS (2.84 g, 15.9 mmol, 1 eq) was added portionwise at 20 °C, the reaction mixture was reacted at 25 °C for 16 h, LCMS detection reaction was completed. After the reaction solution was concentrated under reduced pressure, purified by silica gel column (SiO2, Petroleum ether / EtOAc = 10 / 1 to 1 / 1) to obtain the target compound P142I1 (2.6 g, 9.73 mmol, 61.1% yield) as a yellow solid. ESI-MS: [M+H] +,267.1&269.0.

[1033] 2) Synthesis steps of intermediate P142I2

[1034]

[1035] Compound P142I1 (2 g, 7.49 mmol, 1 eq) was dissolved in dioxane (30 mL), and compound P142S2 (3.0 g, 8.24 mmol, 1.1 eq) and Pd(pph3)2Cl2 (263 mg, 374 μmol, 0.05 eq) were added at 20 °C. The reaction mixture was reacted at 100 °C for 16 hours under a nitrogen atmosphere, and the reaction was confirmed to be complete by LC-MS. The reaction mixture was cooled to room temperature, and HCl (2M, 5 mL) was added at 25°C. The mixture was stirred at 25°C for one hour. The reaction solution was then added to a mixture of saturated potassium fluoride aqueous solution (50 mL) and EtOAc (50 mL). A large amount of green solid was formed. The suspension was filtered under normal pressure, and the filtrate was extracted with EtOAc (50 mL * 3). The organic phases were combined, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the target compound P142I2 (1.2 g, 5.2 mmol, 69.6% yield) as a yellow solid. ESI-MS: [M + H] + ,231.2

[1036] 3) Synthesis steps of intermediate P142I3

[1037]

[1038] Compound P142I2 (150 mg, 572 μmol, 1 eq), common intermediate C1 (158 mg, 686 μmol, 1.2 eq), and Ti(i-PrO)4 (228 mg, 800 μmol, 236 μL, 1.4 eq) were sequentially dissolved in EtOH (3 mL). The reaction mixture was stirred at 50 °C for 5 hours. Then, NaBH3CN (71.9 mg, 1.14 mmol, 2 eq) was added to the reaction mixture at 25 °C. The reaction mixture was reacted at 50 °C for 16 hours, and the reaction was confirmed to be complete by LCMS. The reaction mixture was then added to water (5 mL) and extracted with EtOAc (2 mL x 3). The organic phases were combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure and purified by silica gel plate separation (SiO2, petroleum ether / EtOAc = 2 / 1) to obtain the target compound P142I3 (105 mg, 106 μmol, 18.5% yield, 48% purity) as a yellow solid. ESI-MS: [M+H] + ,477.3.

[1039] 4) Synthesis procedure of compound P142

[1040]

[1041] Compound P142I3 (105 mg, 106 µmol, 1 eq) and TFA (0.4 mL) were dissolved in DCM (1.6 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3·H2O, purified by high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-35% B in 8.0 min) to obtain the target compound P142 (33.3 mg, 65.5 µmol, 62.0% yield, 96.5% purity, TFA) as a white solid. ESI-MS: [M+H] + ,375.2

[1042] 1 H NMR (400 MHz, DMSO-d6) δ = 8.29 (br s, 1H), 8.09 (br d, J = 9.3 Hz, 1H), 7.82 (br s, 1H), 7.44 (br d, J = 7.9 Hz, 1H), 7.23-7.07 (m, 3H), 7.02 (br s, 1H), 6.79 (br d, J = 8.0 Hz, 1H), 4.25 (br d, J = 5.6 Hz, 1H), 3.94 (s, 3H), 3.87 (br s, 2H), 3.79 (s, 3H), 3.70-3.47 (m, 2H), 2.95-2.62 (m, 4H), 1.50 (br d, J = 6.3 Hz, 3H)

[1043] Example 130: Compound P143.

