Pyrimidoheterocyclic compounds and application thereof

Abstract

A class of pyrimido-heterocyclic compounds, specifically disclosed are compounds of formula (III) or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of the invention patent application with the application number 202180021254.X and the application date of 2021.03.11, and the invention name of "Pyrimido-heterocyclic compounds and uses thereof".

[0002] The present application claims the priority of:

[0003] CN202010172140.2, application date of 2020.03.12;

[0004] CN202010323035.4, application date of 2020.04.22;

[0005] CN202010953203.8, application date of 2020.09.11;

[0006] CN202011593642.9, application date of 2020.12.29. TECHNICAL FIELD

[0007] The present application relates to a class of pyrimido-heterocyclic compounds, in particular to a compound represented by formula (III) or a pharmaceutically acceptable salt thereof. BACKGROUND

[0008] RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS and NRAS), and 85% of RAS-driven cancers are caused by mutations in the KRAS subtype. KRAS mutations are common in solid tumors, such as lung adenocarcinoma, pancreatic ductal carcinoma and colorectal cancer, etc. In KRAS mutant tumors, 80% of oncogenic mutations occur at codon 12, and the most common mutations include: p.G12D (41%), p.G12V (28%) and p.G12C (14%).

[0009] The full name of the KRAS gene is Kirsten rat sarcoma viral oncogene homolog. KRAS plays a pivotal role in the signal regulation of cell growth. After receiving external signals, cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 in the upstream transmit the signals to the downstream through RAS protein. When KRAS protein is not activated, it is tightly combined with GDP (guanine nucleotide diphosphate). After being activated by SOS1 and other guanine nucleotide exchange factors, it is combined with GTP (guanine nucleotide triphosphate) and becomes a kinase active state. After the KRAS gene is mutated, it can transmit growth and proliferation signals to the downstream pathway independently of the upstream growth factor receptor signal, causing uncontrolled cell growth and tumor progression. Whether the KRAS gene is mutated is also an important indicator of tumor prognosis.

[0010] Although KRAS is the first discovered oncogene, it has been considered as an undruggable target for a long time. Until 2019, Amgen and Mirati Therapeutics successively announced the clinical research results of KRAS small molecule inhibitors AMG510 and MRTX849, which first confirmed the effectiveness of KRAS inhibitors in treating tumors in clinical practice. AMG510 and MRTX849 are both irreversible small molecule inhibitors, which inhibit KRAS activity by forming irreversible covalent bonds with cysteine residues of KRAS G12C mutant proteins.

[0011] Statistical results show that 12-36% of lung adenocarcinoma patients are driven by KRAS mutation; 27-56% of colon cancer patients are driven by KRAS, in addition to 90% of pancreatic cancer, 21% of endometrial cancer and 12-36% of lung adenocarcinoma, etc. are driven by KRAS, and the patient population is huge; among the KRAS gene mutations, 97% of the mutations occur in the 12th or 13th amino acid residues, of which G12D, G12V and G13D are three mutations, but the drugability of these three mutations is poor. KRAS (G12C) mutation: after the 12th glycine is replaced by cysteine, it provides a good direction for the development of covalent inhibitors. SUMMARY

[0012] The present application provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

[0013]

[0014] wherein,

[0015] T1 is selected from O and N;

[0016] R1is selected from C 6-10 aryl and 5-10 membered heteroaryl, said C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R a substituents; when T1is selected from O, R2is absent;

[0017] when T1is selected from N, R2is selected from H, C 1-3 alkyl, -C(=O)-C 1-3 alkyl, and -S(=O)2-C 1-3 alkyl, said C 1-3 alkyl, -C(=O)-C 1-3 alkyl, and -S(=O)2-C 1-3 alkyl are optionally substituted with 1, 2, or 3 R b substituents;

[0018] R3is selected from C 1-3 alkyl, said C 1-3 alkyl are optionally substituted with 1, 2, or 3 R c substituents;

[0019] R4is selected from H and C 1-3 alkyl, said C 1-3 alkyl are optionally substituted with 1, 2, or 3 R d substituents;

[0020] R5, R6, and R7are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, said C 1-3 alkyl are optionally substituted with 1, 2, or 3 F;

[0021] R8is selected from H and CH3;

[0022] R a are each independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl, and C 2-3 alkenyl, said C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl, and C 2-3 alkenyl are optionally substituted with 1, 2, or 3 F;

[0023] R b are each independently selected from F, Cl, Br, I, OH, and NH2;

[0024] R ceach R is independently selected from the group consisting of F, Cl, Br, I, OH, NH2, and CN;

[0025] R d each R is independently selected from the group consisting of F, Cl, Br, I, OH, NH2, and CN;

[0026] R is independently selected from the group consisting of H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy, and -C 1-3 alkyl-O-CO-C 1-3 alkylamino;

[0027] provided that when R1is selected from naphthyl, said naphthyl is optionally substituted with F, Cl, Br, OH, NH2, CF3, CH2CH3, and -C≡CH, and R5, R6, and R7are each independently selected from H.

[0028] In some embodiments of the application, each R a is independently selected from the group consisting of F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH, said CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH are optionally substituted with 1, 2, or 3 F, and other variables are as defined in the application.

[0029] In some embodiments of the application, each R a is independently selected from the group consisting of F, OH, NH2, CH3, CF3, CH2CH3, and -C≡CH, and other variables are as defined in the application.

[0030] In some embodiments of the application, R1is selected from the group consisting of phenyl, naphthyl, indolyl, and indazolyl, said phenyl, naphthyl, indolyl, and indazolyl are optionally substituted with 1, 2, or 3 R a , and other variables are as defined in the application.

[0031] In some embodiments of the application, R1is selected from the group consisting of and other variables are as defined in the application.

[0032] In some embodiments of the application, R2is selected from the group consisting of H, CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2are optionally substituted with 1, 2, or 3 R b , and other variables are as defined in the application.

[0033] In some embodiments of the application, R2is selected from H and CH3, and the other variables are as defined in the application.

[0034] In some embodiments of the application, each R is independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3, and the other variables are as defined in the application.

[0035] In some embodiments of the application, R c is selected from tetrahydropyrrolyl and hexahydro-lH-pyrrolizidinyl, optionally substituted with 1, 2, or 3 R, and the other variables are as defined in the application.

[0036] In some embodiments of the application, R c is selected from the other variables are as defined in the application.

[0037] In some embodiments of the application, R c is selected from the other variables are as defined in the application.

[0038] In some embodiments of the application, R3is selected from CH3, optionally substituted with 1, 2, or 3 R c the other variables are as defined in the application.

[0039] In some embodiments of the application, R3is selected from the other variables are as defined in the application.

[0040] In some embodiments of the application, R3is selected from the other variables are as defined in the application.

[0041] In some embodiments of the application, R4is selected from H and CH3, optionally substituted with 1, 2, or 3 R d the other variables are as defined in the application.

[0042] In some embodiments of the application, R4is selected from H, CH3, and CH2CN, and the other variables are as defined in the application.

[0043] The present application provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof,

[0044]

[0045] wherein,

[0046] T1is selected from O and N;

[0047] R1is selected from phenyl, naphthyl and indazolyl, said phenyl, naphthyl and indazolyl being optionally substituted with 1, 2, 3, 4 or 5 R a substituted;

[0048] when T1is selected from O, R2is absent;

[0049] when T1is selected from N, R2is selected from H, C 1-3 alkyl, -C(=O)-C 1-3 alkyl and -S(=O)2-C 1-3 alkyl, said C 1-3 alkyl, -C(=O)-C 1-3 alkyl and -S(=O)2-C 1-3 alkyl, said C b substituted;

[0050] R3is selected from C 1-3 alkyl, said C 1-3 alkyl, said C c substituted;

[0051] R4is selected from H and C 1-3 alkyl, said C 1-3 alkyl, said C d substituted;

[0052] R5, R6and R7are each independently selected from H, F, Cl, Br, I, OH and NH2;

[0053] R8is selected from H and CH3;

[0054] R a are each independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3and OCH3;

[0055] R b are each independently selected from F, Cl, Br, I, OH and NH2;

[0056] R c are each independently selected from tetrahydropyrrolyl and hexahydro-1 H- pyrrorylidinyl, said tetrahydropyrrolyl and hexahydro-1 H-pyrrorylidinyl being substituted with 1, 2 or 3 R

[0057] R d are each independently selected from F, Cl, Br, I, OH, NH2and CN;

[0058] R are each independently selected from H, F, Cl, Br and CH3.

[0059] In some embodiments of the application, the above-mentioned compound, or a pharmaceutically acceptable salt thereof, is selected from,

[0060]

[0061] wherein,

[0062] R4is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R d substituents;

[0063] T1, R1, R2, R3, R5, R6, R7, and R d as defined herein;

[0064] the carbon atom with an “*” is a chiral carbon atom, and exists as a single enantiomer in the (R) or (S) form or enriched in one enantiomeric form.

[0065] In some embodiments of the application, the above R1is selected from phenyl, naphthyl, and said phenyl, naphthyl, and is optionally substituted with 1, 2, or 3 R a substituents, and other variables are as defined herein.

[0066] In some embodiments of the application, the above R1is selected from and other variables are as defined herein.

[0067] In some embodiments of the application, the above R2is selected from H, CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2are optionally substituted with 1, 2, or 3 R b substituents, and other variables are as defined herein.

[0068] In some embodiments of the application, the above R2is selected from H and CH3, and other variables are as defined herein.

[0069] In some embodiments of the application, the above R c is selected from and other variables are as defined herein.

[0070] In some embodiments of the application, the above R c is selected from and other variables are as defined herein.

[0071] In some embodiments of the application, the above R3is selected from CH3, said CH3is optionally substituted with 1, 2, or 3 R c substituents, and other variables are as defined herein.

[0072] In some embodiments of the application, the above R3is selected from and other variables are as defined herein.

[0073] In some embodiments of the present invention, R3 is selected from... Other variables are as defined in this invention.

[0074] In some embodiments of the present invention, R4 is selected from H and CH3, wherein CH3 is optionally divided by 1, 2, or 3 Rs. d Replacement, other variables as defined in this invention.

[0075] In some embodiments of the present invention, R4 is selected from H, CH3 and CH2CN, and other variables are as defined in the present invention.

[0076] This invention provides compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0077]

[0078] in,

[0079] T1 is selected from O and N;

[0080] R1 is selected from phenyl, naphthyl, and indazole, wherein the phenyl, naphthyl, and indazole are optionally surrounded by 1, 2, 3, 4, or 5 R1 groups. a replace;

[0081] When T1 is selected from O, R2 does not exist;

[0082] When T1 is selected from N, R2 is selected from H and C. 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl, the C 1-3 Alkyl, -C(=O)-C 1-3 Alkyl groups and -S(=O)2-C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. b replace;

[0083] R3 is selected from C 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. c replace;

[0084] R4 is selected from H and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. d replace;

[0085] R5, R6 and R7 are independently selected from H, F, Cl, Br, I, OH and NH2, respectively;

[0086] R8 is selected from H and CH3;

[0087] R aeach independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, and OCH3;

[0088] R b each independently selected from F, Cl, Br, I, OH, NH2, and CH3;

[0089] R c each independently selected from tetrahydropyrrolyl, said tetrahydropyrrolyl being substituted with 1, 2, or 3 R;

[0090] R d each independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0091] R each independently selected from F, Cl, Br, and CH3.

[0092] In some embodiments of the present application, the above-mentioned compound, or a pharmaceutically acceptable salt thereof, is selected from,

[0093]

[0094] wherein T1, R1, R2, R3, R4, R5, R6, and R7 are as defined in the present application;

[0095] The carbon atom marked with “*” is a chiral carbon atom, and exists as an (R) or (S) single enantiomer or in a form enriched in one enantiomer.

[0096] In some embodiments of the present application, the above-mentioned R1is selected from phenyl, naphthyl, and said phenyl, naphthyl, and optionally substituted with 1, 2, or 3 R a and other variables are as defined in the present application.

[0097] In some embodiments of the present application, the above-mentioned R1is selected from and other variables are as defined in the present application.

[0098] In some embodiments of the present application, the above-mentioned R2is selected from H, CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2being optionally substituted with 1, 2, or 3 R b and other variables are as defined in the present application.

[0099] In some embodiments of the present application, the above-mentioned R2is selected from H and CH3, and other variables are as defined in the present application.

[0100] In some embodiments of the present application, the above-mentioned R c is selected from and other variables are as defined in the present application.

[0101] In some embodiments of the application, R3is selected from CH3optionally substituted with 1, 2, or 3 R c and other variables are as defined in the application.

[0102] In some embodiments of the application, R3is selected from and other variables are as defined in the application.

[0103] In some embodiments of the application, R4is selected from CH3optionally substituted with 1, 2, or 3 R d and other variables are as defined in the application.

[0104] In some embodiments of the application, R4is selected from CH2CN and other variables are as defined in the application.

[0105] The present application provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof,

[0106]

[0107] wherein,

[0108] T1is selected from O and N;

[0109] R1is selected from phenyl and naphthyl optionally substituted with 1, 2, or 3 R a ; and other variables are as defined in the application.

[0110] when T1is selected from O, R2is absent;

[0111] when T1is selected from N, R2is selected from C 1-3 alkyl, -C(=O)-C 1-3 alkyl, and -S(=O)2-C 1-3 alkyl optionally substituted with 1, 2, or 3 R 1-3 alkyl, -C(=O)-C 1-3 alkyl, and -S(=O)2-C 1-3 alkyl optionally substituted with 1, 2, or 3 R b ; and other variables are as defined in the application.

[0112] R3is selected from C 1-3 alkyl optionally substituted with 1, 2, or 3 R 1-3 alkyl optionally substituted with 1, 2, or 3 R c ; and other variables are as defined in the application.

[0113] R4is selected from C 1-3 alkyl optionally substituted with 1, 2, or 3 R 1-3 alkyl optionally substituted with 1, 2, or 3 R d ; and other variables are as defined in the application.

[0114] R5, R6, and R7are each independently selected from H, F, Cl, Br, I, OH, and NH2;

[0115] R a are each independently selected from F, CI, Br, I, OH, NH2, CN, CH3, and OCH3;

[0116] R b are each independently selected from F, CI, Br, I, OH, NH2, and CH3;

[0117] R c are each independently selected from tetrahydropyrrolyl, said tetrahydropyrrolyl being substituted with 1, 2, or 3 R;

[0118] R d are each independently selected from F, CI, Br, I, OH, NH2, and CN;

[0119] R are each independently selected from F, CI, Br, and CH3;

[0120] The carbon atom marked with an “*” is a chiral carbon atom, and exists as a single enantiomer of (R) or (S) or enriched in one enantiomeric form.

[0121] In some embodiments of the application, R1 is selected from naphthyl, said naphthyl being optionally substituted with 1, 2, or 3 R a and the other variables are as defined in the application.

[0122] In some embodiments of the application, R1 is selected from and the other variables are as defined in the application.

[0123] In some embodiments of the application, R2 is selected from CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2 being optionally substituted with 1, 2, or 3 R b and the other variables are as defined in the application.

[0124] In some embodiments of the application, R2 is selected from CH3 and the other variables are as defined in the application.

[0125] In some embodiments of the application, R c is selected from and the other variables are as defined in the application.

[0126] In some embodiments of the application, R3 is selected from CH3, said CH3 being optionally substituted with 1, 2, or 3 R c and the other variables are as defined in the application.

[0127] In some embodiments of the application, R3 is selected from and the other variables are as defined in the application.

[0128] In some embodiments of the application, R4 is selected from CH3, which CH3 is optionally substituted with 1, 2, or 3 R d substituted, and the other variables are as defined in the application.

[0129] In some embodiments of the application, R4 is selected from CH2CN, and the other variables are as defined in the application.

[0130] The present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0131]

[0132] wherein,

[0133] R1 is selected from phenyl and naphthyl, which phenyl and naphthyl are optionally substituted with 1, 2, or 3 R a substituted;

[0134] R2 is selected from C 1-3 alkyl, -C(=O)-C 1-3 alkyl, and -S(=O)2-C 1-3 alkyl, which C 1-3 alkyl, -C(=O)-C 1-3 alkyl, and -S(=O)2-C 1-3 alkyl is optionally substituted with 1, 2, or 3 R b substituted;

[0135] R3 is selected from C 1-3 alkyl, which C 1-3 alkyl is optionally substituted with 1, 2, or 3 R c substituted;

[0136] R4 is selected from C 1-3 alkyl, which C 1-3 alkyl is optionally substituted with 1, 2, or 3 R d substituted;

[0137] R5, R6, and R7 are each independently selected from H, F, Cl, Br, I, OH, and NH2;

[0138] R a and R b are each independently selected from F, Cl, Br, I, OH, NH2, and CH3;

[0139] R c are each independently selected from tetrahydropyrrolyl, which tetrahydropyrrolyl is substituted with 1, 2, or 3 R

[0140] R d are each independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0141] R is independently selected from F, CI, Br, and CH3;

[0142] The carbon atom with an asterisk is a chiral carbon atom, and exists as an (R) or (S) single enantiomer or enriched in one enantiomeric form.

[0143] In some embodiments of the application, R1 is selected from naphthyl, and the other variables are as defined in the application.

[0144] In some embodiments of the application, R1 is selected from and the other variables are as defined in the application.

[0145] In some embodiments of the application, R2 is selected from CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2 are optionally substituted with 1, 2, or 3 R b and the other variables are as defined in the application.

[0146] In some embodiments of the application, R2 is selected from CH3, and the other variables are as defined in the application.

[0147] In some embodiments of the application, R c is selected from and the other variables are as defined in the application.

[0148] In some embodiments of the application, R3 is selected from CH3, said CH3 is optionally substituted with 1, 2, or 3 R c and the other variables are as defined in the application.

[0149] In some embodiments of the application, R3 is selected from and the other variables are as defined in the application.

[0150] In some embodiments of the application, R4 is selected from CH3, said CH3 is optionally substituted with 1, 2, or 3 R d and the other variables are as defined in the application.

[0151] In some embodiments of the application, R4 is selected from CH2CN, and the other variables are as defined in the application.

[0152] In some embodiments of the application, the compound or pharmaceutically acceptable salt thereof is selected from,

[0153]

[0154] wherein R1, R5, R c are as defined in the application;

[0155] R4 is selected from C 1-3 alkyl, said C 1-3alkyl is optionally substituted with 1, 2, or 3 R d substituted;

[0156] R d each independently is selected from F, Cl, Br, I, OH, NH2, and CN;

[0157] The carbon atom with “*” is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or rich in one enantiomeric form.

[0158] In some embodiments of the present application, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,

[0159]

[0160] wherein,

[0161] R1, R2, R4, R5, R6, R7, R8, and R are as defined in the present application.

[0162] Some embodiments of the present application are also derived from any combination of the above-mentioned variables.

[0163] The present application provides a compound of the following formula or a pharmaceutically acceptable salt thereof,

[0164]

[0165]

[0166] In some embodiments of the present application, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,

[0167]

[0168]

[0169] In some embodiments of the present application, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,

[0170]

[0171]

[0172]

[0173] The present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with KRAS G12C mutant protein.

[0174] Technical effects

[0175] The compound has good cell proliferation inhibition activity on the MIA-PA-CA-2 cell line, NCI-H358 cells of KRAS G12C mutation. It has good liver microsomal, hepatocyte, plasma, whole blood stability, good PK property, and significant tumor inhibition effect.

[0176] Related Definitions

[0177] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as undefined or unclear without a specific definition, but should be understood according to the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0178] The term "pharmaceutically acceptable" as used herein, with respect to compounds, materials, compositions, and / or dosage forms, means those that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0179] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, which is prepared from a compound of the present application having the specific substituents discovered herein with a relatively nontoxic acid or base. Alkali addition salts can be prepared from compounds of the present application having relatively acidic functionalities by contacting such compounds in pure solution or in a suitable inert solvent with a sufficient amount of a base to produce the desired salt. Pharmaceutically acceptable alkali addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. Acid addition salts can be prepared from compounds of the present application having relatively basic functionalities by contacting such compounds in pure solution or in a suitable inert solvent with a sufficient amount of an acid to produce the desired salt. Examples of pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, bicarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, hydrosulfuric, hydroiodic, phosphorous, and the like; and organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, and methanesulfonic acid and the like; also salts of amino acids such as arginine and the like, and salts of organic acids like glucuronic acid and the like. Certain specific compounds of the present application contain both basic and acidic functionalities and, as such, are capable of conversion into either base or acid addition salts.

[0180] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acid or a base moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.

[0181] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, e.g., mixtures of enantiomers or diastereomers, all of which are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0182] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, enhanced efficacy, and increased biological half-life. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0183] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the described event or circumstance occurs and instances where it does not.

[0184] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, which can include variations of deuterium and hydrogen, provided that the valency of the particular atom is not exceeded and that the substituted compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that the group can or can not be substituted, and unless otherwise specified, the types and number of substituents are any that are chemically feasible.

[0185] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is substituted with 0-2 R groups, then the group is optionally substituted with up to two R groups, and the R groups in each occurrence are selected independently.

[0186] When the number of linking groups is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0187] When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, such as when L represents a single bond in A-L-Z, it means that the structure is actually A-Z.

[0188] When the linking groups are listed without indicating the direction of attachment, the direction of attachment is arbitrary, for example, where the linking group L is -M-W-, then -M-W- can be attached to ring A and ring B to form either in the same direction as the reading order from left to right, as in or in the opposite direction as the reading order from left to right, as in The combination of substituents, or variables, is permissible only if the combination results in a stable compound.

[0189] Unless otherwise specified, when a group has one or more attachable sites, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the chemical bond is not directional and there is an H atom at the site, the number of H atoms at the site is reduced by the number of chemical bonds attached to it to form the corresponding valence group. The chemical bond by which the site is attached to other groups can be represented by a straight solid line a straight dashed line or a wavy line. For example, the straight solid line in -OCH3represents attachment to other groups through the oxygen atom in the group; the straight dashed line in -NH2represents attachment to other groups through both ends of the nitrogen atom in the group; and the wavy line in -Ph represents attachment to other groups through the 1 and 2 carbon atoms in the phenyl group; which means that any of the attachable sites on the piperidinyl group can be attached to other groups by 1 chemical bond, including at least The 4 ways of attachment, even though H atoms are drawn on the -N-, still include ​Such a group connected in this way has one less H at the point of attachment than the corresponding monovalent piperidinyl group when connected by a single bond.

[0190] Unless otherwise indicated, the use of the term "wedge" is intended to indicate a solid line and the use of the term "open wedge" is intended to indicate a dashed line Unless otherwise indicated, the use of the term "straight" is intended to indicate a solid line and the use of the term "open straight" is intended to indicate a dashed line Unless otherwise indicated, the use of the term "wavy" is intended to indicate a wavy line Unless otherwise indicated, the use of the term "wedge" is intended to indicate a solid line or a dashed line or the use of the term "wavy" is intended to indicate a wavy line Unless otherwise indicated, the use of the term "straight" is intended to indicate a solid line or a dashed line As represents represents

[0191] Unless otherwise indicated, the term "enriched in an isomer," "isomerically enriched," "enriched in an enantiomer," or "enantiomerically enriched" means that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0192] Unless otherwise indicated, the term "excess of an isomer" or "excess of an enantiomer" means the difference between the relative percentages of the two isomers or the two enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the excess of the isomer or enantiomer (the ee value) is 80%.

[0193] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the compound with an appropriate optically active acid or base can be formed, and the diastereomeric salt separated by conventional means, and the desired enantiomer recovered by cleavage of the bond to the auxiliary group. In addition, separation of the enantiomers and diastereomers is typically accomplished by the use of chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of a carbamate from an amine).

[0194] Unless otherwise specified, the term "C 1-6 alkyl" is used to denote a straight or branched chain saturated carbon hydride group consisting of from 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6and C5alkyl groups, etc.; which can be monovalent (e.g., methyl), divalent (e.g., methylene) or multivalent (e.g., methine). Examples of C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.

[0195] Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated carbon hydride group consisting of from 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; which can be monovalent (e.g., methyl), divalent (e.g., methylene) or multivalent (e.g., methine). Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.

[0196] Unless otherwise specified, the term "C 1-3 alkoxy" denotes those alkyl groups containing from 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3, C3 and C2 alkoxy groups, and the like. C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy (including n-propyloxy and isopropyloxy), and the like.

