Pyrimidoheterocyclic compounds and application thereof

Abstract

A class of pyrimidoheterocyclic compounds, and specifically disclosed is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

Description

Pyrimido-heterocyclic compounds and uses thereof

[0001] The present application claims priority to the following:

[0002] CN202010172140.2, filed on March 12, 2020;

[0003] CN202010323035.4, filed on April 22, 2020;

[0004] CN202010953203.8, filed on September 11, 2020;

[0005] CN202011593642.9, filed on December 29, 2020. TECHNICAL FIELD

[0006] 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

[0007] 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), of which 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, the most common mutations include: p.G12D (41%), p.G12V (28%) and p.G12C (14%).

[0008] The full name of 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, the cell surface receptors such as EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4 in the upstream will transmit the signal 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 KRAS gene mutation, it can transmit growth and proliferation signals to the downstream pathway independently without relying on the upstream growth factor receptor signal, causing uncontrolled cell growth and tumor progression. At the same time, whether KRAS gene has mutation is also an important indicator of tumor prognosis.

[0009] Although KRAS is the first discovered oncogene, it has long been considered an undruggable target. 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 both belong to irreversible small molecule inhibitors, which inhibit KRAS activity by forming irreversible covalent bonds with cysteine residues of KRAS G12C mutant proteins.

[0010] Statistics show that 12-36% of lung adenocarcinoma patients are driven by KRAS mutations; 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 the three most common 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.

[0011] 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] R1 is 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;

[0017] when T1 is selected from O, R2 is absent;

[0018] when T1 is selected from N, R2 is 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 bsubstituted;

[0019] R3is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R c substituted;

[0020] R4is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R d substituted;

[0021] R5, R6, and R7are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 F;

[0022] R8is selected from H and CH3;

[0023] 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 is optionally substituted with 1, 2, or 3 F;

[0024] R b are each independently selected from F, Cl, Br, I, OH, and NH2;

[0025] R c are each independently selected from 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R

[0026] R d are each independently selected from F, Cl, Br, I, OH, NH2, and CN;

[0027] R are each independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy, and -C 1-3 alkyl-O-CO-C 1-3 alkyl; 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 Ra each R is independently selected from F, CI, 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 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 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 , and other variables are as defined in the application.

[0032] In some embodiments of the application, R2is selected from H, CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2 are 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 other variables are as defined in the application.

[0034] In some embodiments of the application, each R is independently selected from H, F, CI, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3, and , and 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, said tetrahydropyrrolyl and hexahydro-lH-pyrrolizidinyl are optionally substituted with 1, 2, or 3 R, and other variables are as defined in the application.

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

[0037] In some embodiments of the application, R cselected from the group consisting of other variables are as defined herein.

[0038] In some embodiments of the application, R3 is selected from CH3optionally substituted with 1, 2, or 3 R c other variables are as defined herein.

[0039] In some embodiments of the application, R3 is selected from other variables are as defined herein.

[0040] In some embodiments of the application, R3 is selected from other variables are as defined herein.

[0041] In some embodiments of the application, R4 is selected from H and CH3optionally substituted with 1, 2, or 3 R d other variables are as defined herein.

[0042] In some embodiments of the application, R4 is selected from H, CH3, and CH2CN, other variables are as defined herein.

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

[0044]

[0045] wherein,

[0046] T1 is selected from O and N;

[0047] R1 is selected from phenyl, naphthyl, and indazolyl, said phenyl, naphthyl, and indazolyl optionally substituted with 1, 2, 3, 4, or 5 R a ;

[0048] when T1 is selected from O, R2 is absent;

[0049] when T1 is selected from N, R2 is 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 optionally substituted with 1, 2, or 3 R b ;

[0050] R3 is selected from C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2, or 3 R c ;

[0051] R4is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R d substituents;

[0052] R5, R6, and 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, CF3, and 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-lH-pyrrolizinyl, said tetrahydropyrrolyl and hexahydro-lH-pyrrolizinyl being substituted with 1, 2, or 3 R

[0057] R d are each independently selected from F, Cl, Br, I, OH, NH2, and CN;

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

[0059] In some embodiments of the present 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 in the present application;

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

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

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

[0067] In some embodiments of the application, 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 substituted, and other variables are as defined herein.

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

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

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

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

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

[0073] In some embodiments of the application, R3is selected from other variables are as defined herein.

[0074] In some embodiments of the application, R4is selected from H, CH3, said CH3is optionally substituted with 1, 2, or 3 R d substituted, and other variables are as defined herein.

[0075] In some embodiments of the application, R4is selected from H, CH3, and CH2CN, and other variables are as defined herein.

[0076] The present application provides a compound of Formula (III), or a pharmaceutically acceptable salt thereof,

[0077]

[0078] wherein,

[0079] T1is selected from O and N;

[0080] 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;

[0081] when T1is selected from O, R2is absent;

[0082] 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;

[0083] R3is selected from C 1-3 alkyl, said C 1-3 alkyl, said C c substituted;

[0084] R4is selected from H and C 1-3 alkyl, said C 1-3 alkyl, said C d substituted;

[0085] R5, R6and R7are each independently selected from H, F, Cl, Br, I, OH and NH2;

[0086] R8is selected from H and CH3;

[0087] R a are each independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3and OCH3;

[0088] R b are each independently selected from F, Cl, Br, I, OH, NH2and CH3;

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

[0090] R d are each independently selected from F, Cl, Br, I, OH, NH2and CN;

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

[0092] In some embodiments of the 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 herein;

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

[0096] In some embodiments of the present application, R1 is selected from phenyl, naphthyl, and said phenyl, naphthyl, and optionally substituted with 1, 2, or 3 R a and other variables are as defined herein.

[0097] In some embodiments of the present application, R1 is selected from and other variables are as defined herein.

[0098] In some embodiments of the present application, R2 is selected from H, CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2 being optionally substituted with 1, 2, or 3 R b and other variables are as defined herein.

[0099] In some embodiments of the present application, R2 is selected from H and CH3, and other variables are as defined herein.

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

[0101] In some embodiments of the present application, R3 is selected from CH3, said CH3 being optionally substituted with 1, 2, or 3 R c and other variables are as defined herein.

[0102] In some embodiments of the present application, R3 is selected from and other variables are as defined herein.

[0103] In some embodiments of the present application, R4 is selected from CH3, said CH3 being optionally substituted with 1, 2, or 3 R d and other variables are as defined herein.

[0104] In some embodiments of the present application, R4 is selected from CH2CN, and other variables are as defined herein.

[0105] The present application provides a compound represented by 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, said phenyl and naphthyl being optionally substituted with 1, 2 or 3 R a substituents;

[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, said C 1-3 alkyl, -C(=O)-C 1-3 alkyl and -S(=O)2-C 1-3 alkyl being optionally substituted with 1, 2 or 3 R b substituents;

[0112] R3is selected from C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with 1, 2 or 3 R c substituents;

[0113] R4is selected from C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with 1, 2 or 3 R d substituents;

[0114] R5, R6and R7are each independently selected from H, F, Cl, Br, I, OH and NH2;

[0115] R a are each independently selected from F, Cl, Br, I, OH, NH2, CN, CH3and OCH3;

[0116] R b are each independently selected from F, Cl, Br, I, OH, NH2and 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, Cl, Br, I, OH, NH2and CN;

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

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

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

[0122] In some embodiments of the application, R1 is selected from and 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 optionally substituted with 1, 2, or 3 R b and other variables are as defined in the application.

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

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

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

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

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

[0129] In some embodiments of the application, R4 is selected from CH2CN and 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 optionally substituted with 1, 2, or 3 R a ;

[0134] R2 is selected from C 1-3 alkyl, -C(=O)-C 1-3 alkyl, and -S(=O)2-C1-3 alkyl, said C 1-3 alkyl, -C(=O)-C 1-3 alkyl and -S(=O)2-C 1- 3alkyl is optionally substituted with 1, 2, or 3 R b substituents;

[0135] R3is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R c substituents;

[0136] R4is selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R d substituents;

[0137] R5, R6, and R7are 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, said tetrahydropyrrolyl being 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 are each independently selected from F, Cl, Br, and CH3;

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

[0143] In some embodiments of the present application, the above R1is selected from naphthyl, and the other variables are as defined in the present application.

[0144] In some embodiments of the present application, the above R1is selected from and the other variables are as defined in the present application.

[0145] In some embodiments of the present application, the above R2is selected from CH3, CH2CH3, and CH(CH3)2, said CH3, CH2CH3, and CH(CH3)2being optionally substituted with 1, 2, or 3 R b substituents, and the other variables are as defined in the present application.

[0146] In some embodiments of the present application, the above R2is selected from CH3, and the other variables are as defined in the present application.

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

[0148] In some embodiments of the application, the above R3is selected from CH3, said CH3being optionally substituted with 1, 2 or 3 R c The other variables are as defined in the application.

[0149] In some embodiments of the application, the above R3is selected from The other variables are as defined in the application.

[0150] In some embodiments of the application, the above R4is selected from CH3, said CH3being optionally substituted with 1, 2 or 3 R d The other variables are as defined in the application.

[0151] In some embodiments of the application, the above R4is selected from CH2CN, the other variables being as defined in the application.

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

[0153]

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

[0155] R4is selected from C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with 1, 2 or 3 R d ;

[0156] R d are each independently selected from F, Cl, Br, I, OH, NH2and CN;

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

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

[0159]

[0160] wherein

[0161] R1, R2, R4, R5, R6, R7, R8and R are as defined in the application.

[0162] The application also provides some embodiments resulting from any combination of the above 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]

[0174] 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.

[0175] Technical effects

[0176] The compound of the present application has good cell proliferation inhibition activity on 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 properties, and significant tumor inhibition effect.

[0177] Related definitions

[0178] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as being indefinite or unclear if it is not specifically defined, but should be understood according to the ordinary meaning. When a trade name appears in the present application, it is intended to refer to its corresponding product or active ingredient thereof.

[0179] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0180] The term "pharmaceutically acceptable salts" means salts of the compounds of the present application that are within the scope of sound medical judgment, which are found to be suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, as well as the zwitterion forms, where the

[0181] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, the salt will 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 both.

[0182] 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 the racemic mixtures and other mixtures thereof, such as pure or enriched mixtures of enantiomeric or diastereomeric forms, all of which are within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0183] 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 tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterium- containing drugs, which have advantages over non-deuterated drugs in reducing side effects, increasing drug stability, increasing efficacy, and increasing the biological half-life of the drug. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0184] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0185] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, which can include variations of deuterium and hydrogen, provided that the valency of the designated atom is not exceeded and that the substitution results in a stable compound. 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 moiety can or can not be substituted and that the types and number of substituents are any that are chemically possible, unless otherwise specified.