[1044] 1) Synthesis procedure of intermediate P143I1

[1045]

[1046] Compound P143S1 (2 g, 12.5 mmol, 1 eq) was dissolved in DMF (40 mL), K2CO3 (10.4 g, 74.9 mmol, 6 eq) and CH3I (10.6 g, 74.9 mmol, 6 eq) were added successively at 20 °C, the reaction mixture was reacted at 25 °C for 16 hours, LCMS detection reaction was completed. There were always solid insoluble in the reaction liquid, first reduced pressure filtration, water (250 mL) was added to the filtrate, the aqueous phase was extracted with EtOAc (100 mL*3), the organic phase was combined, concentrated under reduced pressure and dried, purified by silica gel column (SiO2, petroleum ether / EtOAc = 10 / 1 to 1 / 1) to obtain the target compound P143I1 (150 mg, 797 μmol, 3.19% yield) as a white solid. ESI-MS: [M+H] + , 189.2.

[1047] 2) Synthesis operation steps of intermediate P143I2

[1048]

[1049] Compound P143I1 (150 mg, 797 μmol, 1 eq) was dissolved in DCM (6 mL), NBS (142 mg, 797 μmol, 1 eq) was added at 20 °C in batches, the reaction mixture was reacted at 25 °C for 16 hours, LCMS detection reaction was completed. The reaction liquid was concentrated under reduced pressure, and purified by silica gel plate (petroleum ether / EtOAc = 5 / 1) to obtain the target compound P143I2 (100 mg, 374 μmol, 47.0% yield) as a yellow solid. ESI-MS: [M+H] + , 267.1 & 269.1.

[1050] 3) Synthesis operation steps of intermediate P143I3

[1051]

[1052] Compound P143I2 (100 mg, 374 pmol, 1 eq) was dissolved in dioxane (2 mL), compound P143S2 (149 mg, 412 pmol, 1.1 eq) and Pd(pph3)2Cl2 (13.1 mg, 18.7 pmol, 0.05 eq) were added at 20 °C. The reaction mixture was reacted at 100 °C for 16 h under nitrogen atmosphere, LCMS detection showed the reaction was completed. The reaction mixture was cooled to room temperature, HCl (2 M, 1 mL) was added at 25 °C, the mixture was stirred at 25 °C for one hour, then the reaction solution was added to saturated aqueous potassium fluoride solution (5 mL), green solid was generated, the suspension was filtered under normal pressure, the filtrate was extracted with EtOAc (5 mL*3), the organic phase was combined and concentrated under reduced pressure, purification by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to give the target compound P143I3 (60 mg, 261 pmol, 69.6% yield) as a yellow solid. ESI-MS: [M+H] + , 231.2

[1053] 4) Synthesis procedure of intermediate P143I4

[1054]

[1055] Compound P143I3 (68.4 mg, 261 pmol, 1.2 eq), common intermediate C1 (50 mg, 217 pmol, 1 eq) and Ti(i-PrO)4 (0.5 mL) were sequentially dissolved in EtOH (1 mL), the reaction mixture was stirred at 50 °C for 5 h, NaBH3CN (27.3 mg, 434 pmol 2 eq) was added to the above reaction solution at 25 °C, the reaction mixture was reacted at 50 °C for 16 h, LCMS detection showed 20% of starting material remained, the main peak was the product peak. H2O (5 mL) was added to the reaction solution, yellow insoluble substance was generated, the suspension was filtered, the filtrate was extracted with EtOAc (2 mL*3), the organic phase was combined and washed with saturated sodium chloride (5 mL). The washed organic phase was concentrated under reduced pressure, purification by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to give the target compound P143I4 (23 mg, 39.1 pmol, 18.0% yield, 81% purity) as a yellow oil. ESI-MS: [M+H] + , 477.2.

[1056] 5) Synthesis procedure of compound P143

[1057]

[1058] Compound P143I4 (23 mg, 39.1 μmol, 1 eq) and TFA (0.1 mL) were dissolved in DCM (0.4 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reaction mixture was rotary evaporated under reduced pressure, CH3CN (2 mL) was added, the solution pH was adjusted to 8-9 with NH3·H2O, and the target compound P143 (9.2 mg, 18.1 μmol, 46.3% yield, 96.4% purity, TFA) was obtained as a white solid by purification through high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-25% B in 8.0 min). ESI-MS: [M+H] + ,377.2

[1059] 1 H NMR (400 MHz, DMSO-d6) d = 8.26 (s, 1H), 7.96 (br d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.18-7.12 (m, 1H), 7.11-7.06 (m, 1H), 7.02 (s, 1H), 6.91 (dd, J = 3.5, 7.9 Hz, 2H), 4.23 (br d, J = 5.4 Hz, 1H), 3.90-3.79 (m, 8H), 3.68-3.62 (m, 1H), 3.58-3.52 (m, 1H), 2.84-2.64 (m, 4H), 1.46 (d, J = 6.5 Hz, 3H)

[1060] Examples 131-132: Compound P144 and Compound P145.