[0197] The term "C 1-3 "Alkylamino" denotes those alkyl groups, containing from 1 to 3 carbon atoms, attached to the remainder of the molecule through an amino group. The C 1-3 Alkylamino groups include C 1-2 , C3 and C2 alkylamino groups, and the like. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0198] The term "C 2-3 "Alkenyl" is used to denote a straight or branched chain hydrocarbon group consisting of from 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position in the group. The C 2-3 Alkenyl groups include C3 and C2 alkenyl groups; the C 2-3 Alkenyl groups can be monovalent, divalent or multivalent. C 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0199] The term "C 2-3 "Alkynyl" is used to denote a straight or branched chain hydrocarbon group consisting of from 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position in the group. It can be monovalent, divalent or multivalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. C 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0200] The term "C 6-10 "Aryl" and "C 6-10 "Aryl" are used interchangeably, the term "C 6-10 "Aryl" or "C 6-10 "Aryl" denotes a cyclic hydrocarbon group of from 6 to 10 carbon atoms having a conjugated pi electron system, which can be a monocyclic, fused bicyclic, or fused tricyclic ring system in which each ring is aromatic. It can be monovalent, divalent or multivalent, C 6-10 Aryl groups include C 6-9 , C9, C 10 , and C6 aryl groups, and the like. C 6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like).

[0201] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" can be used interchangeably, and the term "5-10 membered heteroaryl" means a cyclic group consisting of 5 to 10 ring atoms having a conjugated pi electron system, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic system, in which each ring is aromatic. Nitrogen atoms therein are optionally quaternized, and nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p p is 1 or 2). The 5-10 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or carbon atom. The 5-10 membered heteroaryl includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl, and the like. Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, and the like), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, and the like), furanyl (including 2-furanyl and 3-furanyl, and the like), thiophenyl (including 2-thiophenyl and 3-thiophenyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, and the like), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, and the like), benzothiazolyl (including 5-benzothiazolyl, and the like), purinyl, benzimidazolyl (including 2-benzimidazolyl, and the like), benzoxazolyl, indolyl (including 5-indolyl, and the like), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, and the like), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, and the like), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, and the like).

[0202] Unless otherwise specified, the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms, means a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring systems include spiro, fused, and bridged rings. Further, with respect to this "4-8 membered heterocycloalkyl," a heteroatom can occupy the position of attachment of the heterocycloalkyl to the rest of the molecule. The 4-8 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, etc. Examples of 4-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxepanyl, etc.

[0203] Unless otherwise specified, C n-n+m or C n -C n+m includes any one particular instance of n to n+m carbons, for example, C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 includes any one range of n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; likewise, n-membered to n+m-membered means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3 membered ring, 4 membered ring, 5 membered ring, 6 membered ring, 7 membered ring, 8 membered ring, 9 membered ring, 10 membered ring, 11 membered ring, and 12 membered ring, also includes any one range of n to n+m, for example, 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.

[0204] The term "leaving group" refers to a functional group or atom that can be displaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction. For example, representative leaving groups include triflate; chloro, bromo, iodo; sulfonate groups such as mesylate, tosylate, brosylate, cumylsulfonate, and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

[0205] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for blocking the amino nitrogen from unwanted reactions. Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for blocking the hydroxyl group from unwanted reactions. Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0206] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0207] The compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD), a single crystal is grown and diffracted intensity data is collected using a Bruker D8 venture diffractometer with Cu Kα radiation, scanning mode: After the relevant data is collected, the crystal structure is further resolved using the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0208] The solvents used in the present application are commercially available.

[0209] Compounds are named according to the principles of nomenclature in the art or using Aldrich® software nomenclature, and commercially available compounds use the supplier catalog name. BRIEF DESCRIPTION OF DRAWINGS

[0210] Figure 1 . Tumor volume change over time with different dosages

[0211] Figure 2 . Animal weight change over time with different dosages DETAILED DESCRIPTION

[0212] The present application is described in detail below by way of Examples, but it is not meant to be limited by any of the Examples. The present application has been described in detail by specific embodiments, and it is obvious to those skilled in the art that various changes and modifications can be made thereto without departing from the spirit and scope of the present application.

[0213] Example 1

[0214]

[0215]

[0216] Step 1: Synthesis of compound 1-2

[0217] Compound 1-1 (10 g, 64.03 mmol, 8.70 mL, 1 eq) and tert-butylsulfonamide (7.76 g, 64.03 mmol, 1 eq) were dissolved in tetrahydrofuran (100 mL), then tetraethyl titanate (29.21 g, 128.06 mmol, 26.56 mL, 2 eq) was added, and stirred at 25 °C for 10 hr. After the reaction was completed, 10 g of ice was added under ice water bath, and a large amount of solid was precipitated. Tetrahydrofuran (100 mL) was added again, filtered, and the filtrate was collected and concentrated to obtain compound 1-2, which was directly used in the next step reaction. 1 H NMR (400 MHz, CDCl3) δ = 9.17 (s, 1H), 9.05 (d, J = 8.5 Hz, 1H), 8.05 (dd, J = 7.9, 10.8 Hz, 2H), 7.94 (d, J = 8.1 Hz, 1H), 7.72-7.63 (m, 1H), 7.59 (t, J = 7.6 Hz, 2H), 1.34 (s, 9H); LCMS m / z = 260.1 [M+1] + .

[0218] Step 2: Synthesis of compound 1-3

[0219] Methyl acetate (4.28 g, 57.83 mmol, 4.60 mL, 1.5 eq) was dissolved in tetrahydrofuran (100 mL), and the solution was cooled to -78 °C under nitrogen protection. Lithium hexamethyldisilazide (1 M, 59.76 mL, 1.55 eq) was slowly added dropwise into the reaction solution. After stirring at -78 °C for 1 h, compound 1-2 (10 g, 38.56 mmol, 1 eq) was slowly added dropwise into the reaction solution, and the solution was continuously stirred at this temperature for 1 h. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (80 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 ~ 1 / 1) to obtain compound 1-3. 1 H NMR (400 MHz, CDC13) δ = 8.17 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 6.8 Hz, 2H), 7.54-7.52 (m, 1H), 7.52-7.44 (m, 2H), 4.78 (d, J = 2.4 Hz, 1H), 3.69 (s, 3H), 3.09 (d, J = 6.4 Hz, 2H), 1.25-1.22 (s, 9H); LCMS m / z = 334.1 [M+1] + .

[0220] Step 3: Synthesis of compound 1-4

[0221] Methyl acetate (5.55 g, 74.98 mmol, 5.96 mL, 5 eq) was dissolved in tetrahydrofuran (50 mL), and the solution was cooled to -78 °C under nitrogen protection. Sodium hexamethyldisilazide (1 M, 74.98 mL, 5 eq) was added into the reaction solution. After stirring at -78 °C for 1 h, compound 1-3 (5 g, 15.00 mmol, 1 eq) was slowly added dropwise into the reaction solution, and the solution was continuously stirred at this temperature for 1 h. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1-4, which was directly used in the next reaction. LCMS m / z = 376.1 [M+1] + .

[0222] Step 4: Synthesis of compound 1-5

[0223] Compound 1-4 (5 g, 13.32 mmol, 11.92 mL, 1 eq) was dissolved in toluene (50 mL), N,N-dimethylformamide dimethyl acetal (15.87 g, 133.16 mmol, 17.69 mL, 10 eq) was added, and the reaction was stirred at 19 °C for 10 hr. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution (80 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 100 / 1 ~ 10 / 1) to obtain compound 1-5. LCMS m / z = 431.1 [M+1] + .

[0224] Step 5: Synthesis of compound 1-6

[0225] Compound 1-5 (2.4 g, 5.57 mmol, 1 eq) was dissolved in hydrochloric acid dioxane (4 M, 60.00 mL), and stirred at 18 °C for 10 hr. After the reaction was completed, the reaction solution was directly concentrated to obtain hydrochloride of compound 1-6, which was directly used in the next reaction. LCMS m / z = 282.1 [M+1] + .

[0226] Step 6: Synthesis of compound 1-7

[0227] Compound 1-6 hydrochloride (2 g, 6.29 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (6.15 g, 18.88 mmol, 3 eq), iodomethane (1.79 g, 12.59 mmol, 783.65 μL, 2 eq) were added in sequence, and stirred at 18 °C for 10 hr. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 50 / 1 ~ 10 / 1) to obtain compound 1-7. 1 H NMR (400 MHz, CDCl3) δ = 8.47 (s, 1H), 7.96-7.88 (m, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.62-7.51 (m, 2H), 7.48-7.41 (m, 1H), 7.35 (d, J = 7.0 Hz, 1H), 5.52-5.39 (m, 1H), 3.83 (s, 3H), 3.19 (s, 3H), 3.23-3.14 (m, 1H), 2.98-2.87 (m, 1H).

[0228] Step 7: Synthesis of compound 1-8

[0229] Compound 1-7 (20 mg, 67.72 μmol, 1 eq) was dissolved in ethanol (0.2 mL), 1,4 dioxane (1 mL). Then nickel chloride hexahydrate (19.32 mg, 81.26 μmol, 1.2 eq) was added. After cooling to 5-10 °C, sodium borohydride (1.28 mg, 33.86 μmol, 0.5 eq) was added and reacted at 10 °C for 0.5 hr. After the reaction was completed, it was poured into saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by thin layer chromatography preparation plate (developing fluid: petroleum ether / ethyl acetate = 3 / 1) to give compound 1-8. 1 H NMR (400 MHz, CDC13) δ = 11.99-11.85 (m, 1H), 8.67-8.49 (m, 1H), 7.92-7.85 (m, 1H), 7.85-7.77 (m, 1H), 7.57-7.41 (m, 4H), 3.82 (s, 3H), 3.56-3.51 (m, 1H), 3.16-2.95 (m, 2H), 2.68-2.47 (m, 1H), 2.15 (s, 3H).

[0230] Step 8: Synthesis of compound 1-9

[0231] Compound 1-8 (240 mg, 807.14 μmol, 1 eq), urea (242.36 mg, 4.04 mmol, 216.40 μL, 5 eq) were dissolved in ethanol (5 mL), and sodium methoxide (130.80 mg, 2.42 mmol, 3 eq) was added. After reacting at 85 °C for 10 hr, the reaction solution was slowly poured into water, and ethyl acetate (5 mL) was added, and a solid was precipitated. Filtration and collection of the solid gave compound 1-9. LCMS m / z = 308.1 [M+1] + .

[0232] Step 9: Synthesis of compound 1-10

[0233] Compound 1-9 (400 mg, 1.30 mmol, 1 eq) was dissolved in phosphorus oxychloride (132.00 g, 860.89 mmol, 80 mL). After the reaction was heated to 105 °C for 10 h, the excess phosphorus oxychloride was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and added to saturated aqueous sodium bicarbonate solution (20 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was separated and purified by thin layer chromatography column (eluent: petroleum ether / ethyl acetate = 20 / 1 ~ 0 / 1) to give compound 1-10. LCMS m / z = 344.0 [M+1] + .

[0234] Step 10: Synthesis of compound 1-11

[0235] Compound 1-10 (250 mg, 726.24 μmol, 1 eq), intermediate 1-10A hydrochloride (279.24 mg, 944.12 μmol, 1.3 eq) were dissolved in isopropanol (2 mL), and N, N-diisopropylethylamine (375.44 mg, 2.90 mmol, 505.98 μL, 4 eq) was added. After the reaction was heated to 110 °C for 12 h, the reaction solution was directly concentrated. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 1) to give compound 1-11. 1 H NMR (400 MHz, CDC13) δ = 8.60-8.48 (m, 1H), 7.93-7.87 (m, 1H), 7.86-7.80 (m, 1H), 7.58-7.34 (m, 9H), 5.21 (m, 2H), 4.77-4.61 (m, 1H), 4.06 (m, 2H), 3.97-3.75 (m, 2H), 3.62-3.40 (m, 3H), 3.30-3.00 (m, 4H), 2.78-2.64 (m, 1H), 2.26 (s, 1.5H), 2.21 (s, 1.5H); LCMS m / z = 567.3 [M+1] + .

[0236] Step 11: Synthesis of compound 1-12

[0237] Compound 1-11 (100 mg, 176.34 μmol, 1 eq), 1-11A (60.93 mg, 529.03 μmol, 62.81 μL, 3 eq) were dissolved in 1,4-dioxane (1.5 mL), then cesium carbonate (172.37 mg, 529.03 μmol, 3 eq), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (16.46 mg, 35.27 μmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (32.30 mg, 35.27 μmol, 0.2 eq) were added. The reaction was stirred at 90 °C for 24 hr under nitrogen atmosphere. After the reaction was completed, the reaction mixture was directly concentrated. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 100 / 1 ~ 10 / 1) to give compound 1-12. LCMS m / z = 646.4 [M+1] + .

[0238] Step 12: Synthesis of compound 1-13

[0239] Compound 1-12 (50 mg, 77.42 μmol, 1 eq) was dissolved in tetrahydrofuran (50 mL), then Pd / C (77.4 mg, 10% purity) was added, and the reaction system was replaced with H2 for three times. The reaction was stirred at 20 °C for 10 hr under 15 psi. After the reaction was completed, the reaction mixture was filtered to give a tetrahydrofuran solution (70 mL) of compound 1-13, which was directly used in the next step. LCMS m / z = 512.3 [M+1] + .

[0240] Step 13: Synthesis of compound 1

[0241] To the tetrahydrofuran solution (70 mL) of compound 1-13 obtained in the previous step, N,N-diisopropylethylamine (17.18 mg, 132.90 μmol, 23.15 μL, 2 eq) was added, and then the temperature was lowered to -20 ~ -30 °C, and acryloyl chloride (6.01 mg, 66.45 μmol, 5.42 μL, 1 eq) was added. After the reaction was stirred at this temperature for 30 min, the reaction mixture was poured into water (10 mL). Then, the reaction mixture was extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by high performance liquid chromatography column (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [10 mM NH4HCO3 aqueous solution-acetonitrile]; acetonitrile%: 30% ~ 60%, 7 min) to give compound 1, which was identified by SFC to consist of two diastereoisomers (Chiralcel OD-3 column, P1 Rt= 1.93 min, P2 Rt= 2.08 min, P1:P2= 50.6:49.4). 1H NMR (400 MHz, CDC13) δ = 8.66-8.53 (m, 1H), 7.93-7.87 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.56-7.41 (m, 4H), 6.70-6.50 (m, 1H), 6.47-6.34 (m, 1H), 5.84 (d, J = 7.2 Hz, 1H), 4.38 (m, 1H), 4.27-4.09 (m, 2H), 4.05-3.78 (m, 4H), 3.60-3.35 (m, 3H), 3.23-3.01 (m, 4H), 2.84-2.60 (m, 3H), 2.50-2.41 (m, 3H), 2.30-2.21 (m, 4H), 2.10-1.98 (m, 1H), 1.90-1.66 (m, 4H). LCMS m / z = 566.4 [M+1] + .

[0242] Examples 2 and 3

[0243]

[0244] Step 1: Synthesis of compound 2-2

[0245] Compound 2-1 (2.2 g, 9.11 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to -78 °C under nitrogen protection. Then n-BuLi (2.5 M, 3.64 mL, 1 eq) was added dropwise, and the reaction was stirred at -78 °C for 1 hr. N,N-dimethylformamide (3.33 g, 45.55 mmol, 3.50 mL, 5 eq) was added, and the stirring was continued at -78 °C for 0.5 hr. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), and then water (10 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column (ethyl acetate / petroleum ether = 0-15%) to obtain compound 2-2. 1 H NMR (400 MHz, CDC13) δ = 11.32 (s, 1H), 8.04 (dd, J = 1.2, 8.0 Hz, 1H), 7.92 (dd, J = 1.2, 7.2 Hz, 1H), 7.87 (dd, J = 1.2, 8.4 Hz, 1H), 7.71 (dd, J = 1.2, 7.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.51-7.44 (m, 1H).

[0246] Step 2: Synthesis of compound 2-3

[0247] Sodium hydride (248.01 mg, 6.20 mmol, 60% purity, 1.2 eq) was suspended in anhydrous tetrahydrofuran (5 mL) and cooled to 0 °C under nitrogen protection, then methyl acetoacetate (600 mg, 5.17 mmol, 555.56 μL, 1 eq) was added dropwise. After stirring for 10 min, n-butyllithium (2.5 M, 2.27 mL, 1.1 eq) was added dropwise, and the reaction was continued to stir at 0 °C for 20 min. The reaction system was cooled to -78 °C with a dry ice acetone bath, and a tetrahydrofuran (6 mL) solution of compound 2-2 (1.08 g, 5.68 mmol, 1.1 eq) was added dropwise. The reaction was stirred for 30 min, and then slowly warmed to room temperature and stirred for 30 min. The reaction was quenched with water (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried over sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound 2-3. 1 H NMR (400 MHz, CDC13) δ = 8.07 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.63-7.49 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 6.92 (br d, J = 9.6 Hz, 1H), 3.75 (s, 3H), 3.55 (s, 2H), 3.37 (dd, J = 1.6, 18.1 Hz, 1H), 3.24 (d, J = 1.2 Hz, 1H), 2.86-2.77 (m, 1H).

[0248] Step 3: Synthesis of compound 2-4

[0249] Compound 2-3 (520 mg, 1.70 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and then N, N-dimethylformamide dimethyl acetal (202.01 mg, 1.70 mmol, 225.20 μL, 1 eq) was added. The resulting reaction solution was stirred at 25 °C for 1 hr, and then boron trifluoride etherate (240.60 mg, 1.70 mmol, 209.22 μL, 1 eq) was added. The reaction solution was stirred at 25 °C for 18 hrs. The reaction solution was concentrated under vacuum, and the residue was adjusted to pH ~ 3-4 with 2M hydrochloric acid, and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-35%) to obtain compound 2-4. 1H NMR (400 MHz, CDC13) δ = 8.56 (d, J = 0.8 Hz, 1H), 7.91 (t, J = 8.0 Hz, 2H), 7.85 (dd, J = 1.2, 8.4 Hz, 1H), 7.65 (dd, J = 1.6, 7.6 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.44 - 7.35 (m, 2H), 3.87 (s, 3H), 3.27 - 3.17 (m, 1H), 2.92 - 2.82 (m, 1H). LCMS m / z = 317.0 [M+H] + .

[0250] Step 4: Synthesis of compound 2-5

[0251] Compound 2-4 (780 mg, 2.46 mmol, 1 eq) was dissolved in tetrahydrofuran (3 mL) and cooled to -78 °C under nitrogen protection. Then lithium tri-sec-butylborohydride (1 M, 2.46 mL, 1 eq) was added dropwise, and the reaction was stirred at -78 °C for 1 hr. The reaction was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated in vacuo to give the crude product. The crude product was purified by column (ethyl acetate / petroleum ether = 0-15%) to give compound 2-5. 1 H NMR (400 MHz, CDC13) δ = 8.56 (d, J = 0.8 Hz, 1H), 7.91 (t, J = 8.0 Hz, 2H), 7.85 (dd, J = 1.2, 8.4 Hz, 1H), 7.65 (dd, J = 1.6, 7.6 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.44 - 7.35 (m, 2H), 3.87 (s, 3H), 3.27 - 3.17 (m, 1H), 2.92 - 2.82 (m, 1H). LCMS m / z = 317.0 [M+H]

[0252] Step 5: Synthesis of compound 2-6

[0253] Compound 2-5 (497 mg, 1.56 mmol, 1 eq) was dissolved in methanol (2 mL), then 2-methylthiourea sulfate (528.27 mg, 2.81 mmol, 1.8 eq) and sodium methoxide (421.14 mg, 7.80 mmol, 5 eq) were added, and the resulting reaction solution was stirred at 25 °C for 18 hrs under nitrogen protection. The methanol was removed under reduced pressure, water (1 mL) was added to the residue, and the pH was adjusted to 5-6 with 2M hydrochloric acid, and a large amount of white solid was precipitated. The solid was collected by filtration and dried in vacuo to give compound 2-6. The crude product was used directly in the next reaction. LCMS m / z = 359.1 [M+H] + .

[0254] Step 6: Synthesis of compound 2-7

[0255] Compound 2-6 (440.00 mg, 1.23 mmol, 1 eq) and N,N-diisopropylethylamine (316.95 mg, 2.45 mmol, 427.15 μL, 2 eq) were added to anhydrous dichloromethane (5 mL) and cooled to 0 °C, then triflic anhydride (449.74 mg, 1.59 mmol, 263.00 μL, 1.3 eq) was added thereto. After addition, the reaction was stirred at 0 °C for 60 min. The reaction solution was concentrated under vacuum to obtain a crude product, which was purified by column (ethyl acetate / petroleum ether = 0-6%) to obtain compound 2-7. 1 H NMR (400 MHz, CDC13) d = 7.99 (d, J = 7.2 Hz, 1H), 7.90-7.82 (m, 2H), 7.66-7.54 (m, 2H), 7.44-7.33 (m, 1H), 6.46 (dd, J = 2.4, 10.4 Hz, 1H), 5.12-5.04 (m, 1H), 4.97-4.89 (m, 1H), 3.63 (dd, J = 2.0, 18.0 Hz, 1H), 3.05-2.90 (m, 1H), 2.57 (s, 3H). LCMS m / z = 491.0 [M+H] + .

[0256] Step 7: Synthesis of compound 2-8

[0257] Compound 2-7 (121 mg, 246.48 μmol, 1 eq) and N,N-diisopropylethylamine (95.57 mg, 739.45 μmol, 128.80 μL, 3 eq) were added to N,N-dimethylformamide (1.5 mL), then compound 1-10A hydrochloride (70.31 mg, 237.71 μmol, 1.1 eq) was added, and the resulting reaction solution was replaced with nitrogen and stirred in a 100 °C oil bath for 1 hr. The reaction solution was concentrated under vacuum to obtain a crude product, which was purified by column (ethyl acetate / petroleum ether = 0-30%) to obtain compound 2-8. LCMS m / z = 600.2 [M+H] + .

[0258] Step 8: Synthesis of compound 2-9

[0259] Compound 2-8 (125 mg, 208.29 μmol, 1 eq) was dissolved in dichloromethane (1 mL), then m-chloroperoxybenzoic acid (84.57 mg, 416.58 μmol, 85% purity, 2 eq) was added, the resulting reaction solution was stirred at 20 °C for 8 hr. The reaction solution was filtered to remove the insoluble matter, the filtrate was concentrated under vacuum to obtain a crude product, which was purified by column (ethyl acetate / petroleum ether = 0-60%) to obtain compound 2-9. LCMS m / z = 632.3 [M+H] + .

[0260] Step 9: Synthesis of compound 2-10

[0261] Compound 2-9 (101 mg, 159.78 μmol, 1 eq) and 1-11A (55.21 mg, 479.34 μmol, 56.91 μL, 3 eq) were dissolved in toluene (0.8 mL). The resulting solution was cooled to -5 °C, then t-BuONa (30.71 mg, 319.56 μmol, 2 eq) was added, the resulting reaction solution was stirred at -5-0 °C for 1 hr. The reaction solution was diluted with 3 mL of ethyl acetate, then washed with water (1 mL) and saturated brine (1 mL). The organic phase was concentrated under vacuum to obtain a crude product, which was purified by column (methanol / dichloromethane = 0-8%) to obtain compound 2-10. LCMS m / z = 667.3 [M+H] + .

[0262] Step 10: Synthesis of compound 2-11 and 3-1 mixture

[0263] Compound 2-10 (101 mg, 151.38 μmol, 1 eq) was dissolved in dichloromethane (1 mL), then palladium acetate (6.80 mg, 30.28 μmol, 0.2 eq) and triethylsilane (88.01 mg, 756.90 μmol, 120.90 μL, 5 eq) were added, the resulting reaction solution was stirred at room temperature for 1 hr. The reaction solution was concentrated under vacuum to obtain a mixture of compound 2-11 and 3-1, which was used directly in the next step reaction without purification. Compound 2-11: LCMS m / z = 555.3 [M+Na] + ; Compound 3-1: LCMS m / z = 521.3 [M+Na] + .

[0264] Step 11: Synthesis of compound 2 and 3

[0265] A mixture of compounds 2-11 and 3-1 was dissolved in dichloromethane (1 mL), then triethylamine (45.95 mg, 454.14 μmol, 63.21 μL, 3 eq) was added. The resulting reaction solution was cooled to 0 °C, then allyl chloride (20.55 mg, 227.07 μmol, 18.52 μL, 1.5 eq) was added, and the reaction was stirred for 30 min. The reaction solution was concentrated under vacuum to obtain a crude product, which was separated by high performance liquid chromatography preparation (separation conditions: column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid) - acetonitrile]; acetonitrile%: 15% - 55%, 8 min) to obtain compounds 2 and 3. Compounds 2 and 3 are a pair of diastereoisomers. Compound 2: LCMS m / z = 587.3 [M+H] + ; Compound 3: LCMS m / z = 553.3 [M+H] + .