[0186] When any variable (e.g., R) occurs more than one time in a compound, its definition in each instance is independent of the definition of the other occurrences. 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 at each occurrence R is selected independently. In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0187] When the number of occurrences of a linking group is zero, such as -(CRR)0-, it means that the linking group is a single bond.

[0188] 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, the structure is actually A-Z.

[0189] When the listed linking groups do not indicate the direction of attachment, the direction of attachment is arbitrary, such as where the linking group L is -M-W-, then -M-W- can attach ring A and ring B in either the same direction as the reading order from left to right Ring A and Ring B can also be connected to form Combinations of linking groups, substituents, and / or variations thereof are only permitted if such combinations result in stable compounds.

[0190] 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 attachment of the chemical bond is not defined and there is an H atom at the attachable site, the number of H atoms at the site will correspondingly decrease by one for each chemical bond attached to the group, resulting in a group of the corresponding valence. The chemical bond by which the site is attached to other groups can be represented by a straight solid line bond a straight dashed line bond or a wavy line . For example, the straight solid line bond in -OCH3represents attachment to other groups through the oxygen atom in the group; the straight dashed line bond 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 carbon atoms at positions 1 and 2 in the phenyl group; represents that any attachable site on the piperidinyl group can be attached to other groups by one chemical bond, including at least the four attachment modes, even though H atoms are drawn on -N-, but still include groups in which, when one chemical bond is attached, the H at the site is correspondingly decreased by one to become a corresponding monovalent piperidinyl group.

[0191] Unless otherwise specified, a wedge solid line bond and a wedge dashed line bond represent the absolute configuration of a stereocenter, a straight solid line bond and a straight dashed line bond represent the relative configuration of a stereocenter, and a wavy line represents a wedge solid line bond or a wedge dashed line bond or a wavy line represents a straight solid line bond or a straight dashed line bond as denotes denotes

[0192] The terms "enantiomerically enriched," "enantiomeric excess," "isomerically enriched," or "isomeric excess" mean that one enantiomer or isomer is present in an amount less than 100% and that the enantiomer or isomer is present in an amount 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%, unless otherwise indicated.

[0193] The terms "enantiomerically enriched," "enantiomeric excess," "isomerically enriched," or "isomeric excess" mean that one enantiomer or isomer is present in an amount less than 100% and that the enantiomer or isomer is present in an amount 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%, unless otherwise indicated.

[0194] 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, diastereomeric salts are formed with an appropriate optically active acid or base, and the diastereomeric salt is separated by conventional means, and the pure enantiomer recovered. In addition, separation of the enantiomers and diastereomers is often accomplished by using chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamates from amines).

[0195] Unless otherwise indicated, the term "C 1-6 "alkyl" is used to denote straight or branched chain saturated carbon hydride groups 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). The C 1-6Examples of 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] The term "C 1-3 "alkyl" is used to denote a straight or branched saturated hydrocarbon group consisting of one to three carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, and the like; which can be monovalent (such as methyl), divalent (such as methylene), or multivalent (such as methine). The C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0197] The term "C 1-3 "alkoxy" denotes those alkyl groups containing one to three carbon atoms attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C3, and C2 alkoxy groups, and the like. The C 2-3 alkoxy group can be monovalent or multivalent. The C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy (including n-propyloxy and isopropyloxy), and the like.

[0198] The term "C 1-3 "alkylamino" denotes those alkyl groups containing one to three carbon atoms attached to the rest of the molecule through an amino group. The C 1-3 alkylamino group includes C 1-2 , C3, and C2 alkylamino groups, and the like. The 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.

[0199] The term "C 2-3 "alkenyl" is used to denote a straight or branched hydrocarbon group consisting of two to three carbon atoms containing at least one carbon-carbon double bond, which can be located at any position on the group. The C 2-3 alkenyl group includes C3 and C2 alkenyl groups; the C 2- 3 alkenyl group can be monovalent, divalent, or multivalent. The C 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0200] The term "C 2-3"Alkynyl" is used to denote a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond, consisting of from 2 to 3 carbon atoms, which can be located anywhere in the group. It can be monovalent, divalent or multivalent. The C 2-3 Alkynyl groups include C3and C2alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0201] Unless otherwise specified, the term "C 6-10 "Aryl" and "C 6-10 "Aryl" and "C 6-10 "Aryl" and "C 6-10 "Aryl" and "C 6-10 Aryl groups include C 6-9 , C9, C 10 , and C6aryl 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.

[0202] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably, and the term "5-10 membered heteroaryl" is used to denote a cyclic group consisting of from 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 group can be attached to the rest of the molecule through a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups, and the like. Examples of the 5-10 membered heteroaryl group 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).

[0203] 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, and the remainder of which are carbon atoms, wherein the nitrogen atom is 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.

[0204] 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.

[0205] 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.

[0206] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxyl protecting group," or a "thiol protecting group." The term "amino protecting group" refers to protecting groups suitable for blocking the amino nitrogen against side 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 "hydroxyl protecting group" refers to protecting groups suitable for blocking the hydroxyl group against side reactions. Representative hydroxyl 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.

[0207] 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.

[0208] 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.

[0209] The solvents used in the present application are commercially available.

[0210] Compounds are named according to the nomenclature conventions of the art or using Aldrich® software naming, commercially available compounds use the supplier catalog name. BRIEF DESCRIPTION OF DRAWINGS

[0211] Figure 1 is the change of tumor volume with time at different dosages.

[0212] Figure 2 is the change of animal weight with time at different dosages. DETAILED DESCRIPTION

[0213] 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 way of specific embodiments, and it will be apparent to those skilled in the art that various changes and modifications can be made thereto without departing from the spirit and scope of the application.

[0214] Example 1

[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, 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 then 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 then 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 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 of compound 1-13 (70 mL), 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 of compound 1-13 (70 mL) 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 it 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 separated and 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. Compound 1 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 = 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]

[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), and then triethylamine (45.95 mg, 454.14 μmol, 63.21 μL, 3 eq) was added. The resulting reaction solution was cooled to 0 °C, and then allyl chloride (20.55 mg, 227.07 μmol, 18.52 μL, 1.5 eq) was added, and the mixture was stirred for 30 min. The reaction solution was concentrated under vacuum to obtain a crude product, which was then preparatively separated by high-performance liquid chromatography (HPLC) (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 diastereomers. Compound 2: LCMS m / z = 587.3 [M+H] + Compound 3: LCMS m / z = 553.3 [M+H] + .

[0266] Example 4

[0267]

[0268]

[0269] Synthesis of intermediate 4-14A

[0270] Step 1: Synthesis of compound 4-21

[0271] Compound 4-20 (3 g, 8.35 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL), and wet palladium on carbon (1.2 g, 10% by mass) was added. Hydrogen gas (562.02 μg, 278.23 μmol, 1 eq) was added three times, and the reaction was carried out at room temperature (25 °C) for 2 hours at 15 Psi. The reaction solution was filtered, the mother liquor was collected, and concentrated to obtain the product, compound 4-21. LCMS m / z = 170.1 [M-55+H] + .

[0272] Step 2: Synthesis of compound 4-22

[0273] Compound 4-21 (0.2 g, 887.76 μmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and triethylamine (269.50 mg, 2.66 mmol, 370.70 μL, 3 eq) was added. Under nitrogen protection, the mixture was cooled to 0 °C, and then trifluoroacetic anhydride (205.10 mg, 976.53 μmol, 135.83 μL, 1.1 eq) was added. The mixture was then heated to 0 °C. ℃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] + .

[0274] Step 3: Synthesis of compound 4-14A

[0275] 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] +

[0276] Synthesis of Example 4

[0277] Step 1: Synthesis of compound 4-2

[0278] 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).

[0279] Step 2: Synthesis of compound 4-3

[0280] 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] + .

[0281] Step 3: Synthesis of compound 4-4

[0282] 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] + .

[0283] Step 4: Synthesis of compound 4-5

[0284] 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 in turn, and the reaction was carried out at room temperature 20 °C for 12 h. After adding 200 mL of water to the reaction system, the reaction liquid 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 the 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] + , 331.0 [M+3H] + .

[0285] Step 5: Synthesis of compound 4-6

[0286] 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 dropwise, 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, and the reaction was continued for 0.5 h. After adding 250 mL of saturated ammonium chloride solution to the reaction system, the liquid was separated, and the organic phase was washed once with 150 mL of saturated brine, then dried by adding anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 45 °C. The oil was mixed with 7 mL of ethyl acetate and slurried for 20 min, then 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] + .

[0287] Step 6: Synthesis of compound 7

[0288] 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] + .

[0289] Step 7: Synthesis of compound 4-8

[0290] 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) δ = 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] + .

[0291] Step 8: Synthesis of compound 4-9

[0292] 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.

[0293] Step 9: Synthesis of compound 4-10

[0294] Compound 4-9 (50 mg, 90.40 m mol, 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. The hydrochloride salt of compound 4-10 was obtained. LCMS m / z = 320.0 [M+H] +

[0295] Step 10: Synthesis of compound 4-11

[0296] Compound 4-10 (5.00 g, 14.04 mmol, 1 eq, HC1) 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. The treatment was combined 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, CDC13) d = 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] + .

[0297] Step 11: Synthesis of compound 4-12

[0298] 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] + .

[0299] Step 12: Synthesis of compound 4-13

[0300] 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] + .

[0301] Step 13: Synthesis of compound 4-14

[0302] 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] + .

[0303] Step 14: Synthesis of compound 4-15

[0304] 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 get the crude product. Purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 ~ 1 / 1), TLC: petroleum ether / ethyl acetate = 0 / 1 to get 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] + .

[0305] Step 15: Synthesis of compound 4-16

[0306] 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 get the crude product. The crude product was purified by column chromatography (SiO2 100 mesh, petroleum ether / ethyl acetate = 50 / 1 ~ 1 / 1, TLC: petroleum ether / ethyl acetate = 2 / 1) to get compound 4-16. LCMS m / z = 697.1 [M-100+H] + .

[0307] Step 16: Synthesis of compound 4-17

[0308] 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] + .

[0309] Step 17: Synthesis of compound 4-18

[0310] 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] + .

[0311] Step 18: Synthesis of compounds 4A and 4B

[0312] 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: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.1% TFA) - acetonitrile]; acetonitrile%: 5% - 30%, 8 min, the sample was added with 0.05 mL of 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] +

[0313] Example 5

[0314]

[0315] Step 1: Synthesis of compound 5-1

[0316] 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] + .

[0317] Step 2: Synthesis of compound 5-2

[0318] 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.

[0319] Step 3: Synthesis of compound 5-3

[0320] 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] +

[0321] Step 4: Synthesis of compound 5-4

[0322] 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] + .