[1061] 1) Intermediate P144I1 synthesis procedure

[1062]

[1063] Compound P144S1 (8 g, 30.2 mmol, 1 eq) was dissolved in dioxane (120 mL), and tributyl(1-ethoxyvinyl)tin (12.0 g, 33.2 mmol, 1.1 eq) and Pd(pph3)2Cl2 (1.06 g, 1.51 mmol, 0.05 eq) were added at 20 °C. The reaction mixture was reacted at 100 °C for 16 h under nitrogen atmosphere. The reaction was detected to be completed by LCMS. The reaction mixture was cooled to room temperature, and HCl (2 M, 15 mL) was added at 25 °C. The mixture was stirred at 25 °C for 1 h, and then the reaction solution was added to a mixture of saturated aqueous potassium fluoride solution (100 mL) and EtOAc (100 mL). A large amount of green solid was generated, and the suspension was filtered at normal pressure. The filtrate was extracted with EtOAc (100 mL*3), and the organic phases were combined and washed with saturated sodium chloride (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. MTBE (10 mL) was added to the concentrate, which was stirred for 5 min and then filtered at normal pressure. The filter cake was collected to give the target compound P144I1 (5.2 g, 22.8 mmol, 75.5% yield) as a yellow solid. ESI-MS: [M+H] + , 229.2.

[1064] 2) Synthesis procedure of intermediate P144I2

[1065]

[1066] Compound P144I1 (5.17 g, 22.6 mmol, 1.2 eq), compound P144S2 (4 g, 18.9 mmol, 1 eq), and Ti(i-PrO)4 (7.50 g, 26.4 mmol, 7.79 mL, 1.4 eq) were sequentially dissolved in EtOH (80 mL). The reaction mixture was stirred at 50 °C for 5 h, and NaBH3CN (2.37 g, 37.7 mmol 2 eq) was added to the reaction solution at 25 °C. The reaction mixture was reacted at 50 °C for 16 h, and the reaction was detected to be completed by LCMS. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (SiO2, petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1) to give the target compound P144I2 (4.8 g, 10.4 mmol, 55.2% yield, 92% purity) as a yellow solid. ESI-MS: [M+H] + , 424.1 & 426.1.

[1067] 3) Synthesis procedure of intermediate P144I3

[1068]

[1069] Compound P144I2 (1.5 g, 3.53 mmol, 1 eq) was dissolved in THF (30 mL), Ti(i-PrO)4 (1.51 g, 5.30 mmol, 1.56 mL, 1.5 eq) and EtMgBr (3 M, 3.53 mL, 3 eq) were added dropwise successively under nitrogen protection at -70 °C, the reaction mixture was reacted at -70 °C for 0.5 h, then slowly increased to room temperature, and continued to react at 25 °C for 16 h. LCMS detection showed that 30% of the raw material remained, and 20% of the product was generated. 1 N HCl (15 mL) was slowly added to the reaction solution at 0 °C, then extracted with EtOAc (20 mL*3), the organic phase was combined, concentrated under reduced pressure and dried in vacuo, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 4 / 1) to obtain the target compound P144I3 (0.65 g, 1.54 mmol, 43.5% yield) as a yellow solid. ESI-MS: [M+H] + , 422.2 & 424.2.

[1070] 4) Synthesis procedure of intermediates P144I4 and P144I5

[1071]

[1072] Compound P144I3 (0.32 g, 758 μmol, 1 eq) was dissolved in MeNO2 (6.4 mL) and dioxane (1.3 mL), and Cs2CO3 (272 mg, 833 μmol, 1.1 eq), 4AMS (100 mg), XPhos (72.2 mg, 152 μmol, 0.2 eq) and Pd2(dba)3 (9.38 mg, 75.8 μmol, 0.1 eq) were added successively at 20 °C. The reaction mixture was reacted at 60 °C for 7 h under nitrogen protection, and LCMS detection showed that the reaction was completed. Water (10 mL) was added to the reaction mixture, extracted with EtOAc (5 mL*3), the organic phase was combined, concentrated under reduced pressure and dried in vacuo, and purified by silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1) to obtain a mixture of P144I4 (0.18 g, 152. μmol, 20.1% yield, 34% purity) and compound P144I5 (0.18 g, 195 μmol, 26.1% yield, 44% purity) as a yellow solid. P144I4, ESI-MS: [M+H] + , 403.2; P144I5: ESI-MS: [M+H] + , 405.2.