[0266] Example 4

[0267]

[0268]

[0269]

[0270] Synthesis of intermediate 4-14A

[0271] Step 1: Synthesis of compound 4-21

[0272] Compound 4-20 (3 g, 8.35 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL), wet palladium on carbon (1.2 g, 10% mass content) was added, and hydrogen gas (562.02 μg, 278.23 μmol, 1 eq) was replaced three times. The reaction was carried out at room temperature 25 °C for 2 hr under 15 Psi. The reaction solution was filtered, and the mother liquor was collected and concentrated to obtain the product. Compound 4-21 was obtained. LCMS m / z = 170.1 [M-55+H] + .

[0273] Step 2: Synthesis of compound 4-22

[0274] Compound 4-21 (0.2 g, 887.76 μmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), triethylamine (269.50 mg, 2.66 mmol, 370.70 μL, 3 eq) was added, and the reaction was protected under nitrogen. The reaction was cooled to 0 °C, and trifluoroacetic anhydride (205.10 mg, 976.53 μmol, 135.83 μL, 1.1 eq) was added. The reaction was stirred at 0 ℃The reaction was carried out for 0.5 hours. Saturated ammonium chloride aqueous solution (10 mL) was poured in, followed by the addition of ethyl acetate (5 mL * 2), and washing with saturated brine (5 mL). The mixture was then purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 1, TLC: petroleum ether / ethyl acetate = 3 / 1) to give compound 4-22. 1 H NMR (400MHz, CDCl3) δ = 4.86 (s, 1H), 4.51-4.06 (m, 2H), 3.88 (d, J = 14.0Hz, 1H), 3.52-3.33 (m, 1H), 3. 24(dd,J=4.0,14.2Hz,1H),3.12-2.92(m,1H),2.91-2.73(m,1H),2.67(s,1H),1.50(s,9H); LCMS:MS m / z=222.0[M-100+H] + .

[0275] Step 3: Synthesis of compound 4-14A

[0276] Compound 4-22 (150 mg, 466.86 μmol, 1 eq) was dissolved in dioxane hydrochloride (5 M, 8 mL, 85.68 eq) under nitrogen protection and reacted at 18 °C for 1 hr. The solution was directly evaporated to dryness to give the hydrochloride salt of compound 4-14A. LC-MS: MS m / z = 222.0 [M+H] +

[0277] Synthesis of Example 4

[0278] Step 1: Synthesis of compound 4-2

[0279] After mixing water (210 mL) and hydrochloric acid (210 mL, 36–38% by mass), compound 4-1 (36.00 g, 176.44 mmol, 1 eq) was added, and the temperature was raised to 65 °C, reacting for 1 hour. Then, the temperature was lowered to 0–5 °C, and sodium nitrite (14.61 g, 211.72 mmol, 1.2 eq) dissolved in water (70 mL) was added dropwise, stirring for 15 minutes. Cuprous chloride (26.20 g, 264.65 mmol, 6.33 mL, 1.5 eq) was dissolved in hydrochloric acid (350 mL, 36–38% by mass), and the temperature was lowered to 0–5 °C. This solution was then added dropwise, and the reaction continued for 6 hours. After adding 750 mL of dichloromethane to the reaction system and stirring for 20 min, the mixture was separated. The organic phase was washed once with 350 mL of saturated brine, dried with 30.00 g of anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C to obtain compound 4-2. 1H NMR (400 MHz, CDC13) δ = 7.24-7.21 (m, 1H), 6.94 (dd, J = 2.8, 8.8 Hz, 1H), 2.43 (s, 3H).

[0280] Step 2: Synthesis of compound 4-3

[0281] Tetrahydrofuran (395 mL), compound 4-2 (39.50 g, 176.76 mmol, 1 eq) was added to a previously prepared clean reaction bottle, and stirring was started. After the temperature was lowered to -70 ~ -65 °C, lithium diisopropylamine (2 M, 106.05 mL, 1.2 eq) was added dropwise. The reaction was continued for 1 hr. Then N,N-dimethylformamide (18.76 g, 256.70 mmol, 19.75 mL, 1.45 eq) was added, and the reaction was continued for 1 hr. After 500 mL of saturated ammonium chloride solution was added to the reaction system, the liquid was separated, and the organic phase was washed once with 300 mL of saturated brine. After 20 g of anhydrous sodium sulfate was added to dry the organic phase, it was filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C. Compound 4-3 was obtained. 1 H NMR (400 MHz, CDC13) δ = 7.24-7.21 (m, 1H), 6.94 (dd, J = 2.8, 8.8 Hz, 1H), 2.43 (s, 3H). + ,247.0 [M+3H] + .

[0282] Step 3: Synthesis of compound 4-4

[0283] Dimethyl sulfoxide (300 mL), compound 4-3 (20.00 g, 79.53 mmol, 1 eq) was added to a previously prepared clean reaction bottle, and stirring was started. Then hydrazine hydrate (48.75 g, 954.35 mmol, 47.33 mL, 98% mass content, 12 eq) was added, and the temperature was raised to 130 °C. The reaction was continued for 3 hr. After the small test reaction liquid was combined, the reaction liquid was poured into 700 mL of water, and then filtered. The filter cake was washed with water (100 mL x 3 times). The obtained filter cake was dissolved with 300 mL of ethyl acetate, and then separated. The organic phase was dried by adding 50.00 g of anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C. Compound 4-4 was obtained. 1 H NMR (400 MHz, CDC13) δ = 7.24-7.21 (m, 1H), 6.94 (dd, J = 2.8, 8.8 Hz, 1H), 2.43 (s, 3H). + ,247.0 [M+3H] + .

[0284] Step 4: Synthesis of compound 4-5

[0285] Dichloromethane (200 mL), compound 4-4 (20.00 g, 81.47 mmol, 1 eq) was added to a previously prepared clean reaction bottle, and stirring was started; then p-toluenesulfonic acid pyridine salt (2.05 g, 8.15 mmol, 0.1 eq), 2-methoxy-3,4-dihydropyran (20.56 g, 244.40 mmol, 22.35 mL, 3 eq) were added thereto in turn, and the reaction was carried out at room temperature 20 °C for 12 h. After 200 mL of water was added to the reaction system, the reaction solution was directly separated, and the organic phase was dried by adding 20.00 g of anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C to obtain a crude compound. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 ~ 70 / 30, TLC: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 4-5. 1 H NMR (400 MHz, CDC13) δ = 7.95 (s, 1H), 7.44 (s, 1H), 5.67 (dd, J = 2.8, 8.8 Hz, 1H), 4.02-3.98 (m, 1H), 3.79-3.71 (m, 1H), 2.57 (s, 3H), 2.54-2.46 (m, 1H), 2.18-2.05 (m, 2H), 1.80-1.66 (m, 3H); LCMS m / z = 329.0 [M+H]

[0286] 329.0 [M+H] + , 331.0 [M+3H] + .

[0287] Step 5: Synthesis of compound 4-6

[0288] Tetrahydrofuran (160 mL), compound 4-5 (16 g, 48.54 mmol, 1 eq) was added to a previously prepared clean reaction bottle, and stirring was started. After the temperature was lowered to -70 ~ -65 °C, n-butyllithium (2.5 M, 21.36 mL, 1.1 eq) was slowly added thereto, and the reaction was carried out for 1 h; then N,N-dimethylformamide (35.48 g, 485.41 mmol, 37.35 mL, 10 eq) was added thereto, and the reaction was continued for 0.5 h. After 250 mL of saturated ammonium chloride solution was added to the reaction system, the solution was separated, and the organic phase was washed once with 150 mL of saturated brine, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C to obtain a solid. The oil was mixed with 7 mL of ethyl acetate and slurried for 20 min, filtered, and the filter cake was rotary evaporated under reduced pressure at 45 °C. Compound 4-6 was obtained. 1H NMR (400 MHz, CDC13) δ = 10.72 (s, 1H), 8.63 (s, 1H), 7.74 (s, 1H), 5.70 (dd, J = 2.8, 8.8 Hz, 1H), 3.98-3.94 (m, 1H), 3.75-3.68 (m, 1H), 2.55 (s, 3H), 2.53-2.45 (m, 1H), 2.16-2.05 (m, 2H), 1.83-1.61 (m, 3H); LCMS m / z = 279.1 [M+H] + .

[0289] Step 6: Synthesis of compound 7

[0290] Tetrahydrofuran (54 mL), compound 4-6 (5.4 g, 19.37 mmol, 1 eq) were added into a previously prepared clean reaction flask, and stirring was started; then tert-butylsulfinamide (2.58 g, 21.31 mmol, 232.15 μL, 1.1 eq), titanium tetraisopropoxide (8.84 g, 38.75 mmol, 8.04 mL, 2 eq) were added into the flask in turn, and the reaction was carried out at 20 °C for 12 hr. After 50 mL saturated ammonium chloride solution was added into the reaction system, the mixture was separated, and the organic phase was dried by adding 3.00 g anhydrous sodium sulfate, then filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 ~ 50 / 50, TLC: petroleum ether / ethyl acetate = 10 / 1) to obtain compound 4-7. LCMS m / z = 382.2 [M+H] + .

[0291] Step 7: Synthesis of compound 4-8

[0292] Tetrahydrofuran (35 mL), sodium hydride (829.50 mg, 20.74 mmol, 60% mass content, 1.2 eq) were added into a previously prepared clean reaction flask, and stirring was started, then the temperature was lowered to 0-5 °C, after which methyl acetoacetate (2.41 g, 20.74 mmol, 2.23 mL, 1.2 eq) was added dropwise thereto, and the reaction was continued for 20 min. Then n-butyllithium (2.5 M, 7.60 mL, 1.1 eq) was added dropwise thereto, and the reaction was continued for 20 min, then the temperature was lowered to -70 to -65 °C, after which compound 4-7 (6.60 g, 17.28 mmol, 1 eq) dissolved in tetrahydrofuran (35 mL) was added dropwise thereto, and the reaction was continued for 20 min, then the temperature was slowly increased to room temperature 20 °C, and the reaction was continued for 0.5 hr. The reaction solution was poured into 100 mL of saturated ammonium chloride solution, combined with 1 g batches, and then separated, the organic phase was dried by adding 3.00 g of anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 20 / 80, TLC: PE / EtOAc = 0:1) to obtain compound 4-8. 1 H NMR (400 MHz, CDC13) d = 8.20 (s, 1H), 7.44 (d, J = 5.6 Hz, 1H), 5.72-5.64 (m, 2H), 4.04-3.99 (m, 1H), 3.77-3.69 (m, 4H), 3.57-3.46 (m, 2H), 3.15-3.08 (m, 1H), 2.59-2.52 (m, 4H), 2.16-2.05 (m, 2H), 1.83-1.65 (m, 4H), 1.20-1.18 (m, 9H); LCMS m / z = 498.2 [M+H] + .

[0293] Step 8: Synthesis of compound 4-9

[0294] Toluene (66 mL), compound 4-8 (6.60 g, 13.25 mmol, 1 eq) were added into a previously prepared clean reaction flask, and stirring was started, then N,N-dimethylformamide dimethyl acetal (4.74 g, 39.76 mmol, 5.28 mL, 3 eq) was added thereto, and the reaction was continued at room temperature 20 °C for 12 hr. After 60 mL of water and 60 mL of ethyl acetate were added to the reaction system, stirring was continued for 5 min; the organic phase was washed once with 60 mL of saturated brine, then dried by adding 5.00 g of anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 50 °C to obtain compound 4-9, which was used directly in the next step.

[0295] Step 9: Synthesis of compound 4-10

[0296] Compound 4-9 (50 mg, 90.40 μmol, 1 eq) was dissolved in hydrochloric acid ethyl acetate (3 mL) and added to the reaction, stirred at 18 °C for 20 min. Directly concentrated to get the crude product. Compound 4-10 hydrochloride was obtained. LCMS m / z = 320.0 [M+H] +

[0297] Step 10: Synthesis of compound 4-11

[0298] Compound 4-10 (5.00 g, 14.04 mmol, 1 eq, HCl) was dissolved in dichloromethane (50 mL), triethylamine (5.97 g, 58.96 mmol, 8.21 mL, 4.2 eq), tert-butyl dicarbonate (12.25 g, 56.15 mmol, 12.90 mL, 4 eq), 4-dimethylaminopyridine (1.71 g, 14.04 mmol, 1 eq) were added to the reaction, stirred at 18 °C for 10 hr. Treated with 0.5 g batch, quenched with saturated aqueous ammonium chloride (100 mL), extracted with dichloromethane (30 mL*2 times), combined organic phase, dried over anhydrous sodium sulfate and concentrated to get the crude product. The crude product was column chromatographed (petroleum ether / ethyl acetate = 50 / 1 ~ 0 / 1, TLC: petroleum ether / ethyl acetate = 1 / 1) to get compound 4-11. 1 H NMR (400 MHz, CDCl3) δ = 9.02 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 6.16 (dd, J = 5.2, 8.8 Hz, 1H), 3.77 (s, 3H), 3.10 (dd, J = 8.4, 16.0 Hz, 1H), 2.82 (m, 1H), 2.48 (s, 3H), 1.63 (s, 9H), 1.18 (s, 9H). LCMS m / z = 520.1 [M+H] + .

[0299] Step 11: Synthesis of compound 4-12

[0300] Compound 4-11 (3.00 g, 5.77 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL), cooled to -78 °C, and lithium tri-sec-butylborohydride (1 M, 5.77 mL, 1 eq) was added dropwise to the reaction solution under nitrogen protection, and stirred for 0.5 hr. Quenched with saturated aqueous ammonium chloride (30 mL), extracted with ethyl acetate (20 mL x 2 times), combined organic phase, dried over anhydrous sodium sulfate and concentrated to get the crude product to get compound 4-12. LCMS m / z = 522.2 [M+H] + , 466.1 [M-56+H] + .

[0301] Step 12: Synthesis of compound 4-13

[0302] Compound 4-12 (2.30 g, 4.41 mmol, 1 eq), 2-methyl-2-thiohydantoin hydrogen sulfate (1.66 g, 8.81 mmol, 2 eq, H2SO4) were dissolved in methanol (430 mL), sodium methoxide (476.05 mg, 8.81 mmol, 2 eq) was added, stirred at 18 °C for 1.5 hr, then sodium methoxide (357.04 mg, 6.61 mmol, 1.5 eq) was added to the reaction solution, stirred at 18 °C for 10 hrs. Rotary evaporation, add water (50 mL), adjust pH = 2~3 with 1M dilute hydrochloric acid, white solid precipitated, filter to collect the solid. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1~0 / 1, TLC: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 4-13. LCMS m / z = 562.1 [M+H] + .

[0303] Step 13: Synthesis of compound 4-14

[0304] Compound 4-13 (0.328 g, 583.55 μmol, 1 eq), N,N-diisopropylethylamine (377.09 mg, 2.92 mmol, 508.21 μL, 5 eq) were dissolved in dichloromethane (10 mL), triflic anhydride (246.96 mg, 875.32 μmol, 144.42 μL, 1.5 eq) was added at 0 °C, stirred at 0 °C for 1 hr. Processed with 0.56 g batch, combined and poured into saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (20 mL x 3 times), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1~5 / 1) TLC (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 4-14. 1 H NMR (400 MHz, CDCl3) δ = 8.21-8.11 (m, 1H), 8.00-7.90 (m, 1H), 5.86-5.69 (m, 1H), 5.25-5.09 (m, 1H), 4.68-4.46 (m, 1H), 3.57-3.42 (m, 1H), 3.27-3.08 (m, 1H), 2.66-2.41 (m, 6H), 1.79-1.67 (m, 9H), 1.21-1.07 (m, 9H); LCMS m / z = 637.9 [M-56+H] + , 639.8 [M-56+3H] + Step 14: Synthesis of compound 4-15

[0305] Compound 4-14 (630 mg, 907.60 μmol, 1 eq), compound 4-14A (420.90 mg, 1.63 mmol, 1.8 eq, HC1) were dissolved in N,N-dimethylformamide (15 mL), N,N-diisopropyl ethylamine (469.19 mg, 3.63 mmol, 632.33 μL, 4 eq) was added, stirred at 20 °C for 2 hr. Pour into water (30 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product. Purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 ~ 1 / 1), TLC: petroleum ether / ethyl acetate = 0 / 1 to give compound 4-15. 1 H NMR (400 MHz, CDC13) δ = 8.18-8.05 (m, 1H), 8.04-7.93 (m, 1H), 5.75-5.45 (m, 1H), 5.06-4.89 (m, 1H), 4.66-4.35 (m, 1H), 4.19-3.84 (m, 3H), 3.82-3.45 (m, 1H), 3.43-3.12 (m, 2H), 3.06-2.75 (m, 6H), 2.61-2.38 (m, 5H), 1.79-1.60 (m, 9H), 1.14-0.85 (s, 9H); LCMS m / z = 765.0 [M+H] + .

[0306] Step 15: Synthesis of compound 4-16

[0307] Compound 4-15 (400.00 mg, 522.71 μmol, 1 eq) was dissolved in dichloromethane (8 mL), m-chloroperoxybenzoic acid (200.00 mg, 985.11 μmol, 85% mass content, 1.88 eq) was added, stirred at 20 °C for 2 hr. The reaction solution was treated with 200 mg batch, washed with aqueous sodium sulfite solution (20 mL, 10%), dried over anhydrous sodium sulfate, filtered, concentrated to give the crude product. The crude product was purified by column chromatography (Si02 100 mesh, petroleum ether / ethyl acetate = 50 / 1 ~ 1 / 1, TLC: petroleum ether / ethyl acetate = 2 / 1) to give compound 4-16. LCMS m / z = 697.1 [M-100+H] + .

[0308] Step 16: Synthesis of compound 4-17

[0309] Compound 1-11A (57.79 mg, 501.73 umol, 59.57 uL, 4 eq) was dissolved in toluene (1 mL), and sodium tert-butoxide (42.19 mg, 439.01 umol, 3.5 eq) was added at 0 °C and stirred for 15 min. Compound 4-16 (100.00 mg, 125.43 umol, 1 eq) was dissolved in 0.1 mL of toluene and slowly added to the reaction solution. The reaction was carried out at 0 °C for 30 min. Water (5 mL) was added for quenching, and ethyl acetate (5 mL x 2) was used for extraction, and the organic phases were combined. Compound 4-17 was obtained. LCMS m / z = 636.1 [M+H] + .

[0310] Step 17: Synthesis of compound 4-18

[0311] Compound 4-17 (79.80 mg, 125.44 umol, 1 eq) was dissolved in dichloromethane (2 mL), and N, N-diisopropyl ethylamine (81.06 mg, 627.18 umol, 109.24 uL, 5 eq) was added at 18 °C. The temperature was lowered to -78 °C, and acryloyl chloride (4.54 mg, 50.17 umol, 4.09 uL, 0.4 eq) was slowly added to the reaction solution. The reaction was carried out at -78 °C for 0.5 hr. An additional 8.00 mg of acryloyl chloride was added, and the reaction was carried out for 1 hr. Saturated aqueous ammonium chloride solution (5 mL) was added for quenching, and dichloromethane (5 mL*2) was used for extraction, and the organic phases were combined. The crude product was stirred in potassium carbonate (1.7 M, 1 mL) / methanol (1 mL) at 18 °C for 1 hr. Compound 4-18 was obtained by detecting the product (time = 0.943). LCMS m / z = 690.3 [M+H] + .

[0312] Step 18: Synthesis of compounds 4A and 4B

[0313] Compound 4-18 (100 mg, 144.88 umol, 1 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (3.08 g, 27.01 mmol, 2.00 mL, 186.45 eq) was added at 18 °C and the reaction was carried out for 1 hr. Compound 4-19 was obtained by concentration. Compound 4-19 was separated and purified by high performance liquid chromatography column: column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.1% TFA) - acetonitrile]; acetonitrile%: 5% - 30%, 8 min, sample was added with 0.05 mol / L dilute hydrochloric acid 0.2 mL, and concentrated under vacuum to obtain the hydrochloride salt of compound 4A (time of emergence: 2.417 min). LCMS m / z = 590.1 [M+H]+, 295.9 [M / 2+H] +; and hydrochloride salt of compound 4B (retention time: 2.388 min). LCMS m / z = 590.1 [M+H]+, 295.9 [M / 2+H] +

[0314] Example 5

[0315]

[0316] Step 1: Synthesis of compound 5-1

[0317] Tetrahydrofuran (27 mL), sodium hydride (789.28 mg, 19.73 mmol, 60% mass content, 2 eq) were added into a previously prepared clean reaction flask, and stirring was started, then the temperature was reduced to 0-5 °C, after which methyl acetoacetate (2.29 g, 19.73 mmol, 2.12 mL, 2 eq) was added dropwise thereto, and the reaction was continued for 30 min. Then n-butyllithium (2.5 M, 7.50 mL, 1.9 eq) was added dropwise thereto, and after the reaction was continued for 30 min, the temperature was reduced to -70 to -65 °C, then compound 4-6 (2.75 g, 9.87 mmol, 1 eq) dissolved in tetrahydrofuran (27 mL) was added dropwise thereto, and the reaction was continued for 0.5 hr. After the reaction mixture was quenched by pouring into 50 mL of saturated ammonium chloride solution, the organic phase was dried by adding 1.50 g of anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 70 / 30, TLC: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5-1. 1 H NMR (400 MHz, CDC13) δ = 8.40 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 11.6 Hz, 1H), 5.95-5.91 (m, 1H), 5.69-5.64 (m, 1H), 4.04-3.98 (m, 1H), 3.78-3.70 (m, 4H), 3.56 (d, J = 0.8 Hz, 2H), 3.37 (d, J = 3.2, 8.4 Hz, 1H), 3.08-2.99 (m, 2H), 2.61-2.54 (m, 1H), 2.50 (s, 3H), 2.18-2.04 (m, 2H), 1.81-1.70 (m, 2H). LCMS: MS m / z = 395.0 [M+H] + .

[0318] Step 2: Synthesis of compound 5-2

[0319] Dichloromethane (25 mL), compound 5-1 (1.6 g, 4.05 mmol, 1 eq) was added to a previously prepared clean reaction flask, and stirring was started; then N,N-dimethylformamide dimethyl acetal (724.30 mg, 6.08 mmol, 807.47 μL, 1.5 eq) was added thereto, and reaction was performed at room temperature 20 °C for 12 hr. Then, the temperature was lowered to 0-5 °C, and boron trifluoride etherate (575.13 mg, 4.05 mmol, 500.11 μL, 1 eq) was added thereto, and reaction was continued at room temperature 20 °C for 1 hr. The reaction solution was subjected to rotary evaporation under reduced pressure at 30 °C to obtain compound 5-2, which was directly used in the next step.

[0320] Step 3: Synthesis of compound 5-3

[0321] Tetrahydrofuran (58 mL), compound 5-2 (3.9 g, 8.40 mmol, 87.233% mass content, 1 eq) was added to a previously prepared clean reaction flask, and stirring was started; after the temperature was lowered to -70 to -65 °C, lithium tri-sec-butylborohydride (1 M, 9.24 mL, 1.1 eq) was added dropwise thereto, and reaction was performed for 0.5 hr. After the reaction solution was poured into 50 mL of a saturated ammonium chloride solution, the organic phase was dried by adding 2.00 g of anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 70 / 30, TLC: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 5-3. LCMS: MS m / z = 407.0 [M+H] +

[0322] Step 4: Synthesis of compound 5-4

[0323] Methanol (4 mL), compound 5-3 (0.65 g, 1.60 mmol, 1 eq), methyl isothiourea sulfate (1.22 g, 6.39 mmol, 4 eq, H2SO4) was added to a previously prepared reaction flask, and stirring was started. Then, sodium methoxide (172.61 mg, 3.20 mmol, 2 eq) was added thereto, and reaction was performed at room temperature 25 °C for 1 hr, and after additional sodium methoxide (172.62 mg, 3.20 mmol, 2 eq) was added, reaction was continued for 15 hr. The reaction solution was subjected to rotary evaporation under reduced pressure at 45 °C to obtain a white solid, which was extracted with 10 mL of water and 10 mL of ethyl acetate. The organic phase was washed once with 10 mL of saturated brine, dried by adding 0.50 g of anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 40 / 60, TLC: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5-4. LCMS: MS m / z = 447.0 [M+H] + .

[0324] Step 5: Synthesis of compound 5-5

[0325] Dichloromethane (20 mL), compound 5-4 (610 mg, 1.36 mmol, 1 eq) were added into a previously prepared clean reaction flask, and stirring was started. After the temperature was lowered to 0-5 °C, N,N-diisopropylethylamine (617.36 mg, 4.78 mmol, 832.02 μL, 3.5 eq), triflic anhydride (770.13 mg, 2.73 mmol, 450.37 μL, 2 eq) were added into it, and the reaction was allowed to proceed for 0.5 hr. After the reaction solution was poured into 20 mL saturated ammonium chloride solution, it was partitioned, and the organic phase was washed once with 10 mL saturated brine solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 ~ 70 / 30, TLC: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 5-5.1H NMR (400 MHz, CDCI3) δ = 8.26 (d, J = 5.2 Hz, 1H), 7.48 (d, J = 14.4 Hz, 1H), 5.73-5.67 (m, 1H), 5.53-5.49 (m, 1H), 5.15 (dd, J = 3.2, 15.6 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 4.06-3.99 (m, 1H), 3.80-3.72 (m, 1H), 3.30-3.25 (m, 1H), 3.12-3.04 (m, 1H), 2.61-2.49 (m, 7H), 2.19-2.07 (m, 2H), 1.83-1.68 (m, 3H).

