TWI795129B - Pyridopyrimidinone compounds - Google Patents

Abstract

A kind of pyridopyrimidinone compounds, specifically relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, and application of the compound of formula (I) and the pharmaceutically acceptable salt thereof in preparation of a medicine for treatment of related diseases.

Description

Pyridopyrimidinones

The application relates to a class of pyridopyrimidinone compounds, specifically to compounds of formula (I) and pharmaceutically acceptable salts thereof, and the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the preparation of medicines for treating related diseases application.

This application claims the following priority: CN202011508100.7, application date December 18, 2020; CN202110560291.X, application date May 21, 2021; CN202111522022.0, application date December 13, 2021.

The RAS gene is the first oncogene identified in human tumors. The RAS protein can bind to guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP). Cell growth, differentiation, cytoskeleton, protein transport and secretion are all affected, and its activity is regulated by binding to GTP or GDP: when the RAS protein binds to GDP, it is in a dormant state, that is, "inactive" State; when stimulated by specific upstream cell growth factors, RAS protein is induced to exchange GDP and combine with GTP, which is called "activated" state. The RAS protein combined with GTP can activate downstream proteins for signal transmission. RAS protein itself has a weak hydrolysis activity to hydrolyze GTP and can hydrolyze GTP to GDP. This allows for the transition from the active state to the inactive state. In this hydrolysis process, GAP (GTPase activating proteins, GTPase activating proteins) is also required to participate. It works with RAS Protein function, greatly promoting its ability to hydrolyze GTP to GDP. The mutation of RAS protein will affect its interaction with GAP, which also affects its ability to hydrolyze GTP to GDP, making it always in an activated state. The activated RAS protein continues to give downstream protein growth signals, which eventually leads to the continuous growth and differentiation of cells, and finally produces tumors. There are many members of the RAS gene family, among which the subfamilies closely related to various cancers mainly include Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus oncogene homolog (HRAS) and neuroblast Tumor rat sarcoma viral oncogene homologue (NRAS). It has been found that about 30% of human tumors carry certain mutated RAS genes, among which KRAS mutations are the most prominent, accounting for 86% of all RAS mutations. KRAS mutations are frequently associated with resistance to targeted therapy and poor prognosis in cancer patients. According to statistics, about 13% of non-small cell lung cancer (NSCLC) and 1%-3% of colorectal cancer and other cancers will have KRAS p.G12C mutation.

KRAS G12C mutant protein is a frontier and popular target. In recent years, many products have entered the clinical research stage, but there is still no approved selective KRAS G12C small molecule inhibitor. In recent years, Araxes Pharma has applied for several patents on KRAS G12C inhibitors, such as WO2016164675 and WO2016168540. ARS-3248 developed by Araxes Pharma is currently in Phase I clinical trials. Amgen has published several patents on KRAS G12C inhibitors since 2018: WO2018119183, WO2018217651, WO2019051291, WO2019213516, WO2020050890, etc. The KRAS G12C inhibitor MRTX849 developed by MIRATI has entered phase II clinical trials. AMG 510 is the fastest clinically progressing selective small molecule KRAS G12C inhibitor. AMG 510 is expected to become a new option for the treatment of metastatic non-small cell lung cancer (NSCLC), and it can be used in combination with other antitumor drugs to produce better efficacy. The U.S. Food and Drug Administration (FDA) has granted breakthrough drug designation (BTD) and real-time oncology review designation (RTOR) to the targeted cancer drug AMG 510 for the treatment of patients with KRAS G12C mutations confirmed by FDA-approved assays Patients with locally advanced or NSCLC.

The application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Wherein, X is selected from CR ₁₃ and N; Q and Y are independently selected from CH and N; R ₁ is selected from H, F, Cl, Br, I, C _1-3 alkyl, said C _1-3 alkane The group is optionally substituted by 1, 2 or 3 halogens; R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from H, F, Cl, Br, I, OH, C _1-3 alkyl , NH ₂ and -NH-C _1-3 alkyl, said C _1-3 alkyl is optionally substituted by 1, 2 or 3 halogens; R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from H and CH ₃ ; R ₁₁ is selected from H and F; R ₁₂ and R ₁₃ are independently selected from H, C _1-6 alkyl, cyclopropyl and C _1-3 alkoxy.

In some aspects of the present application, the aforementioned X is selected from CR ₁₃ , and other variables are as defined in the present application.

In some aspects of the present application, the above-mentioned Y is selected from N, and other variables are as defined in the present application.

In some schemes of the present application, the above-mentioned Q is selected from CH, and other variables are as defined in the present application.

In some schemes of the present application, the above R ₁ is selected from H, F, Cl, Br, I, CH ₃ , the CH ₃ is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present application.

In some aspects of the present application, the above-mentioned R ₁ is selected from H, F and CF ₃ , and other variables are as defined in the present application.

In some aspects of the present application, the above R ₁ is selected from CF ₃ , and other variables are as defined in the present application.

In some schemes of the present application, the above R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from H, F, Cl, Br, I, OH, CF ₃ , CH ₃ , NH ₂ and - NHCH ₃ , other variables are as defined herein.

In some schemes of the present application, the above-mentioned R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from H, F, Cl, Br, CF ₃ , CH ₃ , NH ₂ and -NHCH ₃ , other Variables are as defined herein.

In some aspects of the present application, the above-mentioned R ₂ is selected from H, F, NH ₂ and -NHCH ₃ , and other variables are as defined in the present application.

In some schemes of the present application, the above-mentioned R ₃ is selected from H, F and Cl, and other variables are as defined in the present application.

In some schemes of the present application, the above-mentioned R ₄ is selected from H and F, and other variables are as defined in the present application.

In some aspects of the present application, the above R ₅ is selected from H, F, Cl and CH ₃ , and other variables are as defined in the present application.

In some aspects of the present application, the above-mentioned R ₆ is selected from H, F and CF ₃ , and other variables are as defined in the present application.

In some schemes of the present application, the above-mentioned R ₇ is selected from H, and other variables are as defined in the present application.

In some schemes of the present application, the above-mentioned R ₁₀ is selected from H, and other variables are as defined in the present application.

In some schemes of the present application, the above-mentioned R ₁₁ is selected from H, and other variables are as defined in the present application.

，其他變量如本申請所 定義。 In some schemes of the present application, the above-mentioned R ₁₂ is selected from

, and other variables are as defined in this application.

In some schemes of the present application, the above-mentioned R ₁₃ is selected from CH ₃ and OCH ₃ , and other variables are as defined in the present application.

In some aspects of the present application, the above-mentioned X is selected from CR ₁₃ , Y is selected from N, Q is selected from CH, and other variables are as defined in the present application.

In some schemes of the present application, the above-mentioned X is selected from CR ₁₃ , Y is selected from N, Q is selected from CH, R ₂ is selected from F, R ₆ is selected from F, and other variables are as defined in the present application.

，R₁₃選自CH₃，其他變量如本申請所定義。 In some schemes of the present application, the above X is selected from CR ₁₃ , Y is selected from N, Q is selected from CH, R ₁₂ is selected from

, R ₁₃ is selected from CH ₃ , and other variables are as defined in the present application.

選自

、

、

、

和

，其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

,

,

,

and

, and other variables are as defined in this application.

選自

， 其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

, other variables are as defined in this application.

選自

， 其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

, other variables are as defined in this application.

選自

其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

Other variables are as defined herein.

選自

、

、

、

和

，其他變量如本申 請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

,

,

,

and

, and other variables are as defined in this application.

選自

、

、

和

，其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

,

,

and

, and other variables are as defined in this application.

選自

， 其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

, other variables are as defined in this application.

選自

、

，其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

,

, and other variables are as defined in this application.

選自

， 其他變量如本申請所定義。 In some solutions of the present application, the above-mentioned structural units

selected from

, other variables are as defined in this application.

其中，R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂和R₁₃如本申請所定義。 In some schemes of the present application, the above compounds are selected from

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in this application.

其中，R₁、R₃、R₄、R₅、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂和R₁₃如本申請所定義。 In some schemes of the present application, the above compounds are selected from

Wherein, R ₁ , R ₃ , R ₄ , R ₅ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in this application.

其中，R₂、R₃、R₄、R₅、R₆、R₈、和R₉如本申請所定義。 In some schemes of the present application, the above compounds are selected from

Wherein, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , and R ₉ are as defined in this application.

其中，R₂、R₃、R₄、R₅、R₆、R₈、和R₉如本申請所定義。 In some schemes of the present application, the above compounds are selected from

Wherein, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , and R ₉ are as defined in this application.

In some schemes of the present application, the above-mentioned compounds are not selected from the following compounds:

The application also provides a compound or a pharmaceutically acceptable salt thereof, which is selected from

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

There are also some schemes in the present application that are formed by any combination of the above-mentioned variables.

The present application also provides the application of the above compound or a pharmaceutically acceptable salt thereof in the preparation of KRAS G12C mutant protein inhibitors.

The application also provides the application of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating non-small cell lung cancer.

technical effect

The compound of the application is a potent KRAS G12C mutant protein inhibitor. The compound of the present application shows higher cell anti-proliferation activity for KRAS G12C mutant cell NCI-H358, and weak anti-proliferation activity for wild-type A375 cell, reflecting high selectivity.

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to the salts of the compounds of the present application, which are prepared from the compounds with specific substituents found in the present application and relatively non-toxic acids or bases. When the compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. When the compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Certain specific compounds of the present application contain basic and acidic functional groups and thus can be converted into either base or acid addition salts.

The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

Unless otherwise specified, the terms "effective amount" or "therapeutically effective amount" refer to a non-toxic amount that achieves the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the subject, and also on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art of the present invention according to routine experiments.

The compounds of the present application may exist in particular geometric or stereoisomeric forms. This application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, ( R )- and ( S )-enantiomers, diastereomers isomers, ( D )-isomers, ( L )-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are included in this within the scope of the application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this application.

Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.

Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.

Unless otherwise specified, "(+)" means dextrorotation, "(-)" means levorotation, and "(±)" means racemization.

)和楔形虛線鍵(

)表示 一個立體中心的絕對構型，用直形實線鍵(

)和直形虛線鍵(

)表示 立體中心的相對構型，用波浪線(

)表示楔形實線鍵(

)或楔形虛 線鍵(

)，或用波浪線(

)表示直形實線鍵(

)或直形虛線鍵(

)。 Unless otherwise noted, keys with wedge-shaped solid lines (

) and dotted wedge keys (

) represents the absolute configuration of a stereocenter, with a straight solid line bond (

) and straight dotted key (

) represents the relative configuration of the stereocenter, and the wavy line (

) represents a wedge-shaped solid line bond (

) or dotted wedge key (

), or use the tilde (

) means a straight solid line key (

) or straight dotted key (

).

Unless otherwise stated, the term "tautomer" or "tautomeric form" means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved. For example, Proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization . Valence isomers (valence tautomers) include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers The content is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96% %, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

Unless otherwise stated, the terms "isomer excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, where one isomer or enantiomer is 90% present and the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

Optically active ( R )- and ( S )-isomers as well as 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 present application is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure obtained Enantiomers are required. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).

The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur .

The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of. When a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced.

The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

)、直形 虛線鍵(

)、或波浪線(

)表示。例如-OCH₃中的直形實線鍵表示 通過該基團中的氧原子與其他基團相連；

中的直形虛線鍵表示通過該 基團中的氮原子的兩端與其他基團相連；

中的波浪線表示通過該 苯基基團中的1和2位碳原子與其他基團相連；

表示該哌啶基上的任 意可連接位點可以通過1個化學鍵與其他基團相連，至少包括

、

、

、

這4種連接方式，即使-N-上畫出了H原子， 但是

仍包括

這種連接方式的基團，只是在連接1個化學鍵 時，該位點的H會對應減少1個變成相應的一價哌啶基。 Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group. The chemical bond that described site is connected with other groups can use straight solid line bond (

), straight dashed key (

), or tilde (

)express. For example, the straight-shaped solid-line bond in _-OCH3 indicates that it is connected to other groups through the oxygen atom in the group;

The straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;

The wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;

Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least

,

,

,

These 4 connection methods, even if the H atom is drawn on -N-, but

still include

For groups with this connection method, only when a chemical bond is connected, the H at this site will be reduced by one to become the corresponding monovalent piperidinyl group.

Unless otherwise specified, the term "C _1-6 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 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 , C ₆ and C ₅ alkyl, etc.; it can be Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C _1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl , s -butyl and t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl and so on.

Unless otherwise specified, the term "C _1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C _1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), and the like.

Unless otherwise specified, the term "C _1-3 alkoxy" denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy groups and the like. Examples of C _1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art of the present invention, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the technical aspects of the present invention. Equivalent alternatives well known to the personnel, and preferred implementations include but are not limited to the examples of the present application.

The structures of the compounds of the present application can be confirmed by conventional methods well known to those skilled in the art of the present invention. If the application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method is φ/ω scanning. After collecting relevant data, the direct method is further adopted (Shelxs97) By analyzing the crystal structure, the absolute configuration can be confirmed.

The solvents used in this application are commercially available.

This application uses the following abbreviations: aq stands for water; eq stands for equivalent, equivalent; CDI stands for carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMAc stands for N,N-dimethylacetamide; PyBrOP stands for tripyrrolidinylphosphonium bromide hexafluorophosphate; DMSO stands for dimethylsulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for Benzyloxycarbonyl is an amine protecting group; BOC stands for tertiary butoxycarbonyl and is a kind of amine protecting group; Pd ₂ dba ₃ stands for tris(dibenzylideneacetone) dipalladium, NaH stands for sodium hydride, and SiO ₂ stands for Silica gel, HOAc stands for acetic acid; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine ; TsOH represents p-toluenesulfonic acid; NCS represents 1-chloropyrrolidine-2,5-dione.

The following examples describe the present application in detail, but it does not imply any unfavorable limitation to the present application. The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art of the present invention, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the technical aspects of the present invention. Equivalent alternatives well known to the personnel, and preferred implementations include but are not limited to the examples of the present application. It will be apparent to those skilled in the art that various changes and improvements can be made to the specific embodiments of the application without departing from the spirit and scope of the application.

Synthesis of Intermediate A

The first step: add compound A-2 (5 grams), cesium carbonate (10.27 grams) and BrettPhos Pd G3 (1.43 grams) in the tertiary-butanol (50 milliliters) solution of compound A-1 (5 grams), The reaction system was replaced with nitrogen for 3 times, and under the protection of nitrogen, the reaction solution was reacted at 105 degrees Celsius for 36 hours. The reaction solution was filtered with diatomaceous earth, the filter cake was rinsed with ethyl acetate (50 ml*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO ₂ , eluent: petroleum ether: acetic acid Ethyl ester=10:1~2:1) to obtain compound A-3. LCMS (ESI) m/z: 451.1 (m+1) ⁺ .

The second step: at 0-10 degrees Celsius, add N-bromosuccinimide (5.37 grams) to compound A-3 (14.75 grams, 92.2% purity) in dichloromethane (150 milliliters) solution, reaction solution React at 0-10 degrees Celsius for 0.5 hours. The reaction solution was quenched with saturated sodium sulfite solution (40 ml) at 0-10 degrees Celsius, and then stood to separate layers. The organic phase was washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A -4. LCMS (ESI) m/z: 531.0 (m+1) ⁺ .

The third step: add iron powder (8.44 grams) and ammonium chloride (8.09 grams) in the mixed solution of compound A-4 (16 grams) ethanol (160 milliliters) and water (40 milliliters), reaction solution is at 80 degrees Celsius The reaction was carried out for 2 hours. The reaction solution was cooled to 25 degrees Celsius, then filtered with Celite, the filter cake was rinsed with methanol (50 ml*3), the filtrate was concentrated under reduced pressure to obtain a residue, the residue was water (50 ml) and ethyl acetate (150 ml) After dilution, the organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A-5. LCMS (ESI) m/z: 501.0 (m+1) ⁺ .

The 4th step: add zinc powder (0.96 gram) in the N,N-dimethylformamide (150 milliliters) solution of compound A-5 (15 gram), zinc cyanide (2.76 gram), DPPF (3.33 gram ), Pd ₂ (dba) ₃ (2.75 grams) and zinc bromide (338.27 mg), then the reaction system was replaced with nitrogen three times, and under the protection of nitrogen, the reaction solution was reacted at 120 degrees Celsius for 14 hours. Filter the reaction liquid pad with diatomaceous earth, wash the filter cake with ethyl acetate (50 ml*4), dilute the filtrate with water (600 ml), then stand to separate the layers, wash the organic phase with saturated brine (100 ml), anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue, which is purified by column chromatography (SiO ₂ , eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound A-6. LCMS (ESI) m/z: 446.0 (m+1) ⁺ .

Step 5: Add sodium hydroxide (969.82 mg) and peroxide to compound A-6 (10.8 g) in a mixed solution of dimethylsulfoxide (108 ml) and water (27 ml) at 0-10°C Hydrogen (28.01 grams, mass percentage: 30%), the reaction solution was reacted at 0-10 degrees Celsius for 0.5 hours, and the temperature was raised to 25 degrees Celsius for 1 hour. The reaction solution was quenched with saturated sodium sulfite solution (500 ml), extracted with ethyl acetate (100 ml*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , eluent: petroleum ether: ethyl acetate=1:1~1:2) to obtain compound A-7. LCMS (ESI) m/z: 464.1 (m+1) ⁺ .

Step 6: Add carbonyldiimidazole (5.60 grams) and sodium hydride (2.07 grams, mass percent: 60%) to compound A-7 (8 grams) in anhydrous THF (80 milliliters) solution at 0-10 degrees Celsius , the reaction solution was reacted at 25 degrees Celsius for 2 hours. The reaction solution was added to 1 mol/liter of hydrochloric acid (80 milliliters), then the pH value of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, the layers were left to stand, and the aqueous phase was extracted with ethyl acetate (50 milliliters). The organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate A. LCMS (ESI) m/z: 490.1 (m+1) ⁺ .

Example 1

Step 1: Add DIEA (184.39 mg), PyBrOP (997.63 mg) and Compound 1-1 (664.29 mg) to a solution of Intermediate A (400 mg) in N,N-dimethylformamide (3 mL) , the reaction solution was reacted at 50 degrees Celsius for 10 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was passed through a preparative HPLC (column model: Phenomenex luna C18 250*50mm*15 μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 34%-64%, 10 minutes) to obtain compound 1-2. LCMS (ESI) m/z: 658.2. (M+1) ⁺ .

Second step: Add p-toluenesulfonic acid (60.43 mg) and N-chlorosuccinimide (93.72 mg) to a solution of compound 1-2 (300 mg) in acetonitrile (3 ml), under nitrogen protection, The reaction solution was reacted at 60° C. for 1 hour. Saturated aqueous sodium sulfite (15 mL) was added to the reaction solution, and stirred at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and finally extracted with ethyl acetate (30 ml*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 compound 1-3. LCMS (ESI) m/z: 728.1 (M+3) ⁺ .

Step 3: Trifluoroacetic acid (2.31 g) was added to a solution of compound 1-3 (310 mg) in dichloromethane (4.5 ml), and the reaction solution was reacted at 25° C. for 20 minutes. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 1-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 626.0 (M+1) ⁺ .

the fourth step: To compound 1-4 (400 mg) in tetrahydrofuran (5 ml) and water (2 ml) mixed solution, potassium carbonate (194.09 mg) and compound 1-5 (63.55 mg) were added successively, and the reaction solution was reacted at 20 degrees Celsius 10 minutes. The reaction solution was extracted with ethyl acetate (10 ml*2), the organic phase was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was passed through a preparative HPLC (column model: Phenomenex luna C18 150*25mm*10 μm; Mobile phase: [0.225% formic acid aqueous solution-acetonitrile]; Gradient: acetonitrile, 32%-62%, 10 minutes) purify, obtain compound 1.

Compound 1 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 50%-50%, 2.5 minutes; 40 minutes) to obtain Compound 1A and Compound 1B.

Compound 1A and compound 1B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B% ): 40%-40%] to obtain: the residence time of compound 1A is 0.867min, and the ee value is 100%; the residence time of compound 1B is 1.760min, and the ee value is 100%. Compound 1A (retention time=0.867min): ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.46(br d, J =4.89Hz,1H),7.40(d, J =7.15Hz,1H),6.97-7.19( m,2H),6.62(dd, J =16.75,10.48Hz,1H),6.29-6.50(m,1H),5.83(dd, J =10.48,1.44Hz,1H),4.06-4.32(m,2H) ,3.94(br s,8H),2.57-2.78(m,1H),2.12(s,3H),1.22(br d, J =6.65Hz,3H),1.13(br d, J =6.65Hz,3H) ; LCMS (ESI) m/z: 680.1 (M+1) ⁺ .

Compound 1B (retention time=1.760min): ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.49(d, J =4.89Hz, 1H), 7.41(d, J =7.15Hz, 1H), 7.11(br d, J =4.39Hz,1H),7.05(s,1H),6.63(dd, J =16.75,10.35Hz,1H),6.37-6.47(m,1H),5.84(d, J =11.54Hz,1H), 4.06-4.29(m,2H),3.74-4.05(m,8H),2.72-2.95(m,1H),2.12(s,3H),1.28(br d, J =6.40Hz,3H),1.20(br d, J = 6.53 Hz, 3H); LCMS (ESI) m/z: 680.2 (M+1) ⁺ .

Example 2

The first step: DIEA (79.22 mg), PyBrOP (429 mg) and Compound 2-1 (307 mg) were added to a solution of Intermediate A (150 mg) in tetrahydrofuran (3 ml), and the reaction solution was reacted at 70 degrees Celsius for 10 Hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column model: Phenomenex luna C18 (250*50mm*15 μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 35%-65% , 10 minutes) separation and purification to obtain compound 2-2. LCMS (ESI) m/z: 672.3. (M+1) ⁺ .

The second step: acetonitrile (3 milliliters) solution of compound 2-2 (50 mg) was cooled to 0 degrees Celsius, p-toluenesulfonic acid (12.82 mg) and NCS (19.88 mg) were added to the reaction solution at 0 degrees Celsius, Under nitrogen protection, the reaction solution was reacted at 60° C. for 1 hour. Saturated aqueous sodium sulfite (2 ml) was added to the reaction solution, and stirred at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and finally extracted three times with ethyl acetate (10 ml*3). The organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate obtained compound 2-3. LCMS (ESI) m/z: 740.2 (M+1) ⁺ .

Step 3: Trifluoroacetic acid (462 mg) was added to a solution of compound 2-3 (50 mg) in dichloromethane (0.9 ml), and the reaction solution was reacted at 25° C. for 0.5 hour. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 2-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 640.4 (M+1) ⁺ .

the fourth step: Compound 2-4 (130 mg, trifluoroacetate) was dissolved in a mixed solution of tetrahydrofuran (3 ml) and water (1 ml), potassium carbonate (62.06 mg) and compound 1-5 (20.32 mg) were added successively, and the reaction The solution was reacted at 25°C for 10 minutes. The reaction solution was extracted with ethyl acetate (10 ml*2), the organic phase was washed once with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; Mobile phase: [0.225% formic acid aqueous solution-acetonitrile]; Gradient: 29%-59%, 10 minutes) purification to obtain compound 2.

Compound 2 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45%, 2.0 minutes; 40 minutes) separation and purification Compound 2A and Compound 2B. Compound 2A and compound 2B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B% ): 40%-40%] to obtain: the residence time of compound 2A is 0.702min, e.e. value is 100%; the residence time of compound 2B is 1.158min, e.e. value is 100%.

Compound 2A (retention time = 0.702 min): LCMS (ESI) m/z: 694.2 (M+1) ⁺ .

Compound 2B (retention time = 1.158 min): LCMS (ESI) m/z: 694.2 (M+1) ⁺ .

Example 3

The first step: DIPEA (79.22 mg), PyBrOP (429 mg) and compound 3-1 (328 mg) were added to a solution of intermediate A (150 mg) in tetrahydrofuran (5 ml), and the reaction solution was reacted at 70 degrees Celsius for 10 Hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column model: Phenomenexluna C18 250*50mm*15 μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 35%-65%, 10 minutes) Purification afforded compound 3-2. LCMS (ESI) m/z: 686.3. (M+1) ⁺ .

The second step: acetonitrile (3 milliliters) solution of compound 3-2 (70 mg) was cooled to 0 degrees Celsius, p-toluenesulfonic acid (17.58 mg) and NCS (27.26 mg) were added to the reaction solution at 0 degrees Celsius, Under nitrogen protection, the reaction solution was reacted at 60° C. for 1 hour. Saturated aqueous sodium sulfite (2 ml) was added to the reaction solution, and stirred at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 ml*3), the organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate obtained compound 3-3. LCMS (ESI) m/z: 754.4 (M+1) ⁺ .

Step 3: Trifluoroacetic acid (690.90 mg) was added to a solution of compound 3-3 (80 mg) in dichloromethane (1.2 ml), and the reaction solution was reacted at 25° C. for 0.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 3-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 654.4 (M+1) ⁺ .

the fourth step: Add potassium carbonate (84.57 mg) and compound 1-5 (27.69 mg) successively to compound 3-4 (180 mg) in tetrahydrofuran (4 ml) and water (1 ml) mixed solution, and the reaction solution reacts at 20 degrees Celsius for 10 minute. The reaction solution was extracted twice with ethyl acetate (10 mL*2), the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (column model: Phenomenex luna C18 150*25mm*10 μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 31%-64%, 10 minutes) to obtain compound 3 .

Compound 3 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45%, 2.3 minutes; 40 minutes) to obtain Compound 3A and Compound 3B.

Compound 3A and compound 3B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B% ): 5%-40%] to obtain: the residence time of compound 3A is 2.104min, and the e.e. value is 100%; the residence time of compound 3B is 2.654min, and the e.e. value is 100%.

Compound 3A (retention time=2.104min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.32(d, J =4.77Hz, 1H), 7.66(d, J =7.46Hz, 1H), 7.04-7.18( m,2H),6.82(ddd, J =16.60,12.68,10.58Hz,1H),6.11-6.28(m,3H),5.67-5.81(m,1H),4.48-4.81(m,2H),3.71- 4.22(m,4H),2.62-2.75(m,1H),2.03(d, J =3.42Hz,3H),1.28-1.37(m,3H),1.15-1.27(m,3H),1.03(br d , J =6.60Hz, 3H), 0.93(d, J =6.60Hz, 3H); LCMS (ESI) m/z: 708.2(M+1) ⁺ .

Compound 3B (retention time=2.654min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.31(d, J =4.77Hz, 1H), 7.68(d, J =7.58Hz, 1H), 7.04-7.14( m,2H),6.84(dt, J =16.60,10.84Hz,1H),6.13-6.28(m,3H),5.68-5.81(m,1H),4.45-4.83(m,2H),3.44-4.16( m, 4H), 2.82(dq, J =13.36, 6.63Hz, 1H), 1.95(s, 3H), 1.31-1.37(m, 3H), 1.17-1.26(m, 3H), 1.03(br d, J =6.60 Hz, 6H); LCMS (ESI) m/z: 708.3 (M+1) ⁺ .

Example 4

Step 1: To a solution of Intermediate A (200 mg) in acetonitrile (4 mL) were added N-chlorosuccinimide (109.14 mg) and toluenesulfonic acid monohydrate (105.55 mg). The reaction solution was reacted at 60°C for 2 hours, quenched by adding saturated sodium sulfite water (5 ml) solution after the reaction solution, extracted with ethyl acetate (10 ml), and the organic phase was concentrated to obtain compound 4-1. LCMS (ESI) m/z: 558.3 (M+1) ⁺ .

The second step: Compound 4-2 (537.38 mg) and PyBROP (935.18 mg), N,N-diisopropylethylamine (129.63 mg ). The reaction solution was reacted at 60° C. for 12 hours, and the reaction concentrate was obtained to obtain compound 4-3. LCMS (ESI) m/z: 754.5 (M+1) ⁺ .

Third step: To a solution of compound 4-3 (80 mg) in dichloromethane (3 ml) was added trifluoroacetic acid (10.88 mg). The reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction concentrate was obtained to obtain compound 4-4. LCMS (ESI) m/z: 654.3 (M+1) ⁺ .

the fourth step: Potassium carbonate (395.95 mg) and compound 1-5 (25.93 mg) were added to compound 4-4 (375 mg) in tetrahydrofuran: water = 3:1 (4 ml: 1 ml). The reaction solution was reacted at 0° C. for half an hour, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Unisil 3-100 C18 Ultra (150*50mm*3μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 40%-60%, 10 minutes] to obtain compound 4.

Compound 4 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 35%-35%, 2.2 minutes; 40 minutes) separation and purification Compound 4A and Compound 4B.

Compound 4A and compound 4B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol+acetonitrile (0.05% diethylamine); gradient ( B%): 40% methanol+acetonitrile (0.05% diethylamine)] to obtain: the retention time of compound 4A is 0.552min, and the e.e. value is 100%; the retention time of compound 4B is 0.807min, and the e.e. value is 100%.

Compound 4A (retention time=0.552 minutes): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.24-8.40(m, 1H), 7.66(d, J =7.58Hz, 1H), 7.29(s, 1H), 7.09(d, J =4.77Hz,1H),6.82(dd, J =16.57,10.45Hz,1H),6.14-6.23(m,3H),5.68-5.84(m,1H),4.52-4.74(m, 2H),4.28(br d, J =13.82Hz,1H),4.12(br d, J =14.18Hz,1H), 3.46-3.57(m,2H),3.44-3.59(m,1H),2.08(s ,3H), 1.37(br dd, J =11.74,7.09Hz,6H),1.01(d, J =6.60Hz,3H),0.91(d, J =6.72Hz,3H). LCMS (ESI) m/z: 708.3 (M+1) ⁺ .