[1073] 5) Synthesis procedure of compounds P144 and P145

[1074]

[1075] Raney-Ni (120 mg) was added to the reaction flask under argon protection, and MeOH was added to replace the water in the catalyst for three times. A mixture of compound P144I4 (0.12 g, 101.37 µmol, 1 eq) and P144I5 (0.12 g, 131 µmol, 1.29 eq) was added to the flask, and the reaction mixture was stirred at 25 °C for 7 h under hydrogen (50 Psi). LCMS showed the reaction was completed. The reaction was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The target compound P144 (21.7 mg, 56.8 µmol, 56.0% yield, 97.5% purity) and compound P145 (11.5 mg, 26.9 µmol, 26.5% yield, 87.6% purity) were obtained as yellow solids after purification by high performance liquid chromatography (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 10% - 30% B in 8.0 min). + , 373.2; P145, ESI-MS: [M+H] + , 375.1

[1076] P144: 1 H NMR (400 MHz, DMSO-d6) d = 8.62 (br d, J = 8.4 Hz, 1H), 8.50 (br d, J = 8.8 Hz, 1H), 8.32 (br s, 2H), 7.61-7.53 (m, 2H), 7.53-7.46 (m, 2H), 7.20-7.14 (m, 1H), 7.13-7.07 (m, 1H), 7.04 (br s, 1H), 4.33 (br s, 1H), 3.86 (br s, 2H), 3.78-3.67 (m, 1H), 3.65-3.50 (m, 1H), 2.83-2.67 (m, 4H), 1.57-1.44 (m, 3H), 1.13 (br s, 1H), 0.94-0.84 (m, 2H)

[1077] P145: 1H NMR (400 MHz, DMSO-d6) d = 8.49 (br d, J = 7.0 Hz, 1H), 8.31 (br s, 1H), 8.22 - 8.09 (m, 1H), 7.66 - 7.56 (m, 2H), 7.53 - 7.44 (m, 2H), 7.19 - 7.11 (m, 1H), 7.11 - 7.06 (m, 1H), 7.01 (br s, 1H), 5.22 (br dd, J = 4.3, 7.6 Hz, 1H), 4.45 - 4.27 (m, 1H), 3.83 (br s, 2H), 3.75 - 3.65 (m, 1H), 3.62 - 3.49 (m, 1H), 2.91 - 2.61 (m, 4H), 1.90 - 1.75 (m, 1H), 1.73 - 1.61 (m, 1H), 1.50 (br d, J = 6.5 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H)

[1078] Example 133: Compound P146.

[1079] 1) Synthesis procedure of intermediate P146I1

[1080]

[1081] Compound P146S1 (1 g, 4.48 mmol, 1 eq) was dissolved in DMF (20 mL), K2CO3 (2.48 g, 17.9 mmol, 4 eq) and 2-iodo-1,1,1-trifluoroethane (1.41 g, 6.72 mmol, 660 μL, 1.5 eq) were added successively at 25 °C. The reaction mixture was reacted at 100 °C for 16 hours under nitrogen protection, and LCMS detection showed that the reaction was completed. Water (50 mL) was added to the reaction mixture, extracted with EtOAc (10 mL*3), and the organic phase was combined and washed with saturated sodium chloride (15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and rotary evaporated under reduced pressure, and purified by column separation (SiO2, petroleum ether / EtOAc = 20 / 1 to 10 / 1) to give the target compound P146I1 (1.05 g, 3.44 mmol, 76.8% yield) as a yellow oil. ESI-MS: [M+H] + ,304.5.