[0326] Step 6: Synthesis of compound 5-6

[0327] N,N-dimethylformamide (5 mL), compound 5-5 (0.33 g, 569.94 μmol, 1 eq) were added into a previously prepared clean reaction flask, and stirring was started. Then N,N-diisopropylethylamine (368.29 mg, 2.85 mmol, 496.35 μL, 5 eq), compound 5-5a (143 mg, 1.14 mmol, 2.00 eq, 2HCl) were added into it, and the temperature was raised to 100 °C, and the reaction was allowed to proceed for 1 hr. After the reaction solution was poured into 20 mL saturated ammonium chloride solution, it was dissolved in 10 mL ethyl acetate solution, partitioned, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C. The crude product was purified by column chromatography (dichloromethane / methanol = 100 / 0 ~ 85 / 15, TLC: dichloromethane / methanol = 15 / 1) to obtain compound 5-6. 1H NMR (400 MHz, CDC13) δ = 8.22 (d, J = 4.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 5.71-5.66 (m, 1H), 5.57-5.53 (m, 1H), 4.89-4.80 (m, 2H), 4.05-3.86 (m, 2H), 3.77-3.32 (m, 1H), 3.60-3.57 (m, 1H), 3.39-3.38 (m, 1H), 3.31-3.26 (m, 1H), 3.23-3.17 (m, 1H), 3.12-2.96 (m, 3H), 2.93-2.83 (m, 2H), 2.57-2.56 (m, 1H), 2.54-2.52 (m, 7H), 2.16-2.04 (m, 2H), 1.79-1.71 (m, 3H). LCMS: MS m / z = 554.0 [M+H] + .

[0328] Step 7: Synthesis of compound 5-7

[0329] After compound 5-6 (190 mg, 342.90 μmol, 1 eq) was dissolved in tetrahydrofuran (2 mL), stirring was started. Then the temperature was reduced to 0-5 °C, trifluoroacetic anhydride (108.03 mg, 514.34 μmol, 71.54 μL, 1.5 eq), triethylamine (121.44 mg, 1.20 mmol, 167.04 μL, 3.5 eq) were added, and the reaction was allowed to proceed for 0.5 hr. After the reaction solution was poured into 10 mL saturated ammonium chloride solution, 10 mL dichloromethane was added for extraction. After the organic phase was washed with saturated brine once, anhydrous sodium sulfate was added for drying, filtration was performed, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C to obtain compound 5-7. LCMS: MS m / z = 650.2 [M+H] + .

[0330] Step 8: Synthesis of compound 5-8

[0331] Dichloromethane (5 mL), compound 5-7 (0.2 g, 290.04 μmol, 94.281% mass content, 1 eq) was added to a previously prepared clean reaction bottle, and stirring was started. Then m-chloroperoxybenzoic acid (143.96 mg, 667.37 μmol, 80% mass content, 2.30 eq) was added thereto, and reaction was performed at room temperature 25 °C for 0.5 hr. After the reaction solution was poured into 20 mL of a sodium thiosulfate solution (10%), 15 mL of dichloromethane was added for extraction, and the organic phase was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C. The crude product was purified by column chromatography (dichloromethane / methanol = 100 / 0 ~ 85 / 15, TLC: dichloromethane / methanol = 15 / 1) to obtain compound 5-8. LCMS: MS m / z = 682.0 [M+H] +

[0332] Step 9: Synthesis of compound 5-9

[0333] Toluene (5 mL), compound 1-11A (148.59 mg, 1.29 mmol, 153.18 μL, 4 eq) was added to a previously prepared clean reaction bottle, and stirring was started. Then the temperature was lowered to 0 ~ 5 °C, and sodium tert-butoxide (123.98 mg, 1.29 mmol, 4 eq) was added thereto, and reaction was performed for 15 min. Then compound 5-8 (0.22 g, 322.53 μmol, 1 eq) was dissolved in 0.2 mL of toluene, and quickly added thereto, and reaction was performed for 0.5 hr. After the reaction solution was poured into 10 mL of a saturated ammonium chloride solution, 10 mL of dichloromethane was added for extraction, and the organic phase was washed once with 10 mL of saturated brine, and then dried by adding 0.50 g of anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C to obtain compound 5-9. LCMS: MS m / z = 621.4 [M+H] +

[0334] Step 10: Synthesis of compound 5-10

[0335] Dichloromethane (5 mL), compound 5-9 (98.26 mg, 125.80 pmol, 79.529% mass content, 1 eq) was added to the pre-prepared reaction bottle, and stirring was started. Then the temperature was reduced to -60 °C, and then N, N-diisopropyl ethylamine (162.59 mg, 1.26 mmol, 219.12 pL, 10 eq) was added thereto, and acryloyl chloride (17.08 mg, 188.70 pmol, 15.39 pL, 1.5 eq) dissolved in 0.3 mL of dichloromethane was added dropwise thereto, and the reaction was carried out for 10 min. After the reaction solution was poured into 5 mL of saturated ammonium chloride solution, it was separated, and the organic phase was washed once with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 35 °C. Compound 5-10 was obtained, which was directly used in the next step. LCMS: MS m / z = 675.1 [M+H] +

[0336] Step 11: Synthesis of compounds 5A and 5B

[0337] Dichloromethane / trifluoroacetic acid (4 mL, 5 / 3), compound 5-10 (0.1 g, 148.10 pmol, 1 eq) was added to the reaction bottle, and the reaction was carried out at room temperature 25 °C for 0.5 hr. After the reaction solution was slowly added dropwise to 15 mL of saturated sodium bicarbonate solution, 10 mL of dichloromethane was added for extraction, and the organic phase was washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was subjected to rotary evaporation under reduced pressure at 30 °C. The crude product was separated and purified by high-performance liquid chromatography column, method: chromatography column: Phenomenex Gemini-NX 150*30 mm*5 pm; mobile phase: [H2O (0.1% TFA)-acetonitrile]; acetonitrile%: 20%-50%, 9 min, to obtain compound 5-11. Compound 5-11 was subjected to SFC resolution, method: chromatography column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 pm); mobile phase: [0.1% NH3H2O EtOH]; ethanol: 50%-50%, 15 min.

[0338] 5A (chiral column peak time: 1.516) was obtained. SFC analysis method (column: Chiralpak AD-3, 50*4.6 mm, I.D., 3 pm; mobile phase: A (CO2) and B (isopropanol containing 0.05% diethanolamine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 91.04%. 1H NMR (400 MHz, CDC13) δ = 8.26 (s, 1H), 7.37 (s, 1H), 6.62-6.56 (m, 1H), 6.42-6.38 (m, 1H), 5.84 (d, J = 11.6 Hz, 1H), 5.58 (dd, J = 4.0, 11.2 Hz, 1H), 4.94 (s, 2H), 4.55-4.43 (m, 1H), 4.27-4.18 (m, 1H), 4.02-3.87 (m, 1H), 3.76-3.73 (m, 1H), 3.23-3.18 (m, 4H), 3.07 - 2.98 (m, 2H), 2.87-2.74 (m, 3H), 2.56-2.53 (m, 6H), 2.13-2.07 (m, 1H), 1.82-1.76 (m, 3H), 1.37-1.29 (m, 3H). LCMS: MS m / z = 591.2 [M+H] + .

[0339] Obtained 5B (Chiral column peak time: 1.800). SFC analysis method (column: Chiralpak AD-3, 50 x 4.6 mm, I.D., 3 um; mobile phase: A (C02) and B (isopropyl alcohol containing 0.05% diethanolamine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 99.74%. 1 H NMR (400 MHz, CDC13) δ = 8.26 (s, 1H), 7.37 (s, 1H), 6.62-6.56 (m, 1H), 6.42-6.38 (m, 1H), 5.84 (d, J = 11.6 Hz, 1H), 5.58 (dd, J = 4.0, 11.2 Hz, 1H), 4.94 (s, 2H), 4.55-4.43 (m, 1H), 4.27-4.18 (m, 1H), 4.02-3.87 (m, 1H), 3.76-3.73 (m, 1H), 3.23-3.18 (m, 4H), 3.07 - 2.98 (m, 2H), 2.87-2.74 (m, 3H), 2.56-2.53 (m, 6H), 2.13-2.07 (m, 1H), 1.82-1.76 (m, 3H), 1.37-1.29 (m, 3H). LCMS: MS m / z = 591.2 [M+H] + .

[0340] Example 6

[0341]

[0342] Step 1: Synthesis of compound 6-1

[0343] Compound 4-17 (190 mg, 298.65 μmol, 1 eq), N, N-diisopropyl ethylamine (192.99 mg, 1.49 mmol, 260.10 μL, 5 eq) were dissolved in dichloromethane (5 mL), trifluoroacetic anhydride (94.09 mg, 447.98 μmol, 62.31 μL, 1.5 eq) was added at 0 °C, and the reaction was allowed to proceed at 0 °C for 0.5 hr. Saturated aqueous ammonium chloride solution (5 mL) was added for quenching, dichloromethane (5 mL*2) was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 6-1. LCMS: MS m / z = 732.3 [M+H] +

[0344] Step 2: Synthesis of compound 6-2

[0345] Compound 6-1 (200 mg, 273.15 μmol, 1 eq) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 98.89 eq) was added at 0 °C, and the reaction was allowed to proceed at 18 °C for 0.5 hr. It was directly rotary evaporated to give the crude product, which was separated and purified by high performance liquid chromatography column: Phenomenex Gemini-NX 150*30 mm*5 μm; mobile phase: [H2O (0.1% TFA) - acetonitrile]; acetonitrile%: 30% - 60% for 9 min to give compound 6-2. LCMS: MS m / z = 632.3 [M+H] +

[0346] Step 3: Synthesis of compound 6-3

[0347] Compound 6-2 (110 mg, 174.03 μmol, 1 eq), paraformaldehyde (88.91 mg, 1.74 mmol, 10 eq) were dissolved in 1, 2-dichloroethane (1 mL), methanol (1 mL), and ice acetic acid (1.05 mg, 17.40 μmol, 9.95 e-1 μL, 0.1 eq) was added, stirred for 30 min, sodium cyanoborohydride (21.87 mg, 348.06 μmol, 2 eq) was added, and the reaction was allowed to proceed at 25 °C for 10 hr. It was poured into saturated aqueous ammonium chloride solution (10 mL), dichloromethane (5 mL x 3) was added for extraction, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-3. LCMS: MS m / z = 646.1 [M+H] + , 647.7 [M+2H] +

[0348] Step 4: Synthesis of compound 6-4

[0349] Compound 6-3 (90 mg, 139.30 μmol, 1 eq) was dissolved in methanol (3 mL), potassium carbonate (1.7 M, 2.70 mL, 32.95 eq) was added, 18 ℃ The reaction was allowed to react for 1 hr. Saturated aqueous ammonium chloride solution (5 mL) was added for quenching, ethyl acetate (5 mL x 2) was used for extraction, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 6-4. LCMS: MS m / z = 550.2 [M+H] + , 551.8 [M+2H] + .

[0350] Step 5: Synthesis of compound 6A and 6B

[0351] Compound 6-4 (76 mg, 138.16 umol, 1 eq) was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (267.83 mg, 2.07 mmol, 360.96 uL, 15 eq) was added, acryloyl chloride (12.50 mg, 138.16 umol, 11.27 uL, 1 eq) was added at -60 °C, and the reaction was allowed to proceed at -60 °C for 0.5 hr. The reaction was quenched with saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (5 mL x 2), and the organic phase was combined and concentrated to give compound 6-5, which was separated and purified by high performance liquid chromatography column: Column: Phenomenex Gemini-NX C18 75*30mm*3um; Mobile Phase: [H2O (0.04% NH3H2O + 10 mM NH4HCO3) - ACN]; Acetonitrile%: 25%-55% in 6 min, which was subjected to SFC: Column: Phenomenex Gemini-NX C18 75*30mm*3um; Mobile Phase: [H2O (0.04% NH3H2O + 10 mM NH4HCO3) - ACN]; Acetonitrile%: 25%-55% in 6 min, which gave compound 6A (Chiral column retention time = 1.435 min), SFC analysis method (Column: Chiralpak AD-3, 50 x 4.6 mm, I.D., 3 um; Mobile Phase: A (CO2) and B (Isopropanol with 0.05% Diethanolamine); Gradient: B% = 5-50% in 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi. Optical purity: 87.38%. LCMS: MS m / z = 604.1 [M+H]+, and compound 6B (Chiral column retention time = 1.643), SFC analysis method (Column: Chiralpak AD-3, 50 x 4.6 mm, I.D., 3 um; Mobile Phase: A (CO2) and B (Isopropanol with 0.05% Diethanolamine); Gradient: B% = 5-50% in 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi. Optical purity: 100%. LCMS: MS m / z = 604.1 [M+H]+.

[0352] Example 7

[0353]

[0354] Step 1: Synthesis of compound 7-1

[0355] N,N-dimethylformamide (6 mL), compound 5-9 (150 mg, 193.18 pmol, 80% mass content, 1 eq) were added into a previously prepared reaction bottle, stirring was started, then the temperature was reduced to 0-5 °C, then 2-fluoropropenoic acid (26.10 mg, 289.78 pmol, 3.08 pL, 1.5 eq), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (110.18 mg, 289.78 pmol, 1.5 eq), N,N-diisopropylethylamine (74.90 mg, 579.55 pmol, 100.94 pL, 3 eq) were added into it in turn, and the reaction was carried out for 0.5 hr. After the reaction solution was poured into 15 mL of saturated ammonium chloride solution, 20 mL of ethyl acetate was added for extraction, the aqueous phase was washed with 15 mL of ethyl acetate once, and the combined organic phase was washed with 15 mL of saturated brine once, then anhydrous sodium sulfate was added for drying, filtration was performed, and the filtrate was subjected to rotary evaporation under reduced pressure at 45 °C. The crude product was purified by column chromatography (dichloromethane / methanol = 50 / 1, 30 / 1, 20 / 1, 15 / 1, 10 / 1, TLC: dichloromethane / methanol = 10 / 1) to obtain compound 7-1. 1 H NMR (400 MHz, CDC13) d = 8.24-8.21 (m, 1H), 7.48-7.43 (m, 1H), 5.71-5.65 (m, 1H), 5.61-5.55 (m, 1H), 5.27-5.23 (m, 1H), 4.97-4.84 (m, 2H), 4.60-4.56 (m, 2H), 4.06-4.00 (m, 2H), 3.76-3.67 (m, 5H), 3.57-3.37 (m, 2H), 3.21-3.15 (m, 4H), 3.04-2.97 (m, 4H), 2.93-2.81 (m, 3H), 2.54 (s, 3H), 2.38-2.33 (m, 1H), 2.19-2.05 (m, 6H), 1.79-1.66 (m, 3H). LCMS: MS m / z = 693.2 [M+H] + .

[0356] Step 2: Synthesis of compounds 7A and 7B

[0357] Dichloromethane / trifluoroacetic acid (7 mL, 5 / 3), compound 7-1 (70 mg, 100.98 pmol, 1 eq) was added into the reaction bottle, and the mixture was stirred at room temperature for 3 h. The reaction solution was slowly added into 15 mL saturated sodium bicarbonate solution, mixed with the small test reaction solution, and then 10 mL dichloromethane was added for extraction. The organic phase was washed with 10 mL saturated brine once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 30 °C to obtain a crude product. The crude product was separated and purified by high performance liquid chromatography column, and the method was as follows: column: Phenomenex lpm C18 100*40 mm*5 pm; mobile phase: [H2O (0.1% TFA)-acetonitrile]; acetonitrile%: 10%-35%, 8 min. Compound 7-2 was obtained and purified by SFC resolution, and the method was as follows: column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm); mobile phase: [0.1% NH3H2O EtOH]; EtOH%: 40%-40%, 15 min. Compound 7A (chiral column peak time: 1.263 min) was obtained. SFC analysis method (column: Chiralcel OJ-3, 50*4.6 mm I.D., 3 pm; mobile phase: A (CO2) and B (ethanol containing 0.05% diisopropylamine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 91.94%. 1 HNMR (400 MHz, CDCl3) δ = 8.29 (s, 1H), 7.35 (s, 1H), 5.61-5.57 (m, 1H), 5.48-5.32 (m, 1H), 5.28-5.24 (m, 1H), 4.95-4.86 (m, 3H), 4.44-4.43 (m, 1H), 4.20-4.16 (m, 2H), 3.97-3.93 (m, 1H), 3.80-3.78 (m, 1H), 3.50-3.48 (m, 1H), 3.27-3.22 (m, 1H), 3.14-2.95 (m, 4H), 2.81-2.71 (m, 3H), 2.52-2.50 (m, 7H), 2.34-2.28 (m, 1H), 2.08-2.02 (m, 1H), 1.91-1.84 (m, 2H). LCMS: MS m / z = 609.2 [M+H] + .

[0358] Compound 7B was obtained (chiral column peak time: 1.393 min). SFC analysis method (column: Chiralcel OJ-3, 50 x 4.6 mm I.D., 3 um; mobile phase: A (C02) and B (ethanol with 0.05% diisopropylamine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 82.48%. 1 HNMR (400 MHz, CDC13) δ = 8.26 (s, 1H), 7.35 (s, 1H), 5.59-5.55 (m, 1H), 5.48-5.36 (m, 1H), 5.29-5.24 (m, 1H), 4.93 (s, 2H), 4.42-4.40 (m, 1H), 4.24-4.20 (m, 2H), 3.73-3.70 (m, 1H), 3.24-2.98 (m, 8H), 2.90-2.71 (m, 3H), 2.53-2.48 (m, 7H), 2.33-2.31 (m, 1H), 2.09-2.04 (m, 1H), 1.89-1.85 (m, 2H). LCMS: MS m / z = 609.1 [M+H] + .

[0359] Example 8

[0360]

[0361]

[0362] Step 1: Synthesis of compound 8-2

[0363] In a dry 2 L three-necked flask (water-free and oxygen-free environment), sodium hydride (39.12 g, 978.08 mmol, 60% mass content, 2.4 eq) was added to N,N-dimethylformamide (510 mL), the reaction system was a heterogeneous gray color, cooled to 0 °C, and a solution of compound 8-1 (51 g, 407.53 mmol, 1 eq) in N,N-dimethylformamide (200 mL) was added dropwise under nitrogen protection. The reaction was carried out at 0 °C for 0.5 hr, and p-methoxychlorobenzene (140.41 g, 896.57 mmol, 122.10 mL, 2.2 eq) was added. The reaction system was a reddish brown color, and the reaction was carried out at 20 °C for 7.5 hr under nitrogen protection. The reaction solution was slowly added to 200 mL of saturated ammonium chloride, extracted with (200 mL x 2) methyl tert-butyl ether, and the organic phases were combined. The mixture was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated by an automatic column machine COMBI-FLASH (gradient elution: petroleum ether: ethyl acetate = 10:0-10:1, petroleum ether: ethyl acetate = 10:1), and purified to give compound 8-2. 1 H NMR (400 MHz, CDCl3) δ = 7.23-7.18 (m, 4H), 6.91-6.87 (m, 1H), 6.82-6.76 (m, 4H), 6.65-6.59 (m, 2H), 4.20 (s, 4H), 3.79 (s, 6H), 2.19 (s, 3H). LCMS: MS m / z = 366.1 [M+H] + .

[0364] Step 2: Synthesis of compound 8-3

[0365] To a solution of compound 8-2 (27 g, 73.88 mmol, 1 eq) in THF (60 mL) was added 2,2,6,6-tetramethylpiperidine (31.31 g, 221.65 mmol, 37.63 mL, 3 eq) at -5 °C, then n-butyllithium (2.5 M, 94.57 mL, 3.2 eq) was added dropwise at -5 ~ 0 °C for 15 min. The mixture was cooled to -60 °C, and N,N-dimethylformamide (108.00 g, 1.48 mol, 113.69 mL, 20 eq) was added quickly at -60 °C for 10 min. The reaction was quenched by adding 400 mL of saturated ammonium chloride solution, and extracted with 200 mL x 2 of methyl tert-butyl ether. The organic phase was combined and washed with 200 mL of saturated brine. The filtrate was concentrated to give the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-10:1) to give compound 8-3. 1 H NMR (400 MHz, CDCl3) δ = 10.43-10.35 (m, 1H), 7.21-7.18 (m, 5H), 6.92-6.81 (m, 5H), 4.25 (s, 4H), 3.80 (s, 6H), 2.23 (s, 3H). LCMS: MS m / z = 394.2 [M+H] + .

[0366] Step 3: Synthesis of compound 8-4

[0367] Compound 8-3 (17.8 g, 45.24 mmol, 1 eq) was added to N,N-dimethylformamide (170 mL), and bromosuccinimide (8.05 g, 45.24 mmol, 1 eq) was added at 20 °C for 20 min. The reaction mixture was added to 300 mL of water, extracted with 150 mL x 2 of methyl tert-butyl ether, and the organic phase was combined and washed with 100 mL x 2 of saturated brine. The filtrate was concentrated, and the crude product was slurried with a mixture of ethyl acetate and methyl tert-butyl ether (1:1) for 0.5 hr, filtered, and the filter cake was dried to give compound 8-4. 1 H NMR (400 MHz, CDCl3) δ = 10.39 (s, 1H), 7.17 (d, J = 8.8 Hz, 4H), 6.89 (d, J = 8.8 Hz, 1H), 6.85-6.82 (m, 4H), 4.22 (s, 4H), 3.79 (s, 6H), 2.28 (s, 3H). LCMS: MS m / z = 472.1 [M+H] +, 474.1 [M+3H] + .

[0368] Step 4: Synthesis of compound 8-5

[0369] Compound 8-4 (19.3 g, 40.86 mmol, 1 eq) was added to N,N-dimethylformamide (190 mL), cuprous iodide (15.56 g, 81.72 mmol, 2 eq) and methyl fluorosulfonyldifluoroacetate (39.25 g, 204.30 mmol, 25.99 mL, 5 eq) were added under nitrogen at 100 °C for 1 hr, the reaction solution was filtered with celite, the filtrate was added to 300 mL of water, extracted with 150 mL x 2 of methyl tert-butyl ether, the organic phase was combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-10:1, petroleum ether: ethyl acetate = 5:1) to give compound 8-5. 1 H NMR (400 MHz, CDC13) δ = 10.37 (q, J = 4.0 Hz, 1H), 7.18-7.11 (m, 4H), 6.89-6.82 (m, 4H), 6.73 (d, J = 8.8 Hz, 1H), 4.36 (s, 4H), 3.81 (s, 6H), 2.37-2.29 (m, 3H). LCMS: MS m / z = 484.0 [M+Na] + .

[0370] Step 5: Synthesis of compound 8-6

[0371] Anhydrous tetrahydrofuran (50 mL) and sodium hydride (1.17 g, 29.26 mmol, 60% mass content, 3 eq) were added to a dry three-necked flask, cooled to 0 °C, and methyl acetoacetate (3.40 g, 29.26 mmol, 3.15 mL, 3 eq) was added dropwise under nitrogen at 0 °C for 0.5 hr, n-butyllithium (2.5 M, 11.70 mL, 3 eq) was added dropwise at 0 °C for 0.5 hr, and compound 8-5 (4.5 g, 9.75 mmol, 1 eq) in tetrahydrofuran (20 mL) was added dropwise at -60 °C for 0.5 hr. A saturated ammonium chloride solution (100 mL) was added to the reaction solution, extracted with 30 mL of ethyl acetate, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-3:1, petroleum ether: ethyl acetate = 3:1) to give compound 8-6 as a yellow oil. 1H NMR (400 MHz, CDC13) δ = 7.18-7.15 (m, 4H), 6.90-6.78 (m, 4H), 6.61 (d, J = 8.8 Hz, 1H), 5.72-5.57 (m, 1H), 4.31 (m, 4H), 3.81 (s, 6H), 3.76 (s, 3H), 3.56 (s, 2H), 3.50-3.38 (m, 1H), 2.98-2.93 (m, 1H), 2.38-2.26 (m, 3H). LCMS: MS m / z = 578.1 [M+H] + .