Compound 4B (retention time=0.807 minutes): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.31(d, J =5.01Hz, 1H), 7.60-7.74(m, 1H), 7.27(s, 1H), 7.07(d, J =5.14Hz,1H),6.72-6.90(m,1H),6.11-6.27(m,3H),5.71-5.81(m,1H),4.51-4.74(m,2H),4.06- 4.28(m,2H),3.48-3.58(m,2H),2.92(br d, J =6.72Hz,1H),1.89(s,3H),1.33-1.44(m,6H),0.98-1.10(m ,6H). LCMS (ESI) m/z: 708.3 (M+1) ⁺ .

Example 5

The first step: DIPEA (263.65 mg), PyBrOP (1.90 g) and compound 5-1 (1.63 g) were added to a solution of intermediate A (500 mg) in tetrahydrofuran (10 ml), and the reaction was carried out at 70 degrees Celsius for 15 hours . The reaction mixture was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column model: Phenomenex Synergi Max-RP (250*50mm*10 μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 36%- 66%, 18 minutes) was purified to obtain compound 5-2. LCMS (ESI) m/z: 672.5 (M+1) ⁺ .

The second step: Add p-toluenesulfonic acid (76.91 mg) and N-chlorosuccinimide (79.52 mg) successively to a solution of compound 5-2 (200 mg) in acetonitrile (6 ml), under nitrogen protection , the mixture was reacted at 60°C for 1 hour. Saturated aqueous sodium sulfite (20 ml) was added to the reaction solution, extracted with ethyl acetate (20 ml*2), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-3. LCMS (ESI) m/z: 740.3 (M+1) ⁺ .

Step 3: Trifluoroacetic acid (924 mg) was added to a solution of compound 5-3 (200 mg) in dichloromethane (1 ml), and the reaction system was reacted at 10°C for 0.5 hour under the protection of nitrogen. The reaction solution was directly concentrated under reduced pressure to obtain compound 5-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 640.4 (M+1) ⁺ .

the fourth step: Compound 5-4 (250 mg) was dissolved in a mixed solution of tetrahydrofuran (4 ml) and water (1 ml), and potassium carbonate (119.35 mg) and compound 1-5 (26.05 mg) were added successively, and the reaction was carried out at 10 degrees Celsius 30 minutes. Add saturated aqueous sodium bicarbonate (15 mL) to the reaction mixture, extract with ethyl acetate (10 mL*3), wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , the residue obtained by preparing HPLC (column model: Phenomenex luna C18 (150*25mm*10 μm); mobile phase: [0.225% formic acid aqueous solution-acetonitrile]; gradient: 28%-58%, 2 minutes) purified to obtain compound 5.

Compound 5 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 40%-40%, 2.6 minutes; 40 minutes) to obtain Compound 5A and Compound 5B.

Compound 5A and compound 5B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B% ): 40%-40%] Obtained: the retention time of compound 5A was 0.785min, and the e.e. value was 99.30%; the retention time of compound 5B was 1.090min, and the e.e. value was 98.98%.

Compound 5A (retention time = 0.785 min): LCMS (ESI) m/z: 694.1 (M+1) ⁺ .

Compound 5B (retention time = 1.090 min): LCMS (ESI) m/z: 694.1 (M+1) ⁺ .

Example 6

The first step: in compound 6-1 (18.45 grams), add 180 milliliters of N, N-dimethylformamide and compound 6-2 (18.56 grams), then add sodium hydride ( 6.36 grams, mass percentage: 60%), after adding, the reaction solution was reacted at 0-10 degrees Celsius for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (200 ml) at 0-10 degrees Celsius, then diluted with water (600 ml) and ethyl acetate (400 ml), the aqueous phase was extracted once with ethyl acetate (400 ml), and combined The organic phase was washed with water (200 ml) and saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , eluent: petroleum ether: acetic acid Ethyl ester=3:1~1:1) to obtain compound 6-3. LCMS (ESI) m/z: 313.0 (m+1) ⁺ .

Second step: Add compound 6-4 (2.45 g), cesium carbonate (8.85 g), Pd ₂ (dba) to a solution of compound 6-3 (4.25 g) in 1,4-dioxane (42.5 ml) ₃ (1.24 g) and Xantphos (1.57 g), the reaction system was replaced with nitrogen three times, and under the protection of nitrogen, the reaction solution was reacted at 100 degrees Celsius for 12 hours. The reaction solution was filtered with Celite, the filter cake was rinsed with ethyl acetate (30 ml*3) each time, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO ₂ , eluent: petroleum Ether:ethyl acetate=3:1~1:1) to obtain compound 6-5. LCMS (ESI) m/z: 383.2 (m+1) ⁺ .

The third step: at 0-10 degrees Celsius, in a solution of compound 6-5 (8.3 grams) in tetrahydrofuran (160 milliliters), add N-bromosuccinimide (3.86 grams), and the reaction solution reacts at 25 degrees Celsius for 1 Hours. The reaction solution was quenched with saturated sodium sulfite solution (40 mL), and then the layers were separated, the aqueous phase was extracted with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure to obtain a residue, the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound 6-6. LCMS (ESI) m/z: 463.0 (m+3) ⁺ .

The fourth step: Add iron powder (4.06 grams) and ammonium chloride (3.88 grams) to compound 6-6 (6.7 grams) in ethanol (90 milliliters) and water (30 milliliters) solution, reaction solution reacts at 80 degrees Celsius 2 Hour.The reaction solution is filtered with diatomaceous earth, the filter cake is washed with ethyl acetate (30 ml*3), the filtrate is concentrated under reduced pressure to obtain a residue, and the residue is diluted with water (20 ml) and ethyl acetate (100 ml) , the organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate=2:1 to 1:1) to obtain compound 6-7. LCMS (ESI) m/z: 433.3 (m+3) ⁺ .

The fifth step: Add N,N-dimethylformamide (50 milliliters) to compound 6-7 (5.3 grams), then add zinc powder (0.4 grams), zinc cyanide (1.16 grams), DPPF (1.36 gram), Pd ₂ (dba) ₃ (1.13 grams) and zinc bromide (138.37 mg), then the reaction system was replaced with nitrogen three times, and under the protection of nitrogen, the reaction solution was reacted at 120 degrees Celsius for 12 hours. The reaction solution was filtered with diatomaceous earth, the filter cake was rinsed with ethyl acetate (30 ml*3), the filtrate was diluted with water (200 ml), and the layers were left to stand, and the aqueous phase was washed with ethyl acetate (50 ml) for 2 Once, the combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate=2: 1 to 1:2) to obtain compound 6-8. LCMS (ESI) m/z: 378.4 (m+1) ⁺ .

Step 6: Concentrated sulfuric acid (43 ml, w%=98%) was added to compound 6-8 (4.3 g), and the reaction solution was reacted at 60° C. for 5 hours. The reaction solution was slowly added to ice water (200 ml), then 67 grams of solid sodium hydroxide was dissolved in 200 ml of water, and added to the above mixture at 0-10 degrees Celsius, and then the mixed solution was adjusted with saturated sodium bicarbonate solution pH value to 8, the mixture was filtered with pad diatomaceous earth, the filter cake was rinsed with ethyl acetate (50 ml*3), the filtrate was allowed to stand for layers, the aqueous phase was extracted with ethyl acetate (50 ml), and the organic The phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The above diatomaceous earth filter cake was rinsed with methanol (50 ml) three times each time, and the filtrate was concentrated under reduced pressure to obtain compound 6-9. LCMS (ESI) m/z: 396.2 (m+1) ⁺ .

Step 7: Add carbonyldiimidazole (2.55 grams) and sodium hydride (628.12 milligrams, mass percent: 60% to compound 6-9 (2.07 grams) in N, N-dimethylformamide (40 milliliters) solution ), and the reaction solution reacted for 0.5 hour at 25 degrees Celsius. 4 milliliters of concentrated hydrochloric acid was diluted with 200 milliliters of water, and the reaction solution was slowly added to the above-mentioned acidic solution, then the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, and the layers were left to stand, and the aqueous phase was washed with ethyl acetate (100 milliliters *2) Extraction, the combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6-10. LCMS (ESI) m/z: 422.2 (m+1) ⁺ .

Step 8: To a solution of compound 6-10 (1.62 g, 3.84 mmol, 1 eq) in acetonitrile (32 mL) was added N-chlorosuccinimide (1.03 g, 7.69 mmol, 2 eq) and p-toluenesulfonic acid (1.32 g, 7.69 mmol, 2 equivalents), and the reaction solution was reacted at 60 degrees Celsius for 2 hours. The reaction solution was cooled to 25°C, then quenched by adding saturated aqueous sodium sulfite (10 ml), and then the reaction solution was concentrated under reduced pressure to obtain a residue, which was washed with saturated sodium bicarbonate solution (40 ml) and ethyl acetate (40 ml ), the aqueous phase was extracted with ethyl acetate (40 milliliters), the combined organic phases were washed with saturated brine (50 milliliters), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, and the residue was purified by preparative HPLC [column Model: Phenomenex luna C18 150*40mm* 15 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 20%-50%, 10 minutes] to obtain compound 6-11. LCMS (ESI) m/z: 490.1 (m+1) ⁺ .

Step 9: Add compound 2-1 (1.60 g) and PyBrOP (1.86 g) to compound 6-11 (490 mg) in N,N-dimethylacetamide (10 ml) solution, and the reaction solution is at 75 The reaction solution was added to water (40 ml) and then extracted with ethyl acetate (20 ml*2). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain a residue, and the residue is purified by preparative HPLC [column model: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60%, 20 minutes] to obtain compound 6-12. LCMS (ESI) m/z: 672.4 (m+1) ⁺ .

Step 10: Add trifluoroacetic acid (2.31 g) to a solution of compound 6-12 (450 mg) in dichloromethane (4.5 ml), and react the reaction solution at 25°C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, then the residue was diluted with saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL), the aqueous phase was extracted with ethyl acetate (5 mL), and the combined organic phases were used for Wash with saturated brine (5 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the trifluoroacetic acid salt of compound 6-13. LCMS (ESI) m/z: 572.2 (m+1) ⁺ .

Eleventh step: Potassium carbonate (86.43 mg) and compound 1-5 (28.30 mg) were added to a solution of compound 6-13 (179 mg) in tetrahydrofuran (6 ml) and water (2 ml), and the reaction solution was reacted at 25 degrees Celsius for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and then the residue was diluted with saturated brine (10 mL) and ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The material was purified by preparative HPLC [column model: Phenomenex Synergi C18 (150*25mm* 10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 15%-45%, 10 minutes] to obtain compound 6 .

Compound 6 was separated by preparative SFC (column model: DAICEL CHIRALCEL OD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 45%-45%, 45 minutes, 50 minutes] Compounds 6A and 6AM.

6AM was separated and purified by preparative SFC (column model: Daicel ChiralPak IG (250*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.8 minutes, 45 minutes) Compounds 6B and 6BM were obtained.

6BM was separated and purified by preparative SFC (column model: Daicel ChiralPak IG (250*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.8 minutes, 45 minutes) Compound 6C and Compound 6D were obtained.

Compound 6A was detected by SFC [column model: Chiralpak IJ-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] to obtain: the residence time of compound 6A was 2.494min, and the e.e. value was 96.34%.

Compound 6B was detected by SFC [column model: Cellucoat 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5%-40 %] Obtained: the residence time of compound 6B was 1.066min.

Compound 6C and compound 6D were detected by SFC [column model: Chiralpak OJ-3 50×4.6mm I.D., 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B% ): 5%-40%] to obtain: the residence time of compound 6C is 1.368min, and the e.e. value is 100%; the residence time of compound 6D is 1.492min, and the e.e. value is 100%.

Compound 6A (retention time=2.494min): ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.47(d, J =4.9Hz, 1H), 7.39(d, J =7.1Hz, 1H), 7.04(d, J =4.8Hz, 1H), 6.89(br d, J =7.0Hz, 1H), 6.62(br s, 1H), 6.52-6.32(m, 2H), 5.82(br d, J =10.9Hz, 1H), 5.11-4.45(m, 2H), 4.43-4.12(m, 1H), 3.93-3.42(m, 3H), 3.31-2.86(m, 1H), 2.83-2.60(m, 1H), 2.15(br s, 3H), 1.44 (br s, 3H), 1.24-1.10 (m, 6H); LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

Compound 6B (retention time = 1.606 min): LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

Compound 6C (retention time=1.368min): ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.47(d, J =4.9Hz, 1H), 7.39(d, J =7.2Hz, 1H), 7.04(d, J =4.9Hz, 1H), 6.90(d, J =7.5Hz, 1H), 6.75-6.53(m, 1H), 6.52-6.34(m, 2H), 5.82(dd, J =1.7, 10.4Hz, 1H) , 5.05-4.15(m, 3H), 3.94-3.38(m, 3H), 3.32-2.95(m, 1H), 2.80-2.54(m, 1H), 2.16(s, 3H), 1.54-1.36(m, 3H), 1.24-1.08 (m, 6H); LCMS (ESI) m/z: 626.3 (M+1) ⁺ .

Compound 6D (retention time=1.492min): ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.47(d, J =4.9Hz, 1H), 7.39(d, J =7.1Hz, 1H), 7.04(d, J =4.9Hz, 1H), 6.89(s, 1H), 6.75-6.53(m, 1H), 6.51-6.28(m, 2H), 5.82(dd, J =1.5, 10.5Hz, 1H), 5.17-4.47( m, 2H), 4.43-4.12(m, 1H), 3.97-3.37(m, 3H), 3.34-2.92(m, 1H), 2.89-2.60(m, 1H), 2.11(s, 3H), 1.44( br s, 3H), 1.29-1.13 (m, 6H); LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

Example 7

Step 1: Add compound 7-2 (8.01 g) dropwise to a solution of compound 7-1 (8 g) in dichloromethane (80 ml) at 0-10°C. After the addition is complete, the reaction solution is reacted at 25°C 12 hours. LCMS detected the remaining raw materials, and then added compound 7-2 (3.34 g) to the reaction system, and reacted at 25 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, the residue was diluted with dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (100 ml), the layers were separated, the aqueous phase was extracted with dichloromethane (50 ml), and the combined organic The phase was washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-3. LCMS (ESI) m/z: 264.3 (m+1) ⁺ .

The second step: Add cesium carbonate (17.30 grams) to the acetonitrile (140 milliliters) solution of compound 7-3 (14 grams), then add compound 7-4 (9.11 grams) at 0-10 degrees Celsius, and the reaction solution is at 25 degrees Celsius React for 1 hour. The reaction solution was filtered with celite, and the filter cake was rinsed with ethyl acetate (30 ml*3) each time, and then the filtrate was concentrated under reduced pressure to obtain compound 7-5. LCMS (ESI) m/z: 385.8 (m+1) ⁺ .

Step 3: Triethylamine (14.69 g) was added to a solution of compound 7-5 (28 g) in trifluoroethanol (140 ml), and the reaction solution was reacted at 80° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and then the residue was diluted with ethyl acetate (150 ml) and water (100 ml), and the pH value of the aqueous phase was adjusted to 1 with 1 mol/L aqueous hydrochloric acid solution, and then allowed to stand The layers were separated, the aqueous phase was extracted with ethyl acetate (50 ml), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-6. LCMS (ESI) m/z: 354.0 (m+1) ⁺ .

Step 4: Add 4A molecular sieves (18.3 g) and triethylamine (10.47 g) to a solution of compound 7-6 (18.3 g) in tertiary butanol (183 ml), and then stir at 80°C for 2 hours. DPPA (15.99 g, 98% purity) was added to the reaction system, and the reaction solution was reacted at 80 degrees Celsius for 1 hour. The reaction solution was filtered and the filter cake was washed with ethyl acetate (50 ml*3) each time, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was diluted with 10% citric acid solution (150 ml) and ethyl acetate (150 ml), The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic phases were washed with saturated brine (50 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-7. LCMS (ESI) m/z: 369.2 (m+1-56) ⁺ .

Step 5: To a solution of compound 7-7 (28 g) in methanol (140 ml) was added methanolic hydrochloric acid (4 mol/L, 140.00 ml), and the reaction solution was reacted at 40°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, the residue was diluted with saturated sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL), the organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 4:1) to obtain compound 7-8. LCMS (ESI) m/z: 325.0 (m+1) ⁺ .

The sixth step: Add compound A-2 (4.30 grams), cesium carbonate (8.73 grams) and BrettPhos Pd (1.21 grams) in the tertiary-butanol (45 milliliters) solution of compound 7-8 (4.35 grams), react The system was replaced with nitrogen for 3 times, and reacted at 100 degrees Celsius for 12 hours under the protection of nitrogen. The reaction solution was filtered with celite, the filter cake was washed with ethyl acetate (50 ml*3) each time, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate =10:1~5:1) to obtain compound 7-9. LCMS (ESI) m/z: 458.3 (m+1) ⁺ .

Step 7: Add N-bromosuccinimide (1.76 grams) to a solution of compound 7-9 (4.52 grams) in dichloromethane (45 milliliters) at 0-10 degrees Celsius, and the reaction solution is at 0 React for 1 hour at -10 degrees Celsius, quench the reaction solution with saturated sodium sulfite solution (20 ml), then stand to separate layers, wash the organic phase with saturated brine (20 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Compounds 7-10. LCMS (ESI) m/z: 538.2 (m+3) ⁺ .

Step 8: Add zinc powder (0.33 g), zinc cyanide (0.86 g), DPPF (997.78 mg ), Pd ₂ (dba) ₃ (824.06 mg) and zinc bromide (101.33 mg), then the reaction system was replaced with nitrogen three times, and under the protection of nitrogen, the reaction solution was reacted at 120 degrees Celsius for 12 hours. Filter the reaction liquid pad with diatomaceous earth, wash the filter cake with ethyl acetate (30ml*3), dilute the filtrate with water (250ml), then let the layers stand, wash the water phase with ethyl acetate (50ml*2) , the combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate=5:1 to 3:1) to obtain compound 7-11. LCMS (ESI) m/z: 483.2 (m+1) ⁺ .

Step 9: Add concentrated sulfuric acid (25 milliliters) to compound 7-11 (2.48 grams), react the reaction solution at 60 degrees Celsius for 12 hours, slowly add the reaction solution to ice water (80 milliliters), and then oxidize the hydrogen Sodium solid (32 grams) was dissolved in (100 ml) water, then added to the above mixture at 0-10 degrees Celsius, and then the pH of the mixed solution was adjusted to 8 with sodium bicarbonate solid, and the mixed solution was filtered with diatomaceous earth. The cake was washed with ethyl acetate (50 ml*2), the filtrate was allowed to stand and separated, the aqueous phase was extracted with ethyl acetate (50 ml), the combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and filtered , concentrated under reduced pressure to obtain compound 7-12. LCMS (ESI) m/z: 501.2 (m+1) ⁺ .

Step 10: Add carbonyldiimidazole (1.85 g) and sodium hydride (455.23 mg, mass percent: 60%) to a solution of compound 7-12 (1.9 g) in anhydrous tetrahydrofuran (40 ml), and the reaction solution is heated at 25 degrees Celsius React for 1 hour, dilute concentrated hydrochloric acid (2 ml) with water (40 ml), slowly add the reaction solution to the above acidic solution, then neutralize with saturated sodium bicarbonate solution (40 ml), let stand to separate layers, and the aqueous phase Extracted with ethyl acetate (40 ml), the combined organic phases were washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-13. LCMS (ESI) m/z: 527.2 (m+1) ⁺ .

The eleventh step: Compound 1-1 (1.77 g) and PyBrOP (2.21 g) were added to a solution of compound 7-13 (500 mg) in tetrahydrofuran (5 ml), and the reaction solution was reacted at 60 degrees Celsius for 12 hours, and the reaction liquid filtration, the filter cake was washed with ethyl acetate (5 ml*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was prepared by HPLC [column model: Phenomenex luna c18 250mm*100mm*10 μm; mobile phase: [water (0.225 % formic acid)-acetonitrile]; Gradient: 40%-60%, 20 minutes] purified to obtain compound 7-14. LCMS (ESI) m/z: 695.3 (m+1) ⁺ .

Step 12: Add trifluoroacetic acid (7.70 g) to a solution of compound 7-14 (1.65 g) in dichloromethane (15 ml), react the reaction solution at 25 degrees Celsius for half an hour, and concentrate the reaction solution under reduced pressure to obtain The residue was then diluted with saturated sodium bicarbonate solution (20 ml) and ethyl acetate (40 ml), the organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Trifluoroacetate salts of compounds 7-15. LCMS (ESI) m/z: 595.1 (m+1) ⁺ .

The thirteenth step: Add potassium carbonate (341.47 mg) to a solution of compound 7-15 (1.47 g) in tetrahydrofuran (14 ml) and water (4 ml) at 0-10 degrees Celsius, and then dissolve compound 1-5 In anhydrous tetrahydrofuran (2 ml), it was added to the above reaction solution, and the reaction system was reacted at 25° C. for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and then the residue was diluted with saturated brine (20 ml) and ethyl acetate (40 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The product was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm* 15 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 25%-55%, 10 minutes] to obtain compound 7 . LCMS (ESI) m/z: 649.4 (m+1) ⁺ .

Example 8

first step: At minus 78 degrees Celsius, n-butyllithium (2.5 mol/liter, 15.3 milliliters) was added to a solution of compound 8-1 (7.0 g) in tetrahydrofuran (70 milliliters), and the reaction solution was stirred at minus 78 degrees Celsius for 1 hour, and then The reaction solution was poured into dry ice, the reaction solution was acidified with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate (150 ml*2), the obtained organic phase was washed with saturated brine (150 ml) and then washed with anhydrous sodium sulfate Dry and concentrate under reduced pressure to obtain compound 8-2. The crude product was used directly in the next step.

Step two: 4A molecular sieves (10.0 g) and triethylamine (7.58 g) were added to a solution of compound 8-2 (8.5 g) in tertiary butanol (90 ml) at room temperature, and the reaction solution was stirred at 80°C for 1 hour, Then diphenylphosphoryl azide (10.82 g) was added, the reaction solution was stirred at 80°C for 11 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (200 ml*3), and the filtrate was concentrated to obtain a residue. The residue was diluted with ethyl acetate (250 mL), washed with 10% citric acid (200 mL*2), saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-3. The crude product was used directly in the next step.

third step: Compound 8-3 (11.0 g) was dissolved in ethyl acetate hydrochloride (4.0 mol/L, 110.0 ml) at room temperature, the reaction solution was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated to obtain intermediate 8-4 . The crude product was used directly in the next step.

Step 4: Dissolve compound 8-4 (9.0 g, hydrochloride) and compound 8-5 (6.29 g) in dichloromethane (90 ml) at room temperature, and stir the reaction solution at room temperature for 12 hours , the reaction solution was concentrated to obtain compound 8-6. The crude product was used directly in the next step. LCMS (ESI) m/z: 298.0 (M+1) ⁺ .

Step 5: Dissolve compound 8-6 (10.0 g), compound 8-7 (5.92 g) and cesium carbonate (10.93. g) in acetonitrile (120 ml) at room temperature, and stir the reaction solution at room temperature After 1 hour, the reaction solution was poured into water (250 ml), and then extracted with ethyl acetate (250 ml*3). The obtained organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound 8-8. The crude product was used directly in the next step. LCMS (ESI) m/z: 420.0 (M+1) ⁺ .

Step 6: Dissolve compound 8-8 (14.0 g) and triethylamine (6.74 g) in trifluoroethanol (140 ml) at room temperature, and stir the reaction solution at 80°C for 12 hours. 1/L of hydrochloric acid (250 ml) was acidified, then extracted with ethyl acetate (250 ml*2), the resulting organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8- 9. The crude product was used directly in the next step. LCMS (ESI) m/z: 388.0 (M+1) ⁺ .

Step 7: Add 4Å molecular sieves (13.0 grams) and triethylamine (6.78 grams) to a solution of compound 8-9 (13.0 grams) in tertiary butanol (130 milliliters) at room temperature, and the reaction solution is stirred at 80 degrees Celsius for 1 hours, then diphenylphosphoryl azide (9.68 g) was added, the reaction solution was stirred at 80°C for 11 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (250 ml*3), and the filtrate was concentrated to obtain a residue. The residue was diluted with ethyl acetate (250 mL), washed with 10% citric acid (250 mL*2), saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-10. The product was used directly in the next step without purification. LCMS (ESI) m/z: 403.1 (M+1-56) ⁺ .

Step 8: Dissolve compound 8-10 (15.0 g) in ethyl acetate hydrochloride (4.0 mol/L, 100.0 ml) at room temperature, stir the reaction solution at room temperature for 0.5 hour, and concentrate the reaction solution to obtain the residue The residue was separated by reverse phase chromatography column (column type: Welch Ultimate XB_C18 (20-40 μm; 120 A), mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 15-70%, 30 minutes; 70%, 30 minutes) to obtain compound 8-11. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47-8.37 (m, 1H), 7.05-6.97 (m, 1H), 6.59-6.50 (m, 1H), 6.46-6.25 (m, 2H). LCMS (ESI) m/z: 359.0 (M+1) ⁺ .

Step 9: Add compound A-2 (2.24 g), BrettPhos Pd G3 (631.13 mg) and cesium carbonate (4.54 g), the reaction solution was reacted at 105 degrees Celsius for 3 hours under nitrogen protection conditions, the reaction solution was filtered, the filter cake was washed with ethyl acetate (150 ml*3), the filtrate was concentrated to obtain a residue, and the residue was separated by reverse phase chromatography ( Column model: Welch Ultimate XB_C18 20-40 μm; 120 A; mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 60%, 10 minutes) to obtain compounds 8-12. LCMS (ESI) m/z: 492.1 (M+1) ⁺ .

Step 10: Add N-bromosuccinimide (686.96 mg) to a solution of compound 8-12 (1.9 g) in dichloromethane (20 ml) at 0°C, and the reaction solution is maintained at 0°C Stirring for 0.5 hours, the reaction solution was quenched with saturated sodium sulfite (20 ml) at 0°C, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a residue, and methanol ( 10 ml), stirred at room temperature for 0.5 hour, the mixture was filtered, and the filter cake was dried to obtain compound 8-13. LCMS (ESI) m/z: 572.0 (M+3) ⁺ .

Step 11: Add zinc powder (54.95 mg) and zinc cyanide (131.58 mg) to a solution of compound 8-13 (0.8 g) in N,N-dimethylformamide (5 ml) at room temperature, Zinc bromide (15.77 mg), 1,1'-bis(diphenylphosphino)ferrocene (155.30 mg) and tris(dibenzylideneacetone)dipalladium (128.26 mg), the reaction solution was at 120 degrees Celsius, nitrogen Stir under protective conditions for 2 hours, filter the reaction solution, wash the filter cake with ethyl acetate (150 mL*3), concentrate the filtrate to obtain a residue, add methanol (10 mL) to the residue, stir at room temperature for 0.5 hours, and filter the mixture , and the filter cake was dried to obtain compound 8-14. LCMS (ESI) m/z: 517.3 (M+1) ⁺ .

Step 12: Dissolve compound 8-14 (0.6 g) in concentrated sulfuric acid (12.0 ml) at room temperature, stir the reaction solution at 60°C for 4 hours, and slowly add the reaction solution dropwise to 2 mol/L of hydrogen Sodium oxide (250 ml) aqueous solution, and then extracted with ethyl acetate (250 ml*2), the obtained organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-15. The product was used directly in the next step without purification. LCMS (ESI) m/z: 535.3 (M+1) ⁺ .

Step 13: Add sodium hydride (186.80 mg, mass percent: 60%) and 1,1-carbonyldiimidazole (454.37 mg) to a solution of compound 8-15 (0.5 g) in tetrahydrofuran (25 ml) at room temperature , the reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was poured into a saturated ammonium chloride (150 ml) aqueous solution to quench, then extracted with ethyl acetate (150 ml*3), and the resulting organic phase was subjected to saturated brine (150 ml) was washed, dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain a residue, methanol (5 ml) was added to the residue, stirred at room temperature for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 8-16. LCMS (ESI) m/z: 561.3 (M+1) ⁺ .

Step 14: Add N,N-diisopropylethylamine (345.39 mg) and Tripyrrolidinylphosphonium bromide hexafluorophosphate (1.25 grams), the reaction solution was stirred at 80 degrees Celsius for 24 hours, the reaction solution was poured into water (150 milliliters), and then extracted with ethyl acetate (150 milliliters * 3), The obtained organic phase was washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-17. The product was used directly in the next step without purification. LCMS (ESI) m/z: 729.4 (M+1) ⁺ .

Step 15: Add trifluoroacetic acid (13.86 g) to a solution of compound 8-17 (0.3 g) in dichloromethane (9 ml) at room temperature, stir the reaction solution at room temperature for 0.5 hour, and concentrate the reaction solution The trifluoroacetic acid salt of compound 8-18 was obtained. The product was used directly in the next step without purification. LCMS (ESI) m/z: 629.4 (M+1) ⁺ .