[0323] Step 5: Synthesis of compound 5-5

[0324] Into a pre-prepared clean reaction flask was placed dichloromethane (20 mL), compound 5-4 (610 mg, 1.36 mmol, 1 eq) and stirring was initiated. After the temperature was lowered to 0-5 °C, N,N-diisopropylethylamine (617.36 mg, 4.78 mmol, 832.02 μL, 3.5 eq) and triflic anhydride (770.13 mg, 2.73 mmol, 450.37 μL, 2 eq) were added sequentially and the reaction was allowed to proceed for 0.5 hr. After the reaction was poured into 20 mL of saturated ammonium chloride solution, the solution was partitioned and the organic phase was washed once with 10 mL of saturated brine solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated 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 give compound 5-5.1H NMR (400 MHz, CDC13) 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).

[0325] Step 6: Synthesis of compound 5-6

[0326] Into a pre-prepared clean reaction flask was placed N,N-dimethylformamide (5 mL), compound 5-5 (0.33 g, 569.94 μmol, 1 eq) and stirring was initiated. Then N,N-diisopropylethylamine (368.29 mg, 2.85 mmol, 496.35 μL, 5 eq) and compound 5-5a (143 mg, 1.14 mmol, 2.00 eq, 2HCl) were added sequentially and the temperature was raised to 100 °C and the reaction was allowed to proceed for 1 hr. After the reaction was poured into 20 mL of saturated ammonium chloride solution and then into 10 mL of ethyl acetate solution, the solution was partitioned and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 °C. The crude product was purified by column chromatography (dichloromethane / methanol = 100 / 0 to 85 / 15, TLC: dichloromethane / methanol = 15 / 1) to give 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] + .

[0327] Step 7: Synthesis of compound 5-7

[0328] 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] + .

[0329] Step 8: Synthesis of compound 5-8

[0330] 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] +

[0331] Step 9: Synthesis of compound 5-9

[0332] 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] +

[0333] Step 10: Synthesis of compound 5-10

[0334] 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] +

[0335] Step 11: Synthesis of compounds 5A and 5B

[0336] 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*30mm*5pm; 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 (250mm*30mm, 10pm); mobile phase: [0.1% NH3H2O EtOH]; ethanol: 50%-50%, 15 min.

[0337] 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 (C02) 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] + .

[0338] Obtained 5B (Chiral column peak time: 1.800). SFC analysis method (column: Chiralpak AD-3, 50 x 4.6 mm, I.D., 3 pm; mobile phase: A (C02) 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: 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] + .

[0339] Example 6

[0340]

[0341] Step 1: Synthesis of compound 6-1

[0342] 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] +

[0343] Step 2: Synthesis of compound 6-2

[0344] 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*30mm*5μm; 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] +

[0345] Step 3: Synthesis of compound 6-3

[0346] 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, 9.95e-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] +

[0347] Step 4: Synthesis of compound 6-4

[0348] 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] + .

[0349] Step 5: Synthesis of compound 6A and 6B

[0350] Compound 6-4 (76 mg, 138.16 μmol, 1 eq) was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (267.83 mg, 2.07 mmol, 360.96 μL, 15 eq) was added, acryloyl chloride (12.50 mg, 138.16 μmol, 11.27 μL, 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*3μm; 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*3μm; 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 μm; mobile phase: A (CO2) and B (isopropanol with 0.05% diethanolamine); gradient: B% = 5~50%, 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 μm; mobile phase: A (CO2) and B (isopropanol with 0.05% diethanolamine); gradient: B% = 5~50%, 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]+.

[0351] Example 7

[0352]

[0353] Step 1: Synthesis of compound 7-1

[0354] 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] + .

[0355] Step 2: Synthesis of compounds 7A and 7B

[0356] 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 reaction was carried out at room temperature for 3 h. The reaction solution was slowly added to 15 mL of saturated sodium bicarbonate solution, mixed with the small test reaction solution, and then 10 mL of dichloromethane was added for extraction. The organic phase was washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure at 30°C to obtain the crude product. High performance liquid chromatography column separation and purification were carried out with the following method: 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 with the following method: column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 pm); mobile phase: [0.1% NH3H2O EtOH]; EtOH%: 40%-40%, 15 min.

[0357] Compound 7A was obtained (chiral column peak time: 1.263 min). 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, CDC13) 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 μm; 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 then 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 and washed with 200 mL of saturated brine. After drying over anhydrous sodium sulfate, the mixture was 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. 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. 1H NMR (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 H NMR (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 μm; 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] + ; to obtain the hydrochloride salt of compound 8B (retention time: 1.789 min). SFC analysis method (column: Chiralcel OD-3, 50 x 4.6 mm I.D., 3 μm; 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 μL, 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, then 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) were added. 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, then compound 9-5 (0.14 g, 251.54 μmol, 1 eq) was added, and 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 column {(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 {(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 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: 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-thiohydantoin 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 pm); mobile phase: [0.1% NH 3。 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, the temperature was lowered to 0-10 °C, triflic anhydride (1.34 g, 4.76 mmol, 786.11 μL, 1.5 eq) was slowly added to the system, and the reaction was carried out at this temperature for 15 min. Pour into saturated aqueous ammonium chloride solution (15 mL), separate the liquid, the aqueous phase was extracted with dichloromethane (15 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was column chromatographed (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, 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 raw material disappeared and a new spot appeared. Methyl tert-butyl ether (10 mL) was added to the reaction liquid, washed with saturated ammonium chloride solution (20 mL x 2), then washed with saturated brine (10 mL), 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. 1H NMR (400MHz, CDCl3) δppm 7.12(d,J=8.80Hz,4H)6.81(d,J=8.80Hz,4H)6.60(d,J=8.80Hz,1H)5.19(d,J=8.0 0Hz,1H)4.72(s,2H)4.37-4.22(m,4H)3.88(d,J=13.2Hz,1H)3.77(s,6H)3.71-3.56 (dd,J=12.80,13.20Hz,2H)3.40(dd,J=12.40,12.40Hz,1H)3.31(m,2H)3.20(s,1H) 3.03-2.91(m,2H)2.50(s,3H)2.35-2.25(m,3H)1.46(s,9H)1.13(d,J=6.80Hz,3H).

[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 3: 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 4: Synthesis of compound 10⁻⁶

[0420] Dichloromethane (5 mL) was added to a dry reaction flask, followed by compound 10⁻⁵ (0.16 g, 182.03 μmol, 1 eq) and trifluoroacetic acid (1.25 mL). The reaction mixture was stirred at 18 °C for 1.5 h. Trifluoroacetic acid (0.25 mL) was added, and the reaction continued for another 1.5 h. Water (5 mL) was added to the reaction mixture, and the aqueous phase was collected. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified solution was used directly in the next step to obtain compound 10⁻⁶. LCMS m / z = 539.2 [M + H] + .

[0421] Step 5: Synthesis of Compound 10

[0422] Dichloromethane (5 mL) was added to a dry reaction flask, followed by acrylic acid (5.54 mg, 76.87 μmol, 5.28 μL, 2 eq), 10⁻⁶ (23 mg, 38.43 μmol, 90% purity, 1 eq), and N,N-diisopropylethylamine (14.90 mg, 115.30 μmol, 20.08 μL, 3 eq). The reaction system was cooled to -60 °C, and then O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (17.54 mg, 46.12 μmol, 1.2 eq) was added. The mixture was then stirred for 0.5 hours. The reaction was combined with a batch of compound 10-6 (19.49 mg). Water (5 ml) was added to the reaction solution, and the mixture was separated. The organic phase was concentrated under reduced pressure, and then separated by high-performance liquid chromatography (HPLC). The purification method was {Column: Phenomenex Luna C18 80*40mm*3μm; : [H2O (0.04% HCl)-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, followed by 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). The reaction system was reacted at 50 °C under nitrogen protection for 1 hour. The reaction mixture was combined with the batch of compound 10-2 (50 mg). Methyl tert-butyl ether (10 mL) was added to the reaction solution, and the mixture was washed with saturated ammonium chloride solution (10 mL x 2), followed by washing with saturated brine (10 mL). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The unpurified mixture was used directly in the next step to obtain compound 11-2. 1H NMR (400MHz, CDCl3) δppm 7.14 (d, J = 8.80Hz, 4H), 6.84 (d, J = 8.40Hz, 4H), 6.62 (d, J = 8.80Hz, 1H), 5.19 (br d,J=8.00Hz,1H),4.76(s,2H),4.37-4.22(m,5H),3.80(s,7H),3.58-3.35(m,3H),3.22(s,2H), 3.04-2.93(m,1H),2.52(s,3H),2.38-2.30(m,3H),1.49(s,9H),1.34(dd,J=6.80,6.40Hz,6H).