[0372] Step 6: Synthesis of compound 8-7

[0373] Compound 8-6 (3 g, 5.19 mmol, 1 eq) was added to anhydrous dichloromethane (30 mL), N, N-dimethylformamide dimethyl acetal (742.74 mg, 6.23 mmol, 828.02 μL, 1.2 eq) was added, 20 °C for 16 hr, boron trifluoride ether (884.66 mg, 6.23 mmol, 769.27 μL, 1.2 eq) was added, 20 °C for 1 hr. The reaction solution was added to 20 mL of saturated sodium bicarbonate solution, liquid separation, the aqueous phase was further extracted with 20 mL of dichloromethane, the combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column (petroleum ether: ethyl acetate = 100:0-3:1, petroleum ether: ethyl acetate = 3:1) to obtain compound 8-7. 1 H NMR (400 MHz, CDC13) δ = 7.18-7.15 (m, 4H), 6.90-6.78 (m, 4H), 6.61 (d, J = 8.8 Hz, 1H), 5.72-5.57 (m, 1H), 4.31 (m, 4H), 3.81 (s, 6H), 3.76 (s, 3H), 3.56 (s, 2H), 3.50-3.38 (m, 1H), 2.98-2.93 (m, 1H), 2.38-2.26 (m, 3H). LCMS: MS m / z = 578.1 [M+H] + .

[0374] Step 7: Synthesis of compound 8-8

[0375] Compound 8-7 (2.1 g, 3.57 mmol, 1 eq) was added to anhydrous tetrahydrofuran (21 mL), cooled to -60 °C, and lithium tri-sec-butylborohydride (1 M, 4.29 mL, 1.2 eq) was added under nitrogen protection. The reaction was stirred at -60 °C for 0.5 hr. The reaction was added to 30 mL of saturated ammonium chloride, and the organic phase was extracted with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the product as a crude. The crude was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-3:1, petroleum ether: ethyl acetate = 3:1) to give compound 8-8. 1 H NMR (400 MHz, CDC13) δ = 7.167-7.14 (m, 4H), 6.87-6.83 (m, 4H), 6.63 (d, J = 8.8 Hz, 1H), 5.05-5.00 (m, 1H), 4.61-4.58 (m, 1H), 4.42-4.24 (m, 5H), 3.85-3.73 (m, 10H), 3.13-3.05 (m, 1H), 2.47-2.38 (m, 1H), 2.35-2.31 (m, 3H). LCMS: MS m / z = 600.1 [M+H] + ,

[0376] Step 8: Synthesis of compound 8-9

[0377] Compound 8-8 (1.27 g, 2.15 mmol, 1 eq) was added to ethanol (15 mL) and water (3 mL), and sodium bicarbonate (3.62 g, 43.08 mmol, 1.68 mL, 20 eq) and methyl isothiourea sulfate (4.05 g, 21.54 mmol, 10 eq) were added. The reaction was stirred at 50 °C for 4 hr. The reaction was added to 40 mL of water, and the organic phase was extracted with 20 mL x 2 of ethyl acetate, washed with 20 mL x 2 of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the product as a crude. The crude was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-1:1, petroleum ether: ethyl acetate = 1:1) to give compound 8-9. 1 H NMR (400 MHz, CDC13) δ = 7.167-7.14 (m, 4H), 6.87-6.83 (m, 4H), 6.63 (d, J = 8.8 Hz, 1H), 5.05-5.00 (m, 1H), 4.61-4.58 (m, 1H), 4.42-4.24 (m, 5H), 3.85-3.73 (m, 10H), 3.13-3.05 (m, 1H), 2.47-2.38 (m, 1H), 2.35-2.31 (m, 3H). LCMS: MS m / z = 600.1 [M+H]+ .

[0378] Step 9: Synthesis of compound 8-10

[0379] Compound 8-9 (0.57 g, 905.25 pmol, 1 eq) was added to anhydrous dichloromethane (6 mL), N,N-diisopropylethylamine (409.48 mg, 3.17 mmol, 551.86 pL, 3.5 eq) and triflic anhydride (510.81 mg, 1.81 mmol, 298.72 pL, 2 eq) were added at 0 °C, and the reaction was allowed to react at 0-5 °C for 0.5 hr. The reaction solution was added to 20 mL of saturated ammonium chloride, extracted with 10 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column (petroleum ether: ethyl acetate = 100:0-5:1, petroleum ether: ethyl acetate = 3:1) to obtain compound 8-10. 1 H NMR (400 MHz, CDC13) d = 7.21-7.11 (m, 4H), 6.90-6.80 (m, 4H), 6.66 (d, J = 8.4 Hz, 1H), 5.19-5.15 (m, 1H), 5.04-4.93 (m, 1H), 4.77-4.72 (m, 1H), 4.41-4.19 (m, 4H), 3.80 (s, 6H), 3.62-3.54 (m, 1H), 3.11-2.97 (m, 1H), 2.56 (s, 3H), 2.42-2.31 (m, 3H). LCMS: MS m / z = 762.2 [M+H] + .

[0380] Step 10: Synthesis of compound 8-11

[0381] Compound 8-10 (0.45 g, 590.76 pmol, 1 eq) was added to N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (229.05 mg, 1.77 mmol, 308.69 pL, 3 eq) and compound 1-10A (306.37 mg, 1.18 mmol, 2 eq, HC1) were added in sequence, and the reaction was allowed to react at 50 °C for 2 hr. The reaction solution was poured into 20 mL of water, filtered, and the filter cake was dissolved in 20 mL of methyl tert-butyl ether, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 8-11. 1HNMR (400 MHz, CDC13) δ = 7.44-7.32 (m, 5H), 7.16-7.13 (m, 4H), 6.85-6.82 (m, 4H), 6.63 (d, J = 7.6 Hz, 1H), 5.21-5.15 (m, 2H), 4.80-4.66 (m, 3H), 4.39-4.22 (m, 4H), 3.93-3.88 (m, 1H), 3.80 (s, 6H), 3.71-3.55 (m, 1H), 3.52-3.29 (m, 2H), 3.25-3.08 (m, 3H), 3.06-2.96 (m, 2H), 2.91-2.77 (m, 1H), 2.71-2.68 (m, 1H), 2.52 (s, 3H), 2.35-2.30 (m, 3H). LCMS: MS m / z = 871.4 [M+H] + .

[0382] Step 11: Synthesis of compound 8-12

[0383] Compound 8-11 (580.00 mg, 665.94 μmol, 1 eq) was added to anhydrous dichloromethane (6 mL), and m-chloroperoxybenzoic acid (359.13 mg, 1.66 mmol, 80% mass content, 2.5 eq) was added. The reaction was carried out at 25 °C for 0.5 hr. After the reaction solution was poured into 20 mL of sodium thiosulfate solution (10%), 10 mL of dichloromethane was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-1:1, petroleum ether: ethyl acetate = 1:1) to obtain compound 8-12. 1 HNMR (400 MHz, CDC13) δ = 7.44-7.32 (m, 5H), 7.16-7.13 (m, 4H), 6.85-6.82 (m, 4H), 6.63 (d, J = 7.6 Hz, 1H), 5.21-5.15 (m, 2H), 4.80-4.66 (m, 3H), 4.39-4.22 (m, 4H), 3.93-3.88 (m, 1H), 3.80 (s, 6H), 3.71-3.55 (m, 1H), 3.52-3.29 (m, 2H), 3.25-3.08 (m, 3H), 3.06-2.96 (m, 2H), 2.91-2.77 (m, 1H), 2.71-2.68 (m, 1H), 2.52 (s, 3H), 2.35-2.30 (m, 3H). LCMS: MS m / z = 871.4 [M+H] + .

[0384] Step 12: Synthesis of compound 8-13

[0385] Compound 8-13 was prepared according to the procedure described in Example 8, Step 12, by using compound 1-11A (117.35 mg, 1.02 mmol, 120.98 μL, 4 eq), sodium tert-butoxide (97.91 mg, 1.02 mmol, 4 eq), and compound 8-12 (230.00 mg, 254.72 μmol, 1 eq). LCMS: MS m / z = 938.2 [M+H] + .

[0386] Step 13: Synthesis of compound 8-14

[0387] Compound 8-14 was prepared according to the procedure described in Example 8, Step 12, by using compound 8-13 (0.15 g, 159.91 μmol, 1 eq), and trifluoroacetic acid (0.5 mL). LCMS: MS m / z = 698.2 [M+H] + .

[0388] Step 14: Synthesis of compound 8-15

[0389] Compound 8-15 was prepared according to the procedure described in Example 8, Step 12, by using compound 8-14 (0.17 g, 243.65 μmol, 1 eq), and palladium on carbon (0.15 g, 10% mass content). LCMS: MS m / z = 564.2 [M+H] + .

[0390] Step 15: Synthesis of compound 8A and 8B

[0391] Compound 8-15 (60 mg, 106.46 μmol, 1 eq) and 2-fluoropropenoic acid (11.50 mg, 127.75 μmol, 1.2 eq) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (60.72 mg, 159.69 μmol, 1.5 eq) were added into N,N dimethylformamide (1 mL), N,N-diisopropylethylamine (41.28 mg, 319.38 μmol, 55.63 μL, 3 eq) was added, and the reaction was allowed to react at 25 °C for 0.5 hr. The reaction was added into 10 mL saturated ammonium chloride, extracted with 5 mL x 2 ethyl acetate, and the organic phase was combined and washed with 5 mL x 2 saturated brine. After drying over anhydrous sodium sulfate, filtration, and concentration, compound 8-16 was obtained. Purification was performed by high performance liquid chromatography column (column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [H2O (0.1% TFA) - ACN]; acetonitrile%: 20% - 50%, 9 min). After concentration under vacuum, 5 mL deionized water and 0.5 mL acetonitrile were added, 2 drops of 1 M hydrochloric acid solution were added, and the mixture was concentrated under vacuum to obtain the hydrochloride salt of compound 8A (retention time: 1.379 min). SFC analysis method (column: Chiralcel OD-3, 50 x 4.6 mm I.D., 3 um; mobile phase: A (CO2) and B (methanol containing 0.05% diisopropylamine); gradient: B% = 5 ~ 50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 80.82%. LCMS: MS m / z = 636.4 [M+H] + The hydrochloride salt of compound 8B was obtained (retention time: 1.789 min). SFC analysis method (column: Chiralcel OD-3, 50 x 4.6 mm I.D., 3 um; mobile phase: A (CO2) and B (methanol containing 0.05% diisopropylamine); gradient: B% = 5 ~ 50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 75.56%. 1H NMR (400 MHz, CDC13) δ = 6.59 (d, J = 8.4 Hz, 1H), 5.50-5.33 (m, 1H), 5.29-5.16 (m, 2H), 4.82-4.69 (m, 2H), 4.39 (dd, J = 5.2, 10.8 Hz, 1H), 4.16 (dd, J = 6.8, 10.4 Hz, 1H), 4.04 (s, 2H), 3.94 (d, J = 14.0 Hz, 1H), 3.68 (d, J = 11.6 Hz, 1H), 3.50-3.32 (m, 2H), 3.10 (br t, J = 7.2 Hz, 1H), 3.05-2.94 (m, 2H), 2.79 (br d, J = 7.2 Hz, 2H), 2.71-2.62 (m, 1H), 2.48 (s, 3H), 2.39 (q, J = 4.0 Hz, 3H), 2.32-2.22 (m, 1H), 2.11-1.99 (m, 1H), 1.93-1.66 (m, 6H). LCMS: MS m / z = 636.4 [M+H] + .

[0392] Example 9

[0393]

[0394] Step 1: Synthesis of compound 9-3A

[0395] Anhydrous tetrahydrofuran (30 mL) was added to a dry reaction bottle, then compound 9-6 (1.5 g, 6.07 mmol, 1 eq) was added, the reaction system was cooled to 10 °C, lithium aluminum hydride (690.66 mg, 18.20 mmol, 3 eq) was added in batches, and the reaction system was reacted at 15 °C for 16 hours. Sodium sulfate (4 g) was added to the reaction solution, stirred for 1 hour, filtered, the filter cake was added to tetrahydrofuran (20 mL x 2), stirred for 0.5 hours, then filtered respectively, the filtrate was combined and concentrated under reduced pressure, and the product was used directly in the next step without purification. Compound 9-3A was obtained. 1 H NMR (400 MHz, CDC13) δ ppm 5.25-4.98 (m, 1H) 3.75-3.65 (m, 1H) 3.61-3.43 (m, 2H) 2.83-2.74 (m, 1H) 2.71-2.56 (m, 1H) 2.39 (s, 3H) 2.14-2.03 (m, 2H). LCMS m / z = 134.2 [M+H] + .

[0396] Step 2: Synthesis of compound 9-2

[0397] N,N-dimethylformamide (6 mL) was added to a dry reaction flask, followed by the addition of compound 8-10 (0.55 g, 722.04 μmol, 1 eq), N,N-diisopropylethylamine (279.95 mg, 2.17 mmol, 377.29 uL, 3 eq) and compound 9-1A (289.22 mg, 1.44 mmol, 2 eq). The reaction system was reacted at 50 °C under nitrogen protection for 50 min, and compound 9-1A (50 mg) was added for continuous reaction for 0.5 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the raw material disappeared and a new spot appeared. After the reaction system was cooled to room temperature (15 °C), the reaction solution was added to saturated ammonium chloride solution (30 mL), extracted with methyl tert-butyl ether (10 mL x 2), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Without purification, it was directly used in the next step. Compound 9-2 was obtained. LCMS m / z = 812.4 [M+H] +

[0398] Step 3: Synthesis of compound 9-3

[0399] Dichloromethane (10 mL) was added to a dry reaction flask, followed by the addition of compound 9-2 (0.65 g, 800.57 μmol, 1 eq) and m-chloroperoxybenzoic acid (207.23 mg, 960.68 μmol, 80% purity, 1.2 eq). The reaction system was reacted at 15 °C for 0.5 h. The reaction solution was poured into water (20 mL), and after the addition of sodium thiosulfate solution (20 mL, 10%), it was tested negative with starch-KI test paper, dichloromethane (20 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 40 °C to obtain the crude product. The crude product was purified by column according to TLC (petroleum ether: ethyl acetate = 0: 1, RF = 0.53) (petroleum ether: ethyl acetate = 3: 1 to 0: 1) to obtain compound 9-3. 1 H NMR (400 MHz, CDC13) δ ppm 7.16 (d, J = 7.60 Hz, 4 H) 6.84 (d, J = 8.40 Hz, 4 H) 6.66 (s, 1 H) 5.26 (d, J = 10.42 Hz, 1 H), 4.85-4.68 (m, 2 H) 4.39-4.20 (m, 4 H) 4.09-3.90 (m, 2 H) 3.89-3.67 (m, 7 H) 3.66-3.42 (m, 2 H) 3.40-3.16 (m, 2 H) 3.14-2.75 (m, 4 H) 2.34 (d, J = 4.00 Hz, 3 H) 1.49 (s, 9 H) 1.43-1.37 (m, 2 H) 1.19 (m, 2 H), LCMS m / z = 828.2 [M+H] +

[0400] Step 4: Synthesis of compound 9-4

[0401] Toluene (6 mL) was added to a dry reaction flask, then compound 9-3A (289.51 mg, 2.17 mmol, 28.68 μL, 4 eq) was added, the reaction system was cooled to 0 °C, sodium tert-butoxide (208.93 mg, 2.17 mmol, 4 eq) was added, the reaction system was reacted at 0-5 °C for 10 min, a solution of compound 9-3 (0.45 g, 543.53 μmol, 1 eq) in toluene (2 mL) was added, the reaction system was reacted at 0-5 °C for 0.5 h. The reaction solution was washed with saturated ammonium chloride (20 mL x 2), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without purification to give compound 9-4. 1 H NMR (400 MHz, CDC13) δ ppm 7.15 (d, J = 7.60 Hz, 4 H) 6.84 (d, J = 8.40 Hz, 4 H) 6.62 (d, J = 7.20 Hz, 1 H) 5.29 - 5.04 (m, 3 H) 4.29 (d, J = 14.80 Hz, 4 H) 3.80 (s, 6 H) 3.44 - 3.34 (m, 2 H) 3.30 - 3.21 (m, 1 H) 3.06 - 2.79 (m, 2 H) 2.68 - 2.52 (m, 5 H) 2.47 (s, 3 H) 2.42 - 2.27 (m, 5 H) 2.25 - 2.08 (m, 5 H) 1.49 (s, 9 H) 1.38 (d, J = 6.40 Hz, 2 H) 1.14 (d, J = 6.80 Hz, 1 H). LCMS m / z = 897.3 [M+H] +

[0402] Step 5: Synthesis of compound 9-5

[0403] Dichloromethane (15 mL) was added to a dry reaction flask, then compound 9-4 (0.6 g, 668.91 μmol, 1 eq) and trifluoroacetic acid (3 mL) were added, the reaction system was reacted at 15 °C for 2.5 h, trifluoroacetic acid (0.5 mL) was added, and the reaction was continued for 1 h, and trifluoroacetic acid (0.5 mL) was added continuously, and the reaction was continued for 1 h. The reaction solution was slowly added to a saturated sodium bicarbonate solution (80 mL), extracted with dichloromethane (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane:methanol = 100:0-1:1) according to TLC (dichloromethane:methanol = 5:1) to give compound 9-5. 1H NMR (400 MHz, CDC13) δ ppm 6.59 (d, J = 8.40 Hz, 1 H) 5.29 - 5.07 (m, 2 H) 4.75 - 4.67 (m, 1 H) 4.52 - 4.38 (m, 1 H) 4.32 - 4.16 (m, 1 H) 4.08 - 3.87 (m, 3 H) 3.66 - 3.26 (m, 4 H) 3.25 - 2.8 (m, 6 H) 2.72 - 2.59 (m, 1 H) 2.54 (d, J = 2.00 Hz, 3 H) 2.44 - 2.26 (m, 3 H) 2.11 - 1.86 (m, 1 H) 1.52 (d, J = 6.80 Hz, 1 H) 1.26 (d, J = 6.80 Hz, 2 H). LCMS m / z = 557.3 [M+H] + .

[0404] Step 6: Synthesis of compounds 9A and 9B

[0405] Dichloromethane (5 mL) was added to a dry reaction flask, followed by the addition of acrylic acid (21.75 mg, 301.85 μmol, 20.72 μL, 1.2 eq) and N,N-diisopropylethylamine (97.53 mg, 754.62 μmol, 131.44 μL, 3 eq). The reaction was cooled to -60 °C, and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (114.77 mg, 301.85 μmol, 1.2 eq) was added. The reaction was stirred at -60 °C for 10 min, and then compound 9-5 (0.14 g, 251.54 μmol, 1 eq) was added. The reaction was stirred for 1 h. The reaction was diluted with dichloromethane (10 mL), washed with saturated ammonium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by high performance liquid chromatography using the following conditions: {(column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [H2O (0.04% HC1)-ACN]; acetonitrile%: 20%-32%, 7 min} followed by lyophilization and chiral separation by SFC using the following conditions: {(column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O MEOH]; MeOH%: 60%-60%, 9 min}. Compound 9A (chiral column retention time: 1.594 min) was obtained. SFC analysis method (column: Chiralcel OD-3, 50 x 4.6 mm I.D., 3 μm; mobile phase: A (C02) and B (methanol with 0.05% diisopropylamine amine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 100%. 1 H NMR (400 MHz, CDC13) δ ppm 6.71-6.49 (m, 2 H) 6.42-6.28 (m, 1 H) 5.77 (d, J=10.80 Hz, 1 H) 5.50-5.04 (m, 3 H) 4.71 (s, 3 H) 4.49-4.22 (m, 2 H) 4.03 (s, 3 H) 3.78 (d, J=9.20 Hz, 1 H) 3.64 (s, 1 H) 3.51-3.17 (m, 4 H) 3.14-3.00 (m, 4 H) 2.64-2.48 (m, 1 H) 2.40 (d, J=4.00 Hz, 4 H) 1.16 (d, J=10.40 Hz, 3 H). LCMS m / z = 611.3 [M+H] + .

[0406] Compound 9B (Chiral peak retention time: 1.903 min) SFC analytical method (Column: Chiralcel OD-3, 50 x 4.6 mm I.D., 3 um; Mobile phase: A (C02) and B (methanol with 0.05% diisopropylamine amine); Gradient: B% = 5-50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi. Optical purity: 100%. 1 H NMR (400 MHz, CDC13) δ ppm 6.69-6.54 (m, 2H) 6.42-6.30 (m, 1H) 5.77 (d, J=10.80 Hz, 1H) 5.47-5.01 (m, 3H) 4.71 (s, 3H) 4.49-4.23 (m, 2H) 4.03 (s, 3H) 3.94-3.72 (m, 1H) 3.64 (s, 1H) 3.53-3.22 (m, 4H) 3.14-3.01 (m, 4H) 2.62-2.49 (m, 1H) 2.40 (d, J=4.00 Hz, 4H) 1.16 (d, J=10.40 Hz, 3H). LCMS m / z = 611.3 [M+H] + .

[0407] Example 10

[0408]

[0409] Step 1: Synthesis of compound 10-1A and 10-1B

[0410] Compound 8-9 (9 g, 15.27 mmol, 1 eq) was dissolved in ethanol (100 mL) water (20 mL), then 2-methyl-2-thioisourea sulfate (42.49 g, 152.65 mmol, 10 eq), sodium bicarbonate (25.65 g, 305.31 mmol, 11.87 mL, 20 eq) were added, stirred at 30 °C for 4 hr. 100 mL saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (100 mL x 2), 80 mL saturated brine was washed, dried over anhydrous sodium sulfate, filtered and concentrated to give the product crude, according to TLC (petroleum ether: ethyl acetate = 0:1) to purify the column petroleum ether: ethyl acetate = 10%-20%-30%. Then SFC resolution column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); Mobile phase: [0.1% NH3. H2O EtOH]; EtOH%: 45%-45%, 6.3 min. Compound 10-1A (peak retention time: 1.665), compound 10-1B (peak retention time: 2.446) were obtained.

[0411] Step 2: Synthesis of compound 10-2

[0412] Compound 10-1A (2 g, 3.18 mmol, 1 eq) was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (1.23 g, 9.53 mmol, 1.66 mL, 3 eq) was added, and the reaction system was cooled to 0-10 °C, and triflic anhydride (1.34 g, 4.76 mmol, 786.11 μL, 1.5 eq) was slowly added. After 15 min at this temperature, the reaction system was poured into saturated aqueous ammonium chloride solution (15 mL), and the mixture was separated, and the aqueous phase was extracted with dichloromethane (15 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (PE / EtOAc = 100 / 1-0 / 1) according to TLC (PE / EtOAc = 10 / 1) to give compound 10-2. LCMS m / z = 762.2 [M+H] + .

[0413] Step 3: Synthesis of compound 10-3

[0414] N,N-dimethylformamide (2 mL) was added to a dry reaction bottle, and then compound 10-2 (0.16 g, 210.05 μmol, 1 eq), N,N-diisopropylethylamine (81.44 mg, 630.15 μmol, 109.76 μL, 3 eq), and compound 10-2A (50.48 mg, 252.06 μmol, 1.2 eq) were added, and the reaction system was reacted at 50 °C under nitrogen protection for 1 h. TLC (petroleum ether: ethyl acetate = 3:1) showed that the starting material disappeared and a new spot appeared. Methyl tert-butyl ether (10 mL) was added to the reaction solution, which was washed with saturated ammonium chloride solution (20 mL x 2) and then saturated brine (10 mL), and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was used directly in the next step without purification to give compound 10-3. 1 H NMR (400 MHz, CDC13) δ ppm 7.12 (d, J = 8.80 Hz, 4 H) 6.81 (d, J = 8.80 Hz, 4 H) 6.60 (d, J = 8.80 Hz, 1 H) 5.19 (d, J = 8.00 Hz, 1 H) 4.72 (s, 2 H) 4.37 - 4.22 (m, 4 H) 3.88 (d, J = 13.2 Hz, 1 H) 3.77 (s, 6 H) 3.71 - 3.56 (dd, J = 12.80, 13.20 Hz, 2 H) 3.40 (dd, J = 12.40, 12.40 Hz, 1 H) 3.31 (m, 2 H) 3.20 (s, 1 H) 3.03 - 2.91 (m, 2 H) 2.50 (s, 3 H) 2.35 - 2.25 (m, 3 H) 1.46 (s, 9 H) 1.13 (d, J = 6.80 Hz, 3 H).