Step sixteen: At 0 degrees Celsius, potassium carbonate (219.58 mg) was added to a solution of compound 8-18 (0.2 g) in tetrahydrofuran (10 ml) and water (2 ml), then compound 1-5 (28.76 mg) was added, and the reaction solution was Stir at 0°C for 0.5 hours, pour the reaction solution into water (50 ml), and then extract with ethyl acetate (50 ml*3), the obtained organic phase is washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain a residue, and the residue is separated by a preparative chromatographic column (column model: Phenomenex Gemini-NX C18 (75*30mm*3μm), mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile%: 32% -62%, 7 minutes) purification, the obtained compound 8.

Compound 8 was then prepared by SFC (column model: DAICEL CHIRALCEL OD (250mm*30mm, 10um; mobile phase: [methanol (0.1% ammonia water)]; gradient: carbon dioxide critical fluid: 30%-30%, 3.3 minutes, 50 minutes) Afterwards, they were separated by preparative chromatographic column (column type: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile%: 32%-62%, 7 minutes) to obtain the compound 8A and compound 8B.

Compound 8A (retention time=1.688min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.51-8.37(m,1H),8.37-8.30(m,1H),7.41-7.28(m,1H),7.16 -7.05(m,1H),6.92-6.77(m,1H),6.28-6.12(m,1H),5.83-5.69(m,1H),4.02-3.66(m,9H),2.02-1.96(m, 3H), 1.07-1.04(m,3H), 1.01-0.95(m,3H). LCMS (ESI) m/z: 683.4 (M+1) ⁺ .

Compound 8B (retention time=1.808min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.49-8.38(m,1H),8.36-8.31(m,1H),7.42-7.28(m,1H),7.17 -7.04(m,1H),6.92-6.76(m,1H),6.28-6.08(m,1H),5.84-5.63(m,1H),4.03-3.68(m,9H), 2.04-1.94(m, 3H), 1.12-1.03 (m, 3H), 1.01-0.93 (m, 3H). LCMS (ESI) m/z: 683.4 (M+1) ⁺ .

Example 9

Step 1: Heat a solution of intermediate A (2.5 g) in formic acid (12.5 ml) to 100°C and react at 100°C for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 ml) at 15°C, then extracted with ethyl acetate (10 ml*3), the combined organic phases were washed with saturated brine (10 ml), anhydrous sodium sulfate Dry and filter. The filtrate was concentrated under reduced pressure to obtain compound 9-1. LCMS (ESI) m/z: 518.2 (M+1) ⁺ .

The second step: Add boron trifluoride ether solution (1 mol/L, 30.92 ml) dropwise to compound 9-1 (2.0 g) in tetrahydrofuran (50 ml) at 0°C React for 1 hour. Water (30 mL) was added dropwise to the reaction mixture. Then it was extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 9-2. LCMS (ESI) m/z: 504.0 (M+1) ⁺ .

third step:

To a solution of compound 9-2 (1.6 g) in tetrahydrofuran (100 ml) were added PyBrOP (5.93 g) and compound 1-1 (4.74 g), and the reaction was carried out at 70° C. for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column model: Phenomenex luna C18 (250*70mm*10 μm); mobile phase: [0.225% formic acid aqueous solution-acetonitrile]; acetonitrile: 30% -60%, 22 minutes) purification, the obtained product was purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45% , 2.5 minutes; 50 minutes) were separated and purified to obtain compound 9-3A (retention time=1.851min) and compound 9-3B (retention time=2.297min).

LCMS (ESI) m/z: 672.5 (M+1) ⁺ .

the fourth step:

A solution of compound 9-3A (200 mg) in acetonitrile (10 ml) was cooled to 0° C., p-toluenesulfonic acid (51.27 mg) and NCS (39.76 mg) were added to the reaction solution at 0° C., under nitrogen protection , the mixture was reacted at 60°C for 2 hours. Add saturated aqueous sodium sulfite (20 ml) and saturated aqueous sodium bicarbonate (20 ml) to the reaction solution, Extracted twice with ethyl acetate (30 ml*2), the organic phase was washed once with saturated brine (20 ml), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (dioxide Silicon: Petroleum ether: Ethyl acetate: Methanol = 8: 3: 1) purification to obtain compounds 9-4A (Rf = 0.26) and 10-1A (Rf = 0.18), respectively.

Compound 9-4A: ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.25-8.43(m,1H),7.17-7.27(m,2H),6.94(s,1H),6.91(br d, J =4.75Hz ,1H),6.26-6.43(m,1H),3.80(br d, J =4.13Hz,4H),3.53-3.69(m,4H),2.66-2.73(m,3H),2.55-2.65(m, 1H) 1.97-2.08(m, 3H), 1.44(s, 9H), 1.02-1.18(m, 6H). LCMS (ESI) m/z: 706.2 (M+1) ⁺ .

Compound 10-1A: LCMS (ESI) m/z: 706.3 (M+1) ⁺ . A solution of compound 9-3B (200 mg) in acetonitrile (10 ml) was cooled to 0° C., p-toluenesulfonic acid (51.27 mg) and NCS (39.76 mg) were added to the reaction solution at 0° C., and under nitrogen protection , the mixture was reacted at 60°C for 2 hours. Add saturated aqueous sodium sulfite (20 ml) and saturated aqueous sodium bicarbonate (20 ml) to the reaction solution, extract twice with ethyl acetate (30 ml*2), and use saturated brine (20 ml) for the organic phase Washed once, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (silicon dioxide: petroleum ether: ethyl acetate: methanol = 8:3:1) to obtain compound 9-4B respectively (Rf=0.30) and 10-1B (Rf=0.35).

Compound 9-4B: LCMS (ESI) m/z: 706.3 (M+1) ⁺ .

Compound 10-1B: LCMS (ESI) m/z: 706.2 (M+1) ⁺ .

the fifth step:

Trifluoroacetic acid (462 mg) was added to a solution of compounds 9-4A and 9-4B (70 mg) in dichloromethane (0.9 ml), respectively, and the reaction was carried out at 10° C. for 0.5 hr. The reaction solution was directly concentrated under reduced pressure to obtain crude trifluoroacetate salts of compounds 9-5A and 9-5B, which were directly used in the next reaction. LCMS (ESI) m/z: 606.3 (M+1) ⁺ .

Step six:

Compounds 9-5A and 9-5B (100 mg) were dissolved in a mixed solution of THF (4 ml) and water (1 ml) respectively, potassium carbonate (49.71 mg) and compound 1-5 (10.85 mg) were added successively, the The reaction was carried out at 15°C for 30 minutes. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phase was washed once with saturated brine (10 mL), and anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column model: Phenomenex luna C18 (150*25mm*10 μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 25%- 55%, 10 minutes) were purified to obtain compounds 9A and 9B, respectively. Compound 9A: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.36(d, J =5.14Hz, 1H), 7.32-7.39(m, 1H), 7.29(s, 1H), 7.24(br d, J = 5.01Hz,1H),6.83(dd, J =16.75,10.64Hz,1H),6.51(dd, J =9.29,1.34Hz,1H),6.30(dd, J =16.75,1.96Hz,1H),5.80- 5.87(m,1H),3.86-4.12(m,8H),2.82(dt, J =13.54,6.86Hz,1H),2.75(s,3H),2.17(s,3H),1.18-1.21(m, 3H), 1.11 (d, J =6.85Hz, 3H). LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

Compound 9B: ¹ H NMR (400MHz, METHANOL- d ₄ ) δ 8.36(d, J =5.01Hz, 1H), 7.37(dd, J =8.93, 5.87Hz, 1H), 7.33(s, 1H), 7.19( d, J =5.01Hz,1H),6.84(dd, J =16.81,10.58Hz,1H),6.49(t, J =8.93Hz,1H),6.31(dd, J =16.81,1.90Hz,1H), 5.78-5.89(m,1H),3.90-4.11(m,8H),2.74-2.86(m,1H),2.67(s,3H),2.12(s,3H),1.19(d, J =6.72Hz, 3H), 1.10 (d, J = 6.72 Hz, 3H); LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

Example 10

10-1A → 10-2A → 10A

10-1B → 10-2B → 10B

first step:

Trifluoroacetic acid (471.33 mg) was added to a solution of compounds 10-1A and 10-1B (90 mg) in dichloromethane (0.9 mL), respectively, and the reaction was carried out at 10° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain trifluoroacetic acid salts of compounds 10-2A and 10-2B, and the crude products were directly used in the next reaction. LCMS (ESI) m/z: 606.4 (M+1) ⁺ .

Step two:

Compounds 10-2A and 10-2B (150 mg) were dissolved in a mixed solution of tetrahydrofuran (4 ml) and water (1 ml), and potassium carbonate (102.63 mg) and compound 1-5 (22.40 mg) were added successively. The reaction was carried out at 15°C for 30 minutes. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL*2), the combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through a preparative HPLC (column model: Phenomenex luna C18 (150*25mm*10 μm), mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: acetonitrile %: 20% -50%, 10 min) to obtain the formate salt of compound 10A and the formate salt of 10B, respectively. LCMS (ESI) m/z: 660.4 (M+1) ⁺ .

Formate salt of compound 10A: ¹ H NMR (400MHz, METHANOL- d ₄ ) δ 8.36(d, J =5.01Hz, 1H), 7.37(dd, J =8.93, 5.87Hz, 1H), 7.33(s, 1H ),7.19(d, J =5.01Hz,1H),6.84(dd, J =16.81,10.58Hz,1H),6.49(t, J =8.93Hz,1H),6.31(dd, J =16.81,1.90Hz ,1H),5.78-5.89(m,1H),3.90-4.11(m,8H),2.74-2.86(m,1H),2.67(s,3H),2.12(s,3H),1.19(d, J =6.72Hz, 3H), 1.10(d, J =6.72Hz, 3H). LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

Formate salt of compound 10B: ¹ H NMR (400MHz, METHANOL- d ₄ ) δ 8.36(d, J =5.01Hz, 1H), 7.36(dd, J =8.86, 5.93Hz, 1H), 7.32(s, 1H ),7.15-7.20(m,1H), 6.84(dd, J =16.75,10.64Hz,1H),6.48(t, J =8.99Hz,1H),6.31(dd, J =16.75,1.83Hz,1H) ,5.84(dd, J =10.58,1.90Hz,1H),3.85-4.20(m,8H),2.96(dt, J =13.51,6.69Hz,1H),2.67(s,3H),2.04(s,3H ), 1.14-1.25 (m, 6H); LCMS (ESI) m/z: 660.2 (M+1) ⁺ .

Example 11

first step: Aqueous ammonia (182 g, mass percentage: 34%) was added at one time to a solution of compound 11-1 (20 g) in ethanol (200 ml) at 20-30°C. The reaction solution was reacted at 75 degrees Celsius for 16 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (80 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11-2.

Second step: Add triethylamine (1.56 g) and methylmalonyl chloride (1.57 g ), the reaction solution was reacted for 4 hours at 20-30 degrees Celsius. Citric acid was added to the reaction solution to pH=6-7, the reaction solution was separated, the aqueous phase was extracted with dichloromethane (50 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=20:1 to 3:1) to obtain compound 11-3. ¹ H NMR (400MHz, CDCl ₃ )δ 10.32(br s,1H),8.25-8.15(m,1H),7.59-7.48(m,1H),7.11-6.98(m,1H),3.85(s,3H ), 3.56(s,2H). LCMS (ESI) m/z: 257.1 (M+1) ⁺ .

The third step: at 20-30 degrees Celsius, cesium carbonate (19.08 g) and 4-ethoxy-1,1,1-tri Fluoro-3-buten-2-one (7.87 grams), the reaction solution was reacted at 20-30 degrees Celsius for 3 hours under the protection of nitrogen. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 0:1) to obtain compound 11-4. LCMS (ESI) m/z: 379.0 (M+1) ⁺ .

The fourth step: at 20-30 degrees Celsius, add ammonium chloride (3.54 grams) and reduced iron powder (3.69 gram), and the reaction solution was reacted at 80 degrees Celsius for 16 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 0:1) to obtain compound 11-5. LCMS (ESI) m/z: 317.0 (M+1) ⁺ .

Step 5: NCS (84.46 mg) was added to compound 11-5 (0.2 g) in acetic acid (2 ml) at 20-30°C, and the reaction solution was reacted at 20-30°C for 16 hours. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=0:1) to obtain compound 11-6. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.19-8.03 (m, 1H), 7.43-7.26 (m, 1H), 7.18-7.00 (m, 2H), 5.65 (br s, 2H). LCMS (ESI) m/z: 351.0 (M+1) ⁺ .

Step 6: To a solution of compound 11-6 (1.1 g) in pyridine (15 ml) was added liquid bromine (1.55 g) in one go at 20-30°C. The reaction solution was reacted at 50° C. for 12 hours under the protection of nitrogen. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 11-7. LCMS (ESI) m/z: 386.9 (M+3) ⁺ .

Step 7: Add 2-isopropyl-4-methylpyridine-3 sequentially to a solution of compound 11-7 (1.6 g) in 1,4-dioxane (20 ml) at 20-30°C -amine (498.74 mg), tris(dibenzylideneacetone)dipalladium (380.03 mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (480.26 mg), cesium carbonate ( 2.7 grams). The reaction solution was reacted at 100° C. for 6 hours under the protection of nitrogen. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:2) to obtain compound 11-8. LCMS (ESI) m/z: 455.1 (M+1) ⁺ .

Step 8: To a solution of compound 11-8 (0.3 g) in DMF (3 mL) was added N-bromosuccinimide (176.09 mg) in one portion at 20-30°C. The reaction solution was reacted for one hour at 20-30 degrees Celsius. Water (40 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to obtain compound 11-9. LCMS (ESI) m/z: 534.9 (M+3) ⁺ .

The ninth step: at 20-30 degrees Celsius, add zinc powder (210 mg) and zinc cyanide ( 300 mg), zinc bromide (71.73 mg), 1,1-bis(diphenylphosphino)ferrocene (96.33 mg) and tris(dibenzylideneacetone)dipalladium (85.00 mg). The reaction solution was reacted at 100 degrees Celsius for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether: ethyl acetate = 1:1) to obtain compound 11-10. LCMS (ESI) m/z: 480.0 (M+1) ⁺ .

Step 10: Compound 11-10 (46 mg) was reacted with concentrated sulfuric acid (1.41 g) at 60°C for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate (50 ml), extracted with ethyl acetate (20 ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11-11. LCMS (ESI) m/z: 498.1 (M+1) ⁺ .

Step 11: Add sodium hydride (12.05 mg, mass percentage: 60%) to compound 11-11 (30 mg) in tetrahydrofuran (1 ml) at 0°C, and react at 0°C After 0.3 hours, 1,1-carbonyldiimidazole (29.31 mg) was added in one portion. The reaction solution was reacted at 0-25 degrees Celsius for 0.7 hours. The reaction solution was added to a saturated ammonium chloride (20 mL) solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to obtain compound 11-12. LCMS (ESI) m/z: 524.0 (M+1) ⁺ .

Step 12: Add N,N-diisopropylethylamine (29.60 mg) and tripyrrolidine all at once to a solution of compound 11-12 (30 mg) in THF (2 ml) at 20-30°C Phosphonium bromide hexafluorophosphate (106.79 mg), the reaction solution was reacted at 20-30°C for 1 hour, and then compound 1-1 (42.66 mg) was added in one batch, and the reaction solution was reacted at 80°C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=0:1) to obtain compound 11-13. LCMS (ESI) m/z: 692.1 (M+1) ⁺ .

Step Thirteen: To a solution of compound 11-13 (22 mg) in dichloromethane (0.6 mL) was added trifluoroacetic acid (308.00 mg) in one portion at 10-25 °C. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetic acid salt of compound 11-14, and the crude product was directly used in the next step.

Step Fourteen:

At 0°C, anhydrous potassium carbonate (21.53 mg), acryloyl chloride (2.82 mg). The reaction solution was reacted at 0°C for 0.5 hours. Reverse Water (10 mL) was added to the solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (dichloromethane:methanol=7:1) to obtain compound 11.

Compound 11 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 5 minutes, 50 minutes) Example 11AM (mixture of residence time=3.325min and residence time=4.538min) and Example 11CM (mixture of residence time=1.622min and residence time=1.789min).

11AM was then separated by preparative SFC (column model: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 5.7 minutes, 40 minutes) Purification afforded Compound 11A, and Compound 11B.

11CM was then separated by preparative SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 5.8 minutes, 40 minutes) Purification afforded Compound 11C and Compound 11D.

Compound 11A and compound 11B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B% ): 5%-40%] obtained: the residence time of compound 11A was 4.538min, and the e.e. value was 100%; the residence time of compound 11B was 3.318min, and the e.e. value was 100%.

Compound 11C and compound 11D were detected by SFC [column model: Chiralcel OJ-3 50×4.6mm I.D., 3 μm; mobile phase: phase A was supercritical carbon dioxide, phase B was isopropanol (0.05% diethylamine); gradient ( B%): 5%-40%] Obtained: the residence time of compound 11C is 1.314min, e.e. value is 100%; the residence time of compound 11D is 1.471min, e.e. value is 100%.

Compound 11A (retention time = 4.538 min): LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

Compound 11B (retention time = 3.318 min): LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

Compound 11C (retention time=1.314min): ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.36-8.30(m,1H),7.25-7.22(m,1H),7.19-7.13(m,2H),6.94 -6.84(m,1H),6.83-6.80(m,1H),6.35-6.26(m,1H),5.88-5.81(m,1H),4.10-4.00(m,4H),3.98-3.87(m, 4H), 2.97-2.76(m, 1H), 2.17-2.06(m, 3H), 1.22-1.08(m, 6H). LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

Compound 11D (retention time=1.471min): ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.25-8.17(m,1H),7.14-7.08(m,1H),7.08-6.99(m,2H),6.83 -6.66(m,2H),6.25-6.15(m,1H),5.77-5.69(m,1H),4.00-3.90(m,4H),3.87-3.74(m,4H),2.86-2.63(m, 1H), 2.06-1.94(m, 3H), 1.12-0.95(m, 6H). LCMS (ESI) m/z: 646.1 (M+1) ⁺ .

Example 12

Step 1: To a solution of compound A (600 mg) in THF (20 ml) were added PYBROP (2.29 g), DIEA (633.77 mg) and compound 3-1 (2.10 g). The reaction solution was reacted at 70° C. for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10μm), mobile phase: water (0.225% formic acid)-acetonitrile: 35%-65%, 20 minutes] to obtain compound 12-1. LCMS (ESI) m/z: 686.3. (M+1) ⁺ .

Second step: 12-1 (300 mg) was dissolved in a mixed solution of dichloromethane (3 ml) and trifluoroformic acid (1 ml). The reaction solution was reacted at 25° C. for 1 hour, and the reaction solution was concentrated to obtain the trifluoroacetic acid salt of crude compound 12-2, which was directly used in the next step. LCMS (ESI) m/z: 586.2. (M+1) ⁺ .

third step: Potassium carbonate (203.83 mg) was added to a mixed solution of compound 12-2 (400 mg) in tetrahydrofuran (4 ml) and water (1 ml), and after adjusting the pH to 8, compound 1-5 (44.50 mg) was added to the reaction solution. mg). React the reaction solution at 0°C for 15 minutes, add saturated aqueous sodium bicarbonate solution to the reaction solution, adjust the pH to 8, extract with ethyl acetate (10 ml*2), and wash the organic phase with saturated brine (5 ml*2) It was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi C18 (150*25mm*10 μm), mobile phase: water (0.1% formic acid)-acetonitrile: 25%-55%, 10 minutes] to obtain compound 12.

Compound 12 was separated by preparative SFC (column model: DAICEL CHIRALPAK AS-H (250mm*30mm, 5μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 4.7 minutes, 145 minutes) Compound 12A and Compound 12B were obtained.

Compound 12A and compound 12B were detected by SFC [column model: Chiralpak AS-3 50×4.6mm I.D, 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient ( B%): 5%-40%] Obtained: the residence time of compound 12A is 1.014min, e.e. value is 98.16%; the residence time of compound 12B is 1.104min, e.e. value is 99.28%.

Compound 12A (retention time=1.014min): ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.50-8.35(m,1H),7.20-7.12(m,1H),7.05-6.96(m,2H),6.68- 6.49(m,3H),6.46-6.34(m,1H),5.86-5.77(m,1H),5.16-4.78(m,2H),4.52-4.32(m,1H),4.29-4.13(m,1H ),3.98-3.85(m,2H),3.81-3.64(m,2H),2.85-2.68(m,1H),2.17-2.10(m,3H),1.49-1.40(m,6H),1.26(br s,3H), 1.18(br d, J =2.0Hz,3H). LCMS (ESI) m/z: 640.3. (M+1) ⁺ .

Compound 12B (retention time=1.104min): 1H NMR (400MHz, CHLOROFORM- d )δ 1.11(br s,3H),1.20-1.24(m,3H),1.29-1.37(m,3H),1.43-1.46( m,3H),2.02-2.18(m,3H),2.65-2.73(m,1H),3.46-3.54(m,1H),3.60-3.65(m,2H),3.69-3.78(m,1H), 3.82-3.95(m,2H),4.37-4.58(m,1H),4.98-5.13(m,1H),5.77-5.87(m,1H),6.36-6.46(m,1H),6.54-6.59(m ,2H), 6.91-7.09(m,2H), 7.14-7.22(m,1H), 7.34-7.56(m,1H), 8.34-8.54(m,1H). LCMS (ESI) m/z: 640.3. (M+1) ⁺ .

Example 13

The first step: Add p-toluenesulfonic acid (526.94 mg) and N-chlorosuccinimide (544.81 mg) successively to intermediate A (1 gram) in acetonitrile (15 milliliters) solution, under nitrogen protection, The reaction solution was reacted at 60° C. for 1 hour. Add saturated aqueous sodium sulfite (10 ml) to the reaction solution, extract with ethyl acetate (20 ml*3), wash the organic phase with saturated brine (20 ml), dry over anhydrous sodium sulfate and filter, and concentrate the filtrate to obtain compound 13-1. LCMS (ESI) m/z: 558.0 (M+1) ⁺ .

The second step: DIEA (770.86 mg), PyBrOP (3.71 g) and compound 1-1 (2.96 g) were added to a solution of compound 13-1 (1.11 g) in tetrahydrofuran (20 ml), and the reaction solution was reacted at 70 degrees Celsius 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-2. LCMS (ESI) m/z: 726.1 (M+1) ⁺ .

Step 3: To a solution of compound 13-2 (2.3 g) in ethyl acetate (10 ml) was added a solution of ethyl acetate hydrochloride (4 mol/L, 10 ml), and the reaction solution was reacted at 15°C for 1 hour. The reaction solution was filtered, and the filter cake was dissolved in ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL), and the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-3. LCMS (ESI) m/z: 626.2 (M+1) ⁺ .

the fourth step: DIEA (165.05 mg) and HATU (242.79 mg) were sequentially added to a solution of compound 13-4 (28.75 mg) in N,N-dimethylformamide (5 mL), and the reaction solution was reacted at 15°C for 30 minutes. Then compound 13-3 was added, and the reaction was continued for 1 hour at 15°C. The reaction solution was poured into water (20 ml), extracted with ethyl acetate (20 ml*3), the organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue Compound 13 was purified by preparative HPLC (column model: Phenomenex luna C18 150*25mm*10 μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 34%-64%, 2 minutes).

Compound 13 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 50%-50%, 2.5 minutes; 430 minutes) separation and purification Compound 13A (retention time = 0.649 min) and compound 13B (retention time = 1.218 min).

Compound 13A and compound 13B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B% ): 40%-40%] obtained: the residence time of compound 13A was 0.649min, and the ee value was 100%; the residence time of compound 13B was 1.218min, and the ee value was 100%. Compound 13A (retention time = 0.649 min): LCMS (ESI) m/z: 698.1 (M+1) ⁺ .

Compound 13B (retention time = 1.218 min): LCMS (ESI) m/z: 698.1 (M+1) ⁺ .

Example 14

The first step: at 10-20 degrees Celsius, add triethylamine (30.79 grams) and compound 7-2 (43.73 grams) successively in the dichloromethane (500 milliliters) solution of compound 14-1 (50 grams), react The solution was reacted at 10-20 degrees Celsius for 12 hours. Water (500 ml) was added to the reaction solution, and the reaction solution was separated into layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 1:1) to obtain compound 14-2. LCMS m/z (ESI): 257.0 (M+1) ⁺ .

Step 2: Add wet palladium carbon (5 g, purity: 10%) to a solution of compound 14-2 (50 g) in methanol (500 ml) under the protection of nitrogen, and replace with nitrogen and hydrogen three times respectively. The reaction mixture was reacted under a hydrogen atmosphere (1 atm) at 50°C for 20 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 1:1) to obtain compound 14-3. LCMS m/z (ESI): 209.0 (M+1-18) ⁺ .

Step 3: Add triethylamine (8.95 g) to a solution of compound 14-3 (20 g) in acetonitrile (200 ml), and add acetyl chloride (10.41 g) dropwise to the reaction solution at 15-20°C , the reaction was carried out at 20°C for 2 hours. Saturated brine (200 mL) was added to the reaction mixture, followed by extraction three times with ethyl acetate (200 mL*3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product of compound 14-4, which was directly used in the next reaction. LCMS m/z (ESI): 269.0 (M+1) ⁺ .

Step 4: Add cesium carbonate (26.72 g) and compound 7-4 (16.55 g) sequentially to a solution of compound 14-4 (22 g) in acetonitrile (220 ml), and react at 20°C for 4 hours. Saturated brine (200 ml) was added to the reaction mixture, extracted twice with ethyl acetate (200 ml*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 14-5, which was directly for the next reaction. LCMS m/z (ESI): 390.9 (M+1) ⁺ .

Step 5: Triethylamine (19.70 g) was added to a solution of compound 14-5 (38 g) in trifluoroethanol (300 ml), and the reaction was carried out at 100° C. for 12 hours. The reaction solution was concentrated to obtain a residue, and the residue was dissolved with saturated brine (100 ml), then saturated brine (200 ml) was added to the reaction mixture, and the pH value of the system was adjusted to 2 with 1 mole per liter of hydrochloric acid solution. , and extracted three times with ethyl acetate (200 ml*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 14-6, which was directly used in the next reaction. LCMS m/z (ESI): 359.0 (M+1) ⁺ .

Step 6: Potassium phosphate (26.02 g) and tribromopyridinium salt (58.81 g) were successively added to a solution of compound 14-6 (24 g) in acetonitrile (250 ml), and the reaction was carried out at 50° C. for 2 hours. Add saturated aqueous sodium sulfite (200 ml) to the reaction mixture, adjust the pH of the system to 2 with 1 mole per liter of hydrochloric acid solution, then extract twice with ethyl acetate (200 ml*2), and use saturated salt for the organic phase Washed once with water (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue, the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain compound 14 -7. LCMS m/z (ESI): 393.0 (M+1) ⁺ .

Step 7: Add compound 6-4 (4.20 g), potassium carbonate (7.03 g), 4,5-bis-diphenyl Phosphine-9,9-dimethylxanthene (2.94 g) and tris(dibenzylideneacetone) dipalladium (2.33 g), the reaction was carried out at 100° C. for 6 hours under the protection of nitrogen. The reaction mixture was filtered through celite, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=3:1 to 1:1) to obtain compound 14-8. LCMS m/z (ESI): 463.2 (M+1) ⁺ .

Step 8: Add N-bromosuccinimide (2.77 g) to a solution of compound 14-8 (5.90 g) in dichloromethane (60 ml), and react for 1 hour at 10°C under nitrogen protection . Saturated aqueous sodium sulfite (10 mL) was added to the reaction solution, and extracted twice with dichloromethane (5 mL*2). The organic phase was washed once with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-9. LCMS m/z (ESI): 541.0 (M+1) ⁺ .

Step 9: Add zinc powder (773.08 mg), zinc cyanide (1.74 g), and zinc bromide to a solution of compound 14-9 (8.00 g) in N,N-dimethylformamide (80 ml) in sequence (332.80 mg), 1,1-bis(diphenylphosphino)ferrocene (1.64 g) and tris(dibenzylideneacetone) dipalladium (1.35 g), the reaction was carried out at 120°C under nitrogen protection 2 hours. The reaction mixture was filtered through celite, the filtrate was added dropwise to water (300 mL), and extracted twice with ethyl acetate (100 mL*2). The organic phase was concentrated to give a residue. The residue was dissolved in a mixed solvent of water (100 ml) and ethyl acetate (100 ml), and the pH of the system was adjusted to 2 with 1 mole per liter of hydrochloric acid solution, then the layers were separated, and the aqueous phase was adjusted with saturated aqueous sodium bicarbonate solution. The pH was brought to 8, extracted three times with ethyl acetate (50 ml*3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue 14-10. LCMS m/z (ESI): 487.9 (M+1) ⁺ .

Step 10: Compound 14-10 (2.5 g) was added into a reaction flask filled with concentrated sulfuric acid (13 ml), and the reaction was carried out at 60° C. for 10 hours under the protection of nitrogen. The reaction solution was added dropwise to water (130 mL), the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate (30 mL*3). The organic phase was washed once with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-11. LCMS m/z (ESI): 464.2 (M+1) ⁺ .