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

[0428] Dichloromethane (5 mL) was added to a dry reaction flask, followed by 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). The reaction system was reacted at 15 °C for 0.5 hours, and the reaction mixture was combined with a batch of compound 11-2 (50 mg). 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 (10 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 0:1) (petroleum ether: ethyl acetate = 10:1 to 0:1) to obtain a mixture of compounds 11-3 and 11-3A. 1 H NMR (400MHz, CDCl3) δppm 7.17(d,J=6.40Hz,4H)6.84(d,J=8.40Hz,4H)6.67(s,1H)5.23(d,J=11.20Hz,1H)4.90-4.74(m,2H)4.32(d,J=12.00Hz,4H)3.8 4-3.75(m,9H)3.68-3.39(m,3H)3.31-3.10(m,3H)2.89(d,J=10.40Hz,2H)2.34(d,J=3.60Hz,3H)1.49(s,9H)1.42-1.29(m,6H). 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, followed by compound 1-11A (46.51 mg, 403.82 μmol, 4 eq). The reaction system was cooled to 0 °C, and sodium tert-butoxide (38.81 mg, 403.82 μmol, 4 eq) was added. After reacting for 10 minutes, a toluene mixture (1 mL) containing a mixture of compound 11-3 (0.085 g, 100.96 μmol, 1 eq) and 11-3A (86.62 mg, 100.96 μmol, 1 eq) was added. The reaction system was stirred for 0.5 hours. The mixture was combined with a batch of compound 11-3 (10 mg). 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 solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified solution was used directly 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, followed by compound 11-4 (0.13 g, 145.57 μmol, 1 eq) and trifluoroacetic acid (1.25 mL). The reaction system was reacted at 18 °C for 1.5 h. Trifluoroacetic acid (0.25 mL) was added, and the reaction was continued for another 1.5 h. The reaction mixture was then combined with batch 11-4 (15 mg). Water (5 mL) was added to the reaction solution, and 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified solution was used directly 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, followed by 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). The reaction system was cooled to -60 °C. O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (44.59 mg, 117.26 μmol, 1.2 eq) was added, and the mixture was stirred for 0.5 hours. The reaction was combined with batches of compound 11-5 (20 mg). Water (5 ml) was added to the reaction solution, the mixture was separated, the organic phase was concentrated under reduced pressure, and the high performance liquid chromatography (HPLC) column was used for purification. The HPLC column was: Phenomenex luna C18 80*40 mm*3 μm; mobile phase: [H2O (0.04% HCl)-ACN]; acetonitrile %: 15%-40%, 7 min. Compound 11 was obtained. 1 H NMR(400MHz, 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 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 incubated at 50 °C under nitrogen protection for 30 minutes. Compound 9-1A (30 mg, 0.6 eq) was then added, and the reaction was continued for another 30 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted with methyl tert-butyl ether (5 mL). The organic phase solution was washed successively with saturated ammonium chloride solution (10 mL) and saturated brine solution (10 mL). After drying with anhydrous sodium sulfate and filtering, the solution was concentrated under reduced pressure. The unpurified solution was used directly in the next step to obtain compound 12-2. 1 ¹H NMR (400MHz, CDCl₃) δppm 7.14(d,J=8.80Hz,4H)6.84(d,J=8.40Hz,4H)6.62(d,J=8.80Hz,1H)5.2 1(d,J=7.20Hz,1H)4.78-4.63(m,2H)4.38-4.15(m,4H)4.00-3.82(m,2H )3.80(s,6H)3.73-3.60(m,1H)3.48-3.33(m,1H)3.22(s,2H)3.16-2.80 (m,3H)2.51(s,3H)2.38-2.30(m,3H)1.49(s,9H)1.38(d,J=6.80Hz,3H). 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 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 hours. The mixture was then combined with a batch of compound 12-2 (30 mg). Sodium thiosulfate (10 mL, 10%) solution was added to the reaction solution. After a negative result with starch-KI test paper, the mixture was extracted with dichloromethane (3 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) by column chromatography (petroleum ether: ethyl acetate = 10:1 to 0:1) to obtain compound 12-3. 1H NMR (400MHz, CDCl3) δppm 7.17 (br s, 4H) 6.84 (br d, J = 8.40Hz, 4H) 6.67 (br s, 1H) 5.25 (br d, J = 9.60Hz, 1H) 4.89-4.64 (m, 2H) 4.32 (br d,J=10.40Hz,4H)4.09-3.86(m,3H)3.84-3.68(m,7H)3.64-3.51(m,1H) 3.37-2.97(m,4H)2.95-2.81(m,3H)2.34(br d,J=3.60Hz,3H)1.49(s,9H)1.41(br s,3H). 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, followed by compound 12-3A (66.52 mg, 471.06 μmol, 3 eq). The reaction system was cooled to 0 °C, and then sodium tert-butoxide (45.27 mg, 471.06 μmol, 3 eq) was added. After stirring for 10 minutes, a toluene solution (0.5 mL) containing compound 12-3 (0.13 g, 157.02 μmol, 1 eq) was added, and the mixture was stirred for 0.5 hours. This solution was combined with a batch of compound 12-3 (20 mg). 10 mL of ethyl acetate was added to the reaction mixture, followed by washing with 10 mL of saturated ammonium chloride solution and saturated brine, respectively. After drying with anhydrous sodium sulfate and filtering, the solution was concentrated under reduced pressure. The unpurified solution was used directly in the next step 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, followed by compound 12-4 (0.18 g, 198.89 μmol, 1 eq) and trifluoroacetic acid (1.5 mL). The reaction mixture was stirred at 18 °C for 3.5 hours. Water (5 mL) was added to the reaction mixture, and the aqueous phase was collected. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified solution was used directly in the next step 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 flask and stirred. Then, 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 system was cooled to -60 °C, and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (36.37 mg, 95.64 μmol, 1.2 eq) was added. The mixture was then stirred for 0.5 hours. This reaction was combined with a batch of compound 12-5 (20 mg). Water (5 ml) was added to the reaction solution, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) {column: Phenomenex luna C18 80*40mm*3μm; mobile phase: [H2O(0.04% HCl)-ACN]; acetonitrile %: 15%-40%, 7 min}, yielding compound 12 (elution time: 1.509). SFC analysis was performed (column: Chiralcel OD-3, 50×4.6mm ID, 3μm; 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: 99.4%}. 1 H NMR (400MHz, CD3OD) δ=6.89-6.71(m,1H),6.71-6.65(d,J=8.8Hz,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,1 H),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] N,N-Dimethylformamide (4 mL) was added to a dry reaction flask, followed by compound 10-2 (220 mg, 288.82 μmol, 1 eq) and compound 13-1 (115.69 mg, 577.64 μmol, 2 eq). Stirring was initiated, and then N,N-diisopropylethylamine (111.98 mg, 866.45 μmol, 150.92 μL, 3 eq) was added. The reaction mixture was heated to 50 °C and stirred for 1 hour. Ethyl acetate (30 mL) was added to the reaction solution for extraction. The mixture was washed once with saturated ammonium chloride (15 mL) solution and once with saturated brine (15 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step without purification to obtain compound 13-2. LCMS m / z = 812.2 [M+H] + .

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

[0452] Dichloromethane (10 mL) was added to a dry reaction flask, followed by compound 13-2 (200.00 mg, 246.33 μmol, 1 eq). Stirring was initiated, and then m-chloroperoxybenzoic acid (60.01 mg, 295.59 μmol, 85% purity, 1.2 eq) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was diluted with dichloromethane (20 mL), then washed once each with 5% sodium thiosulfate solution (10 mL) and saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (petroleum ether:ethyl acetate = 1:1) and column chromatography (petroleum ether:ethyl acetate = 90:10 to 50:50) to obtain the product, 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, followed by compound 1-11A (112.68 mg, 978.35 μmol, 4.5 eq). Stirring was initiated, followed by sodium tert-butoxide (94.02 mg, 978.35 μmol, 4.5 eq). The reaction mixture was cooled to 0 °C and stirred for 10 minutes. Then, compound 13-3 (180 mg, 217.41 μmol, 1 eq) was added, and the reaction mixture was stirred at 0 °C for 1 hour. This reaction was combined with a batch of compound 13-3 (60 mg). The reaction mixture was extracted with ethyl acetate (30 mL). The organic phase was washed once with saturated ammonium chloride (10 mL) and once with saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step without purification to obtain compound 13-4. LCMS m / z = 879.3 [M+H] + .

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

[0456] Dichloromethane (5 mL) was added to a dry reaction flask, followed by compound 13-4 (260 mg, 295.79 μmol, 1 eq). Stirring was initiated, and then potassium acetate (2.82 g, 24.70 mmol, 1.83 mL, 83.50 eq) was added. The reaction mixture was stirred at 20 °C for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was separated. The aqueous phase was adjusted to pH 9 with saturated sodium bicarbonate and then extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step 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, followed by acrylic acid (10.84 mg, 150.40 μmol, 10.32 μL, 1 eq), 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). The mixture was stirred until the reaction system was cooled to -60 °C. O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (68.62 mg, 180.47 μmol, 1.2 eq) was added, and the mixture was stirred for 0.5 hours. The reaction was combined with a batch of compound 13-5 (30 mg). Water (5 mL) was added to the reaction solution, and the mixture was separated. The organic phase solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) {column: Welch Xtimate C18 100*25mm*3μm; mobile phase: [H2O (0.05% HCl)-ACN]; acetonitrile %: 15%-45%, 8 min} to obtain compound 13 (elution time: 1.683). SFC analysis method (column: Chiralcel OD-3, 50×4.6mm ID, 3μm; 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: 95.48%). 1 H NMR (400MHz, CD3OD) δ=6.87-6.73(m,1H),6.68(d,J=8.4Hz,1H),6.25(dd,J=3.8,16.6Hz,1H),5.78(d,J=11.6 Hz,1H),5.20(dd,J=4.0,11.2Hz,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=6.6Hz,3H),LCMS m / z=593.3[M+H] + .

[0459] Example 14

[0460]

[0461] Step 1: Synthesis of Compound 14-2

[0462] N,N-Dimethylformamide (4 mL) was added to a dry reaction flask, followed by 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). The mixture was stirred at 50 °C for 1 hour. Ethyl acetate (30 mL) was added to the reaction solution for extraction. The collected organic phase was washed once with saturated ammonium chloride (15 mL) and once with saturated brine (15 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step without purification to obtain compound 14-2. LCMS m / z = 826.3 [M+H] + .

[0463] Step 2: Synthesis of Compound 14-3

[0464] Dichloromethane (10 mL) was added to a dry reaction flask, followed by compound 14-2 (350.18 mg, 423.97 μmol, 1 eq). Stirring was initiated, and then m-chloroperoxybenzoic acid (109.75 mg, 508.77 μmol, 80% purity, 1.2 eq) was added. The reaction mixture was stirred at 25 °C for 1 hour. A principal spot with increased polarity was detected. The reaction solution was diluted with dichloromethane (10 mL), then washed once each with 5% sodium thiosulfate solution (10 mL) and saturated brine (10 mL). After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (petroleum ether:ethyl acetate = 0:1) and column chromatography (petroleum ether:ethyl acetate = 90:10 to 50:50) to give compound 14-3. LCMS m / z = 842.3 [M+H] + .

[0465] Step 3: Synthesis of compound 14-4

[0466] Toluene (5 mL) was added to a dry reaction flask, followed by compound 1-11A (98.73 mg, 857.24 μmol, 4.5 eq). Stirring was initiated, and then sodium tert-butoxide (82.38 mg, 857.24 μmol, 4.5 eq) was added. The reaction mixture was cooled to 0 °C and stirred for 10 minutes. Then, a toluene solution (2 mL) containing compound 14-3 (160.39 mg, 190.50 μmol, 1 eq) was added, and the reaction mixture was stirred at 0 °C for 1 hour. This reaction was combined with a batch of compound 14-3 (50 mg). The reaction mixture was extracted with ethyl acetate (30 mL), and the organic phase was collected and washed once each with saturated ammonium chloride (10 mL) and saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification to obtain compound 14-4. LCMS m / z = 893.4 [M+H] + .

[0467] Step 4: Synthesis of Compounds 14-5

[0468] Dichloromethane (5 mL) was added to a dry reaction flask, followed by compound 14-4 (260 mg, 291.15 μmol, 1 eq). Stirring was initiated, and then trifluoroacetic acid (2.77 g, 24.31 mmol, 1.8 mL, 83.50 eq) was added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was diluted with 20 mL of dichloromethane solution, followed by 20 mL of water. The aqueous phase was separated and the pH was adjusted to 8 with saturated sodium bicarbonate. Extraction was then performed with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step to yield compound 14-5. LCMS m / z = 553.2 [M+H] + .

[0469] Step 5: Synthesis of Compound 14

[0470] Dichloromethane (5 mL) was added to a dry reaction flask, followed by acrylic acid (10.56 mg, 146.58 μmol, 10.06 μL, 1 eq), compound 14-5 (90 mg, 146.58 μmol, 90% purity, 1 eq), and N,N-diisopropylethylamine (56.83 mg, 439.73 μmol, 76.59 μL, 3 eq). Stirring was initiated, and the reaction system was cooled to -60 °C. O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (66.88 mg, 175.89 μmol, 1.2 eq) was added, and the mixture was stirred for 0.5 hours. Water (5 mL) was added to quench the reaction mixture, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) using the following method: {Column: Welch Xtimate C18 100*25mm*3μm; Mobile phase: [H2O(0.05%HCl)-ACN]; Acetonitrile %: 15%-45%, 8min}, yielding compound 14. 1 H NMR(400MHz, CDCl3)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] + .