[1082] 2) Synthesis procedure of intermediate P146I2

[1083]

[1084] Compound P146I1 (500 mg, 1.64 mmol, 1 eq) was dissolved in dioxane (7.5 mL), and compound tributyl(1-ethoxyvinyl)tin (651 mg, 1.80 mmol, 609 μL, 1.1 eq) and Pd(pph3)2Cl2 (57.5 mg, 81.9 μmol, 0.05 eq) were added successively into the reaction solution at 20 °C. The reaction mixture was reacted at 100 °C for 16 hours under nitrogen atmosphere. The reaction was detected to be completed by LCMS. HCl (2 M, 2 mL) was added at 0 °C, and the reaction mixture was stirred at 20 °C for one hour. Then the reaction solution was poured into saturated aqueous potassium fluoride solution (10 mL), and a large amount of green solid was generated. The reaction solution was filtered, and the filtrate was extracted with EtOAc (5 mL*3). The combined organic phase was washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target compound P146I2 (210 mg, 481 μmol, 45.3% yield) was obtained as a white solid by purification through a silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1). ESI-MS: [M+H] + , 269.1.

[1085] 3) Synthesis procedure of intermediate P146I3

[1086]

[1087] Compound P146I2 (300 mg, 1.12 mmol, 1 eq), compound P146S2 (284 mg, 1.34 mmol, 1.2 eq) and Ti(i-PrO)4 (953 mg, 3.36 mmol, 990 μL, 3 eq) were successively dissolved in EtOH (6 mL). The reaction mixture was stirred at 50 °C for 5 hours. NaBH3CN (140.57 mg, 2.24 mmol, 2 eq) was added to the above reaction solution at 20 °C, and the reaction mixture was reacted at 50 °C for 16 hours. The reaction was detected to be completed by LCMS. The reaction solution was concentrated under reduced pressure, and H2O (10 mL) was added thereto. The reaction solution was extracted with EtOAc (3 mL*3), and the combined organic phase was washed with saturated sodium chloride (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The target compound P146I3 (250 mg, 538 μmol, 48.1% yield) was obtained as a white solid by purification through a silica gel plate (SiO2, petroleum ether / EtOAc = 2 / 1). ESI-MS: [M+H] + , 464.1.

[1088] 4) Synthesis procedure of intermediate P146I4

[1089]

[1090] Compound P146I3 (250 mg, 538 pmol, 1 eq) and compound P146S3 (153 mg, 646 pmol, 1.2 eq) were dissolved in dioxane (2.5 mL) and H2O (0.75 mL), and then Cs2CO3 (526 mg, 1.62 mmol, 3 eq), Ruphos (25.1 mg, 53.8 pmol, 0.1 eq) and Pd(OAc)2 (12.1 mg, 53.8 pmol, 0.1 eq) were added successively. The reaction mixture was reacted at 100 °C for 16 h under nitrogen atmosphere. LCMS detection showed that the reaction was completed. It was added into H2O (10 mL), extracted with EtOAc (3 mL*3), and the combined organic phase was washed with saturated sodium chloride (10 mL), and then concentrated under reduced pressure and dried by rotary evaporation. Purification was performed by silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1) to obtain the target compound P146I4 (120 mg, 233 pmol, 43.3% yield) as a white solid. ESI-MS: [M+H] + , 515.3.

[1091] 5) Synthesis procedure of compound P146

[1092]

[1093] Compound P146I4 (120 mg, 233 pmol, 1 eq) and TFA (0.4 mL) were dissolved in DCM (2 mL), and the reaction mixture was reacted at 25 °C for 1 h. LCMS detection showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure and dried by rotary evaporation. CH3CN (2 mL) was added, and the solution pH was adjusted to 7-8 with NH3·H2O. Purification was performed by high performance liquid chromatography (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%-45% B in 8.0 min) to obtain the target compound P146 (45.8 mg, 111 pmol, 47.4% yield) as a white solid. ESI-MS: [M+H] + , 415.2.

[1094] 1H NMR (400 MHz, Methanol-d4) d = 8.33 (br d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.47 - 7.39 (m, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.09 (s, 1H), 4.76 - 4.53 (m, 3H), 4.10 - 3.95 (m, 3H), 3.82 (br d, J = 15.0 Hz, 1H), 3.11 - 2.77 (m, 4H), 1.67 (d, J = 6.5 Hz, 3H)

[1095] Example 134: Compound P147.