Eleventh step:

Add carbonyldiimidazole (1.68 g) and sodium hydride (552.35 mg, mass percent: 60%) successively to compound 14-11 (1.6 g) in tetrahydrofuran (20 ml) solution, the reaction is under nitrogen protection, 20 degrees Celsius reaction 1 hour. The reaction solution was added dropwise to water (100 milliliters), the pH of the system was adjusted to 2 with 1 mole of aqueous hydrochloric acid, and then the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate, and ethyl acetate (50 milliliters *2) Extracted twice. The organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-12. LCMS m/z (ESI): 490.0 (M+1) ⁺ .

Compound 14-12 (racemate) was prepared by HPLC (column type: Phenomenex luna C18 (250*70mm, 15μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 40%-70%, 35 minutes) and then purified by preparative SFC (column type: REGIS (s, s) WHELK-O1 (250mm*50mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50 %, 4.4 minutes, 90 minutes) separation and purification to obtain compound 14-12A (retention time = 1.348min) and 14-12M (a mixture of 14-12B, 14-12C and 14-12D).

Step twelve:

To a solution of 14-12M (1.70 g) in tetrahydrofuran (30 ml) was added successively tripyrrolidinylphosphonium bromide hexafluorophosphate (2.94 g), compound 1-1 (2.03 g) and DIEA (0.81 g), the The reaction was carried out at 70° C. for 10 hours under nitrogen protection. LC-MS detected that the target product had been formed. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The obtained residue was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 (250*70mm, 15 μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 40%-70%, 35 minutes) to obtain 14 - 13M (mixture of 14-13B, 14-13C and 14-13D). LCMS m/z (ESI): 686.3 (M+1) ⁺ .

14-13A was synthesized from 14-12A according to the preparation method of 14-13M.

Step Thirteen:

To a 14-13M (920 mg) solution in dichloromethane (6 ml) was added trifluoroacetic acid (3.08 g), and the reaction was carried out at 15°C for 1 hour under nitrogen protection. The reaction liquid was concentrated under reduced pressure to obtain 14-14M (the mixture of 14-14B, 14-14C and 14-14D) trifluoroacetate crude product, 14-14M trifluoroacetate salt, the crude product was directly used in the next reaction. LCMS m/z (ESI): 586.1 (M+1) ⁺ .

14-14A was synthesized from 14-13A according to the preparation method of 14-14M.

Step fourteen:

Potassium carbonate (0.66 g) and compound 1-5 (130.33 mg) were added successively to a mixed solution of compound 14-14M (1.3 g, trifluoroacetate) in tetrahydrofuran (20 ml) and water (4 ml), and the reaction React at 15°C for 10 minutes. Saturated brine (20 mL) was added to the reaction mixture, extracted twice with ethyl acetate (30 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 15%-45%, 20 minutes) to obtain 14M (mixture of 14B, 14C and 14D).

14A was synthesized from 14-14A according to the preparation method of 14M.

14M was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 4 minutes, 75 minutes) separation and purification Compound 14B (retention time = 2.084 min) and 14-P (mixture of retention time = 1.937 min and retention time = 2.093 min).

14-P was then passed through preparative SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide Critical fluid 35%-35%, 3 minutes, 90 minutes) were separated and purified to obtain compound 14C (retention time = 1.387min) and compound 14D (retention time = 1.910min).

Compound 14B was detected by SFC [column model: Chiralpak IG-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] to obtain: the retention time of compound 14B was 2.084min, and the e.e. value was 100%.

Compound 14C and compound 14D were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B% ): 40%-40%] Obtained: the residence time of compound 14C is 1.387min, and the e.e. value is 100%; the residence time of compound 14D is 1.910min, and the e.e. value is 100%.

Compound 14A: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.34(d, J =4.8Hz, 1H), 7.23-7.02(m, 3H), 6.98-6.81(m, 2H), 6.55(dt, J =5.6,8.0Hz,1H),6.33-6.19(m,1H),5.82(ddd, J =2.1,7.3,9.9Hz,1H),5.42(s,2H),4.85-4.48(m,2H), 4.13-3.54(m,4H),2.95-2.79(m,1H),2.05(s,3H),1.46-1.34(m,3H),1.31-1.21(m,3H),1.14-1.02(m,6H ). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

Compound 14B (retention time=2.084min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.29(d, J =4.9Hz, 1H), 7.13-7.05(m, 2H), 7.00(s, 1H), 6.84(td, J =10.7,16.6Hz,1H),6.67(br d, J =7.9Hz,1H),6.50(dt, J =5.5,8.1Hz,1H),6.27-6.15(m,1H), 5.82-5.71(m,1H),5.43(s,2H),4.84-4.47(m,2H),4.20-3.71(m,4H),2.72(td, J =6.9,13.4Hz,1H),2.03( d, J =3.8Hz, 3H), 1.33(br t, J =6.8Hz, 3H), 1.27-1.14(m, 3H), 1.05(br d, J =6.6Hz, 3H), 0.96(d, J =6.5Hz, 3H). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

Compound 14C (retention time=1.387min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.29(d, J =4.8Hz, 1H), 7.19-6.96(m, 3H), 6.93-6.77(m, 1H ),6.70(br d, J =8.1Hz,1H),6.49(dt, J =5.5,8.1Hz,1H),6.27-6.13(m,1H),5.81-5.70(m,1H),5.38(s , 2H),4.81-4.43(m,2H),4.16-3.45(m,4H),2.59(quin, J =6.7Hz,1H),2.12(s,3H),1.33(br t, J =6.1Hz ,3H), 1.26-1.11(m,3H),0.98(dd, J =6.8,10.1Hz,6H). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

Compound 14D (retention time=1.910min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.28(d, J =4.9Hz, 1H), 7.13-6.95(m, 3H), 6.88-6.77(m, 2H ),6.48(dt, J =5.6,8.0Hz,1H),6.19(dd, J =2.4,16.4Hz,1H),5.81-5.70(m,1H),5.36(s,2H),4.82-4.44( m,2H),4.16-3.42(m,4H),3.09-2.92(m,1H),1.90(d, J =2.4Hz,3H),1.32(br t, J =6.3Hz,3H),1.25- 1.14(m,3H),1.07(br dd, J =6.5,15.7Hz,6H). LCMS (ESI) m/z: 640.3 (M+1) ⁺ .

Example 15

The first step: In the tetrahydrofuran (10 milliliters) solution of compound 11-12 (400 mg), add tripyrrolidinyl phosphonium bromide hexafluorophosphate (1.01 g), compound 3-2 (930.74 mg) and DIEA ( 280.66 mg), the reaction was reacted at 70 degrees Celsius for 10 hours under nitrogen protection. LC-MS detected that the target product had been formed. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound 15-1. The obtained crude product was directly used in the next reaction. LCMS m/z (ESI): 720.3 (M+1) ⁺ .

Step 2: Trifluoroacetic acid (1.54 g) was added to a solution of compound 15-1 (500 mg) in dichloromethane (3 ml), and the reaction was carried out at 10° C. for 20 minutes under nitrogen protection. The reaction solution was concentrated to obtain the trifluoroacetic acid salt of compound 15-2, and the crude product was directly used in the next reaction. LCMS m/z (ESI): 620.2 (M+1) ⁺ .

third step:

Add potassium carbonate (293.34 mg) and compound 1-5 (64.03 mg) successively to compound 15-2 (600.00 mg, trifluoroacetate) in tetrahydrofuran (6 ml) and water (2 ml) mixed solution, the reaction is React for 10 minutes at 10°C. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and extracted three times with ethyl acetate (30 mL*3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative plate (dichloromethane:methanol=20:1). Compound 15 was obtained.

Compound 15 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC 250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 55%-55%, 38 minutes, 40 minutes) to obtain the compound 15A and 15-P1.

15-P1 was then prepared by SFC (REGIS(S,S)WHELK-O1 250mm*25mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.3 minutes, 570 minutes ) separation and purification to obtain compound 15B (and 15-P2.

15-P2 is then prepared by SFC (column model: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 35%-35%, 4.1 minutes, 50 minutes ) separation and purification to obtain compound 15C and compound 15D.

Compound 15A was detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 40 %-40%] to obtain: the retention time of compound 15A was 0.760min, and the e.e. value was 100%.

Compound 15B, compound 15C and compound 15D were detected by SFC [column type: (s,s) Whelk-OI 100×4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethyl amine); Gradient (B%): 40%-40%] to obtain: the retention time of compound 15B is 2.255min, and the e.e. value is 100%; the retention time of compound 15C is 2.641min, and the e.e. value is 100%; The residence time is 2.503min, and the e.e. value is 100%.

Compound 15A (retention time=0.760min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.29(d, J =4.8Hz,1H),7.30(dd, J =2.2,11.0Hz,1H),7.10- 7.03(m,1H),6.99(s,1H),6.89-6.75(m,2H),6.19(br d, J =16.5Hz,1H),5.83-5.70(m,1H),5.66(s,2H ),4.84-4.47(m,2H),4.20-3.64(m,4H),2.74(td, J =3.3,6.4Hz,1H),2.01(br d, J =4.0Hz,3H),1.33(br t, J =6.7Hz, 3H), 1.25-1.15(m, 3H), 1.04(br d, J =6.4Hz, 3H), 0.96(br d, J =6.5Hz, 3H). LCMS (ESI) m/z: 674.3 (M+1) ⁺ .

Compound 15B (retention time=2.255min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(d, J =4.9Hz,1H),7.30(dd, J =2.2,10.9Hz,1H),7.14- 7.06(m,1H),7.03(s,1H),6.92(s,1H),6.88-6.73(m,1H),6.26-6.15(m,1H),5.81-5.71(m,1H),5.62 ( s,2H),4.82-4.45(m,2H),4.10-3.76(m,4H),3.55-3.46(m,1H),2.16-2.06(m,3H),1.33(br t, J =6.0Hz ,3H),1.24-1.12(m,3H),0.98(br d, J =6.6Hz,6H). LCMS (ESI) m/z: 674.2 (M+1) ⁺ .

Compound 15C (retention time=2.641min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(d, J =4.8Hz,1H),7.28(dd, J =2.3,11.0Hz,1H),7.07- 7.02(m,2H),7.01(s,1H),6.84(ddd, J =5.6,10.6,16.5Hz,1H),6.20(br dd, J =2.1,16.6Hz,1H),5.76(ddd, J =2.2,7.4,10.0Hz,1H),5.60(s,2H),4.81-4.45(m,2H),4.17-3.68(m,4H),2.99(td, J =6.4,13.1Hz,1H), 1.91(d, J =2.5Hz, 3H), 1.36-1.29(m, 3H), 1.22-1.13(m, 3H), 1.10-1.08(m, 3H), 1.05(s, 3H). LCMS (ESI) m/z: 674.2 (M+1) ⁺ .

Compound 15D (retention time=2.503min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(d, J =4.8Hz,1H),7.28(dd, J =2.3,11.0Hz,1H),7.07- 7.02(m,2H),7.01(s,1H),6.84(ddd, J =5.6,10.6,16.5Hz,1H),6.20(br dd, J =2.1,16.6Hz,1H),5.76(ddd, J =2.2,7.4,10.0Hz,1H),5.60(s,2H),4.81-4.45(m,2H),4.17-3.75(m,4H),2.99(td, J =6.4,13.1Hz,1H), 1.91(d, J =2.5Hz, 3H), 1.39-1.29(m, 3H), 1.23-1.13(m, 3H), 1.10-1.07(m, 3H), 1.05(s, 3H). LCMS (ESI) m/z: 674.2 (M+1) ⁺ .

Example 16 and Example 17

first step:

To intermediate A (1.00 g) in N,N-dimethylacetamide (10 ml) solution, add tripyrrolidinylphosphonium bromide hexafluorophosphate (1.91 g), compound 3-1 (1.75 g ) and DIEA (0.53 g), the reaction was reacted at 70 degrees Celsius for 10 hours under nitrogen protection. The reaction solution was poured into water (30 ml), a solid precipitated out, filtered, and the filter cake was dried to obtain a crude product. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 30%-50%, 35 minutes) to obtain a racemate. The racemate was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.4 minutes, 45 minutes) Compound 16-1A (retention time=0.615 min) and compound 16-1B (retention time=1.066 min) were obtained.

Compound 16-1A (retention time = 0.615 min): LCMS m/z (ESI): 686.3 (M+1)+.

Compound 16-1B (retention time = 1.910 min): LCMS m/z (ESI): 686.3 (M+1)+.

Step two:

To a solution of compounds 16-1A and 16-1B (280 mg) in acetonitrile (10 ml), N-chlorosuccinimide (52.86 mg) and p-toluenesulfonic acid (68.17 mg) were added successively, the The reaction was carried out at 60° C. for 1 hour under the protection of nitrogen. Saturated aqueous sodium sulfite solution (20 mL) was added to the reaction solution, and extracted twice with ethyl acetate (30 mL*2). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a residue. The residue was purified on a silica gel plate (petroleum ether: ethyl acetate: methanol = 8:3:1) to obtain compound 16-2A, compound 17-1A, compound 16-2B and compound 17-1B, respectively.

16-2A and 16-2B: LCMS m/z (ESI): 720.3 (M+1) ⁺ .

17-1A and 17-1B: LCMS m/z (ESI): 720.1 (M+1) ⁺ .

Compound 16-2A: ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.37(d, J =4.9Hz, 1H), 7.24-7.18(m, 1H), 6.96-6.88(m, 2H), 6.42(t, J =8.9Hz,1H),4.83-4.62(m,1H),4.58-4.29(m,1H),3.97-3.84(m,1H),3.78-3.71(m,1H),3.48(br d, J =13.5Hz,1H),2.63-2.57(m,1H),2.01(s,3H),1.44(s,9H),1.36(br d, J =6.5Hz,3H),1.21-1.19(m,3H ), 1.12(d, J =6.6Hz, 3H), 1.02(d, J =6.8Hz, 3H).

third step:

Add trifluoroacetic acid (770.00 mg) to a solution of compound 16-2A, compound 17-1A, compound 16-2B and compound 17-1B (90 mg) in dichloromethane (1.5 ml) respectively, and the reaction is under nitrogen protection , 10 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 16-3A, the trifluoroacetate salt of compound 17-2A, the trifluoroacetate salt of compound 16-3B and the trifluoroacetate salt of compound 17-2B, and the crude product was directly used in Next reaction.

16-3A and 16-3B: LCMS m/z (ESI): 620.3 (M+1) ⁺ .

17-2A and 17-2B: LCMS m/z (ESI): 620.0 (M+1) ⁺ .

the fourth step:

Potassium carbonate ( 49.38 mg) and compound 1-5 (10.78 mg), the reaction was carried out at 10 degrees Celsius for 20 minutes. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and extracted three times with ethyl acetate (20 mL*3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The resulting residues were Example 16A, 16B, 17A and 17B.

Compound 16A: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(d, J =4.9Hz, 1H), 7.35(dd, J =5.8, 8.9Hz, 1H), 7.12-7.00(m, 2H), 6.92-6.72(m,1H),6.46(t, J =9.1Hz,1H),6.20(br d, J =16.6Hz,1H),6.00(s,2H),5.81-5.67(m,1H), 4.85-4.46(m,2H),4.21-3.66(m,4H),2.72-2.60(m,1H),2.03(d, J =3.4Hz,3H),1.33(t, J =7.4Hz,3H) ,1.28-1.17(m,3H),1.07-1.00(m,3H),0.93(d, J =6.6Hz,3H). LCMS m/z (ESI): 674.2 (M+1) ⁺ .

Compound 16B: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(br d, J =4.5Hz,1H),7.35(br dd, J =5.8,8.3Hz,1H),7.06(br s,2H) ,6.92-6.75(m,1H),6.46(br t, J =8.9Hz,1H),6.19(br d, J =16.5Hz,1H),5.97(br s,2H),5.83-5.66(m, 1H),4.834.44(m,2H),4.18-3.66(m,4H),2.90-2.73(m,1H),1.92(br s,3H),1.33(br t, J =6.4Hz,3H) ,1.28-1.13(m,3H),1.03(br d, J =5.8Hz,6H). LCMS m/z (ESI): 674.2 (M+1) ⁺ .

Compound 17A: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.31(d, J =4.8Hz, 1H), 7.26(t, J =8.7Hz, 1H), 7.11-7.02(m, 2H), 6.83( td, J =10.9,16.5Hz,1H),6.52(dd, J =1.3,9.2Hz,1H),6.26-6.14(m,1H),5.89(s,2H),5.75(ddd, J =2.3, 6.1,10.3Hz,1H),4.85-4.45(m,2H),4.21-3.40(m,4H),2.73-2.61(m,1H),2.01(d, J =3.5Hz,3H),1.37-1.28 (m,3H),1.27-1.15(m,3H),1.04(d, J =6.6Hz,3H),0.95(d, J =6.6Hz,3H). LCMS m/z (ESI): 674.3 (M+1) ⁺ .

Compound 17B: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(d, J =4.9Hz, 1H), 7.25(t, J =8.7Hz, 1H), 7.11-7.04(m, 2H), 6.83( td, J =9.7,16.6Hz,1H),6.52(dd, J =1.2,9.2Hz,1H),6.25-6.14(m,1H),5.88(s,2H),5.80-5.70(m,1H) , 4.82-4.43(m,2H),4.14-3.47(m,4H),2.78(qd, J =6.6,13.3Hz,1H),1.95(s,3H),1.37-1.29(m,3H),1.24 -1.14(m,3H),1.03-0.97(m,6H). LCMS m/z (ESI): 674.3 (M+1) ⁺ .

Example 18

Step 1: Potassium carbonate (1.59 g) and compound 7-2 (4.71 g) were added at one time to a solution of compound 18-1 (5 g) in acetonitrile (50 ml) at 0°C. The reaction solution was reacted at 25-30 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-2. LCMS (ESI) m/z: 275.04 (M+1) ⁺ .

Step 2: Add cesium carbonate (5.94 g) and 4-ethoxy-1,1,1,-tri Fluoro-3-buten-2-one (3.22 g). The reaction solution was reacted at 25-30 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-3. LCMS (ESI) m/z: 397.04 (M+1) ⁺ .

Step 3: To a solution of compound 18-3 (5 g) in trifluoroethanol (50 ml) was added triethylamine (2.55 g) in one portion at 20-30°C. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was diluted with water (50 ml) and then adjusted to pH 8 by adding sodium hydroxide (4 mol/L), extracted with ethyl acetate (20 ml*3), and the combined aqueous phases were washed with hydrochloric acid (1 M ear/liter) to adjust the pH to 3, then extracted with ethyl acetate (20 ml*3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate to obtain compound 18-4. LCMS (ESI) m/z: 365.01 (M+1) ⁺ .

Step 4: To a solution of compound 18-4 (2 g) in acetonitrile (20 ml) was added tribromopyridine (3.51 g) and potassium phosphate (1.40 g) in one go at 0°C. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was diluted with water (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-5. LCMS (ESI) m/z: 398.93 (M+1) ⁺ .

Step 5: Add cesium carbonate (5.72 g) and 4,5-bisdiphenylphosphine all at once to a solution of compound 18-5 (3.5 g) in dioxane (35 ml) at 20-30°C -9,9-dimethylxanthene (507.48 mg), tris(dibenzylideneacetone) dipalladium (401.56 mg) and 2-isopropyl-4-methylpyridin-3-amine (1.58 g ). The reaction solution was reacted at 100 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was diluted with water (20 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-6. LCMS (ESI) m/z: 469.12 (M+1) ⁺ .

Step 6: To a solution of compound 18-6 (275 mg) in dichloromethane (5 mL) was added N-bromosuccinimide (125.4 mg) in one portion at 0°C. The reaction solution was reacted at 25 degrees Celsius for 2 hours. Add saturated sodium sulfite aqueous solution to the reaction solution to quench the reaction, concentrate to obtain a residue, dilute with water (20 ml), extract with ethyl acetate (10 ml*3), combine organic phases and dry over anhydrous sodium sulfate, filter, and concentrate the filtrate Compound 18-7 was obtained. LCMS (ESI) m/z: 547.03 (M+1) ⁺ .

Step 7: At 20-30 degrees Celsius, add ammonium chloride (146.61 mg) and reduced iron in one go to the mixed solution (5 ml) of compound 18-7 (300 mg) in ethanol and water (5:1) Powder (153.06 mg. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was filtered and concentrated to obtain a residue, diluted with water (10 ml), extracted with ethyl acetate (10 ml*3), combined the organic phases, and washed with anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate to obtain compound 18-8. LCMS (ESI) m/z: 517.06 (M+1) ⁺ .

Step 8: At 20-30 degrees Celsius, add zinc powder (22.37 mg) and zinc cyanide to the solution of compound 18-8 (354 mg) in N,N-dimethylformamide (5 ml) at one time (64.29 mg), zinc bromide (7.71 mg), tris(dibenzylideneacetone)dipalladium (401.56 mg) and 1,1-bis(diphenylphosphine)palladium chloride (75.88 g). The reaction solution was reacted at 120 degrees Celsius for 12 hours. The reaction solution was filtered, washed with ethyl acetate three times (5 mL*3) and concentrated to obtain a residue, diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), and the organic phases were combined and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated to obtain compound 18-9. LCMS (ESI) m/z: 464.14 (M+1) ⁺ .

Step 9: Compound 18-9 (2 g) was directly dissolved in a solution of concentrated sulfuric acid (5 ml) at 20-30°C. The reaction solution was reacted at 60° C. for 12 hours. The reaction solution was directly added dropwise to ice water (10 ml) solution to quench the reaction, and after adjusting the pH to 8 with saturated aqueous sodium bicarbonate solution, extracted and concentrated with ethyl acetate (10 ml*3) to obtain a residue, combined the organic phases for Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 18-10. LCMS (ESI) m/z: 482.15 (M+1) ⁺ .

Step 10: At 0°C, carbonyldiimidazole (1.17 g) and sodium hydrogen (481.91 mg, mass percent: 60%) were added in one go to a solution of compound 18-10 (1.16 g) in tetrahydrofuran (12 ml). The reaction solution was reacted at 25 degrees Celsius for 2 hours. The reaction solution was quenched by adding saturated ammonium chloride aqueous solution, extracted and concentrated with ethyl acetate (10 ml*3) to obtain a residue, combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-11. LCMS (ESI) m/z: 508.13 (M+1) ⁺ .

Step 11: At 20-30°C, add tripyrrolidinyl phosphorus bromide hexafluorophosphate (1.10 g), diiso Propylethylamine (152.82 mg) and Compound 3-1 (633.54 mg). The reaction solution was reacted at 60° C. for 12 hours. The reaction solution was diluted with water (20 mL), extracted and concentrated with ethyl acetate (10 mL*3) to obtain a residue, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-12. LCMS (ESI) m/z: 704.29 (M+1) ⁺ .

Step 12: To a solution of compound 18-12 (245 mg) in dichloromethane (3 ml) was added trifluoroacetic acid (1.80 g) in one portion at 20-30°C. The reaction solution was reacted at 25° C. for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 18-13. LCMS (ESI) m/z: 604.24 (M+1) ⁺ . The crude product was used directly in the next step.

Step Thirteen:

At 0 degrees Celsius, anhydrous potassium carbonate (251.88 mg), acryloyl chloride (16.49 mg). The reaction solution was reacted at 0°C for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative column HPLC (column model: Phenomenex Synergi C18 150*25mm*10μm), mobile phase (0.225% formic acid water: acetonitrile), gradient: 21%-54%, 11 minutes, to obtain compound 18.

Compound 18 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 5 minutes, 40 minutes) Compounds 18A and 18-P1.

18-P1 was then prepared by SFC (column model: DAICEL CHIRALCELOD-H (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 30%-30%, 5 minutes, 40 minutes) separation and purification to obtain compound 18B, and 18-P2.

18-P2 was then prepared by SFC (column type: Kromasil (S, S) Whelk-O1 (250mm*30mm, 5μm), mobile phase: isopropanol (0.05% diethylamine), gradient: carbon dioxide critical fluid 40%- 40%, 5 minutes, 40 minutes) separation and purification to obtain compound 18C and compound 18D.

Compound 18A was detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] to obtain: the residence time of compound 18A was 1.952min, and the e.e. value was 100%.

Compound 18B was detected by SFC [column model: CHIRALPAK OD 50×4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5%- 40%] to obtain: the retention time of compound 18B was 1.471min, and the e.e. value was 100%.

Compound 18C and compound 18D were detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B% ): 40%-40%] Obtained: the residence time of compound 18C is 1.900min, and the ee value is 100%; the residence time of compound 18D is 2.322min, and the ee value is 100%. Compound 18A: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.31-8.31(m,1H),7.06-7.03(m,2H),6.85-6.78(m,1H),6.38-6.19(m,3H) ,6.21-6.03(m,2H),6.17-5.13(m,1H),4.79-4.52(m,2H),3.93-3.92(m,3H),3.46-3.39(m,1H),3.25-3.24( m, 1H), 2.00-2.00(m, 3H), 1.34-1.31(m, 3H), 1.25-1.16(m, 3H), 1.05-1.03(m, 3H), 0.95-0.93(m, 3H). LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

Compound 18B: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.32-8.30(m,1H),7.09-7.08(m,2H),6.84-6.77(m,1H),6.35-6.15(m,3H) ,6.02-5.99(m,2H),5.770-5.716(m,1H),4.74-4.46(m,2H),3.96-3.73(m,3H),3.46-3.43(m,1H),3.26-3.23( m, 1H), 2.09(m, 3H), 1.34-1.15(m, 6H), 0.90-0.91(m, 6H). LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

Compound 18C: 1H NMR (400MHz, DMSO- d ₆ )δ 8.30-8.29(m,1H),7.07-7.02(m,2H),6.85-6.78(m,1H),6.34-6.16(m,3H), 6.01(m,2H),5.77-5.72(m,1H),4.74-4.48(m,2H),4.00-3.76(m,3H),3.48-3.45(m,1H),3.43-3.42(m,1H ), 1.85(m,3H), 1.32-1.14(m,6H), 1.08-1.00(m,6H). LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

Compound 18D: 1H NMR (400MHz, DMSO- d ₆ )δ 8.31-8.29(m,1H),7.07-7.02(m,2H),6.85-6.78(m,1H),6.34-6.16(m,3H), 6.01(m,2H),5.77-5.72(m,1H),4.74-4.48(m,2H),4.01-3.76(m,3H),3.48-3.45(m,1H),3.43-3.42(m,1H ), 1.85(m,3H), 1.32-1.14(m,6H), 1.08-1.02(m,6H). LCMS (ESI) m/z: 658.2 (M+1) ⁺ .

Example 19

The first step: at 20-30 degrees Celsius, add triethylamine (10.7 grams) and methyl malonate chloride (78.04 grams ), the reaction solution was reacted for 16 hours at 20-30 degrees Celsius. Citric acid was added to the reaction solution to pH=6-7, the reaction solution was separated, the aqueous phase was extracted with dichloromethane (50 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-2. LCMS (ESI) m/z: 274.9 (M+1) ⁺ .

Step two: Raney-Ni (1.4 g) was added to a solution of compound 19-2 (14 g) in methanol (150 ml) at 20-30 °C, and the reaction solution was reacted at 25 °C under a hydrogen atmosphere of 15 Psi for 8 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 3:1) to obtain compound 19-3. LCMS (ESI) m/z: 245.0 (M+1)+.

The third step: at 0 degrees Celsius, add pyridine solution (5.18 grams) to compound 19-3 (8 grams) in acetonitrile (100 milliliters) and the solution, and add acetyl chloride (3.09 grams) dropwise, and the reaction solution is in React at 15°C for 16 hours. Water (100 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-4. ¹ H NMR(400MHz,DMSO-d6)δ 9.69(s,1H),9.25(s,1H),7.70(br d,J=11.0Hz,1H),7.19-6.97(m,1H),3.67(s ,3H), 3.62(s,2H), 2.07(s,3H). LCMS (ESI) m/z: 287.1 (M+1)+.

The fourth step: at 20-30 degrees Celsius, cesium carbonate (10.24 mg), 4-ethoxy-1,1,1-tri The reaction solution of fluoro-3-buten-2-one (5.81 g) was reacted at 20-30 degrees Celsius for 3 hours. Water (100 ml) was added to the reaction solution, and then extracted with ethyl acetate (50 ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-5. LCMS (ESI) m/z: 409.0 (M+1) ⁺ .

Step 5: To a solution of compound 19-5 (15 g) in trifluoroethanol (150 ml) was added triethylamine (7.44 g) at 20-30°C. The reaction solution was reacted at 100° C. for 12 hours. Add aqueous sodium bicarbonate solution to the reaction solution to adjust the pH to about 8, then extract with ethyl acetate (50 ml*2), adjust the pH to about 2 with 0.1 mol/liter of dilute hydrochloric acid in the aqueous phase, and use ethyl acetate ( 50 ml*2) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-6. LCMS (ESI) m/z: 377.1 (M+1) ⁺ .

Step 6: Potassium phosphate (12.19 g) and tribromopyridine (24.48 g) were sequentially added to a solution of compound 19-6 (7.2 g) in acetonitrile (80 ml) at 20-30°C. The reaction solution was reacted at 50° C. for 2 hours under the protection of nitrogen. Sodium sulfite solution (100 ml) was added to the reaction solution, followed by extraction with ethyl acetate (50 ml*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-7. LCMS (ESI) m/z: 412.9 (M+3) ⁺ .

Step 7: Add 2-isopropyl-4-methylpyridin-3-amine (8 g), tris(dibenzylideneacetone)dipalladium (1.78 g), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.669 g), cesium carbonate (12.68 g). The reaction solution was reacted at 100° C. for 16 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-8. LCMS (ESI) m/z: 481.1 (M+1) ⁺ .