[0415] Step 4: Synthesis of compound 10⁻⁴

[0416] Dichloromethane (5 mL) was added to a dry reaction flask, followed by compound 10⁻³ (0.21 g, 258.64 μmol, 1 eq) and m-chloroperoxybenzoic acid (66.95 mg, 310.37 μmol, 80% purity, 1.2 eq). The reaction system was reacted at 15 °C for 0.5 h. Sodium thiosulfate (15 mL, 10%) solution was added to the reaction solution. After a negative result with starch-KI test paper, the mixture was extracted with dichloromethane (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (petroleum ether: ethyl acetate = 0:1) column chromatography (petroleum ether: ethyl acetate = 10:1 to 0:1) to obtain compounds 10⁻⁴ and 10⁻⁴A. 1 H NMR (400MHz, CDCl3) δppm 7.20(s,4H),6.84(d,J=8.80Hz,4H),6.79~6.62(s,1H),5.24(d,J=10. 80Hz,1H),4.87-4.74(m,2H),4.36(s,4H),3.99-3.83(m,3H),3.83-3. 71(m,7H),3.62-3.43(m,2H),3.40-3.27(m,3H),3.22-3.06(m,2H),2. 92(d,J=5.20Hz,1H),2.34(s,3H),1.49(s,9H),1.16(d,J=6.80Hz,3H). LCMS m / z = 828.2M+H + .

[0417] Step 5: Synthesis of compound 10-5

[0418] Toluene (1 mL) was added to a dry reaction flask, followed by compound 1-11A (38.95 mg, 338.19 μmol, 4 eq). The reaction system was cooled to 0 °C, and sodium tert-butoxide (32.50 mg, 338.19 μmol, 4 eq) was added. After reacting for 10 minutes, a toluene mixture (1 mL) containing a mixture of compound 10-4 (0.07 g, 84.55 μmol, 1 eq) and 10-4A (71.35 mg, 84.55 μmol, 1 eq) was added, and the reaction was allowed to proceed for 0.5 hours. 10 mL of ethyl acetate was added to the reaction solution, followed by washing with 10 mL of saturated ammonium chloride solution and saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified phase was used directly in the next step. Compound 10-5 was obtained. LCMS m / z = 879.3 [M+H] + .

[0419] Step 6: Synthesis of compound 10-6

[0420] Dichloromethane (5 mL) was added to a dry reaction flask, then compound 10-5 (0.16 g, 182.03 μmol, 1 eq) and trifluoroacetic acid (1.25 mL) were added, the reaction system was stirred at 18 °C for 1.5 h. Trifluoroacetic acid (0.25 mL) was added, and the reaction was continued for 1.5 h. Water (5 mL) was added to the reaction solution, and the aqueous phase was collected and adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was used directly in the next step without purification. Compound 10-6 was obtained. LCMS m / z = 539.2 [M+H] + .

[0421] Step 7: Synthesis of compound 10

[0422] Dichloromethane (5 mL) was added to a dry reaction flask, then compound 10-6 (23 mg, 38.43 μmol, 90% purity, 1 eq) and N,N-diisopropyl ethylamine (14.90 mg, 115.30 μmol, 20.08 μL, 3 eq) were added, and the reaction system was cooled to -60 °C, then O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (17.54 mg, 46.12 μmol, 1.2 eq) was added, and then stirred for 0.5 h. The reaction was combined with compound 10-6 (19.49 mg) batch processing, water (5 mL) was added to the reaction solution, and the organic phase was concentrated under reduced pressure. The product was separated by high performance liquid chromatography column, and the purification method was {chromatography column: Phenomenex luna C18 80*40mm*3μm; [H2O (0.04% HC1)-ACN]; Acetonitrile%: 20%-40%, 7 min} to obtain compound 10. LCMS m / z = 593.4 [M+H] + .

[0423] Example 11

[0424]

[0425] Step 1: Synthesis of compound 11-2

[0426] N,N-dimethylformamide (2 mL) was added to a dry reaction flask, then compound 10-2 (0.16 g, 210.05 μmol, 1 eq), N,N-diisopropylethylamine (81.44 mg, 630.15 μmol, 109.76 μL, 3 eq) and compound 11-1 (54.02 mg, 252.06 μmol, 1.2 eq) were added. The reaction system was reacted at 50 °C for 1 h under the protection of nitrogen. The batches were combined and treated with compound 10-2 (50 mg), then methyl tert-butyl ether (10 mL) was added to the reaction solution, which was washed with saturated ammonium chloride solution (10 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was directly used in the next step to obtain compound 11-2. 1 H NMR (400 MHz, CDC13) δ ppm 7.14 (d, J = 8.80 Hz, 4 H), 6.84 (d, J = 8.40 Hz, 4 H), 6.62 (d, J = 8.80 Hz, 1 H), 5.19 (br d, J = 8.00 Hz, 1 H), 4.76 (s, 2 H), 4.37 - 4.22 (m, 5 H), 3.80 (s, 7 H), 3.58 - 3.35 (m, 3 H), 3.22 (s, 2 H), 3.04 - 2.93 (m, 1 H), 2.52 (s, 3 H), 2.38 - 2.30 (m, 3 H), 1.49 (s, 9 H), 1.34 (dd, J = 6.80, 6.40 Hz, 6 H).

[0427] Step 2: Synthesis of compound 11-3

[0428] Methylene chloride (5 mL) was added to a dry reaction flask, then compound 11-2 (0.20 g, 242.14 μmol, 1 eq) and m-chloroperoxybenzoic acid (62.68 mg, 290.57 μmol, 80% purity, 1.2 eq) were added. The reaction system was reacted at 15 °C for 0.5 h. The batches were combined and treated with compound 11-2 (50 mg). A solution of sodium thiosulfate (15 mL, 10%) was added to the reaction solution, which was tested negative with starch-KI paper, extracted with methylene chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated under reduced pressure. The crude product was purified by column according to TLC (petroleum ether: ethyl acetate = 0:1) (petroleum ether: ethyl acetate = 10:1 to 0:1) to obtain a mixture of compound 11-3 and compound 11-3A. 1H NMR (400 MHz, CDC13) δ ppm 7.17 (d, J = 6.40 Hz, 4 H) 6.84 (d, J = 8.40 Hz, 4 H) 6.67 (s, 1 H) 5.23 (d, J = 11.20 Hz, 1 H) 4.90 - 4.74 (m, 2 H) 4.32 (d, J = 12.00 Hz, 4 H) 3.84 - 3.75 (m, 9 H) 3.68 - 3.39 (m, 3 H) 3.31 - 3.10 (m, 3 H) 2.89 (d, J = 10.40 Hz, 2 H) 2.34 (d, J = 3.60 Hz, 3 H) 1.49 (s, 9 H) 1.42 - 1.29 (m, 6 H). LCMS m / z = 842.2 [M+H] + .

[0429] Step 3: Synthesis of compound 11-4

[0430] Toluene (1 mL) was added to a dry reaction flask, then compound 1-11A (46.51 mg, 403.82 umol, 4 eq) was added, the reaction system was cooled to 0°C, and sodium tert-butoxide (38.81 mg, 403.82 umol, 4 eq) was added. After 10 minutes of reaction, a mixture containing compound 11-3 (0.085 g, 100.96 umol, 1 eq) and 11-3A (86.62 mg, 100.96 umol, 1 eq) was added to toluene (1 mL), and the reaction system was stirred for 0.5 hours. The batch was combined and treated with compound 11-3 (10 mg). 10 mL of ethyl acetate was added to the reaction solution, then it was washed with 10 mL of saturated ammonium chloride solution and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was directly used in the next step to obtain compound 11-4. LCMS m / z = 893.4 [M+H] + .

[0431] Step 4: Synthesis of compound 11-5

[0432] Dichloromethane (5 mL) was added to a dry reaction flask, then compound 11-4 (0.13 g, 145.57 umol, 1 eq) and trifluoroacetic acid (1.25 mL) were added, and the reaction system was reacted at 18°C for 1.5 hours. Trifluoroacetic acid (0.25 mL) was added, and the reaction was continued for 1.5 hours. The batch was combined and treated with compound 11-4 (15 mg). Water (5 mL) was added to the reaction solution, the aqueous phase was collected, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was directly used in the next step to obtain compound 11-5. LCMS m / z = 553.2 [M+H] + .

[0433] Step 5: Synthesis of compound 11

[0434] Dichloromethane (5 mL) was added to a dry reaction flask, then compound acrylic acid (14.08 mg, 195.44 μmol, 13.41 μL, 2 eq), compound 11-5 (60.00 mg, 97.72 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (37.89 mg, 293.16 μmol, 51.06 μL, 3 eq) were added, and the reaction system was cooled to -60 °C. O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (44.59 mg, 117.26 μmol, 1.2 eq) was added, and then stirred for 0.5 h. The reaction was combined with the compound 11-5 (20 mg) batch, water (5 ml) was added to the reaction, and the organic phase was concentrated under reduced pressure. The high performance liquid chromatography column separation and purification method was {chromatography column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [H2O (0.04% HC1)-ACN]; acetonitrile%: 15%-40%, 7 min} to give compound 11. 1 H NMR (400 MHz, CD3OD) δ = 6.92-6.75 (m, 1H), 6.74-6.70 (m, 1H), 6.33-6.24 (m, 1H), 5.88-5.77 (m, 1H), 5.28-5.18 (m, 1H), 4.82-4.63 (m, 2H), 4.56-4.43 (m, 1H), 4.42-4.23 (m, 1H), 4.01-3.81 (m, 2H), 3.79-3.59 (m, 2H), 3.57-3.41 (m, 1H), 3.32-3.20 (m, 5H), 3.17-3.02 (m, 3H), 2.84 (m, 2H), 2.51-2.35 (m, 3H), 2.31-1.99 (m, 3H), 1.49-1.29 (m, 6H). LCMS m / z = 607.5 [M+H] + .

[0435] Example 12

[0436]

[0437] Step 1: Synthesis of compound 12-2

[0438] N,N-dimethylformamide (2 mL) was added to a dry reaction flask, followed by the addition of compound 10-2 (0.2 g, 262.56 μmol, 1 eq), N,N-diisopropylethylamine (101.80 mg, 787.69 μmol, 137.20 μL, 3 eq) and compound 9-1A (63.10 mg, 315.07 μmol, 1.2 eq). The reaction system was reacted at 50 °C for 30 min under the protection of nitrogen. Compound 9-1A (30 mg, 0.6 eq) was added, and the reaction was continued for 30 min. A saturated ammonium chloride solution (10 mL) was added to the reaction solution, which was extracted with methyl tert-butyl ether (5 mL). The organic phase solution was washed with saturated ammonium chloride solution (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was directly used in the next step. Compound 12-2 was obtained. 1 H NMR (400 MHz, CDC13) δ ppm 7.14 (d, J = 8.80 Hz, 4 H) 6.84 (d, J = 8.40 Hz, 4 H) 6.62 (d, J = 8.80 Hz, 1 H) 5.21 (d, J = 7.20 Hz, 1 H) 4.78 - 4.63 (m, 2 H) 4.38 - 4.15 (m, 4 H) 4.00 - 3.82 (m, 2 H) 3.80 (s, 6 H) 3.73 - 3.60 (m, 1 H) 3.48 - 3.33 (m, 1 H) 3.22 (s, 2 H) 3.16 - 2.80 (m, 3 H) 2.51 (s, 3 H) 2.38 - 2.30 (m, 3 H) 1.49 (s, 9 H) 1.38 (d, J = 6.80 Hz, 3 H). LCMS m / z = 812.3 [M+H] + .

[0439] Step 2: Synthesis of compound 12-3

[0440] Dichloromethane (5 mL) was added to a dry reaction flask, followed by the addition of compound 12-2 (0.18 g, 221.70 μmol, 1 eq) and m-chloroperoxybenzoic acid (57.39 mg, 266.03 μmol, 80% purity, 1.2 eq). The reaction system was reacted at 15 °C for 0.5 h. The batch of compound 12-2 (30 mg) was combined and treated. A saturated sodium thiosulfate solution (10 mL, 10%) was added to the reaction solution, which was extracted with dichloromethane (3 mL) after testing negative with starch-KI paper. The crude product was obtained by drying over anhydrous sodium sulfate and concentrating under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 0: 1) according to TLC (petroleum ether: ethyl acetate = 0: 1) to obtain compound 12-3. 1H NMR (400 MHz, CDC13) δ ppm 7.17 (br s, 4 H) 6.84 (br d, J=8.40 Hz, 4 H) 6.67 (br s, 1 H) 5.25 (br d, J=9.60 Hz, 1 H) 4.89 - 4.64 (m, 2 H) 4.32 (br d, J=10.40 Hz, 4 H) 4.09 - 3.86 (m, 3 H) 3.84 - 3.68 (m, 7 H) 3.64 - 3.51 (m, 1 H) 3.37 - 2.97 (m, 4 H) 2.95 - 2.81 (m, 3 H) 2.34 (br d, J=3.60 Hz, 3 H) 1.49 (s, 9 H) 1.41 (br s, 3 H). LCMS m / z = 828.2 [M+H] + .

[0441] Step 3: Synthesis of compound 12-4

[0442] Toluene (1 mL) was added to a dry reaction flask, then compound 12-3A (66.52 mg, 471.06 μmol, 3 eq) was added, the reaction system was cooled to 0°C, then sodium tert-butoxide (45.27 mg, 471.06 μmol, 3 eq) was added, stirred for 10 minutes, then a toluene solution (0.5 mL) containing compound 12-3 (0.13 g, 157.02 μmol, 1 eq) was added, and stirred for 0.5 hours. The batches were combined and treated with compound 12-3 (20 mg), 10 mL of ethyl acetate was added to the reaction solution, then 10 mL of saturated ammonium chloride solution and saturated brine were used for washing respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was used directly in the next step without purification to obtain compound 12-4. LCMS m / z = 905.3 [M+H] + .

[0443] Step 4: Synthesis of compound 12-5

[0444] Dichloromethane (6 mL) was added to a dry reaction flask, then compound 12-4 (0.18 g, 198.89 μmol, 1 eq) and trifluoroacetic acid (1.5 mL) were added, and the reaction system was stirred at 18°C for 3.5 hours. Water (5 mL) was added to the reaction solution, the aqueous phase was collected, the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was used directly in the next step without purification to obtain compound 12-5. LCMS m / z = 565.2 [M+H] + .

[0445] Step 5: Synthesis of compound 12

[0446] Dichloromethane (5 mL) was added to a dry reaction vial and stirring was started, then compound acrylic acid (11.49 mg, 159.40 μmol, 10.94 μL, 2 eq), compound 12-5 (50 mg, 79.70 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (30.90 mg, 239.10 μmol, 41.65 μL, 3 eq) were added, the reaction was cooled to -60 °C, then O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (36.37 mg, 95.64 μmol, 1.2 eq) was added, then stirred for 0.5 h. This reaction was combined with compound 12-5 (20 mg) batch. Water (5 ml) was added to the reaction, the liquid was separated, the organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by high performance liquid chromatography column {chromatography column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [H2O (0.04% HC1)-ACN]; acetonitrile%: 15%-40%, 7 min} to obtain compound 12 (retention time: 1.509). SFC analysis method (column: Chiralcel OD-3, 50*4.6 mm I.D., 3 um; mobile phase: A (CO2) and B (methanol containing 0.05% diisopropylamine amine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi. Optical purity: 99.4%. 1 H NMR (400 MHz, CD3OD) δ = 6.89-6.71 (m, 1H), 6.71-6.65 (d, J = 8.8 Hz, 1H), 6.32-6.19 (m, 1H), 5.84-5.75 (m, 1H), 5.26-5.15 (m, 1H), 4.68-4.60 (m, 1H), 4.52 (s, 2H), 4.50-4.45 (m, 1H), 4.39-4.32 (m, 1H), 4.27-4.16 (m, 1H), 4.15-3.89 (m, 2H), 3.76-3.61 (m, 2H), 3.60-3.32 (m, 2H), 3.28-3.13 (m, 3H), 3.09-3.00 (m, 1H), 2.96-2.85 (m, 1H), 2.38-2.32 (m, 3H), 2.32-2.24 (m, 2H), 2.24-2.12 (m, 4H), 2.12-2.03 (m, 2H), 1.42-1.31 (m, 3H). LCMS m / z = 619.3 [M+H] + .

[0447] Example 13

[0448]

[0449] Step 1: Synthesis of compound 13-2

[0450] Into a dry reaction vial, was placed N,N-dimethylformamide (4 mL), then compound 10-2 (220 mg, 288.82 μmol, 1 eq) and compound 13-1 (115.69 mg, 577.64 μmol, 2 eq) were added and stirred, followed by the addition of N,N-diisopropylethylamine (111.98 mg, 866.45 μmol, 150.92 μL, 3 eq), the reaction was stirred at 50 °C for 1 h. The reaction was diluted with ethyl acetate (30 mL), washed with saturated ammonium chloride (15 mL) and saturated brine (15 mL) for one time each, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude was used directly in the next step without purification to give compound 13-2. LCMS m / z = 812.2 [M+H] + .

[0451] Step 2: Synthesis of compound 13-3

[0452] Into a dry reaction vial, was placed dichloromethane (10 mL), then compound 13-2 (200.00 mg, 246.33 μmol, 1 eq) was added and stirred, followed by the addition of m-chloroperoxybenzoic acid (60.01 mg, 295.59 μmol, 85% purity, 1.2 eq), the reaction was stirred at 25 °C for 1 h. The reaction was diluted with dichloromethane (20 mL), washed with 5% sodium thiosulfate (10 mL) and saturated brine (10 mL) for one time each, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column (petroleum ether: ethyl acetate = 1:1 to 50:50) to give the product to give compound 13-3. LCMS m / z = 828.3 [M+H] + .

[0453] Step 3: Synthesis of compound 13-4

[0454] Toluene (5 mL) was added to a dry reaction flask, then compound 1-11A (112.68 mg, 978.35 μmol, 4.5 eq) was added to start stirring, then sodium tert-butoxide (94.02 mg, 978.35 μmol, 4.5 eq) was added, the reaction system was cooled to 0 °C and stirred for 10 minutes, then compound 13-3 (180 mg, 217.41 μmol, 1 eq) was added, the reaction system was stirred at 0 °C for 1 hour. The reaction was combined and treated with compound 13-3 (60 mg) batch. Ethyl acetate (30 mL) was added to the reaction liquid to extract, and the organic phase solution was washed with saturated ammonium chloride (10 mL) and saturated brine (10 mL) respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was directly used in the next step without purification to obtain compound 13-4. LCMS m / z = 879.3 [M+H] + .

[0455] Step 4: Synthesis of compound 13-5

[0456] Dichloromethane (5 mL) was added to a dry reaction flask, then compound 13-4 (260 mg, 295.79 μmol, 1 eq) was added to start stirring, then potassium acetate (2.82 g, 24.70 mmol, 1.83 mL, 83.50 eq) was added, and the reaction system was stirred at 20 °C for 2 hours. Water (30 mL) was added to the reaction liquid to separate, and the aqueous phase was adjusted to pH = 9 with saturated sodium bicarbonate, then extracted with ethyl acetate (15 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was directly used in the next step without purification to obtain compound 13-5. LCMS m / z = 539.2 [M+H] + .

[0457] Step 5: Synthesis of compound 13

[0458] Dichloromethane (5 mL) was added to a dry reaction flask, then compound 13-5 (90 mg, 150.40 μmol, 90% purity, 1 eq) and N,N-diisopropylethylamine (58.31 mg, 451.19 μmol, 78.59 μL, 3 eq) were added and stirred, the reaction system was cooled to -60 °C, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (68.62 mg, 180.47 μmol, 1.2 eq) was added, then stirred for 0.5 h. The reaction was combined with compound 13-5 (30 mg) batch processing, water (5 mL) was added to the reaction and separated, the organic phase solution was directly concentrated under reduced pressure to obtain the crude product, which was separated and purified by high performance liquid chromatography column {chromatography column: Welch Xtimate C18 100*25mm*3μm; mobile phase: [H2O (0.05% HC1)-ACN]; acetonitrile%: 15%-45%, 8 min} to obtain compound 13 (peak time: 1.683). SFC analysis method (column: Chiralcel OD-3, 50*4.6mm I.D., 3um; mobile phase: A (CO2) and B (methanol containing 0.05% diisopropylamine amine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi, optical purity: 95.48%. 1 H NMR (400 MHz, CD3OD) δ = 6.87-6.73 (m, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.25 (dd, J = 3.8, 16.6 Hz, 1H), 5.78 (d, J = 11.6 Hz, 1H), 5.20 (dd, J = 4.0, 11.2 Hz, 1H), 4.83-4.75 (m, 2H), 4.74-4.61 (m, 2H), 4.60-4.45 (m, 2H), 4.32 (d, J = 13.0 Hz, 1H), 4.17-3.92 (m, 1H), 3.90-3.80 (m, 1H), 3.71-3.57 (m, 2H), 3.55-3.42 (m, 1H), 3.39-3.32 (m, 1H), 3.27-3.18 (m, 2H), 3.04 (s, 3H), 2.99-2.85 (m, 2H), 2.41-2.30 (m, 4H), 2.22-1.95 (m, 3H), 1.11 (d, J = 6.6 Hz, 3H), LCMS m / z = 593.3 [M+H] + .

[0459]

[0460] Step 1: Synthesis of compound 14-2

[0461] Into a dry reaction vial was placed N,N-dimethylformamide (4 mL), then compound 10-2 (220 mg, 288.82 μmol, 1 eq), compound 14-1 (123.79 mg, 577.64 μmol, 2 eq) and N,N-diisopropylethylamine (111.98 mg, 866.45 μmol, 150.92 μL, 3 eq) was added and the reaction was stirred at 50 °C for 1 h. The reaction was diluted with ethyl acetate (30 mL), and the organic phase was collected and washed with saturated ammonium chloride (15 mL) and saturated brine (15 mL) once. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without purification to give compound 14-2. LCMS m / z = 826.3 [M+H] + .

[0462] Step 2: Synthesis of compound 14-3

[0463] Into a dry reaction vial was placed dichloromethane (10 mL), then compound 14-2 (350.18 mg, 423.97 μmol, 1 eq) was added and the reaction was stirred, then meta-chloroperoxybenzoic acid (109.75 mg, 508.77 μmol, 80% purity, 1.2 eq) was added. The reaction was stirred at 25 °C for 1 h. One major spot with increased polarity was detected. The reaction was diluted with dichloromethane (10 mL), then 5% sodium thiosulfate (10 mL) and saturated brine (10 mL) were added and washed once. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column (petroleum ether: ethyl acetate = 90: 10 to 50: 50) to give compound 14-3. LCMS m / z = 842.3 [M+H] + .

[0464] Step 3: Synthesis of compound 14-4

[0465] Toluene (5 mL) was added to a dry reaction flask, then compound 1-11A (98.73 mg, 857.24 umol, 4.5 eq) was added, stirring was started, then sodium tert-butoxide (82.38 mg, 857.24 umol, 4.5 eq) was added, the reaction system was cooled to 0 °C and stirred for 10 minutes, then a solution of compound 14-3 (160.39 mg, 190.50 umol, 1 eq) in toluene (2 mL) was added, the reaction system was stirred at 0 °C for 1 hour. The reaction was combined with compound 14-3 (50 mg) batch processing. Ethyl acetate (30 mL) was added to the reaction solution, the organic phase was collected and washed with saturated ammonium chloride solution (10 mL) and saturated brine (10 mL) respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was used directly in the next step without purification to give compound 14-4. LCMS m / z = 893.4 [M+H] + .

[0466] Step 4: Synthesis of compound 14-5

[0467] Dichloromethane (5 mL) was added to a dry reaction flask, then compound 14-4 (260 mg, 291.15 umol, 1 eq) was added and stirring was started, then trifluoroacetic acid (2.77 g, 24.31 mmol, 1.8 mL, 83.50 eq) was added, the reaction system was stirred at 20 °C for 2 hours. Dichloromethane (20 mL) was added to dilute the reaction solution, then water (20 mL) was added to separate the liquid, the aqueous phase was adjusted to pH = 8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (20 mL x 2), the organic phase was combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was used directly in the next step without purification to give compound 14-5. LCMS m / z = 553.2 [M+H] + .

[0468] Step 5: Synthesis of compound 14

[0469] Dichloromethane (5 mL) was added to a dry reaction flask, then compound acrylic acid (10.56 mg, 146.58 umol, 10.06 uL, 1 eq), compound 14-5 (90 mg, 146.58 umol, 90% purity, 1 eq) and N,N-diisopropylethylamine (56.83 mg, 439.73 umol, 76.59 uL, 3 eq) were added and stirred, the reaction system was cooled to -60 °C, then O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (66.88 mg, 175.89 umol, 1.2 eq) was added, and then stirred for 0.5 h. Water (5 mL) was added to quench the reaction, and the organic phase was separated, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by high performance liquid chromatography column {chromatography column: Welch Xtimate C18 100*25mm*3um; mobile phase: [H2O (0.05% HC1)-ACN]; acetonitrile%: 15%-45%, 8 min} to give compound 14. 1 H NMR (400 MHz, CDC13) 6.69-6.62 (m, 1H), 6.62-6.48 (m, 1H), 6.47-6.34 (m, 1H), 5.91-5.76 (m, 1H), 5.34 (s, 1H), 5.25-5.14 (m, 1H), 5.10-4.99 (m, 1H), 4.86-4.64 (m, 2H), 4.62-4.30 (m, 2H), 4.21-4.11 (m, 1H), 4.06-3.93 (m, 2H), 3.90-3.73 (m, 2H), 3.71-3.59 (m, 1H), 3.57-3.49 (m, 3H), 3.47-3.33 (m, 1H), 3.28-3.15 (m, 2H), 3.09-2.92 (m, 1H), 2.50-2.35 (m, 4H), 2.26-2.09 (m, 2H), 1.43-1.32 (m, 4H), 1.31-1.25 (m, 2H), LCMS m / z = 607.4 [M+H] + .