[0471] Example 15

[0472]

[0473]

[0474] Step 1: Synthesis of Compound 15-2

[0475] N,N-dimethylformamide (3 mL) was added to a dry reaction flask, followed by compound 10-2 (200 mg, 262.56 μmol, 1 eq). Stirring was initiated, followed by N,N-diisopropylethylamine (101.80 mg, 787.69 μmol, 137.20 μL, 3 eq) and compound 15-1 (78.88 mg, 393.84 μmol, 1.5 eq). The reaction mixture was incubated at 50 °C for 30 minutes. The reaction mixture was combined with a batch of compound 10-2 (10 mg). The reaction solution was poured into a saturated ammonium chloride aqueous solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification. Compound 15-2 was obtained. LCMS m / z = 812.2 [M+H] + .

[0476] Step 2: Synthesis of Compound 15-3

[0477] Dichloromethane (3 mL) was added to a dry reaction flask, followed by compound 15-2 (0.24 g, 295.59 μmol, 1 eq). Stirring was initiated, and then m-chloroperoxybenzoic acid (66.95 mg, 310.37 μmol, 80% purity, 1.05 eq) was added. The reaction mixture was reacted at 25 °C for 30 minutes. The reaction solution was quenched with 5 mL of 5% sodium sulfite aqueous solution. After separation, the aqueous phase was extracted with dichloromethane (5 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The aqueous phase was tested with starch-potassium iodide paper; after confirming the absence of oxidizing properties, the aqueous phase was discarded. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1, product Rf = 0.51) according to TLC (petroleum ether:ethyl acetate = 50:1 to 0:1) to obtain the product, compound 15-3. 1 H NMR(400MHz, CDCl3)δ=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),2.8 8-2.78(m,3H),2.32-2.20(m,3H),1.47-1.37(m,9H),1.32-1.23(m,3H). LCMS m / z=828.3M+H] + .

[0478] Step 3: Synthesis of Compound 15-4

[0479] Toluene (1 mL) was added to a dry reaction flask, followed by compound 15-3 (180 mg, 217.41 μmol, 1 eq). Stirring was initiated, and the reaction mixture was cooled to 0–5 °C. Sodium tert-butoxide (2.68 mg, 652.23 μmol, 3 eq) was added, and the mixture was stirred for 10 minutes. Toluene (0.3 mL) containing compound 1-11A (75.12 mg, 652.23 μmol, 77.44 μL, 3 eq) was added to the reaction mixture, and the reaction was carried out at 0–5 °C for 30 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (5 mL), extracted with ethyl acetate (5 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification. Compound 15-4 was obtained. LCMS m / z = 879.4 [M+H] + .

[0480] Step 4: Synthesis of Compound 15-5

[0481] Dichloromethane (4 mL) was added to a dry reaction flask, followed by compound 15-4 (160 mg, 182.03 μmol, 1 eq). Stirring was initiated, and the reaction mixture was cooled to 0–5 °C. Trifluoroacetic acid (1.23 g, 10.81 mmol, 800.00 μL, 59.36 eq) was added, and the mixture was stirred for 4 hours. The reaction solution was then added to a saturated sodium bicarbonate aqueous solution (10 mL), separated, and extracted with dichloromethane (5 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step to yield compound 15-5. LCMS m / z = 539.2 [M+H] + .

[0482] Step 5: Synthesis of Compound 15

[0483] Dichloromethane (10 mL) was added to a dry reaction flask, followed by 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). The mixture was stirred, and 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-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (63.54 mg, 167.11 μmol, 1.5 eq) was added. The reaction system was then allowed to react at -60 °C for 0.5 hours. The product was combined with a batch of compound 15-5 (20 mg) and treated. Dichloromethane (5 mL) was added to the reaction solution, and the mixture was washed with saturated ammonium chloride solution (5 mL x 2). Anhydrous sodium sulfate was added, and the mixture was dried and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by high-performance liquid chromatography (HPLC) using the following method: {Column: Phenomenex Luna C18 200*40 mm*10 μm; Mobile phase: [H2O (0.04% HCl)-ACN]; Acetonitrile %: 1%-50%, 8 min}. One drop of ammonia was added to the separated solution, which showed an alkaline pH. After concentration to remove the organic solvent, the solution was lyophilized to obtain compound 15. 1 H NMR (400MHz, CD3OD) δ = 7.24-7.07 (m, 2H), 6.80 (dd, J = 10.8, 16.8Hz, 1H), 6.71 (d, J = 8.6Hz, 1H) ,6.24(d,J=16.8Hz,1H),5.79(d,J=11.7Hz,1H),5.24-5.16(m,1H),4.76(d,J=13.8Hz,3H),4.5 7(dd,J=7.2,12.5Hz,2H),4.07-3.86(m,3H),3.73(s,1H),3.17(d,J=11.4Hz,3H),3.07(s,3H) ,2.90(d,J=14.8Hz,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] + .

[0484] Example 16

[0485]

[0486] Step 1: Synthesis of Compound 16-2

[0487] N,N-Dimethylformamide (3 mL) was added to a dry reaction flask, followed by compound 10-2 (200 mg, 262.56 μmol, 1 eq). Stirring was initiated, then N,N-diisopropylethylamine (101.80 mg, 787.69 μmol, 137.20 μL, 3 eq) and compound 16-1 (78.02 mg, 393.84 μmol, 1.5 eq, 2 HCl) were added. The reaction mixture was reacted at 50 °C for 30 minutes. The reaction mixture was then combined and poured into a saturated ammonium chloride aqueous solution (15 mL). Extraction was performed with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step to obtain compound 16-2. LCMS m / z = 737.2 [M+H] + .

[0488] Step 2: Synthesis of Compound 16-3

[0489] N,N-Dimethylformamide (3 mL) was added to a dry reaction flask, followed by compound 16-2 (230 mg, 312.15 μmol, 1 eq). Stirring was initiated, and then N,N-diisopropylethylamine (121.03 mg, 936.46 μmol, 163.11 μL, 3 eq) and di-tert-butyl dicarbonate (74.94 mg, 343.37 μmol, 78.88 μL, 1.1 eq) were added. The reaction mixture was incubated at 20 °C for 10 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution (15 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 16-3. 1H NMR (400MHz, CDCl3) δ = 7.16 (d, J = 8.4Hz, 4H), 6.85 (d, J = 8.6Hz, 4H), 6.64 (d, J = 8.0Hz, 1 H),5.22(d,J=7.2Hz,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=11.0Hz,2H),3.30(s,1H),3.24-3.02(m,2H),2. 90(d,J=2.0Hz,1H),2.78-2.58(m,2H),2.55(s,3H),2.34(d,J=4.0Hz,3H),1.51(s,9H). LCMS m / z=837.2[M+H] + .

[0490] Step 3: Synthesis of Compound 16-4

[0491] Dichloromethane (0.3 mL) was added to a dry reaction flask, followed by compound 16-3 (230 mg, 274.81 μmol, 1 eq). Stirring was initiated, and then m-chloroperoxybenzoic acid (61.37 mg, 302.29 μmol, 85% purity, 1.1 eq) was added. The reaction mixture was incubated at 20°C for 1 hour. The reaction solution was poured into a 5% sodium sulfite aqueous solution (5 mL), and the mixture was separated. The aqueous phase was extracted with dichloromethane (5 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The aqueous phase was tested with starch-potassium iodide paper; after confirming the absence of oxidizing properties, the aqueous phase was discarded. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) using TLC (petroleum ether:ethyl acetate = 100:1-0:1) to obtain compound 16-4.

[0492] LCMS m / z = 853.2[M+H] + .

[0493] Step 4: Synthesis of Compound 16-5

[0494] Toluene (2 mL) was added to a dry reaction flask, followed by compound 16-4 (158 mg, 185.24 μmol, 1 eq). Stirring was initiated, and the reaction mixture was cooled to 0 °C. Sodium tert-butoxide (35.60 mg, 370.49 μmol, 2 eq) was then added, and the mixture was stirred for 15 minutes. Compound 12-3A (65.40 mg, 463.11 μmol, 2.5 eq) was then added, and the reaction mixture was allowed to react at 0 °C for 30 minutes. The reaction solution was poured into a saturated ammonium chloride aqueous solution (5 mL), extracted with ethyl acetate (5 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step to give compound 16-5. LCMS m / z = 930.4 [M+H] + .

[0495] Step 5: Synthesis of Compound 16-6

[0496] Dichloromethane (5 mL) was added to a dry reaction flask, followed by compound 16-5 (0.18 g, 193.54 μmol, 1 eq). Stirring was initiated, and then trifluoroacetic acid (1 mL) was added. The reaction mixture was incubated at 18 °C for 3 hours. Water (10 mL) was added to the reaction mixture for extraction and separation. The aqueous phase was collected, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was then performed with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step without purification to obtain compound 16-6. LCMS m / z = 590.2 [M+H] +

[0497] Step 6: Synthesis of Compound 16

[0498] Compound 16-6 (62.77 mg, 106.46 μmol, 1 eq), 2-fluoroacrylic acid (19.17 mg, 212.92 μmol, 2 eq), and 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-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (48.58 mg, 127.75 μmol, 1.2 eq) was added, and the mixture was stirred for 0.5 hr. This was then combined with a batch of compound 16-6 (20.92 mg). Add 5 mL of water to the reaction solution, separate the liquid and concentrate the organic phase, and purify by high performance liquid chromatography (HPLC). Purification method: {Column: Phenomenex luna C18 80*40mm*3μm; Mobile phase: [H2O(0.04% HCl)-ACN]; Acetonitrile %: 20%-40%, 7 min} to obtain compound 16. 1 H NMR (400MHz, CD3OD) δ = 6.73 (d, J = 8.6Hz, 1H), 5.45-5.21 (m, 3H), 4.87-4.80 (m, 2H), 4.57 (s, 2H), 4.19 (br d, J = 13.7Hz, 1H), 3.98 (br d,J=13.1Hz,1H),3.75-3.66(m,2H),3.56-3.49(m,1H),3.37(s,3H),3.32-3.27(m,2H),3.2 6-3.11(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] + .