Step 8: To a solution of compound 19-8 (4 g) in dichloromethane (50 ml) was added N-bromosuccinimide (1.48 g) in one portion at 0°C. The reaction solution was reacted at 20 degrees Celsius for one hour. Sodium sulfite solution (50 ml) was added to the reaction solution, followed by extraction with dichloromethane (20 ml*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 19-9. LCMS (ESI) m/z: 558.9 (M+1) ⁺ .

Step 9: At 60°C, add zinc powder (526.09 mg) and zinc cyanide to the solution of compound 19-9 (4 g) in N,N-dimethylformamide (40 ml) and (1.89 g), zinc bromide (362.36 mg), 1,1-bis(diphenylphosphino)ferrocene (892.04 mg) and tris(dibenzylideneacetone)dipalladium (736.73 mg). The reaction solution was reacted at 120 degrees Celsius for 3 hours. The reaction solution was filtered, diluted with ethyl acetate (100 mL), washed with water (50 mL*3) and saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-10. LCMS (ESI) m/z: 506.0 (M+1) ⁺ .

Step 10: Compound 19-10 (4 g) was reacted with concentrated sulfuric acid (20 ml) at 60°C for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate (50 ml), extracted with ethyl acetate (20 ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-11. LCMS (ESI) m/z: 481.9 (M+1) ⁺ .

Step 11: Add 1,1-carbonyldiimidazole (2.83 g) to compound 19-11 (2.8 g) in tetrahydrofuran (30 ml) at 0°C, and react at 0°C for 0.3 Hour, then add sodium hydride (697.87 mg, mass percent: 60%) in one go. The reaction solution was reacted at 0-25 degrees Celsius for 0.7 hours. The reaction solution was added to water (100 ml), adjusted to pH=3-4 with 0.1 mol/L dilute hydrochloric acid (30 ml), then adjusted to pH=7-8 with saturated aqueous sodium bicarbonate (50 ml) , extracted with ethyl acetate (30 ml*3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate to obtain the residual compound 19-12. LCMS (ESI) m/z: 508.2 (M+1) ⁺ .

Step twelve:

To a solution of compound 19-12 (1 g) in tetrahydrofuran (15 ml) were added PYBROP (1.84 g), DIEA (764.11 mg) and compound 3-1 (1.06 g). The reaction solution was reacted at 70° C. for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi Max-RP (250*50mm*10μm), mobile phase: water (0.225% formic acid)-acetonitrile: 30%-60%, 22 minutes] to obtain compound 19-13. LCMS (ESI) m/z: 704.4 (M+1) ⁺ .

Compound 19-13 was prepared by SFC (column model: REGIS (R, R) WHELK-O1 (250mm*25mm, 10μm), mobile phase: isopropanol (0.1% ammonia isopropanol), gradient: carbon dioxide critical fluid 50% -50%, 4.5 minutes, 90 minutes) separation and purification to obtain compound 19-14A (retention time = 1.098min), and 19-14M (retention time = 1.869min, which is a mixture of 19-14B, 19-14C and 19-14D ).

Step Thirteen:

To a solution of compound 19-14A (460 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) in one portion at 10-25 °C. The reaction solution reacts at 10-25 degrees Celsius for 0.5 Hour. The reaction solution was concentrated to obtain the trifluoroacetic acid salt of compound 19-15A, and the crude product was directly used in the next step.

To a 19-14M (420 mg) solution in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) in one portion at 10-25 °C. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetic acid salt of compound 19-15M (a mixture of 19-15B, 19-15C and 19-15D), and the crude product was directly used in the next step.

Step Fourteen: At 0°C, anhydrous potassium carbonate (74.79 mg), acryloyl chloride (16.32 mg). The reaction solution was reacted at 0°C for 0.25 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by preparative SFC (column model: Phenomenex Gemini-NX C18 (75mm*30mm, 3 μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: carbon dioxide critical fluid 20%-50%, 5 minutes) Compound 19A was obtained.

At 0°C, anhydrous potassium carbonate (224.36 mg), acryloyl chloride (48.97 mg). The reaction solution was reacted at 0°C for 0.25 hours. Water (10 ml) was added to the reaction solution, extracted with ethyl acetate (10 ml*3), and combined And the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by preparative SFC (column model: Phenomenex Gemini-NX C18 (75mm*30mm, 3 μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: carbon dioxide critical fluid 20%-50%, 7 minutes) Compounds 19B and 19-P1 were obtained.

19-P1 was then separated by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10um), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 35%-35%, 4.9 minutes, 80 minutes) Purification afforded Compound 19C and Compound 19D.

Compound 19A was detected by SFC [column type: (R,R)Whelk-O1-3 50×4.6mm I.D., 1.8μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine ); Gradient (B%): 40%-40%] Obtained: the residence time of compound 19A is 1.653min.

Compound 19B was detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] to obtain: the retention time of compound 19B was 2.22min, and the e.e. value was 100%.

Compound 19C and compound 19D were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B% ): 40%-40%] Obtained: the residence time of compound 19C was 1.653min, and the e.e. value was 100%; the residence time of compound 19D was 2.139min, and the e.e. value was 100%.

Compound 19A (retention time = 0.967 min): LCMS (ESI) m/z: 658.3 (M+1) ⁺ .

Compound 19B (retention time = 2.222 min): LCMS (ESI) m/z: 658.3 (M+1) ⁺ .

Compound 19C (retention time=1.653min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.29(d, J =4.8Hz, 1H), 7.30-7.15(m, 1H), 7.10-6.95(m, 2H ),6.93-6.70(m,2H),6.27-6.10(m,1H),5.83-5.63(m,1H),5.39-5.15(m,2H),4.83-4.39(m,2H), 4.02-3.90 (m,2H),3.59-3.40(m,1H),2.88-2.60(m,2H),2.04-1.96(m,3H),1.33-0.97(m,12H).LCMS(ESI)m/z: 658.3(M+1) ⁺ .

Compound 19D (retention time=2.139min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(br d, J =4.8Hz, 1H), 7.29-7.15(m, 1H), 7.12-7.05(m, 1H),7.00(s,1H),6.90-6.78(m,1H),6.76-6.70(m,1H),6.24-6.15(m,1H),5.80-5.71(m,1H),5.42-5.23( m,2H),4.85-4.47(m,2H),3.96-3.89(m,2H),3.53-3.43(m,1H),2.67(br s,2H),2.08-1.95(m,3H),1.33 -0.95(m,12H). LCMS (ESI) m/z: 658.3 (M+1) ⁺ .

Example 20

The first step: Add compound 20-2 (1.22 g), tetratriphenyl palladium phosphine (1.20 g) and potassium carbonate (4.30 g). After the reaction liquid nitrogen was replaced three times, the reaction was carried out at 100°C for 2 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (30 mL), washed with brine (30 mL), and the organic phase was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound 20-3. LCMS (ESI) m/z: 199.0 (M+1) ⁺ .

Step 2: To a solution of compound 20-3 (1.6 g) in methanol (10 mL) was added sodium methoxide in methanol (1.45 g, 10 mL, 30% by mass) at 10-15°C. The reaction solution was reacted at 15°C for 0.5 hour. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL), washed with brine (50 mL), and the organic phase was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain compound 20-4. LCMS (ESI) m/z: 195.1 (M+1) ⁺ .

Step 3: To a solution of compound 20-4 (1.50 g) in methanol (20 mL) was added wet palladium on carbon (0.5 g, 10% purity) at 10-15 °C. The reaction solution was replaced three times with hydrogen, and reacted at 15 degrees Celsius for 2 hours. The reaction solution was filtered, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to obtain compound 20-5. LCMS (ESI) m/z: 167.2 (M+1) ⁺ .

Step 4: Add compound 20-5A (0.76 g), Pd ₂ (dba) ₃ (420.52 mg ), Xantphos (531.43 mg) and cesium carbonate (4.49 g). The reaction liquid was replaced with nitrogen three times and then reacted at 100°C for 2 hours. The reaction solution was concentrated to obtain a residue. Water (100 mL) and ethyl acetate (100 mL) were added to the residue. The organic phase was separated and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 1:1) to obtain compound 20-6. ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.48(d, J =5.5Hz, 1H), 8.22-8.11(m, 1H), 7.73(dt, J =5.3, 8.4Hz, 1H), 7.63(dt, J =1.2,8.3Hz,1H),6.81-6.74(m,2H),6.60(s,1H),5.96(d, J =7.8Hz,1H),3.87(s,3H),3.29(td, J =6.8,13.6Hz,1H),1.30-1.21(m,6H). LCMS (ESI) m/z: 467.0 (M+1) ⁺ .

Step 5: To a solution of compound 20-6 (0.8 g) in dichloromethane (10 mL) was added NBS (305.30 mg) at 10-15 °C. After the reaction liquid nitrogen was replaced three times, the reaction was carried out at 15° C. for 2 hours. Saturated aqueous sodium sulfite (50 mL) was added to the reaction solution, the organic phase was separated, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 20-7. LCMS (ESI) m/z: 546.9 (M+3) ⁺ .

Step 6: Add iron powder (768.11 mg) and ammonium chloride (735.74 mg) to a mixed solution of compound 20-7 (1.5 g) in ethanol (50 ml) and water (25 ml) at 10-15°C . The reaction solution was reacted at 60° C. for 2 hours. The reaction solution was concentrated to obtain a residue, brine (50 mL) and ethyl acetate (50 mL) were added to the residue, the organic phase was separated and concentrated to obtain compound 20-8. LCMS (ESI) m/z: 515.0 (M+1) ⁺ .

Step 7: Add zinc powder (355.31 mg), zinc cyanide (638.06 mg), Pd ₂ (dba) ₃ (248.79 mg), zinc bromide (611.83 mg) and DPPF (301.24 mg). After the reaction liquid nitrogen was replaced three times, the reaction was carried out at 110 degrees Celsius for 12 hours. Water (30 mL) and ethyl acetate (30 mL) were added to the reaction solution, the mixture was filtered, the filter cake was washed with ethyl acetate (30 mL), the organic phase was separated and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 20-9. LCMS (ESI) m/z: 462.1 (M+1) ⁺ .

Step 8: A mixture of compound 20-9 (1.1 g) and concentrated sulfuric acid (18.40 g) was reacted at 80°C for 2 hours at 10-15°C. The reaction solution was slowly poured into ice water (1.0 L), stirred, and solid sodium carbonate was added in batches until the pH was about 9, extracted with ethyl acetate (100 ml*2), the organic phases were combined, and concentrated to obtain compound 20-10 . LCMS (ESI) m/z: 480.1 (M+1) ⁺ .

Step 9: Add sodium hydride (116.80 mg, mass percent: 60%) and carbonyldiimidazole (473.50 mg) to a solution of compound 20-10 (0.7 g) in tetrahydrofuran (15 ml) at 15°C. After the reaction liquid nitrogen was replaced three times, the reaction was carried out at 15° C. for 2 hours. The reaction solution was poured into water (30 ml), extracted with ethyl acetate (20 ml*2), the organic phases were combined, washed with saturated brine (30 ml), the organic phase was separated, and concentrated to obtain compound 20-11. LCMS (ESI) m/z: 506.1 (M+1) ⁺ .

Step 10: Add compound 3-1 (864.98 mg), PYBROP (1.25 g) to a solution of compound 20-11 (680 mg) in N,N-dimethylacetamide (30 ml) at 15°C and DIPEA (521.66 mg). After the reaction liquid nitrogen was replaced three times, the reaction was carried out at 80°C for 2 hours. The reaction solution was poured into water (50 ml), extracted with ethyl acetate (50 ml*2), the organic phases were combined, washed with saturated brine (50 ml), the organic phase was separated, concentrated to obtain a residue, and the residue was prepared by preparative TLC ( Petroleum ether: ethyl acetate = 0:1) to obtain compound 20-12. LCMS (ESI) m/z: 702.2 (M+1) ⁺ .

Step 11: To a solution of compound 20-12 (500 mg) in dichloromethane (15 ml) was added trifluoroacetic acid (4.81 g) at 15°C. The reaction solution was reacted at 15° C. for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetic acid salt of compound 20-13, and the crude product was directly used in the next step. LCMS (ESI) m/z: 602.2 (M+1) ⁺ .

Step twelve:

To a solution of compound 20-13 (500 mg) in THF (10 mL) and water (10 mL) were added potassium carbonate (193.13 mg) and acryloyl chloride (63.24 mg) at 15°C. The reaction solution was reacted at 15° C. for 15 minutes. Water (30 milliliters) was added to the reaction solution, extracted with ethyl acetate (30 milliliters), the organic phase was separated, concentrated to obtain a residue, and the residue was prepared by preparative HPLC (column model: Phenomenex Gemini-NX C18 75*30mm*3um, mobile phase : [Water (0.225% formic acid-acetonitrile]; 15%-45%, 7 minutes) was purified to obtain compound 20.

Compound 20 was obtained by SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: 0.1% ammonia water-methanol, gradient: carbon dioxide critical fluid 60%-60%, 2.2 minutes, 50 minutes) to obtain 20A and 20B.

Compound 20A and compound 20B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B% ): 40%-40%] Obtained: the residence time of compound 20A is 0.815min, and the e.e. value is 100%; the residence time of compound 20B is 2.118min, and the e.e. value is 100%.

Compound 20A (retention time=0.815min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.41-8.27(m,1H),7.09(dt, J =6.8,8.2Hz,1H),7.01(s,1H ),6.91(d, J =5.8Hz,1H),6.89-6.75(m,1H),6.50(d, J =8.4Hz,1H),6.38-6.29(m,1H),6.19(br d, J =16.5Hz,1H),5.80-5.70(m,1H),5.63(s,2H),4.86-4.59(m,1H),4.83-4.43(m,1H),4.13(br dd, J =2.4, 13.8Hz,1H),3.95-3.75(m,3H),3.70(s,3H),2.71-2.59(m,1H),1.30(br t, J =7.3Hz,3H),1.27-1.16(m, 3H), 1.06-1.01(m, 3H), 0.96(d, J =6.6Hz, 3H). LCMS (ESI) m/z: 656.3 (M+1) ⁺ .

Compound 20B (retention time=2.118min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.39-8.28(m,1H),7.14-7.04(m,1H),7.03-6.98(m,1H),6.91 -6.87(m,1H),6.82(br dd, J =10.1,16.5Hz,1H),6.48(d, J =8.3Hz,1H),6.38-6.29(m,1H),6.25-6.13(m, 1H),5.81-5.70(m,1H),5.68-5.58(m,2H),4.82-4.43(m,2H),4.16-4.01(m,1H),3.93-3.84(m,1H),3.65( s,2H),3.74-3.58(m,1H),1.36-1.28(m,3H),1.27-1.27(m,1H),1.26-1.20(m,1H),1.26-1.20(m,1H), 1.16(br d, J =6.5Hz, 2H), 1.11-1.05(m, 4H), 1.01(br d, J =6.6Hz, 3H). LCMS (ESI) m/z: 656.3 (M+1) ⁺ .

Example 21

Step 1: To a solution of compound 21-1 (10 g) and potassium carbonate (5.35 g) in acetonitrile (100 ml) was slowly added compound 7-2 (12.69 g) at 0°C. The reaction solution was reacted at 20 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was extracted twice with ethyl acetate (50 mL), the combined organic phase was washed with water (50 mL) and saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Ethyl acetate and petroleum ether (120 ml, 1:5) were added to the residue, stirred for one hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-2. LCMS (ESI) m/z: 230.1 (m+1) ⁺ .

The second step: at 0 degrees Celsius, compound 7-4 (9.86 grams) was added dropwise to a solution of compound 21-2 (13.18 grams) and cesium carbonate (18.74 grams) in acetonitrile (140 milliliters), and the reaction solution was heated at 15 degrees Celsius The reaction was carried out for 2 hours. The reaction solution was filtered, the filtrate was concentrated, water (100 mL) was added, and extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. To the residue was added methyl tert-butyl ether (40 mL) and stirred at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-3. LCMS (ESI) m/z: 352.1 (m+1) ⁺ .

Step 3: Triethylamine (10.47 g) was added to a solution of compound 21-3 (18.17 g, 100% purity) in trifluoroethanol (100 ml), and the reaction solution was incubated at 80°C for 14 hours. The reaction solution was concentrated to obtain a residue. The residue was washed with ethyl acetate (50 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was washed with ethyl acetate (50 mL), the pH of the aqueous phase was adjusted to 1 with aqueous hydrochloric acid (3 mol per liter), and then the aqueous phase was extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-4. LCMS (ESI) m/z: 320.1 (m+1) ⁺ .

Step 4: Add potassium phosphate (18.49 grams) and tribromopyridinium salt (41.78 grams) successively to a solution of compound 21-4 (13.9 grams) in acetonitrile (280 milliliters), and the reaction solution reacts at 50 degrees Celsius for 2 Hour. The reaction was quenched with saturated sodium sulfite (200 mL), followed by extraction twice with ethyl acetate (100 mL). The combined organic phases were washed with aqueous hydrochloric acid (150 mL, 1 mol per L) and saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-5. LCMS (ESI) m/z: 353.9 (M+1) ⁺ .

Step 5: Under a nitrogen atmosphere, add compound 6-4 to compound 21-5 (15.4 g) and tris(dibenzylideneacetone) dipalladium (3.98 g) in dioxane (300 ml) in sequence (7.84 grams), Xantphos (5.03 grams) and cesium carbonate (28.34 grams), the reaction solution was reacted at 100 degrees Celsius for 2 hours. The reaction solution was filtered, and ethyl acetate hydrochloride solution (200 ml, 1 mol per liter) was added to the filtrate, and stirred at 15° C. for 1 hour. The mixture was filtered, and the filter cake was dissolved with ethyl acetate (100 mL) and saturated sodium carbonate (200 mL). Then the aqueous phase was extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Ethanol (30 ml) was added to the residue, followed by stirring at room temperature for 1 hour. After filtration, the filter cake was dried under reduced pressure to obtain compound 21-6. LCMS (ESI) m/z: 424.1 (M+1) ⁺ .

Step 6: To a solution of compound 21-6 (11.85 g) in dichloromethane (120 ml) was added N-bromosuccinimide (6.48 g) in one portion at 0°C. The reaction solution was reacted at 15° C. for 1 hour. Saturated sodium sulfite (200 ml) was added to the reaction solution, then extracted twice with dichloromethane (100 ml), the combined organic phases were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue . Add methyl tertiary butyl ether and petroleum ether (90 ml, 1:5) to the residue, stir for 12 hours, filter, and dry the filter cake under reduced pressure to obtain compound 21-7. LCMS (ESI) m/z: 504.2 (M+3) ⁺ .

Step 7: Under nitrogen atmosphere, add zinc powder (1.47 g), zinc bromide (634.42 mg ), zinc cyanide (3.31 g), tris(dibenzylideneacetone) dipalladium (1.29 g) and DPPF (1.56 g). The reaction solution was reacted at 120° C. for 3 hours under nitrogen protection. The reaction solution was filtered, and saturated brine (400 ml) was added to the filtrate, then extracted twice with ethyl acetate (200 ml), the combined organic phases were washed twice with saturated brine (200 ml), dried over anhydrous sodium sulfate, and filtered , and the filtrate was concentrated to give a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 3:1 (containing 5% methanol)) to obtain compound 21-8. LCMS (ESI) m/z: 449.1 (M+1) ⁺ .

Step 8: A solution of compound 21-8 (12.4 g) in concentrated sulfuric acid (128.8 g) was reacted at 60°C for 3 hours. The reaction solution continued to react at 60° C. for 14 hours. The reaction solution was cooled to 15°C. The reaction solution was added to ice water (1000 ml), and a solution of sodium hydroxide (100 g) in water (300 ml) was slowly added at 0°C, and then the pH was adjusted to 8 with solid sodium bicarbonate. Ethyl acetate (500 ml) was added to the mixture, filtered, the filtrate was extracted with ethyl acetate (200 ml*2), the combined organic phases were washed with saturated brine (200 ml*2), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated to give compound 21-9. LCMS (ESI) m/z: 467.2 (M+1) ⁺ .

Step 9: Under a nitrogen atmosphere, CDI (5.21 g) was added to a solution of compound 21-9 (5.0 g) in DMA (50 ml), followed by the slow addition of sodium hydride (1.29 g, mass percent: 60%). The reaction solution was reacted at 15° C. for 1 hour). The reaction solution was added to ice water (200 ml), adjusted to pH 3 with aqueous hydrochloric acid (1 mol per liter), and then adjusted to pH 8 with solid sodium bicarbonate. The mixture was extracted twice with ethyl acetate (200 ml), the combined organic phase was washed twice with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Methanol (15 ml ) and stirred for 2 hours. After filtration, the filter cake was dried under reduced pressure to obtain 21-10. LCMS (ESI) m/z: 493.2 (M+1) ⁺ .

Step 10: Under a nitrogen atmosphere, add tripyrrolidinylphosphonium bromide hexafluorophosphate (2.84 g) and compound 1-1 (2.27 g) to a solution of compound 21-10 (0.6 g) in tetrahydrofuran (10 ml). ), and the reaction solution was reacted at 60 degrees Celsius for 14 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10 μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 30%-60%, 20 minutes] to obtain compound 21- 11. LCMS (ESI) m/z: 661.4 (M+1) ⁺ .

Step eleven: To a solution of compound 21-11 (0.9 g) in dichloromethane (10 ml) was added trifluoroacetic acid (4.62 g) in one portion. The reaction solution was reacted at 15° C. for 0.5 hour. The reaction solution was concentrated and dissolved in ethyl acetate (10 mL). The ethyl acetate solution was added dropwise to saturated sodium bicarbonate (40 mL). The mixture was extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the trifluoroacetate salt of compound 21-12. LCMS (ESI) m/z: 561.3 (M+1) ⁺ .

Step twelve:

In a nitrogen atmosphere, at 0 degrees Celsius, potassium carbonate (136.85 mg) was added to a mixed solution of compound 21-12 (0.37 g) in tetrahydrofuran (8 ml) and water (2 ml), and compound 1- 5 (65.72 mg). The reaction solution was reacted at 0° C. for 30 minutes, water (20 ml) was added to the reaction solution, extracted twice with ethyl acetate (20 ml), the organic phase was washed with saturated brine (20 ml) and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to give a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm*15um), mobile phase: water (0.225% formic acid)-acetonitrile: 28%-58%, 13 minutes], and the product obtained was purified by preparative SFC ( Column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 3.5 minutes, 20 minutes) were separated to obtain compound 21A and compound 21B.

Compound 21A and compound 21B were detected by SFC [column model: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol + acetonitrile (0.05% diethylamine); gradient ( B%): 40% methanol+acetonitrile (0.05% diethylamine)] to obtain: the retention time of compound 21A is 0.760min, and the e.e. value is 100%; the retention time of compound 21B is 1.548min, and the e.e. value is 100%.

Compound 21A (retention time=0.760min): ¹ H NMR (400MHz, MeOH- d ₄ )δ 8.32(d, J =4.9Hz, 1H), 7.66-7.52(m, 1H), 7.32(s, 1H), 7.22-7.10(m,3H),6.81(dd, J =16.8,10.6Hz,1H),6.29(dd, J =16.8,1.7Hz,1H),5.82(dd, J =10.6,1.7Hz,1H) ,4.04(br d, J =5.9Hz,4H),3.92(br s,4H),2.84(td, J =13.5,6.7Hz,1H),2.09(s,3H),1.18(d, J =6.8 Hz,3H), 1.09(d, J =6.8Hz,3H). LCMS (ESI) m/z: 615.3 (m+1) ⁺ .

Compound 21B (retention time=1.548min): ¹ H NMR (400MHz, MeOH- d ₄ )δ 8.32(d, J =4.9Hz, 1H), 7.66-7.53(m, 1H), 7.32(s, 1H), 7.23-7.11(m,3H),6.82(dd, J =16.8,10.6Hz,1H),6.29(dd, J =16.8,1.6Hz,1H),5.82(dd, J =10.5,1.6Hz,1H) ,4.12-4.00(m,4H),3.92(br s,4H),2.84(td, J =13.6,6.8Hz,1H),2.09(s,3H),1.18(d, J =6.7Hz,3H) ,108(d, J =6.8Hz,3H). LCMS (ESI) m/z: 615.3 (m+1) ⁺ .

Example 22

Step 1: Add tripyrrolidinylphosphonium bromide hexafluorophosphate (951.01 mg) and DIPEA (263.66 mg) to a solution of compound 21-10 (0.5 g) in DMAc (10 ml) under a nitrogen atmosphere After reacting at 15 degrees Celsius for 1 hour, compound 3-1 (655.77 mg) was added, and the reaction solution was reacted at 100 degrees Celsius for 14 hours. Water (20 ml) was added to the reaction solution, extracted twice with ethyl acetate (20 ml), the combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 22-1 . LCMS (ESI) m/z: 689.4 (M+1) ⁺ .

Second step: To a solution of compound 22-1 (0.9 g) in dichloromethane (10 mL) was added trifluoroacetic acid (4.62 g) in one portion at 0°C. The reaction solution was reacted at 15° C. for 0.5 hour. The reaction solution was spin-dried and dissolved in ethyl acetate (10 mL). The ethyl acetate solution was added dropwise to saturated sodium bicarbonate (40 mL). The mixture was extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 22-2. LCMS (ESI) m/z: 589.4 (M+1) ⁺ .

third step:

In a nitrogen atmosphere, at 0°C, potassium carbonate (193.72 mg) was added to a mixed solution of compound 22-2 (0.55 g) in tetrahydrofuran (4 ml) and water (1 ml), and then compound 1- 5 (93.03 mg). The reaction solution was reacted at 0° C. for 30 minutes, water (10 ml) was added to the reaction solution, extracted twice with ethyl acetate (10 ml), the organic phase was washed with saturated brine (10 ml) and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to give a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm* 15um), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 25%-55%, 13 minutes] to obtain compound 22.

Compound 22 was separated by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 8.0 minutes, 40 minutes) to obtain the compound 22A and compound 22B.

Compound 22A and compound 22B were detected by SFC [column model: Column: Chiralpak IC-3 50×4.6mm ID, 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] obtained: the residence time of compound 22A was 1.478min, and the ee value was 100%; the residence time of compound 22B was 2.993min, and the ee value was 99.47%. Compound 22A (retention time=1.478min): ¹ H NMR (400MHz, MeOD- d ₄ )δ 8.33(d, J =5.0Hz, 1H), 7.70-7.52(m, 1H), 7.25-7.10(m, 4H ),6.95-6.73(m,1H),6.29(ddd, J =16.7,6.1,1.8Hz,1H),5.82(ddd, J =10.6,7.0,1.8Hz,1H),5.02-4.90(m,2H ),4.62-4.14(m,2H),3.98-3.81(m,2H),2.87(qd, J =11.0,6.8Hz,1H),2.07(s,3H),1.49(d, J =6.6Hz, 3H), 1.41-1.29(m, 3H), 1.18(dd, J =6.7, 1.6Hz, 3H), 1.09(dd, J =6.7, 1.6Hz, 3H). LCMS (ESI) m/z: 643.4 (m+1) ⁺ .

Compound 22B (retention time=2.993min): ¹ H NMR (400MHz, MeOD- d ₄ )δ 8.33(d, J =4.9Hz, 1H), 7.68-7.54(m, 1H), 7.24-7.13(m, 4H ),6.92-6.74(m,1H),6.30(ddd, J =16.8,6.4,1.8Hz,1H),5.87-5.77(m,1H),4.98-4.89(m,2H),4.60-4.16(m ,2H),3.97-3.80(m,2H),2.73(quin, J =6.8Hz,1H),2.13(s,3H),1.48(d, J =6.6Hz,3H),1.40-1.28(m, 3H), 1.16(d, J =6.7Hz, 3H), 1.07(d, J =6.8Hz, 3H). LCMS (ESI) m/z: 643.4 (m+1) ⁺ .

Example 23

The first step: Add potassium carbonate (2.35 grams) in the acetonitrile (50 milliliters) solution of compound 23-1 (5 grams), cool to 0 degrees Celsius, add compound 7-2 (5.57 grams) in batches, then at 25 degrees Celsius Stir for 16 hours. Filtration, concentration to dryness, concentration to dryness, beating in a mixed solvent of ethyl acetate and petroleum ether (volume ratio 1:1) at room temperature for 2 hours, filtration and concentration to obtain compound 23-2. LCMS (ESI) m/z: 248.0 (M+1) ⁺ .

Step 2: Add cesium carbonate (8.83 g) to compound 23-2 (6.7 g) in acetonitrile (100 ml), then add compound 7-4 (4.65 g) in portions at 0-5°C and stir at 25°C After 2 hours, it was filtered and concentrated to dryness to obtain compound 23-3. LCMS (ESI) m/z: 369.9 (M+1) ⁺ .

Step 3: Triethylamine (5.48 g) was added to a solution of compound 23-3 (10 g) in trifluoroethanol (50 ml), and the mixed system was stirred at 90° C. for 16 hours. Concentrate to dryness, dilute with 50 ml of water, adjust the pH to 8 with 1 mol/L aqueous sodium hydroxide solution, extract and discard with ethyl acetate (50 ml), and adjust the pH of the aqueous phase with 1 mol/L aqueous hydrochloric acid From 3 to 4, a yellow solid precipitated out, extracted with ethyl acetate (100 ml), washed with brine (20 ml), dried and concentrated over anhydrous sodium sulfate to obtain compound 23-4. ¹ H NMR (400 MHz, CHLOROFORM- d ) δ 13.10-12.64 (m, 1H), 8.84-8.67 (m, 1H), 7.55-7.40 (m, 1H), 7.23-7.10 (m, 2H). LCMS (ESI) m/z: 337.9 (M+1) ⁺ .