[0470] Example 15

[0471]

[0472] Step 1: Synthesis of compound 15-2

[0473] N,N-dimethylformamide (3 mL) was added to a dry reaction flask, compound 10-2 (200 mg, 262.56 umol, 1 eq) was added and stirred, N,N-diisopropylethylamine (101.80 mg, 787.69 umol, 137.20 uL, 3 eq) and compound 15-1 (78.88 mg, 393.84 umol, 1.5 eq) were added, the reaction was stirred at 50 °C for 30 min. The reaction was combined and treated with compound 10-2 (10 mg) batch, the reaction was poured into saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was used directly in the next step without purification. Compound 15-2 was obtained. LCMS m / z = 812.2 [M+H] + .

[0474] Step 2: Synthesis of compound 15-3

[0475] Methylene chloride (3 mL) was added to a dry reaction flask, compound 15-2 (0.24 g, 295.59 umol, 1 eq) was added and stirred, m-chloroperoxybenzoic acid (66.95 mg, 310.37 umol, 80% purity 1.05 eq) was added, the reaction was stirred at 25 °C for 30 min. The reaction was quenched by adding aqueous sodium sulfite solution (5 mL 5%), the reaction was divided into liquid, the aqueous phase was extracted with methylene chloride (5 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The aqueous phase was detected by starch iodide paper, there was no oxidizing property, and the aqueous phase was discarded. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 50:1 to 0:1) according to TLC (petroleum ether: ethyl acetate = 1:1, product Rf= 0.51) to give the product. Compound 15-3 was obtained. 1 H NMR (400 MHz, CDC13) d = 7.17-7.06 (m, 4H), 6.83-6.72 (m, 4H), 6.71-6.60 (m, 1H), 5.24-5.10 (m, 1H), 4.87-4.64 (m, 2H), 4.44-4.17 (m, 4H), 3.98-3.81 (m, 2H), 3.78-3.69 (m, 6H), 3.67-3.43 (m, 2H), 3.20-2.97 (m, 4H), 2.88-2.78 (m, 3H), 2.32-2.20 (m, 3H), 1.47-1.37 (m, 9H), 1.32-1.23 (m, 3H). LCMS m / z = 828.3 M+H] + .

[0476] Step 3: Synthesis of compound 15-4

[0477] Toluene (1 mL) was added to a dry reaction flask, compound 15-3 (180 mg, 217.41 μmol, 1 eq) was added and stirring was started, the reaction system was cooled to 0-5 °C, sodium tert-butoxide (2.68 mg, 652.23 μmol, 3 eq) was added, stirring for 10 min, toluene (0.3 mL) containing compound 1-11A (75.12 mg, 652.23 μmol, 77.44 μL, 3 eq) was added to the above reaction liquid, the reaction system was reacted at 0-5 °C for 30 min. The reaction liquid was poured into saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined and washed with saturated brine (5 mL), anhydrous sodium sulfate was added to dryness, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without purification. Compound 15-4 was obtained. LCMS m / z = 879.4 [M+H] + .

[0478] Step 4: Synthesis of compound 15-5

[0479] Dichloromethane (4 mL) was added to a dry reaction flask, compound 15-4 (160 mg, 182.03 μmol, 1 eq) was added and stirring was started, the reaction system was cooled to 0-5 °C, trifluoroacetic acid (1.23 g, 10.81 mmol, 800.00 μL, 59.36 eq) was added, and stirring was carried out for 4 h. The reaction liquid was added to saturated aqueous sodium bicarbonate solution (10 mL), the liquid was separated, extracted with dichloromethane (5 mL x 2), the organic phase was combined, anhydrous sodium sulfate was added to dryness, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without purification to give compound 15-5. LCMS m / z = 539.2 [M+H] + .

[0480] Step 5: Synthesis of compound 15

[0481] Dichloromethane (10 mL) was added to a dry reaction flask, compound 15-5 (0.06 g, 111.40 μmol, 1 eq) and compound acrylic acid (16.06 mg, 222.81 μmol, 15.29 μL, 2 eq) were added and stirred, then N, N-diisopropylethylamine (28.80 mg, 222.81 μmol, 38.81 μL, 2 eq) was added, the reaction system was cooled to -60 °C, and O-(7-azabenzotriazol-1-yl)-N, N, N, N-tetramethyluronium hexafluorophosphate (63.54 mg, 167.11 μmol, 1.5 eq) was added. The reaction system was reacted at -60 °C for 0.5 h. Compound 15-5 (20 mg) was combined and treated in batches, dichloromethane (5 mL) was added to the reaction solution, washed with saturated ammonium chloride solution (5 mL x 2), dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. High performance liquid chromatography column separation and purification were carried out, and the method was {chromatography column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [H2O (0.04% HC1)-ACN]; acetonitrile %: 1% -50%, 8 min}. One drop of ammonia was added to the machine liquid, the solution showed alkaline, and after the organic solvent was removed by concentration, it was freeze-dried to obtain compound 15. 1 H NMR (400 MHz, CD3OD) δ = 7.24-7.07 (m, 2H), 6.80 (dd, J = 10.8, 16.8 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.24 (d, J = 16.8 Hz, 1H), 5.79 (d, J = 11.7 Hz, 1H), 5.24-5.16 (m, 1H), 4.76 (d, J = 13.8 Hz, 3H), 4.57 (dd, J = 7.2, 12.5 Hz, 2H), 4.07-3.86 (m, 3H), 3.73 (s, 1H), 3.17 (d, J = 11.4 Hz, 3H), 3.07 (s, 3H), 2.90 (d, J = 14.8 Hz, 1H), 2.46-2.34 (m, 4H), 2.33-2.30 (m, 1H), 2.26-1.95 (m, 3H), 1.41 (s, 3H). LCMS m / z = 593.2 [M+H] + .

[0482] Example 16

[0483]

[0484] Step 1: Synthesis of compound 16-2

[0485] N,N-dimethylformamide (3 mL) was added to a dry reaction flask, compound 10-2 (200 mg, 262.56 umol, 1 eq) was added and stirred, then N,N-diisopropyl ethylamine (101.80 mg, 787.69 umol, 137.20 uL, 3 eq) and compound 16-1 (78.02 mg, 393.84 umol, 1.5 eq, 2HCl) were added, and the reaction system was reacted at 50 °C for 30 min. The reaction was combined and treated, the reaction was poured into saturated aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was directly used in the next step without purification to give compound 16-2. LCMS m / z = 737.2 [M+H] + Step 2: synthesis of compound 16-3

[0486] N,N-dimethylformamide (3 mL) was added to a dry reaction flask, compound 16-2 (230 mg, 312.15 umol, 1 eq) was added and stirred, then N,N-diisopropyl ethylamine (121.03 mg, 936.46 umol, 163.11 uL, 3 eq) and di-tert-butyl dicarbonate (74.94 mg, 343.37 umol, 78.88 uL, 1.1 eq) were added, and the reaction system was reacted at 20 °C for 10 h. The reaction was poured into saturated aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (10 mL x 2), the organic phase was combined and washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:1-0:1) according to TLC (petroleum ether: ethyl acetate = 3:1) to give compound 16-3. 1 H NMR (400 MHz, CDCl3) d = 7.16 (d, J = 8.4 Hz, 4H), 6.85 (d, J = 8.6 Hz, 4H), 6.64 (d, J = 8.0 Hz, 1H), 5.22 (d, J = 7.2 Hz, 1H), 4.90-4.68 (m, 2H), 4.61 (s, 1H), 4.41-4.21 (m, 4H), 4.04 (s, 1H), 3.80 (s, 6H), 3.71 (s, 1H), 3.50 (d, J = 11.0 Hz, 2H), 3.30 (s, 1H), 3.24-3.02 (m, 2H), 2.90 (d, J = 2.0 Hz, 1H), 2.78-2.58 (m, 2H), 2.55 (s, 3H), 2.34 (d, J = 4.0 Hz, 3H), 1.51 (s, 9H). LCMS m / z = 837.2 [M+H]+ .

[0487] Step 3: Synthesis of compound 16-4

[0488] Into a dry reaction vial, was placed dichloromethane (0.3 mL), then compound 16-3 (230 mg, 274.81 umol, 1 eq) was added and stirred, then m-chloroperoxybenzoic acid (61.37 mg, 302.29 umol, 85% purity, 1.1 eq) was added, the reaction was stirred at 20 °C for 1 h. The reaction was poured into 5% aqueous sodium sulfite solution (5 mL), the aqueous phase was extracted with dichloromethane (5 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 100:1-0:1) to give compound 16-4.

[0489] LCMS m / z = 853.2 [M+H] + .

[0490] Step 4: Synthesis of compound 16-5

[0491] Into a dry reaction vial, was placed toluene (2 mL), then compound 16-4 (158 mg, 185.24 umol, 1 eq) was added and stirred, the reaction was cooled to 0 °C, then sodium tert-butoxide (35.60 mg, 370.49 umol, 2 eq) was added and stirred for 15 min, then compound 12-3A (65.40 mg, 463.11 umol, 2.5 eq) was added, the reaction was stirred at 0 °C for 30 min. The reaction was poured into saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was used directly in the next step to give compound 16-5. LCMS m / z = 930.4 [M+H] + .

[0492] Step 5: Synthesis of compound 16-6

[0493] Dichloromethane (5 mL) was added to a dry reaction flask, compound 16-5 (0.18 g, 193.54 μmol, 1 eq) was added and stirred, trifluoroacetic acid (1 mL) was added, the reaction system was reacted at 18 °C for 3 h. Water (10 mL) was added to the reaction solution, extracted and separated, the aqueous phase was collected, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (20 mL x 2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without purification to obtain compound 16-6. LCMS m / z = 590.2 [M+H] +

[0494] Step 6: synthesis of compound 16

[0495] Compound 16-6 (62.77 mg, 106.46 μmol, 1 eq), 2-fluoropropenoic acid (19.17 mg, 212.92 μmol, 2 eq), N, N-diisopropylethylamine (41.28 mg, 319.38 μmol, 55.63 μL, 3 eq) were dissolved in DCM (5 mL) and cooled to -60 °C. O-(7-azabenzotriazol-1-yl)-N, N, N, N-tetramethyluronium hexafluorophosphate (48.58 mg, 127.75 μmol, 1.2 eq) was added, and then stirred for 0.5 hr. Compound 16-6 (20.92 mg) was treated in batches. 5 mL of water was added to the reaction solution, separated, the organic phase was concentrated, and purified by high performance liquid chromatography column, and the purification method was {chromatography column: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [H2O (0.04% HC1)-ACN]; acetonitrile%: 20%-40%, 7 min} to obtain compound 16. 1 H NMR (400 MHz, CD3OD) δ = 6.73 (d, J = 8.6 Hz, 1H), 5.45-5.21 (m, 3H), 4.87-4.80 (m, 2H), 4.57 (s, 2H), 4.19 (br d, J = 13.7 Hz, 1H), 3.98 (br d, J = 13.1 Hz, 1H), 3.75-3.66 (m, 2H), 3.56-3.49 (m, 1H), 3.37 (s, 3H), 3.32-3.27 (m, 2H), 3.26-3.11 (m, 1H), 3.06-2.87 (m, 1H), 3.06-2.87 (m, 1H), 3.06-2.87 (m, 1H), 2.44-2.03 (m, 12H). LCMS m / z = 662.4 [M+H] + .

[0496] Example 17

[0497]

[0498] Step 1: Synthesis of compound 17-2

[0499] N,N-dimethylformamide (30 mL) was added to a dry reaction flask, then compound 10-2 (2.8 g, 3.68 mmol, 1 eq) was added and stirred, then N,N-diisopropyl ethylamine (1.43 g, 11.03 mmol, 1.92 mL, 3 eq) and compound 16-1 (873.80 mg, 4.41 mmol, 1.2 eq, 2HCl) were added, the reaction system was reacted at 50°C under nitrogen protection for 1 hour. The batches were combined and treated with compound 10-2 (0.2 g), methyl tert-butyl ether (30 mL) was added to the reaction solution, washed twice with saturated ammonium chloride solution (30 mL x 2) and saturated brine (30 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was not purified and was directly used in the next step to obtain compound 17-2. 1 HNMR (400 MHz, CDC13) δ ppm 7.15 (d, J = 8.80 Hz, 4H), 6.84 (d, J = 8.40 Hz, 4H), 6.63 (d, J = 8.40 Hz, 1H), 5.22 (dd, J = 11.20, 4.00 Hz, 1H), 4.71 (s, 2H), 4.36-4.20 (m, 4H), 4.06 (d, J = 12.80 Hz, 1H), 3.80 (s, 6H), 3.61-3.50 (m, 2H), 3.43 (dd, J = 18.80, 11.60 Hz, 2H), 3.27-3.15 (m, 2H), 3.12-2.98 (m, 2H), 2.85-2.66 (m, 2H), 2.53 (s, 3H), 2.38-2.31 (m, 3H), LCMS m / z = 737.2 [M+H] + .

[0500] Step 2: Synthesis of compound 17-3

[0501] Dichloromethane (30 mL) was added to a dry reaction flask, then compound 17-3 (2.6 g, 3.12 mmol, 1 eq) was added to start stirring, then m-chloroperoxybenzoic acid (697.20 mg, 3.43 mmol, 85% purity, 1.1 eq) was added, the reaction system was reacted at 18 °C for 0.5 h. Compound 17-3 (0.2 g) batch was combined and treated, sodium thiosulfate solution (20 mL 10%) was added to the reaction liquid, and it was negative after starch-KI test paper was used for extraction with dichloromethane (20 mL x 2), dried and filtered with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column according to TLC (petroleum ether: ethyl acetate = 0:1) (petroleum ether: ethyl acetate = 10:1-0:1) to obtain compound 17-4. 1 H NMR (400 MHz, CDCl3) δ ppm 7.15 (d, J = 8.40 Hz, 4H), 6.84 (d, J = 8.40 Hz, 4H), 6.65 (br d, J = 8.40 Hz, 1H), 5.29-5.20 (m, 1H), 4.77 (s, 2H), 4.38-4.24 (m, 4H), 4.05-3.88 (m, 2H), 3.80 (s, 6H), 3.78-3.60 (m, 2H), 3.59-3.37 (m, 2H), 3.14-2.99 (m, 2H), 2.98-2.93 (m, 1H), 2.91-2.86 (m, 1H), 2.78 (t, J = 6.80 Hz, 1H), 2.53 (s, 3H), 2.39-2.30 (m, 3H), LCMS m / z = 833.1 [M+H] + .

[0502] Step 3: Synthesis of compound 17-4

[0503] Dichloromethane (30 mL) was added to a dry reaction flask, then compound 17-3 (2.6 g, 3.12 mmol, 1 eq) was added to start stirring, then m-chloroperoxybenzoic acid (697.20 mg, 3.43 mmol, 85% purity, 1.1 eq) was added, the reaction system was reacted at 18 °C for 0.5 h. Compound 17-3 (0.2 g) batch was combined and treated, sodium thiosulfate solution (20 mL 10%) was added to the reaction liquid, and it was negative after starch-KI test paper was used for extraction with dichloromethane (20 mL x 2), dried and filtered with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column according to TLC (petroleum ether: ethyl acetate = 0:1) (petroleum ether: ethyl acetate = 10:1-0:1) to obtain compound 17-4. 1H NMR (400 MHz, CDC13) δ ppm 7.15 (d, J = 8.40 Hz, 4H), 6.84 (d, J = 8.40 Hz, 4H), 6.66 (d, J = 8.40 Hz, 1H), 5.27 (d, J = 9.20 Hz, 1H), 4.93 - 4.982 (m, 2H), 4.38 - 4.24 (m, 4H), 4.10 - 3.99 (m, 2H), 3.98 - 3.88 (m, 1H), 3.87 - 3.68 (m, 8H), 3.67 - 3.54 (m, 1H), 3.54 - 2.98 (m, 3H), 2.93 - 2.79 (m, 4H), 2.78 - 2.65 (m, 1H), 2.35 (d, J = 3.60 Hz, 3H), LCMS m / z = 849.1 [M+H] + .

[0504] Step 4: Synthesis of compound 17-5

[0505] Toluene (1 mL) was added to a dry reaction flask, then compound 17-4A (78.77 mg, 494.80 umol, 3 eq) was added to start stirring, the reaction system was cooled to 0°C, sodium tert-butoxide (47.55 mg, 494.80 umol, 3 eq) was added, stirred for 10 minutes, then a toluene solution (0.5 mL) containing compound 17-4 (0.14 g, 164.93 umol, 1 eq) was added, and the reaction was continued for 0.5 hours. Compound 17-4 (20 mg) batches were combined and treated, ethyl acetate (5 mL) was added to dilute the reaction solution, which was washed with saturated ammonium chloride solution (10 mL x 2) and saturated brine (10 mL) in turn, dried with anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without purification to obtain compound 17-5. LCMS m / z = 848.3 [M+H] + .

[0506] Step 5: Synthesis of compound 17-6

[0507] Dichloromethane (12 mL) was added to a dry reaction flask, then compound 17-5 (160.00 mg, 188.70 umol, 1 eq) was added to start stirring, then trifluoroacetic acid (2 mL) was added, and the reaction system was reacted at 18°C for 2 hours. Compound 17-5 (20 mg) batches were combined and treated, water (10 mL) was added to the reaction solution, which was extracted with dichloromethane (10 mL x 2), the aqueous phase was extracted with saturated sodium bicarbonate solution until pH = 8, then extracted with dichloromethane (10 mL x 2), dried with anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without purification to obtain compound 17-6. LCMS m / z = 608.3 [M+H]+ .

[0508] Step 6: Synthesis of compound 17

[0509] Dichloromethane (5 mL) was added to a dry reaction flask, then compound 17-6 (50 mg, 82.29 pmol, 1 eq) and 2-fluoropropenoic acid (14.82 mg, 164.58 pmol, 2 eq) and N,N-diisopropylethylamine (31.90 mg, 246.87 pmol, 43.00 pL, 3 eq) were added and stirred, the reaction system was cooled to -60 °C, then O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (37.55 mg, 98.75 pmol, 1.2 eq) was added, and then stirred for 0.5 h. The combined treatment was added to the reaction solution, the reaction was quenched by adding water (5 mL), the organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography column {chromatography column: Welch Xtimate C18 100*25 mm*3 pm; mobile phase: [H20 (0.05% HC1)-ACN]; acetonitrile%: 20%-50%, 8 min} to obtain compound 17. SFC analysis method (column: Chiralcel OD-3, 50*4.6 mm I.D., 3 pm; mobile phase: A (C02) and B (methanol containing 0.05% diisopropylamine amine); gradient: B% = 5-50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi, optical purity: 99.21%, peak time: 1.840. 1 H NMR (400 MHz, CD3OD) d = 6.80-6.68 (m, 1H), 5.73-5.51 (m, 1H), 5.46-5.19 (m, 3H), 5.05-4.90 (m, 3H), 4.74-4.58 (m, 2H), 4.37-4.26 (m, 1H), 4.20-4.06 (m, 2H), 4.05-3.84 (m, 3H), 3.79-3.59 (m, 2H), 3.54-3.43 (m, 1H), 3.42-3.35 (m, 1H), 3.31-3.24 (m, 1H), 3.13-2.89 (m, 3H), 2.82-2.52 (m, 2H), 2.50-2.42 (m, 1H), 2.41-2.30 (m, 5H), 2.29-2.18 (m, 1H).

[0510] Example 18

[0511]

[0512] Step 1: Synthesis of compound 18-1

[0513] To 1-11A (194.75 mg, 1.69 mmol, 200.78 μL, 4 eq) was added anhydrous toluene (16 mL), cooled to 0 °C, added sodium tert-butoxide (162.50 mg, 1.69 mmol, 4 eq), 0-5 °C for 10 min, added compound 9-3 (0.35 g, 422.74 μmol, 1 eq) in toluene (5 mL), 0-5 °C for 0.5 h, the reaction was treated with 20 mL x 2 saturated ammonium chloride, 20 mL saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 18-1. MS m / z = 879.2 [M+H] + .

[0514] Step 2: Synthesis of compound 18-2

[0515] To compound 18-1 (0.4 g, 455.07 μmol, 1 eq) was added anhydrous dichloromethane (12 mL), added trifluoroacetic acid (2.4 mL), 25 °C for 1.5 h, the reaction was treated with compound 18-1 (50 mg) in batches, slowly added saturated sodium bicarbonate to the reaction solution to pH 7-8, extracted with 20 mL dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give compound 18-2. LCMS m / z = 539.1 [M+H] +

[0516] Step 3: Synthesis of compound 18A and 18B

[0517] Compound 18-2 (36.80 mg, 510.60 umol, 35.04 uL, 1.1 eq), acrylic acid (36.80 mg, 510.60 umol, 35.04 uL, 1.1 eq) and N,N- diisopropylethylamine (179.97 mg, 1.39 mmol, 242.55 uL, 3 eq) were added into anhydrous dichloromethane (5 mL), cooled to -60 °C, O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (176.50 mg, 464.18 umol, 1 eq) was added, and the reaction was allowed to proceed at -60 °C for 30 min. The reaction was diluted with 10 mL of dichloromethane, washed with 10 mL x 2 of saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed by high performance liquid chromatography column (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.1% TFA) - ACN]; acetonitrile%: 10% - 40%, 8 min), followed by lyophilization and chiral separation by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: [0.1% NH3H2O ETOH]; ethanol%: 50% - 50%, 15 min) to give compound 18A (chiral retention time: 1.479). SFC analysis method (column: Chiralcel OD-3, 50*4.6mm I.D., 3um; mobile phase: A (CO2) and B (methanol with 0.05% diisopropylamine amine); gradient: B% = 5~50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi, optical purity 100%. MS m / z = 593.3 [M+H] + , 1H NMR (400 MHz, CDC13) δ = 6.66 - 6.50 (m, 2H), 6.36 (d, J = 16.8 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.20 (d, J = 7.6 Hz, 1H), 4.58 - 4.53 (m, 1H), 4.45 - 4.20 (m, 2H), 4.01 (s, 3H), 3.85 - 3.23 (m, 6H), 3.04 - 2.86 (m, 2H), 2.67 (s, 2H), 2.47 - 2.33 (m, 3H), 2.22 - 1.53 (m, 8H), 1.23 - 1.04 (m, 3H). Compound 18B (Chiral peak time: 1.642) was obtained by SFC analysis method (Column: Chiralcel OD-3, 50 x 4.6 mm I.D., 3 pm; Mobile phase: A (C02) and B (methanol with 0.05% diisopropylamine); Gradient: B% = 5-50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, optical purity 97.8%. LCMS m / z = 593.3 [M+H] + . 1 H NMR (400 MHz, CDC13) δ = 6.66 - 6.50 (m, 2H), 6.36 (d, J = 16.8 Hz, 1H), 5.76 (d, J = 10.0 Hz, 1H), 5.20 (d, J = 7.6 Hz, 1H), 4.58 - 4.53 (m, 1H), 4.45 - 4.20 (m, 2H), 4.01 (s, 3H), 3.85 - 3.23 (m, 6H), 3.04 - 2.86 (m, 2H), 2.67 (s, 2H), 2.47 - 2.33 (m, 3H), 2.22 - 1.53 (m, 8H), 1.23 - 1.04 (m, 3H). Compound 18B (Chiral peak time: 1.642) was obtained by SFC analysis method (Column: Chiralcel OD-3, 50 x 4.6 mm I.D., 3 pm; Mobile phase: A (C02) and B (methanol with 0.05% diisopropylamine); Gradient: B% = 5-50%, 3 min; Flow rate: 3.4 mL / min; Wavelength: 220 nm; Pressure: 1800 psi, optical purity 97.8%. LCMS m / z = 593.3 [M+H]

[0518] Example 19

[0519]

[0520] Step 1: Synthesis of compound 19

[0521] Dichloromethane (5 mL) was added to a dry reaction flask, followed by compound 17-6 (25 mg, 42.40 μmol, 1 eq), acrylic acid (6.11 mg, 84.80 μmol, 5.82 μL, 2 eq), and N,N-diisopropylethylamine (16.44 mg, 127.20 μmol, 22.16 μL, 3 eq). The mixture was stirred and cooled to 0 °C. Then, O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (19.35 mg, 50.88 μmol, 1.2 eq) was added, and the mixture was stirred at 20 °C for 3 hours. The reaction was quenched by adding water (5 mL), the mixture was separated, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) using a Phenomenex Luna C18 column (80*40mm*3 μm); mobile phase: [H2O(0.04% HCl)-ACN]; B%: 18%-34%, 7 min; yielding compound 19. LCMS m / z = 622.2 [M+H]+.