[0499] Example 17

[0500]

[0501] Step 1: Synthesis of Compound 17-2

[0502] N,N-dimethylformamide (30 mL) was added to a dry reaction flask, followed by compound 10-2 (2.8 g, 3.68 mmol, 1 eq). Stirring was initiated, and then N,N-diisopropylethylamine (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 mixture was reacted at 50 °C under nitrogen protection for 1 hour. The mixture was combined with compound 10-2 (0.2 g) in batches. Methyl tert-butyl ether (30 mL) was added to the reaction mixture, and the mixture was washed twice each with saturated ammonium chloride solution (30 mL x 2) and saturated brine solution (30 mL x 2). The mixture was dried and filtered after adding anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was not purified and was used directly in the next step to obtain compound 17-2. 1 ¹H NMR (400MHz, CDCl₃) δppm 7.15(d,J=8.80Hz,4H),6.84(d,J=8.40Hz,4H),6.63(d,J=8.40Hz,1H),5.22(dd ,J=11.20,4.00Hz,1H),4.71(s,2H),4.36-4.20(m,4H),4.06(d,J=12.80Hz,1H) ,3.80(s,6H),3.61-3.50(m,2H),3.43(dd,J=18.80,11.60Hz,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] + .

[0503] Step 2: Synthesis of Compound 17-3

[0504] Dichloromethane (25 mL) was added to a dry reaction flask, followed by compound 17-2 (2.3 g, 3.12 mmol, 1 eq). Stirring was initiated, and the reaction mixture was cooled to 0 °C. Triethylamine (789.67 mg, 7.80 mmol, 1.09 mL, 2.5 eq) and trifluoroacetic anhydride (983.42 mg, 4.68 mmol, 651.27 μL, 1.5 eq) were added, and the reaction mixture was reacted at 0–5 °C for 0.5 hours. The mixture was combined with the 0.3 g batch of compound 17-2. After washing with saturated ammonium chloride solution (20 mL x 2), the mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was not purified and used directly in the next step. Compound 17-3 was obtained. 1H NMR (400MHz, CDCl3) δppm 7.15 (d, J = 8.40Hz, 4H), 6.84 (d, J = 8.40Hz, 4H), 6.65 (br d,J=8.40Hz,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=6.80Hz,1H),2.53(s,3H),2.39-2.30(m,3H), LCMS m / z=833.1[M+H] + .

[0505] Step 3: Synthesis of Compound 17-4

[0506] Dichloromethane (30 mL) was added to a dry reaction flask, followed by compound 17-3 (2.6 g, 3.12 mmol, 1 eq). Stirring was initiated, and then m-chloroperoxybenzoic acid (697.20 mg, 3.43 mmol, 85% purity, 1.1 eq) was added. The reaction mixture was reacted at 18 °C for 0.5 hours. The mixture was then combined with a batch of compound 17-3 (0.2 g). Sodium thiosulfate solution (20 mL, 10%) was added to the reaction solution. After a negative result using starch-KI test paper, the mixture was extracted with dichloromethane (20 mL x 2). The solution was dried with anhydrous sodium sulfate, filtered, and the filtrate was 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 = 10:1-0:1) to obtain compound 17-4. 1 H NMR (400MHz, CDCl3) δppm 7.15(d,J=8.40Hz,4H),6.84(d,J=8.40Hz,4H),6.66(d,J=8.40Hz,1H),5. 27(d,J=9.20Hz,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=3.60Hz,3H),LCMS m / z = 849.1 [M+H] + .

[0507] Step 4: Synthesis of Compound 17-5

[0508] Toluene (1 mL) was added to a dry reaction flask, followed by compound 17-4A (78.77 mg, 494.80 μmol, 3 eq). Stirring was initiated, and the reaction mixture was cooled to 0 °C. Sodium tert-butoxide (47.55 mg, 494.80 μmol, 3 eq) was added, and stirring was continued for 10 minutes. Then, a toluene solution (0.5 mL) containing compound 17-4 (0.14 g, 164.93 μmol, 1 eq) was added, and the reaction was continued for 0.5 hours. The mixture was combined with a batch of compound 17-4 (20 mg). The reaction solution was diluted with ethyl acetate (5 mL), washed successively with saturated ammonium chloride solution (10 mL x 2) and saturated saline solution (10 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was not purified and was used directly in the next step to obtain compound 17-5. LCMS m / z = 848.3 [M+H] + .

[0509] Step 5: Synthesis of Compound 17-6

[0510] Dichloromethane (12 mL) was added to a dry reaction flask, followed by compound 17-5 (160.00 mg, 188.70 μmol, 1 eq). Stirring was initiated, and then trifluoroacetic acid (2 mL) was added. The reaction mixture was reacted at 18°C ​​for 2 hours. The reaction mixture was combined with a batch of compound 17-5 (20 mg). Water (10 mL) was added to the reaction mixture, and the mixture was extracted separately. The aqueous phase was diluted to pH 8 with saturated sodium bicarbonate solution and then extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was not purified and was used directly in the next step to obtain compound 17-6. LCMS m / z = 608.3 [M+H] + .

[0511] Step 6: Synthesis of Compound 17

[0512] Dichloromethane (5 mL) was added to a dry reaction flask, followed by compound 17-6 (50 mg, 82.29 μmol, 1 eq), 2-fluoroacrylic acid (14.82 mg, 164.58 μmol, 2 eq), and N,N-diisopropylethylamine (31.90 mg, 246.87 μmol, 43.00 μL, 3 eq). The mixture was stirred and cooled to -60 °C. Then, O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (37.55 mg, 98.75 μmol, 1.2 eq) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was combined, and water (5 mL) was added to quench the reaction. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) {column: Welch Xtimate C18 100*25mm*3μm; mobile phase: [H2O(0.05% HCl)-ACN]; acetonitrile %: 20%-50%, 8 min}, yielding compound 17. SFC analysis was performed using (column: Chiralcel OD-3, 50×4.6mm ID, 3μm; 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: 99.21%; elution time: 1.840). 1 H NMR (400MHz, CD3OD) δ=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).

[0513] Example 18

[0514]

[0515] Step 1: Synthesis of Compound 18-1

[0516] 1-11A (194.75 mg, 1.69 mmol, 200.78 μL, 4 eq) was added to anhydrous toluene (16 mL), cooled to 0 °C, and sodium tert-butoxide (162.50 mg, 1.69 mmol, 4 eq) was added. The reaction was carried out at 0-5 °C for 10 minutes. Then, a toluene solution (5 mL) of compound 9-3 (0.35 g, 422.74 μmol, 1 eq) was added, and the reaction was carried out at 0-5 °C for 0.5 hours. This solution was combined with a batch of compound 9-3 (50 mg). The reaction solution was washed with 20 mL x 2 saturated ammonium chloride solution, then washed with 20 mL saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 18-1. MS m / z = 879.2 [M+H] + .

[0517] Step 2: Synthesis of Compound 18-2

[0518] Compound 18-1 (0.4 g, 455.07 μmol, 1 eq) was added to anhydrous dichloromethane (12 mL), followed by trifluoroacetic acid (2.4 mL). The reaction was carried out at 25 °C for 1.5 h. This reaction was then combined with a batch of compound 18-1 (50 mg). Saturated sodium bicarbonate was slowly added to the reaction mixture until the pH reached 7-8. The mixture was extracted with 20 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and then evaporated to dryness to obtain compound 18-2. LCMS m / z = 539.1 [M+H] +

[0519] Step 5: Synthesis of compounds 18A and 18B

[0520] Compound 18-2 (36.80 mg, 510.60 μmol, 35.04 μL, 1.1 eq), acrylic acid (36.80 mg, 510.60 μmol, 35.04 μL, 1.1 eq), and N,N-diisopropylethylamine (179.97 mg, 1.39 mmol, 242.55 μL, 3 eq) were added to anhydrous dichloromethane (5 mL). The mixture was cooled to -60 °C, and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine salt (176.50 mg, 464.18 μmol, 1 eq) was added. The mixture was reacted at -60 °C for 30 min. The reaction solution was diluted with 10 mL of dichloromethane, washed with 10 mL x 2 saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was then purified by high-performance liquid chromatography (HPLC) column separation (Phenomenex column). After lyophilization using a luna C18 column (100*40mm*5μm; mobile phase: [H2O(0.1%TFA)-ACN]; acetonitrile %: 10%-40%, 8min), the compound was chirally separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [0.1%NH3H2O ​​ETOH]; ethanol %: 50%-50%, 15min), yielding compound 18A (chiral elution time: 1.479). SFC analytical method (column: Chiralcel OD-3, 50 × 4.6 mm ID, 3 μm; 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 100%). MS m / z = 593.3 [M+H] + , 1 H NMR (400MHz, CDCl3) δ=6.66-6.50(m,2H),6.36(d,J=16.8Hz,1H),5.76(d,J=10.0Hz,1H),5.20(d,J=7.6Hz,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).

[0521] Compound 18B (chiral elution time: 1.642) was obtained using SFC analysis (column: Chiralcel OD-3, 50 × 4.6 mm ID, 3 μm; 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: 97.8%). LCMS m / z = 593.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ = 6.72-6.48 (m, 2H), 6.35 (dd, J = 1.6, 16.8Hz, 1H), 5.76 (d, J = 10.4Hz, 1H), 5.20 (d, J = 7.6Hz, 1H), 4.83-4.57 (m, 3H), 4.18-3.99(m,3H),3.94-3.51(m,2H),3.50-3.20(m,2H),3.11-2.75(m,6H),2.43-2.35(m,3H),2.35-1.80(m,8H),1.38(d,J=6.4Hz,3H).

[0522] Example 19

[0523]

[0524] Step 1: Synthesis of Compound 19

[0525] 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 until the temperature dropped 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, and the organic phase was dried over anhydrous sodium sulfate and filtered. 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*3um); mobile phase: [H2O(0.04% HCl)-ACN]; B%: 18%-34%, 7 min; yielding compound 19. LCMS m / z = 622.2 [M+H] + .

[0526] Example 20

[0527]

[0528] Step 1: Preparation of Intermediate 20-1

[0529] 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] + Step 2: Preparation of intermediate 20-2

[0530] 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] + .

[0531] Step 3: Preparation of compound 20-3

[0532] Compound 20-2 (45 mg, 48.75 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at 20 °C for 2 hours. The solvent was removed under reduced pressure, and the crude product was dissolved in 20 mL of dichloromethane. 3 g of solid sodium bicarbonate was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the organic solvent was removed under reduced pressure to obtain crude product 20-3. This compound was used directly in the next reaction without further purification.

[0533] Step 5: Preparation of Compound 20

[0534] 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 mixture was stirred at this temperature for 16 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by high-performance liquid chromatography (HPLC) (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 of compound 20. MS m / z = 637.4 [M+H] + .

[0535] Biological test data:

[0536] Experimental Example 1: Compounds on KRAS G12C Tests on the inhibitory effect of mutant MIA-PA-CA-2 cell proliferation

[0537] 1.1 Experimental Objective

[0538] Test compound for KRAS G12C The IC50 of mutant MIA-PA-CA-2 cells inhibits cell proliferation. 50 .