Step 4: Add potassium phosphate (8.44 g) and tribromopyridinium salt (19.07 g) to a solution of compound 23-4 (6.7 g) in acetonitrile (100 ml), then stir at 50 degrees Celsius for 2 hours, then wash with aqueous sodium sulfite (50 mL) to quench the reaction, extracted three times with ethyl acetate (50 mL*3), combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-5. LCMS (ESI) m/z: 371.7 (M+1) ⁺ .

Step 5: Add Pd ₂ (dba) to compound 23-5 (7 g) and 2-isopropyl-4-methyl-pyridin-3-amine (3.11 g) in dioxane (20 ml) ₃ (861.42 mg) and Xantphos (1.09 g, cesium carbonate (12.26 g), the reaction system was replaced with nitrogen, heated to 100 degrees Celsius and stirred for 18 hours. Cooled to 25 degrees Celsius, filtered, concentrated, added hydrochloric acid ethyl acetate solution (( 1 mol/liter, 120 milliliters), solid filtration, suspension in water (100 milliliters) and ethyl acetate (200 milliliters) solution, adjust pH=8～9 with saturated sodium sulfite aqueous solution, organic phase water (50 milliliters) Washed, then washed with saturated brine (50 ml), dried with anhydrous sulfuric acid, filtered, and concentrated to obtain compound 23-6. LCMS (ESI) m/z: 442.0 (M+1) ⁺ .

Step 6: Add NBS (3.48 g) in batches to a solution of compound 23-6 (8.1 g) in dichloromethane (100 ml) at 0°C, stir at 0-25°C for half an hour, add saturated sodium sulfite (50 milliliter) aqueous solution, the separated organic phase was washed once with saturated brine (50 milliliters), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was beaten for 12 hours at room temperature with a mixed system of petroleum ether and methyl tertiary butyl ether, and filtered , and dried to give compound 23-7. ¹ H NMR (400MHz,CHLOROFORM- d )δ 8.44(d, J =4.9Hz,1H),7.48-7.35(m,1H),7.16-6.97(m,3H),6.96-6.91(m,1H), 3.45-3.32(m, 1H), 2.20(d, J =2.8Hz, 3H), 1.36-1.31(m, 3H), 1.26-1.20(m, 3H). LCMS (ESI) m/z: 521.9 (M+3) ⁺ .

Step 7: Add zinc bromide to a solution of compound 23-7 (7.5 g), zinc cyanide (3.21 g), zinc powder (894.00 mg) in N,N-dimethylformamide (100 ml) (153.94 mg), replaced with nitrogen, added DPPF (1.52 g) and Pd ₂ (dba) ₃ (1.25 g), and stirred at 100 degrees Celsius for 16 hours after nitrogen replacement. Cool to room temperature, filter and pour the mother liquor into pure water (300 ml), filter the solid, dissolve in ethyl acetate (200 ml), wash with water (50 ml*3) three times, dry with anhydrous sodium sulfate, filter and concentrate After drying, it was slurried with a mixed system of petroleum ether and methyl tertiary butyl ether at room temperature for 1 hour, filtered and concentrated to obtain compound 23-8. LCMS (ESI) m/z: 466.9 (M+1) ⁺ .

The eighth step: Compound 23-8 (7 grams) was added to concentrated sulfuric acid (35 ml) in batches, heated to 60 degrees Celsius and stirred for 16 hours, cooled to room temperature, poured into ice water (300 ml), and added 10% aqueous sodium hydroxide solution to pH 8 to 9, extracted with ethyl acetate (500 ml*2), and the combined organic phases were concentrated to obtain compound 23-9. LCMS (ESI) m/z: 484.9 (M+1) ⁺ .

The ninth step: at 0 degrees Celsius, add sodium hydride (1.51 grams, mass percentage: 60%) and carbonyldiimidazole (6.13 grams) in the DMA (65 milliliters) solution of compound 23-9 (6.1 grams), at 0- Stir at 25°C for 1 hour, pour into ice water (200 ml), adjust pH to 4 with 1 molar hydrochloric acid aqueous solution, then adjust pH to 8 with solid sodium bicarbonate, extract with ethyl acetate (100 ml*2) , the combined organic phases were washed once with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-10. LCMS (ESI) m/z: 511.0 (M+1) ⁺ .

Step 10: To a solution of compound 23-10 (3.0 g) in DMAc (30 ml) was added PYBROP (5.48 g) and DIEA (2.28 g), and stirred at 25°C for 2 hours. Compound 1-1 (3.29 g) was added and heated to 100°C for 12 hours. The reaction solution was poured into water (100 ml), the solid was dissolved with ethyl acetate (50 ml), washed with saturated brine (20 ml*3), and the organic phase was concentrated to obtain a residue, which was purified by column chromatography (elution Agent: petroleum ether: ethyl acetate=1:1) to obtain compound 23-11. LCMS (ESI) m/z: 679.1 (M+1) ⁺ .

Step 11: Add trifluoroacetic acid (10 ml) to a solution of compound 23-11 (4.0 g) in dichloromethane (30 ml), stir the reaction solution at 25 degrees Celsius for 30 minutes, and concentrate to obtain compound 23-12. Fluoroacetate. The crude product was used directly in the next step. LCMS (ESI) m/z: 579.0 (M+1) ⁺ .

Step 12: Add potassium carbonate (1.54 g) to a solution of compound 23-12 (3.0 g, trifluoroacetate) in tetrahydrofuran (20 ml) and water (10 ml), and stir the mixture at 25 degrees Celsius for 10 minutes, then Compound 1-5 (504.97 mg) was added and stirred at 25°C for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL), washed with saturated brine (10 mL), and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column model: Phenomenex Synergi Max-RP (250*50mm*10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 25%-55%, 25 minutes) to obtain compound 23 . LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

Step Thirteen:

23M- 1 (mixture of residence time=1.904 and residence time=2.01 min) and 23M-2 (mixture of residence time=1.463 min and residence time=1.569 min).

23M-1 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 5.7 minutes, 800 minutes) Compound 23A and Compound 23B were obtained.

23M-2 was prepared by SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 9 minutes, 530 minutes) Compound 23C and Compound 23D were obtained by separation and purification.

Compound 23A and compound 23B were detected by SFC [column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] Obtained: the residence time of compound 23A was 1.904min, and the e.e. value was 95.12%; the residence time of compound 23B was 2.017min, and the e.e. value was 99.47%.

Compound 23C and compound 23D were detected by SFC [column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); Gradient (B%): 15%-15%] to obtain: the retention time of compound 23C is 1.463 min; the retention time of compound 23D is 1.569 min.

Compound 23A: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.33(d, J =4.8Hz, 1H), 7.90-7.77(m, 1H), 7.52-7.42(m, 1H), 7.32(s, 1H ),7.10(d, J =4.9Hz,1H),6.90-6.79(m,1H),6.24-6.15(m,1H),5.81-5.73(m,1H),3.99-3.76(m,8H), 2.79-2.69 (m, 1H), 1.99 (s, 3H), 1.10-0.93 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

Compound 23B: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.33(d, J =4.9Hz, 1H), 7.9-7.78(m, 1H), 7.47(br t, J =8.8Hz, 1H), 7.32 (s,1H),7.09(d, J =4.9Hz,1H),6.96-6.79(m,1H),6.29-6.17(m,1H),5.92-5.70(m,1H),3.99-3.77(m ,8H), 2.85-2.68(m,1H), 2.03-1.93(m,3H), 1.13-0.93(m,6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

Compound 23C: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.33(d, J =4.8Hz, 1H), 7.90-7.78(m, 1H), 7.53-7.44(m, 1H), 7.32(s, 1H ),7.10(d, J =4.9Hz,1H),6.93-6.76(m,1H),6.27-6.15(m,1H),5.84-5.70(m,1H),3.99-3.73(m,8H), 2.78-2.69 (m, 1H), 1.99 (s, 3H), 0.94-1.06 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

Compound 23D: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.33(d, J =4.8Hz, 1H), 7.92-7.80(m, 1H), 756-7.44(m, 1H), 7.32(s, 1H ),7.09(d, J =5.0Hz,1H),6.94-678(m,1H),630-6.12(m,1H),5.86-5.70(m,1H),4.04-3.72(m,8H), 284-268 (m, 1H), 1.97 (s, 3H), 1.13-0.94 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) ⁺ .

Example 24

first step: At 0-10 degrees Celsius, potassium carbonate (1.93 grams) was added to a solution of compound 24-1 (4 grams) in acetonitrile (40 milliliters), and compound 7-2 (5.72 grams) was added. After the addition, the reaction solution was cooled at 25 degrees Celsius. Respond for 12 hours. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (20 mL*3), and the filtrate was concentrated under reduced pressure to obtain a residue. Petroleum ether (40 mL) was added to the residue, stirred at room temperature for half an hour, filtered, the filter cake was rinsed with petroleum ether (20 mL*3), and concentrated under reduced pressure to obtain compound 24-2. LCMS (ESI) m/z: 244.2 (M+1)+.

The second step: at 0-10 degrees Celsius, add cesium carbonate (11.16 grams) to compound 24-2 (8.33 grams) in acetonitrile (85 milliliters) solution, compound 7-4 (5.87 grams), add the reaction solution in React for 1 hour at 10-15 degrees Celsius. The reaction solution was filtered with celite, the filter cake was rinsed with ethyl acetate (30 ml*3), and the filtrate was concentrated under reduced pressure to obtain compound 24-3. LCMS (ESI) m/z: 366.1 (M+1) ⁺ .

Step 3: Triethylamine (7.20 g) was added to a solution of compound 24-3 (13 g) in trifluoroethanol (65 ml), and the reaction solution was reacted at 80° C. for 11 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was diluted with ethyl acetate (200 ml) and hydrochloric acid (1 mol/L, 50 ml) solution, left to stand for layers, and the organic phase was sequentially washed with hydrochloric acid (1 mol/L, , 50 ml) solution, washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, at 10-15 degrees Celsius, add methyl tertiary butyl ether to the residue (50 ml), stirred for half an hour, filtered, the filter cake was rinsed with methyl tertiary butyl ether (10 ml*3), and concentrated under reduced pressure to obtain compound 24-4. LCMS (ESI) m/z: 334.0 (M+1) ⁺ .

Step 4: Add tribromopyridinium salt (10.56 g) and potassium phosphate (7.01 g) to a solution of compound 24-4 (5.5 g) in acetonitrile (55 ml), and react the reaction solution at 50°C for 2 hours. Sodium sulfite (6 g) was dissolved in water (30 mL) to quench the reaction, then the mixture was filtered, the filter cake was rinsed with ethyl acetate (10 mL*3), and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (200 ml), the mixture was washed with hydrochloric acid (1 mol/L, 50 ml*2) solution, the organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and reduced Concentrate under reduced pressure to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 8:1) to obtain compound 24-5. LCMS (ESI) m/z: 367.8 (M+1) ⁺ .

Step 5: Add 2-isopropyl-4-methylpyridin-3-amine (2.45 g), cesium carbonate (10.62 gram), three (dibenzylideneacetone) dipalladium (1.49 grams) and 4,5-bis-diphenylphosphine-9,9-dimethylxanthene (1.89 grams), the reaction solution was under the protection of nitrogen in React at 100 degrees Celsius for 12 hours. The reaction solution was filtered with Celite, the filter cake was washed with ethyl acetate (30 ml*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column (petroleum ether: ethyl acetate=10:1 to 3: 1) Obtain compound 24-6. LCMS (ESI) m/z: 438.3 (M+1) ⁺ .

Step 6: Add N-bromosuccinimide (2.03 grams) to a solution of compound 24-6 (5 grams) in dichloromethane (50 milliliters) at 0-10 degrees Celsius, and the reaction solution is at 0- The reaction was carried out at 10°C for 1 hour, the reaction solution was quenched with saturated aqueous sodium sulfite (20 ml), and then the layers were separated, the organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound 24-7. LCMS (ESI) m/z: 518.1 (M+3) ⁺ .

Step 7: Add zinc powder (0.46 g), zinc cyanide (0.79 g), bromine Zinc chloride (124.66 mg), 1,1-bis(diphenylphosphino)ferrocene (1.23 g) and tris(dibenzylideneacetone)dipalladium (1.01 g). The reaction solution was reacted at 120° C. for 2 hours under the protection of nitrogen. The reaction solution was filtered with diatomaceous earth, the filter cake was rinsed with ethyl acetate (60 ml*3), the filtrate was diluted with water (240 ml), allowed to stand and separated, and the organic phase was washed with saturated brine (60 ml*2). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound 24-8. LCMS (ESI) m/z: 463.0 (M+1) ⁺ .

Step 8: A solution of compound 24-8 (5.8 g) in concentrated sulfuric acid (55.20 g) was reacted at 60°C for 7 hours. The reaction solution was added to ice water (300 ml) and ethyl acetate (200 ml), and sodium hydroxide (40 g) was dissolved in water (200 ml) at 0-10°C and slowly added dropwise to the above mixture, Use solid sodium bicarbonate to adjust the pH value of the aqueous phase to 7-8, filter the mixture, rinse the filter cake with ethyl acetate (100 ml*3), leave the filtrate to separate layers, and combine the organic phases with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 24-9. LCMS (ESI) m/z: 481.2 (M+1) ⁺ .

Step 9: Add 1,1-carbonyldiimidazole (4.46 g) to a solution of compound 24-9 (4 g) in N,N-dimethylformamide (40 ml), and place Sodium hydrogen (1.10 g, mass percentage: 60%) was added to the above mixture, and the reaction solution was reacted at 10-15 degrees Celsius for 0.5 hours. The reaction solution was slowly added to water (200 ml), the mixture was diluted with ethyl acetate (100 ml), and the pH value of the aqueous phase was adjusted to 2-3 with hydrochloric acid (1 mol/liter) solution, and then washed with sodium bicarbonate The solids adjusted the pH of the aqueous phase to 7-8. The layers were separated, the aqueous phase was extracted with ethyl acetate (100 ml), the combined organic phases were washed with water (50 ml*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-10. LCMS (ESI) m/z: 507.0 (M+1) ⁺ .

Step 10: To a solution of compound 24-10 (637 mg) in N,N-dimethylacetamide (7 mL) was added diisopropylethylamine (483.80 mg) and tripyrrolidinylphosphonium bromide hexa Fluorophosphate (872.53 mg), and then the reaction solution was reacted at 15 degrees Celsius for 1 hour. Compound 1-1 (697.20 mg) was added to the above mixture, and the reaction solution was reacted at 60°C for 12 hours. The reaction solution was diluted with water (50 ml) and ethyl acetate (50 ml), the aqueous phase was extracted with ethyl acetate (25 ml), the combined organic phases were washed with saturated brine (25 ml), dried over anhydrous sodium sulfate, filtered, and reduced Concentrate under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column model: Phenomenex Synergi Max-RP (250*50mm*10μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60%, 22 minutes) to obtain the compound 24-11. LCMS (ESI) m/z: 675.3 (M+1) ⁺ .

Step 11: Trifluoroacetic acid (3.08 g) was added to a solution of compound 24-11 (600 mg) in dichloromethane (6 ml), and the reaction solution was reacted at 15°C for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a residue. After the residue was diluted with saturated sodium bicarbonate (40 mL) solution and ethyl acetate (40 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered , concentrated under reduced pressure to obtain compound 24-12. LCMS (ESI) m/z: 575.2 (M+1) ⁺ .

Step 12: Add potassium carbonate (114.74 mg) to a mixed solution of compound 24-12 in tetrahydrofuran (8 ml) and water (2 ml), then add acryloyl chloride (75.14 mg) at 15 degrees Celsius, and the reaction solution React at 15°C for 10 minutes. The reaction solution was concentrated under reduced pressure to obtain a residue, which was diluted with ethyl acetate (40 mL) and saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24. LCMS (ESI) m/z: 629.3 (M+1) ⁺ .

Example 25

The first step: under nitrogen atmosphere, add 2-phenylcarbodiimide (16.07 grams), cesium carbonate (43.33 grams), palladium acetate successively to the solution of compound 25-1 (23 grams) in toluene (230 milliliters) (995.23 mg) and BINAP (5.52 g). The reaction solution was reacted at 90° C. for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (100 mL) and water (100 mL). The mixture was filtered, the filtrate was separated, the aqueous phase was extracted twice with ethyl acetate (100 ml), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-2. LCMS (ESI) m/z: 360.2 (m+1) ⁺ .

Step two: To a solution of compound 25-2 (32 g) in THF (600 mL) was added aqueous hydrochloric acid (4 mol/L, 130 mL). The reaction solution was reacted at 15° C. for 2 hours. Water (500 ml) was added to the reaction solution, and the pH was adjusted to 5 with aqueous sodium hydroxide solution (1 mol/L), and then adjusted to pH 7 with solid sodium bicarbonate. Extracted twice with ethyl acetate (500 mL), the combined organic phases were washed twice with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 50:1) to obtain compound 25-3.

Step 3: To a solution of compound 25-3 (35 g) and potassium carbonate (12.37 g) in acetonitrile (350 ml) was slowly added compound 7-2 (29.32 g) at 0°C. The reaction solution was reacted at 25 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (200 mL) and saturated sodium bicarbonate (200 mL). The aqueous phase was extracted twice with ethyl acetate (100 mL), the combined organic phase was washed with water (200 mL) and saturated brine (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was slurried with ethyl acetate and petroleum ether (200 ml, 1:5) for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 25-4. LCMS (ESI) m/z: 296.0 (M+1) ⁺ .

The fourth step: at 0 degrees Celsius, compound 7-4 (14.44 grams) was added dropwise to a solution of compound 25-4 (24.9 grams) and cesium carbonate (27.44 grams) in acetonitrile (250 milliliters), and the reaction solution was heated at 15 degrees Celsius. The reaction was carried out for 2 hours. The reaction solution was filtered, the filtrate was concentrated, water (200 mL) was added, and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with water (200 ml) and saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-5. LCMS (ESI) m/z: 418.1 (M+1) ⁺ .

Step 5: Triethylamine (17.44 g) was added to a solution of compound 25-5 (36 g) in trifluoroethanol (180 ml), and the reaction solution was incubated at 80° C. for 14 hours. The reaction solution was concentrated to obtain a residue. The residue was dissolved in ethyl acetate (500 ml), washed twice with aqueous hydrochloric acid (200 ml, 1 mol per liter), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Add methyl tertiary butyl ether and petroleum ether (240 ml, 1:5) to the residue, stir at room temperature for 1 hour, filter, and dry the filter cake under reduced pressure to obtain compound 25-6. LCMS (ESI) m/z: 386.1 (M+1) ⁺ .

Step 6: Add potassium phosphate (11.01 g) and tribromopyridinium salt (24.88 g) successively to a solution of compound 25-6 (10 g) in acetonitrile (200 ml), and react the reaction solution at 50 degrees Celsius for 14 hours . The reaction was quenched with saturated sodium sulfite (200 mL), followed by extraction twice with ethyl acetate (100 mL). The combined organic phases were washed with aqueous hydrochloric acid (200 mL, 1 mol per L) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-7. LCMS (ESI) m/z: 421.7 (M+3) ⁺ .

The seventh step: under a nitrogen atmosphere, compound 6-4 was sequentially added to a solution of compound 25-7 (8.89 g) and tris(dibenzylideneacetone) dipalladium (1.94 g) in dioxane (90 ml) (3.18 grams), Xantphos (2.45 grams) and cesium carbonate (13.78 grams), the reaction solution was reacted at 100 degrees Celsius for 14 hours. The reaction solution was filtered, and ethyl acetate hydrochloride solution (100 ml, 1 mol per liter) was added to the filtrate, and stirred at 15° C. for 1 hour. The mixture was filtered, and the filter cake was dissolved with ethyl acetate (100 mL) and saturated sodium carbonate (100 mL). Then the aqueous phase was extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Petroleum ether (50 ml) was added to the residue, followed by stirring at room temperature for 1 hour. After filtration, the filter cake was dried under reduced pressure to obtain compound 25-8. LCMS (ESI) m/z: 490.2 (M+1) ⁺ .

Step 8: To a solution of compound 25-8 (8.68 g) in dichloromethane (86 ml) was added N-bromosuccinimide (3.15 g) in one portion at 0°C. The reaction solution was reacted at 15° C. for 1 hour. Saturated sodium sulfite (100 ml) was added to the reaction solution, then extracted twice with dichloromethane (100 ml), the combined organic phases were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue . The residue was purified by silica gel column (silica, petroleum ether: ethyl acetate = 3:1) to obtain compound 25-9. LCMS (ESI) m/z: 570.2 (M+3) ⁺ .

Step 9: Under nitrogen atmosphere, add zinc powder (747.33 mg), zinc bromide (257.38 mg ), zinc cyanide (1.34 g), tris(dibenzylideneacetone) dipalladium (523.28 mg) and DPPF (633.59 mg). The reaction solution was reacted at 120° C. for 2 hours under the protection of nitrogen. The reaction solution was filtered, water (100 ml) was added to the filtrate, and then extracted twice with ethyl acetate (100 ml), the combined organic phases were washed with water (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate, Filter and concentrate the filtrate to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 3:1 (containing 5% methanol)) to obtain compound 25-10. LCMS (ESI) m/z: 515.0 (M+1) ⁺ .

Step 10: Compound 25-10 (400 mg) was added in batches to concentrated sulfuric acid (2 ml, 98% purity), heated to 60°C and stirred for 14 hours, cooled to room temperature, and poured into ice water (10 ml) , adding saturated aqueous sodium bicarbonate solution to pH 8, extracted with ethyl acetate (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain compound 25-11. LCMS (ESI) m/z: 532.9 (M+1) ⁺ .

Step 11: Add sodium hydride (120.09 mg, mass percentage: 60%) to a solution of compound 25-11 (400 mg) in tetrahydrofuran (10 ml) at 0°C, add carbonyldiimidazole (365.16 mg), Stir at 25 degrees Celsius for 30 minutes, pour into ice water (20 ml), adjust the pH to 3-4 with 1 mol/liter of hydrochloric acid, then adjust the pH to 7-8 with saturated sodium bicarbonate solution, and use acetic acid Ethyl ester (20 ml) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain compound 25-12. LCMS (ESI) m/z: 558.9 (M+1) ⁺ .

Step 12: Add PYBROP (667.33 mg), DIEA (277.51 mg) and compound 1-1 (399.92 mg) to a solution of compound 25-12 (400 mg) in tetrahydrofuran (10 ml), and heat to 60 degrees Celsius for 12 hours . Concentrate to dryness, dissolve with methanol (20 mL), filter off the undissolved solid, and concentrate the mother liquor to obtain a residue. The residue was purified by preparative HPLC (column model: Phenomenex Gemini-NX C18 (75*30mm*3um); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 40%-70%, 7 minutes)) Compounds 25-13. LCMS (ESI) m/z: 727.0 (M+1) ⁺ .

Step 13: To a solution of compound 25-13 (200 mg) in dichloromethane (3 ml) was added trifluoroacetic acid (1.54 g) in one portion at 20-30°C. The reaction solution was reacted at 25° C. for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetic acid salt of compound 25-14. LCMS (ESI) m/z: 627.0 (M+1) ⁺ . The crude product was used directly in the next step.

Step 14: Add anhydrous potassium carbonate (99.19 mg) sequentially to a mixed solution of compound 25-14 (150 mg, TFA salt) in tetrahydrofuran (3.0 mL) and water (0.5 mL) at 0°C, Compound 1-5 (21.65 mg). The reaction solution was reacted at 0°C for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative column HPLC (column type: Shim-pack C18 150*25mm*10μm), mobile phase (0.225% formic acid water: acetonitrile), gradient: 8%-38%, 10 minutes). Compound 25 was obtained. ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.32-8.31(m,1H),7.56-7.52(m,1H),7.28-7.23(m,1H),7.18(m,1H),7.07-7.05( m,2H),6.87-6.78(m,1H),6.01-5.96(m,1H),5.48-5.43(m,1H),3.49-3.49(m,1H),3.25-3.24(m,4H), 2.99-2.97 (m, 4H), 2.22 (m, 3H), 1.38-1.17 (m, 6H). LCMS (ESI) m/z: 681.17 (M+1) ⁺ .

Example 26

The first step: add potassium carbonate (4.275 grams) in the acetonitrile (100 milliliters) solution of compound 26-1 (10 grams), cool to 0 degree, add compound 7-2 (10.11 grams) in batches, then at 25 degrees Celsius Stir for 16 hours. It was filtered, concentrated to dryness, slurried in a mixed solvent of ethyl acetate and petroleum ether (volume ratio 1:1, 200 ml) at 25°C for 2 hours, filtered and concentrated to obtain compound 26-2. LCMS (ESI) m/z: 261.9 (M+1) ⁺ .

The second step: at 0 DEG C, cesium carbonate (16.15 g) was added to compound 26-2 (13.3 g) in acetonitrile (150 ml), and then trifluoroacetyl vinyl vinyl ether (8.50 g) was added in batches. Stir at 25°C for 2 hours, filter and concentrate to dryness to obtain compound 26-3. LCMS (ESI) m/z: 401.8 (M+1+ _H2O ) ⁺ .

Step 3: Triethylamine (10.54 g) was added to a solution of compound 26-3 (20 g) in trifluoroethanol (100 ml), and the mixed system was stirred at 80° C. for 12 hours. Concentrate to dryness, dilute with water (200 ml) and ethyl acetate (200 ml), adjust the pH to 3 with 1 mol/L hydrochloric acid aqueous solution, extract with ethyl acetate, discard the organic phase, and use 1 mol/L hydrochloric acid for the aqueous phase Adjust the pH to 8 with aqueous sodium hydroxide solution, a yellow solid precipitates, filter the solid, suspend the solid in water (300 ml), adjust the pH to 2 with 1 molar hydrochloric acid, and extract with ethyl acetate (100 ml*2) , the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain compound 26-4. LCMS (ESI) m/z: 351.8 (M+1) ⁺ .

Step 4: Add potassium phosphate (14.47 g) and tribromopyridinium salt (32.70 g) to a solution of compound 26-4 (12 g) in acetonitrile (180 ml), then stir at 50 degrees Celsius for 3 hours, then wash with saturated sodium sulfite (100 ml) to quench the reaction, extracted with ethyl acetate (100 ml), washed the organic phase with saturated brine (50 ml), dried over anhydrous sodium sulfate (10 g), and concentrated to dryness to obtain the crude product, which was dissolved in 50 ml of methyl Stir in tributyl ether at 25°C for 16 hours, filter, and dry the filter cake to obtain compound 26-5. LCMS (ESI) m/z: 387.7 (M+3) ⁺ .

Step 5: Add Pd ₂ (dba) ₃ (1.89 g) and Xantphos (2.39 g) in compound 26-5 (8 g) and compound 6-4 (3.11 g) in dioxane (150 ml), Cesium carbonate (13.47 grams), the reaction system was replaced with nitrogen, heated to 100 degrees Celsius and stirred for 16 hours. Cooled to 25 degrees Celsius, filtered, concentrated to dryness, diluted with ethyl acetate (200 ml), washed with water (20 ml), washed with saturated brine (20 ml), concentrated to dryness to obtain a crude product, column chromatography (eluent: petroleum Ether: ethyl acetate = 10:1 to 20:1) purification to obtain compound 26-6. ¹ H NMR (400MHz, CHLOROFORM- d )δ 8.40(d, J =4.9Hz,1H),7.52-7.39(m,1H),7.23(s,2H),7.03(d, J =4.8Hz,1H) ,6.70(br d, J =4.4Hz,1H),6.62(d, J =7.8Hz,1H),5.73(d, J =7.8Hz,1H),3.25-3.06(m,1H),2.20-2.11 (m,3H), 1.21-1.07(m,6H). LCMS (ESI) m/z: 455.9 (M+1) ⁺ .

Step 6: Add NBS (1.33 g) in portions to a solution of compound 26-6 (3.4 g) in dichloromethane (60 ml) at 0°C, stir at 28°C for 30 minutes, add saturated sodium sulfite (20 ml) , the separated organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was mixed with petroleum ether and methyl tertiary butyl ether (volume ratio 1:1, 50 ml) at 25 degrees Celsius Slurry for 2 hours, filter and dry to obtain compound 26-7. LCMS (ESI) m/z: 535.8 (M+3) ⁺ .

Step 7: Add zinc bromide (168.31 mg) in compound 26-7 (4 g), zinc cyanide (438.82 mg), zinc powder (488.73 mg) in dimethylformamide (60 ml) solution, Nitrogen replacement, DPPF (828.69 g) and Pd ₂ (dba) ₃ (684.41 mg) were added, nitrogen replacement and stirring at 120° C. for 2 hours. After being cooled to room temperature, the mother liquor was filtered and concentrated to dryness to remove dimethylformamide, then diluted with ethyl acetate (150 ml), washed with saturated brine (50 ml), concentrated to dryness to obtain a crude product, and passed through column chromatography (washing Removal of ethyl acetate:petroleum ether=1:10 to 1:3) was purified to obtain compound 26-8. LCMS (ESI) m/z: 480.9 (M+1) ⁺ .