[1096] 1) Synthesis operation steps of intermediate P147I1

[1097]

[1098] Compound P147S1 (1 g, 4.48 mmol, 1 eq) was dissolved in DCM (10 mL), TEA (1.36 g, 13.5 mmol, 1.87 mL, 3 eq) and MsCl (553.3 mg, 4.89 mmol, 374 μL, 1.1 eq) were added successively at 0 °C, the reaction mixture was reacted at 0 °C for 1 h, LCMS detection showed that the reaction was completed. The reaction solution was poured into ice water solution (10 mL), extracted with DCM (3 mL*3), the organic phase was combined. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the concentrate was slurried with tert-butyl methyl ether (10 mL, 25 °C) to obtain the target compound P147I1 (910 mg, 3.02 mmol, 67.4% yield) as a yellow solid. ESI-MS: [M+H] + , 303.0.

[1099] 2) Synthesis operation steps of intermediate P147I2

[1100]

[1101] Compound P147I1 (410 mg, 1.36 mmol, 1 eq) was dissolved in dioxane (4.1 mL), tributyl(1-ethoxyvinyl)tin (540 mg, 1.50 mmol, 506 μL, 1.1 eq) and Pd(pph3)2Cl2(47.8 mg, 68.1 μmol, 0.05 eq) were added at 20 °C, the reaction mixture was reacted at 100 °C for 16 h under nitrogen atmosphere, LCMS detection showed the reaction was completed. HCl (2 M, 2 mL) was added at 0 °C, the reaction mixture was stirred at 20 °C for one hour, then the reaction solution was added to saturated aqueous potassium fluoride solution (10 mL), a large amount of green solid was generated, the suspension was filtered under normal pressure, then the filtrate 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 and concentrated under reduced pressure, the target compound P147I2 (200 mg, 529 μmol, 38.9% yield, 70% purity) was obtained as a white solid by purification on a silica gel plate (SiO2, petroleum ether / EtOAc = 5 / 1). ESI-MS: [M+H] + , 265.1.

[1102] 3) Synthesis procedure of intermediate P147I3

[1103]

[1104] Compound P147I2 (200 mg, 530 mmol, 1 eq), public intermediate C1 (167 mg, 636 μmol, 1.2 eq) and Ti(i-PrO)4(2 mL) were sequentially dissolved in EtOH (6 mL), the reaction mixture was stirred at 50 °C for 5 h, NaBH3CN (140.57 mg, 2.24 mmol, 2 eq) was added to the above reaction solution at 20 °C, the reaction mixture was reacted at 50 °C for 16 h, LCMS detection showed the reaction was completed. The reaction solution was concentrated under reduced pressure, H2O (10 mL) was added, a large amount of yellow solid was generated, the reaction solution was filtered under normal pressure, the filtrate was extracted with EtOAc (3 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 and concentrated under reduced pressure, the target compound P147I3 (90 mg, 106 μmol, 20.0% yield, 60% purity) was obtained as a white solid by purification on a silica gel plate (SiO2, petroleum ether / EtOAc = 3 / 1). ESI-MS: [M+H] + , 511.3.

[1105] 4) Synthesis procedure of compound P147

[1106]

[1107] Compound P147I3 (90 mg, 94.00 µmol, 1 eq) and TFA (0.36 mL) were dissolved in DCM (1.54 mL), the reaction mixture was reacted at 25 °C for 1 h, LCMS detected that the reaction was completed. The reactio...