[0539] 1.2 Reagents

[0540] The main reagents used in this study included CellTiter-Glo (Promega, catalog number: G7573).

[0541] 1.3 Instruments

[0542] The main instrument used in this study is the PerkinElmer EnVision multi-functional microplate reader.

[0543] 1.4 Experimental Methods

[0544] 1) Adherent cells were digested with trypsin to form a cell suspension, and the cell suspension was counted for later use.

[0545] 2) Take an appropriate amount of cells into a centrifuge tube and add cell culture medium to make up to the required volume. Then, plate the cells into a 96-well plate with a final density of 2000 cells / well and 100 μL of culture medium.

[0546] 3) After culturing for 24 hours, the compound was prepared to 10 mM with DMSO and serially diluted 3-fold with DPBS (Dubico phosphate buffer) to 9 wells, with 10 μL added to each well, in duplicate. 10 μL of DPBS was added to each control well (Con).

[0547] 4) On the same day, take a cell culture plate that has not been treated with drugs, add 50 μL of CellTiter Glo, and use EnVision to read the fluorescence value, which is marked as Day 0 reading.

[0548] 5) After culturing the cells for 72 hours following drug treatment, remove the culture plate, add 50 μL of CellTiter Glo to the cell plate, and use EnVision to read the fluorescence value.

[0549] 6) Data Analysis: Calculate the cell inhibition rate of each well using the following formula:

[0550]

[0551] *F Day0 The readings for the number of untreated, untreated cells in the test wells;

[0552] F Con Fluorescence readings of the Con group after 72 hours of incubation.

[0553] F Cpd The fluorescence readings of each compound well were obtained after 72 hours of incubation.

[0554] 7) Use GraphPad Prism software to perform a log(agonist) vs. response-variable slope nonlinear fitting analysis on the inhibition rate data (inhibition rate %) of the compounds to obtain the IC50 of the compounds. 50 The value, and the fitting formula is:

[0555] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0556] 1.5 Experimental Results

[0557] Table 1. Test results of the inhibitory effect of the compounds of the present invention on the proliferation of KRASG12C-mutant MIA-PA-CA-2 cells.

[0558] Compound number IC 50 (nM) 15.218B hydrochloride 2.79B 6.98121.30162.22170.44

[0559] 18B3.29

[0560] Experimental results show that the compounds of this invention have good cell proliferation inhibitory activity against the KRASG12C mutant MIA-PA-CA-2 cell line.

[0561] Experiment Example 2: H358 Cell Experiment

[0562] 2.1 Experimental Objective

[0563] Test compound for KRAS G12C IC50 of mutant H358 cells inhibited proliferation 50 .

[0564] 2.2 Reagents

[0565] The main reagents used in this study included RPMI-1640 medium, penicillin / streptomycin antibiotics purchased from Vicente, and fetal bovine serum purchased from Biosera. CellTiter-Glo (a chemiluminescence immunoassay reagent for cell viability) was purchased from Promega. The NCI-H358 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences.

[0566] 2.3 Instruments

[0567] The main instrument used in this study is the Nivo multilabel analyzer (PerkinElmer).

[0568] 2.4 Experimental Methods:

[0569] 1) Seed NCI-H358 cells into white 96-well plates, 80 μL of cell suspension per well, containing 4000 NCI-H358 cells. Incubate the cell plates overnight in a CO2 incubator.

[0570] 2) Dilute the test compound 5-fold to the 9th concentration using a multi-channel pipette, i.e., from 2 mM to 5.12 nM, and set up a double-duplicate assay. Add 78 μL of culture medium to the intermediate plate, then transfer 2 μL of the serially diluted compound to each well of the intermediate plate according to the corresponding positions. After mixing, transfer 20 μL to each well of the cell plate. The concentration range of the compound transferred to the cell plate is 10 μM to 0.0256 nM. Incubate the cell plate in a CO2 incubator for 5 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. Add 25 μL of chemiluminescent cell viability detection reagent to each well of this cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the values ​​using a multi-label analyzer.

[0571] 3) Add 25 μL of chemiluminescent cell viability detection reagent to each well of the cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the values ​​using a multi-label analyzer.

[0572] Data Analysis:

[0573] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%, IC 50The values ​​can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 2 provides the inhibitory activity of the compounds of this invention on the proliferation of NCI-H358 cells.

[0574] Table 2. Test results of the inhibitory effect of the compounds of the present invention on the proliferation of KRASG12C mutant H358 cells.

[0575] Compound NCI-H358IC 50 (nM) 168.22 19.04 B hydrochloride 27.05 B 12.96 A < 4.6

[0576] 8B hydrochloride <4.69B5.51070116.7122.51332.6159.2161.7170.618B4.7

[0577] Conclusion: Some of the compounds in this invention exhibited good inhibitory activity against the proliferation of NCI-H358 cells.

[0578] Experimental Example 3: Hepatocyte Metabolic Stability

[0579] Experimental objective: To evaluate the metabolic stability of the test compound in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human hepatocytes.

[0580] Experimental Procedure: Prepare several 96-well sample plates, named T0, T15, T30, T60, T90, T120, T0-MC, T120-MC, and blank substrate, respectively. Preheat the resuscitation and incubation media in a 37°C water bath. Remove the frozen hepatocytes from the liquid nitrogen container and immediately immerse them in the 37°C water bath (approximately 90 seconds). After the frozen portion has thawed and loosened, pour the cells into centrifuge tubes containing 40 mL of resuscitation media, gently inverting to resuspend the cells in the resuscitation media. Centrifuge at 100 × g for 5 minutes at room temperature, remove the supernatant, resuspend the hepatocytes in an appropriate volume of incubation media, and calculate cell viability using trypan blue staining. 198 μL of hepatocyte suspension (0.51 × 10⁶ cells / mL) was added to a preheated incubation plate. For the control group, 198 μL of hepatocyte-free culture medium was added to T0-MC and T120-MC incubation plates. All incubation plates were pre-incubated at 37°C for 10 minutes. Then, 2 μL of the test sample and control compound working solutions were added, mixed well, and the incubation plates were immediately placed in a shaker within the incubator. The timer was started to begin the reaction. Two replicates were prepared for each time point of each compound. Incubation conditions were 37°C, saturated humidity, and 5% CO₂. In the test system, the final concentration of the test sample was 1 μM, the final concentration of the control was 3 μM, the final concentration of hepatocytes was 0.5 × 10⁶ cells / mL, and the final concentration of total organic solvents was 0.96%, of which the final concentration of DMSO was 0.1%. At the end of the incubation at the corresponding time point, remove the incubation plate and add 25 μL of the mixture of the compound and control compound with cells to a sample plate containing 125 μL of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and labetalol). For Blank sample plates, add 25 μL of hepatocyte-free incubation medium directly. After sealing all sample plates, shake at 600 rpm for 10 minutes on a shaker, then centrifuge at 3220 × g for 20 minutes. Dilute the supernatant of the test sample and control sample with ultrapure water at a ratio of 1:3. After mixing all samples, analyze them using LC / MS / MS.

[0581] The experimental results are shown in Table 3.

[0582] Table 3. Metabolic stability of the test compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human hepatocytes.

[0583]

[0584]

[0585] Experimental conclusions: Metabolic experiments on hepatocytes of various genera showed that the compounds of this invention have good metabolic stability.

[0586] Experimental Example 4: In vitro study of liver microsomal stability

[0587] Experimental objective: To evaluate the metabolic stability of the test compound in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human liver microsomes.

[0588] Experimental procedure: Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively. Add 445 μL of microsomal working solution (liver microsomal protein concentration of 0.56 mg / mL) to each of the T60 and NCF60 incubation plates, and then place the plates in a 37°C water bath for pre-incubation for about 10 minutes.

[0589] After pre-incubation, add 5 μL of the test sample or control compound working solution to both the T60 and NCF60 incubation plates and mix well. Add 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate to initiate the reaction. Add 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regeneration working solution to the T0 stop plate. Transfer 54 μL of sample from the T60 incubation plate to the T0 stop plate (T0 sample generation). Add 44 μL of NADPH regeneration working solution to each well of the T60 incubation plate to initiate the reaction. Add only 54 μL of microparticle working solution, 6 μL of NADPH regeneration working solution, and 180 μL of stop solution to the Blank plate. Therefore, in the sample of the test or control compound, the final concentration of the compound, testosterone, diclofenac and propafenone was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0590] After incubation for appropriate times (e.g., 5, 15, 30, 45, and 60 minutes), 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) was added to each well of the stop plate. Then, 60 μL of sample was removed from the T60 incubation plate to terminate the reaction. All sample plates were shaken and centrifuged at 3220 × g for 20 minutes. 80 μL of the supernatant from each well was then diluted to 240 μL of pure water for liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis. All samples were analyzed by LC-MS / MS.

[0591] Table 4. Metabolic stability of the test compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human liver microsomes

[0592]

[0593]

[0594] Experimental conclusion: The study on the metabolic stability of liver microsomes showed that the compound of this invention has good metabolic stability.

[0595] Experimental Example 5: Plasma Stability Study

[0596] Experimental objective: To evaluate the stability of the test compound in the plasma of CD1 mice and humans.

[0597] Experimental Procedure: Thaw the frozen plasma for 10–20 minutes. After complete thawing, centrifuge at 3220 × g for 5 minutes to remove suspended solids and precipitates. Prepare 96-well incubation plates, named T0, T10, T30, T60, and T120. Add 98 μL of blank plasma from mice, rats, dogs, monkeys, and humans to the corresponding incubation plates, then add 2 μL of the working solution of the compound or control compound to the corresponding incubation plate. Prepare two parallel wells for each sample. Incubate all samples in a 37°C water bath. The final incubation concentration of the compounds and control compounds (bisacodyl, enalapril maleate, procaine, and propantheline) is 2 μM, and the final organic phase content is 2.0%. At the end of each incubation time point, remove the corresponding incubation plate and add 400 μL of acetonitrile solution containing 200 ng / mL tolbutamide and labetalol to each corresponding sample well to precipitate the protein. After sealing and mixing all sample plates, centrifuge at 3220×g for 20 minutes. Take 50 μL of the supernatant and dilute it with 100 μL of ultrapure water. After mixing all samples, analyze them by LC / MS / MS.

[0598] Table 5. Plasma stability of the test compound CD-1 in mice and humans

[0599]

[0600] Experimental conclusion: The compounds of this invention exhibit good stability in human and mouse plasma.

[0601] Experimental Example 6: Whole Blood Stability Study

[0602] Experimental objective: To evaluate the whole blood stability of the test compound in CD1 mice, SD rats, beagle dogs, and cynomolgus monkeys.