Step 8: Compound 26-8 (1.7 g) was added in batches to concentrated sulfuric acid (35 ml, purity 98%), heated to 60°C and stirred for 16 hours, cooled to room temperature, poured into ice water (200 ml) Add 5 mol/L aqueous sodium hydroxide solution to pH 8, extract with ethyl acetate (200 ml), wash the combined organic phase with brine (120 ml), and dry over anhydrous sodium sulfate (10 g) , and concentrated by filtration to obtain compound 26-9. LCMS (ESI) m/z: 498.9 (M+1) ⁺ .

Step 9: Add sodium hydride (408.52 mg, mass percent: 60%) to a solution of compound 26-9 (1.7 g) in N,N-dimethylacetamide (20 ml) at 0°C, and the reaction solution Stir at room temperature for 10 minutes, add carbonyldiimidazole (1.66 g) in batches, and stir the reaction solution at 0-25 degrees Celsius for 50 minutes. The reaction solution was poured into ice water (100 ml), adjusted to pH 3-4 with 1 mol/liter aqueous hydrochloric acid, then adjusted to pH=7-8 with saturated aqueous sodium bicarbonate, and ) extraction, the organic phase was dried with anhydrous sodium sulfate, and concentrated to dryness to obtain compound 26-10. LCMS (ESI) m/z: 524.9 (M+1) ⁺ .

Step 10: Add PyBrOP (1.77 g) and diisopropylethylamine (738.10 mg) to a solution of compound 26-10 (1.0 g) in N,N-dimethylformamide (10 ml), at 25 Stir for 1 hour at °C. Compound 1-1 (1.06 g) was added and heated to 100° C. for 12 hours. Cool to 25 degrees, dilute with ethyl acetate (100 ml), wash with water (20 ml*3), then wash with saturated brine (50 ml), and concentrate the organic phase to obtain the crude product by preparative HPLC ((column model: Phenomenex Synergi Max-RP (250*50mm*10μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 35%-65%, 22 minutes)) was purified to obtain compound 26-11. LCMS (ESI) m/z: 693.0 (M+1) ⁺ .

Step 11: Add trifluoroacetic acid (3 ml) to a solution of compound 26-11 (800 mg) in dichloromethane (6 ml), stir the reaction solution at 25 degrees Celsius for 30 minutes, and concentrate to dryness to obtain compound 26-12 of trifluoroacetate. The crude product was used directly in the next step. LCMS (ESI) m/z: 593.1 (M+1) ⁺ .

Step twelve: Potassium carbonate (316.29 mg) was added to a solution of compound 26-12 (940 mg, 2 trifluoroacetate salt) in tetrahydrofuran (20 ml) and water (10 ml), the mixture was stirred at 25 degrees Celsius for 10 minutes, and then compound 1- 5 (124.28 mg), stirred at 25°C for 20 minutes. It was extracted with ethyl acetate (50 mL), washed with saturated brine (10 mL), and the organic phase was concentrated to obtain compound 26.

Compound 26 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 5μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 6.7 minutes, 730 minutes) separation and purification Compound 26A and Compound 26B.

Compound 26A and compound 26B were detected by SFC [column model: Column: Chiralceel OD-3 50×4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% Diethylamine); gradient (B%): 5%-40%] to obtain: the retention time of compound 26A is 1.62min, e.e. value is 100%; the retention time of compound 26B is 1.74min, e.e. value is 100%.

Compound 26A (retention time=1.62min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.31(d, J =4.8Hz,1H),7.82(t, J =1.8Hz,1H),7.62(s, 1H),7.44(s,1H),7.17(s,1H),7.07(d, J =4.9Hz,1H),6.93-6.79(m,1H),6.27-6.12(m,1H),5.83-5.71 (m, 1H), 4.06-3.73 (m, 8H), 2.72-2.79 (m, 1H), 2.00 (s, 3H), 1.17-0.92 (m, 6H). LCMS (ESI) m/z: 647.0 (M+1) ⁺ .

Compound 26B (retention time=1.74min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.31(d, J =4.9Hz, 1H), 7.93-7.77(m, 1H), 7.62(s, 1H), 7.44(s,1H),7.29-7.00(m,2H),6.97-6.79(m,1H),6.26-6.12(m,1H),5.89-5.61(m,1H),4.02-3.75(m,8H ), 2.81-2.71(m,1H), 2.04-1.94(m,3H), 1.12-0.95(m,6H). LCMS (ESI) m/z: 647.0 (M+1) ⁺ .

Example 27

The first step: at 20-30 degrees Celsius, add tripyrrolidinyl phosphorus bromide hexafluorophosphate (532.47 mg), diisopropyl Ethylamine (221.43 mg) and compound 3-1 (367.16 mg). The reaction solution was reacted at 60° C. for 12 hours. The reaction liquid was diluted with water (20 ml), extracted with ethyl acetate (10 ml*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 27-1. LCMS (ESI) m/z: 721.4 (M+1) ⁺ .

Step 2: To a solution of compound 27-1 (380 mg) in dichloromethane (3 ml) was added trifluoroacetic acid (2.93 g) in one portion at 20-30°C. The reaction solution was reacted at 25° C. for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 27-2. LCMS (ESI) m/z: 621.1 (M+1) ⁺ . The crude product was used directly in the next step.

third step:

At 0°C, to a mixed solution of compound 27-2 (290 mg, trifluoroacetate) in tetrahydrofuran (3.0 mL) and water (0.5 mL), anhydrous potassium carbonate (64.49 mg), acryloyl chloride were added sequentially in one portion. (42.23 mg). The reaction solution was reacted at 0°C for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first subjected to preparative HPLC (column Model: Phenomenex Gemini-NX C18 75*30mm*3μm), mobile phase (0.225% formic acid water: acetonitrile), gradient: 32%-62%, 7 minutes) purification to obtain compound 27.

Compound 27 was then passed through SFC (column model: Chiralpak IC-3 (250*30mm I.D., 5 μm), mobile phase: isopropanol (0.05% diethylamine), gradient: carbon dioxide critical fluid 40%-40%, 5 minutes, 40 minutes) separation and purification to obtain compound 27A and compound 27B.

Compound 27A and compound 27B were detected by SFC [column model: Column: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient ( B%): 50%-50%] Obtained: the residence time of compound 27A is 2.933min, and the e.e. value is 100%; the residence time of compound 27B is 4.568min, and the e.e. value is 100%.

Compound 27A (retention time = 2.933 min): LCMS (ESI) m/z: 675.18 (M+1) ⁺ .

Compound 27B (retention time=4.568min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.304-8.292(m,1H),7.812(m,1H),7.826(m,1H),7.418(m,1H ),7.067-7.054(m,2H),6.880-6.788(m,1H),6.211-6.189(m,1H),5.770-5.735(m,1H),4.751-4.457(m,2H),4.137-3.745 (m, 4H), 3.553-3.455 (m, 1H), 1.956 (m, 3H), 1.338-1.132 (m, 6H), 1.072-0.989 (m, 6H). LCMS (ESI) m/z: 675.18 (M+1) ⁺ .

Example 28

The first step: at 10-25 degrees Celsius, add tripyrrolidinyl phosphonium bromide hexafluorophosphate (1.77 g) at one time to compound 7-13 (0.5 g) in DMAC (5 ml) solution, compound 2- 1 (1.52 g, 7.59 mmol, 8.0 equivalents), the reaction solution was reacted at 60 degrees Celsius for 12 hours. Water (10 mL) was slowly added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (5 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was prepared and purified to obtain compound 28-1. LCMS (ESI) m/z: 709.2 (M+1) ⁺ .

Step 2: To a solution of compound 28-1 (230 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g) in one portion at 10-25 °C. The reaction solution was reacted at 15° C. for 0.5 hour. The reaction solution was concentrated to obtain a residue. Water (10 ml) was added to the residue, the aqueous phase was adjusted to pH=8 with solid sodium bicarbonate, extracted with ethyl acetate (5 ml*3), the organic phases were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to obtain compound 28-2. LCMS (ESI) m/z: 609.2 (M+1) ⁺ .

third step:

To a mixed solution of compound 28-2 (0.2 g) in tetrahydrofuran (4 ml) and water (1 ml) were added anhydrous potassium carbonate (136.17 mg) and acryl chloride (29.72 mg) in sequence at 0°C. The reaction solution was reacted at 15° C. for 15 minutes. Water (10 ml) was added to the reaction solution, extracted with ethyl acetate (5 ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (petroleum ether: ethyl acetate: methanol = 3:4:1) to obtain compound 28.

Compound 28 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 2.6 minutes, 50 minutes) 28-P1 (mixture of residence time=3.397 min and residence time=3.789 min) and 28-P2 (mixture of residence time=1.402 min and residence time=1.565 min) were obtained.

28-P1 is then prepared by SFC (column model: DAICEL CHIRALPAK AD (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 20%-20%, 4.6 minutes, 120 minutes ) separation and purification to obtain compound 28A and compound 28B.

28-P2 is then prepared by SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 5 minutes, 45 minutes ) separation and purification to obtain compound 28C and compound 28D.

Compound 28A and Compound 28B were detected by SFC [column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); Gradient (B%): 5%-15%] obtained: the retention time of compound 28A was 3.376min, and the e.e. value was 100%; the retention time of compound 28B was 3.789min, and the e.e. value was 100%.

Compound 28C and compound 28D were detected by SFC [column model: Column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] obtained: the retention time of compound 29C was 1.408 min, and the ee value was 100%; the retention time of compound 29D was 1.571 min, and the ee value was 100%. Compound 28A: ¹ H NMR (400MHz, METHANOL- d ₄ ) δ 8.23(d, J =5.0Hz, 1H), 7.64(ddd, J =5.5,8.3,9.1Hz, 1H), 7.19-7.09(m, 2H ),7.06(d, J =5.0Hz,1H),6.81-6.65(m,1H),6.21(br dd, J =3.3,16.9Hz,1H),5.77-5.67(m,1H),4.83-4.79 (m,1H),4.47(s,1H),4.31-4.19(m,1H),3.98(br d, J =13.4Hz,1H),3.70-3.55(m,2H),3.15-3.02(m, 1H),2.79-2.69(m,1H),2.00(s,3H),1.37(d, J =6.6Hz,3H),1.12-1.05(m,3H),0.97(d, J =6.9Hz,3H ). LCMS (ESI) m/z: 663.3 (M+1) ⁺ .

Compound 28B: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.23(d, J =5.0Hz, 1H), 7.70-7.59(m, 1H), 7.20-7.08(m, 2H), 7.04(d, J =5.0Hz,1H),6.82-6.65(m,1H),6.26-6.14(m,1H),5.73(dd, J =1.9,10.5Hz,1H),4.79(br s,1H),4.53-4.31 (m,1H),4.30-4.17(m,1H),4.17-3.92(m,1H),3.72-3.55(m,2H),3.14-3.02(m,1H),2.80-2.71(m,1H) ,1.98(s,3H),1.37(d, J =6.8Hz,3H),1.11-1.06(m,3H),1.02-0.97(m,3H). LCMS (ESI) m/z: 663.4 (M+1) ⁺ .

Compound 28C: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.23(d, J =5.0Hz, 1H), 7.65(dt, J =5.5,8.7Hz, 1H), 7.18-7.09(m, 2H), 7.06(d, J =5.0Hz,1H),6.81-6.64(m,1H),6.26-6.15(m,1H),5.73(dd, J =1.9,10.6Hz,1H),4.81(br s,1H ),4.53-4.31(m,1H),4.30-4.20(m,1H),4.16-3.94(m,1H),3.70-3.44(m,2H),3.19-3.00(m,1H),2.76-2.64 (m,1H),2.01(s,3H),1.38(d, J =6.6Hz,3H),1.10-1.06(m,3H),0.97(d, J =6.8Hz,3H). LCMS (ESI) m/z: 663.2 (M+1) ⁺ .

Compound 28D: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.23(d, J =5.0Hz, 1H), 7.64(dt, J =5.5,8.7Hz, 1H), 7.18-7.09(m, 2H), 7.04(d, J =5.0Hz, 1H), 6.73(dt, J =10.9, 17.5Hz, 1H), 6.21(br d, J =17.2Hz, 1H), 5.77-5.68(m, 1H), 4.83- 4.77(m,1H),4.53-4.32(m,1H),4.31-4.20(m,1H),4.17-3.93(m,1H),3.70-3.43(m,2H),3.20-3.02(m,1H ),2.72(br s,1H),1.99(s,3H),1.37(br d, J =6.6Hz,3H),1.11-1.06(m,3H),0.99(d, J =6.7Hz,3H) . LCMS (ESI) m/z: 663.1 (M+1) ⁺ .

Example 29

The first step: at 10-25 degrees Celsius, add tripyrrolidinylphosphonium bromide hexafluorophosphate (1.77 grams) in one go to compound 7-13 (0.5 grams) in DMAC (10 milliliters) solution, compound 3- 1 (1.63 grams), the reaction solution was reacted at 60 degrees Celsius for 12 hours. Water (10 mL) was slowly added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (5 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was prepared and purified to obtain compound 29-1. LCMS (ESI) m/z: 723.2 (M+1) ⁺ .

Second step: To a solution of compound 29-1 (0.26 g) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g) in one portion at 10-25 °C. The reaction solution was reacted at 15° C. for 0.5 hour. The reaction solution was concentrated to obtain a residue. Add water (10 ml) to the residue, adjust the aqueous phase to pH=8 with solid sodium bicarbonate, extract with ethyl acetate (5 ml*3), combine the organic phases, wash with brine (10 ml*1) anhydrous sodium sulfate Dry, filter, and concentrate the filtrate to obtain compound 29-2. LCMS (ESI) m/z: 623.3 (M+1) ⁺ .

third step:

To a mixed solution of compound 29-2 (0.24 g) in tetrahydrofuran (4 ml) and water (1 ml) were added anhydrous potassium carbonate (159.73 mg) and acryl chloride (34.87 mg) in sequence at 0°C. The reaction solution was reacted at 15° C. for 15 minutes. Water (10 ml) was added to the reaction solution, extracted with ethyl acetate (5 ml*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (petroleum ether: ethyl acetate: methanol = 3:4:1) to obtain compound 29.

Compound 29 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 3.0 minutes, 40 minutes) Example 29-P1 (and Example 29-P2.

29-P1 was then prepared by SFC (column model: DAICEL CHIRALPAK AD (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 5.3 minutes, 260 minutes ) separation and purification to obtain compound 29A and compound 29B.

29-P2 was then prepared by SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide Carbon critical fluid 25%-25%, 5.9 minutes, 240 minutes) separation and purification to obtain compound 29C and compound 29D.

Compound 29A and Compound 29B were detected by SFC [column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); Gradient (B%): 5%-15%] Obtained: the retention time of compound 29A was 3.020min, and the e.e. value was 100%; the retention time of compound 29B was 3.171min, and the e.e. value was 100%.

Compound 29C and compound 29D were detected by SFC [column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] Obtained: the retention time of compound 29C was 1.346 min, and the e.e. value was 100%; the retention time of compound 29D was 1.483 min, and the e.e. value was 100%.

Compound 29A: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.23(d, J =5.0Hz, 1H), 7.64(dt, J =5.5,8.7Hz, 1H), 7.18-7.10(m, 2H), 7.06(d, J =5.1Hz,1H),6.81-6.63(m,1H),6.24-6.14(m,1H),5.72(ddd, J =1.8,7.1,10.6Hz,1H),4.88-4.77( m,1H),4.50-4.39(m,1H),4.29-4.18(m,1H),4.13(br d, J =14.0Hz,1H),3.86-3.70(m,2H),2.76(qd, J =6.7,10.6Hz,1H),1.93(s,3H),1.38(d, J =6.6Hz,3H),1.30-1.19(m,3H),1.08(dd, J =1.6,6.7Hz,3H) ,0.98 (dd, J =1.8,6.7Hz,3H). LCMS (ESI) m/z: 677.1 (M+1) ⁺ .

Compound 29B: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.23(d, J =5.0Hz, 1H), 7.68-7.60(m, 1H), 7.18-7.09(m, 2H), 7.04(d, J =5.5Hz,1H),6.80-6.62(m,1H),6.23-6.14(m,1H),5.77-5.67(m,1H),4.87-4.77(m,1H),4.50-4.40(m,1H ),4.28-4.19(m,1H),4.16-4.08(m,1H),3.86-3.68(m,2H),,2.85-2.72(m,1H),1.95(s,3H),1.38(d, J =6.6Hz, 3H), 1.32-1.19(m, 3H), 1.08(dd, J =1.7, 6.7Hz, 3H), 1.00(dd, J =1.5, 6.8Hz, 3H). LCMS (ESI) m/z: 677.1 (M+1) ⁺ .

Compound 29C: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.23(d, J =5.0Hz, 1H), 7.64(dt, J =5.6, 8.7Hz, 1H), 7.19-7.03(m, 3H), 6.81-6.62(m,1H),6.19(ddd, J =1.7,6.3,16.7Hz,1H),5.72(ddd, J =1.7,7.0,10.5Hz,1H),4.86-4.80(m,1H), 4.48-4.40(m,1H),4.27-4.07(m,2H),3.90-3.69(m,2H),2.63(quin, J =6.8Hz,1H),1.98(s,3H),1.38(d, J =6.6Hz, 3H), 1.28-1.19(m, 3H), 1.05(d, J =6.7Hz, 3H), 0.96(d, J =6.8Hz, 3H). LCMS (ESI) m/z: 677.3 (M+1) ⁺ .

Compound 29D: ¹ H NMR (400MHz, METHANOL- d ₄ )δ 8.24(d, J =4.9Hz, 1H), 7.65(dt, J =5.6, 8.7Hz, 1H), 7.21-7.01(m, 3H), 6.81-6.61(m,1H),6.19(ddd, J =1.5,6.2,16.7Hz,1H),5.77-5.67(m,1H),4.88-4.82(m,1H),4.49-4.40(m,1H ),4.28-4.07(m,2H),3.87-3.71(m,2H),,2.65(td, J =6.7,13.5Hz,1H),1.96(s,3H),1.38(d, J =6.7Hz , 3H), 1.28(br d, J =6.7Hz, 2H), 1.22(s, 1H), 1.06(d, J =6.7Hz, 3H), 0.99(d, J =6.8Hz, 3H). LCMS (ESI) m/z: 677.3 (M+1) ⁺ .

Example 30

The first step: at 20-30 degrees Celsius, compound 7-2 (17.77 grams) and potassium carbonate (7.49 grams) were added to compound 30-1 (14 grams) in acetonitrile (140 milliliters) solution, and the reaction solution was heated at 15 degrees Celsius The reaction was carried out for 16 hours. Ethyl acetate (300 mL) and water (300 mL) were added to the reaction solution, the organic phase was separated, washed with saturated brine (300 mL), and the organic phase was concentrated under reduced pressure to obtain a residue. The residue was slurried with petroleum ether (100 mL) for half an hour, filtered, and the filter cake was dried to obtain compound 30-2. LCMS (ESI) m/z: 230.1 (M+1) ⁺ .

The second step: at 20-30 degrees Celsius, add cesium carbonate (34.83 grams) and compound 7-4 (18.87 grams) successively to the solution of compound 30-2 (24.50 grams) in acetonitrile (245 milliliters), and the reaction solution is heated under nitrogen. React under protection at 15°C for 3 hours. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction solution, the organic phase was separated, washed with saturated brine (200 mL), and the organic phase was concentrated under reduced pressure to obtain a residue. Add petroleum ether:ethyl acetate=10:1 (60 ml) to the residue, stir for half an hour, filter, and dry the filter cake to obtain compound 30-3. LCMS (ESI) m/z: 352.2 (M+1) ⁺ .

The third step: at 20-30 degrees Celsius, add triethylamine (17.29 grams) to the solution of compound 30-3 (20 grams) in trifluoroethanol (200 milliliters), and react the reaction solution at 95 degrees Celsius under nitrogen protection 16 hours. The reaction solution was concentrated to obtain a residue, petroleum ether (100 ml) was added to the residue and stirred for 1 hour, the mixture was filtered, and the filter cake was dried to obtain compound 30-4. LCMS (ESI) m/z: 320.2 (M+1) ⁺ .

The fourth step: at 20-30 degrees Celsius, add tribromopyridinium salt (24.05 grams) and potassium phosphate (11.97 grams) successively to compound 30-4 (12 grams) in acetonitrile (150 milliliters) solution, the reaction solution is in React at 15°C for 18 hours. Saturated aqueous sodium sulfite (100 ml) was added to the reaction solution, the mixture was extracted with ethyl acetate (200 ml), the organic phase was washed with saturated brine (200 ml), and the organic phase was concentrated under reduced pressure to obtain compound 30-5. The crude product was used directly in the next step. LCMS (ESI) m/z: 353.9 (M+1) ⁺ .

Step 5: Add compound 6-4 (4.67 grams), Pd ₂ (dba) ₃ (2.59 gram), Xantphos (3.27 grams) and cesium carbonate (18.40 grams), the reaction liquid nitrogen protection, reacted at 100 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, and the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound 30-6. LCMS (ESI) m/z: 424.1 (M+1) ⁺ .

Step 6: Add NBS (420.39 mg) to a solution of compound 30-6 (1.0 g) in dichloromethane (10 ml) at 20-30°C, and react at 15°C for 13 hours under the protection of reaction liquid nitrogen. Saturated aqueous sodium sulfite (15 mL) was added to the reaction solution, and the organic phase was separated and washed with brine (20 mL). The organic phase was concentrated to obtain a residue, methanol (3 mL) was added to the residue and stirred for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 30-7. LCMS (ESI) m/z: 503.9 (M+3) ⁺ .

Step 7: Add zinc powder (78.11 mg) and zinc cyanide ( 140.27 mg), Pd ₂ (dba) ₃ (109.39 mg), DPPF (132.45 mg) and zinc bromide (53.80 mg), the reaction was protected by liquid nitrogen, and reacted at 110 degrees Celsius for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (15 milliliters), the filtrate was washed with brine (30 milliliters), the organic phase was separated, concentrated to obtain a residue, and the residue was washed with a silica gel column (eluent: petroleum ether: ethyl acetate Ester=10:1 to 3:1) Purification gave compound 30-8. LCMS (ESI) m/z: 449.0 (M+1) ⁺ .

Step 8: A solution of compound 30-8 (0.5 g) in concentrated sulfuric acid (4.60 g) was reacted at 90°C for 1.5 hours. The reaction solution was added to saturated aqueous sodium bicarbonate (250 ml), extracted with ethyl acetate (20 ml*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 30-9. LCMS (ESI) m/z: 467.1 (M+1) ⁺ .

Step 9: Add carbonyldiimidazole (417.19 mg) and sodium hydride (102.91 mg, Mass percentage: 60%), the reaction solution was reacted at 15 degrees Celsius for 0.5 hours. The reaction solution was poured into water (30 mL), and hydrochloric acid (2 mol/L) was slowly added dropwise until the pH was about 1. Add saturated aqueous sodium bicarbonate solution to the mixture until the pH is about 10, extract the mixture with ethyl acetate (30 ml*2), combine the organic phases, wash with saturated brine (50 ml), separate the organic phase, and dry over anhydrous sodium sulfate , filtered, and the filtrate was concentrated to obtain compound 30-10. The crude product was used directly in the next step. LCMS (ESI) m/z: 493.1 (M+1) ⁺ .

Step 10: To a solution of compound 30-10 (500 mg) in N,N-dimethylacetamide (5 mL) was added N,N-diisopropylethylamine (393.72 mg) and tripyrrolidinylphosphonium bromide hexafluorophosphate (946.76 mg) and compound 1-1 (567 mg), the reaction solution was reacted at 110 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (40 mL*2), the organic phases were combined, washed with saturated brine (50 mL), the organic phase was separated, and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 1:1 to 0:1) to obtain compound 30-11. LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

Step 11: To a solution of compound 30-11 (550 mg) in dichloromethane (12 mL) was added trifluoroacetic acid (6.16 g, 54.02 micromoles, 4 mL, 64.89 equiv) at 10-15 °C . The reaction solution was reacted at 15° C. for 1 hour under nitrogen protection. The reaction solution was concentrated to obtain the trifluoroacetic acid salt of compound 30-12. The crude product was used directly in the next step. LCMS (ESI) m/z: 561.1 (M+1) ⁺ .

Step twelve:

To a solution of compound 30-12 (700 mg, trifluoroacetate salt) in THF (14 mL) and water (7 mL) was added potassium carbonate (286.84 mg) and propylene at 10-15 °C Acyl chloride (93.92 mg). The reaction solution was reacted at 15° C. for 15 minutes under nitrogen protection. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, the organic phase was separated, washed with saturated brine (50 mL), and the organic phase was concentrated to obtain racemic compound 30. Compound 30 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IG (250*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4 minutes, 30 minutes) Compound 30A (retention time = 0.540 min) and compound 30B (retention time = 0.735 min).

Compound 30A and compound 30B were detected by SFC [column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] Obtained: the residence time of compound 30A is 0.540min, and the e.e. value is 100%; the residence time of compound 30B is 0.753min, and the e.e. value is 100%.

Compound 30A (retention time=0.540min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.30(d, J =4.9Hz, 1H), 7.47(tt, J =2.2, 9.3Hz, 1H), 7.29( br d, J =8.6Hz,1H),7.16(s,1H),7.14(br d, J =8.6Hz,1H),7.06(d, J =4.9Hz,1H),6.85(dd, J =10.4 ,16.7Hz,1H),6.19(dd, J =2.3,16.7Hz,1H),5.78-5.74(m,1H),3.98-3.72(m,8H),2.75(quin, J =6.7Hz,1H) ,1.99(s,3H),1.08-0.97(m,6H). LCMS (ESI) mz: 615.1 (M+1) ⁺ .

Compound 30B (retention time=0.735min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.29(d, J =4.9Hz, 1H), 7.47(tt, J =2.3, 9.3Hz, 1H), 7.29( br d, J =8.6Hz,1H),7.19-7.10(m,2H),7.06(d, J =5.4Hz,1H),6.85(dd, J =10.4,16.7Hz,1H),6.18(dd, J =2.3,16.7Hz,1H),5.79-5.68(m,1H),3.97-3.71(m,8H),2.74(quin, J =6.6Hz,1H),1.98(s,3H),1.12-0.94 (m,6H). LCMS (ESI) m/z: 615.1 (M+1) ⁺ .

Example 31

Step 1: To a solution of compound 30-10 (300 mg) in DMAC (5 ml) were added PYBROP (568.05 mg), DIEA (157.49 mg) and compound 3-1 (391.70 mg). The reaction solution was reacted at 100° C. for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column type: Phenomenex luna C18 (150*40mm*15μm), mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile, gradient: 29%-59%, 11 minutes] to obtain compound 31- 1. LCMS (ESI) m/z: 689.3. (M+1) ⁺ .

Second step: Compound 31-1 (120 mg) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction solution was reacted at 25°C for 1 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 31-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 589.3 (M+1) ⁺ .

third step:

Potassium carbonate (35.22 mg) was added to a mixed solution of compound 31-2 (150 mg) in tetrahydrofuran (4 ml) and water (1 ml), and after adjusting the pH to 8, compound 1-5 (23.07 mg) was added to the reaction solution. mg). React the reaction solution at 0°C for 15 minutes, add saturated aqueous sodium bicarbonate solution to the reaction solution, adjust the pH to 8, extract with ethyl acetate (10 ml*2), and wash the organic phase with saturated brine (5 ml*2) After drying over anhydrous sodium sulfate and concentrating to obtain compound 31.

Compound 31 was separated by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10um), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 6.7 minutes, 50 minutes) to obtain the compound 31A and compound 31B.

Compound 31A and compound 31B were detected by SFC [column model: Column: Chiralpak IC-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient ( B%): 40%-40%] to obtain: the retention time of compound 31A is 1.845 min; the retention time of compound 31B is 2.980 min.

Compound 31A (retention time = 1.845 min): LCMS (ESI) m/z: 643.3.(M+1) ⁺ .

Compound 31B (retention time = 2.980 min): LCMS (ESI) m/z: 643.3.(M+1) ⁺ .

Example 32

Step 1: Compound 32-1 (10 g) and methyl malonyl chloride (11.26 g) were dissolved in dichloromethane (100 ml), and the reaction solution was reacted at 20° C. for 1 hour. The reaction solution was concentrated to obtain the crude compound 32-2, which was directly used in the next step. LCMS (ESI) m/z: 246.0. (M+1) ⁺ .

Second step: Add cesium carbonate (22.55 g) and 4-ethoxy-1,1,1-trifluoro-3-butene- 2-ketone (12.22 grams), the reaction solution was reacted at 20 degrees Celsius for 1 hour. The reaction solution was poured into water (250 ml), then extracted with ethyl acetate (250 ml*3), the combined organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-3, the crude product was used directly in the next step. LCMS (ESI) m/z: 368.0. (M+1) ⁺ .

Step 3: Compound 32-3 (25 g) and triethylamine (13.76 g) were dissolved in trifluoroethanol (250 ml), and the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was acidified with 1 mol/L hydrochloric acid aqueous solution (250 ml), then extracted with ethyl acetate (250 ml*2), the obtained organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, and filtered , the filtrate was concentrated to obtain crude compound 32-4, which was directly used in the next step. LCMS (ESI) m/z: 336.0. (M+1) ⁺ .