[0522] Example 20

[0523]

[0524] Step 1: Preparation of Intermediate 20-1

[0525] Compound 9-2 (90 mg, 110.85 μmol) was dissolved in dichloromethane (2 mL), and m-chloroperoxybenzoic acid (45.01 mg, 221.70 μmol, 85% purity) was added. The reaction mixture was stirred at 20 °C for 3 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 20:1) to obtain compound 20-1. MS m / z = 844.4 [M+H]+.

[0526] Step 2: Preparation of intermediate 20-2

[0527] Compound 17-4A (12.26 mg, 77.02 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 20 °C. Sodium tert-butoxide (7.40 mg, 77.02 μmol) was added, and the reaction mixture was stirred for 30 minutes. Then, a tetrahydrofuran solution of compound 20-1 (50 mg, 59.25 μmol) (0.5 mL) was added, and the reaction mixture was stirred at the same temperature for 0.5 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to obtain compound 20-2. MS m / z = 923.6 [M+H] + .

[0528] Step 3: Preparation of compound 20-3

[0529] Compound 20-2 (45 mg, 48.75 μmol) was dissolved in anhydrous dichloromethane (2 mL), trifluoroacetic acid (1.5 mL) was added, and the reaction was continued to stir at 20 °C for 2 hours. The solvent was removed under reduced pressure, and the obtained crude product was dissolved in 20 mL dichloromethane, 3 g of solid sodium bicarbonate was added, and the reaction was continued to stir at room temperature for 1 hour. Filtration was performed, and the organic solvent was removed under reduced pressure to obtain the crude product 20-3, which was used directly in the next step without further purification.

[0530] Step 4: Preparation of compound 20

[0531] Compound 20-3 (20 mg, 34.33 μmol) was dissolved in anhydrous dichloromethane (2 mL) at 20 °C, diisopropylethylamine (13.31 mg, 102.99 μmol, 17.94 μL) and allyl chloride (4.66 mg, 51.49 μmol, 4.20 μL) were added, and the reaction was continued to stir at the temperature for 16 hours. The organic solvent was removed under reduced pressure, and the obtained crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [water (0.075% trifluoroacetic acid) - acetonitrile]; acetonitrile: 22% - 52%, 8 min) to obtain the trifluoroacetate salt of compound 20. MS m / z = 637.4 [M+H] + .

[0532] Biological test data:

[0533] Experimental Example 1: Test of the effect of the compound on the proliferation of KRAS G12C mutant MIA-PA-CA-2 cells

[0534] 1.1 Purpose of the experiment

[0535] Test of the IC of the compound on the inhibition of the proliferation of KRAS G12C mutant MIA-PA-CA-2 cells 50 .

[0536] 1.2 Reagents

[0537] The main reagents used in this study include CellTiter-Glo (Promega, Cat. No. G7573).

[0538] 1.3 Instruments

[0539] The main instrument used in this study is PerkinElmer EnVision multifunctional microplate reader.

[0540] 1.4 Experimental Methods

[0541] 1) Adherent cells were trypsinized to make cell suspension and counted for use.

[0542] 2) Appropriate amount of cells were taken to centrifuge tube and made up to the required volume with cell culture medium, plated to 96-well plate, final density 2000 cells / well, 100 μL medium.

[0543] 3) After 24 hr incubation, compounds were prepared in DMSO to 10 mM and diluted with DPBS (Dulbecco's Phosphate Buffered Saline) in 3-fold gradient to 9 points, 10 μL per well, duplicate. Experimental control wells (Con) were added with 10 μL DPBS per well.

[0544] 4) On the same day, one plate of cells without drug treatment was taken and 50 μL CellTiter Glo was added, fluorescence reading was taken by EnVision and labeled as DayO reading.

[0545] 5) After 72 hr incubation, the plate was removed and 50 μL CellTiter Glo was added to the cell plate, fluorescence reading was taken by EnVision.

[0546] 6) Data analysis: the inhibition rate of each well was calculated according to the following formula:

[0547]

[0548] *F Day0 F0 is the reading of the test well without drug treatment of the original cell number;

[0549] F Con F72 is the fluorescence reading of the Con group after 72 hr incubation.

[0550] F Cpd F72 is the fluorescence reading of each compound well after 72 hr incubation.

[0551] 7) The inhibition rate data of the compound (inhibition rate %) was analyzed by GraphPad Prism software for log (agonist) vs. response - Variable slope nonlinear fitting analysis to obtain the IC 50 value of the compound, the fitting formula is:

[0552] Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0553] 1.5 Experimental Results

[0554] Table 1. Test results of the compounds of the present application on the inhibition of the proliferation of MIA-PA-CA-2 cells with KRAS G12C mutation

[0555] Compound No. IC 50 (nM) 1 5.21 Hydrochloride salt of 8B 2.7 9B 6.98 12 1.30 16 2.22 17 0.44 18B 3.29

[0556] The experimental results show that the compounds of the present application have good cell proliferation inhibition activity on the MIA-PA-CA-2 cell line with KRAS G12C mutation.

[0557] Experimental Example 2: H358 cell experiment

[0558] 2.1 Purpose of the experiment

[0559] Test the IC of the compounds on the inhibition of the proliferation of H358 cells with KRAS G12C mutation. 50 .

[0560] 2.2 Reagents

[0561] The main reagents used in this study include RPMI-1640 medium, penicillin / streptomycin antibiotics purchased from Vincents, fetal bovine serum purchased from Biosera. CellTiter-Glo (Cell Viability Chemiluminescent Assay) reagent purchased from Promega. NCI-H358 cell line purchased from the Chinese Academy of Sciences Cell Bank.

[0562] 2.3 Instruments

[0563] The main instrument used in this study is a Nivo Multi-Label Reader (PerkinElmer).

[0564] 2.4 Experimental method:

[0565] 1) NCI-H358 cells were seeded in white 96-well plates, 80 μL of cell suspension per well, containing 4000 NCI-H358 cells. The cell plate was incubated in a carbon dioxide incubator overnight.

[0566] 2) The test compound was diluted 5 times by gun to the 9th concentration, i.e. from 2 mM to 5.12 nM, and a double-replicate well experiment was set up. 78 μL of medium was added to the intermediate plate, and then 2 μL of gradient-diluted compound per well was transferred to the intermediate plate according to the corresponding position, and after mixing, 20 μL per well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10 μM to 0.0256 nM. The cell plate was incubated in a carbon dioxide incubator for 5 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. 25 μL of cell viability chemiluminescent assay reagent was added to each well of the cell plate, and the luminescent signal was allowed to stabilize at room temperature for 10 minutes. A multi-label reader was used to read the signal.

[0567] 3) Add 25 μL / well of CellTiter-Glo® Luminescent Cell Viability Assay reagent to the cell plate and incubate at room temperature for 10 minutes to allow the luminescent signal to stabilize. Read using a Multilabel Reader.

[0568] Data Analysis:

[0569] The raw data was converted to percent inhibition using the equation (Sample-Min) / (Max-Min)*100% and IC50values were determined by four parameter curve fitting (obtained in GraphPad Prism in the "log(inhibitor) vs. response - Variable slope" mode). Table 2 provides the inhibitory activity of the compounds of the application against NCI-H358 cell proliferation. 50

[0570] Table 2. Test results of the compounds of the application against the proliferation of KRAS G12C mutant H358 cells

[0571] Compound NCI-H358 IC 50 (nM)]]> 1 68.2 2 19.0 Hydrochloride salt of 4B 27.0 5B 12.9 6A <4.6 Hydrochloride salt of 8B <4.6 9B 5.5 10 70 11 6.7 12 2.5 13 32.6 15 9.2 16 1.7 17 0.6 18B 4.7

[0572] Conclusion: Some of the compounds of the application exhibit good inhibitory activity against NCI-H358 cell proliferation.

[0573] Experimental Example 3: Hepatocyte Metabolic Stability

[0574] Purpose of the experiment: To assess the metabolic stability of the test compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human hepatocytes, respectively

[0575] ​Experimental operation: Prepare several 96-well sample precipitation plates, respectively named as T0, T15, T30, T60, T90, T120, T0-MC, T120-MC and blank matrix. Take out the recovery culture solution and incubation culture solution in advance and place them in a 37°C water bath for preheating. Take out the frozen liver cells from the liquid nitrogen tank and immediately immerse them in a 37°C water bath (about 90 seconds). After the frozen part is loosened, pour it into a centrifuge tube containing 40 mL of recovery culture solution, and gently invert to resuspend the cells in the recovery culture solution. Centrifuge at 100 x g for 5 minutes at room temperature, remove the supernatant, and resuspend the liver cells with an appropriate volume of incubation culture solution. Calculate the cell viability by trypan blue staining method. Add 198 μL of liver cell suspension (0.51 x 106 cells / mL) to the preheated incubation plate, add 198 μL of incubation culture solution without liver cells to the T0-MC and T120-MC incubation plates, and pre-incubate all incubation plates in a 37°C incubator for 10 minutes. Then add 2 μL of test compound and control compound working solution, mix well, and immediately place the incubation plate in a shaking plate machine in the incubator, start the timer and begin the reaction. Prepare 2 replicates for each time point for each compound. The incubation conditions are 37°C, saturated humidity, and 5% CO2. In the test system, the final concentration of the test compound is 1 μM, the final concentration of the control compound is 3 μM, the final concentration of the liver cells is 0.5 x 106 cells / mL, the final concentration of the total organic solvent is 0.96%, and the final concentration of DMSO is 0.1%. At the corresponding time point, take out the incubation plate, take out 25 μL of the mixture of the compound and the control compound and the cells, and add it to a sample plate containing 125 μL of termination solution (200 ng / mL tolbutamide and labetalol in acetonitrile solution). For the Blank sample plate, directly add 25 μL of incubation culture solution without liver cells. After all the sample plates are sealed, shake them on the shaking plate machine at 600 rpm for 10 minutes, and then centrifuge at 3220 x g for 20 minutes. Dilute the supernatant of the test compound and the control compound with ultrapure water at a ratio of 1:3. Mix all the samples and analyze them by LC / MS / MS method.

[0576] The experimental results are shown in Table 3.

[0577] Table 3. Metabolic stability of the test compound in CD-1 mouse, SD rat, beagle dog, cynomolgus monkey, and human liver cells

[0578]

[0579]

[0580] Experimental conclusion: The liver cell metabolism experiment of multiple species shows that the compound of the present application has good metabolic stability

[0581] Experimental Example 4: In vitro liver microsomal stability study

[0582] Purpose of the experiment: to evaluate the metabolic stability of the test compound in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, human liver microsomes, respectively

[0583] Experimental operation: prepare two 96-well incubation plates, respectively named T60 incubation plate and NCF60 incubation plate. Add 445 μL of microsomal working solution (liver microsomal protein concentration is 0.56 mg / mL) to the T60 incubation plate and the NCF60 incubation plate, respectively, and then place the above-mentioned incubation plates in a 37°C water bath for pre-incubation for about 10 minutes.

[0584] After pre-incubation, add 5 μL of test product or control compound working solution to the T60 incubation plate and the NCF60 incubation plate, respectively, and mix well. Add 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction; add 180 μL of termination solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 uL of NADPH regeneration system working solution to the T0 termination plate, and take 54 μL of sample from the T60 incubation plate to the T0 termination plate (T0 sample production). Add 44 μL of NADPH regeneration system working solution to each well of the T60 incubation plate to start the reaction. In the Blank plate, only add 54 μL of microsomal working solution, 6 uL of NADPH regeneration system working solution and 180 μL of termination solution. Therefore, in the samples of the test product or the control compound, the final reaction concentrations of the compound, testosterone, diclofenac and propafenone are 1 μM, the concentration of liver microsomes is 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system are 0.01% (v / v) and 0.99% (v / v), respectively. After incubation for an appropriate time (such as 5, 15, 30, 45 and 60 minutes), add 180 μL of termination solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) to each sample well of the termination plate, and then take 60 μL of sample from the T60 incubation plate to terminate the reaction. Shake all sample plates and centrifuge at 3220 x g for 20 minutes, then take 80 μL of supernatant from each well and dilute in 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis. Analyze all samples by liquid chromatography tandem mass spectrometry analysis.

[0585] Table 4. Metabolic stability of the test compound in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, human liver microsomes

[0586]

[0587]

[0588] Experimental conclusion: The liver microsomal metabolic stability study shows that the compound of the present application has good metabolic stability

[0589] Experimental Example 5: Plasma stability study

[0590] Experimental purpose: To evaluate the stability of the test compound in the plasma of CD-1 mice and humans, respectively

[0591] Experimental operation: The frozen plasma was thawed for 10-20 minutes, and after the plasma was completely thawed, it was placed in a centrifuge to centrifuge at 3220 x g for 5 minutes to remove the suspended and precipitated substances present therein. A 96-well incubation plate was prepared and named T0, T10, T30, T60, T120, respectively. 98 μL of mouse, rat, dog, monkey and human blank plasma was added to the corresponding incubation plate, and then 2 μL of the working solution of the compound or the control compound was added to the corresponding incubation plate, and two parallel holes were prepared for each sample. All samples were incubated in a 37°C water bath. The final incubation concentration of the compound and the control compound, bisacodyl, enalapril maleate, procaine and prophenpyridamine, was 2 μM, and the final organic phase content was 2.0%. At the end of each incubation time point, the corresponding incubation plate was taken out, and 400 μL of acetonitrile solution containing 200 ng / mL tolbutamide and labetalol was added to each corresponding sample hole to precipitate the protein. After all sample plates were sealed and shaken, they were centrifuged at 3220 x g for 20 minutes. 50 μL of supernatant was added to 100 μL of ultrapure water for dilution, and all samples were mixed and analyzed by LC / MS / MS method.

[0592] Table 5. Plasma stability of the test compound in CD-1 mice and humans

[0593]

[0594] Experimental conclusion: The compound of the present application has good stability in human and mouse plasma.

[0595] Experimental Example 6: Whole blood stability study

[0596] Experimental purpose: To evaluate the stability of the test compound in the whole blood of CD-1 mice, SD rats, beagle dogs and cynomolgus monkeys, respectively

[0597] Experimental operation: On the day of the experiment or the day before the experiment, fresh CD-1 mouse, SD rat, beagle dog, cynomolgus monkey whole blood was collected with anticoagulant EDTA-K2. Before the experiment, the whole blood was mixed with PBS at 1:1 (v:v) and placed in a 37°C water bath for 10-20 minutes. Prepare 96-well incubation plates, respectively named T0, T30, T60, T240. In the corresponding incubation plates, including T0, T30, T60 and T240 incubation plates, mix 2 μL of compound or control compound working solution with 98 μL of mouse, rat, dog, monkey and human blank whole blood, and prepare two parallel holes for each sample. All samples were incubated in a 37°C water bath. The final incubation concentration of the compound was 5 μM, and the final incubation concentration of the control compound was 2 μM. At the end of each time point incubation, the corresponding incubation plate was taken out, 100 μL of ultrapure water was immediately added to the corresponding sample hole, mixed well, and then 800 μL of acetonitrile solution containing 200 ng / mL tolbutamide and labetalol was added to precipitate the protein. After the sample plate was sealed and shaken, it was centrifuged at 3220 x g for 20 minutes. Take 150 μL of supernatant for analysis by LC / MS / MS method.

[0598] Table 6. Stability of test compound CD-1 mouse, SD rat, beagle dog, cynomolgus monkey whole blood

[0599]

[0600] Experimental conclusion: The stability of the compound of the present application in whole blood of various species of dogs is good.

[0601] Experimental example 7: Protein binding rate study

[0602] Experimental purpose: The equilibrium dialysis method is used to determine the protein binding rate of the test compound in the plasma of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and humans.

[0603] Experimental operation: The plasma of the above five species was used to prepare a plasma sample with a compound concentration of 2 μM, which was placed in a 96-well equilibrium dialysis device and dialyzed with phosphate buffer solution at 37±1°C for 4h. Warfarin was used as a control compound in this experiment. The concentration of the test substance in the plasma and dialysis buffer was determined by LC-MS / MS method.

[0604] Table 7. Protein binding rate of test compound CD-1 mouse, SD rat, beagle dog, cynomolgus monkey, human

[0605]

[0606] Experimental conclusion: The plasma binding rate study of various species shows that the compound of the present application has a higher protein unbinding rate in plasma.

[0607] Experimental Example 8: In vivo pharmacokinetic study

[0608] 1) Pharmacokinetic study of test compounds in SD rats by oral and intravenous administration

[0609] The test compound was mixed with 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β- cyclodextrin) solution, vortexed and ultrasonicated to prepare a 1 mg / mL clear solution, which was filtered through a micropore filter and stored for use. Male SD rats aged 7 to 10 weeks were administered the candidate compound solution by intravenous injection and orally. Whole blood was collected for a certain period of time, and plasma was prepared. The drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Corporation, USA). The experimental results are shown in Table 8:

[0610] Table 8. Pharmacokinetic results of test compounds

[0611]

[0612]

[0613] Note: Vd ss , u is the apparent volume distribution (Vd ss , u = Vd ss / PPB (Unbond %)); C max,u， AUC 0-last，u， are the corresponding values of plasma protein unbound (C max,u = C max x PPB (Unbond %); AUC 0-last，u = AUC 0-last x PPB (Unbond %)) Experimental conclusion: The PK study showed that the compounds of the present application had high non-bound plasma exposure and good oral bioavailability in rats. 2) Pharmacokinetic study of test compounds in CD mice by oral and intravenous administration

[0614] The test compound was mixed with 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β- cyclodextrin) solution, vortexed and ultrasonicated to prepare a 1 mg / mL clear solution, which was filtered through a micropore filter and stored for use. Male CD mice aged 7 to 10 weeks were administered the candidate compound solution by intravenous injection and orally. Whole blood was collected for a certain period of time, and plasma was prepared. The drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Corporation, USA). The experimental results are shown in Table 9:

[0615] Table 9. Pharmacokinetic results of test compounds

[0616]

[0617] Note: Vd ss u is the apparent volume of distribution (Vd ss u = Vd ss u x PPB(Unbond%) ); C max,u AUC 0-last，u AUC max,u = C max x PPB(Unbond%); AUC 0-last，u = AUC 0-last x PPB(Unbond%))

[0618] Experimental Conclusion: The PK study shows that the compound of the present application has high non-bound plasma exposure and good oral bioavailability in mice.

[0619] Experimental Example 9: In vivo pharmacodynamics study

[0620] In vivo pharmacodynamics study of human pancreatic cancer Mia PaCa-2 cell subcutaneous transplanted tumor Balb / c Nude mouse model

[0621] 1. Cell culture and tumor tissue preparation

[0622] Cell culture: human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420) were cultured in monolayer in vitro, and the culture conditions were as follows: DMEM medium containing 10% fetal bovine serum, 2.5% horse serum, 37°C, 5% carbon dioxide incubator. Routine digestion treatment was performed with trypsin-EDTA once a week. When the cell saturation was 80%-90% and the number reached the requirement, the cells were collected, counted, resuspended in an appropriate amount of PBS, and 1:1 matrix glue was added to obtain a cell suspension with a cell density of 25x106cells / mL.

[0623] Cell inoculation: 0.2 mL (5x106cells / mouse) of Mia PaCa-2 cells (with matrix glue, volume ratio 1:1) were inoculated subcutaneously in the right back of each mouse. When the average tumor volume reached 190 mm3, the mice were randomly divided according to the tumor volume, and the drug administration was started according to the scheme in Table 10.

[0624] Table 10. Experimental animal grouping and drug administration scheme

[0625]

[0626] Note: PO represents oral administration; QD represents once a day.

[0627] 2. Tumor measurement and experimental index

[0628] The tumor diameter was measured twice a week with a vernier caliper. The tumor volume was calculated according to the formula: V = 0.5a x b, wherein a and b represent the long diameter and the short diameter of the tumor, respectively. 2

[0629] The antitumor effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T / C (%). The relative tumor proliferation rate T / C (%) = TRTV / CRTV x 100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). According to the results of tumor measurement, the relative tumor volume (RTV) was calculated according to the formula RTV = Vt / V0, wherein V0 is the average tumor volume measured at the time of grouping (i.e. D0), and Vt is the average tumor volume at a certain time of measurement, and TRTV and CRTV are the data of the same day.

[0630] TGI (%), reflecting the tumor growth inhibition rate. TGI (%) = [(1- (the average tumor volume at the end of treatment of a certain treatment group - the average tumor volume at the start of treatment of the treatment group)) / (the average tumor volume at the end of treatment of the solvent control group - the average tumor volume at the start of treatment of the solvent control group)] x 100%.

[0631] 3. Experimental results

[0632] The experimental results are shown in Figure 1 , 2 .

[0633] The results at the 22nd day of administration are shown in Table 11

[0634] Table 11. T / C and TGI at the 22nd day of administration

[0635] Compound Dose Mean tumor volume T / C TGI Vehicle N / A 2016.29 mm 3 ]]> N / A N / A 8B 10 mg / kg 745.84 mm 3 ]]> 36.99％ 66.89％ 8B 30 mg / kg 227.15 mm 3 ]]> 11.28％ 94.23％ 17 10 mg / kg 249.87 mm 3 ]]> 12.39％ 93.06％ 17 30 mg / kg 124.14 mm 3 ]] 6.16％ 99.64％

[0636] Experimental conclusion: The compound of the present application has significant antitumor effect, and the body weight of each dose group of mice is stable, without obvious intolerance phenomenon.​

Claims

1. The compound represented by formula (III) or a pharmaceutically acceptable salt thereof, in, T1 is 0; R1 is selected from phenyl, naphthyl, and indazole, wherein the phenyl, naphthyl, and indazole are optionally surrounded by 1, 2, 3, 4, or 5 R1 groups. a replace; R2 does not exist; R3 is selected from C 1-3 Alkyl, the C 1-3 Alkyl group with 1 R c replace; R4 is selected from H and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. d replace; R5, R6, and R7 are independently selected from H, F, Cl, Br, and I, respectively; R8 is selected from H and CH3; R a Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, and OCH3; R c Each is independently selected from tetrahydropyrrole, wherein the tetrahydropyrrole is optionally substituted with 1, 2 or 3 R; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from F, Cl, Br and CH3; and Not the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from phenyl, naphthyl, and... The phenyl, naphthyl and Choose 1, 2, or 3 Rs a replace.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from , , and .

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R c Selected from .

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from CH3, which is reacted by one R c replace.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from .

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from CH3, wherein the CH3 is optionally divided by 1, 2 or 3 R4 groups. d replace.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from CH2CN.

9. The compound shown in formula (III) or a pharmaceutically acceptable salt thereof, in, T1 is 0; R1 is selected from phenyl, naphthyl, and indazole, wherein the phenyl, naphthyl, and indazole are optionally surrounded by 1, 2, 3, 4, or 5 R1 groups. a replace; R2 does not exist; R3 is selected from C 1-3 Alkyl, the C 1-3 Alkyl group with 1 R c replace; R4 is selected from H and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. d replace; R5, R6 and R7 are independently selected from H, F, Cl, Br, I, OH and NH2, respectively; R8 is selected from H and CH3; R a Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, and OCH3; R c Each is independently selected from hexahydro-1H-pyrrolizinyl, wherein the hexahydro-1H-pyrrolizinyl is substituted with 1, 2 or 3 R; R d Each of the following is independently selected from F, Cl, Br, I, OH, NH2, and CN; R is independently selected from H, F, Cl, Br and CH3.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from phenyl, naphthyl, and... The phenyl, naphthyl and Choose 1, 2, or 3 Rs a replace.

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from , , and .

12. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R1 is .

13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R c Selected from , .

14. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R c Selected from , .

15. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from CH3, which is reacted by one R c replace.

16. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from and .

17. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from and .

18. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from H and CH3, wherein the CH3 is optionally divided by 1, 2 or 3 Rs. d replace.

19. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from H, CH3, and CH2CN.

20. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein, R4 is CH2CN.

21. The compound shown in the following formula, or a pharmaceutically acceptable salt thereof, 。 22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from, 。 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from, 。 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

25. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 in the preparation of a medicament for treating diseases related to KRAS.

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