[0603] Experimental Procedure: Fresh whole blood was collected from CD1 mice, SD rats, beagles, and cynomolgus monkeys using the anticoagulant EDTA-K2 on the day of the experiment or the day before. Before the experiment, the whole blood was mixed with PBS at a 1:1 (v:v) ratio and preheated in a 37°C water bath for 10–20 minutes. 96-well incubation plates were prepared and named T0, T30, T60, and T240, respectively. In the corresponding incubation plates (T0, T30, T60, and T240), 2 μL of the working solution of the compound or control compound was mixed with 98 μL of blank whole blood from mice, rats, dogs, monkeys, and humans. Two parallel wells were prepared 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 incubation time point, remove the corresponding incubation plate, immediately add 100 μL of ultrapure water to the corresponding sample well, mix well, and then add 800 μL of acetonitrile solution containing 200 ng / mL tolbutamide and labetalol to precipitate the protein. After sealing the sample plate and shaking well, centrifuge at 3220 × g for 20 minutes. Take 150 μL of the supernatant for analysis using LC / MS / MS.

[0604] Table 6. Whole blood stability of the test compound CD-1 in mice, SD rats, beagle dogs, and cynomolgus monkeys.

[0605]

[0606] Experimental conclusions: Stability studies in the blood of various canine species showed that the compounds of this invention have good stability in whole blood.

[0607] Experimental Example 7: Study on Protein Binding Rate

[0608] Experimental objective: 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 using the balanced dialysis method.

[0609] Experimental Procedure: Plasma samples of the five species were prepared at a compound concentration of 2 μM and placed in a 96-well balanced dialysis apparatus. Dialysis was performed at 37 ± 1 °C with phosphate buffer for 4 h. Warfarin was used as a control compound. The concentrations of the analytes in the plasma and dialysis buffer were determined by LC-MS / MS.

[0610] Table 7. Protein binding rates of the tested compounds in CD-1 mice, SD rats, beagles, cynomolgus monkeys, and humans.

[0611]

[0612]

[0613] Experimental conclusions: Studies on plasma binding rates of various genera show that the compounds of this invention have a higher protein unbinding rate in plasma.

[0614] Experimental Example 8: In vivo pharmacokinetic study

[0615] 1) Pharmacokinetic studies of test compounds administered orally and intravenously to SD rats

[0616] The test compound was mixed with a 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin) solution, vortexed and sonicated to prepare a 1 mg / mL clear solution, which was then filtered through a microporous membrane for later use. Male SD rats aged 7 to 10 weeks were selected and administered the candidate compound solution intravenously or orally. Whole blood was collected over a certain period to prepare plasma, and drug concentration was analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Pharmaceuticals, USA). The experimental results are shown in Table 8.

[0617] Table 8. Pharmacokinetic results of the test compounds

[0618]

[0619] Note: Vd ss u represents the apparent volume distribution of unbound plasma proteins (Vd). ss u=Vd ss / PPB(Unbond%);C max,u， AUC 0-last，u， These are the corresponding values ​​when plasma proteins are not bound (C) max,u =C max x PPB (Unbond%); AUC 0-last，u =AUC 0-last x PPB(Unbond%) Experimental Conclusion: PK studies showed that the compound of this invention has high unbound plasma exposure and good oral bioavailability in rats.

[0620] 2) Pharmacokinetic studies of test compounds administered orally and intravenously to CD mice

[0621] The test compound was mixed with a 5% dimethyl sulfoxide / 95% (10% hydroxypropyl-β-cyclodextrin) solution, vortexed and sonicated to prepare a 1 mg / mL clear solution, which was then filtered through a microporous membrane for later use. Male CD mice aged 7 to 10 weeks were selected and administered the candidate compound solution intravenously or orally. Whole blood was collected over a certain period to prepare plasma, and drug concentration was analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Pharmaceuticals, USA). The experimental results are shown in Table 9.

[0622] Table 9. Pharmacokinetic Results of the Test Compounds

[0623]

[0624] Note: Vd ss u represents the apparent volume distribution of unbound plasma proteins (Vd). ss u=Vd ss / PPB(Unbond%);C max,u， AUC 0-last，u， These are the corresponding values ​​when plasma proteins are not bound (C) max,u =C max x PPB (Unbond%); AUC 0-last，u =AUC 0-last x PPB (Unbond%) Experimental Conclusion: PK studies showed that the compound of this invention has high unbound plasma exposure and good oral bioavailability in mice.

[0625] Experimental Example 9: In vivo pharmacodynamic study

[0626] In vivo pharmacodynamic study of a nude mouse model of human pancreatic cancer Mia PaCa-2 cell subcutaneous tumor transplantation into Balb / c Nude mice.

[0627] 1. Cell culture and tumor tissue preparation

[0628] Cell culture: Human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420) were cultured in vitro as a monolayer under the following conditions: DMEM medium supplemented with 10% fetal bovine serum and 2.5% horse serum, incubated at 37°C in a 5% CO2 incubator. Cells were passaged twice a week using trypsin-EDTA digestion. When cell saturation reached 80%-90% and the desired cell count was achieved, cells were harvested, counted, resuspended in an appropriate amount of PBS, and mixed 1:1 with matrix gel to obtain a cell suspension with a density of 25 x 10⁶ cells / mL.

[0629] Cell inoculation: 0.2 mL (5 × 10⁶ cells / mouse) of Mia PaCa-2 cells (with matrix gel, volume ratio 1:1) were subcutaneously inoculated into the right posterior back of each mouse. When the average tumor volume reached 190 mm³, mice were randomly assigned to groups based on tumor volume and drug administration was initiated according to the protocol in Table 10.

[0630] Table 10. Grouping and Dosing Regimens of Experimental Animals

[0631]

[0632] Note: PO stands for oral administration; QD stands for once daily.

[0633] 2. Tumor Measurement and Laboratory Indicators

[0634] The tumor diameter was measured twice a week using calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0635] The antitumor efficacy of the compounds was evaluated using TGI (%) or relative tumor proliferation rate (T / C) (%). Relative tumor proliferation rate (T / C) (%) = TRTV / CRTV × 100% (TRTV: RTV in the treatment group; CRTV: RTV in the negative control group). Relative tumor volume (RTV) was calculated based on tumor measurements using the formula RTV = Vt / V0, where V0 is the average tumor volume measured at the time of administration (D0), and Vt is the average tumor volume at a specific measurement. TRTV and CRTV data were taken from the same day.

[0636] TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [(1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0637] 3. Experimental Results

[0638] The experimental results are shown in Figures 1 and 2.

[0639] The results after 22 days of administration are shown in Table 11.

[0640] Table 11. T / C and TGI on day 22 after drug administration

[0641] Compound dosage, mean tumor volume (T / CTGI, solvent N / A20), 16.29 mm 3 N / AN / A8B 10mg / kg 745.84mm 3 36.99%66.89%8B30mg / kg227.15mm 3 11.28%94.23%1710mg / kg249.87mm 3 12.39%93.06%1730mg / kg124.14mm 3 6.16% 99.64%

[0642] Experimental conclusion: The compound of this invention has a significant antitumor effect, and the body weight of mice in each dose group remained stable with no obvious intolerance.

Claims

1. A compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein, T 1 selected from O and N; R 1 selected from C 6-10 aryl and 5- to 10-membered heteroaryl, wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 R a substituents; When T 1 is selected from O, R 2 does not exist; When T 1 is selected from N, R 2 is selected from H, C 1-3 alkyl, -C(=O)-C 1-3 alkyl and -S(=O) 2 -C 1-3 alkyl, and the 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 substituents; R 3 selected from C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R c substituents; R 4 selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R d substituted; R 5 、R 6 and R 7 are each independently selected from H, F, Cl, Br, I, C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 Fs; R 8 selected from H and CH 3 ; R a are each independently selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkynyl and C 2-3 alkenyl is optionally substituted with 1, 2 or 3 F; R b each independently selected from F, Cl, Br, I, OH and NH 2 ; R c each independently selected from 4- to 8-membered heterocycloalkyl, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R groups; R d each independently selected from F, Cl, Br, I, OH, NH 2 and CN; R is independently selected from H, F, Cl, Br, OH, CN, C 1-3 alkyl, C 1-3 alkoxy, and -C 1-3 alkyl-O-C(=O)-C 1-3 alkylamino; Provided that when R 1 is selected from naphthyl, the naphthyl is optionally substituted with F, Cl, Br, OH, NH 2 , CF 3 , CH 2 CH 3 and -C≡CH, and R 5 , R 6 and R 7 are each independently selected from H.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , -CH=CH 2 , -CH 2 -CH=CH 2 and -C≡CH, and the CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , -CH=CH 2 , -CH 2 -CH=CH 2 and -C≡CH are optionally substituted with 1, 2 or 3 F atoms.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from F, OH, NH 2 , CH 3 , CF 3 , CH 2 CH 3 and -C≡CH.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, R 1 selected from phenyl, naphthyl, indolyl and indazolyl, wherein the phenyl, naphthyl, indolyl and indazolyl are optionally substituted with 1, 2 or 3 R a substituents.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein, R 1 Selected from 6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 2 selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , wherein the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 is optionally substituted by 1, 2 or 3 R b groups.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein, R 2 selected from H and CH 3 .

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Each R is independently selected from H, F, Cl, Br, OH, CN, CH 3 、CH 2 CH 3 、CH 2 CF 3 、OCH 3 、OCF 3 and 9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R c selected from pyrrolidinyl and hexahydro-1H-pyrrolizinyl, and the pyrrolidinyl and hexahydro-1H-pyrrolizinyl are optionally substituted with 1, 2 or 3 R groups.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein, R c selected from 11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 9 or 10, wherein, R c selected from 12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 3 selected from CH 3 , said CH 3 optionally substituted by 1, 2 or 3 R c substituents.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein, R 3 selected from 14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 12 or 13, wherein, R 3 selected from 15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 4 selected from H and CH 3 wherein said CH 3 is optionally substituted with 1, 2 or 3 R d groups.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein, R 4 selected from H, CH 3 and CH 2 CN.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is selected from, wherein, R 1 as defined in any one of claims 1 to 5; R 4 selected from C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R d substituents; R d are each independently selected from F, Cl, Br, I, OH, NH 2 and CN; R 5 as defined in claim 1; R c as defined in any one of claims 1 or 8 to 11; The carbon atom with "*" is a chiral carbon atom, and exists in the form of (R) or (S) single enantiomer or an enantiomer-rich form.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is selected from, wherein, R 1 as defined in any one of claims 1 to 5; R 2 as defined in any one of claims 1, 6 or 7; R 4 as defined in any one of claims 1, 15 or 16; R 5 、R 6 、R 7 and R 8 as defined in claim 1; R is as defined in claim 1 or 8.

19. A compound represented by the following formula or a pharmaceutically acceptable salt thereof, 20. The compound or a pharmaceutically acceptable salt thereof according to claim 19, which is selected from, 21. The compound or a pharmaceutically acceptable salt thereof according to claim 20, which is selected from, 22. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21 in the preparation of a medicament for treating a KRAS-related disease.

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