Step 4: Add pyridinium tribromide (43.83 g) and potassium phosphate (29.09 g) to a solution of compound 32-4 (23 g) in acetonitrile (250 ml), and stir the reaction solution at 50°C for 12 hours. The reaction solution was poured into water (200 ml), then extracted with ethyl acetate (200 ml*3), the obtained organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-5, the crude product was used directly in the next step. LCMS (ESI) m/z: 369.9. (M+1) ⁺ .

Step 5: To a solution of compound 32-5 (20 g) in dioxane (200 ml) was added 2-isopropyl-4-methylpyridin-3-amine (8.51 g), cesium carbonate (4.54 g ), three (dibenzylidene acetone) dipalladium (4.94 grams) and 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene (6.25 grams), the reaction solution at 100 degrees Celsius , and stirred for 12 hours under nitrogen protection. The reaction solution was filtered, the filter cake was washed with ethyl acetate (150 ml*3), the filtrate was concentrated to obtain a residue, petroleum ether/ethyl acetate (200 ml/200 ml) was added to the residue and stirred for 1 hour, the mixture was filtered, and the The cake was dried to obtain compound 32-6. LCMS (ESI) m/z: 440.1 (M+1) ⁺ .

Step 6: Add N-bromosuccinimide (4.45 g) to a solution of compound 32-6 (11 g) in dichloromethane (120 ml) at 0°C, and stir the reaction solution at 0°C 0.5 hours. The reaction solution was quenched with saturated aqueous sodium sulfite (150 ml) at 0°C, washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-7, which was directly used in the following step. LCMS (ESI) m/z: 518.0.(M+1) ⁺ .

Step 7: Add zinc powder (1.10 g), zinc cyanide (2.5 g), zinc bromide ( 282.19 mg), 1,1'-bis(diphenylphosphino)ferrocene (2.78 grams) and tris(dibenzylideneacetone)dipalladium (2.29 grams), the reaction solution was stirred at 120 degrees Celsius under nitrogen protection 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (250 ml*3), the filtrate was concentrated to obtain a residue, methanol (50 ml) was added to the residue and stirred for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 32-8 . LCMS (ESI) m/z: 465.1 (M+1) ⁺ .

Step 8: A solution of compound 32-8 (8 g) in concentrated sulfuric acid (40 ml) was reacted at 60°C for 12 hours. The reaction solution was slowly added dropwise to 2 mol/L sodium hydroxide (600 ml) aqueous solution, then extracted with ethyl acetate (250 ml*3), the obtained organic phase was washed with saturated brine (250 ml) and washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate to obtain crude compound 32-9, which is directly used in the next step. LCMS (ESI) m/z: 483.1. (M+1) ⁺ .

Step 9: Sodium hydride (1.99 mg, mass percentage: 60%) and 1,1-carbonyldiimidazole (5.37 g) were added at one time to a solution of compound 32-9 (8 g) in tetrahydrofuran (100 ml), and the reaction The solution was stirred at 20 °C for 0.5 h. The reaction solution was poured into water (250 ml), acidified with 1 mol/L hydrochloric acid (50 ml), then extracted with ethyl acetate (150 ml*3), and the obtained organic phase was washed with saturated brine (200 ml) Afterwards, it was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-10, which was directly used in the next step. LCMS (ESI) m/z: 508.9. (M+1) ⁺ .

Step 10: Add N,N-diisopropylethylamine (6.48 g) and tripyrrolidinyl to a solution of compound 32-10 (8.5 g) in N,N-dimethylacetamide (100 ml) Phosphonium bromide hexafluorophosphate (15.57 g). The reaction solution was reacted at 20°C for 2 hours, and then compound 1-1 (9.33 g) was added. The reaction solution was reacted at 80° C. for 10 hours. The reaction solution was poured into water (300 ml), then extracted with ethyl acetate (150 ml*3), the obtained organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue . The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10μm), mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile, gradient: 25%-55%, 20 minutes] to obtain compound 32- 11. LCMS (ESI) m/z: 677.3. (M+1) ⁺ .

Step 11: To a solution of compound 32-11 (11 g) in dichloromethane (100 ml) was added trifluoroacetic acid (30.80 g). The reaction solution was reacted at 20°C for 0.5 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 32-12, and the crude product was directly used in the next step. LCMS (ESI) m/z: 577.3. (M+1) ⁺ .

Step twelve:

At 0°C, anhydrous potassium carbonate (11.0 g), acryl chloride (1.44 gram). The reaction solution was reacted at 0°C for 0.5 hours. Water (250 ml) was added to the reaction solution, extracted with ethyl acetate (250 ml*3), the obtained organic phase was washed with saturated brine (250 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32. Compound 32 was separated and purified by preparative SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 5.5 minutes, 150 minutes) 32-P1 (residence time=1.956min) and 32-P2 (retention time=4.491min).

32-P1 is then prepared by SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 6.0 minutes, 95 minutes ) separation and purification to obtain 32A and 32B.

32-P2 was then separated by preparative SFC (column model: DAICEL CHIRALPAK OD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 30%-30%, 6.2 minutes, 180 minutes) Purification afforded Compound 32C and Compound 32D.

Compound 32A and compound 32B were detected by SFC [column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] Obtained: the retention time of compound 32A was 2.274min, the e.e. value was 56.29%; the retention time of compound 32B was 2.642min, the e.e. value was 28.83%.

Compound 32C and compound 32D were detected by SFC [column model: Column: Chiralpak IC-3 50×4.6mm ID, 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient ( B%): 5%-40%] obtained: the residence time of compound 32C was 1.724min, and the ee value was 66.46%; the residence time of compound 32D was 1.915min, and the ee value was 38.83%. Compound 32A: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.43-8.20(m,1H),7.92-7.72(m,1H),7.52(br t, J =7.5Hz,2H),7.30-7.18( m,1H),7.14-7.00(m,1H),6.92-6.76(m,1H),6.28-6.13(m,1H),5.83-5.69(m,1H),3.97-3.74(m,8H), 2.84-2.68 (m, 1H), 2.05-1.92 (m, 3H), 1.10-1.04 (m, 3H), 1.02-0.95 (m, 3H). LCMS (ESI) m/z: 631.2 (M+1) ⁺ .

Compound 32B: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.35-8.27(m,1H),7.86-7.70(m,1H),7.55-7.36(m,2H),7.30-7.21(m,1H) ,7.14-7.02(m,1H),6.93-6.78(m,1H),6.28-6.13(m,1H),5.83-5.70(m,1H),3.97-3.77(m,8H),2.74-2.67( m, 1H), 2.04-1.94 (m, 3H), 1.10-0.97 (m, 6H). LCMS (ESI) m/z: 631.2 (M+1) ⁺ .

Compound 32C: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.36-8.28(m,1H),7.85-7.75(m,1H),7.54-7.37(m,2H),7.28-7.20(m,1H) ,7.14-7.04(m,1H),6.92-6.79(m,1H),6.26-6.13(m,1H),5.82-5.71(m,1H),3.96-3.75(m,8H),2.84-2.70( m, 1H), 2.03-1.93 (m, 3H), 1.09-1.04 (m, 3H), 1.01-0.96 (m, 3H). LCMS (ESI) m/z: 631.2 (M+1) ⁺ .

Compound 32D: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.35-8.30(m,1H),7.84-7.72(m,1H),7.55-7.34(m,2H),7.28-7.20(m,1H) ,7.12-7.03(m,1H),6.91-6.79(m,1H),6.26-6.14(m,1H),5.80-5.72(m,1H),3.99-3.76(m,8H),2.78-2.67( m, 1H), 2.03-1.94 (m, 3H), 1.08-0.97 (m, 6H). LCMS (ESI) m/z: 631.2 (M+1) ⁺ .

Example 33

Step 1: To a solution of compound 21-10 (500 mg) in DMAC (10 ml) were added PYBROP (1.42 g), DIEA (328.10 mg) and compound 4-2 (870.45 mg). The reaction solution was reacted at 100° C. for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi Max-RP 250*50mm*10μm, mobile phase: water (0.225% formic acid-acetonitrile, gradient: 32%-62%, 20 minutes] to obtain compound 33-1. LCMS (ESI) m/z: 689.1.(M+1) ⁺ .

Second step: Compound 33-1 (100 mg) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The reaction solution was reacted at 25°C for 1 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 33-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 589.2 (M+1) ⁺ .

third step:

Potassium carbonate (71.08 mg) was added to a mixed solution of compound 33-2 (140 mg) in tetrahydrofuran (4 ml) and water (1 ml), and after adjusting the pH to 8, compound 1-5 (15.52 mg) was added to the reaction solution. mg). React the reaction solution at 0°C for 15 minutes, add saturated aqueous sodium bicarbonate solution to the reaction solution, adjust the pH to 8, extract with ethyl acetate (10 ml*2), and wash the organic phase with saturated brine (5 ml*2) After drying over anhydrous sodium sulfate and concentrating to obtain compound 33. Compound 33 was separated by preparative SFC (column model: Phenomenex Gemini-NX C18 (75*30mm*3um), mobile phase: water 0.225% formic acid) acetonitrile, gradient: carbon dioxide critical fluid 28%-58%, 7 minutes) to obtain compound 33A and compound 33B.

Compound 33A and compound 33B were detected by SFC [column model: Column: Chiralpak IG-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol + acetonitrile (0.05% diethylamine); Gradient (B%): 40% methanol + (0.05% diethylamine)] to obtain: the retention time of compound 33A was 0.663 min; the retention time of compound 33B was 1.128 min.

Compound 33A (retention time=0.663min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.32(d, J =4.9Hz, 1H), 7.77-7.61(m, 1H), 7.44-7.30(m, 3H ),7.16-7.05(m,1H),6.89-6.74(m,1H),6.30-6.10(m,1H),5.89-5.68(m,1H),4.70-4.51(m,2H),4.40-4.04 (m,3H), 2.78-2.63(m,2H), 2.02-1.94(m,3H), 1.43-1.34(m,6H), 1.06-0.94(m,6H). LCMS (ESI) m/z: 643.2.(M+1) ⁺

Compound 33B (retention time=1.128min): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.36-8.25(m,1H),775-7.60(m,1H),742-7.30(m,3H),7.13 -7.05(m,1H),6.89-6.74(m,1H),624-614(m,1H),579-5.70(m,1H),4.73-4.51(m,2H),4.36-3.97(m, 3H), 2.75-267(m, 2H), 1.99-1.97(m, 3H), 1.42-1.36(m, 6H), 1.06-0.95(m, 6H). LCMS (ESI) m/z: 643.2. (M+1) ⁺ .

Example 34

The first step: Add PYBROP (3.64 grams) in the dimethylformamide (20 milliliters) solution of compound 23-10 (2 grams), diisopropylethylamine (1.51 grams), at 25 centigrade ++ degree After stirring for 1 hour, compound 3-1 (2.10 g) was added. The reaction solution was reacted at 100 degrees Celsius for 12 hours, the reaction solution was poured into water (50 milliliters), the solid was filtered, the filter cake was dissolved in ethyl acetate (100 milliliters), and separated and purified by column chromatography (eluent: petroleum ether : ethyl acetate=5:1 to 2:1) to obtain compound 34-1. LCMS (ESI) m/z: 707.0 (M+1) ⁺ .

Second step: To a solution of compound 34-1 (3.0 g) in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml). The reaction solution was reacted at 25°C for 1 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 34-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 607.0 (M+1) ⁺ .

third step: To a mixed solution of compound 34-2 (3.0 g) in tetrahydrofuran (20 ml) and water (10 ml) were added potassium carbonate (1.49 g) and compound 1-5 (389.46 mg). The reaction solution was reacted at 25°C for 30 minutes, extracted with ethyl acetate (10 ml*2), the organic phase was washed with saturated brine (5 ml*2), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by preparative HPLC (column model: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60%, 20 minutes) to obtain compound 34. The obtained product was prepared by SFC (column model: DAICEL CHIRALPAK AS-H (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 45%-45%, 5 minutes, 605 minutes) 34-P1 (mixture of 34C and 34D) and 34-P2 were isolated.

Compound 34-P1 (a mixture of 34C and 34D) was detected by SFC [column model: Column: Chiralpak IC-3 50×4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% ethylamine); Gradient (B%): 40%-40%] to obtain: the residence time of compound 34-P1 is 0.977min.

34-P1 (mixture of 34C and 34D): ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.33(d, J =4.9Hz, 1H), 7.94-7.76(m, 1H), 7.57-7.42(m, 1H),7.21(s,1H),7.14-7.06(m,1H),6.92-6.72(m,1H),6.28-6.16(m,1H),5.88-5.65(m,1H),4.87-4.42( m,2H),4.19-3.73(m,4H),2.84-2.71(m,1H),2.00-1.91(m,3H),1.38-1.31(m,3H),1.27-1.16(m,3H), 1.11-1.04(m,3H),1.03-0.95(m,3H). LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

34-P2 (retention time = 1.425min) and then through SFC (column model: DAICEL CHIRALPAK AS-H (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 5%- 40%, 3 minutes, 510 minutes) were separated to give compound 34A (retention time=1.217min) and compound 34B (retention time=1.401min).

Compound 34A and compound 34B were detected by SFC [column model: Column: Chiralpak AD-3 50×4.6mm I.D., 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); Gradient (B%): 5%-40%] obtained: the retention time of compound 34A was 1.217min, and the ee value was 100%; the retention time of compound 34B was 1.401min, and the ee value was 93.15%.

Compound 34A: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.33(d, J =4.9Hz, 1H), 7.94-7.76(m, 1H), 7.57-7.42(m, 1H), 7.21(s, 1H ),7.14-7.06(m,1H),6.92-6.72(m,1H),6.28-6.16(m,1H),5.88-5.65(m,1H),4.87-4.42(m,2H),4.19-3.73 (m,4H),2.84-2.71(m,1H),2.00-1.91(m,3H),1.38-1.31(m,3H),1.27-1.16(m,3H),1.11-1.04(m,3H) ,1.03-0.95(m,3H). LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

Compound 34B: ¹ H NMR (400MHz, DMSO- d ₆ )δ 8.39-8.29(m,1H),7.95-7.75(m,1H),7.58-7.42(m,1H),7.25-7.20(m,1H) ,7.14-7.08(m,1H),6.92-6.75(m,1H),6.26-6.15(m,1H),5.86-5.72(m,1H),4.88-4.43(m,2H),4.20-3.98( m,1H),3.94-3.70(m,2H),3.48-3.38(m,1H),2.72-2.59(m,1H), 2.07-1.99(m,3H),1.39-1.32(m,3H), 1.27-1.17(m,3H),1.06-0.95(m,6H). LCMS (ESI) m/z: 661.1 (M+1) ⁺ .

Experimental Example 1: Cell Experiment

Purpose of the experiment: The purpose of this experiment is to verify the proliferation inhibitory effect of the compound of the application on NCI-H358 human non-small cell lung cancer cells with KRAS G12C mutation and A375 human malignant melanoma cells with KRAS wild type.

Experimental materials: cell line NCI-H358 (purchased from the Cell Bank of the Chinese Academy of Sciences), cell line A375 (purchased from the Cell Bank of the Chinese Academy of Sciences), DMEM medium, penicillin/streptomycin antibiotics were purchased from Vicente, fetal bovine serum was purchased from Biosera . CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.

experimental method:

1) NCI-H358 cell anti-proliferation experiment:

NCI-H358 cells were seeded in a white 96-well plate, 80 μL of cell suspension per well, which contained 4000 NCI-H358 cells. Cell plates were cultured overnight in a carbon dioxide incubator. The compound to be tested was diluted 3 times to the 9th concentration with a row gun, that is, diluted from 2mM to 304nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 20 μL of each well to the cell plate after mixing. Compound concentrations ranged from 10 [mu]M to 1.52 nM were transferred to the cell plate. Cell plates were cultured in a carbon dioxide 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 following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescent detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescent signal. multi-marker Analyzer readings. Add 25 μL per well of cell viability chemiluminescent detection reagent to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer.

2) A375 cell anti-proliferation experiment:

The A375 cells were planted in a white 96-well plate, 80 μL of cell suspension per well, which contained 2000 A375 cells. Cell plates were cultured overnight in a carbon dioxide incubator. The compound to be tested was diluted 3 times to the 9th concentration with a row gun, that is, diluted from 2mM to 304nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 20 μL of each well to the cell plate after mixing. Compound concentrations ranged from 10 [mu]M to 1.52 nM were transferred to the cell plate. Cell plates were cultured in a carbon dioxide 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 following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescent detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer. Add 25 μL per well of cell viability chemiluminescent detection reagent to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer.

Data analysis: use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into inhibition rate, and the value of IC ₅₀ can be obtained by curve fitting with four parameters ("log(inhibitor )vs.response--Variable slope" mode is obtained).

Experimental results: The IC ₅₀ data of the anti-proliferation activity of the compounds of the present application on NCI-H358 (G12C mutation) cells and A375 (wild type) cells are shown in Table 1.

Experimental results: The compound of the present application shows higher cell anti-proliferation activity for KRAS G12C mutant cell NCI-H358, and weak anti-proliferation activity for wild-type A375 cell, reflecting high selectivity.

Experimental Example 2: Plasma Protein Binding Test

Experimental purpose: To determine the protein binding rate of the test compound in CD-1 mice, SD rats, Beagle dogs, cynomolgus monkeys and human plasma by equilibrium dialysis.

Experimental method: firstly, the plasma samples of the test compound and the control compound were prepared respectively with the plasma of the above five species; secondly, these plasma samples were placed in an incubator and pre-incubated at 37±1°C for 4 hours; then, the Buffer samples and dialyzed plasma samples. In this experiment, warfarin was used as the control compound. The concentration of the analyte in the sample was determined by LC-MS/MS method.

Experimental results: The experimental results are shown in Table 2.

Experimental conclusion: the compound of the present application shows moderate plasma protein binding rate in five species.

Experimental Example 3: Pharmacokinetic study of a single intravenous injection and intragastric administration of a test compound in male CD-1 mice

Purpose of the experiment: Using male CD-1 mice as experimental animals, evaluate the pharmacokinetic behavior of the test compound after a single intravenous injection and intragastric administration, and investigate the bioavailability after intragastric administration, for clinical research Provide animal test data.

Experimental program: Experimental animals: 6 male CD-1 mice, 7-9 weeks old, divided into 2 groups, 3 in IV group and 3 in PO group. Animals were purchased from Weitong Lihua Experimental Animal Technology Co., Ltd.

Drug preparation: Group IV: The solvent is 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add a corresponding volume of solvent, vortex to obtain a clear solution, and filter with a 0.22 μm filter membrane.

PO group: the vehicle is 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add corresponding volume of solvent, and vortex to obtain a clear solution.

Administration: 3 animals in the intravenous injection group did not fast before administration, and 3 animals in the intragastric administration group fasted for at least 12 hours before administration, and resumed feeding 4 hours after administration, and the fasting time was not limited. more than 20 hours. On the day of the test, animals in group IV were administered with a single injection of the test compound through tail vein;

Experimental operation: After the intravenous injection group of male CD-1 mice was given the test compound respectively, whole blood samples (about 0.03mL ); After intragastric administration of the test compound, the whole blood samples (about 0.03 mL) were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours respectively, and the actual blood collection time was recorded. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, put it in dry ice quickly, and then store it at -60°C or lower for LC-MS/MS analysis.

Experimental results: see Table 3.

Experimental conclusion: the compound of the application shows higher exposure and oral bioavailability, and has better pharmacokinetic properties.

Experimental Example 4: Pharmacokinetic study of a single intravenous injection and intragastric administration of a test compound in male SD rats

Purpose of the experiment: Using male SD rats as experimental animals, evaluate the pharmacokinetic behavior of the test compound after a single intravenous injection and intragastric administration, investigate the bioavailability after intragastric administration, and provide animals for clinical research. Test data.

Experimental scheme: Experimental animals: 6 male SD rats, aged 7-9 weeks, divided into 2 groups, 3 in IV group and 3 in PO group. Animals were purchased from Weitong Lihua Experimental Animal Technology Co., Ltd.

Drug preparation: Group IV: The solvent is 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add a corresponding volume of solvent, vortex to obtain a clear solution, and filter with a 0.22 μm filter membrane.

PO group: the vehicle is 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add corresponding volume of solvent, and vortex to obtain a clear solution.

Administration: 3 animals in the intravenous injection group did not fast before administration, and 3 animals in the intragastric administration group fasted for at least 12 hours before administration, and resumed feeding 4 hours after administration, and the fasting time was not limited. more than 20 hours hour. On the day of the test, animals in group IV were administered with a single injection of the test compound through tail vein;

Experimental operation: After the intravenous injection group of male SD rats was given the test compound respectively, whole blood samples (about 0.2mL ); After intragastric administration group was given the test compound, the whole blood samples (about 0.2 mL) were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours respectively, and the actual blood collection time was recorded. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, put it in dry ice quickly, and then store it at -60°C or lower for LC-MS/MS analysis.

Experimental Example 5: Pharmacokinetic study of male cynomolgus monkeys after a single intravenous injection or intragastric administration of the test compound

Experimental purpose: male cynomolgus monkeys were used as experimental animals to evaluate the pharmacokinetic behavior of male cynomolgus monkeys after a single intravenous injection or intragastric administration of the test compound.

Experimental scheme: Experimental animals: 2 male cynomolgus monkeys were used for intravenous injection, and 3 male cynomolgus monkeys were used for oral administration, aged 2-5 years.

Drug preparation: intravenous injection Vehicle: 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add a corresponding volume of solvent, vortex to obtain a clear solution, and filter with a 0.22 μm filter membrane.

Oral vehicle: 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add a corresponding volume of solvent, and obtain a clear solution by stirring and ultrasonication.

Experimental operation: Intravenous injection: After intravenous injection of the test compound, the test animals will collect blood samples through the peripheral vein without anesthesia, respectively at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours Whole blood samples (approximately 0.5 mL) were collected, and the actual time of blood collection was recorded. After the blood sample is collected, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower temperature for LC-MS/MS analysis.

Oral administration: After intragastric administration of the test compound, the test animals will collect blood samples through peripheral veins without anesthesia at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours respectively Whole blood sample (about 0.5mL), and record the actual blood collection time. After the blood sample is collected, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower temperature for LC-MS/MS analysis.

Experimental Example 6: Pharmacokinetic Study of Beagle Dogs After Single Intravenous Injection or Oral Administration of Test Compounds

Purpose: Beagle dogs were used as experimental animals to evaluate the pharmacokinetic behavior of male Beagle dogs after a single intravenous injection or intragastric administration of the test compound.

Experimental animals: 2 male Beagle dogs were used for intravenous injection, and 3 male Beagle dogs were used for oral administration.

Solvent: Intravenous injection vehicle: 10%DMSO+30%PEG400+60%water. Weigh an appropriate amount of compound, add a corresponding volume of solvent, vortex to obtain a clear solution, and filter with a 0.22 μm filter membrane.

Oral vehicle: 10%DMSO+30%PEG400+60% water. Weigh an appropriate amount of compound, add a corresponding volume of solvent, and obtain a clear solution by stirring and ultrasonication.

Experimental program: Intravenous injection: after intravenous administration of the test compound, blood samples were collected through peripheral veins, and whole blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and the actual blood collection time was recorded. After the blood sample is collected, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower temperature for LC-MS/MS analysis.

Oral administration: After intragastric administration of the test compound, the test animals will collect blood samples through peripheral veins without anesthesia at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours respectively Whole blood samples were taken and the actual time of blood collection was recorded. After the blood sample is collected, transfer it to a commercial centrifuge tube containing K2-EDTA anticoagulant. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or lower temperature for LC-MS/MS analysis.

Experimental Example 7: Drug efficacy test in vivo (1)

Purpose: To evaluate the in vivo efficacy of the test compound on human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model.

Experimental operation: BALB/c nude mice, female, 6-8 weeks old, weighing 18-23 grams. A total of 48 are required. Provided by the Experimental Animal Management Department of Shanghai Institute of Family Planning Science. NCI-H358 tumor cells were resuspended in PBS, prepared into 0.2mL (1×10 ⁷ ) cell suspension, and subcutaneously inoculated on the right back of each mouse (1×10 ⁷ /mouse) to wait for tumor growth. When the average volume of the tumor reached about 100-150 mm ³ , random grouping of animals was administered, and the frequency of oral gavage administration was once a day, with 8 animals in each group, and the dosage was shown in Table 4. Tumor diameters were measured twice a week with vernier calipers. The calculation formula of the tumor volume is: V=0.5a×b ² , where a and b represent the long diameter and short diameter of the tumor, respectively. The antitumor efficacy of compounds was evaluated by TGI (%). TGI (%), reflecting the tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of solvent control group - Average tumor volume at the start of treatment in the solvent control group)] × 100%.

Experimental results: see Table 4.

Experimental conclusion: the compound of the present application exhibited a significant tumor-inhibiting effect in the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358.

Experimental Example 8: Drug efficacy test in vivo (2)

Experimental purpose: To evaluate the in vivo efficacy of the test compound on the subcutaneous xenograft tumor model of human colon cancer CO-04-0070.

Experimental operation: BALB/c nude mice, female, 6-8 weeks old, weighing 18-20 grams. A total of 48 are required. Provided by Shanghai Lingchang Biotechnology Co., Ltd. Subcutaneously inoculate CO-04-0070FP4 tumor tissue pieces of 20~ ^30mm3 on the right back of each mouse and wait for the tumor to grow. When the average volume of the tumor reaches about ^153mm3 , random group administration will be started, with 8 animals in each group. The frequency of oral administration is once a day, and the dosage is shown in Table 5. Tumor diameters were measured twice a week with vernier calipers. The calculation formula of the tumor volume is: V=0.5a×b ² , where a and b represent the long diameter and short diameter of the tumor, respectively. The antitumor efficacy of compounds was evaluated by TGI (%). TGI (%), reflecting the tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of solvent control group - Average tumor volume at the start of treatment in the solvent control group)] × 100%.

Experimental results: see Table 5.

Experimental conclusion: the compound of the present application exhibits a significant tumor-inhibiting effect in the subcutaneous xenograft tumor model of human colon cancer CO-04-0070, and the dose-effect relationship is clear.

Experimental Example 9: Drug efficacy test in vivo (3)

Experimental purpose: To evaluate the in vivo efficacy of the test compound on human pancreatic cancer MIAPACA2 cell BALB/c nude mouse subcutaneous xenograft tumor model.

Experimental operation: BALB/c nude mice, female, 7-8 weeks old. A total of 48 are required. Provided by the Experimental Animal Management Department of Shanghai Institute of Family Planning Science. Inoculate MIAPACA2 cells in the armpit of the mice, the inoculation volume is 5×10 ⁶ /0.2mL, and random grouping begins when the average tumor volume reaches about 125mm ³ , with 8 animals in each group, and the frequency of oral gavage administration is once a day , and the dosage is shown in Table 6. Tumor diameters were measured twice a week with vernier calipers. The calculation formula of the tumor volume is: V=0.5a×b ² , where a and b represent the long diameter and short diameter of the tumor, respectively. The antitumor efficacy of compounds was evaluated by TGI (%). TGI (%), reflecting the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of the solvent control group - Average tumor volume at the start of treatment in the solvent control group)] × 100%.

Experimental results: see Table 6.

Experimental conclusion: the compound of the present application exhibited a significant tumor inhibitory effect in the human pancreatic cancer MIAPACA2 subcutaneous xenograft tumor model, and the dose-effect relationship was clear.

Claims (19)

a compound of formula (I) or a pharmaceutically acceptable salt thereof,

Wherein, X is selected from CR ₁₃ and N; Q and Y are independently selected from CH and N; R ₁ is selected from H, F, Cl, Br, I, C _1-3 alkyl, said C _1-3 alkane The group is optionally substituted by 1, 2 or 3 halogens; R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from H, F, Cl, Br, I, OH, C _1-3 alkyl , NH ₂ and -NH-C _1-3 alkyl, said C _1-3 alkyl is optionally substituted by 1, 2 or 3 halogens; R ₇ , R ₈ , R ₉ and R ₁₀ are independently selected from H and CH ₃ ; R ₁₁ is selected from H and F; R ₁₂ and R ₁₃ are independently selected from H, C _1-6 alkyl, cyclopropyl and C _1-3 alkoxy. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from

Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in Claim 1. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ₁ is selected from H, F, Cl, Br, I, CH ₃ , and the CH ₃ is optionally replaced by 1, 2 or 3 a halogen substitution. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from H, F and CF ₃ . The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are independently selected from H, F, Cl, Br, I, OH, _CF3 , _CH3 , _NH2 and _-NHCH3 . The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from H, F, NH ₂ and -NHCH ₃ . The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R ₃ is selected from H, F and Cl. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R ₄ is selected from H and F. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R ₅ is selected from H, F, Cl and CH ₃ . The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R ₆ is selected from H, F and CF ₃ . The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, R ₁₂ is selected from

. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁₃ is selected from CH ₃ and OCH ₃ . The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, the structural unit

selected from

,

,

,

and

. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, the structural unit

selected from

,

,

,

,

,

and

. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit

selected from

,

. A compound or a pharmaceutically acceptable salt thereof selected from

The compound or pharmaceutically acceptable salt thereof according to claim 16, which is selected from

An application of the compound according to any one of Claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of KRAS G12C mutant protein inhibitors. A use of the compound according to any one of Claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating non-small cell lung cancer.