Claims

1. A compound of Formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein, R1and R2are each independently selected from hydrogen, halogen, or C1-C6alkyl, or R1and R2together with the carbon atom to which they are attached form a C3-C6cycloalkyl; R3, R4, R5, and R6are each independently selected from hydrogen, halogen, or C1-C6alkyl, or R3and R4, R5and R6are each independently together with the carbon atom to which they are attached form a 3-6 membered ring, or R3and R5form a carbon bridge of length 1 to 2; X1, X2, X3, and X4are each independently selected from hydrogen, halogen, hydroxyl, amino, boronic acid group, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally substituted with halogen, hydroxyl, amino, nitro, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxy, and when multiple substituents selected from C1-C3alkyl, C1-C3hydroxyalkyl, and / or C1-C3alkoxy are present on the same carbon atom, they are optionally annulated; n is selected from 0 or 1 ; and Ar is selected from an 8 to 12 membered fused aryl ring or an 11 to 16 membered biaryl ring, optionally containing one or more heteroatoms, and optionally substituted. The compound of Formula (I) has Formula (la): wherein, R1to R6, L1to L4, and X1to X4are as defined in claim 1 ; L1, L2, L3, and L4are each independently selected from the group consisting of a bond, -(CH2) p NH(CH2) q -, -(CH2) p O(CH2) q -, C1-C6alkylene, C3-C6cycloalkylene, -(CH2) p NHCO(CH2) q -, -(CH2) p NHSO(CH2) q - or -(CH2) p NHSO2(CH2) q -, which is optionally substituted with halogen, hydroxyl, amino, nitro, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxy, and when multiple substituents selected from C1-C3alkyl, C1-C3hydroxyalkyl, and / or C1-C3alkoxy are present on the same carbon atom, it is optionally annulated, wherein each p and q is independently selected from any integer between 0 and 3; each A is independently selected from a carbon, nitrogen, oxygen, or sulfur atom; each n is independently selected from 0 or 1 ; and 3. The compound of Formula (I) according to claim 2 or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein, 2. The compound of formula (I) according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein, Ar is selected from any one of the following, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxy: The compound of Formula (I) has Formula (lb): wherein, R1to R6, L1to L4, and X1to X4are as defined in claim 1 ; each A is independently selected from a carbon, nitrogen, oxygen, or sulfur atom; R7, R8, R9, R 10 and R 11 each independently is selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3acyl, amido, sulfonyl, 3-8 membered heterocycloalkyl, or 5-6 membered heteroaryl, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxy; wherein optionally, any two of R7, R8, R9, R 10 and R 11 together with the ring atoms to which they are attached form a 4-6 membered ring. each n is independently selected from 0 or 1 ; and 5. The compound of Formula (I) according to claim 4 or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein, 4. The compound of formula (I) according to claim 1 or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein, Ar is selected from any one of the following, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxy:

6. The compound of Formula (I) according to claim 1 or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein, ​ ​ ​ R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, phenyl or 5-6 membered heteroaryl, optionally substituted with halogen, hydroxyl, amino, C1-C3alkyl, C1-C3hydroxyalkyl or C1-C3alkoxy. ​ ​ ​ each -L1-X1, -L2-X2, -L3-X3, -L4-X4is independently selected from any one of the following, which is optionally substituted with halogen, hydroxyl, amino, nitro, C1-C3alkyl, C1-C3hydroxyalkyl, or C1-C3alkoxy:

7. The compound of Formula (I) according to any one of claims 1-6, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein, each halo is independently selected from fluorine, chlorine, or bromine; each C1-C3alkyl or C1-C6alkyl is independently selected from methyl, ethyl, n-propyl, or i-propyl; each C1-C3hydroxyalkyl is independently selected from hydroxymethyl, hydroxyethyl, or hydroxypropyl; each C1-C3alkoxy or C1-C6alkoxy is independently selected from methoxy, ethoxy, or propoxy; each C3-C6cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, or cycloethyl; each 3-8 membered heterocycloalkyl is independently selected from aziridinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, or azetidinyl; and / or each 5-6 membered heteroaryl is independently selected from furan, thiophene, pyrrole, imidazole, thiazole, oxazole, pyrazole, pyridine, pyrimidine, pyrazine, or thiazine.

8. A pharmaceutical composition comprising the compound of Formula (I) according to any one of claims 1-7, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers 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, which dosage form is selected from a tablet, a granule, a powder, a syrup, an inhalant, and an injection.

10. Use of the compound of Formula (I) according to any one of claims 1-7, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the manufacture of a medicament for treating or preventing a coronavirus infection or a disease or a symptom caused by a coronavirus in a subject in need thereof.

11. The use according to claim 10, wherein the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), a novel coronavirus (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus OC43 (HCoV-OC43), murine hepatitis coronavirus (MHV), and a coronavirus having greater than 85% homology to any one of the above coronaviruses and having viral activity.

12. The use of claim 10 or 11, wherein the disease or condition caused by a 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, chilliness, tachypnea, and cytokine storm.

Images